Activity

A previous International Lymphoma Epidemiology (InterLymph) Consortium evaluation of joint associations between five immune gene variants and autoimmune conditions reported interactions between B-cell response-mediated autoimmune conditions and the rs1800629 genotype on risk of B-cell non-Hodgkin lymphoma (NHL) subtypes. Here, we extend that evaluation using NHL subtype-specific polygenic risk scores (PRS) constructed from loci identified in genome-wide association studies of three common B-cell NHL subtypes.

In a pooled analysis of NHL cases and controls of Caucasian descent from 14 participating InterLymph studies, we evaluated joint associations between B-cell-mediated autoimmune conditions and tertile (T) of PRS for risk of diffuse large B-cell lymphoma (DLBCL; n = 1,914), follicular lymphoma (n = 1,733), and marginal zone lymphoma (MZL; n = 407), using unconditional logistic regression.

We demonstrated a positive association of DLBCL PRS with DLBCL risk [T2 vs. T1 OR = 1.24; 95% confidence intervalL.Spermatogenic regeneration is key for male fertility and relies on activities of an undifferentiated spermatogonial population. Here, a high-throughput approach with primary cultures of mouse spermatogonia was devised to rapidly predict alterations in functional capacity. Combining the platform with a large-scale RNAi screen of transcription factors, we generated a repository of new information from which pathway analysis was able to predict candidate molecular networks regulating regenerative functions. Extending from this database, the SRCAP-CREBBP/EP300 (Snf2-related CREBBP activator protein-CREB binding protein/E1A binding protein P300) complex was found to mediate differential levels of histone acetylation between stem cell and progenitor spermatogonia to influence expression of key self-renewal genes including the previously undescribed testis-specific transcription factor ZSCAN2 (zinc finger and SCAN domain containing 2). Single cell RNA sequencing analysis revealed that ZSCAN2 deficiency alters key cellular processes in undifferentiated spermatogonia such as translation, chromatin modification, and ubiquitination. In Zscan2 knockout mice, while spermatogenesis was moderately impacted during steady state, regeneration after cytotoxic insult was significantly impaired. Altogether, these findings have validated the utility of our high-throughput screening approach and have generated a transcription factor database that can be utilized for uncovering novel mechanisms governing spermatogonial functions.Wilms’ tumor 1 (Wt1) encodes a zinc finger nuclear transcription factor which is mutated in 15-20% of Wilms’ tumor, a pediatric kidney tumor. Wt1 has been found to be involved in the development of many organs. In gonads, Wt1 is expressed in genital ridge somatic cells before sex determination, and its expression is maintained in Sertoli cells and granulosa cells after sex determination. It has been demonstrated that Wt1 is required for the survival of the genital ridge cells. Homozygous mutation of Wt1 causes gonad agenesis. Recent studies find that Wt1 plays important roles in lineage specification and maintenance of gonad somatic cells. In this review, we will summarize the recent research works about Wt1 in gonadal somatic cell differentiation.Patients with hematologic malignancies relapsing after allogeneic blood or marrow transplantation (BMT) have limited response to conventional salvage therapies, with an expected 1-year overall survival (OS) of less then 20%. We evaluated the safety and clinical outcomes following administration of a novel T-cell therapeutic targeting 3 tumor-associated antigens (TAA-T) in patients with acute leukemia who relapsed or were at high risk of relapse after allogeneic BMT. Lymphocytes obtained from the BMT donor were manufactured to target TAAs WT1, PRAME, and survivin, which are over-expressed and immunogenic in most hematologic malignancies. Patients received TAA-T infusions at doses of 0.5 to 4 × 107/m2. Twenty-three BMT recipients with relapsed/refractory (n = 11) and/or high-risk (n = 12) acute myeloid leukemia (n = 20) and acute lymphoblastic leukemia (n = 3) were infused posttransplant. No patient developed cytokine-release syndrome or neurotoxicity, and only 1 patient developed grade 3 graft-versus-host disease. Of the patients who relapsed post-BMT and received bridging therapy, the majority (n = 9/11) achieved complete hematologic remission before receiving TAA-T. Relapsed patients exhibited a 1-year OS of 36% and 1-year leukemia-free survival of 27.3% post-TAA-T. The poorest prognosis patients (relapsed less then 6 months after transplant) exhibited a 1-year OS of 42.8% postrelapse (n = 7). Median survival was not reached for high-risk patients who received preemptive TAA-T posttransplant (n = 12). Although as a phase 1 study, concomitant antileukemic therapy was allowed, TAA-T were safe and well tolerated, and sustained remissions in high-risk and relapsed patients were observed. Moreover, adoptively transferred TAA-T detected by T-cell receptor V-β sequencing persisted up to at least 1 year postinfusion. This trial was registered at clinicaltrials.gov as #NCT02203903.Mobile phones are an invaluable economic asset for low-income individuals and an important tool for strengthening social ties. They may also help women overcome physical boundaries, especially those who are separated from support networks and are bound within their husbands’ social spheres. Using micro-level data on women and men from recent Demographic and Health Surveys, including new information on mobile phone ownership, this study examines whether women’s ownership of mobile phones is associated with their likelihood of having experienced intimate partner violence (IPV) across 10 low- and middle-income countries. Findings show that women’s ownership of mobile phones is associated with a 9%-12% decreased likelihood of emotional, physical, and sexual violence over the previous 12 months, even after controlling for characteristics proxying for socioeconomic status, household resources, and local development within the community. Estimates are negative in seven out of the 10 countries and results are robust to the use of nonparametric matching techniques and instrumental variables built through georeferenced ancillary sources. In exploring two potential mechanisms, I show that mobile phone ownership is positively associated with women’s decision-making power within the household (decision-making power) and male partners’ lower acceptability of IPV (attitudes). Findings speak to scholars and policymakers interested in how technology diffusion relates to dynamics of women’s empowerment and global development.

