tbuckley/cabot-search huggingface dataset:
Quantifying and Interpreting Efficacy of Reduced-Intensity Chemotherapy With Oxaliplatin and Capecitabine on Cancer Control for Advanced Gastroesophageal Cancer Among an Older Population
Authors: Xuan Wang, Dae Hyun Kim, Lee-Jen Wei
Journal: JAMA Oncology (2021)

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Targeted design of a recombinant tracer for SPECT renal imaging
Authors: Pan Liu, Steven E Johnson, Xinfang Xie, Li Gao, Chad R Haney, Ming Zhao, Jing Jin
Journal: Theranostics (2021)

Rationale: A robust radiopharmaceutical has high uptake in the target and low retention in non-target tissues. However, traditional tracers for renal imaging that chemically chelate 99mTc are excreted through the renal route with transient resident time in the kidney. Following a rational design approach, we constructed a protein-based radiotracer, designated PBT-Fc, to sequentially bind tubular neonatal Fc-receptor and subsequently proximal tubular basement membrane for its targeted sequestration in kidney parenchyma. In this process, the tracer participates in physiologic glomerular filtration and tubular reabsorption while escaping lysosomal catabolism and urinary clearance. Methods: To specifically target renal receptors in navigating the urinary passage in the kidney, we produced a recombinant fusion protein with two separate functional parts: a polybasic PBT segment derived from human Vascular Endothelial Growth Factor and Fc segment of IgG1. The chimeric fusion of PBT-Fc was labeled with radionuclide 99mTc and tested in rodent models of kidney diseases. Planar scintigraphy and single-photon emission computerized tomography (SPECT) were performed to evaluate renal-specificity of the tracer. Results: When injected in mouse and rat, following a brief 10 - 15 min dynamic redistribution phase in circulation, ~ 95% of the [99mTc]-PBT-Fc signal was concentrated in the kidney and lasted for hours without urinary loss or surrounding tissue activities. Long-lasting tracer signals in the kidney cortex in conjunction with SPECT greatly augmented the image quality in detecting pathological lesions in a variety of disease models, including ischemic acute kidney injury, drug-induced renal toxicity, and chronic kidney disease from renin-angiotensin system (RAS) overactivation. Conclusion: Exclusive renal retention of the recombinant radiotracer greatly facilitated static-phase signal acquisition by SPECT and achieved submillimeter spatial resolution of kidney alternations in glomerular and tubular disease models.
In older adults, cannabinoid-based medicines increase adverse events compared with placebo
Authors: Jennifer Watt
Journal: Annals of Internal Medicine (2021)

Source Citation Velayudhan L, McGoohan K, Bhattacharyya S. Safety and tolerability of natural and synthetic cannabinoids in adults aged over 50 years: a systematic review and meta-analysis. PLoS Med. 2021;18:e1003524. 33780450
<i>QuickStats:</i> Percentage* of Children† Aged 3–17 Years Who Ever Received a Diagnosis of Attention-Deficit/Hyperactivity Disorder,§ by Sex and Age Group — National Health Interview Survey,¶ United States, 2019
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Age group (yrs) 15 10 5 Abbreviation: ADHD = attention-deficit/hyperactivity disorder.* With 95% confidence intervals indicated by error bars.† Children are defined here as children and adolescents (i.e., persons aged 3-17 years).§ Based on a response to the question, "Has a doctor or other health professional ever told you that (child's name) had Attention-Deficit/Hyperactivity Disorder or ADHD or Attention-Deficit Disorder or ADD?" ¶ Estimates are based on household interviews of a sample of the civilian, noninstitutionalized U.S. population.Overall, in 2019, 8.8% of children aged 3-17 years had ever received a diagnosis of ADHD.Boys (11.7%) were more likely than girls (5.7%) to receive a diagnosis of ADHD overall and within each age group.Among both boys and girls, the percentage of children who had ever received a diagnosis of ADHD increased with increasing age group.
Abstract 13210: Concomitant Septal Myectomy Can Improve Left Ventricular and Atrial Function Detected by 2d Speckle Echocardiography as Well as Long term Survival In Patients Undergoing Aortic Valve Replacement With Marked Ventricular Hypertrophy
Authors: Kishio Kuroda, Tomoko S Kato, Kenji Kuwaki, Kenta Uto, Saeko Yoshizawa, Toshio Nishikawa, Atsushi Amano
Journal: Circulation (2015)

