tbuckley/cabot-search huggingface dataset:
The Unrecognized Prevalence of Primary Aldosteronism
Authors: Jenifer M. Brown, Mohammed Siddiqui, David A. Calhoun, Robert M. Carey, Paul N. Hopkins, Gordon H. Williams, Anand Vaidya
Journal: Annals of Internal Medicine (2020)

Primary aldosteronism is a nonsuppressible renin-independent aldosterone production that causes hypertension and cardiovascular disease.To characterize the prevalence of nonsuppressible renin-independent aldosterone production, as well as biochemically overt primary aldosteronism, in relation to blood pressure.Cross-sectional study.4 U.S. academic medical centers.Participants with normotension (n = 289), stage 1 hypertension (n = 115), stage 2 hypertension (n = 203), and resistant hypertension (n = 408).Participants completed an oral sodium suppression test, regardless of aldosterone or renin levels, as a confirmatory diagnostic for primary aldosteronism and to quantify the magnitude of renin-independent aldosterone production. Urinary aldosterone was measured in participants in high sodium balance with suppressed renin activity. Biochemically overt primary aldosteronism was diagnosed when urinary aldosterone levels were higher than 12 μg/24 h.Every blood pressure category had a continuum of renin-independent aldosterone production, where greater severity of production was associated with higher blood pressure, kaliuresis, and lower serum potassium levels. Mean adjusted levels of urinary aldosterone were 6.5 μg/24 h (95% CI, 5.2 to 7.7 μg/24 h) in normotension, 7.3 μg/24 h (CI, 5.6 to 8.9 μg/24 h) in stage 1 hypertension, 9.5 μg/24 h (CI, 8.2 to 10.8 μg/24 h) in stage 2 hypertension, and 14.6 μg/24 h (CI, 12.9 to 16.2 μg/24 h) in resistant hypertension; corresponding adjusted prevalence estimates for biochemically overt primary aldosteronism were 11.3% (CI, 5.9% to 16.8%), 15.7% (CI, 8.6% to 22.9%), 21.6% (CI, 16.1% to 27.0%), and 22.0% (CI, 17.2% to 26.8%). The aldosterone-renin ratio had poor sensitivity and negative predictive value for detecting biochemically overt primary aldosteronism.Prevalence estimates rely on arbitrary and conventional thresholds, and the study population may not represent nationwide demographics.The prevalence of primary aldosteronism is high and largely unrecognized. Beyond this categorical definition of primary aldosteronism, there is a prevalent continuum of renin-independent aldosterone production that parallels the severity of hypertension. These findings redefine the primary aldosteronism syndrome and implicate it in the pathogenesis of "essential" hypertension.National Institutes of Health.
Mesoporous silica nanoparticles inflame tumors to overcome anti-PD-1 resistance through TLR4-NFκB axis
Authors: Mayu Sun, Pengfei Gu, Yang Yang, Luodan Yu, Zheshun Jiang, Jingquan Li, Yingying Le, Yu Chen, Qian Ba, Hui Wang
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background The clinical benefits of antiprogrammed cell death protein 1 (PD-1) therapy are compromised by resistance in immunologically cold tumors. Convergence of immunotherapy and bioengineering is potential to overcome the resistance. Mesoporous silica nanoparticles (MSNs) are considered the most promising inorganic biological nanomaterials for clinical transformation, however, the fundamental influence of MSNs on immunotherapy is unclear. In this study, we aimed to investigate the role of MSNs in tumor resensitization and explore the feasibility of MSNs combined with anti-PD-1 in cancer therapy. Methods Intrinsic and acquired resistant tumors, as well as spontaneous and secondary tumor recurrence models, were used to evaluate the influence of MSNs and the synergistical effect with anti-PD-1 therapy. The roles of CD8 + cytotoxic T-lymphocytes (CTLs) and macrophages were assessed in Rag-1 -/- mice, ovalbumin/OT-1 TCR transgenic T-cell system, and other blocking mice models. Mechanistic studies were processed by transcriptomics analysis and conducted in primary cells, in vitro coculture systems, and Toll-like receptor 4 (TLR4) knockout mice. Results