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26 Jan 2022 at 01:34
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Bibliography on: Publications by FHCRC Researchers


Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 26 Jan 2022 at 01:34 Created: 

Publications by FHCRC Researchers

The Fred Hutchinson Cancer Research Center began in 1975, with critical help from Washington State's U.S. Senator Warren Magnuson. Fred Hutch quickly became the permanent home to Dr. E. Donnall Thomas, who had spent decades developing an innovative treatment for leukemia and other blood cancers. Thomas and his colleagues were working to cure cancer by transplanting human bone marrow after otherwise lethal doses of chemotherapy and radiation. At the Hutch, Thomas improved this treatment and readied it for widespread use. Since then, the pioneering procedure has saved hundreds of thousands of lives worldwide. While improving bone marrow transplantation remains central to Fred Hutch's research, it is now only part of its efforts. The Hutch is home to five scientific divisions, three Nobel laureates and more than 2,700 faculty, who collectively have published more than 10,000 scientific papers, presented here as a full bibliography.

NOTE: From 1995 to 2009 I served as the Hutch's vice president for information technology — hence my interest in the organization. Although my role was in the admin division, if you dig through this bibliography, you will find a couple of papers with me as an author.

Created with PubMed® Query: "Fred Hutchinson Cancer Research"[AFFL] or FHCRC[AFFL] or "Fred Hutch"[AFFL] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)


RevDate: 2022-01-20

Gagelmann N, Wolschke C, Salit RB, et al (2022)

Reduced intensity hematopoietic stem cell transplantation for myelofibrosis in accelerated-phase.

Blood advances pii:483613 [Epub ahead of print].

Accelerated-phase (AP) myelofibrosis, currently defined by circulating blasts 10-19%, usually confers very high risk for progression and poor outcome. The outcome of hematopoietic stem cell transplantation for AP myelofibrosis has not been evaluated yet. We analyzed the outcome of 349 clinically and genetically annotated patients with primary or secondary myelofibrosis undergoing reduced intensity transplantation, of whom 35 had AP myelofibrosis. In comparison with chronic-phase (CP, <10% blasts), median leukocyte counts were higher, more patients had constitutional symptoms, and RAS mutations were detected more frequently in the AP group. After a median follow-up of 5.9 years, estimated 5-year overall survival was 65% (95% confidence interval, 49-81%) versus 64% (95% confidence interval, 59-69%) for the CP group (P=0.91), and median overall survival was not reached. In terms of relapse-free survival, estimated 5-year outcome for the AP group was 49% (95% confidence interval, 32-67%) versus 55% (95% confidence interval, 50-61%) for the CP group (P=0.65). Estimated 5-year non-relapse mortality was 20% (95% CI, 8-33%) for the AP group versus 30% (95% confidence interval, 24-35%; P=0.25) for the CP group. In terms of relapse, 5-year incidence was 30% (95% confidence interval, 14-46%) for the AP group versus 15% (95% confidence interval, 11-19%) for the CP group (P=0.02). Results were confirmed in multivariable analysis and propensity score matching. Increase in circulating blasts was associated with increased risk for relapse, showing strongest increase in risk for ≥10% blasts. In conclusion, reduced intensity transplantation showed excellent survival but higher relapse for AP myelofibrosis.

RevDate: 2022-01-20

Halpern AB, Martins TJ, Jonlin EC, et al (2020)

Case of Chemotherapy-Refractory, RAS-Mutated Chronic Myelomonocytic Leukemia Responsive to Single-Agent Trametinib Based on Results From a High-Throughput Drug Screen.

JCO precision oncology, 4:1367-1373.

RevDate: 2022-01-20

Garduno AC, LaCroix AZ, LaMonte MJ, et al (2022)

Associations of Daily Steps and Step Intensity With Incident Diabetes in a Prospective Cohort Study of Older Women: The OPACH Study.

Diabetes care, 45(2):339-347.

OBJECTIVE: The primary aim was to assess associations between total steps per day and incident diabetes, whereas the secondary aim was to assess whether the intensity and/or cadence of steps is associated with incident diabetes.

RESEARCH DESIGN AND METHODS: Women without physician-diagnosed diabetes (n = 4,838; mean [SD] age 78.9 [6.7] years) were followed up to 6.9 years; 395 developed diabetes. Hip-worn ActiGraph GT3X+ accelerometers worn for 1 week enabled measures of total, light-intensity, and moderate- to vigorous-intensity (MV-intensity) steps per day. Using Cox proportional hazards analysis we modeled adjusted change in the hazard rate for incident diabetes associated with total, light-intensity, and MV-intensity steps per day. We further estimated the proportion of the steps-diabetes association mediated by BMI.

RESULTS: On average, participants took 3,729 (SD 2,114) steps/day, of which 1,875 (791) were light-intensity steps and 1,854 ± 1,762 were MV-intensity. More steps per day were associated with a lower hazard rate for incident diabetes. Confounder-adjusted models for a 2,000 steps/day increment yielded hazard ratio (HR) 0.88 (95% CI 0.78-1.00; P = 0.046). After further adjustment for BMI, HR was 0.90 (95% CI 0.80-1.02; P = 0.11). BMI did not significantly mediate the steps-diabetes association (proportion mediated = 17.7% [95% CI -55.0 to 142.0]; P = 0.09]). The relationship between MV-intensity steps per day (HR 0.86 [95% CI 0.74-1.00]; P = 0.04) and incident diabetes was stronger than for light-intensity steps per day (HR 0.97 [95% CI 0.73-1.29]; P = 0.84).

CONCLUSIONS: These findings suggest that for older adults, more steps per day are associated with lower incident diabetes and MV-intensity steps are most strongly associated with a lower hazard of diabetes. This evidence supports that regular stepping is an important risk factor for type 2 diabetes prevention in older adults.

RevDate: 2022-01-20

Murphy N, Song M, Papadimitriou N, et al (2022)

Associations Between Glycemic Traits and Colorectal Cancer: A Mendelian Randomization Analysis.

Journal of the National Cancer Institute pii:6512063 [Epub ahead of print].

BACKGROUND: Glycemic traits-such as hyperinsulinemia, hyperglycemia, and type-2 diabetes-have been associated with higher colorectal cancer risk in observational studies; however, causality of these associations is uncertain. We used Mendelian randomization (MR) to estimate the causal effects of fasting insulin, 2-hour glucose, fasting glucose, glycated hemoglobin (HbA1c), and type-2 diabetes with colorectal cancer.

METHODS: Genome-wide association study summary data were used to identify genetic variants associated with circulating levels of fasting insulin (n = 34), 2-hour glucose (n = 13), fasting glucose (n = 70), HbA1c (n = 221), and type-2 diabetes (n = 268). Using two-sample MR, we examined these variants in relation to colorectal cancer risk (48,214 cases and 64,159 controls).

RESULTS: In inverse-variance models, higher fasting insulin levels increased colorectal cancer risk (odds ratio [OR] per 1-standard deviation [SD]=1.65, 95% CI = 1.15-2.36). We found no evidence of any effect of 2-hour glucose (OR per 1-SD = 1.02, 95% CI = 0.86-1.21) or fasting glucose (OR per 1-SD = 1.04, 95% CI = 0.88-1.23) concentrations on colorectal cancer risk. Genetic liability to type-2 diabetes (OR per 1-unit increase in log odds = 1.04, 95% CI = 1.01-1.07) and higher HbA1c levels (OR per 1-SD = 1.09, 95% CI = 1.00-1.19) increased colorectal cancer risk, although these findings may have been biased by pleiotropy. Higher HbA1c concentrations increased rectal cancer risk in men (OR per 1-SD = 1.21, 95% CI = 1.05-1.40), but not in women.

CONCLUSIONS: Our results support a causal effect of higher fasting insulin, but not glucose traits or type-2 diabetes, on increased colorectal cancer risk. This suggests that pharmacological or lifestyle interventions that lower circulating insulin levels may be beneficial in preventing colorectal tumorigenesis.

RevDate: 2022-01-20

Ferjan Ramírez N, Hippe DS, Correa L, et al (2022)

Habla conmigo, daddy! Fathers' language input in North American bilingual Latinx families.

Infancy : the official journal of the International Society on Infant Studies [Epub ahead of print].

This study examines the language environments of bilingually raised Latinx infants (n = 37) in mother-father families of diverse socioeconomic backgrounds, with a focus on paternal parentese, a speaking style distinguished by higher pitch, slower tempo, and exaggerated intonation. Two daylong audio recordings were collected on weekends, when both parents were at home. Paternal, maternal, and infant speech variables were quantified through automatic and manual analyses. Most infants experienced Spanish and English within child-directed speech, and language mixing was common in mothers and fathers. Adjusting for demographic variables, infants heard 50.4% less talk from men compared to women, and 43.4% less parentese from fathers compared to mothers. However, when controlling for overall speech amount, the rate of parentese use did not differ between mothers and fathers, demonstrating that, contrary to the stereotype, fathers in Latinx families adjust their speech in verbal interactions with their infants. An asymmetry emerged, where paternal parentese was associated with paternal knowledge of language development but not with paternal involvement in childcare responsibilities; the opposite was true for paternal speech amount. Controlling for maternal contributions, paternal parentese was predictive of concurrent parent-infant turn-taking and infant language vocalizations, demonstrating its important role in infant language development.

RevDate: 2022-01-20

Sun Q, Crowley CA, Huang L, et al (2022)

From GWAS variant to function: A study of ∼148,000 variants for blood cell traits.

HGG advances, 3(1):100063 pii:S2666-2477(21)00044-0.

Genome-wide association studies (GWASs) have identified hundreds of thousands of genetic variants associated with complex diseases and traits. However, most variants are noncoding and not clearly linked to genes, making it challenging to interpret these GWAS signals. We present a systematic variant-to-function study, prioritizing the most likely functional elements of the genome for experimental follow-up, for >148,000 variants identified for hematological traits. Specifically, we developed VAMPIRE: Variant Annotation Method Pointing to Interesting Regulatory Effects, an interactive web application implemented in R Shiny. This tool efficiently integrates and displays information from multiple complementary sources, including epigenomic signatures from blood-cell-relevant tissues or cells, functional and conservation summary scores, variant impact on protein and gene expression, chromatin conformation information, as well as publicly available GWAS and phenome-wide association study (PheWAS) results. Leveraging data generated from independently performed functional validation experiments, we demonstrate that our prioritized variants, genes, or variant-gene links are significantly more likely to be experimentally validated. This study not only has important implications for systematic and efficient revelation of functional mechanisms underlying GWAS variants for hematological traits but also provides a prototype that can be adapted to many other complex traits, paving the path for efficient variant-to-function (V2F) analyses.

RevDate: 2022-01-20

Jarvik GP, Wang X, Fontanillas P, et al (2020)

Hemochromatosis risk genotype is not associated with colorectal cancer or age at its diagnosis.

HGG advances, 1(1):100010 pii:S2666-2477(20)30010-5.

Homozygotes for the higher penetrance hemochromatosis risk allele, HFE c.845G>A (p.Cys282Tyr, or C282Y), have been reported to be at a 2- to 3-fold increased risk for colorectal cancer (CRC). These results have been reported for small sample size studies with no information about age at diagnosis for CRC. An association with age at diagnosis might alter CRC screening recommendations. We analyzed two large European ancestry datasets to assess the association of HFE genotype with CRC risk and age at CRC diagnosis. The first dataset included 59,733 CRC or advanced adenoma cases and 72,351 controls from a CRC epidemiological study consortium. The second dataset included 13,564 self-reported CRC cases and 2,880,218 controls from the personal genetics company, 23andMe. No association of the common hereditary hemochromatosis (HH) risk genotype and CRC was found in either dataset. The odds ratios (ORs) for the association of CRC and HFE C282Y homozygosity were 1.08 (95% confidence interval [CI], 0.91-1.29; p = 0.4) and 1.01 (95% CI, 0.78-1.31, p = 0.9) in the two cohorts, respectively. Age at CRC diagnosis also did not differ by HFE C282Y/C282Y genotype in either dataset. These results indicate no increased CRC risk in individuals with HH genotypes and suggest that persons with HH risk genotypes can follow population screening recommendations for CRC.

RevDate: 2022-01-20

Wang WJ, Ramsey SD, Bennette CS, et al (2022)

Racial Disparities in Access to Prostate Cancer Clinical Trials: A County-Level Analysis.

JNCI cancer spectrum, 6(1):pkab093 pii:pkab093.

Background: African American men have a higher burden of prostate cancer compared with other populations. We sought to determine if they experience disparities in access to prostate cancer clinical trials.

Methods: We created a database of all US counties by linking prostate cancer clinical trial data with county-level socioeconomic, demographic, and health-care facility data derived from several external data sources. Using this data linkage, we examined 2 potential access barriers. We investigated the relationship between the proportion of African Americans and access to cancer facilities, adjusting for county population size and other characteristics. Additionally, among counties with cancer facilities, we investigated the relationship between the proportion of African Americans and number of available prostate cancer trials per capita per year. We addressed these questions using logistic and negative binomial regression, respectively.

Results: Between 2008 and 2015, 613 prostate cancer trial sites were found among 3145 US counties. Counties with a higher proportion of African Americans were less likely to have cancer facilities (adjusted odds ratio = 0.85, 95% confidence interval = 0.78 to 0.92). Among counties with cancer facilities, those with a higher proportion of African Americans had statistically significantly fewer prostate cancer trials per capita per year (rate ratio per 10% increase in African Americans = 0.90, 95% confidence interval = 0.83 to 0.96).

Conclusions: Counties with higher proportions of African Americans seem less likely to have access to cancer facilities. Among counties with cancer facilities, those with higher proportions of African Americans appear to have fewer prostate cancer trials available per capita per year. Clinical trials in prostate cancer therapy should ensure adequate availability of enrollment sites in regions with high concentrations of African Americans.

RevDate: 2022-01-19

Qin G, Knijnenburg TA, Gibbs DL, et al (2022)

A functional module states framework reveals transcriptional states for drug and target prediction.

Cell reports, 38(3):110269.

Cells are complex systems in which many functions are performed by different genetically defined and encoded functional modules. To systematically understand how these modules respond to drug or genetic perturbations, we develop a functional module states framework. Using this framework, we (1) define the drug-induced transcriptional state space for breast cancer cell lines using large public gene expression datasets and reveal that the transcriptional states are associated with drug concentration and drug targets, (2) identify potential targetable vulnerabilities through integrative analysis of transcriptional states after drug treatment and gene knockdown-associated cancer dependency, and (3) use functional module states to predict transcriptional state-dependent drug sensitivity and build prediction models for drug response. This approach demonstrates a similar prediction performance as approaches using high-dimensional gene expression values, with the added advantage of more clearly revealing biologically relevant transcriptional states and key regulators.

RevDate: 2022-01-19

Long JE, Sanchez H, Dasgupta S, et al (2022)

Self-reported knowledge of HIV status among cisgender male sex partners of transgender women in Lima, Peru.

Journal of acquired immune deficiency syndromes (1999) pii:00126334-900000000-95711 [Epub ahead of print].

BACKGROUND: Knowledge of HIV status is a critical first step in the HIV care cascade. Cisgender male sex partners of transgender women (MSTW) are at a disproportionately high risk of HIV, but little is known about their access to HIV testing or knowledge of HIV status.

METHODS: We used cross-sectional data from a respondent-driven sampling study to analyze self-reported HIV status and predictors of knowledge of HIV status among MSTW in Lima, Peru. Mixed effects models were used to generate crude and adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) for the association between knowledge of HIV status and predictors of interest, including socio-demographics and recent sexual behavior.

RESULTS: From February - July 2018, 196 eligible MSTW enrolled, of which 90 (46%) reported not knowing their HIV status. Recent casual or one-time partners were reported by 84% of MSTW, and 54% reported purchasing sex. In adjusted analyses, MSTW participants were less likely to know their HIV status if they reported buying sex (aPR 0.43, 95% CI:0.32-0.59) or reported ≥16 recent sex partners compared to ≤5 partners (aPR 0.32, [0.20-0.50]). Those who reported male sex partners were 80% more likely to know their status (aPR 1.80, [1.33-2.44]).

CONCLUSIONS: Reported knowledge of HIV status was low among MSTW in Lima, and unknown HIV status was associated with behaviors linked to HIV acquisition. MSTW who reported male partners were more likely to know their status, potentially indicating that HIV testing is more accessible to men who have sex with men (MSM).

RevDate: 2022-01-19

Chen X, Fromm JR, KN Naresh (2022)

"Blasts" in myeloid neoplasms - how do we define blasts and how do we incorporate them into diagnostic schema moving forward?.

Leukemia [Epub ahead of print].

RevDate: 2022-01-18

Van Benschoten V, Roy C, Gupta R, et al (2022)

Incidence and risk factors of transplant-associated thrombotic microangiopathy (TA-TMA): a systematic review and meta-analysis.

Transplantation and cellular therapy pii:S2666-6367(22)00029-X [Epub ahead of print].

BACKGROUND: Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized post-transplant complication, yet the overall incidence of the disease remains debated.

OBJECTIVES: To determine the pooled incidence of TA-TMA in a systematic review of literature and to identify consistent risk factors.

STUDY DESIGN: We performed a systematic review using Medline, Embase, and CENTRAL databases to identify cohort studies that reported incidence of and risk factors for TA-TMA from 2004 to 2020. We conducted a meta-analysis of proportion to estimate the pooled incidence of TA-TMA using a random-effects model. We assessed moderators of heterogeneity through subgroup analysis, risk of bias through ROBINS-I, and publication bias through funnel plot.

RESULTS: Among 21 cohort studies with 36,163 adult and pediatric patients that underwent allogeneic transplant, the pooled incidence of TA-TMA was 12% (95% CI 9-16). The diagnostic criteria used to define the disease was the most significant contributor identified to the high inter-study heterogeneity (I2 98%). Studies using provider/clinician diagnosis instead of laboratory diagnosis reported the lowest incidence at 3%. The most salient risk factor for TA-TMA reported in 14 studies was preceding acute graft-versus-host disease (GVHD). Other risk predictors described in 5 or more studies included preceding infection, prior transplant, mismatched donor, and myeloablative conditioning.

CONCLUSION: With a pooled incidence at 12% among a significantly heterogeneous population, TA-TMA is an important but relatively uncommon post-transplant complication. Given the divergence between laboratory-based and provider-based incidence, as well as the multitude of risk factors beyond acute GVHD, future studies should focus on risk stratifying the subset of TA-TMA patients who would benefit from therapeutic intervention.

RevDate: 2022-01-18

Nahleh Z, Lyman GH, Schilsky RL, et al (2022)

Use of Biosimilar Medications in Oncology.

JCO oncology practice [Epub ahead of print].

PURPOSE: The increased number and expanded utilization of biosimilars raise important considerations for their safe and appropriate use in oncology practice. This report provides an update on currently approved oncology biosimilars and identifies current knowledge gaps in the management of patients with cancer.

METHODS: An Expert Panel was convened to review the medical literature and to provide a practical summary of currently approved biosimilar therapeutics for cancer treatment or supportive care in the United States.

