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Osimertinib, a mutant-specific third generation EGFR TKI, is emerging as the preferred first-line therapy for EGFR mutant lung cancer, yet resistance inevitably develops in patients. We modeled acquired resistance to osimertinib in transgenic mouse models of EGFR L858R-induced lung adenocarcinoma and found that it is mediated largely through secondary mutations in EGFR - either C797S or L718V/Q. Analysis of circulating free DNA data from patients revealed that L718Q/V mutations almost always occur in the context of an L858R driver mutation. Therapeutic testing in mice revealed that both erlotinib and afatinib caused regression of osimertinib-resistant C797S-containing tumors, whereas only afatinib was effective on L718Q mutant tumors. Combination first-line osimertinib plus erlotinib treatment prevented the emergence of secondary mutations in EGFR. These findings highlight how knowledge of the specific characteristics of resistance mutations are important for determining potential subsequent treatment approaches and suggest strategies to overcome or prevent osimertinib resistance in vivo. Copyright ©2020, American Association for Cancer Research.Multiple myeloma (MM) is an incurable refractory hematological malignancy arising from plasma cells in the bone marrow. Here we investigated miR-26a function in MM and tested single-wall carbon nanotube delivery of miR-26a in vitro and in vivo. miR-26a was downregulated in patient MM cells compared with plasma cells from healthy donors. miR-26a overexpression inhibited proliferation and migration and induced apoptosis in MM cell lines. To identify the targets of miR-26a, RPMI8226-V-miR-26-GFP and RPMI8226-V-GFP cells were cultured using Stable isotope labeling by amino acids in cell culture (SILAC) medium followed by mass spectrometry analysis. In MM cells overexpressing miR-26a, CD38 protein was downregulated and subsequently confirmed to be a direct target of miR-26a. Depletion of CD38 in MM cells duplicated the MM inhibition observed with exogenous expression of miR-26a, whereas restoration of CD38 overcame the inhibition of miR-26a in MM cells. In a human MM xenograft mouse model, overexpression of miR-26a inhibited CD38 expression, provoked cell apoptosis, and inhibited cell proliferation. Daratumumab is the first CD38 antibody drug for monotherapy and combination therapy for MM patients, but eventually resistance develops. In MM cells, CD38 remained at low level during daratumumab treatment, but a high quality response is sustained. In daratumumab-resistant MM cells, CD38 expression was completely restored but failed to correlate with daratumumab-induced cell death. Therefore, a therapeutic strategy to confer selection pressure to maintain low CD38 expression in MM cells may have clinical benefit. Copyright ©2020, American Association for Cancer Research.Quiescent cancer cells are believed to cause cancer progression after chemotherapy through unknown mechanisms. We show here that human non-small-cell lung cancer (NSCLC) cell line-derived, quiescent-like, slow-cycling cancer cells (SCC) and residual patient-derived xenograft (PDX) tumors after chemotherapy experience activating transcription factor 6 (ATF6)-mediated upregulation of various cytokines, which acts in a paracrine manner to recruit fibroblasts. Cancer-associated fibroblasts (CAF) underwent transcriptional upregulation of COX2 and type I collagen (Col-I), which subsequently triggered a slow-to-active-cycling switch in SCC through prostaglandin E2 (PGE2)- and integrin/Src-mediated signaling pathways, leading to cancer progression. Both antagonism of ATF6 and cotargeting of Src/COX2 effectively suppressed cytokine production and slow-to-active cell cycling transition in SCC, withholding cancer progression. Expression of COX2 and Col-I and activation of Src were observed in NSCLC patients who progressed while receiving chemotherapy. Public data analysis revealed significant association between COL1A1 and SRC expression and NSCLC relapse. Overall, these findings indicate that a proinflammatory niche created by the interplay between SCC and CAF triggers tumor progression. Copyright ©2020, American Association for Cancer Research.The extracellular matrix (ECM) surrounding cells is indispensable for regulating their behavior. The dynamics of ECM signaling are tightly controlled throughout growth and development. During tissue remodeling, matricellular proteins (MCPs) are secreted into the ECM. These factors do not serve classical structural roles, but rather regulate matrix proteins and cell-matrix interactions to influence normal cellular functions. In the tumor microenvironment, it is becoming increasingly clear that aberrantly expressed MCPs can support multiple hallmarks of carcinogenesis by interacting with various cellular components that are coupled to an array of downstream signals. Moreover, MCPs also reorganize the biomechanical properties of the ECM to accommodate metastasis and tumor colonization. This realization is stimulating new research on MCPs as reliable and accessible biomarkers in cancer, as well as effective and selective therapeutic targets. Copyright ©2020, American Association for Cancer Research.Estrogen receptor α (ERα) is a key transcriptional regulator in the majority of breast cancers. ERα-positive patients are frequently treated with tamoxifen, but resistance is common. In this study, we refined a previously identified 111-gene outcome prediction-classifier, revealing FEN1 as the strongest determining factor in ERα-positive patient prognostication. FEN1 levels were predictive of outcome in tamoxifen-treated patients, and FEN1played a causal role in ERα-driven cell growth. FEN1 impacted the transcriptional-activity of ERα by facilitating coactivator