Introduction: Patients requiring aortic valve replacement (AVR) frequently have left ventricular hypertrophy (LVH) /sigmoid septum, which causes persistent outflow obstruction (LVOTO) postoperatively. Surgical AVR enables such patients to undergo concomitant septal myomectomy. However, the effect on their postoperative myocardial function and long-term outcome is yet to be elucidated. Hypothesis: Concomitant myectomy may be beneficial for selected patients undergoing surgical AVR and possible LVOTO. Methods: Postoperative outcome and myocardial functional changes before and after surgery were assessed by conventional and 2D speckle tracking echocardiography in patients undergoing AVR and myectomy (Group M, n=16, male 21%, mean age 76.0 years) The results were compared with age/sex-matched controls who had marked LVH/LVOTO undergoing AVR alone (Group C, n=27). The relation between preoperative echo-derived local myocardial function and histology of resected myocardium in Group M was also investigated. Results: Preoperative echo parameters were not different between the groups. However, a decrease in LV E/E’ and an increase in the absolute value of basal septum longitudinal strain were seen postoperatively only in Group M (17.3±4.3 to 15.2±2.6, p=0.013, -9.3±4.5 to -12.8±3.8%, p=0.008, respectively). Peak LA strain values increased in both groups, but the improvement was more apparent in Group M (Group M; 20.6±5.3 to 28.3±7.1%, p=0.008, Group C; 21.9±5.9 to 26.9±6.0%, p=0.046,). Survival following surgery was better in Group M than Group C (30 days, 1 and 5 year, 100.0% vs 88.2%, 100.0% vs 75.6%, 100.0% vs 68.8%, respectively, p=0.028). Histology of resected myocardium in Group M showed remarkable fibrosis (mean 6.8%, range 1-17%) and thickness of endocardium (mean 1031μm, range 287-2505μm), and the degree of fibrotic area was significantly correlated with preoperative basal septum strain value (r2=0.6, p=0.041). Conclusions: Concomitant septal myectomy with AVR improves postoperative LV diastolic function, as well as LA function. Furthermore, it improved short and long-term survival as compared to those undergoing AVR alone. AVR with myectomy may be a beneficial option for patients with marked LVH /sigmoid septum-related LVOTO.
G protein-coupled receptor-effector macromolecular membrane assemblies (GEMMAs)
Authors: Sergi Ferré, Francisco Ciruela, Carmen W. Dessauer, Javier González-Maeso, Terence E. Hébert, Ralf Jockers, Diomedes E. Logothetis, Leonardo Pardo
Journal: Pharmacology & Therapeutics (2021)