RESULTS: A total of 17 cancer or cancer-related biosimilar products have been approved by the US Food and Drug Administration since 2015. Despite years of clinical experience with oncology biosimilars, variance in their use persists. ASCO supports that biosimilars and reference products are considered equally efficacious for the purpose of inclusion in ASCO clinical practice guideline recommendations.

CONCLUSION: The use of biosimilars might provide competitive, lower-cost alternatives to biologics used in cancer care, and specific mention in ASCO guidelines and other evidence products is supported where appropriate.

RevDate: 2022-01-18

Xu J, Guertin KA, Gaddis NC, et al (2022)

Change in plasma alpha-tocopherol associations with attenuated pulmonary function decline and with CYP4F2 missense variation.

The American journal of clinical nutrition pii:6510812 [Epub ahead of print].

BACKGROUND: Vitamin E (vitE) is hypothesized to attenuate age-related decline in pulmonary function.

OBJECTIVES: We investigated the association between change in plasma vitE (∆vitE) and pulmonary function decline (forced expiratory volume in the first second [FEV1]) and examined genetic and non-genetic factors associated with ∆vitE.

DESIGN: We studied 1,144 men randomized to vitE in the Selenium and Vitamin E Cancer Prevention Trial. ∆vitE was the difference between baseline and year 3 vitE concentrations measured with gas chromatography-mass spectrometry. FEV1 was measured longitudinally by spirometry. We genotyped 555 men (vitE-only arm) using the Illumina MEGAex array. We used mixed-effects linear regression modeling to examine the ∆vitE-FEV1 association.

RESULTS: Higher ∆vitE was associated with lower baseline α-tocopherol, higher baseline γ-tocopherol, higher baseline free cholesterol, European ancestry (vs. African) (all P < 0.05), and the minor allele of a missense variant in CYP4F2 (rs2108622-T; 2.4 µmol/L higher ∆vitE, SE = 0.8, P = 0.0032). Higher ∆vitE was associated with attenuated FEV1 decline, with stronger effects in adherent participants (≥80% of supplements consumed): a statistically significant ∆vitE × time interaction (P = 0.014) indicated that a 1-unit increase in ∆vitE was associated with a 2.2 mL/year attenuation in FEV1 decline (SE = 0.9). The effect size for 1 standard deviation higher ∆vitE (+4 µmol/mmol free-cholesterol-adjusted α-tocopherol) is ∼¼ of the effect of one year of aging, but in the opposite direction. The ∆vitE-FEV1 association was similar in never smokers (2.4 mL/year attenuated FEV1 decline, SE = 1.0, P = 0.017, n = 364), and current smokers (2.8 mL/year, SE = 1.6, P = 0.079, n = 214), but there was little to no effect in former smokers (-0.64 mL/year, SE = 0.9, P = 0.45, n = 564).

CONCLUSIONS: Greater response to vitamin E supplementation was associated with attenuated FEV1 decline. The response to supplementation differed by rs2108622 such that individuals with the C allele, compared to the T allele, may need a higher dietary intake to reach the same plasma vitamin E concentration. Clinical Trial Registry Number: The ClinicalTrials.gov identifier of the SELECT trial is NCT00006392 (https://clinicaltrials.gov/ct2/show/NCT00006392) and the identifier of the RAS trial is NCT00063453 (https://clinicaltrials.gov/ct2/show/NCT00063453).

RevDate: 2022-01-18

Gorzelitz JS, Trentham Dietz A, Hampton JM, et al (2022)

Mortality risk and physical activity across the lifespan in endometrial cancer survivors.

Cancer causes & control : CCC [Epub ahead of print].

PURPOSE: Physical activity (pre- and post-diagnosis) has been studied in prevention and survivorship contexts for endometrial cancer. However, the association of physical activity (PA) across the lifespan on mortality risk among endometrial cancer survivors is understudied. The study's objective was to identify the association of lifetime PA on mortality risk in endometrial cancer survivors.

METHODS: Seven hundred forty-five endometrial cancer survivors drawn from a population-based cancer registry (diagnosed between 1991 and 1994) reported the frequency (sessions/week) of moderate- and vigorous intensity physical activity (MVPA) at age 12, age 20, and 5 years pre-interview (post-diagnosis). Cox proportional hazards were used to estimate hazard ratios (HR) and 95% confidence intervals for the association between PA, all-cause, and cardiovascular disease mortality as assessed in 2016. MVPA was modeled using natural cubic splines.

RESULTS: Diagnosis age, body mass index, and smoking (pack-years) were each positively associated with increased all-cause mortality risk. Those who did one session of MVPA 5 years pre-interview had a lower mortality risk (HR 0.61; 95% CI 0.41-0.92) compared to those with no MVPA. Those reporting one session of MVPA was similarly observed at age 12 (HR 0.95; 95% CI 0.86-1.06) and at age 20 (HR 0.87; 95% CI 0.65-1.16).

CONCLUSION: Those who participated in PA, compared to those who did not, in the 5 years before diagnosis had a lower mortality risk. While PA was not independently protective against mortality risk at ages 12 or 20, PA is still important for endometrial cancer survivors for other non-mortality outcomes.

RevDate: 2022-01-18

Su Y, Cochrane BB, Reding K, et al (2022)

Mediterranean Diet and Fatigue among Community-Dwelling Postmenopausal Women.

Journal of nutrition in gerontology and geriatrics [Epub ahead of print].

We investigated cross-sectional relationships between the Mediterranean diet and overall fatigue, energy, and weariness scores among 4,563 women aged 65+ from the Women's Health Initiative study. We also used the Isocaloric Substitution approach to explore whether the substitution of fish for red and processed meat, whole for non-whole grains, and whole fruit for fruit juice relate to RAND-36 measured overall fatigue and its subdomains. The alternate Mediterranean Diet (aMED) Index quintiles (Q1-Q5) and selected Mediterranean foods available on a Food Frequency Questionnaire were exposure measures. Results showed aMED Q5 was associated with 2.99 (95% CI: 0.88, 5.11), 4.01 (95% CI: 1.51, 6.53), and 2.47 (95% CI: 0.24, 4.70) point improvements in fatigue, energy, and weariness scores, respectively, compared with aMED Q1. Substituting fish for red and processed meat and whole for non-whole grains was associated with more favorable fatigue scores, whereas substituting whole fruit for juice was not.

RevDate: 2022-01-17

Li C, Wang H, Gil S, et al (2022)

Safe and efficient in vivo hematopoietic stem cell transduction in nonhuman primates using HDAd5/35++ vectors.

Molecular therapy. Methods & clinical development, 24:127-141 pii:S2329-0501(21)00189-3.

We tested a new in vivo hematopoietic stem cell (HSC) transduction/selection approach in rhesus macaques using HSC-tropic, integrating, helper-dependent adenovirus vectors (HDAd5/35++) designed for the expression of human γ-globin in red blood cells (RBCs) to treat hemoglobinopathies. We show that HDAd5/35++ vectors preferentially transduce HSCs in vivo after intravenous injection into granulocyte colony-stimulating factor (G-CSF)/AMD3100-mobilized animals and that transduced cells return to the bone marrow and spleen. The approach was well tolerated, and the activation of proinflammatory cytokines that are usually associated with intravenous adenovirus vector injection was successfully blunted by pre-treatment with dexamethasone in combination with interleukin (IL)-1 and IL-6 receptor blockers. Using our MGMTP140K-based in vivo selection approach, γ-globin+ RBCs increased in all animals with levels up to 90%. After selection, the percentage of γ-globin+ RBCs declined, most likely due to an immune response against human transgene products. Our biodistribution data indicate that γ-globin+ RBCs in the periphery were mostly derived from mobilized HSCs that homed to the spleen. Integration site analysis revealed a polyclonal pattern and no genotoxicity related to transgene integrations. This is the first proof-of-concept study in nonhuman primates to show that in vivo HSC gene therapy could be feasible in humans without the need for high-dose chemotherapy conditioning and HSC transplantation.

RevDate: 2022-01-18

De Rosa SC, Cohen KW, Bonaparte M, et al (2022)

Whole-blood cytokine secretion assay as a high-throughput alternative for assessing the cell-mediated immunity profile after two doses of an adjuvanted SARS-CoV-2 recombinant protein vaccine candidate.

Clinical & translational immunology, 11(1):e1360.

Objectives: We previously described the Phase I-II evaluation of SARS-CoV-2 recombinant protein candidate vaccine, CoV2-PreS-dTM, with AF03- or AS03-adjuvant systems (ClinicalTrials.gov, NCT04537208). Here, we further characterise the cellular immunogenicity profile of this vaccine candidate using a whole-blood secretion assay in parallel to intracellular cytokine staining (ICS) of cryopreserved peripheral blood mononuclear cells (PBMCs).

Methods: A randomly allocated subset of 90 healthy, SARS-CoV-2-seronegative adults aged ≥ 18 years who had received (random allocation) one or two separate injections (on study day [D]1 and D22) of saline placebo or CoV2-PreS-dTM formulated with AS03 or AF03 were included. Cytokine secretion was assessed using a TruCulture® whole-blood stimulation system in combination with multiplex bead array, and intracellular cytokine profiles were evaluated on thawed PBMCs following ex vivo stimulation with recombinant S protein at pre-vaccination (D1), post-dose 1 (D22) and post-dose 2 (D36).

Results: Both methods detected similar vaccine-induced responses after the first and second doses. We observed a Th1 bias (Th1/Th2 ratio > 1.0) for most treatment groups when analysed in whole blood, mainly characterised by increased IFN-γ, IL-2 and TNF-α secretion. Among participants aged ≥ 50 years, the Th1/Th2 ratio was higher for those who received vaccine candidate with AS03 versus AF03 adjuvant. ICS revealed that this higher Th1/Th2 ratio resulted from higher levels of IFN-γ expression and that the vaccine induced polyfunctional CD4+ T cells.

Conclusions: The whole-blood cytokine secretion assay is a high-throughput alternative for assessing the quantity and character of vaccine-induced cellular responses.

RevDate: 2022-01-16

Sillah A, Peters U, Watson NF, et al (2022)

Associating sleep problems with advanced cancer diagnosis, and immune checkpoint treatment outcomes: a pilot study.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer [Epub ahead of print].

BACKGROUND: Sleep problems (SP) are common in cancer patients but have not been previously assessed in patients receiving immune checkpoint inhibitors (ICI).

METHODS: We collected questionnaire data on sleep apnea risk, insomnia, and general sleep patterns. We used an adjusted multivariate Poisson regression to calculate prevalence ratios (PRs) and associated 95% confidence intervals (CIs) for associations between these SP and metastatic versus localized cancer stage (M1 vs. M0), and adjusted logistic regression models to calculate ORs for associations between SP with the number of ICI infusions completed (6 + vs. < 6).

RESULTS: Among 32 patients who received ICI treatment, the prevalence of low, intermediate, and high-risk OSA risk was 36%, 42%, and 21%, respectively. Overall, 58% of participants reported clinically significant insomnia. We did not find a significant association between intermediate or high risk OSA (vs. low risk) and metastatic cancer status (PR = 1.01 (95% CI: 0.28, 3.67)). Patients in the cohort who reported taking > 15 min to fall asleep were 3.6 times more likely to be diagnosed with metastatic cancer compared to those reporting shorter sleep latency (95% CI (1.74, 7.35)). We did not find a significant association between SP and number of ICI infusions completed.

CONCLUSION: Our data associating sleep apnea risk, insomnia, and sleep patterns with more advanced cancer encourages further exploration in larger-scale observational studies and suggests interventional clinical trials focused on sleep quality improvement that could result in better outcomes for these patients.

RevDate: 2022-01-16

Wang Z, Liu Y, Peng L, et al (2022)

Role of fibrosarcoma-induced CD11b+ myeloid cells and tumor necrosis factor-α in B cell responses.

Oncogene [Epub ahead of print].

The role of B cells in the anti-tumor immune response remains controversial. An increase in the number of B cells in the peripheral blood of some tumor patients has been associated with poor immunotherapy efficacy. However, the mechanism leading to the generation of these cells is not well-described. Using a fibrosarcoma model, we show that intraperitoneal administration of a xenogeneic antigen in tumor-bearing mice evokes large increases in antigen-specific serum immunoglobulin formation compared to tumor-naïve mice. An inability of tumor-bearing mice to induce enhanced antibody production after myeloid cell depletion suggests the antibody responses are CD11b+ myeloid cell-dependent. In vitro, CD11b+ myeloid cells promoted B cell proliferation, activation, and survival. High levels of tumor necrosis factor (TNF)-α were produced by CD11b+ cells, and TNF-α blockade inhibited B cell responses. CD11b+ cells appear to be important promoters of B cell responses and targeting B cells may increase the efficacy of immunotherapy in tumor-bearing hosts.

RevDate: 2022-01-18

Mousa A, Winskill P, Watson OJ, et al (2021)

Social contact patterns and implications for infectious disease transmission - a systematic review and meta-analysis of contact surveys.

eLife, 10: pii:70294.

Background: Transmission of respiratory pathogens such as SARS-CoV-2 depends on patterns of contact and mixing across populations. Understanding this is crucial to predict pathogen spread and the effectiveness of control efforts. Most analyses of contact patterns to date have focused on high-income settings.

Methods: Here, we conduct a systematic review and individual-participant meta-analysis of surveys carried out in low- and middle-income countries and compare patterns of contact in these settings to surveys previously carried out in high-income countries. Using individual-level data from 28,503 participants and 413,069 contacts across 27 surveys, we explored how contact characteristics (number, location, duration, and whether physical) vary across income settings.

Results: Contact rates declined with age in high- and upper-middle-income settings, but not in low-income settings, where adults aged 65+ made similar numbers of contacts as younger individuals and mixed with all age groups. Across all settings, increasing household size was a key determinant of contact frequency and characteristics, with low-income settings characterised by the largest, most intergenerational households. A higher proportion of contacts were made at home in low-income settings, and work/school contacts were more frequent in high-income strata. We also observed contrasting effects of gender across income strata on the frequency, duration, and type of contacts individuals made.

Conclusions: These differences in contact patterns between settings have material consequences for both spread of respiratory pathogens and the effectiveness of different non-pharmaceutical interventions.

Funding: This work is primarily being funded by joint Centre funding from the UK Medical Research Council and DFID (MR/R015600/1).

RevDate: 2022-01-15

Neal ML, Duffy FJ, Du Y, et al (2022)

Preimmunization correlates of protection shared across malaria vaccine trials in adults.

NPJ vaccines, 7(1):5.

Identifying preimmunization biological characteristics that promote an effective vaccine response offers opportunities for illuminating the critical immunological mechanisms that confer vaccine-induced protection, for developing adjuvant strategies, and for tailoring vaccination regimens to individuals or groups. In the context of malaria vaccine research, studying preimmunization correlates of protection can help address the need for a widely effective malaria vaccine, which remains elusive. In this study, common preimmunization correlates of protection were identified using transcriptomic data from four independent, heterogeneous malaria vaccine trials in adults. Systems-based analyses showed that a moderately elevated inflammatory state prior to immunization was associated with protection against malaria challenge. Functional profiling of protection-associated genes revealed the importance of several inflammatory pathways, including TLR signaling. These findings, which echo previous studies that associated enhanced preimmunization inflammation with protection, illuminate common baseline characteristics that set the stage for an effective vaccine response across diverse malaria vaccine strategies in adults.

RevDate: 2022-01-15

Palomba ML, Till BG, Park SI, et al (2021)

Combination of Atezolizumab and Obinutuzumab in Patients with Relapsed/Refractory Follicular Lymphoma and Diffuse Large B-Cell Lymphoma: Results from a Phase 1b Study.

Clinical lymphoma, myeloma & leukemia pii:S2152-2650(21)02479-4 [Epub ahead of print].

BACKGROUND: This was an open-label, phase 1b study assessing the safety, tolerability, preliminary efficacy and pharmacokinetics of the combination of atezolizumab and obinutuzumab in patients with relapsed/refractory follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL). There is a mechanistic rationale suggesting that this combination may enhance recruitment of both innate and adaptive immunity and be effective against CD20+ B-cell malignancies.

MATERIALS AND METHODS: The study consisted of a safety evaluation stage and an expansion stage. Patients received obinutuzumab 1000 mg intravenously (IV) in cycle (C) 1, obinutuzumab plus atezolizumab 1200 mg IV for C2-8, and atezolizumab only from C9. Primary endpoints were to identify a recommended phase 2 dose (RP2D) for atezolizumab, and safety and tolerability in the safety and expansion stages.

RESULTS: A total of 49 patients were enrolled (FL, n = 26; DLBCL, n = 23), with a median of 2 prior lines of treatment. The RP2D for atezolizumab was 1200 mg IV every 3 weeks. Adverse events reported in ≥ 20% of patients were fatigue (15 patients [31%]), nausea (13 patients [27%]), cough, and diarrhea (10 patients [20%] each). Objective response rate was 54% in the FL cohort (complete response [CR] rate: 23%) and 17% in the DLBCL cohort (CR: 4%). Median progression-free survival was 9 months for FL and 3 months for DLBCL. Median overall survival was not estimable for FL and 9 months for DLBCL.

CONCLUSION: The combination of obinutuzumab and atezolizumab was determined to be safe and tolerable, with no new toxicities observed.

RevDate: 2022-01-15

Musa FB, Brouwer E, Ting J, et al (2022)

Trends in treatment patterns and costs of care among patients with advanced stage cervical cancer.

Gynecologic oncology pii:S0090-8258(21)01696-6 [Epub ahead of print].

BACKGROUND: Current treatments for recurrent or metastatic cervical cancer (r/mCC) do not offer satisfactory clinical benefits, with most patients progressing beyond first-line (1L) treatment. With new treatments under investigation, understanding current treatment patterns, the impact of newly approved therapies, and total costs of care for r/mCC are important.

METHODS: A retrospective analysis of a US commercial insurance claims database to identify adult patients with r/mCC between 2015 and Q1-2020; defining 1L treatment as the first administration of systemic treatment without concomitant chemoradiation or surgery. Patient characteristics, treatment regimens, duration of therapy, and total costs of care were evaluated for each line of therapy.

RESULTS: 1323 women initiated 1L treatment for r/mCC (mean age, 56.1 years; mean follow-up, 16.5 months). One-third (n = 438) had evidence of second-line (2L) treatment; of these, 129 (29%) had evidence of third-line (3L) treatment. No regimen represented a majority among 2L+ treatments. The 2018 approval of pembrolizumab led to increased 2L immunotherapy use (0% in 2015, 37% in 2019/Q1-2020). However, only a small proportion of patients stayed on immunotherapy for a prolonged period. Mean per-patient-per-month total costs of care during treatment were $47,387 (1L), $77,661 (2L), and $53,609 (3L), driven primarily by outpatient costs.

CONCLUSIONS: No clear standard of care was observed in 2L+. Although immunotherapy is increasingly used in 2L+, only a small subset of patients stayed on immunotherapy for a prolonged period, suggesting a need for more therapeutic options. Better understanding of disease biology and the introduction of new therapies may address these unmet needs.