Both granular and rod-shaped MSNs efficiently overcame tumor resistance with dependence on diameter and aspect ratio. Only once injection of MSNs in prior to anti-PD-1 markedly improved the treatment efficacy, protective immunity, and prognosis. MSNs per se boosted infiltration of CTLs as the early event (days 2–3); and synergistically with anti-PD-1 therapy, MSNs rapidly established a T cell-inflamed microenvironment with abundant high-activated (interferon-γ/tumor necrosis factor-α/Perforin/GranzymeB) and low-exhausted (PD-1/lymphocyte-activation gene 3 (LAG-3)/T-cell immunoglobulin and mucin-domain containing-3 (TIM-3)) CTLs. Chemokines Ccl5/Cxcl9/Cxcl10, which were produced predominantly by macrophages, promoted MSNs-induced CTLs infiltration. MSNs led to high Ccl5/Cxcl9/Cxcl10 production in vitro and in mice through regulating TLR4-NFκB axis. Blocking TLR4-NFκB axis in macrophages or CTLs infiltration abrogated MSNs-induced resensitization to anti-PD-1 therapy. Conclusions MSNs efficiently and rapidly inflame immunologically cold tumors and resensitize them to anti-PD-1 therapy through TLR4-NFκB-Ccl5/Cxcl9/Cxcl10 axis. MSNs-based theranostic agents can serve as sensitizers for patients with resistant tumors to improve immunotherapy.
Anti-PD-1 monotherapy in patients with malignant mesothelioma: A retrospective single institution experience.
Authors: Atif Ali, Hudson Holmes, Hannah Wang, Lyndsey L. Prather, Anita Lyn Sabichi, Bryan M. Burt, R. Taylor Ripley, Hyun-Sung Lee, Daniel Ying Wang
Journal: Journal of Clinical Oncology (2021)

e20564 Background: Malignant mesothelioma (MM) patients historically have poor outcomes, but immune checkpoint inhibitors have shown promising results in certain patients. We aimed to retrospectively assess efficacy and safety with use of anti-PD-1 monotherapy (aPD-1 Tx) in patients with MM at our institution from Dec 2015 to Dec 2020. Methods: We identified patients with MM treated with nivolumab or pembrolizumab. Clinical details including demographics, efficacy, and toxicity were collected. Efficacy was characterized based on overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Survival curves were generated using the Kaplan-Meier method, and intergroup comparisons were performed with the log-rank test. Univariable Cox regression analysis was used to determine whether variables were associated with survival. Results: We identified 61 patients treated with aPD-1 Tx for MM. Majority of patients (90%) had malignant pleural mesothelioma. Forty-two (69%) patients were male. The median age of initiation was 65 years (range: 30-84). Most patients (66%) had an ECOG performance status (PS) of 0-1. Known asbestos exposure was noted in 19 (31%) patients. Most patients had received prior chemotherapy (74%) and treated with nivolumab (89%). Only 66% of patients with known PD-L1 had positive expression ( &gt; = 1%). There were 43 (70%) patients with epithelioid histology. Median follow-up was 22.2 months. ORR was 33% with stable disease in 25% of patients. In first-line aPD-1 Tx, ORR was 50%. PFS and OS at 12 months were 26% and 65%, respectively. The median PFS and OS were 5.1 and 15.6 months, respectively. PD-L1 positivity was not associated with improved PFS or OS. Univariable analysis demonstrated that ECOG PS 0-1 had significantly better OS with hazard ratio (HR) 0.40 (95% CI 0.20 – 0.83; p = 0.01). Immune-related adverse events (irAE) were seen in 33% of patients with 13 patients with grade 3 or higher (nephritis, pneumonitis, arthritis, leukocytosis, dermatitis, colitis, type 1 diabetes mellitus, tongue angioedema, and thrombocytopenia). One patient had grade 5 irAE due to severe thrombocytopenia. Patients who developed an irAE had significantly improved median OS (32.1 vs 12.1 months, p = 0.01). Conclusions: Anti-PD-1 monotherapy showed clinical efficacy and safety in malignant mesothelioma as both a first-line treatment and in pre-treated patients based on our real-world experience. The development of irAE may predict benefit, although fatal side effects can occur.
