Modeling sex differences in humans using isogenic induced pluripotent stem cells.

Biological sex is a fundamental trait influencing development, reproduction, pathogenesis, and medical treatment outcomes. Modeling sex differences is challenging because of the masking effect of genetic variability and the hurdle of differentiating chromosomal versus hormonal effects. In this work we developed a cellular model to study sex differences in humans. Somatic cells from a mosaic Klinefelter syndrome patient were reprogrammed to generate isogenic induced pluripotent stem cell (iPSC) lines with different sex chromosome complements: 47,XXY/46,XX/46,XY/45,X0. Transcriptional analysis of the hiPSCs revealed novel and known genes and pathways that are sexually dimorphic in the pluripotent state and during early neural development. Female hiPSCs more closely resembled the naive pluripotent state than their male counterparts. Moreover, the system enabled differentiation between the contributions of X versus Y chromosome to these differences. Taken together, isogenic hiPSCs present a novel platform for studying sex differences in humans and bear potential to promote gender-specific medicine in the future.

Trends in Women's Leadership of Oncology Clinical Trials.

It has been widely reported that women are underrepresented in leadership positions within academic medicine. This study aimed to assess trends in women representation as principal investigators (PIs) in oncology clinical trials and to characterize trends in women's leadership in such trials conducted between 1999 and 2019. The gender of 39,240 PIs leading clinical trials was determined using the gender prediction software Genderize.io. In total, 11,516 (27.7%) women served as PIs. Over the past 20 years, an annual increase of 0.65% in women PIs was observed. Analysis by geographic distribution revealed higher women representation among PIs in North America and Europe compared to Asia. Industry-funded trials were associated with lower women PI representation than academic-funded trials (31.4% vs. 18.8%, p<0.001). Also, women PIs were found to be underrepresented in late-phase as compared to early-phase studies (27.9%, 25.7%, 21.6%, and 22.4% in phase I, II, III, and IV, respectively; Cochran-Armitage test for trend, p<0.001). Furthermore, an association was found between the PI's gender and enrolment of female subjects (50% vs. 43% female participants led by women vs men PIs, respectively, p<0.001). Taken together, while the gender gap in women's leadership in oncology trials has been steadily closing, prominent inequalities remain in non-Western countries, advanced study phases, industry-funded trials and appear to be linked to a gender gap in patient accrual. These observations can serve for the development of strategies to increase women's representation and to monitor progress toward gender equality in PIs of cancer clinical trials.

Psychosocial perspectives among cancer patients during the coronavirus disease 2019 (COVID-19) crisis: An observational longitudinal study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) crisis and consequent changes in medical practice have engendered feelings of distress in diverse populations, potentially adversely affecting the psychological well-being of cancer patients. AIM: The purpose of this observational longitudinal study was to evaluate psychosocial perspectives among patients with cancer on intravenous treatment during the COVID-19 pandemic. METHODS AND RESULTS: The study recruited 164 cancer patients undergoing intravenous anti-neoplastic therapy in a tertiary cancer center. Psychosocial indices were assessed at two points in time, corresponding with the beginning of the first wave of COVID-19 pandemic in Israel (March 2020) and the time of easing of restrictions implemented to curtail spread of infection (May 2020). At Time 1 (T1), elevated COVID-19 distress levels (score 1 and 2 on 5-point scale) were observed in 44% of patients, and associated with pre-existing hypertension and lung disease in multivariate analyses but no demographic or cancer related factors. At Time 2 (T2), 10% had elevated anxiety and 24% depression as indicated by Hospital Anxiety and Depression Scale (HADS-A/D). COVID-19 distress at T1 was related to higher levels of HADS-A at T2 (Spearman 0.33 p < .01), but not HADS-D. Patients with breast cancer expressed greater COVID-19 distress compared with other cancer types (p < .01), while both HADS-A and HADS-D were highest for patients with GI cancer. Patient report of loneliness and decreased support from relatives were factors associated with HADS-A (p = .03 and p < .01, respectively), while HADS-D was not similarly related to the factors evaluated. CONCLUSION: Patients with cancer undergoing intravenous treatment may be vulnerable to acute adverse psychological ramifications of COVID-19, specifically exhibiting high levels of anxiety. These appear unrelated to patient age or disease stage. Those with underlying comorbidities, breast cancer or reduced social support may be at higher risk.

Laminin111-based defined culture promoting self-renewing human pluripotent stem cells with properties of the early post-implantation epiblast.

In the mammalian embryo, a formative pluripotent phase is proposed to exist at the early post-implantation period, during the transition from the pre-implantation naive-to the post-implantation primed-epiblast. By recapitulating a laminin component of the extracellular matrix niche during embryonic formative transition, and defined culture conditions, we generated cultures highly enriched for self-renewing human pluripotent stem cells (hPSCs), exhibiting properties of early post-implantation epiblast cells. These hPSCs display post-implantation-epiblast gene expression profiles. FGF and TGF-ß signaling maintain their self-renewal for multiple passages. They have inactive canonical Wnt signaling, do not express primitive streak markers, and are competent to initiate differentiation toward germline and somatic fates. hPSCs exhibiting early post-implantation epiblast properties may shed light on human embryonic PSCs development and may serve for initiating somatic and germ cell specification.

