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Allogeneic Transplantation and Chimeric Antigen Receptor-Engineered T-Cell Therapy for Relapsed or Refractory Mantle Cell Lymphoma

Hematol Oncol Clin North Am

2020 Jordan Gauthier; David Maloney

Mantle cell lymphoma (MCL) accounts for fewer than 10% of non-Hodgkin lymphoma. There is a high initial response rate to chemotherapy and rituximab, but a nearly universal risk of relapse. Allogeneic hematopoietic cell transplantation (allo-HCT) provides one of the only curative options. We review the role of allo-HCT for relapsed and refractory (R/R) MCL and discuss a novel promising approach using autologous chimeric antigen receptor-engineered T (CAR-T) cells. We review preliminary safety and efficacy data of 2 pivotal trials investigating the use of CD19-targeted CAR-T cells for R/R MCL after ibrutinib failure and discuss potential timing of these approaches.

Purification of Human CD34+CD90+ HSCs Reduces Target Cell Population and Improves Lentiviral Transduction for Gene Therapy

Mol Ther Methods Clin Dev

2020 Yan-Yi Chan; Andrew Berger; Mark Enstrom; Thomas Eunson; Hans-Peter Kiem; Stefan Radtke; Anai Perez; Stefanie Schmuck; Margaret Cui; Jennifer Adair; Dnyanada Pande

Hematopoietic stem cell (HSC) gene therapy has the potential to cure many genetic, malignant, and infectious diseases. We have shown in a nonhuman primate gene therapy and transplantation model that the CD34+CD90+ cell fraction was exclusively responsible for multilineage engraftment and hematopoietic reconstitution. In this study, we show the translational potential of this HSC-enriched CD34 subset for lentivirus-mediated gene therapy. Alternative HSC enrichment strategies include the purification of CD133+ cells or CD38low/- subsets of CD34+ cells from human blood products. We directly compared these strategies to the isolation of CD90+ cells using a good manufacturing practice (GMP) grade flow-sorting protocol with clinical applicability. We show that CD90+ cell selection results in about 30-fold fewer target cells in comparison to CD133+ or CD38low/- CD34+ hematopoietic stem and progenitor cell (HSPC) subsets without compromising the engraftment potential in vivo. Single-cell RNA sequencing confirmed nearly complete depletion of lineage-committed progenitor cells in CD90+ fractions compared to alternative selections. Importantly, lentiviral transduction efficiency in purified CD90+ cells resulted in up to 3-fold higher levels of engrafted gene-modified blood cells. These studies should have important implications for the manufacturing of patient-specific HSC gene therapy and gene-engineered cell products.

Accelerometer-assessed physical activity and incident diabetes in a population covering the adult life span: the Hispanic Community Health Study/Study of Latinos

Am J Clin Nutr

2020 Robert Kaplan

BACKGROUND: The association between accelerometer-assessed physical activity and risk of diabetes remains unclear, especially among US Hispanic/Latino adults who have lower levels of physical activity and a higher diabetes burden compared with other racial/ethnical populations in the country. OBJECTIVES: To examine the association between accelerometer-assessed physical activity and incident diabetes in a US Hispanic/Latino population. METHODS: We included 7280 participants of the Hispanic Community Health Study/Study of Latinos who aged 18-74 y and free of diabetes at baseline. Data on moderate-to-vigorous physical activity (MVPA) were collected using a 7-d accelerometer measurement. Incident diabetes was assessed after a mean SD of 6.0 0.8 y using standard procedures including blood tests. RRs and 95% CIs of diabetes associated with MVPA were estimated using survey Poisson regressions. The associations of MVPA with 6-y changes in adiposity measures were also examined. RESULTS: A total of 871 incident cases of diabetes were identified. MVPA was inversely and nonlinearly associated with risk of diabetes (P-nonlinearity=0.006), with benefits accruing rapidly at the lower end of MVPA range (<30 min/d) and leveling off thereafter. The association differed by population age (P-interaction=0.006). Higher MVPA was associated with lower risk of diabetes among individuals older than 50 y (RRQ4 versus Q1=0.50; 95% CI: 0.35, 0.73; P-trend<0.001) but not among younger individuals (RRQ4 versus Q1=0.98; 95% CI: 0.66, 1.47; P-trend=0.92). An inverse association between MVPA and 6-y gain in waist circumference was also limited to the older group (P-interaction with age<0.001). CONCLUSIONS: Among US Hispanic/Latino adults, baseline accelerometer-derived MVPA was inversely associated with incident diabetes only among individuals aged 50 y and older. Further studies are needed to confirm our findings and to clarify potential mechanisms underlying the possible age differences in the MVPA-diabetes association. This study was registered at clinicaltrials.gov as NCT02060344.

