New Bone Cell Type Identified as Driver of Drug Resistance in Multiple Myeloma: The Bone Marrow Adipocyte

Multiple myeloma (MM) is a hematological malignancy that is characterized by clonal proliferation of transformed plasma cells within the bone marrow (BM) and severe bone disease. Although MM cells are initially sensitive to many therapies, patients eventually relapse with refractory disease. Because MM cells show a dependency on the BM microenvironment for survival and proliferation, and BM adipocytes (BMAs) demonstrate a unique, endocrine signaling capacity and lipid composition, it is likely that there is cross-talk between MM cells and BMAs that leads to tumor support. Unlike the influences of osteoblasts and osteoclasts, the effect of BMAs on MM cells is poorly understood and few studies have investigated the relationship between bone marrow adipose tissue (BMAT) and cancer. We predict there to be a strong link between MAT and MM, as obesity is a risk factor for MM and also correlates with increased MAT in humans. Moreover, MAT has been shown to support other tumors and correlates with bone diseases such as osteoporosis, anorexia, and aging. Thus, we explored here the novel hypothesis that BMAs induce drug resistance in MM cells through direct cell-cell contact signaling and/or secreted signaling molecules

Inhibiting Fatty Acid Binding Protein Family Members Decreases Multiple Myeloma Cell Proliferation Through Effecting the myc Pathway

FABP inhibition leads to increased survival of myeloma bearing mice and decreased cell growth by inhibiting MYC signaling.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1016/thumbnail.jp

Investigation of the relationship between obesity, weight cycling, and tumor progression in murine myeloma models

We investigated this relationship in two murine myeloma models with a high fat diet (HFD) to induce obesity, and a diet cycling (DC) regimen to model weight cycling.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1025/thumbnail.jp

Multiple myeloma cells Graphs and Figures inhibit adipogenesis, increase senescencerelated and inflammatory gene transcript expression, and alter metabolism in preadipocytes

Myeloma cells alter metabolism & induce senescence in adipocyte-lineage cells, suggesting that senescence-associated proteins are involved in multiple myeloma.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1032/thumbnail.jp

Generation of a homozygous and a heterozygous SNCA gene knockout human-induced pluripotent stem cell line by CRISPR/Cas9 mediated allele-specific tuning of SNCA expression

Aggregation of alpha-synuclein (aSyn) is closely linked to Parkinson's disease, probably due to the loss of physiological functions and/or gain of toxic functions of aggregated aSyn. Significant efforts have been made elucidating the physiological structure and function of aSyn, however, with limited success thus far in human-derived cells, partly because of restricted resources. Here, we developed two human-induced pluripotent stem cell lines using CRISPR/Cas9-mediated allele-specific frame-shift deletion of the aSyn encoding gene SNCA, resulting in homo- and heterozygous SNCA knockout. The generated cell lines are promising cellular tools for studying aSyn dosage-dependent functions and structural alterations in human neural cells

Common concerns, barriers to care, and the lived experience of individuals with hepatitis B: a qualitative study.

BACKGROUND: An estimated between 257 and 292 million people live with chronic HBV globally. While much is known about the causes, and epidemiology of HBV, little is understood about the quality of life and impact of HBV on those living with the infection. METHODS: A random sample of HBV-related email queries sent to the Hepatitis B Foundation, a U.S.-based non-profit organization, over a 12-month period in 2018-2019 were retrieved, tabulated, and analyzed qualitatively to highlight information needs and explore the experiences of people living with HBV and their families and loved ones. Codebook development was informed by the literature and through line-by-line reading of a sub-sample of queries. Data analysis was facilitated by NVivo12 software. Data were coded independently by two members of the research team and intercoder reliability was assessed to assure coding accuracy throughout the coding phase. RESULTS: A total of 338 queries from people around the globe were identified and analyzed. The analysis revealed three thematic groups: 1) health-specific challenges associated with diagnosis and treatment, 2) emotional needs related to experiences with HBV stigma, discrimination, fear, social isolation, and distress and 3) informational needs related to HBV prevention and transmission, and interpretation of laboratory tests. CONCLUSIONS: People living with HBV are in need of information to manage their disease and prevent its spread. Analysis of queries uncovered significant misconceptions about HBV transmission and treatment. Additionally, the emotional and psychological impact of an HBV diagnosis on those living with the infection is significant. There is a clear need for patient and community education to expand knowledge and awareness of HBV globally to achieve 2030 WHO HBV elimination goals

Need for high-resolution genetic analysis in iPSC: results and lessons from the ForIPS consortium

Genetic integrity of induced pluripotent stem cells (iPSCs) is essential for their validity as disease models and for potential therapeutic use. We describe the comprehensive analysis in the ForIPS consortium: an iPSC collection from donors with neurological diseases and healthy controls. Characterization included pluripotency confirmation, fingerprinting, conventional and molecular karyotyping in all lines. In the majority, somatic copy number variants (CNVs) were identified. A subset with available matched donor DNA was selected for comparative exome sequencing. We identified single nucleotide variants (SNVs) at different allelic frequencies in each clone with high variability in mutational load. Low frequencies of variants in parental fibroblasts highlight the importance of germline samples. Somatic variant number was independent from reprogramming, cell type and passage. Comparison with disease genes and prediction scores suggest biological relevance for some variants. We show that high-throughput sequencing has value beyond SNV detection and the requirement to individually evaluate each clone

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research