RevDate: 2022-01-15

Darst BF, Hughley R, Pfennig A, et al (2022)

A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry.

European urology pii:S0302-2838(21)02271-5 [Epub ahead of print].

A rare African ancestry-specific germline deletion variant in HOXB13 (X285K, rs77179853) was recently reported in Martinican men with early-onset prostate cancer. Given the role of HOXB13 germline variation in prostate cancer, we investigated the association between HOXB13 X285K and prostate cancer risk in a large sample of 22 361 African ancestry men, including 11 688 prostate cancer cases. The risk allele was present only in men of West African ancestry, with an allele frequency in men that ranged from 0.40% in Ghana and 0.31% in Nigeria to 0% in Uganda and South Africa, with a range of frequencies in men with admixed African ancestry from North America and Europe (0-0.26%). HOXB13 X285K was associated with 2.4-fold increased odds of prostate cancer (95% confidence interval [CI] = 1.5-3.9, p = 2 × 10-4), with greater risk observed for more aggressive and advanced disease (Gleason ≥8: odds ratio [OR] = 4.7, 95% CI = 2.3-9.5, p = 2 × 10-5; stage T3/T4: OR = 4.5, 95% CI = 2.0-10.0, p = 2 × 10-4; metastatic disease: OR = 5.1, 95% CI = 1.9-13.7, p = 0.001). We estimated that the allele arose in West Africa 1500-4600 yr ago. Further analysis is needed to understand how the HOXB13 X285K variant impacts the HOXB13 protein and function in the prostate. Understanding who carries this mutation may inform prostate cancer screening in men of West African ancestry. PATIENT SUMMARY: A rare African ancestry-specific germline deletion in HOXB13, found only in men of West African ancestry, was reported to be associated with an increased risk of overall and advanced prostate cancer. Understanding who carries this mutation may help inform screening for prostate cancer in men of West African ancestry.

RevDate: 2022-01-14

DePriest BP, Li H, Bidgoli A, et al (2022)

Regenerating Islet-Derived 3-alpha is a Prognostic Biomarker for Gastrointestinal Chronic Graft-Versus-Host Disease.

Blood advances pii:483532 [Epub ahead of print].

Prognostic biomarkers used to identify likelihood of disease progression have not been identified for chronic graft-versus-host disease (cGVHD), the leading cause of late non-relapse mortality (NRM) in survivors of allogenic hematopoietic cell transplantation. Gastrointestinal cGVHD (GI-cGVHD) has been particularly challenging to classify. Here, we analyzed three proteomics markers [Regenerating-islet-derived-3-alpha (Reg3α), C-X-C-motif-ligand (CXCL9) and Stimulation-2 (ST2)] in two independent cohorts of patients with cGVHD totaling 289 patients. Plasma concentrations of Reg3α were significantly increased in patients with GI-cGVHD compared to those without (p=0.0012, p=0.01 respectively), CXCL9 and ST2 were not. Patients with high Reg3α (≥72ng/mL) vs. low Reg3α had higher NRM (23% vs. 11%, p=0.015). Since Reg3α has been identified as a lower GI-tract marker in acute GVHD, we correlated Reg3α with lower acute-like GI-cGVHD vs. classical fibrotic-like esophageal manifestations and found Reg3a did not differ between the subtypes. No difference was observed between upper and lower subtypes. Patients with extremely high Reg3α (≥180 ng/mL) had higher GI-scores but not higher lower-GI-scores. In multivariate Cox regression model, patients with high Reg3α were 1.9 times more likely to die without relapse. Our findings demonstrate the utility of Reg3α as a prognostic marker for GI-cGVHD. These data warrant prospective biomarker validation studies.

RevDate: 2022-01-14

Harris HR, Korkes KMN, Li T, et al (2022)

Endometriosis, psoriasis and psoriatic arthritis: A prospective cohort study.

American journal of epidemiology pii:6507342 [Epub ahead of print].

Endometriosis, psoriasis and psoriatic arthritis (PsA) are chronic inflammatory disorders that have etiologies that remain poorly understood but may be correlated, as endometriosis has been associated with other inflammatory disorders. We investigated the bi-directional associations between laparoscopically-confirmed endometriosis, and physician-diagnosed psoriasis and PsA in the Nurses' Health Study II cohort (n=116,429 aged 25-42 years in 1989). During 22 years of follow-up (1991-2013), 4,112 incident cases of laparoscopically-confirmed endometriosis (mean age at diagnosis=40.3 years) and 697 validated physician-diagnosed cases of psoriasis (mean age at diagnosis=43.6 years), 110 of whom had concomitant PsA, were confirmed. A history of psoriasis with concomitant PsA was associated with a 2-fold higher risk of endometriosis (HR=2.01, 95% CI=1.23-3.30), however no association was observed between psoriasis without PsA and endometriosis risk (HR=0.93, 95% CI=0.68-1.26). When endometriosis was the exposure, it was not associated with a risk of subsequent psoriasis (HR=1.28, 95% CI=0.95-1.72). The risk of psoriasis with PsA was notably higher, however the sample size was small with wide confidence intervals (HR=1.77, 95% CI=0.89-3.52). Our findings suggest that psoriasis with concomitant PsA is associated with greater risk of laparoscopically-confirmed endometriosis. In addition, there was a suggestive association between endometriosis diagnosis and subsequent risk of psoriasis with PsA.

RevDate: 2022-01-14

O'Brien MP, Forleo-Neto E, Sarkar N, et al (2022)

Effect of Subcutaneous Casirivimab and Imdevimab Antibody Combination vs Placebo on Development of Symptomatic COVID-19 in Early Asymptomatic SARS-CoV-2 Infection: A Randomized Clinical Trial.

JAMA pii:2788256 [Epub ahead of print].

Importance: Easy-to-administer anti-SARS-CoV-2 treatments may be used to prevent progression from asymptomatic infection to symptomatic disease and to reduce viral carriage.

Objective: To evaluate the effect of combination subcutaneous casirivimab and imdevimab on progression from early asymptomatic SARS-CoV-2 infection to symptomatic COVID-19.

Randomized, double-blind, placebo-controlled, phase 3 trial of close household contacts of a SARS-CoV-2-infected index case at 112 sites in the US, Romania, and Moldova enrolled July 13, 2020-January 28, 2021; follow-up ended March 11, 2021. Asymptomatic individuals (aged ≥12 years) were eligible if identified within 96 hours of index case positive test collection. Results from 314 individuals positive on SARS-CoV-2 reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) testing are reported.

Interventions: Individuals were randomized 1:1 to receive 1 dose of subcutaneous casirivimab and imdevimab, 1200 mg (600 mg of each; n = 158), or placebo (n = 156).

Main Outcomes and Measures: The primary end point was the proportion of seronegative participants who developed symptomatic COVID-19 during the 28-day efficacy assessment period. The key secondary efficacy end points were the number of weeks of symptomatic SARS-CoV-2 infection and the number of weeks of high viral load (>4 log10 copies/mL).

Results: Among 314 randomized participants (mean age, 41.0 years; 51.6% women), 310 (99.7%) completed the efficacy assessment period; 204 were asymptomatic and seronegative at baseline and included in the primary efficacy analysis. Subcutaneous casirivimab and imdevimab, 1200 mg, significantly prevented progression to symptomatic disease (29/100 [29.0%] vs 44/104 [42.3%] with placebo; odds ratio, 0.54 [95% CI, 0.30-0.97]; P = .04; absolute risk difference, -13.3% [95% CI, -26.3% to -0.3%]). Casirivimab and imdevimab reduced the number of symptomatic weeks per 1000 participants (895.7 weeks vs 1637.4 weeks with placebo; P = .03), an approximately 5.6-day reduction in symptom duration per symptomatic participant. Treatment with casirivimab and imdevimab also reduced the number of high viral load weeks per 1000 participants (489.8 weeks vs 811.9 weeks with placebo; P = .001). The proportion of participants receiving casirivimab and imdevimab who had 1 or more treatment-emergent adverse event was 33.5% vs 48.1% for placebo, including events related (25.8% vs 39.7%) or not related (11.0% vs 16.0%) to COVID-19.

Conclusions and Relevance: Among asymptomatic SARS-CoV-2 RT-qPCR-positive individuals living with an infected household contact, treatment with subcutaneous casirivimab and imdevimab antibody combination vs placebo significantly reduced the incidence of symptomatic COVID-19 over 28 days.

Trial Registration: ClinicalTrials.gov Identifier: NCT04452318.

RevDate: 2022-01-14

Cable J, Rappuoli R, Klemm EJ, et al (2022)

Innovative vaccine approaches-a Keystone Symposia report.

Annals of the New York Academy of Sciences [Epub ahead of print].

The rapid development of COVID-19 vaccines was the result of decades of research to establish flexible vaccine platforms and understand pathogens with pandemic potential, as well as several novel changes to the vaccine discovery and development processes that partnered industry and governments. And while vaccines offer the potential to drastically improve global health, low-and-middle-income countries around the world often experience reduced access to vaccines and reduced vaccine efficacy. Addressing these issues will require novel vaccine approaches and platforms, deeper insight how vaccines mediate protection, and innovative trial designs and models. On June 28-30, 2021, experts in vaccine research, development, manufacturing, and deployment met virtually for the Keystone eSymposium "Innovative Vaccine Approaches" to discuss advances in vaccine research and development.

RevDate: 2022-01-14

Chuang YC, GR Smith (2022)

Dynamic configurations of meiotic DNA-break hotspot determinant proteins.

Journal of cell science pii:274015 [Epub ahead of print].

Appropriate DNA double-strand-break (DSB) and crossover distributions are required for proper meiotic chromosome segregation. Schizosaccharomyces pombe linear element proteins (LinEs) determine DSB hotspots; LinE-bound hotspots form 3D clusters over ∼200 kb chromosomal regions. Here, we investigated LinE configurations and distributions in live cells using super-resolution fluorescence microscopy. We found LinEs form two chromosomal structures, dot-like and linear structures, in both zygotic and azygotic meiosis. Dot-like LinE structures appeared around the time of meiotic DNA replication, underwent dotty-to-linear-to-dotty configurational transitions, and disassembled before the first meiotic division. DSB formation and repair did not detectably influence LinE structure formation, but failure of DSB formation delayed disassembly. Recombination-deficient LinE missense mutants formed dot-like but not linear LinE structures. Our quantitative study reveals a transient form of LinE structures and suggests a novel role for LinE proteins in regulating meiotic events, such as DSB repair. We discuss the relation of LinEs and the synaptonemal complex in other species.

RevDate: 2022-01-14

Huang D, Chowdhury S, Wang H, et al (2021)

Multiomic analysis identifies CPT1A as a potential therapeutic target in platinum-refractory, high-grade serous ovarian cancer.

Cell reports. Medicine, 2(12):100471 pii:S2666-3791(21)00343-8.

Resistance to platinum compounds is a major determinant of patient survival in high-grade serous ovarian cancer (HGSOC). To understand mechanisms of platinum resistance and identify potential therapeutic targets in resistant HGSOC, we generated a data resource composed of dynamic (±carboplatin) protein, post-translational modification, and RNA sequencing (RNA-seq) profiles from intra-patient cell line pairs derived from 3 HGSOC patients before and after acquiring platinum resistance. These profiles reveal extensive responses to carboplatin that differ between sensitive and resistant cells. Higher fatty acid oxidation (FAO) pathway expression is associated with platinum resistance, and both pharmacologic inhibition and CRISPR knockout of carnitine palmitoyltransferase 1A (CPT1A), which represents a rate limiting step of FAO, sensitize HGSOC cells to platinum. The results are further validated in patient-derived xenograft models, indicating that CPT1A is a candidate therapeutic target to overcome platinum resistance. All multiomic data can be queried via an intuitive gene-query user interface (https://sites.google.com/view/ptrc-cell-line).

RevDate: 2022-01-14

Lange M, Bergen V, Klein M, et al (2022)

CellRank for directed single-cell fate mapping.

Nature methods [Epub ahead of print].

Computational trajectory inference enables the reconstruction of cell state dynamics from single-cell RNA sequencing experiments. However, trajectory inference requires that the direction of a biological process is known, largely limiting its application to differentiating systems in normal development. Here, we present CellRank (https://cellrank.org) for single-cell fate mapping in diverse scenarios, including regeneration, reprogramming and disease, for which direction is unknown. Our approach combines the robustness of trajectory inference with directional information from RNA velocity, taking into account the gradual and stochastic nature of cellular fate decisions, as well as uncertainty in velocity vectors. On pancreas development data, CellRank automatically detects initial, intermediate and terminal populations, predicts fate potentials and visualizes continuous gene expression trends along individual lineages. Applied to lineage-traced cellular reprogramming data, predicted fate probabilities correctly recover reprogramming outcomes. CellRank also predicts a new dedifferentiation trajectory during postinjury lung regeneration, including previously unknown intermediate cell states, which we confirm experimentally.

RevDate: 2022-01-14

Dareng EO, Tyrer JP, Barnes DR, et al (2022)

Polygenic risk modeling for prediction of epithelial ovarian cancer risk.

European journal of human genetics : EJHG [Epub ahead of print].

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

RevDate: 2022-01-14

Schmid S, Jiang M, Brown MC, et al (2022)

Accounting for EGFR mutations in epidemiological analyses of non-small cell lung cancers: Examples based on the International Lung Cancer Consortium data.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-21-0747 [Epub ahead of print].

INTRODUCTION: Somatic EGFR mutations define a subset of non-small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiological datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiological datasets and evaluated the clinical utility of these approaches.

METHODS: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiological datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cutpoint, and a second epidemiological, multiple imputation approach to ILCCO survival analyses that did and did not account for EGFR-status.

RESULTS: Of 35,356 ILCCO patients with NSCLC, EGFR-mutation-status was available in 4231 patients. A model regressing known EGFR-mutation-status on clinical and demographic variables achieved a concordance-index of 0.75 (95%CI: 0.74-0.77) in the training and 0.77 (95%CI: 0.74-0.79) in the testing dataset. At an optimal cut-point of probability-score=0.335, sensitivity=69% and specificity=72.5% for determining EGFR-wildtype status. In both restriction-based and imputation-based regression analyses of the individual roles of BMI on overall survival of NSCLC patients, similar results were observed between overall and EGFR-mutation-negative cohort analyses of patients of all ancestries. However, our approach identified some differences: EGFR-mutated Asian patients did not incur a survival benefit from being obese, as observed in EGFR-wildtype Asian patients.

CONCLUSION: We introduce a pragmatic method to evaluate the potential impact of EGFR-status on epidemiological analyses of NSCLC.

IMPACT: The proposed method is generalizable in the common occurrence in which EGFR-status data are missing.

RevDate: 2022-01-14

Kantor ED, O'Connell K, Liang PS, et al (2022)

Glucosamine Use and Risk of Colorectal Cancer: Results from UK Biobank.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-21-1171 [Epub ahead of print].

BACKGROUND: Use of the dietary supplement glucosamine has been associated with reduced risk of colorectal cancer (CRC); however, it remains unclear if the association varies by screening status, time, and other factors.

METHODS: We therefore evaluated these questions in UK Biobank. Multivariable-adjusted Hazard Ratios (HRs) and 95% Confidence Intervals (95% CI) were estimated using Cox proportional hazards regression.

RESULTS: No association was observed between use of glucosamine and risk of CRC overall (HR: 0.94; 95% CI: 0.85-1.04). However, the association varied by screening status (p-interaction:0.05), with an inverse association observed only among never-screened individuals (HR: 0.86; 95% CI: 0.76-0.98). When stratified by study time, an inverse association was observed in early follow-up among those entering the cohort in early years (2006-2008, HR: 0.80; 95% CI: 0.67-0.95). No heterogeneity was observed by age, sex, body mass index, smoking status, or use of non-steroidal anti-inflammatory drugs.

CONCLUSIONS: While there was no association between glucosamine use and CRC overall, the inverse association among never-screened individuals mirrors our observations in prior exploratory analyses of US cohorts. The National Health Service Bowel Cancer Screening Program started in 2006 in England and was more widely implemented across the UK by 2009. In line with this, we observed an inverse association limited to early follow-up in those surveyed 2006-2008, before screening was widely implemented.

IMPACT: These data suggest that unscreened individuals may benefit from use of glucosamine; however, further studies are needed to confirm the interplay of screening and timing.

RevDate: 2022-01-13

Santiago-Torres M, Mull KE, Sullivan BM, et al (2021)

Efficacy and utilization of smartphone applications for smoking cessation among low-income adults: Secondary analysis of the iCanQuit randomized trial.

Drug and alcohol dependence, 231:109258 pii:S0376-8716(21)00753-5 [Epub ahead of print].

INTRODUCTION: Evidence of digital interventions that are efficacious among low-income populations is scarce. In a secondary analysis, we determined the efficacy and utilization of an Acceptance and Commitment Therapy (ACT)-based smartphone application (iCanQuit) versus a U.S. Clinical Practice Guidelines (USCPG)-based smartphone application (QuitGuide) for smoking cessation in low-income adults enrolled in the iCanQuit randomized trial.

METHODS: Participants were randomized to receive iCanQuit (n = 437) or QuitGuide (n = 460) for 12-months. Consistent with the main trial, the primary outcome was self-reported complete-case 30-day point prevalence abstinence (PPA) at 12-months. Secondary outcomes were 7-day PPA, missing-as-smoking and multiple imputation, prolonged abstinence, and cessation of all tobacco products at 12-months. Outcome data retention, utilization, and change in ACT-based processes were compared across arms.

RESULTS: Participants were recruited from 48 U.S. states. Retention rate was 88% at 12-months and did not differ by arm. At 12-months, iCanQuit was 1.46 times more efficacious than QuitGuide for smoking cessation (27% vs. 20%; OR=1.46 95% CI: 1.04, 2.06). Findings were similar for missing-as-smoking imputation (23% vs. 18%; OR=1.41 95% CI: 1.01, 1.97) and multiple imputation at 12-months (27% vs. 20%; OR=1.51 95% CI: 1.07, 2.14). Treatment utilization was significantly higher among iCanQuit than QuitGuide participants. Increased acceptance of cues to smoke mediated the effect of treatment on cessation.

CONCLUSIONS: The iCanQuit smartphone application was more efficacious and engaging for smoking cessation among low-income adults than a USCPG-based smartphone application. A nationwide dissemination trial of iCanQuit is warranted to determine whether iCanQuit may alleviate cessation-related disparities among low-income adults.

RevDate: 2022-01-13

Archambault AN, Jeon J, Lin Y, et al (2022)

Risk Stratification for Early-Onset Colorectal Cancer Using a Combination of Genetic and Environmental Risk Scores: An International Multi-Center Study.

Journal of the National Cancer Institute pii:6506525 [Epub ahead of print].

BACKGROUND: Incidence of colorectal cancer (CRC) among individuals aged less than 50 years has been increasing. As screening guidelines lower the recommended age of screening initiation, concerns including the burden on screening capacity and costs have been recognized, suggesting that an individualized approach may be warranted. We developed risk prediction models for early-onset CRC that incorporate an environmental risk score (ERS), including 16 lifestyle and environmental factors, and a polygenic risk score (PRS), of 141 variants.