Socioeconomic position is associated with glycemic control in youth and young adults with type 1 diabetes

Pediatr Diabetes

2020 Jason Mendoza

OBJECTIVE: Health inequities persist in youth and young adults(YYA) with type 1diabetes in achieving optimal glycemic control. The purpose of this study was to assess the contribution of multiple indicators of social needto these inequities. RESEARCH DESIGN AND METHODS: 222YYAwithtype 1 diabetes enrolled in the SEARCH Food Insecurity Study in South Carolina and Washington between the years 2013-2015 were included. Latent class analysis was used to identify socioeconomic profiles based on household income, parental education, health insurance,household food insecurity, and food assistance. Profileswere evaluated in relation to glycemic control using multivariable linear andlogistic regression, with HbA1c > 9%(75 mmol/mol) defined as high-riskglycemic control. RESULTS: Twoprofiles were identified: alower socioeconomic profile included YYA whose parents had lower income and/or education,and weremore likely to be uninsured, receive food assistance, and be food insecure.A higher socioeconomic profileincluded YYA whose circumstances were opposite to those in the lower socioeconomic profile.Those with a lower socioeconomic profile were more likely to have high-riskglycemic control relative to thosewith a higher socioeconomic profile (OR=2.24, 95%CI=1.16-4.33). CONCLUSIONS: Lower socioeconomic profilesare associated with high-riskglycemic controlamong YYA with type 1 diabetes. This supports recommendations that care providers of YYA with type 1 diabetes assess individual social needs in tailoring diabetes management plans to the social context of the patient. This article is protected by copyright. All rights reserved.

Histone deposition pathways determine the chromatin landscapes of H3.1 and H3.3 K27M oncohistones

Elife

2020 Steven Henikoff; Michael Meers; Christina Lockwood; Patrick Paddison; Nicholas Vitanza; Heather Feldman; Kamran Ahmad; Jorja Henikoff; Derek Janssens; Jay Sarthy; James Olson

Lysine 27-to-methionine (K27M) mutations in the H3.1 or H3.3 histone genes are characteristic of pediatric diffuse midline gliomas (DMGs). These oncohistone mutations dominantly inhibit histone H3K27 trimethylation and silencing, but it is unknown how oncohistone type affects gliomagenesis. We show that the genomic distributions of H3.1 and H3.3 oncohistones in human patient-derived DMG cells are consistent with the DNA replication-coupled deposition of histone H3.1 and the predominant replication-independent deposition of histone H3.3. Although H3K27 trimethylation is reduced for both oncohistone types, H3.3K27M-bearing cells retain some domains, and only H3.1K27M-bearing cells lack H3K27 trimethylation. Neither oncohistone interferes with PRC2 binding. Using Drosophila as a model, we demonstrate that inhibition of H3K27 trimethylation occurs only when H3K27M oncohistones are deposited into chromatin and only when expressed in cycling cells. We propose that oncohistones inhibit the H3K27 methyltransferase as chromatin patterns are being duplicated in proliferating cells, predisposing them to tumorigenesis.

Effectiveness and safety of rivaroxaban compared with low-molecular-weight heparin in cancer-associated thromboembolism

Blood Adv

2020 Gary Lyman

Guidelines provide differing recommendations regarding direct-acting oral anticoagulants vs low-molecular-weight heparin (LMWH) for treatment of cancer-associated thrombosis (CAT). This study was undertaken to evaluate the effectiveness and safety of rivaroxaban vs LMWH for treatment of CAT. Using US Surveillance, Epidemiology and End Results-Medicare-linked data from 2013 through 2016, we evaluated adults with active breast, lung, ovarian, or pancreatic cancer, who were admitted to the hospital or treated in the emergency department for CAT and were prescribed rivaroxaban or LMWH for outpatient anticoagulation. Patients with luminal gastrointestinal or genitourinary cancers were excluded. Rivaroxaban and LMWH users were 1:1 propensity score matched. Outcomes included the composite of recurrent thrombosis or major bleeding, each outcome separately, and mortality at 6 months, using an intent-to-treat approach. On-treatment analysis after 12 months was also performed. Proportional hazards models for the subdistribution of competing risk were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). We included 529 rivaroxaban- and 529 LMWH-treated patients with CAT. Rivaroxaban was not associated with differences in risk of the composite outcome (HR, 0.71; 95% CI, 0.41-1.22), major bleeding (HR, 1.01; 95% CI, 0.50-2.01), or mortality (HR, 0.87; 95% CI, 0.70-1.07) vs LMWH, but it reduced recurrent thrombosis (HR, 0.37; 95% CI, 0.15-0.95). On-treatment analysis at 12 months showed similar results. Rivaroxaban may be a reasonable alternative to LMWH for patients with CAT without gastrointestinal or genitourinary cancer.