Accuracy of depression score: a positive HADS score may only be the tip of the iceberg
Authors: Julian Ahmed, Jessica A Eccles
Journal: BMJ (2021)

<h3>Abstract</h3> Osteoporosis is a common bone and metabolic disease that is characterized by bone density loss and microstructural degeneration. Human bone marrow-derived mesenchymal stem cells (hMSCs) are multipotent progenitor cells with the potential to differentiate into various cell types, including osteoblasts, chondrocytes, and adipocytes, which have been utilized extensively in the field of bone tissue engineering and cell-based therapy. Although fluid shear stress plays an important role in bone osteogenic differentiation, the cellular and molecular mechanisms underlying this effect remain poorly understood. Here, an LNA/DNA nanobiosensor was exploited to monitor mRNA gene expression of hMSCs that were exposed to physiologically relevant fluid shear stress to examine the regulatory role of Notch signaling during osteogenic differentiation. First, the effects of fluid shear stress on cell viability, proliferation, morphology, and osteogenic differentiation were investigated and compared. Our results showed shear stress modulates hMSCs morphology and osteogenic differentiation depending on the applied shear and duration. By incorporating this LNA/DNA nanobiosensor and alkaline phosphatase (ALP) staining, we further investigated the role of Notch signaling in regulating osteogenic differentiation. Pharmacological treatment is applied to disrupt Notch signaling to investigate the mechanisms that govern shear stress induced osteogenic differentiation. Our experimental results provide convincing evidence supporting that physiologically relevant shear stress regulates osteogenic differentiation through Notch signaling. Inhibition of Notch signaling mediates the effects of shear stress on osteogenic differentiation, with reduced ALP enzyme activity and decreased Dll4 mRNA expression. In conclusion, our results will add new information concerning osteogenic differentiation of hMSCs under shear stress and the regulatory role of Notch signaling. Further studies may elucidate the mechanisms underlying the mechanosensitive role of Notch signaling in stem cell differentiation.
Label-free imaging of human brain tissue at subcellular resolution for potential rapid intra-operative assessment of glioma surgery
Authors: Defu Chen, David W Nauen, Hyeon-Cheol Park, Dawei Li, Wu Yuan, Ang Li, Honghua Guan, Carmen Kut, Kaisorn L Chaichana, Chetan Bettegowda, Alfredo Quiñones-Hinojosa, Xingde Li
Journal: Theranostics (2021)

Background: Frozen section and smear preparation are the current standard for intraoperative histopathology during cancer surgery. However, these methods are time-consuming and subject to limited sampling. Multiphoton microscopy (MPM) is a high-resolution non-destructive imaging technique capable of optical sectioning in real time with subcellular resolution. In this report, we systematically investigated the feasibility and translation potential of MPM for rapid histopathological assessment of label- and processing-free surgical specimens. Methods: We employed a customized MPM platform to capture architectural and cytological features of biological tissues based on two-photon excited NADH and FAD autofluorescence and second harmonic generation from collagen. Infiltrating glioma, an aggressive disease that requires subcellular resolution for definitive characterization during surgery, was chosen as an example for this validation study. MPM images were collected from resected brain specimens of 19 patients and correlated with histopathology. Deep learning was introduced to assist with image feature recognition. Results: MPM robustly captures diagnostic features of glioma including increased cellularity, cellular and nuclear pleomorphism, microvascular proliferation, necrosis, and collagen deposition. Preliminary application of deep learning to MPM images achieves high accuracy in distinguishing gray from white matter and cancer from non-cancer. We also demonstrate the ability to obtain such images from intact brain tissue with a multiphoton endomicroscope for intraoperative application. Conclusion: Multiphoton imaging correlates well with histopathology and is a promising tool for characterization of cancer and delineation of infiltration within seconds during brain surgery.