METHODS: Relying on risk score weights for ERS and PRS derived from studies of CRC at all ages, we evaluated risks for early-onset CRC in 3,486 cases and 3,890 controls aged less than 50 years. Relative and absolute risks for early-onset CRC were assessed according to values of the ERS and PRS. The discriminatory performance of these scores was estimated using the covariate-adjusted area under the receiver operating characteristic curve.

RESULTS: Increasing values of ERS and PRS were associated with increasing relative risks for early-onset CRC (odds ratio per standard deviation of ERS = 1.14, 95% confidence interval [CI] = 1.08, 1.20; odds ratio per standard deviation of PRS = 1.59, 95% CI = 1.51, 1.68), both contributing to case-control discrimination (area under the curve = 0.631, 95% CI = 0.615, 0.647). Based on absolute risks, we can expect 26 excess cases per 10,000 men and 21 per 10,000 women, among those scoring at the 90th percentile for both risk scores.

CONCLUSIONS: Personal risk scores have the potential to identify individuals at differential relative and absolute risk for early-onset CRC. Improved discrimination may aid in targeted CRC screening of younger, high-risk individuals, potentially improving outcomes.

RevDate: 2022-01-13

Mills MG, Bruce E, Huang ML, et al (2022)

An international, interlaboratory ring trial confirms the feasibility of an extraction-less "direct" RT-qPCR method for reliable detection of SARS-CoV-2 RNA in clinical samples.

PloS one, 17(1):e0261853 pii:PONE-D-21-32309.

Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is used worldwide to test and trace the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). "Extraction-less" or "direct" real time-reverse transcription polymerase chain reaction (RT-PCR) is a transparent and accessible qualitative method for SARS-CoV-2 detection from nasopharyngeal or oral pharyngeal samples with the potential to generate actionable data more quickly, at a lower cost, and with fewer experimental resources than full RT-qPCR. This study engaged 10 global testing sites, including laboratories currently experiencing testing limitations due to reagent or equipment shortages, in an international interlaboratory ring trial. Participating laboratories were provided a common protocol, common reagents, aliquots of identical pooled clinical samples, and purified nucleic acids and used their existing in-house equipment. We observed 100% concordance across laboratories in the correct identification of all positive and negative samples, with highly similar cycle threshold values. The test also performed well when applied to locally collected patient nasopharyngeal samples, provided the viral transport media did not contain charcoal or guanidine, both of which appeared to potently inhibit the RT-PCR reaction. Our results suggest that direct RT-PCR assay methods can be clearly translated across sites utilizing readily available equipment and expertise and are thus a feasible option for more efficient COVID-19 coronavirus disease testing as demanded by the continuing pandemic.

RevDate: 2022-01-13

Kwan ML, Cheng RK, Iribarren C, et al (2022)

Risk of Cardiometabolic Risk Factors in Women With and Without a History of Breast Cancer: The Pathways Heart Study.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: The incidence of cardiometabolic risk factors in breast cancer (BC) survivors has not been well described. Thus, we compared risk of hypertension, diabetes, and dyslipidemia in women with and without BC.

METHODS: Women with invasive BC diagnosed from 2005 to 2013 at Kaiser Permanente Northern California (KPNC) were identified and matched 1:5 to noncancer controls on birth year, race, and ethnicity. Cumulative incidence rates of hypertension, diabetes, and dyslipidemia were estimated with competing risk of overall death. Subdistribution hazard ratios (sHRs) were estimated by Fine and Gray regression, adjusted for cardiovascular disease-related risk factors, and stratified by treatment and body mass index (BMI).

RESULTS: A total of 14,942 BC cases and 74,702 matched controls were identified with mean age 61.2 years and 65% non-Hispanic White. Compared with controls, BC cases had higher cumulative incidence rates of hypertension (10.9% v 8.9%) and diabetes (2.1% v 1.7%) after 2 years, with higher diabetes incidence persisting after 10 years (9.3% v 8.8%). In multivariable models, cases had higher risk of diabetes (sHR, 1.16; 95% CI, 1.07 to 1.26) versus controls. Cases treated with chemotherapy (sHR, 1.23; 95% CI, 1.11 to 1.38), left-sided radiation (sHR, 1.29; 95% CI, 1.13 to 1.48), or endocrine therapy (sHR, 1.23; 95% CI, 1.12 to 1.34) continued to have higher diabetes risk. Hypertension risk was higher for cases receiving left-sided radiation (sHR, 1.11; 95% CI, 1.02 to 1.21) or endocrine therapy (sHR, 1.10; 95% CI, 1.03 to 1.16). Normal-weight (BMI < 24.9 kg/m2) cases had higher risks overall and within treatment subgroups versus controls.

CONCLUSION: BC survivors at KPNC experienced elevated risks of diabetes and hypertension compared with women without BC depending on treatments received and BMI. Future studies should examine strategies for cardiometabolic risk factor prevention in BC survivors.

RevDate: 2022-01-13

Guru Murthy GS, Kim S, Hu ZH, et al (2022)

Relapse and Disease-Free Survival in Patients With Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Cell Transplantation Using Older Matched Sibling Donors vs Younger Matched Unrelated Donors.

JAMA oncology pii:2788054 [Epub ahead of print].

Importance: Matched sibling donors (MSDs) are preferred for allogeneic hematopoietic cell transplantation (allo-HCT) in myelodysplastic syndrome even if they are older. However, whether older MSDs or younger human leukocyte antigen-matched unrelated donors (MUDs) are associated with better outcomes remains unclear.

Objective: To investigate whether allo-HCT for myelodysplastic syndrome using younger MUDs would be associated with improved disease-free survival and less relapse compared with older MSDs.

This retrospective cohort study assessed data reported to the Center for International Blood and Marrow Transplant Research database from 1761 adults 50 years or older with myelodysplastic syndrome who underwent allo-HCT using an older MSD or younger MUD between January 1, 2011, and December 31, 2017, with a median follow-up of 48 months. Data analysis was performed from January 8, 2019, to December 30, 2020.

Interventions/Exposures: Allo-HCT from an older MSD (donor age ≥50 years) or a younger MUD (donor age ≤35 years).

Main Outcomes and Measures: The primary outcome was disease-free survival. Secondary outcomes were overall survival, relapse, nonrelapse mortality, acute graft-vs-host disease (GVHD), chronic GVHD, and GVHD-free relapse-free survival.

Results: Of 1761 patients (1162 [66%] male; median [range] age, 64.9 [50.2-77.6] years in the MSD cohort and 66.5 [50.4-80.9] years in MUD cohort), 646 underwent allo-HCT with an older MSD and 1115 with a younger MUD. In multivariable analysis, the rate of disease-free survival was significantly lower in allo-HCTs with older MSDs compared with younger MUDs (hazard ratio [HR], 1.17; 95% CI, 1.02-1.34; P = .02), whereas the difference in overall survival rate of allo-HCT with younger MUDs vs older MSDs was not statistically significant (HR, 1.13; 95% CI, 0.98-1.29; P = .07). Allo-HCT with older MSDs was associated with significantly higher relapse (HR, 1.62; 95% CI, 1.32-1.97; P < .001), lower nonrelapse mortality (HR, 0.76; 95% CI, 0.59-0.96; P = .02), lower acute GVHD (HR, 0.52; 95% CI, 0.42-0.65; P < .001), chronic GVHD (HR, 0.77; 95% CI, 0.64-0.92; P = .005), and a lower rate of GVHD-free relapse-free survival beyond 12 months after allo-HCT (HR, 1.42; 95% CI, 1.02-1.98; P = .04).

Conclusions and Relevance: This cohort study found higher disease-free survival and lower relapse for allo-HCT in myelodysplastic syndrome using younger MUDs compared with older MSDs. The risk of nonrelapse mortality and GVHD was lower with older MSDs. These results suggest that the use of younger MUDs should be considered in the donor selection algorithm for myelodysplastic syndrome, in which it is pivotal to minimize relapse given limited treatment options for managing relapsed disease.

RevDate: 2022-01-13

Nemirovsky A, Ilan K, Lerner L, et al (2022)

Brain-immune axis regulation is responsive to cognitive behavioral therapy and mindfulness intervention: Observations from a randomized controlled trial in patients with Crohn's disease.

Brain, behavior, & immunity - health, 19:100407 pii:S2666-3546(21)00210-6.

Background and aims: Crohn's disease (CD) is a chronic inflammatory bowel disease associated with psychological stress that is regulated primarily by the hypothalamus-pituitary-adrenal (HPA) axis. Here, we determined whether the psychological characteristics of CD patients associate with their inflammatory state, and whether a 3-month trial of cognitive-behavioral and mindfulness-based stress reduction (COBMINDEX) impacts their inflammatory process.

Methods: Circulating inflammatory markers and a wide range of psychological parameters related to stress and well-being were measured in CD patients before and after COBMINDEX. Inflammatory markers in CD patients were also compared to age- and sex-matched healthy controls (HCs).

Results: CD patients exhibited increased peripheral low-grade inflammation compared with HCs, demonstrated by interconnected inflammatory modules represented by IL-6, TNFα, IL-17, MCP-1 and IL-18. Notably, higher IL-18 levels correlated with higher score of stress and a lower score of wellbeing in CD patients. COBMINDEX was accompanied by changes in inflammatory markers that coincided with changes in cortisol: changes in serum levels of cortisol correlated positively with those of IL-10 and IFNα and negatively with those of MCP-1. Furthermore, inflammatory markers of CD patients at baseline predicted COBMINDEX efficacy, as higher levels of distinct cytokines and cortisol at baseline, correlated negatively with changes in disease activity (by Harvey-Bradshaw Index) and psychological distress (global severity index measure) following COBMINDEX.

Conclusion: CD patients have a characteristic immunological profile that correlates with psychological stress, and disease severity. We suggest that COBMINDEX induces stress resilience in CD patients, which impacts their well-being, and their disease-associated inflammatory process.

RevDate: 2022-01-13

Mollan KR, Eron JJ, Krajewski TJ, et al (2021)

Infectious Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Virus in Symptomatic Coronavirus Disease 2019 (COVID-19) Outpatients: Host, Disease, and Viral Correlates.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:6433715 [Epub ahead of print].

BACKGROUND: Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectious virus isolation in outpatients with coronavirus disease 2019 (COVID-19) has been associated with viral RNA levels and symptom duration, little is known about the host, disease, and viral determinants of infectious virus detection.

METHODS: COVID-19 adult outpatients were enrolled within 7 days of symptom onset. Clinical symptoms were recorded via patient diary. Nasopharyngeal swabs were collected to quantitate SARS-CoV-2 RNA by reverse transcriptase polymerase chain reaction and for infectious virus isolation in Vero E6-cells. SARS-CoV-2 antibodies were measured in serum using a validated ELISA assay.

RESULTS: Among 204 participants with mild-to-moderate symptomatic COVID-19, the median nasopharyngeal viral RNA was 6.5 (interquartile range [IQR] 4.7-7.6 log10 copies/mL), and 26% had detectable SARS-CoV-2 antibodies (immunoglobulin (Ig)A, IgM, IgG, and/or total Ig) at baseline. Infectious virus was recovered in 7% of participants with SARS-CoV-2 antibodies compared to 58% of participants without antibodies (prevalence ratio [PR] = 0.12, 95% confidence interval [CI]: .04, .36; P = .00016). Infectious virus isolation was also associated with higher levels of viral RNA (mean RNA difference +2.6 log10, 95% CI: 2.2, 3.0; P < .0001) and fewer days since symptom onset (PR = 0.79, 95% CI: .71, .88 per day; P < .0001).

CONCLUSIONS: The presence of SARS-CoV-2 antibodies is strongly associated with clearance of infectious virus. Seropositivity and viral RNA levels are likely more reliable markers of infectious virus clearance than subjective measure of COVID-19 symptom duration. Virus-targeted treatment and prevention strategies should be administered as early as possible and ideally before seroconversion.


RevDate: 2022-01-13

Koup RA, Donis RO, Gilbert PB, et al (2022)

Publisher Correction: Community evaluation of glycoproteomics informatics solutions reveals high-performance search strategies for serum glycopeptide analysis.

RevDate: 2022-01-13

Greenberg PD, Disis ML, Margolin KA, et al (2022)

Mac Cheever (1944-2021): a tribute to a life of achievement and service.

Journal for immunotherapy of cancer, 10(1):.

RevDate: 2022-01-13

Hoff FW, Van Dijk AD, Qiu Y, et al (2022)

Clinical relevance of proteomic profiling in de novo pediatric acute myeloid leukemia: a Children's Oncology Group study.

Haematologica [Epub ahead of print].

Pediatric acute myeloid leukemia (AML) remains a fatal disease for at least 30% of patients, stressing the need for improved therapies and better risk stratification. As proteins are the unifying feature of (epi)genetic and environmental alterations, and are often targeted by novel chemotherapeutic agents, we studied the proteomic landscape of pediatric AML. Protein expression and activation levels were measured in 500 bulk leukemic patient samples and 30 control CD34+ samples, using the reverse phase protein arrays with 296 strictly validated antibodies. The multi-step "MetaGalaxy" analysis methodology was applied and identified nine protein expression signatures (PrSIG), based on strong recurrent protein expression patterns. PrSIGs were associated with cytogenetics and mutational state, and with both favorable or unfavorable prognosis. Analysis based on treatment (i.e., ADE vs. ADE plus bortezomib (ADEB)) identified three PrSIGs that did better with ADEB vs. ADE. When PrSIGs were studied in the context of genetic subgroups, PrSIGs were independently prognostic after multivariate analysis, suggesting a potential value for proteomics in combination with current classification systems. Proteins with universally increased (n=7) or decreased (n=17) expression were observed across PrSIGs. Expression of certain proteins significantly differentially expressed from normal could be identified, forming a hypothetical platform for personalized medicine.

RevDate: 2022-01-12

Goyal A, Gardner M, Mayer BT, et al (2022)

Estimation of the in vivo neutralization potency of eCD4Ig and conditions for AAV-mediated production for SHIV long-term remission.

Science advances, 8(2):eabj5666.

[Figure: see text].

RevDate: 2022-01-11

Prentice RL, Pettinger M, Zheng C, et al (2022)

Biomarkers for Components of Dietary Protein and Carbohydrate with Application to Chronic Disease Risk Among Postmenopausal Women.

The Journal of nutrition pii:6500205 [Epub ahead of print].

BACKGROUND: We recently developed protein and carbohydrate intake biomarkers using metabolomics profiles in serum and urine, and used them to correct self-reported dietary data for measurement error. Biomarker-calibrated carbohydrate density was inversely associated with chronic disease risk, while protein density associations were mixed.

OBJECTIVE: To elucidate and extend this earlier work through biomarker development for protein and carbohydrate components, including animal protein and fiber.

METHODS: Prospective disease association analyses in WHI cohorts of postmenopausal U.S. women, aged 50-79 when enrolled at 40 U.S. Clinical Centers. Biomarkers are developed using an embedded human feeding study (n = 153). Calibration equations for protein and carbohydrate components are developed using a WHI nutritional biomarker study (n = 436). Calibrated intakes are associated with chronic disease incidence in WHI cohorts (n = 81,954) over a 20-year (median) follow-up period, using hazard ratio regression methods.

RESULTS: Previously reported elevations in cardiovascular disease (CVD) with higher protein diets tended to be explained by animal protein density. For example, for coronary heart disease a 20% increment in animal protein density had hazard ratio (HR) and 95% confidence interval (CI) of 1.20 (1.02, 1.42) relative to the HR for total protein density. In comparison, cancer and diabetes risk showed little association with animal protein density beyond that attributable to total protein density. Inverse carbohydrate density associations with total CVD were mostly attributable to fiber density, with 20% increment HR (95% CI) factor of 0.89 (0.83, 0.94). Cancer risk showed little association with fiber density, while diabetes risk has 20% increment HR (95% CI) of 0.93 (0.88, 0.98) relative to the HRs for total carbohydrate density.

CONCLUSIONS: In a population of postmenopausal U.S. women, CVD risk is associated with high animal protein and low fiber diets, cancer risk is associated with low carbohydrate diets, and diabetes risk is associated with low fiber/low carbohydrate diets.This study is registered with clinicaltrials.gov identifier: NCT00000611.

RevDate: 2022-01-11

Trasanidis N, Katsarou A, Ponnusamy K, et al (2022)

Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma.

Blood pii:483430 [Epub ahead of print].

Understanding the biological and clinical impact of copy number aberrations (CNA) for the development of precision therapies in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring adverse prognosis in several types of cancer, including in the blood cancer multiple myeloma (MM). Although several genes across chr1q portend high-risk MM disease, the underpinning molecular aetiology remains elusive. Here, with reference to the 3D chromatin structure, we integrate MM patient multi-omics datasets with genetic variables to obtain an associated clinical risk map across chr1q and to identify 103 adverse prognosis genes in chr1q-amp MM. Prominent amongst these genes, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed super-enhancers, PBX1 directly regulates critical oncogenic pathways and a FOXM1-dependent transcriptional programme. Together, PBX1 and FOXM1 activate a proliferative gene signature which predicts adverse prognosis across multiple types of cancer. Notably, pharmacological disruption of the PBX1-FOXM1 axis with existing agents (thiostrepton) and a novel PBX1 small-molecule inhibitor (T417) is selectively toxic against chr1q-amplified myeloma and solid tumour cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes and proposes novel CNA-targeted therapy strategies in multiple myeloma and other types of cancer.

RevDate: 2022-01-11

Anywaine Z, Barry H, Anzala O, et al (2022)

Safety and immunogenicity of 2-dose heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola vaccination in children and adolescents in Africa: A randomised, placebo-controlled, multicentre Phase II clinical trial.

PLoS medicine, 19(1):e1003865 pii:PMEDICINE-D-21-02242.

BACKGROUND: Reoccurring Ebola outbreaks in West and Central Africa have led to serious illness and death in thousands of adults and children. The objective of this study was to assess safety, tolerability, and immunogenicity of the heterologous 2-dose Ad26.ZEBOV, MVA-BN-Filo vaccination regimen in adolescents and children in Africa.