G protein-coupled receptors (GPCRs) are the largest group of receptors involved in cellular signaling across the plasma membrane and a major class of drug targets. The canonical model for GPCR signaling involves three components — the GPCR, a heterotrimeric G protein and a proximal plasma membrane effector — that have been generally thought to be freely mobile molecules able to interact by 'collision coupling'. Here, we synthesize evidence that supports the existence of GPCR–effector macromolecular membrane assemblies (GEMMAs) comprised of specific GPCRs, G proteins, plasma membrane effector molecules and other associated transmembrane proteins that are pre-assembled prior to receptor activation by agonists, which then leads to subsequent rearrangement of the GEMMA components. The GEMMA concept offers an alternative and complementary model to the canonical collision-coupling model, allowing more efficient interactions between specific signaling components, as well as the integration of the concept of GPCR oligomerization as well as GPCR interactions with orphan receptors, truncated GPCRs and other membrane-localized GPCR-associated proteins. Collision-coupling and pre-assembled mechanisms are not exclusive and likely both operate in the cell, providing a spectrum of signaling modalities which explains the differential properties of a multitude of GPCRs in their different cellular environments. Here, we explore the unique pharmacological characteristics of individual GEMMAs, which could provide new opportunities to therapeutically modulate GPCR signaling.
Aberrant Extrafollicular B Cells, Immune Dysfunction, Myeloid Inflammation, and MyD88-Mutant Progenitors Precede Waldenstrom Macroglobulinemia
Authors: Akhilesh Kaushal, Ajay K. Nooka, Allison R. Carr, Katherine E. Pendleton, Benjamin G. Barwick, Julia Manalo, Samuel S. McCachren, Vikas A. Gupta, Nisha S. Joseph, Craig C. Hofmeister, Jonathan L. Kaufman, Leonard T. Heffner, Stephen M. Ansell, Lawrence H. Boise, Sagar Lonial, Kavita M. Dhodapkar, Madhav V. Dhodapkar
Journal: Blood Cancer Discovery (2021)

Abstract Waldenstrom macroglobulinemia (WM) and its precursor IgM gammopathy are distinct disorders characterized by clonal mature IgM-expressing B-cell outgrowth in the bone marrow. Here, we show by high-dimensional single-cell immunogenomic profiling of patient samples that these disorders originate in the setting of global B-cell compartment alterations, characterized by expansion of genomically aberrant extrafollicular B cells of the nonmalignant clonotype. Alterations in the immune microenvironment preceding malignant clonal expansion include myeloid inflammation and naïve B- and T-cell depletion. Host response to these early lesions involves clone-specific T-cell immunity that may include MYD88 mutation–specific responses. Hematopoietic progenitors carry the oncogenic MYD88 mutations characteristic of the malignant WM clone. These data support a model for WM pathogenesis wherein oncogenic alterations and signaling in progenitors, myeloid inflammation, and global alterations in extrafollicular B cells create the milieu promoting extranodal pattern of growth in differentiated malignant cells. Significance: These data provide evidence that growth of the malignant clone in WM is preceded by expansion of extrafollicular B cells, myeloid inflammation, and immune dysfunction in the preneoplastic phase. These changes may be related in part to MYD88 oncogenic signaling in pre–B progenitor cells and suggest a novel model for WM pathogenesis. This article is highlighted in the In This Issue feature, p. 549
Insulin Increases Migration and Invasion in Androgen Deprived Prostate Cancer Cells.
Authors: Phoebe Sarkar, Jennifer H. Gunter, Amy Lubik, Nataly Stylianou, Brett Hollier, Colleen Nelson
Journal: Endocrine Reviews (2014)