Serologic Status and Toxic Effects of the SARS-CoV-2 BNT162b2 Vaccine in Patients Undergoing Treatment for Cancer.

Importance: The efficacy and safety profile of SARS-CoV-2 vaccines have been acquired from phase 3 studies; however, patients with cancer were not represented in these trials. Owing to the recommendation to prioritize high-risk populations for vaccination, further data are warranted. Objective: To evaluate the use and safety of the BNT162b2 vaccine in patients undergoing treatment for cancer. Design, Setting, and Participants: In January 2021, mass SARS-CoV-2 vaccination of high-risk populations, including patients with cancer, was initiated in Israel. This cohort study prospectively enrolled and followed up patients with cancer and healthy participants between January 15 and March 14, 2021. The study was conducted at the Division of Oncology of Rambam Health Care Campus, the major tertiary (referral) medical center of northern Israel. Participants included 232 patients with cancer who were receiving active treatment after the first and second doses of the BNT162b2 vaccine and 261 healthy, age-matched health care workers who served as controls. Exposures: Serum samples were collected after each vaccine dose and in cases of seronegativity. Questionnaires regarding sociodemographic characteristics and adverse reactions were administered at serum collection. A regulatory agencies-approved assay was used to assess IgG at all time points. Patients' electronic medical records were reviewed for documentation of COVID-19 infection and results of blood cell counts, liver enzyme levels, and imaging studies. Main Outcomes and Measures: Seroconversion rate after the first and second doses of the BNT162b2 vaccine and documented COVID-19 infection. Results: Of the 232 patients undergoing treatment for cancer, 132 were men (57%); mean (SD) age was 66 (12.09) years. After the first dose of BNT162b2 vaccine, 29% (n = 25) patients were seropositive compared with 84% (n = 220) of the controls (P < .001). After the second dose, the seropositive rate reached 86% (n = 187) in the patients. Testing rate ratios per 1000 person-days after the first dose were 12.5 (95% CI, 3.4-45.7) for the patients and 48.5 (95% CI, 37.2-63.2) for the controls. Patients undergoing chemotherapy showed reduced immunogenicity (odds ratio, 0.41; 95% CI, 0.17-0.98). In seronegative patients, the rate of documented absolute leukopenia reached 39%. No COVID-19 cases were documented throughout the study period; however, 2 cases in the patient cohort were noted immediately after the first dose. Reported adverse events were similar to data in former trials comprising mostly healthy individuals. Conclusions and Relevance: In this cohort study, the SARS-CoV-2 BNT162b2 vaccine appeared to be safe and achieve satisfactory serologic status in patients with cancer. There was a pronounced lag in antibody production compared with the rate in noncancer controls; however, seroconversion occurred in most patients after the second dose. Future real-world data are warranted to determine the long-term efficacy of the vaccine with regard to type of anticancer treatment.

Six-Month Efficacy and Toxicity Profile of BNT162b2 Vaccine in Cancer Patients with Solid Tumors.

We had previously reported short-term efficacy, immunogenicity, and safety of the BNT162b2 vaccine among cancer patients with solid tumors. We aimed to evaluate these outcomes at six months postvaccination. The study cohort comprised patients who were on treatment during vaccination and throughout six months postvaccination. Serologic tests were performed after second vaccination and six months afterward. An age-matched cohort of health care workers served as controls. Documentation of COVID-19 infection, blood tests, and imaging studies during the study period was reviewed. Participants included 154 patients and 135 controls. Six months postvaccination, 122 (79%) patients were seropositive compared with 114 (84%) controls (P = 0.32). Serology titer dramatically decreased in a similar manner in both cohorts. No COVID-19 cases were documented in controls, and one case occurred in patient cohort. All previously reported adverse effects resolved. Taken together, the pattern of immunogenicity, efficacy, and safety of BNT162b2 in patients with cancer with solid tumors at six months postvaccination resembles that of the general population. SIGNIFICANCE: Evidence regarding efficacy and safety of COVID-19 vaccines in patients with cancer indicate a favorable short-term profile. Immunomodulation due to anticancer treatments may affect immunity and immunogenicity of patients with cancer to the BNT162b2 vaccine over time. Our study sheds light on these long-term outcomes and portrays a trend that resembles the general population.This article is highlighted in the In This Issue feature, p. 2355.

Gender Gap in Leadership of Clinical Trials.

This cross-sectional study investigates representation of women as principal investigators of clinical trials by study phase, medical specialty, and representation of women trial participants.