METHODS AND FINDINGS: In this multicentre, randomised, observer-blind, placebo-controlled Phase II study, 131 adolescents (12 to 17 years old) and 132 children (4 to 11 years old) were enrolled from Eastern and Western Africa and randomised 5:1 to receive study vaccines or placebo. Vaccine groups received intramuscular injections of Ad26.ZEBOV (5 × 1010 viral particles) and MVA-BN-Filo (1 × 108 infectious units) 28 or 56 days apart; placebo recipients received saline. Primary outcomes were safety and tolerability. Solicited adverse events (AEs) were recorded until 7 days after each vaccination and serious AEs (SAEs) throughout the study. Secondary and exploratory outcomes were humoral immune responses (binding and neutralising Ebola virus [EBOV] glycoprotein [GP]-specific antibodies), up to 1 year after the first dose. Enrolment began on February 26, 2016, and the date of last participant last visit was November 28, 2018. Of the 263 participants enrolled, 217 (109 adolescents, 108 children) received the 2-dose regimen, and 43 (20 adolescents, 23 children) received 2 placebo doses. Median age was 14.0 (range 11 to 17) and 7.0 (range 4 to 11) years for adolescents and children, respectively. Fifty-four percent of the adolescents and 51% of the children were male. All participants were Africans, and, although there was a slight male preponderance overall, the groups were well balanced. No vaccine-related SAEs were reported; solicited AEs were mostly mild/moderate. Twenty-one days post-MVA-BN-Filo vaccination, binding antibody responses against EBOV GP were observed in 100% of vaccinees (106 adolescents, 104 children). Geometric mean concentrations tended to be higher after the 56-day interval (adolescents 13,532 ELISA units [EU]/mL, children 17,388 EU/mL) than the 28-day interval (adolescents 6,993 EU/mL, children 8,007 EU/mL). Humoral responses persisted at least up to Day 365. A limitation of the study is that the follow-up period was limited to 365 days for the majority of the participants, and so it was not possible to determine whether immune responses persisted beyond this time period. Additionally, formal statistical comparisons were not preplanned but were only performed post hoc.

CONCLUSIONS: The heterologous 2-dose vaccination was well tolerated in African adolescents and children with no vaccine-related SAEs. All vaccinees displayed anti-EBOV GP antibodies after the 2-dose regimen, with higher responses in the 56-day interval groups. The frequency of pyrexia after vaccine or placebo was higher in children than in adolescents. These data supported the prophylactic indication against EBOV disease in a paediatric population, as licenced in the EU.

TRIAL REGISTRATION: ClinicalTrials.gov NCT02564523.

RevDate: 2022-01-11

Wei X, Roudier MP, Kwon OJ, et al (2022)

Paracrine Wnt signaling is necessary for prostate epithelial proliferation.

The Prostate [Epub ahead of print].

INTRODUCTION: The Wnt proteins play key roles in the development, homeostasis, and disease progression of many organs including the prostate. However, the spatiotemporal expression patterns of Wnt proteins in prostate cell lineages at different developmental stages and in prostate cancer remain inadequately characterized.

METHODS: We isolated the epithelial and stromal cells in the developing and mature mouse prostate by flow cytometry and determined the expression levels of Wnt ligands. We used Visium spatial gene expression analysis to determine the spatial distribution of Wnt ligands in the mouse prostatic glands. Using laser-capture microscopy in combination with gene expression analysis, we also determined the expression patterns of Wnt signaling components in stromal and cancer cells in advanced human prostate cancer specimens. To investigate how the stroma-derived Wnt ligands affect prostate development and homeostasis, we used a Col1a2-CreERT2 mouse model to disrupt the Wnt transporter Wntless specifically in prostate stromal cells.

RESULTS: We showed that the prostate stromal cells are a major source of several Wnt ligands. Visium spatial gene expression analysis revealed a distinct spatial distribution of Wnt ligands in the prostatic glands. We also showed that Wnt signaling components are highly expressed in the stromal compartment of primary and advanced human prostate cancer. Blocking stromal Wnt secretion attenuated prostate epithelial proliferation and regeneration but did not affect cell survival and lineage maintenance.

DISCUSSION: Our study demonstrates a critical role of stroma-derived Wnt ligands in prostate development and homeostasis.

RevDate: 2022-01-11

Tordoff DM, Greninger AL, Roychoudhury P, et al (2021)

Phylogenetic estimates of SARS-CoV-2 introductions into Washington State.

Lancet Regional Health. Americas, 1:100018.

Background: The first confirmed case of SARS-CoV-2 in North America was identified in Washington state on January 21, 2020. We aimed to quantify the number and temporal trends of out-of-state introductions of SARS-CoV-2 into Washington.

Methods: We conducted a molecular epidemiologic analysis of 11,422 publicly available whole genome SARS-CoV-2 sequences from GISAID sampled between December 2019 and September 2020. We used maximum parsimony ancestral state reconstruction methods on time-calibrated phylogenies to enumerate introductions/exports, their likely geographic source (US, non-US, and between eastern and western Washington), and estimated date of introduction. To incorporate phylogenetic uncertainty into our estimates, we conducted 5,000 replicate analyses by generating 25 random time-stratified samples of non-Washington reference sequences, 20 random polytomy resolutions, and 10 random resolutions of the reconstructed ancestral state.

Findings: We estimated a minimum 287 introductions (range 244-320) into Washington and 204 exported lineages (range 188-227) of SARS-CoV-2 out of Washington. Introductions began in mid-January and peaked on March 29, 2020. Lineages with the Spike D614G variant accounted for the majority (88%) of introductions. Overall, 61% (range 55-65%) of introductions into Washington likely originated from a source elsewhere within the US, while the remaining 39% (range 35-45%) likely originated from outside of the US. Intra-state transmission accounted for 65% and 28% of introductions into eastern and western Washington, respectively.

Interpretation: The SARS-CoV-2 epidemic in Washington was continually seeded by a large number of introductions. Our findings highlight the importance of genomic surveillance to monitor for emerging variants due to high levels of inter- and intra-state transmission of SARS-CoV-2.

Funding Source: None.

RevDate: 2022-01-11

James CA, Xu Y, Aguilar MS, et al (2022)

CD4 and CD8 co-receptors modulate functional avidity of CD1b-restricted T cells.

Nature communications, 13(1):78.

T cells recognize mycobacterial glycolipid (mycolipid) antigens presented by CD1b molecules, but the role of CD4 and CD8 co-receptors in mycolipid recognition is unknown. Here we show CD1b-mycolipid tetramers reveal a hierarchy in which circulating T cells expressing CD4 or CD8 co-receptor stain with a higher tetramer mean fluorescence intensity than CD4-CD8- T cells. CD4+ primary T cells transduced with mycolipid-specific T cell receptors bind CD1b-mycolipid tetramer with a higher fluorescence intensity than CD8+ primary T cells. The presence of either CD4 or CD8 also decreases the threshold for interferon-γ secretion. Co-receptor expression increases surface expression of CD3ε, suggesting a mechanism for increased tetramer binding and activation. Targeted transcriptional profiling of mycolipid-specific T cells from individuals with active tuberculosis reveals canonical markers associated with cytotoxicity among CD8+ compared to CD4+ T cells. Thus, expression of co-receptors modulates T cell receptor avidity for mycobacterial lipids, leading to in vivo functional diversity during tuberculosis disease.

RevDate: 2022-01-11

Rimbach R, Yamada Y, Sagayama H, et al (2022)

Total energy expenditure is repeatable in adults but not associated with short-term changes in body composition.

Nature communications, 13(1):99.

Low total energy expenditure (TEE, MJ/d) has been a hypothesized risk factor for weight gain, but repeatability of TEE, a critical variable in longitudinal studies of energy balance, is understudied. We examine repeated doubly labeled water (DLW) measurements of TEE in 348 adults and 47 children from the IAEA DLW Database (mean ± SD time interval: 1.9 ± 2.9 y) to assess repeatability of TEE, and to examine if TEE adjusted for age, sex, fat-free mass, and fat mass is associated with changes in weight or body composition. Here, we report that repeatability of TEE is high for adults, but not children. Bivariate Bayesian mixed models show no among or within-individual correlation between body composition (fat mass or percentage) and unadjusted TEE in adults. For adults aged 20-60 y (N = 267; time interval: 7.4 ± 12.2 weeks), increases in adjusted TEE are associated with weight gain but not with changes in body composition; results are similar for subjects with intervals >4 weeks (N = 53; 29.1 ± 12.8 weeks). This suggests low TEE is not a risk factor for, and high TEE is not protective against, weight or body fat gain over the time intervals tested.

RevDate: 2022-01-11

Kim J, Bhupathiraju SN, Harrington LB, et al (2022)

Oral postmenopausal hormone therapy and genetic risk on venous thromboembolism: gene-hormone interaction results from a large prospective cohort study.

Menopause (New York, N.Y.) pii:00042192-900000000-96848 [Epub ahead of print].

OBJECTIVE: Oral postmenopausal hormone therapy (HT) has been shown to be associated with venous thromboembolism (VTE), but whether this association is modified by VTE-associated genetic susceptibility is unknown. We examined interactions between oral HT use and a genetic risk score (GRS) of VTE.

METHOD: Eligible women were postmenopausal women who had data on oral HT use, VTE incidence between 1990 and 2012, and genetic data in the Nurses' Health Study. We built a GRS aggregating 16 VTE-related genetic variants. We used Cox regression to estimate associations of HT use with incident VTE and assessed interactions between HT use and VTE GRS. We also estimated incidence of VTE between age 50 and 79 years for groups of women defined by HT use and VTE GRS.

RESULTS: We identified 432 incident VTE cases. Current HT users were at higher risk of VTE than never users (HR: 1.9, 95% CI: 1.5-2.6), with slightly higher risk for estrogen plus progestin HT than estrogen only (HR: 2.4 vs 1.9). The GRS was associated with VTE risk (HR comparing 4th quartile to 1st: 2.0, 95% CI: 1.2-3.4). We did not observe significant multiplicative interactions between HT use and GRS. The estimated VTE risk difference (per 10,000 person-years) comparing 50-year-old current HT users to never users was 22.5 for women in the highest GRS quartile and 9.8 for women in the lowest GRS quartile.

CONCLUSION: The VTE GRS might inform clinical guidance regarding the balance of risks and benefits of HT use, especially among younger women.

RevDate: 2022-01-11

Arthur RS, Mossavar-Rahmani Y, Prentice RL, et al (2022)

The association of predicted resting energy expenditure with risk of breast cancer among postmenopausal women in the Women's Health Initiative cohort.

Cancer prevention research (Philadelphia, Pa.) pii:1940-6207.CAPR-21-0467 [Epub ahead of print].

Obesity and obesity-related metabolic disorders, such as obesity and chronic inflammation, have been positively associated both with postmenopausal breast cancer and with resting energy expenditure (REE). However, there is limited epidemiological evidence on the associations between REE and risk of postmenopausal breast cancer. We used multivariable Cox proportional hazards models to examine the association between predicted REE (calculated using the Ikeda, Livingston and Mifflin equations) and risk of postmenopausal breast cancer overall and by subtypes, and by level of body fat) among 137,305 postmenopausal women in the Women's Health Initiative (WHI). All predicted REEs were positively associated with risk of invasive breast cancer (HRq5 vs q1: 1.69; 95% CI: 1.57-1.81, HR: 1.69; 95% CI: 1.57-1.82 and HR: 1.68; 95% CI: 1.56-1.80 for Ikeda, Livingston and Mifflin, respectively). These positive associations were observed irrespective of the hormone receptor subtype, grade and stage of the tumors, but were most pronounced for estrogen receptor positive/progesterone receptor positive tumors. After additional adjustment for BMI, the associations were mostly attenuated and remained statistically significant for most of the outcomes. We also observed an interaction between the predicted REEs and BMI, with the associations being somewhat stronger among normal weight and overweight women than among obese women (pinteractions <0.05). Our findings indicate that relatively high REE is associated with increased risk of invasive breast cancer among postmenopausal women (particularly for the obesity-related tumor subtypes), irrespective of the equation used. Further studies using more objective measures of REE are, however, needed to confirm our findings.

RevDate: 2022-01-11

Wieduwilt MJ, Metheny L, Zhang MJ, et al (2022)

Haploidentical vs sibling, unrelated, or cord blood hematopoietic cell transplantation for acute lymphoblastic leukemia.

Blood advances, 6(1):339-357.

The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLA-matched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P = .02), grade 3 to 4 aGVHD (HR, 1.59; P = .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P = .01) and increased NRM (HR, 2.13; P ≤ .001), grade 3 to 4 aGVHD (HR, 1.86; P = .003), and cGVHD (HR, 1.72; P ≤ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (≤18 months; HR, 1.93; P < .001), worse early LFS (HR, 1.40; P = .007) and increased incidences of NRM (HR, 2.08; P < .001) and grade 3 to 4 aGVHD (HR, 1.97; P < .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission.

RevDate: 2022-01-10

Bleakley M, Sehgal A, Seropian S, et al (2022)

Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: Graft-versus-host disease (GVHD) causes morbidity and mortality following allogeneic hematopoietic cell transplantation. Naive T cells (TN) cause severe GVHD in murine models. We evaluated chronic GVHD (cGVHD) and other outcomes in three phase II clinical trials of TN-depletion of peripheral blood stem-cell (PBSC) grafts.

METHODS: One hundred thirty-eight patients with acute leukemia received TN-depleted PBSC from HLA-matched related or unrelated donors following conditioning with high- or intermediate-dose total-body irradiation and chemotherapy. GVHD prophylaxis was with tacrolimus, with or without methotrexate or mycophenolate mofetil. Subjects received CD34-selected PBSC and a defined dose of memory T cells depleted of TN. Median follow-up was 4 years. The primary outcome of the analysis of cumulative data from the three trials was cGVHD.

RESULTS: cGVHD was very infrequent and mild (3-year cumulative incidence total, 7% [95% CI, 2 to 11]; moderate, 1% [95% CI, 0 to 2]; severe, 0%). Grade III and IV acute GVHD (aGVHD) occurred in 4% (95% CI, 1 to 8) and 0%, respectively. The cumulative incidence of grade II aGVHD, which was mostly stage 1 upper gastrointestinal GVHD, was 71% (95% CI, 64 to 79). Recipients of matched related donor and matched unrelated donor grafts had similar rates of grade III aGVHD (5% [95% CI, 0 to 9] and 4% [95% CI, 0 to 9]) and cGVHD (7% [95% CI, 2 to 13] and 6% [95% CI, 0 to 12]). Overall survival, cGVHD-free, relapse-free survival, relapse, and nonrelapse mortality were, respectively, 77% (95% CI, 71 to 85), 68% (95% CI, 61 to 76), 23% (95% CI, 16 to 30), and 8% (95% CI, 3 to 13) at 3 years.

CONCLUSION: Depletion of TN from PBSC allografts results in very low incidences of severe acute and any cGVHD, without apparent excess risks of relapse or nonrelapse mortality, distinguishing this novel graft engineering strategy from other hematopoietic cell transplantation approaches.

RevDate: 2022-01-10

Wald A (2022)

Booster Vaccination to Reduce SARS-CoV-2 Transmission and Infection.

JAMA pii:2788105 [Epub ahead of print].

RevDate: 2022-01-10

Stankiewicz Karita HC, Dong TQ, Johnston C, et al (2022)

Trajectory of Viral RNA Load Among Persons With Incident SARS-CoV-2 G614 Infection (Wuhan Strain) in Association With COVID-19 Symptom Onset and Severity.

JAMA network open, 5(1):e2142796 pii:2787768.

Importance: The SARS-CoV-2 viral trajectory has not been well characterized in incident infections. These data are needed to inform natural history, prevention practices, and therapeutic development.

Objective: To characterize early SARS-CoV-2 viral RNA load (hereafter referred to as viral load) in individuals with incident infections in association with COVID-19 symptom onset and severity.

This prospective cohort study was a secondary data analysis of a remotely conducted study that enrolled 829 asymptomatic community-based participants recently exposed (<96 hours) to persons with SARS-CoV-2 from 41 US states from March 31 to August 21, 2020. Two cohorts were studied: (1) participants who were SARS-CoV-2 negative at baseline and tested positive during study follow-up, and (2) participants who had 2 or more positive swabs during follow-up, regardless of the initial (baseline) swab result. Participants collected daily midturbinate swab samples for SARS-CoV-2 RNA detection and maintained symptom diaries for 14 days.

Exposure: Laboratory-confirmed SARS-CoV-2 infection.

Main Outcomes and Measures: The observed SARS-CoV-2 viral load among incident infections was summarized, and piecewise linear mixed-effects models were used to estimate the characteristics of viral trajectories in association with COVID-19 symptom onset and severity.

Results: A total of 97 participants (55 women [57%]; median age, 37 years [IQR, 27-52 years]) developed incident infections during follow-up. Forty-two participants (43%) had viral shedding for 1 day (median peak viral load cycle threshold [Ct] value, 38.5 [95% CI, 38.3-39.0]), 18 (19%) for 2 to 6 days (median Ct value, 36.7 [95% CI, 30.2-38.1]), and 31 (32%) for 7 days or more (median Ct value, 18.3 [95% CI, 17.4-22.0]). The cycle threshold value has an inverse association with viral load. Six participants (6%) had 1 to 6 days of viral shedding with censored duration. The peak mean (SD) viral load was observed on day 3 of shedding (Ct value, 33.8 [95% CI, 31.9-35.6]). Based on the statistical models fitted to 129 participants (60 men [47%]; median age, 38 years [IQR, 25-54 years]) with 2 or more SARS-CoV-2-positive swab samples, persons reporting moderate or severe symptoms tended to have a higher peak mean viral load than those who were asymptomatic (Ct value, 23.3 [95% CI, 22.6-24.0] vs 30.7 [95% CI, 29.8-31.4]). Mild symptoms generally started within 1 day of peak viral load, and moderate or severe symptoms 2 days after peak viral load. All 535 sequenced samples detected the G614 variant (Wuhan strain).

Conclusions and Relevance: This cohort study suggests that having incident SARS-CoV-2 G614 infection was associated with a rapid viral load peak followed by slower decay. COVID-19 symptom onset generally coincided with peak viral load, which correlated positively with symptom severity. This longitudinal evaluation of the SARS-CoV-2 G614 with frequent molecular testing serves as a reference for comparing emergent viral lineages to inform clinical trial designs and public health strategies to contain the spread of the virus.

RevDate: 2022-01-10

Xiao H, Liu F, He Y, et al (2022)

Unequal impact of the COVID-19 pandemic on paediatric cancer care: a population-based cohort study in China.

The Lancet regional health. Western Pacific, 19:100347.

Background: The COVID-19 pandemic has had widespread adverse collateral effects on health care delivery for non-COVID-19 disease conditions. Paediatric oncology care is reliant on prompt testing and diagnosis and on timely and coordinated multimodal treatment, all of which have been impacted by the pandemic. This study aimed to quantify the initial and enduring effects of the COVID-19 pandemic on the utilization of paediatric cancer care and to examine whether the pandemic differentially impacted specific demographic groups.

Method: We performed an interrupted time series analysis using negative binomial regression to estimate the change in the monthly admissions for paediatric cancer patients (Age 0-17) associated with the COVID-19 pandemic and subsequent lockdown policies. We obtained data from deidentified individual electronic medical records of paediatric cancer inpatients admitted between January 1, 2015 and May 31, 2021 to a tertiary hospital that provides general and specialized healthcare services to an estimated population of 8.4 million in Jining China. Relative risk (RR) estimates representing monthly admissions compared with expected admissions had the pandemic not occurred were derived. The number of inpatient admissions lost due to the pandemic were estimated.