Advanced prostate cancer (PCa) is treated with androgen deprivation therapy (ADT), as prostate tumours are dependent on androgens for survival. Unfortunately, ADT offers a temporary remission and prostate tumours begin to capitalise on additional intratumoural or adrenal sources of androgens. This has led to continued development of antagonists to the androgen receptor (AR) and inhibitors of androgen synthesis to combat PCa which result in extended time to progression and cancer specific survival in advanced PCa patients.  A major side effect of ADT is the induction of features of the metabolic syndrome, including persistent hyperinsulinaemia, which is specifically associated with poor outcomes, including rapid progression and increased cancer mortality. Using patient databases (Oncomine™, Compendia Bioscience, Ann Arbor, MI) we observed that insulin receptor and IRS-2 are upregulated from primary versus metastatic primary tumours across eight clinical datasets. We hypothesized that following androgen withdrawal, high insulin levels promote an adaptive response that drives castrate resistance PCa progression.  To address this we undertook transcriptional profiling of AR-responsive LNCaP cell line following insulin treatment with or without androgens. We identified a number of pathways uniquely up-regulated by insulin including genes associated with increased potential for migration and invasion. We observed that in the absence of androgens, insulin promoted up to 3.4 fold increased migration through transwell and wound healing assays in LNCaP, DU145 and 22RV1 cells; and increased Matrigel invasion of LNCaP (2.5 fold, p=0.0106), DU145 (1.9 fold, p=0.007) and 22RV1 (2.4 fold, p=0.004) cells. AR inhibitor, bicalutamide, increased cell migration of LNCaP and 22RV1 by 72% and 45%, respectively. Insulin and bicalutamide do not appear to be additive suggesting a common pathway. Importantly, insulin- induced migration was blocked by inhibitors of insulin receptor, BMS-745807-04 (48%) and CP-751871 (42%), and by the MAPK inhibitor U0126 (46%). In agreement with our microarray data, QRT-PCR revealed insulin-induced molecular changes within the cells reminiscent of an epithelial-to-mesenchymal transition (EMT); androgen deprivation alone increased expression of vimentin and the SNAIL and ZEB1 transcription factors, which was further increased with insulin. Changes to protein expression and transcription factor localisation were consistent with mRNA. Recent studies report ‘obesity factors’ promoting EMT in prostate cancer cells. Our data indicates insulin can promote this plasticity. These novel results show insulin promotes PCa cell migration and invasion, possibly by inducing EMT-like changes within PCa cells and make a strong case for investigating the clinical efficacy of using insulin-sensitizing drugs such as metformin as an adjuvant therapy for PCa treatment.
Machine learning approach to differentiation of peripheral schwannomas and neurofibromas: A multi-center study
Authors: Michael Zhang, Elizabeth Tong, Sam Wong, Forrest Hamrick, Maryam Mohammadzadeh, Vaishnavi Rao, Courtney Pendleton, Brandon W Smith, Nicholas F Hug, Sandip Biswal, Jayne Seekins, Sandy Napel, Robert J Spinner, Mark A Mahan, Kristen W Yeom, Thomas J Wilson
Journal: Neuro-Oncology (2021)

Abstract Background Non-invasive differentiation between schwannomas and neurofibromas is important for appropriate management, preoperative counseling, and surgical planning, but has proven difficult using conventional imaging. The objective of this study was to develop and evaluate machine learning approaches for differentiating peripheral schwannomas from neurofibromas. Methods We assembled a cohort of schwannomas and neurofibromas from 3 independent institutions and extracted high-dimensional radiomic features from gadolinium-enhanced, T1-weighted MRI using the PyRadiomics package on Quantitative Imaging Feature Pipeline. Age, sex, neurogenetic syndrome, spontaneous pain, and motor deficit were recorded. We evaluated the performance of 6 radiomics-based classifier models with and without clinical features and compared model performance against human expert evaluators. Results One hundred and seven schwannomas and 59 neurofibromas were included. The primary models included both clinical and imaging data. The accuracy of the human evaluators (0.765) did not significantly exceed the no-information rate (NIR), whereas the Support Vector Machine (0.929), Logistic Regression (0.929), and Random Forest (0.905) classifiers exceeded the NIR. Using the method of DeLong, the AUCs for the Logistic Regression (AUC = 0.923) and K Nearest Neighbor (AUC = 0.923) classifiers were significantly greater than the human evaluators (AUC = 0.766; p = 0.041). Conclusions The radiomics-based classifiers developed here proved to be more accurate and had a higher AUC on the ROC curve than expert human evaluators. This demonstrates that radiomics using routine MRI sequences and clinical features can aid in differentiation of peripheral schwannomas and neurofibromas.
COVID-19 pandemic and worldwide organ transplantation: a population-based study
Authors: Olivier Aubert, Daniel Yoo, Dina Zielinski, Emanuele Cozzi, Massimo Cardillo, Michael Dürr, Beatriz Domínguez-Gil, Elisabeth Coll, Margarida Ivo Da Silva, Ville Sallinen, Karl Lemström, Karsten Midtvedt, Camilo Ulloa, Franz Immer, Annemarie Weissenbacher, Natalie Vallant, Nikolina Basic-Jukic, Kazunari Tanabe, Georgios Papatheodoridis, Georgia Menoudakou, Martin Torres, Carlos Soratti, Daniela Hansen Krogh, Carmen Lefaucheur, Gustavo Ferreira, Helio Tedesco Silva, David Hartell, John Forsythe, Lisa Mumford, Peter P Reese, François Kerbaul, Christian Jacquelinet, Serge Vogelaar, Vassilios Papalois, Alexandre Loupy
Journal: The Lancet Public Health (2021)
Systems of cissexism and the daily production of stress for transgender and gender diverse people
Authors: Jae A. Puckett, Alix B. Aboussouan, Allura L. Ralston, Brian Mustanski, Michael E. Newcomb
Journal: International Journal of Transgender Health (2021)