Association of blood inflammatory/immune markers with outcomes in (neo)adjuvant breast cancer: A large single institutional study.
Authors: Hanis Mariyah Mohd Ishak, Phyu Nitar, Fuh-Yong Wong, Grace Kusumawidjaja, Lester Leong, Yirong Sim, Mohamed Hakim, Wen Yee Chay, Ru Xin Wong
Journal: Journal of Clinical Oncology (2021)

e12540 Background: An inflammatory state in various cancer populations may correlate with mortality. Neutrophil-lymphocyte ratio is a surrogate marker of an inflammatory state. A recent meta-analysis showed the predictive value of neutrophil to lymphocyte ratio in breast cancers, but series are generally small. We aim to study the associations of Neutrophil-Lymphocyte Ratio (NLR) with outcomes in stage I–III breast cancer in patients who received neo-adjuvant chemotherapy (NAC) or upfront surgery. The endpoints are overall survival (OS) and breast cancer-specific survival (BCSS). In the NAC group, association with pathological complete response (PCR) rate was also studied. Methods: Data of patients with stage I–III breast cancer treated from 2011–2017 were extracted from a prospectively maintained registry and merged with full blood count (FBC) results from a clinical management software. FBC were performed within one-month pre-chemo for NAC patients and one-month pre-surgery for upfront surgery patients. PCR is defined as stage ypT0/isN0M0. OS is defined as death from any cancer from diagnosis date, censored at last follow-up. BCSS is defined as death from breast cancer from diagnosis date, censored at last follow up or death from any cause. The NLR values with the maximal Youden’s indexes calculated for each outcome were used as cut-off, logistic regression was used to determine PCR association and cox regression and log rank for OS and BCSS. Results: A total of 2,479 eligible patients were analysed. Overall, treatment compliance was high (87.6% of ER+ patients received endocrine treatment, and 94.1% of HER2+ NAC patients had targeted therapy). In the NAC group (n = 357), 23% achieved PCR. NLR did not show any statistically significant association with PCR. In unadjusted analysis, high NLR was associated with worse BCSS (log-rank p = 0.003 figure 1). In multivariable analysis (MVA), only triple negative and HER-enriched cancers were significantly associated with PCR. In NAC patients, NLR was associated with OS (cut-off 2.63; OR 1.6, p = 0.077) and BCSS (cut-off 3.58; OR 2.2, p = 0.003) in MVA. In patients treated with up-front surgery (n = 2122), unadjusted analysis showed high NLR was associated with worse BCSS (OR 1.55, p = 0.05; figure 2). In MVA, NLR (cut-off 2.13, OR 1.57, p = 0.005), triple negative histology, stage and age were significant predictors of OS. BCSS was not significantly associated with NLR (OR 1.38 95%CI 0.90-2.12 p = 0.145). Conclusions: Using a large cohort of patients, a high NLR was found to be associated with worse outcomes in NAC and upfront surgery breast cancer patients.
Reducing the global burden of sepsis: a positive legacy for the COVID-19 pandemic?