Findings: The overall denominator for the paediatric population was 1 858 209 individuals in January 2015, which increased to 2 043 803 by May 2021. In total, there were 4 901 admissions for paediatric cancer during the study period, including 1 479 (30%) since February 2020 when the lockdown was implemented. A 33% reduction (95% CI: -43% to -22%) in admissions was observed in February 2020, with the largest relative reduction (-48%, 95% CI: -64% to -24%) among first-time admissions and admissions for patients from rural districts (-46%, 95% CI: -55% to -36%). Admissions quickly rebounded in March 2020 when many government-imposed mobility restrictions were lifted, and continued to resume gradually over time since April 2020, leading to a full recovery as of November 2020. However, the recovery for first-time admissions, and among female patients, younger patients (<5 years) and patients from rural districts was slower over time and incomplete (first-time admissions and rural patients) as of January 2021.

Interpretation: The COVID-19 pandemic has had substantial impact on the timely utilization of paediatric oncology services in China, particularly in the early stage of the first wave. Importantly, some population groups were disproportionately affected and the recovery of admissions among those subgroups has been slow and incomplete, warranting targeted approaches to address potentially exacerbated gender and socio-economic inequalities in access to healthcare resources.

RevDate: 2022-01-10

Huang L, Little P, Huyghe JR, et al (2021)

A Statistical Method for Association Analysis of Cell Type Compositions.

Statistics in biosciences, 13(3):373-385.

Gene expression data are often collected from tissue samples that are composed of multiple cell types. Studies of cell type composition based on gene expression data from tissue samples have recently attracted increasing research interest and led to new method development for cell type composition estimation. This new information on cell type composition can be associated with individual characteristics (e.g., genetic variants) or clinical outcomes (e.g., survival time). Such association analysis can be conducted for each cell type separately followed by multiple testing correction. An alternative approach is to evaluate this association using the composition of all the cell types, thus aggregating association signals across cell types. A key challenge of this approach is to account for the dependence across cell types. We propose a new method to quantify the distances between cell types while accounting for their dependencies, and use this information for association analysis. We demonstrate our method in two applied examples: to assess the association between immune cell type composition in tumor samples of colorectal cancer patients versus survival time and SNP genotypes. We found immune cell composition has prognostic value, and our distance metric leads to more accurate survival time prediction than other distance metrics that ignore cell type dependencies. In addition, survival time-associated SNPs are enriched among the SNPs associated with immune cell composition.

RevDate: 2022-01-10

Brzyski D, Karas M, Ances BM, et al (2021)

Connectivity-informed adaptive regularization for generalized outcomes.

The Canadian journal of statistics = Revue canadienne de statistique, 49(1):203-227.

One of the challenging problems in neuroimaging is the principled incorporation of information from different imaging modalities. Data from each modality are frequently analyzed separately using, for instance, dimensionality reduction techniques, which result in a loss of mutual information. We propose a novel regularization method, generalized ridgified Partially Empirical Eigenvectors for Regression (griPEER), to estimate associations between the brain structure features and a scalar outcome within the generalized linear regression framework. griPEER improves the regression coefficient estimation by providing a principled approach to use external information from the structural brain connectivity. Specifically, we incorporate a penalty term, derived from the structural connectivity Laplacian matrix, in the penalized generalized linear regression. In this work, we address both theoretical and computational issues and demonstrate the robustness of our method despite incomplete information about the structural brain connectivity. In addition, we also provide a significance testing procedure for performing inference on the estimated coefficients. Finally, griPEER is evaluated both in extensive simulation studies and using clinical data to classify HIV+ and HIV- individuals.

RevDate: 2022-01-10

Yang T, Huang Y, Y Fong (2021)

Change Point Inference in the Presence of Missing Covariates for Principal Surrogate Evaluation in Vaccine Trials.

Biometrika, 108(4):829-843.

We consider the use of threshold-based regression models for evaluating immune response biomarkers as principal surrogate markers of a vaccine's protective effect. Threshold-based regression models, which allow the relationship between a clinical outcome and a covariate to change dramatically across a threshold value in the covariate, have been studied by various authors under fully observed data. Limited research, however, has examined these models in the presence of missing covariates, such as the counterfactual potential immune responses of a participant in the placebo arm of a standard vaccine trial had s/he been assigned to the vaccine arm instead. Based on a hinge model for a threshold effect of the principal surrogate on vaccine efficacy, we develop a regression methodology that consists of two components: (1) The estimated likelihood method is employed to handle missing potential outcomes, and (2) a penalty is imposed on the estimated likelihood to ensure satisfactory finite sample performance. We develop a method that allows joint estimation of all model parameters as well as a two-step method that separates the estimation of the threshold parameter from the rest of the parameters. Stable iterative algorithms are developed to implement the two methods and the asymptotic properties of the proposed estimators are established. In simulation studies, the proposed estimators are shown to have satisfactory finite sample performance. The proposed methods are applied to analyze a real dataset collected from dengue vaccine efficacy trials to predict how vaccine efficacy varies with an individual's potential immune response if receiving vaccine.

RevDate: 2022-01-10

Tordoff DM, Zangeneh S, Khosropour CM, et al (2022)

Geographic variation in HIV testing among transgender and non-binary adults in the US.

Journal of acquired immune deficiency syndromes (1999) pii:00126334-900000000-95718 [Epub ahead of print].

BACKGROUND: Transgender and non-binary (TNB) populations are disproportionately impacted by HIV and few local health departments or HIV surveillance systems collect/report data on TNB identities. Our objective was to estimate the prevalence of HIV testing among TNB adults by US county and state, with a focus on the Ending the HIV Epidemic (EHE) geographies.

METHODS: We applied a Bayesian hierarchical spatial small area estimation model to data from the 2015 US Transgender Survey (USTS), a large national cross-sectional internet-based survey. We estimated the county- and state-level proportion of TNB adults who ever tested or tested for HIV in the last year by gender identity, race/ethnicity, and age.

RESULTS: Our analysis included 26,100 TNB participants with valid zip codes who resided in 1,688 counties (54% of all 3,141 counties that cover 92% of the US population). The median county-level proportion of TNB adults who ever tested for HIV was 44% (range 10-80%) and who tested in the last year was 17% (range 4-44%). Within most counties, testing was highest among transgender women, Black respondents, and people age ≥25. HIV testing was lowest among non-binary people and young adults age <25. The proportion of TNB adults who tested within the last year was very low in most EHE counties and in all 7 rural states.

CONCLUSIONS: HIV testing among TNB adults is likely below national recommendations in the majority of EHE geographies. Geographic variation in HIV testing patterns among TNB adults indicates that testing strategies need to be tailored to local settings.

RevDate: 2022-01-09

Pauleck S, Gigic B, Cawthon RM, et al (2022)

Association of circulating leukocyte telomere length with survival in patients with colorectal cancer.

Journal of geriatric oncology pii:S1879-4068(21)00272-1 [Epub ahead of print].

INTRODUCTION: Telomere shortening, as seen with aging, can cause chromosomal instability and promote cancer progression. We investigated the association between circulating telomere length and overall and disease-free survival in a sub-cohort of patients with colorectal cancer.

METHODS: Baseline genomic DNA from blood leukocytes was extracted from N = 92 newly diagnosed stage I-IV patients with colorectal cancer enrolled at the ColoCare Study site in Heidelberg, Germany. Detailed information on clinicodemographic (including age) and lifestyle risk factors, and clinical outcomes (including recurrence and survival) was collected. Telomere length was measured in DNA using multiplex quantitative polymerase chain reaction. Kaplan Meier survival curves were generated comparing shorter to longer telomere lengths with log-rank testing.

RESULTS: The mean T/S ratio for study patients was 0.5 (range: 0.3-0.9). Shorter telomeres were associated with older age at baseline. Patients with shorter telomeres experienced a worse overall and disease-free survival, although this association did not reach statistical significance. Kaplan-Meier survival curves for those with circulating telomere length below vs. above the median showed poorer overall (log-rank p = 0.31) and disease-free survival (long-rank p = 0.23).

CONCLUSIONS: Our results suggest that individuals with shorter telomeres, as seen with aging, may experience a worse overall and disease-free survival after colorectal cancer diagnosis. Larger sample sizes with longer follow-up are needed to further evaluate telomere length as a prognostic biomarker in colorectal cancer progression.

RevDate: 2022-01-10

Sajulga R, Bolon YT, Maiers MJ, et al (2022)

Assessment of HLA-B genetic variation with an HLA-B leader tool and implications in clinical transplantation.

Blood advances, 6(1):270-280.

Sequence variation in the HLA-B gene is critically linked to differential immune responses. A dimorphism at -21 of HLA-B exon 1 gives rise to leader peptides that are markers for risk of acute graft-versus-host disease, relapse, and mortality after unrelated donor and cord blood transplantation. To optimize the selection of stem cell transplant sources based on the HLA-B leader, an HLA-BLeader Assessment Tool (BLEAT) was developed to automate the assignment of leader genotypes, define HLA-B leader match statuses, and rank order candidate stem cell sources according to clinical risk. The base cohort consisted of 9 417 614 registered donors from the Be The Match Registry with HLA-B typing. Among these donors, the performance of BLEAT was assessed in 1 098 358 donors with sequence data for HLA-B exon 1 (2 196 716 haplotypes). The accuracy of leader assignment was then assessed in a second cohort of 1259 patients and their unrelated transplant donors. We furthermore established the frequencies of HLA-B leader genotype (MM, MT, TT) representations in broad racial categories in the 9.42 million donors. BLEAT has direct applications for the selection of optimal stem cell sources for transplantation and broad utility in basic and clinical research in pharmacogenomics, vaccine development, and cancer and infectious disease studies of human populations.

RevDate: 2022-01-08

Whitfield DL, Nelson LE, Komárek A, et al (2022)

Implementation of Client-Centered Care Coordination for HIV Prevention with Black Men Who Have Sex with Men: Activities, Personnel Costs, and Outcomes-HPTN 073.

Journal of racial and ethnic health disparities [Epub ahead of print].

BACKGROUND: Black men who have sex with men (MSM) experience disproportionate rates of HIV infection in the USA, despite being no more likely to engage in sexual risk behaviors than other MSM racial/ethnic groups. HIV pre-exposure prophylaxis (PrEP) has been shown to reduce risk of HIV acquisition; however, rates of PrEP use among Black MSM remain low. Clinical, psychosocial, and structural factors have been shown to impact PrEP use and adherence among Black MSM. Care coordination of HIV prevention services has the potential to improve PrEP use and adherence for Black MSM, as it has been shown to improve HIV-related care outcomes among people living with HIV.

METHODS: Client-centered care coordination (C4) is a multi-level intervention designed to address clinical, psychosocial, and structural barriers to HIV prevention services for Black MSM within HPTN 073, a PrEP demonstration project among Black MSM in three cities in the USA. The current study examined the implementation process of C4, specifically investigating the activities, cost, time, and outcomes associated with the C4 intervention.

RESULTS: On average, participants engaged in five care coordination encounters. The vast majority of care coordination activities were conducted by counselors, averaging 30 min per encounter. The cost of care coordination was relatively low with a mean cost of $8.70 per client encounter.

CONCLUSION: Although client-centered care coordination was initially implemented in well-resourced communities with robust HIV research and service infrastructure, our findings suggest that C4 can be successfully implemented in resource constrained communities.

RevDate: 2022-01-08

Othus M, Zhang MJ, RP Gale (2022)

Clinical trials: design, endpoints and interpretation of outcomes.

RevDate: 2022-01-08

Labadie JD, Savas S, Harrison TA, et al (2022)

Genome-wide association study identifies tumor anatomical site-specific risk variants for colorectal cancer survival.

Scientific reports, 12(1):127.

Identification of new genetic markers may improve the prediction of colorectal cancer prognosis. Our objective was to examine genome-wide associations of germline genetic variants with disease-specific survival in an analysis of 16,964 cases of colorectal cancer. We analyzed genotype and colorectal cancer-specific survival data from a consortium of 15 studies. Approximately 7.5 million SNPs were examined under the log-additive model using Cox proportional hazards models, adjusting for clinical factors and principal components. Additionally, we ran secondary analyses stratifying by tumor site and disease stage. We used a genome-wide p-value threshold of 5 × 10-8 to assess statistical significance. No variants were statistically significantly associated with disease-specific survival in the full case analysis or in the stage-stratified analyses. Three SNPs were statistically significantly associated with disease-specific survival for cases with tumors located in the distal colon (rs698022, HR = 1.48, CI 1.30-1.69, p = 8.47 × 10-9) and the proximal colon (rs189655236, HR = 2.14, 95% CI 1.65-2.77, p = 9.19 × 10-9 and rs144717887, HR = 2.01, 95% CI 1.57-2.58, p = 3.14 × 10-8), whereas no associations were detected for rectal tumors. Findings from this large genome-wide association study highlight the potential for anatomical-site-stratified genome-wide studies to identify germline genetic risk variants associated with colorectal cancer-specific survival. Larger sample sizes and further replication efforts are needed to more fully interpret these findings.

RevDate: 2022-01-07

Martin PJ, Levine D, Storer BE, et al (2022)

Genetic Associations with Immune-mediated Outcomes after Allogeneic Hematopoietic Cell Transplantation.

Blood advances pii:483373 [Epub ahead of print].

Previous studies have identified more than 200 genetic variants associated with acute or chronic graft-versus-host disease (GVHD) or recurrent malignancy after allogeneic hematopoietic cell transplantation (HCT). We tested these candidate donor and recipient variants in a cohort of 4270 HCT recipients of European ancestry and in sub-cohorts of 1827 sibling and 1447 unrelated recipients who had 10/10 HLA-A, B, C, DRB1, DQB1-matched donors. We also carried out a genome-wide association study (GWAS) for these same outcomes. The discovery and replication analysis of candidate variants identified a group of closely linked recipient HLA-DPB1 single-nucleotide polymorphisms (SNPs) associated with an increased risk of acute GVHD and a corresponding decreased risk of recurrent malignancy after unrelated HCT. These results reflect correlation with the level of HLA-DPB1 expression previously shown to affect the risks of acute GVHD and relapse in unrelated recipients. Our GWAS identified an association of chronic GVHD with a locus of X-linked recipient intron variants in NHS, a gene that regulates actin remodeling and cell morphology. Evaluation of this association in a second replication cohort did not confirm the original replication results, and we did not reach any definitive conclusion regarding the validity of this discovery. The cohort used for our study is larger than those used in most previous HCT studies but is smaller than those typically used for other genotype-phenotype association studies. Genomic and disease data from our study are available for further analysis in combination with data from other cohorts.

RevDate: 2022-01-07

Paras G, Morsink LM, Othus M, et al (2022)

Conditioning Intensity and Peri-Transplant Flow Cytometric MRD Dynamics in Adult AML.

Blood pii:483372 [Epub ahead of print].

In acute myeloid leukemia (AML), measurable residual disease (MRD) before or after allogeneic hematopoietic cell transplantation (HCT) is an established, independent indicator of poor outcome. To address how peri-HCT MRD dynamics could refine risk assessment across different conditioning intensities, we analyzed 810 adults transplanted in remission after myeloablative conditioning (MAC; n=515) or non-MAC (n=295) who underwent multiparameter flow cytometry-based MRD testing before and 20-40 days after allografting. Patients without pre- and post-HCT MRD (MRDneg/MRDneg) had the lowest risks of relapse and highest relapse-free survival (RFS) and overall survival (OS). Relative to those patients, outcomes for MRDpos/MRDpos and MRDneg/MRDpos patients were poor regardless of conditioning intensity. Outcomes for MRDpos/MRDneg patients were intermediate. Among 161 patients with MRD before HCT, MRD was cleared more commonly with a MAC (85/104 [81.7%]) than non-MAC (33/57 [57.9%]) regimen (P=0.002). Although non-MAC regimens were less likely to clear MRD, if they did the impact on outcome was greater. Thus, there was a significant interaction between conditioning intensity and "MRD conversion" for relapse (P=0.020), RFS (P=0.002), and OS (P=0.001). Similar findings were obtained in the subset of 590 patients receiving HLA-matched allografts. C-statistic values were higher (indicating higher predictive accuracy) for peri-HCT MRD dynamics compared to the isolated use of pre-HCT MRD status and post-HCT MRD status for prediction of relapse, RFS, and OS. Across conditioning intensities, peri-HCT MRD dynamics improve risk assessment over isolated pre- or post-HCT MRD assessments.

RevDate: 2022-01-07

Fahrmann JF, Marsh T, Irajizad E, et al (2022)

Blood-Based Biomarker Panel for Personalized Lung Cancer Risk Assessment.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: To investigate whether a panel of circulating protein biomarkers would improve risk assessment for lung cancer screening in combination with a risk model on the basis of participant characteristics.

METHODS: A blinded validation study was performed using prostate lung colorectal ovarian (PLCO) Cancer Screening Trial data and biospecimens to evaluate the performance of a four-marker protein panel (4MP) consisting of the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19 fragment in combination with a lung cancer risk prediction model (PLCOm2012) compared with current US Preventive Services Task Force (USPSTF) screening criteria. The 4MP was assayed in 1,299 sera collected preceding lung cancer diagnosis and 8,709 noncase sera.

RESULTS: The 4MP alone yielded an area under the receiver operating characteristic curve of 0.79 (95% CI, 0.77 to 0.82) for case sera collected within 1-year preceding diagnosis and 0.74 (95% CI, 0.72 to 0.76) among the entire specimen set. The combined 4MP + PLCOm2012 model yielded an area under the receiver operating characteristic curve of 0.85 (95% CI, 0.82 to 0.88) for case sera collected within 1 year preceding diagnosis. The benefit of the 4MP in the combined model resulted from improvement in sensitivity at high specificity. Compared with the USPSTF2021 criteria, the combined 4MP + PLCOm2012 model exhibited statistically significant improvements in sensitivity and specificity. Among PLCO participants with ≥ 10 smoking pack-years, the 4MP + PLCOm2012 model would have identified for annual screening 9.2% more lung cancer cases and would have reduced referral by 13.7% among noncases compared with USPSTF2021 criteria.

CONCLUSION: A blood-based biomarker panel in combination with PLCOm2012 significantly improves lung cancer risk assessment for lung cancer screening.

RevDate: 2022-01-07

Shankaran V, Li L, Fedorenko C, et al (2022)

Risk of Adverse Financial Events in Patients With Cancer: Evidence From a Novel Linkage Between Cancer Registry and Credit Records.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: Although financial toxicity is a growing cancer survivorship issue, no studies have used credit data to estimate the relative risk of financial hardship in patients with cancer versus individuals without cancer. We conducted a population-based retrospective matched cohort study using credit reports to investigate the impact of a cancer diagnosis on the risk of adverse financial events (AFEs).

METHODS: Western Washington SEER cancer registry (cases) and voter registry (controls) records from 2013 to 2018 were linked to quarterly credit records from TransUnion. Controls were age-, sex-, and zip code-matched to cancer cases and assigned an index date corresponding to the case's diagnosis date. Cases and controls experiencing past-due credit card payments and any of the following AFEs at 24 months from diagnosis or index were compared, using two-sample z tests: third-party collections, charge-offs, tax liens, delinquent mortgage payments, foreclosures, and repossessions. Multivariate logistic regression models were used to evaluate the association of cancer diagnosis with AFEs and past-due credit payments.

