Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Functional Myeloid-Derived Suppressor Cell Subsets Recover Rapidly after Allogeneic Hematopoietic Stem/Progenitor Cell Transplantation

AbstractMyeloid-derived suppressor cells (MDSCs) are regulatory cell populations that have the ability to suppress effector T cell responses and promote the development of regulatory T cells (Tregs). They are a heterogeneous population of immature myeloid progenitors that include monocytic and granulocytic subsets. We postulated that given the rapid expansion of myeloid cells post-transplant, these members of the innate immune system may be important contributors to the early immune environment post-transplant. To evaluate the kinetics of recovery and function of MDSCs after allogeneic hematopoietic stem cell transplant (HSCT), 26 patients undergoing allogeneic HSCT were studied at 6 time points in the first 3 months after HSCT. Both MDSC subsets recovered between 2 and 4 weeks, well before the recovery of T and B lymphocytes. MDSC subset recovery positively correlated with T, B, and/or double-negative T cell numbers after HSCT. MDSCs isolated from patients post-transplant were functional in that they suppressed third-party CD4+ T cell proliferation and Th1 differentiation and promoted Treg development. In conclusion, functional MDSC are present early after HSCT and likely contribute to the regulatory cell population post-transplant

Ferroptosis and autophagy induced cell death occur independently after siramesine and lapatinib treatment in breast cancer cells

<div><p>Ferroptosis is a cell death pathway characterized by iron-dependent accumulation of reactive oxygen species (ROS) within the cell. The combination of siramesine, a lysosome disruptor, and lapatinib, a dual tyrosine kinase inhibitor, has been shown to synergistically induce cell death in breast cancer cells mediated by ferroptosis. These treatments also induce autophagy but its role in this synergistic cell death is unclear. In this study, we determined that siramesine and lapatinib initially induced ferroptosis but changes to an autophagy induced cell death after 24 hours. Furthermore, we found that intracellular iron level increased in a time dependent manner following treatment accompanied by an increase in ROS. Using the iron chelator deferoxamine (DFO) or the ROS scavenger alpha-tocopherol decreased both autophagy flux and cell death. We further discovered that decreased expression of the iron storage protein, ferritin was partially dependent upon autophagy degradation. In contrast, the expression of transferrin, which is responsible for the transport of iron into cells, is increased following treatment with lapatinib alone or in combination with siramesine. This indicates that ferroptosis and autophagy induced cell death occur independently but both are mediated by iron dependent ROS generation in breast cancer cells.</p></div

Autophagy flux increases following treatment of cells with siramesine and lapatinib.

<p>(A, B) Western blot determination of autophagy protein LC3-II in the absence and presence of NH₄Cl when MDA MB 231 cells were treated with siramesine and lapatinib for 4and 24 hours. Actin (beta-actin) was used as a loading control (and same hereafter). (C, D) Autophagy was measured by quantifying the number of puncta of a fusion protein of red fluorescent protein LC3 (mRFP-LC3) per cell in MDA MB 231 cells. (E) Western blot determination of autophagy protein LC3-II when SKBR3 cells were treated with siramesine and lapatinib for 4 and 24 hours. (F) Autophagy was measured by quantifying the number of puncta of a fusion protein of red fluorescent protein LC3 (mRFP-LC3) per cell in SKBR3 cells. *p<0.05; **p<0.01.</p

Autophagy inhibitors increase cell death at an early time of siramesine and lapatinib treatment but inhibit cell death at a later time.

<p><b>(A)</b> Inhibition of autophagy by autophagy inhibitors 3-methyladenine (3-MA, 2 mM, and same hereafter) and spautin-1 (3 microM, and same hereafter) under siramesine and lapatinib treatment as demonstrated by LC3-II western blot in MDA MB 231 cells. <b>(B)</b> The effects of 3-MA on cell death under siramesine and lapatinib treatment in MDA MB 231 cells for 4 and 24 hours. <b>(C)</b> The effects of spautin-1 on cell death under siramesine and lapatinib treatment in MDA MB 231 for 4 and 24 hours. Cell death was quantified by flow cytometry as described in the Materials and Methods section (and same hereafter). Before treatment with siramesine and lapatinib, cells were pretreated with 3-MA or spautin-1 for 1 hour (and same hereafter). (D) Inhibition of autophagy by autophagy inhibitors 3-methyladenine (3-MA, 2 mM) and spautin-1 (3 microM) under siramesine and lapatinib treatment as demonstrated by LC3-II western blot in SKBR3 cells. (E) The effects of 3-MA on cell death under siramesine and lapatinib treatment in SKBR3 cells for 4 and 24 hours. These results were representative of three independent experiments (n = 3). *p<0.05; **p<0.01.</p

Autophagy promotes ferritin degradation following siramesine and lapatinib treatment in MDA MB 231 cells.

<p>(A) MDA MB 231 cells were lysed after treatment with DMSO (D), siramesine (S), lapatinib (L) and siramesine and lapatinib (S + L) for 4 and 24 hour. Western blot determination of iron-related proteins ferritin (FTH1) transferrin, transferrin receptor (CD71), ferroportin (FPN) was performed. Actin was used as a loading control. (B) The effects of 3-MA (2mM) and MG132 (1 microM) on expression level of FTH1 following siramesine and lapatinib treatment in MDA MB 231cells for 24 hours respectively. Before treatment under siramesine and lapatinib, cells were pretreated with 3mM and MG132 for 1hour. (C) Effects of knockdown of <i>Atg5</i> on siramesine and lapatinib-induced FTH degradation at 24 hour in MDA MB 231 cells.</p

Knockdown of autophagy genes increases cell death during early treatment times with siramesine and lapatinib but inhibits cell death at a later times.

<p>(A) Knockdown of autophagy genes <i>Atg5</i> and <i>Becn1</i> by siRNAs as demonstrated by western blot of Atg5 and Beclin-1, respectively, in MDA MB 231 cells. The protein level of Atg5 was represented by the Atg5-Atg12 complex since the conjugation between these two proteins is an essential step during a functional autophagy process (and same hereafter). (B) Inhibition of autophagy by knockdown of <i>Atg5</i> as demonstrated by western blot of LC3I/LC3-II in MDA MB 231 cells. <b>(</b>C, D) Effects of knockdown of <i>Atg5</i> or <i>Becn1</i> on siramesine and lapatinib-induced cell death at 4 and 24 hours in MDA MB 231 cells. These results were representative of three independent experiments (n = 3), *p<0.05.</p