Authors: K. Reinhart, M. M. Levy, Simon S. Finfer, F. Machado, L. Kaplan, J. Kesecioglu, A. Rhodes, R. Daniels, N. Kissoon, E. Nsutebu, L. A. Gorordo, I. Malik, A. Alhawsawi, M. Cecconi, E. Giamarellos, G. Martin, L. Schlapbach
Journal: Intensive Care Medicine (2021)
Assessment of Effectiveness of 1 Dose of BNT162b2 Vaccine for SARS-CoV-2 Infection 13 to 24 Days After Immunization
Authors: Gabriel Chodick, Lilac Tene, Tal Patalon, Sivan Gazit, Amir Ben Tov, Dani Cohen, Khitam Muhsen
Journal: JAMA Network Open (2021)

<h3>Importance</h3> The BNT162b2 vaccine showed high efficacy against COVID-19 in a phase III randomized clinical trial. A vaccine effectiveness evaluation in a real-world setting is needed. <h3>Objective</h3> To assess the short-term effectiveness of the first dose of the BNT162b2-vaccine against SARS-CoV-2 infection 13 to 24 days after immunization in a real-world setting. <h3>Design, Setting, and Participants</h3> This comparative effectiveness study used data from a 2.6 million-member state-mandated health care system in Israel. Participants included all individuals aged 16 years and older who received 1 dose of the BNT162b2 vaccine between December 19, 2020, and January 15, 2021. Data were analyzed in March 2021. <h3>Exposure</h3> Receipt of 1 dose of the BNT162b2 vaccine. <h3>Main Outcomes and Measures</h3> Information was collected regarding medical history and positive SARS-CoV-2 polymerase chain reaction test and COVID-19 symptoms from 1 day after first vaccine to January 17, 2021. Daily and cumulative infection rates in days 13 to 24 were compared with days 1 to 12 after the first dose using Kaplan-Meier survival analysis and generalized linear models. <h3>Results</h3> Data for 503 875 individuals (mean [SD] age, 59.7 [14.7] years; 263 228 [52.4%] women) were analyzed, of whom 351 897 had follow-up data for days 13 to 24. The cumulative incidence of SARS-CoV-2 infection was 2484 individuals (0.57%) during days 1 through 12 and 614 individuals (0.27%) in days 13 through 24. The weighted mean (SE) daily incidence of SARS-CoV-2 infection in days 1 through 12 was 43.41 (12.07) infections per 100 000 population and 21.08 (6.16) infections per 100 000 population in days 13 through 24, a relative risk reduction (RRR) of 51.4% (95% CI, 16.3%-71.8%). The decrease in incidence was evident from day 18 after the first dose. Similar RRRs were calculated in individuals aged 60 years or older (44.5%; 95% CI, 4.1%-67.9%), those younger than 60 years (50.2%; 95% CI, 14.1%-71.2%), women (50.0%; 95% CI, 13.5%-71.0%), and men (52.1%; 95% CI, 17.3%-72.2%). Findings were similar in subpopulations (eg, ultraorthodox Jewish: RRR, 53.5% [95% CI, 19.2%-73.2%]) and patients with various comorbidities (eg, cardiovascular diseases: RRR, 47.2% [95% CI, 7.8%-69.8%]). Vaccine effectiveness against symptomatic COVID-19 was 54.4% (95% CI, 21.4%-73.6%). <h3>Conclusions and Relevance</h3> In this comparative effectiveness study of a single dose of the BNT162b2 vaccine, results were comparable to that of the phase III randomized clinical trial.