RESULTS: A total of 190,722 individuals (63,574 cases and 127,148 controls, mean age 66 years) were included. AFEs (4.3% v 2.4%, P < .0001) and past-due credit payments (2.6% v 1.9%, P < .0001) were more common in cases than in controls. After adjusting for age, sex, average baseline credit line, area deprivation index, and index/diagnosis year, patients with cancer had a higher risk of AFEs (odds ratio 1.71; 95% CI, 1.61 to 1.81; P < .0001) and past-due credit payments (odds ratio 1.28; 95% CI, 1.19 to 1.37; P < .0001) than controls.

CONCLUSION: Patients with cancer were at significantly increased risk of experiencing AFEs and past-due credit card payments relative to controls. Studies are needed to investigate the impact of these events on treatment decisions, quality of life, and clinical outcomes.

RevDate: 2022-01-07

Jiang Y, Meyers TJ, Emeka AA, et al (2022)

Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment.

HGG advances, 3(1):.

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9×10-7 and GAB2, p = 2.0×10-6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS-versus treatment for the initial management of patients with low-risk PC.

RevDate: 2022-01-07

Schetelig J, Baldauf H, Koster L, et al (2021)

Corrigendum: Haplotype Motif-Based Models for KIR-Genotype Informed Selection of Hematopoietic Cell Donors Fail to Predict Outcome of Patients With Myelodysplastic Syndromes or Secondary Acute Myeloid Leukemia.

Frontiers in immunology, 12:813838.

[This corrects the article DOI: 10.3389/fimmu.2020.584520.].

RevDate: 2022-01-06

Elsayed AH, Cao X, Mitra AK, et al (2022)

Polygenic Ara-C Response Score Identifies Pediatric Patients With Acute Myeloid Leukemia in Need of Chemotherapy Augmentation.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: To establish a patient-specific polygenic score derived from cytarabine (ara-C) pathway pharmacogenomic evaluation to personalize acute myeloid leukemia (AML) treatment.

MATERIALS AND METHODS: Single nucleotide polymorphisms (SNPs) in the ara-C-pathway genes were analyzed with outcome in patients from the multicenter-AML02 trial (N = 166). Multi-SNP predictor modeling was used to develop 10-SNP Ara-C_SNP score (ACS10) using top SNPs predictive of minimal residual disease and event-free survival (EFS) from the AML02-cohort and four SNPs previously associated with ara-C triphosphate levels in the AML97 trial. ACS10 was evaluated for association with outcomes in each clinical trial arms: the standard low-dose ara-C (LDAC, n = 91) and augmented high-dose ara-C (HDAC, n = 75) arms of AML02 and the standard Ara-C, daunorubicin and etoposide (ADE) (n = 465) and the augmented ADE + gemtuzumab ozogamicin (GO; n = 466) arms of AAML0531 trial.

RESULTS: In the standard LDAC-arm of AML02 cohort, the low-ACS10 score group (≤ 0) had significantly worse EFS (ACS10 low v high hazard ratio [HR] = 2.81; 95% CI, 1.45 to 5.43; P = .002) and overall survival (OS; HR = 2.98; 95% CI, 1.32 to 6.75; P = .009) compared with the high-ACS10 group (score > 0). These results were validated in the standard-ADE arm of AAML0531, with poor outcome in the low-ASC10 group compared with the high-ACS10 group (EFS: HR = 1.35, 95% CI, 1.04 to 1.75, P = .026; OS: HR = 1.64, 95% CI, 1.2 to 2.22, P = .002). Within the augmented arms (AML02-HDAC and AAML0531-ADE + GO), EFS and OS did not differ between low- and high-ACS10 score groups. In both cohorts, patients with low-ACS10 consistently showed a 10-percentage point improvement in 5-year EFS with augmented therapy (AML02-HDAC or AAML0531-ADE + GO arms) than with standard therapy (AML02-LDAC or AAML0531-ADE arms).

CONCLUSION: Patients with low-ACS10 score experienced significantly poor outcome when treated on standard regimen. Augmentation with either high-dose ara-C or GO addition improved outcome in low-ACS10 group. A polygenic ACS10 score can identify patients with unfavorable pharmacogenetic characteristics and offers a potential for an elective augmented therapy option.

RevDate: 2022-01-06

Park YJ, De Marco A, Starr TN, et al (2022)

Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry.

Science (New York, N.Y.) [Epub ahead of print].

[Figure: see text].

RevDate: 2022-01-05

Saha A, Hyzy S, Lamothe TL, et al (2022)

CD45-targeted antibody-drug-conjugate successfully conditions for allogeneic hematopoietic stem cell transplantation.

Blood pii:483334 [Epub ahead of print].

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for patients with non-malignant or malignant blood disorders. Its success has been limited by graft-versus-host disease (GVHD). Current genotoxic conditioning regimens mediate tissue injury and potentially incite and amplify GVHD, limiting use of this potentially curative treatment beyond malignant disorders. Minimizing genotoxic conditioning while achieving alloengraftment without global immune suppression is highly desirable. Antibody-drug-conjugates (ADCs) targeting hematopoietic cells can specifically deplete host stem and immune cells and enable alloengraftment. Here we report an anti-mouse CD45-targeted-ADC (CD45-ADC) that facilitates stable murine multi-lineage donor cell engraftment. Conditioning with CD45-ADC (3mg/kg) was effective as a single agent in both congenic and minor-mismatch transplant models resulting in full donor chimerism comparable to lethal total body irradiation (TBI). In an MHC-disparate allo-HSCT model, pre-transplant CD45-ADC (3mg/kg) combined with low-dose TBI (150cGy) and a short course of costimulatory blockade with anti-CD40 ligand antibody enabled 89% of recipients to achieve stable alloengraftment (mean value: 72%). When CD45-ADC was combined with pre-transplant TBI (50cGy) and post-transplant Rapamycin, Cytoxan or a JAK inhibitor, 90-100% of recipients achieved stable chimerism (mean: 77%, 59%, 78%, respectively). At a higher dose (5mg/kg), CD45-ADC as a single agent was sufficient for rapid, high level multi-lineage chimerism sustained through the 22 weeks observation period. Therefore, CD45-ADC has potential utility to confer the benefit of fully myeloablative conditioning but with substantially reduced toxicity when given as a single agent or at lower doses in conjunction with reduced intensity conditioning.

RevDate: 2022-01-05

Rowe JM, Balduini C, J Radich (2022)

Toward further excellence in Haematologica.

Haematologica, 107(1):2.

RevDate: 2022-01-05

Luk SMH, Wallner K, Glenn MC, et al (2022)

Effect of total body irradiation lung block parameters on lung doses using three-dimensional dosimetry.

Journal of applied clinical medical physics [Epub ahead of print].

PURPOSE: Total body irradiation (TBI) is an integral part of stem cell transplant. However, patients are at risk of treatment-related toxicities, including radiation pneumonitis. While lung dose is one of the most crucial aspects of TBI dosimetry, currently available data are based on point doses. As volumetric dose distribution could be substantially altered by lung block parameters, we used 3D dosimetry in our treatment planning system to estimate volumetric lung dose and measure the impact of various lung block designs.

MATERIALS AND METHODS: We commissioned a TBI beam model in RayStation that matches the measured tissue-phantom ratio under our clinical TBI setup. Cerrobend blocks were automatically generated in RayStation on thoracic Computed Tomography (CT) scans from three anonymized patients using the lung, clavicle, spine, and diaphragmatic contours. The margin for block edge was varied to 0, 1, or 2 cm from the superior, lateral, and inferior thoracic borders, with a uniform margin 2.5 cm lateral to the vertebral bodies. The lung dose was calculated and compared with a prescription dose of 1200 cGy in six fractions (three with blocks and three without).

RESULT: The point dose at midplane under the block and the average lung dose are at the range of 73%-76% and 80%-88% of prescription dose respectively regardless of the block margins. In contrast, the percent lung volume receiving 10 Gy increased by nearly two-fold, from 31% to 60% over the margins from 0 to 2 cm.

CONCLUSIONS: The TPS-derived 3D lung dose is substantially different from the nominal dose assumed with HVL lung blocks. Point doses under the block are insufficient to accurately gauge the relationship between dose and pneumonitis, and TBI dosimetry could be highly variable between patients and institutions as more descriptive parameters are not included in protocols. Much progress remains to be made to optimize and standardize technical aspects of TBI, and better dosimetry could provide more precise dosimetric predictors for pneumonitis risk.

RevDate: 2022-01-05

Gao F, M Bannick (2022)

Statistical considerations for cross-sectional HIV incidence estimation based on recency test.

Statistics in medicine [Epub ahead of print].

Longitudinal cohorts to determine the incidence of HIV infection are logistically challenging, so researchers have sought alternative strategies. Recency test methods use biomarker profiles of HIV-infected subjects in a cross-sectional sample to infer whether they are "recently" infected and to estimate incidence in the population. Two main estimators have been used in practice: one that assumes a recency test is perfectly specific, and another that allows for false-recent results. To date, these commonly used estimators have not been rigorously studied with respect to their assumptions and statistical properties. In this article, we present a theoretical framework with which to understand these estimators and interrogate their assumptions, and perform a simulation study and data analysis to assess the performance of these estimators under realistic HIV epidemiological dynamics. We find that the snapshot estimator and the adjusted estimator perform well when their corresponding assumptions hold. When assumptions on constant incidence and recency test characteristics fail to hold, the adjusted estimator is more robust than the snapshot estimator. We conclude with recommendations for the use of these estimators in practice and a discussion of future methodological developments to improve HIV incidence estimation via recency test.

RevDate: 2022-01-05

Robins LI, Keim EK, Robins DB, et al (2021)

Modifications of IL-6 by Hypochlorous Acids: Effects on Receptor Binding.

ACS omega, 6(51):35593-35599.

Interleukin-6 (IL-6) has been implicated in the pathogenesis of inflammatory events including those seen with COVID-19 patients. Positive clinical responses to monoclonal antibodies directed against IL-6 receptors (IL-6Rs) suggest that interference with IL-6-dependent activation of pro-inflammatory pathways offers a useful approach to therapy. We exposed IL-6 to hypochlorous acid (HOCl) in vitro at concentrations reported to develop in vivo. After HOCl treatment, binding of IL-6 to IL-6R was reduced in a dose-dependent manner using a bioassay with human cells engineered to provide a luminescence response to signal transduction upon receptor activation. Similar results followed the exposure of IL-6 to N-chlorotaurine (NCT) and hypobromous acid (HOBr), two other reactive species produced in vivo. SDS-PAGE analysis of HOCl-treated IL-6 showed little to no fragmentation or aggregation up to 1.75 mM HOCl, suggesting that the modifications induced at concentrations below 1.75 mM took place on the intact protein. Mass spectrometry of trypsin-digested fragments identified oxidative changes to two amino acid residues, methionine 161 and tryptophan 157, both of which have been implicated in receptor binding of the cytokine. Our findings suggest that exogenous HOCl and NCT might bring about beneficial effects in the treatment of COVID-19. Further studies on how HOCl and HOBr and their halogenated amine derivatives interact with IL-6 and related cytokines in vivo may open up alternative therapeutic interventions with these compounds in COVID-19 and other hyperinflammatory diseases.

RevDate: 2022-01-05

Bozic I (2022)

Quantification of the Selective Advantage of Driver Mutations Is Dependent on the Underlying Model and Stage of Tumor Evolution.

Cancer research, 82(1):21-24.

Measuring the selective fitness advantages provided by driver mutations has the potential to facilitate a precise quantitative understanding of cancer evolution. However, accurately measuring the selective advantage of driver mutations has remained a challenge in the field. Early studies reported small selective advantages of drivers, on the order of 1%, whereas newer studies report much larger selective advantages, as high as 1,200%. In this article, we argue that the calculated selective advantages of cancer drivers are dependent on the underlying mathematical model and stage of cancer evolution and that comparisons of numerical values of selective advantage without regard for the underlying model and stage can lead to spurious conclusions.

RevDate: 2022-01-05

Garcia L, Follis S, Thomson CA, et al (2022)

Taking action to advance the study of race and ethnicity: the Women's Health Initiative (WHI).

Women's midlife health, 8(1):1.

"Race" and "ethnicity" are socially constructed terms, not based on biology - in contrast to biologic ancestry and genetic admixture - and are flexible, contested, and unstable concepts, often driven by power. Although individuals may self-identify with a given race and ethnic group, as multidimensional beings exposed to differential life influencing factors that contribute to disease risk, additional social determinants of health (SDOH) should be explored to understand the relationship of race or ethnicity to health. Potential health effects of structural racism, defined as "the structures, policies, practices, and norms resulting in differential access to goods, services, and opportunities of society by "race," have been largely ignored in medical research. The Women's Health Initiative (WHI) was expected to enroll a racially and ethnically diverse cohort of older women at 40 U.S. clinical centers between 1993 and 1998; yet, key information on the racial and ethnic make-up of the WHI cohort of 161,808 women was limited until a 2020-2021 Task Force was charged by the WHI Steering Committee to better characterize the WHI cohort and develop recommendations for WHI investigators who want to include "race" and/or "ethnicity" in papers and presentations. As the lessons learned are of relevance to most cohorts, the essence of the WHI Race and Ethnicity Language and Data Interpretation Guide is presented in this paper. Recommendations from the WHI Race and Ethnicity Language and Data Interpretation Guide include: Studies should be designed to include all populations and researchers should actively, purposefully and with cultural-relevance, commit to recruiting a diverse sample; Researchers should collect robust data on race, ethnicity and SDOH variables that may intersect with participant identities, such as immigration status, country of origin, acculturation, current residence and neighborhood, religion; Authors should use appropriate terminology, based on a participant's self-identified "race" and "ethnicity", and provide clear rationale, including a conceptual framework, for including race and ethnicity in the analytic plan; Researchers should employ appropriate analytical methods, including mixed-methods, to study the relationship of these sociocultural variables to health; Authors should address how representative study participants are of the population to which results might apply, such as by age, race and ethnicity.

RevDate: 2022-01-05

Ahearn TU, Zhang H, Michailidou K, et al (2022)

Common variants in breast cancer risk loci predispose to distinct tumor subtypes.

Breast cancer research : BCR, 24(1):2.

BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear.

METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.

RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions.

CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.

RevDate: 2022-01-04

Hawley JE, Sun T, Chism DD, et al (2022)

Assessment of Regional Variability in COVID-19 Outcomes Among Patients With Cancer in the United States.

JAMA network open, 5(1):e2142046 pii:2787579.

Importance: The COVID-19 pandemic has had a distinct spatiotemporal pattern in the United States. Patients with cancer are at higher risk of severe complications from COVID-19, but it is not well known whether COVID-19 outcomes in this patient population were associated with geography.

Objective: To quantify spatiotemporal variation in COVID-19 outcomes among patients with cancer.

This registry-based retrospective cohort study included patients with a historical diagnosis of invasive malignant neoplasm and laboratory-confirmed SARS-CoV-2 infection between March and November 2020. Data were collected from cancer care delivery centers in the United States.

Exposures: Patient residence was categorized into 9 US census divisions. Cancer center characteristics included academic or community classification, rural-urban continuum code (RUCC), and social vulnerability index.

Main Outcomes and Measures: The primary outcome was 30-day all-cause mortality. The secondary composite outcome consisted of receipt of mechanical ventilation, intensive care unit admission, and all-cause death. Multilevel mixed-effects models estimated associations of center-level and census division-level exposures with outcomes after adjustment for patient-level risk factors and quantified variation in adjusted outcomes across centers, census divisions, and calendar time.

Results: Data for 4749 patients (median [IQR] age, 66 [56-76] years; 2439 [51.4%] female individuals, 1079 [22.7%] non-Hispanic Black individuals, and 690 [14.5%] Hispanic individuals) were reported from 83 centers in the Northeast (1564 patients [32.9%]), Midwest (1638 [34.5%]), South (894 [18.8%]), and West (653 [13.8%]). After adjustment for patient characteristics, including month of COVID-19 diagnosis, estimated 30-day mortality rates ranged from 5.2% to 26.6% across centers. Patients from centers located in metropolitan areas with population less than 250 000 (RUCC 3) had lower odds of 30-day mortality compared with patients from centers in metropolitan areas with population at least 1 million (RUCC 1) (adjusted odds ratio [aOR], 0.31; 95% CI, 0.11-0.84). The type of center was not significantly associated with primary or secondary outcomes. There were no statistically significant differences in outcome rates across the 9 census divisions, but adjusted mortality rates significantly improved over time (eg, September to November vs March to May: aOR, 0.32; 95% CI, 0.17-0.58).

Conclusions and Relevance: In this registry-based cohort study, significant differences in COVID-19 outcomes across US census divisions were not observed. However, substantial heterogeneity in COVID-19 outcomes across cancer care delivery centers was found. Attention to implementing standardized guidelines for the care of patients with cancer and COVID-19 could improve outcomes for these vulnerable patients.

RevDate: 2022-01-04

Shankaran V, Unger JM, Darke AK, et al (2022)

S1417CD: A Prospective Multicenter Cooperative Group-Led Study of Financial Hardship in Metastatic Colorectal Cancer Patients.

Journal of the National Cancer Institute pii:6492636 [Epub ahead of print].

BACKGROUND: Financial toxicity is a growing problem in oncology, but no prior studies have prospectively measured the financial impact of cancer treatment in a diverse national cohort of newly diagnosed cancer patients. S1417CD was the first cooperative group-led multicenter prospective cohort study to evaluate financial hardship in metastatic colorectal cancer (mCRC) patients.

METHODS: Patients aged 18 years or older within 120 days of mCRC diagnosis completed quarterly questionnaires for 12 months. We estimated the cumulative incidence of major financial hardship (MFH), defined as 1 or more of increased debt, new loans from family and/or friends, selling or refinancing home, or 20% or more income decline. We evaluated the association between patient characteristics and MFH using multivariate cox regression and the association between MFH and quality of life using linear regression.

RESULTS: A total of 380 patients (median age = 59.9 years) were enrolled; 77.7% were White, 98.0% insured, and 56.5% had annual income of $50 000 or less. Cumulative incidence of MFH at 12 months was 71.3% (95% confidence interval = 65.7% to 76.1%). Age, race, marital status, and income (split at $50 000 per year) were not statistically significantly associated with MFH. However, income less than $100 000 and total assets less than $100 000 were both associated with greater MFH. MFH at 3 months was associated with decreased social functioning and quality of life at 6 months.

CONCLUSIONS: Nearly 3 out of 4 mCRC patients experienced MFH despite access to health insurance. These findings underscore the need for clinic and policy solutions that protect cancer patients from financial harm.

RevDate: 2022-01-04

Peterson CW, Venkataraman R, Reddy SS, et al (2022)

Intracellular RNase activity dampens zinc finger nuclease-mediated gene editing in hematopoietic stem and progenitor cells.

Molecular therapy. Methods & clinical development, 24:30-39.