recruitment to the ERα transcriptional complex. FEN1 blockade induced proteasome-mediated degradation of activated ERα, resulting in loss of ERα-driven gene expression and eradicated tumor cell proliferation. Finally, a high-throughput 465,195 compound screen identified a novel FEN1 inhibitor, which effectively blocked ERα-function and inhibited proliferation of tamoxifen-resistant cell lines as well as ex-vivo cultured ERα-positive breast tumors. Collectively, these results provide therapeutic proof-of-principle for FEN1 blockade in tamoxifen-resistant breast cancer. Copyright ©2020, American Association for Cancer Research.PARP inhibitor monotherapies effectively treat breast, ovary, prostate, and pancreatic cancer patients with BRCA1 mutations, but not the more frequent BRCA-wildtype cancers. Searching for strategies that would extend the use of PARP inhibitors to BRCA1-proficient tumors, we report here that the stability of BRCA1 protein following ionizing radiation (IR) is maintained by post-phosphorylational prolyl-isomerization adjacent to Ser1191 of BRCA1, which is catalyzed by prolyl-isomerase Pin1. Extinction of Pin1 decreased homologous recombination (HR) to the level of BRCA1-deficient cells. Pin1 stabilized BRCA1 by preventing ubiquitination of BRCA1 at Lys1037. Loss of Pin1 or introduction of a BRCA1 mutant refractory to Pin1 binding decreased the ability of BRCA1 to localize to repair foci and augmented IR-induced DNA damage. In vitro growth of HR-proficient breast, prostate, and pancreatic cancer cells was modestly repressed by Olaparib or Pin1 inhibition using all-trans retinoic acid (ATRA), while combination treatment resulted in near-complete block of cell proliferation. In MDA-MB 231 xenografts and triple-negative breast cancer PDX, either loss of Pin1 or ATRA treatment reduced BRCA1 expression and sensitized breast tumors to Olaparib. Together our study reveals that Pin1 inhibition with widely used ATRA acts as an effective HR disrupter that sensitizes BRCA1-proficient tumors to PARP inhibition. Copyright ©2020, American Association for Cancer Research.The current US opioid health-related crisis underscores the importance for perioperative physicians to optimize various approaches to pain management. [https://www.selleckchem.com/products/bzatp-triethylammonium-salt.html selleck kinase inhibitor] Multimodal techniques and enhanced recovery after surgery (ERAS) protocols are frequently cited as the most effective strategies for improving the experience of pain and reducing opioid exposure. Complementary medicine (CM) techniques, while frequently shown to be effective at reducing opioid and other pharmacologic agent use, are rarely discussed as part of these multimodal strategies. In general, CM therapies are low-cost with minimal associated risk, making them an ideal choice for incorporation into ERAS and other opioid-sparing protocols. In this Daring Discourse, we discuss the benefits and challenges of incorporating CM therapy into anesthetic practice. We hope that anesthesiologists can become more familiar with the current evidence regarding perioperative CM therapy, and begin incorporating these therapies as part of their comprehensive multimodal approach to perioperative pain management. © American Society of Regional Anesthesia &amp; Pain Medicine 2020. No commercial re-use. See rights and permissions. Published by BMJ.BACKGROUND In Canada, increasing numbers of women, especially First Nations women, are affected by diabetes during pregnancy, which is a major risk factor for adverse maternal and neonatal outcomes. The aim of this study was to examine temporal trends in pregnancy outcomes and use of health care services in a population-based cohort of First Nations women compared to other women in Ontario according to diabetes status during pregnancy. METHODS Using health administrative databases, we created annual cohorts of pregnant women from 2002/03 to 2014/15 and identified those with preexisting diabetes and gestational diabetes. We used the Indian Register to identify First Nations women. We estimated rates of adverse maternal and infant outcomes, and measures of use of health care services in each population. RESULTS There were 1 671 337 deliveries among 1 065 950 women during the study period; of these deliveries, 31 417 (1.9%) were in First Nations women, and 1 639 920 (98.1%) were in other women. First Nations womINTERPRETATION Our results confirm disparities in maternal and neonatal outcomes between First Nations women and other women in Ontario. Access to primary care for pregnant women seemed adequate, but access to specialized care, especially for women with preexisting diabetes, needs to improve. Copyright 2020, Joule Inc. or its licensors.BACKGROUND The use of fertility treatments has been growing over the past decade, but these treatments are not without risk. We aimed to quantify the risk of preterm birth associated with the use of ovarian stimulators (OS) and assisted reproductive technologies (ART) overall and by type of fertility treatment. METHODS We conducted a case-control analysis of data from the Quebec Pregnancy Cohort. We included singleton pregnancies ending in a live birth during the time when Quebec operated a universal reimbursement program for assisted reproduction (2010-2015). Fertility treatments were defined dichotomously, and pregnancies resulting from spontaneous conception were used as the reference. We categorized fertility treatments into subgroups ovarian stimulators alone, ART alone and OS and ART combined. Preterm birth was defined as birth before 37 weeks' gestation. We estimated odds ratios (ORs) for the association between type of assisted reproduction and preterm birth using generalized estimating equation models and adjusted ORs for potential confounders.