OMIC-12. PREVALENCE AND SPECTRUM OF GERMLINE PATHOGENIC VARIANTS IN CANCER PREDISPOSITION GENES ACROSS THE CHILDREN’S BRAIN TUMOR NETWORK (CBTN)
Authors: Zalman Vaksman, Shelly McQuaid, Miriam Bornhorst, Yuankun Zhu, Allison Heath, Angela Waanders, Kristina Cole, Suzanne MacFarland, Sharon Diskin
Journal: Neuro-Oncology (2021)

Abstract Germline variants are known to contribute to the pathogenesis of specific central nervous system (CNS) tumor subtypes; however, a large pan-pediatric brain and nervous system cancer germline susceptibility study has not been performed. To define the prevalence and spectrum of pathogenic variants in known cancer predisposition genes (CPGs; n=200), we analyzed whole genome sequencing (WGS) data from 880 pediatric subjects across 19 different cancer types in the Children’s Brain Tumor Network (CTBN). Data were aligned using BWA. Variants were called using GATK and annotated with SnpEff and ANNOVAR. After quality control, variants with a minor allele frequency (MAF) &amp;lt; 0.1% in Gnomad 2.11 or ExAC were retained. Pathogenicity was assessed with American College of Medical Genetics (ACMG) guidelines using a lab-developed modification of ClinVar and InterVar. Automated pathogenic/likely pathogenic (P-LP) calls were manually reviewed by two cancer predisposition clinicians and a bioinformatician. Frequency of P-LP variants was assessed and gene burden testing was performed against Gnomad3.1 (without cancer samples) using Fisher’s exact test with Bonferroni adjustment. We observed 214 P-LP variants involving 190 unique individuals (21.6% of cohort). As expected, the most frequent variants were observed in NF1, NF2, and TP53(n=40 variants in 21% of individuals). ATM, TSC2 and CHEK2 variants (n=23) were observed in another 12% of individuals. An increased burden of P-LP variants was observed for 5 of these 6 genes (p = 1.7x10-25 to 1.4x10-2, CHEK2 p=5.5x10-2). We also identified 5 variants in BRCA2 (3 in high-grade glioma), 7 in REQC helicases (BLM, WRN, REQL4), and 16 variants in Fanconi anemia genes. Overall, cases harbored increased burden in P-LP variants in CPG genes (p=8.8x-18) and the subset of DNA repair genes (p=4.7x10-4). In conclusion we confirmed the association of variants in established predisposition genes while potentially identifying novel variants and genes associated in CNS tumors.
Characterizing safety and efficacy in ovarian cancer patients with thromboembolism treated with rivaroxaban.
Authors: Christine G. Kohn, Jonathan T. Caranfa, Molly Brewer, Meghana Singh, Craig I. Coleman, Olivia S. Costa
Journal: Journal of Clinical Oncology (2021)

e18720 Background: There is a paucity of real-world data regarding rates of recurrent venous thromboembolism (VTE), major bleeding and all-cause mortality among ovarian cancer patients with thrombosis treated with direct oral anticoagulants (DOACs) currently available. We sought to evaluate the effectiveness and safety of rivaroxaban versus low molecular-weight heparin (LMWH) for cancer-associated thrombosis (CAT) treatment in patients with ovarian cancer. Methods: We utilized US Surveillance, Epidemiology and End Results-Medicare–linked data from 2013-2016 to identify adults with active ovarian cancer, undergoing hospitalization/emergency department admission for CAT and prescribed rivaroxaban or LMWH for outpatient anticoagulation. Rivaroxaban and LMWH cohorts were balanced using propensity score overlap weighting . Outcomes included the composite of recurrent thrombosis or major bleeding, each outcome separately and mortality at six-months using an intention-to-treat approach. On-treatment analysis after 12-months was also performed. Hazard ratios (HRs) with 95% confidence intervals using overlap weighted cox regression were reported. Results: We included 33 rivaroxaban and 92 LMWH-managed CAT patients. In each cohort, mean age was 73, 79.5% of patients were white, 46.9% had a history of ≥ stage 3 chronic kidney disease (CKD), two-thirds had metastatic disease at the time of VTE, and 32.6% had a prior VTE. Patients were diagnosed with ovarian cancer an average of 1.40 years prior to the index VTE event and 45.8% had a pulmonary embolism (with or without DVT) as the index event. Our analysis did not detect a significant difference in outcomes with rivaroxaban versus LMWH at six-months (Table). On-treatment analysis at 12-months showed similar results. Conclusions: Rivaroxaban may be a reasonable alternative to LMWH for CAT patients with ovarian cancer. Large observational studies are needed to confirm these results.[Table: see text]