Nrf2 contributes to the weight gain of mice during space travel

Commun Biol

2020 Thomas Kensler

Space flight produces an extreme environment with unique stressors, but little is known about how our body responds to these stresses. While there are many intractable limitations for in-flight space research, some can be overcome by utilizing gene knockout-disease model mice. Here, we report how deletion of Nrf2, a master regulator of stress defense pathways, affects the health of mice transported for a stay in the International Space Station (ISS). After 31 days in the ISS, all flight mice returned safely to Earth. Transcriptome and metabolome analyses revealed that the stresses of space travel evoked ageing-like changes of plasma metabolites and activated the Nrf2 signaling pathway. Especially, Nrf2 was found to be important for maintaining homeostasis of white adipose tissues. This study opens approaches for future space research utilizing murine gene knockout-disease models, and provides insights into mitigating space-induced stresses that limit the further exploration of space by humans.

Architectural RNA in chromatin organization

Biochem Soc Trans

2020 Jitendra Thakur; Steven Henikoff

RNA plays a well-established architectural role in the formation of membraneless interchromatin nuclear bodies. However, a less well-known role of RNA is in organizing chromatin, whereby specific RNAs have been found to recruit chromatin modifier proteins. Whether or not RNA can act as an architectural molecule for chromatin remains unclear, partly because dissecting the architectural role of RNA from its regulatory role remains challenging. Studies that have addressed RNA's architectural role in chromatin organization rely on in situ RNA depletion using Ribonuclease A (RNase A) and suggest that RNA plays a major direct architectural role in chromatin organization. In this review, we will discuss these findings, candidate chromatin architectural long non-coding RNAs and possible mechanisms by which RNA, along with RNA binding proteins might be mediating chromatin organization.

A prospective, blinded study of a PF4-dependent assay for HIT diagnosis

Blood

2020 Mary Redman; Daniel Sabath; David Garcia

Heparin-induced thrombocytopenia (HIT) is a life-threatening, pro-thrombotic, antibody-mediated disorder. To maximize the likelihood of recovery, early and accurate diagnosis is critical. Widely available HIT assays such as the Platelet Factor 4-Heparin ELISAs lack specificity, and the "gold standard" C14-labeled serotonin release assay (SRA) is of limited value for early patient management due to availability only through reference laboratories. Recent studies demonstrate that "pathogenic" HIT antibodies selectively activate PF4-treated platelets and that a technically simpler assay, the PF4-dependent P-selectin Expression Assay (PEA), may provide an option for rapid and conclusive results. Four hundred and nine consecutive adults suspected of HIT were classified as disease-positive, -negative or -indeterminate based upon predefined criteria that combined 4Ts scores and HIT ELISA results. Patients deemed "HIT-indeterminate" were considered disease-negative in the primary analysis and disease-positive in a sensitivity analysis. The ability of PEA and SRA to identify patients judged to have HIT was compared using receiver operating characteristic curve statistics. Using these predefined criteria, the diagnostic accuracy of PEA was high (Area under the curve [AUC] of 0.94; 0.87-1.0, 95% CI) and similar to that of SRA (0.91; 0.82-1.0, 95% CI). In sensitivity analysis, the AUCs of PEA and SRA were also similar at 0.88 (0.78-0.98, 95% CI) and 0.86 (0.77-0.96, 95% CI), respectively. The PEA, a technically simple non-radioactive assay that uses ~20-fold fewer platelets compared to the SRA had high accuracy for diagnosing HIT. Widespread use of the PEA may facilitate timely and more effective management of patients with suspected HIT.

Two Steps Forward and One Step Back for Precision in Prostate Cancer Treatment

J Clin Oncol

2020 Robert Montgomery; Peter Nelson; Heather Cheng; Michael Schweizer

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