To investigate the standardized incidence ratios (SIR) of stroke in patients with head and neck cancer and their relationship to radiotherapy.

Patients with head and neck cancer ages 20-85 years were enrolled from 2007 to 2016 using the Taiwan Cancer Registry. The study endpoint was fatal and non-fatal ischemic stroke, ascertained by the National Health Insurance Research Database. Age- and sex-adjusted SIRs, categorized by 10-year age standardization, were used to compare the patients with head and neck cancer with a randomly selected 2,000,000 general population. We compared the risk of stroke in patients with head and neck cancer who received radiotherapy or surgery alone. Multivariable adjusted hazard ratios (HR) and 95% confidence intervals (CI) were obtained from Cox regression analysis with competing risk.

Among 41,266 patients (mean age, 54.1 years; men, 90.6%) in the median follow-up period of 3.9 years, 1,407 strokes occurred. Compared with the general population, the overall SIR of stroke was 1.37 (95% CI, 1.30-1.44) in patients with head and neck cancer. In patients with head and neck cancer, the fully adjusted HR of stroke in those who received radiotherapy was 0.96 (95% CI, 0.83-1.10), compared with those who received surgery alone.

Patients with head and neck cancer had a higher risk of fatal or non-fatal ischemic stroke. The risk of stroke was not higher in patients initially treated with radiotherapy.

Oncologists should emphasize stroke prevention in all patients with head and neck cancer, not only in those who received radiotherapy.

Oncologists should emphasize stroke prevention in all patients with head and neck cancer, not only in those who received radiotherapy.

Tumor-infiltrating lymphocytes (TIL) confer a survival benefit among patients with ovarian cancer; however, little work has been conducted in racially diverse cohorts.

The current study investigated racial differences in the tumor immune landscape and survival of age- and stage-matched non-Hispanic Black and non-Hispanic White women with high-grade serous ovarian carcinoma (HGSOC) enrolled in two population-based studies (n = 121 in each racial group). We measured TILs (CD3+), cytotoxic T cells (CD3+CD8+), regulatory T cells (CD3+FoxP3+), myeloid cells (CD11b+), and neutrophils (CD11b+CD15+) via multiplex immunofluorescence. Multivariable Cox proportional hazard regression was used to estimate the association between immune cell abundance and survival overall and by race.

Overall, higher levels of TILs, cytotoxic T cells, myeloid cells, and neutrophils were associated with better survival in the intratumoral and peritumoral region, irrespective of tissue compartment (tumor, stroma). Improved survival was noted for T-regulatory cells in the peritumoral region and in the stroma of the intratumoral region, but no association for intratumoral T-regulatory cells. Despite similar abundance of immune cells across racial groups, associations with survival among non-Hispanic White women were consistent with the overall findings, but among non-Hispanic Black women, most associations were attenuated and not statistically significant.

Our results add to the existing evidence that a robust immune infiltrate confers a survival advantage among women with HGSOC; however, non-Hispanic Black women may not experience the same survival benefit as non-Hispanic White women with HGSOC.

This study contributes to our understanding of the immunoepidemiology of HGSOC in diverse populations.

This study contributes to our understanding of the immunoepidemiology of HGSOC in diverse populations.Several cancers and rare genetic diseases are caused by dysregulation in the RAS signaling pathway. read more RAS proteins serve as molecular switches that regulate pathways involved in cellular growth, differentiation and survival. These pathways have been an intense area of investigation for four decades, since the initial identification of somatic RAS mutations linked to human cancers. In the past few years, inhibitors against several RAS effectors, as well as direct inhibitors of the K-RAS mutant G12C, have been developed. This Special Issue in DMM includes original Research articles on RAS-driven cancers and RASopathies. The articles provide insights into mechanisms and biomarkers, and evaluate therapeutic targets. Several articles also present new disease models, whereas others describe technologies or approaches to evaluate the function of RAS in vivo. The collection also includes a series of Review articles on RAS biology and translational aspects of defining and treating RAS-driven diseases. In this Editorial, we summarize this collection and discuss the potential impact of the articles within this evolving area of research.