Over the past decade, numerous gene-editing platforms which alter host DNA in a highly specific and targeted fashion have been described. Two notable examples are zinc finger nucleases (ZFNs), the first gene-editing platform to be tested in clinical trials, and more recently, CRISPR/Cas9. Although CRISPR/Cas9 approaches have become arguably the most popular platform in the field, the therapeutic advantages and disadvantages of each strategy are only beginning to emerge. We have established a nonhuman primate (NHP) model that serves as a strong predictor of successful gene therapy and gene-editing approaches in humans; our recent work shows that ZFN-edited hematopoietic stem and progenitor cells (HSPCs) engraft at lower levels than CRISPR/Cas9-edited cells. Here, we investigate the mechanisms underlying this difference. We show that optimized culture conditions, including defined serum-free media, augment engraftment of gene-edited NHP HSPCs in a mouse xenograft model. Furthermore, we identify intracellular RNases as major barriers for mRNA-encoded nucleases relative to preformed enzymatically active CRISPR/Cas9 ribonucleoprotein (RNP) complexes. We conclude that CRISPR/Cas9 RNP gene editing is more stable and efficient than ZFN mRNA-based delivery and identify co-delivered RNase inhibitors as a strategy to enhance the expression of gene-editing proteins from mRNA intermediates.

RevDate: 2021-12-31

Prater KE, Green KJ, Chiou KL, et al (2021)

Microglia subtype transcriptomes differ between Alzheimer Disease and control human postmortem brain samples.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 17 Suppl 2:e058474.

BACKGROUND: Microglia-mediated neuroinflammation is hypothesized to contribute to disease progression in neurodegenerative diseases such as Alzheimer's Disease (AD). Microglia subtypes are complex, with beneficial and harmful phenotypes. Understanding the gene expression networks which define the spectrum of microglia phenotypes is critical to identifying specific targets for neuroinflammation modulating therapies.

METHOD: Our study utilized post-mortem brain tissue from 22 total (7 male) participants; 12 (3 male) had significant AD neuropathic change. Nuclei isolated from prefrontal cortex were sorted for the myeloid marker PU.1 using fluorescence activated nucleus sorting (FANS). The FANS approach yields larger numbers of nuclei annotated as microglia with high quality sequence from each individual. We performed single-nucleus RNA-seq using the 10X Genomics Chromium platform.

RESULTS: We isolated more than 120,000 microglia nuclei, facilitating group comparisons based on disease state. Unbiased clustering revealed 10 microglia clusters and improved resolution of microglia heterogeneity compared to standard single-cell approaches. We identify clusters of microglia enriched for biological pathways implicating defined myeloid roles including interferon-stimulated, endo/lysosomal, neurodegenerative with a "disease-associated microglia" (DAM) signature, as well as a metabolically active and autophagic cluster. Interestingly, the cluster proportionately enriched for AD individuals' nuclei is not the DAM cluster but instead one of the clusters in which endo/lysosomal genes are highly upregulated. Furthermore, many of the genes in known AD risk loci are strongly differentially regulated in this AD associated cluster. We also identify a cluster of microglia that is proportionately enriched for control samples with upregulated cell cycle and proliferation genes. Trajectory analysis suggests that the paths AD and control nuclei take from unactivated "homeostatic" to various phenotypic states are also distinct.

CONCLUSION: Using human AD tissue collected with uniform protocols we characterize the transcriptomic profiles of microglia subtypes in human brain. By enriching for myeloid cells prior to analysis we can resolve microglia subtypes revealing the diversity of microglia which are "inflammatory" as well as other microglia subtypes responding with induction of metabolic and lysosomal pathways. Our data identifies subtypes of microglia that are unique to AD and control individuals. These results support the possibility of pharmacological targeting of specific subtypes of microglia to alter AD progression.

RevDate: 2021-12-31

Zhang S, LeBlanc ML, YQ Zhao (2021)

Restricted survival benefit with right-censored data.

Biometrical journal. Biometrische Zeitschrift [Epub ahead of print].

The hazard ratio is widely used to quantify treatment effects. However, it may be difficult to interpret for patients and practitioners, especially when the hazard ratio is not constant over time. Alternative measures of the treatment effects have been proposed such as the difference of the restricted mean survival times, the difference in survival proportions at some fixed follow-up time, or the net chance of a longer survival. In this paper, we propose the restricted survival benefit (RSB), a quantity that can incorporate multiple useful measurements of treatment effects. Hence, it provides a framework for a comprehensive assessment of the treatment effects. We provide estimation and inference procedures for the RSB that accommodate censored survival outcomes, using methods of the inverse-probability-censoring-weighted U -statistic and the jackknife empirical likelihood. We conduct extensive simulation studies to examine the numerical performance of the proposed method, and we analyze data from a randomized Phase III clinical trial (SWOG S0777) using the proposed method.

RevDate: 2021-12-30

Nguyen P, Chien S, Dai J, et al (2021)

Unsupervised discovery of dynamic cell phenotypic states from transmitted light movies.

PLoS computational biology, 17(12):e1009626 pii:PCOMPBIOL-D-21-00214 [Epub ahead of print].

Identification of cell phenotypic states within heterogeneous populations, along with elucidation of their switching dynamics, is a central challenge in modern biology. Conventional single-cell analysis methods typically provide only indirect, static phenotypic readouts. Transmitted light images, on the other hand, provide direct morphological readouts and can be acquired over time to provide a rich data source for dynamic cell phenotypic state identification. Here, we describe an end-to-end deep learning platform, UPSIDE (Unsupervised Phenotypic State IDEntification), for discovering cell states and their dynamics from transmitted light movies. UPSIDE uses the variational auto-encoder architecture to learn latent cell representations, which are then clustered for state identification, decoded for feature interpretation, and linked across movie frames for transition rate inference. Using UPSIDE, we identified distinct blood cell types in a heterogeneous dataset. We then analyzed movies of patient-derived acute myeloid leukemia cells, from which we identified stem-cell associated morphological states as well as the transition rates to and from these states. UPSIDE opens up the use of transmitted light movies for systematic exploration of cell state heterogeneity and dynamics in biology and medicine.

RevDate: 2021-12-30

Cheng TD, Ilozumba MN, Balavarca Y, et al (2021)

Associations between Genetic Variants and Blood Biomarkers of One-carbon Metabolism in Postmenopausal Women from the Women's Health Initiative Observational Study.

The Journal of nutrition pii:6490133 [Epub ahead of print].

BACKGROUND: Genetic variation in one-carbon metabolism may affect nutrient levels and biological functions. However, data on genetic variants associated with blood biomarkers of one-carbon metabolism in U.S. postmenopausal women are limited, and whether these associations were affected by the nationwide folic acid (FA) fortification program is unclear.

OBJECTIVE: We investigated associations between genetic variants and biomarkers of one-carbon metabolism using data from the Women's Health Initiative Observational Study.

METHODS: In 1,573 non-Hispanic White (NHW) and 282 Black/African American, American Indian/Alaska Native, Asian/Pacific Islander, and Hispanic/Latino women aged 50-79 years, 288 non-synonymous and tagging single-nucleotide variants (SNVs) were genotyped. Red blood cell (RBC) folate, plasma folate, pyridoxal-5'-phosphate (PLP), vitamin B-12, homocysteine, and cysteine levels were determined in 12-h fasting blood. Multivariable linear regression tested associations per variant allele and for an aggregated genetic risk score. Effect modifications before, during, and after nationwide FA fortification were examined.

RESULTS: After correction for multiple comparisons, among NHW women, 5,10-methylenetetrahydrofolate reductase (MTHFR) rs1801133 (677C→T) variant T was associated with lower plasma folate (-13.0%, 95% CI = -17.3% to -8.6%) and higher plasma homocysteine (3.5%, 95% CI = 1.7% to 5.3%) concentrations. Other associations for non-synonymous SNVs included DNMT3A rs11695471 (T→A) with plasma PLP; EHMT2 rs535586 (G→A), TCN2 rs1131603 (L349S A→G) and TCN2 rs35838082 (R188W G→A) with plasma vitamin B-12; CBS rs2851391 (G→A) with plasma homocysteine; and MTHFD1 rs2236224 (G→A) and rs2236225 (R653Q G→A) with plasma cysteine. The influence of FA fortification on the associations was limited. Highest vs. lowest quartiles of aggregated genetic risk scores from SNVs in MTHFR and MTRR were associated with 14.8% to 18.9% lower RBC folate concentrations. Gene-biomarker associations were similar in women of other races/ethnicities.

CONCLUSIONS: Our findings on genetic variants associated with several one-carbon metabolism biomarkers may help elucidate mechanisms of maintaining B vitamin status in postmenopausal women.

RevDate: 2021-12-30

Global Burden of Disease 2019 Cancer Collaboration, Kocarnik JM, Compton K, et al (2021)

Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019.

JAMA oncology pii:2787350 [Epub ahead of print].

Importance: The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden.

Objective: To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019.

Evidence Review: The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite measure of educational attainment, income per capita, and total fertility rate for those younger than 25 years. Estimates include 95% uncertainty intervals (UIs).

Findings: In 2019, there were an estimated 23.6 million (95% UI, 22.2-24.9 million) new cancer cases (17.2 million when excluding nonmelanoma skin cancer) and 10.0 million (95% UI, 9.36-10.6 million) cancer deaths globally, with an estimated 250 million (235-264 million) DALYs due to cancer. Since 2010, these represented a 26.3% (95% UI, 20.3%-32.3%) increase in new cases, a 20.9% (95% UI, 14.2%-27.6%) increase in deaths, and a 16.0% (95% UI, 9.3%-22.8%) increase in DALYs. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and DALYs globally in 2019. Cancer burden differed across SDI quintiles. The proportion of years lived with disability that contributed to DALYs increased with SDI, ranging from 1.4% (1.1%-1.8%) in the low SDI quintile to 5.7% (4.2%-7.1%) in the high SDI quintile. While the high SDI quintile had the highest number of new cases in 2019, the middle SDI quintile had the highest number of cancer deaths and DALYs. From 2010 to 2019, the largest percentage increase in the numbers of cases and deaths occurred in the low and low-middle SDI quintiles.

Conclusions and Relevance: The results of this systematic analysis suggest that the global burden of cancer is substantial and growing, with burden differing by SDI. These results provide comprehensive and comparable estimates that can potentially inform efforts toward equitable cancer control around the world.

RevDate: 2021-12-30

Washington SL, Gore JL, YA Nyame (2021)

Translating Patient-Centered Research into Educational Resources to Address Racial Inequities in Prostate Cancer.

RevDate: 2021-12-30

Hyppa RW, Cho JD, Nambiar M, et al (2021)

Redirecting meiotic DNA break hotspot determinant proteins alters localized spatial control of DNA break formation and repair.

Nucleic acids research pii:6489955 [Epub ahead of print].

During meiosis, DNA double-strand breaks (DSBs) are formed at high frequency at special chromosomal sites, called DSB hotspots, to generate crossovers that aid proper chromosome segregation. Multiple chromosomal features affect hotspot formation. In the fission yeast S. pombe the linear element proteins Rec25, Rec27 and Mug20 are hotspot determinants - they bind hotspots with high specificity and are necessary for nearly all DSBs at hotspots. To assess whether they are also sufficient for hotspot determination, we localized each linear element protein to a novel chromosomal site (ade6 with lacO substitutions) by fusion to the Escherichia coli LacI repressor. The Mug20-LacI plus lacO combination, but not the two separate lac elements, produced a strong ade6 DSB hotspot, comparable to strong endogenous DSB hotspots. This hotspot had unexpectedly low ade6 recombinant frequency and negligible DSB hotspot competition, although like endogenous hotspots it manifested DSB interference. We infer that linear element proteins must be properly placed by endogenous functions to impose hotspot competition and proper partner choice for DSB repair. Our results support and expand our previously proposed DSB hotspot-clustering model for local control of meiotic recombination.

RevDate: 2021-12-29

Johansson AM, Malhotra U, Kim YG, et al (2021)

Cross-reactive and mono-reactive SARS-CoV-2 CD4+ T cells in prepandemic and COVID-19 convalescent individuals.

PLoS pathogens, 17(12):e1010203 pii:PPATHOGENS-D-21-01849 [Epub ahead of print].

Class II tetramer reagents for eleven common DR alleles and a DP allele prevalent in the world population were used to identify SARS-CoV-2 CD4+ T cell epitopes. A total of 112, 28 and 42 epitopes specific for Spike, Membrane and Nucleocapsid, respectively, with defined HLA-restriction were identified. Direct ex vivo staining of PBMC with tetramer reagents was used to define immunodominant and subdominant T cell epitopes and estimate the frequencies of these T cells in SARS-CoV-2 exposed and naïve individuals. Majority of SARS-CoV-2 epitopes identified have <67% amino acid sequence identity with endemic coronaviruses and are unlikely to elicit high avidity cross-reactive T cell responses. Four SARS-CoV-2 Spike reactive epitopes, including a DPB1*04:01 restricted epitope, with ≥67% amino acid sequence identity to endemic coronavirus were identified. SARS-CoV-2 T cell lines for three of these epitopes elicited cross-reactive T cell responses to endemic cold viruses. An endemic coronavirus Spike T cell line showed cross-reactivity to the fourth SARS-CoV-2 epitope. Three of the Spike cross-reactive epitopes were subdominant epitopes, while the DPB1*04:01 restricted epitope was a dominant epitope. Frequency analyses showed Spike cross-reactive T cells as detected by tetramers were present at relatively low frequency in unexposed people and only contributed a small proportion of the overall Spike-specific CD4+ T cells in COVID-19 convalescent individuals. In total, these results suggested a very limited number of SARS-CoV-2 T cells as detected by tetramers are capable of recognizing ccCoV with relative high avidity and vice versa. The potentially supportive role of these high avidity cross-reactive T cells in protective immunity against SARS-CoV-2 needs further studies.

RevDate: 2021-12-29

Tettero JM, Freeman S, Buecklein V, et al (2022)

Technical Aspects of Flow Cytometry-based Measurable Residual Disease Quantification in Acute Myeloid Leukemia: Experience of the European LeukemiaNet MRD Working Party.

HemaSphere, 6(1):e676.

Measurable residual disease (MRD) quantified by multiparameter flow cytometry (MFC) is a strong and independent prognostic factor in acute myeloid leukemia (AML). However, several technical factors may affect the final read-out of the assay. Experts from the MRD Working Party of the European LeukemiaNet evaluated which aspects are crucial for accurate MFC-MRD measurement. Here, we report on the agreement, obtained via a combination of a cross-sectional questionnaire, live discussions, and a Delphi poll. The recommendations consist of several key issues from bone marrow sampling to final laboratory reporting to ensure quality and reproducibility of results. Furthermore, the experiences were tested by comparing two 8-color MRD panels in multiple laboratories. The results presented here underscore the feasibility and the utility of a harmonized theoretical and practical MFC-MRD assessment and are a next step toward further harmonization.

RevDate: 2021-12-28

Su Y, Cochrane BB, Yu SY, et al (2021)

Fatigue in community-dwelling older adults: A review of definitions, measures, and related factors.

Geriatric nursing (New York, N.Y.), 43:266-279 pii:S0197-4572(21)00388-8 [Epub ahead of print].

Fatigue is a common age-related symptom among community-dwelling adults aged 65 years and older. Yet, a systematic approach has rarely been applied to review definitions, measures, related factors, and consequences of fatigue in this population. A scoping review was conducted in December 2020 to fill the gap, and 36 articles met the inclusion criteria. Definitions, albeit diverse, included at least one of the following attributes: an early indicator of disablement, subjective, a lack of energy, multidimensional, impaired daily activities, and temporal. A summary of fatigue measures used in this population was provided, including a brief overview, number of items, reliability, and validity. In general, different measures were used with considerable variability in the content. Additionally, most measures had limited information on test-retest reliability and validity. Fatigue-related factors mapped into biological, psychological, social, and behavioral factors. Fatigue consequences were primarily declines in physical and cognitive functions. (100-150 words).

RevDate: 2021-12-28

Combes AJ, Samad B, Tsui J, et al (2021)

Discovering dominant tumor immune archetypes in a pan-cancer census.

Cell pii:S0092-8674(21)01426-4 [Epub ahead of print].

Cancers display significant heterogeneity with respect to tissue of origin, driver mutations, and other features of the surrounding tissue. It is likely that individual tumors engage common patterns of the immune system-here "archetypes"-creating prototypical non-destructive tumor immune microenvironments (TMEs) and modulating tumor-targeting. To discover the dominant immune system archetypes, the University of California, San Francisco (UCSF) Immunoprofiler Initiative (IPI) processed 364 individual tumors across 12 cancer types using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained from cell sub-compartments uncovered dominant patterns of immune composition across cancers. These archetypes were profound insofar as they also differentiated tumors based upon unique immune and tumor gene-expression patterns. They also partitioned well-established classifications of tumor biology. The IPI resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune organization and provides a rational path forward to learn how to modulate these to improve therapy.

RevDate: 2021-12-28

Lucier A, Fong Y, Li SH, et al (2021)

Frequent development of broadly neutralizing antibodies in early life in a large cohort of children living with HIV.

The Journal of infectious diseases pii:6486389 [Epub ahead of print].

BACKGROUND: Recent studies have indicated that broadly neutralizing antibodies (bnAbs) in children may develop earlier after HIV infection compared to adults.

METHODS: We evaluated plasma from 212 ART-naïve, children living with HIV (1-3 years-old). Neutralization breadth and potency was assessed using a panel of 10 viruses and compared to adults with chronic HIV. The magnitude, epitope specificity and IgG subclass distribution of Env-specific antibodies were assessed using a binding antibody multiplex assay.

RESULTS: 1-year-old children demonstrated neutralization breadth comparable to chronically-infected adults, while 2 and 3-year olds exhibited significantly greater neutralization breadth (p=0.014). Similarly, binding antibody responses increased with age, with levels in 2 and 3 year-old children comparable to adults. Overall, there was no significant difference in antibody specificities or IgG subclass distribution between the pediatric and adult cohorts. Interestingly, the neutralization activity was mapped to a single epitope (CD4 binding site, V2 or V3 glycans) in only 5 of 38 pediatric broadly neutralizing samples, suggesting most children may develop a polyclonal neutralization response.

CONCLUSIONS: These results contribute to a growing body of evidence suggesting that initiating HIV immunization early in life may present advantages for the development of broadly neutralizing antibody responses.


RJR Experience and Expertise


Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.


Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.


Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.


Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.


While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.


Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.


Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.


Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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Cancer is the generic name for more than 100 diseases in which cells begin to grow and divide in an uncontrolled manner. Usually, when cells get too old or damaged, they die and new cells take their place. Cancer begins when genetic changes impair this orderly process so that some cells start to grow uncontrollably. The Emperor of All Maladies is a "biography" of cancer — from its first documented appearances thousands of years ago through the epic battles in the twentieth century to cure, control, and conquer it to a radical new understanding of its essence. This is a must read book for anyone with an interest in cancer. R. Robbins

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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

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Curriculum Vitae for R J Robbins

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RJR Picks from Around the Web (updated 11 MAY 2018 )