Transgender and gender diverse (TGD) people encounter a range of minority stressors (e.g., harassment, victimization, misgendering) that impact many areas of life. Much of the empirical literature on gender minority stress has utilized frameworks that were developed with a focus on sexual orientation and were often limited to cisgender sexual minorities (lesbian, gay, bisexual, and other non-heterosexual individuals), leaving questions about how well existing models fit the experiences of TGD people.To expand understandings of gender minority stress, we conducted a daily diary study where participants detailed the types of stressors they encountered on a daily basis for 56 days.There were 181 TGD participants recruited into the study (M age = 25.6 years; SD = 5.6), with 167 retained in the daily surveys from which these analyses were conducted.The written responses revealed a variety of stressors, some of which are novel to the literature. Many participants reported instances of non-affirmation, such as misgendering, as well as vicarious stress when learning of oppressive experiences impacting other TGD people and seeing negative media portrayals of the lives of TGD individuals. Participants also reported bodily vigilance when being on alert for how others were perceiving their gender. Other stressors included rejection, political oppression, physical violence, uneasiness from others, and the enforcement of gender binarism.These findings highlight gaps in the existing understandings of marginalization for TGD people that must be addressed to ensure that frameworks include and center the experiences of gender minorities.
Rammya Mathew: Building compassionate and joyful workplaces
Authors: Rammya Mathew
Journal: BMJ (2021)

Whether we like it or not, work is what we spend most of our waking hours doing.So, finding joy in work isn't a nice to have: it's a necessity.An organisation such as the NHS-the world's largest employer of highly skilled professionals-should conceivably have a highly developed approach to ensuring that people have fulfilling and rewarding jobs that they want to keep coming back to.
Heart failure with preserved ejection fraction after left‐sided valve surgery: prevalent and relevant
Authors: Andreas A. Kammerlander, Christian Nitsche, Carolina Donà, Matthias Koschutnik, Varius Dannenberg, Katharina Mascherbauer, Robert Schönbauer, Amna Zafar, Max‐Paul Winter, Philipp E. Bartko, Georg Goliasch, Christian Hengstenberg, Julia Mascherbauer
Journal: European Journal of Heart Failure (2021)

To investigate the epidemiological and prognostic relationship between heart failure with preserved ejection fraction (HFpEF) and left-sided valve surgery using all-cause mortality as a primary endpoint.We studied a total of 973 patients, of whom 673 had undergone left-sided valve surgery (time from surgery to enrolment 50 ± 30 months after valve surgery) and 300 patients with HFpEF without prior surgery served as control group. Among patients after surgery, 67.4% fulfilled all criteria of HFpEF according to current guideline recommendations, 20.6% had no heart failure (HF), and 12.0% had HF with mid-range or reduced ejection fraction (HFmrEF/HFrEF). During 83 ± 39 months of follow-up, a total of 335 (34.4%) patients died. Compared to surgical patients with no subsequent HF, patients with HFpEF and HFmrEF/HFrEF after surgery showed significantly higher all-cause mortality rates [hazard ratio (HR) 1.80, 95% confidence interval (CI) 1.25-2.57, P = 0.001; and HR 1.86, 95% CI 1.16-2.98, P = 0.010, respectively]. This increased mortality rate was similar to the control HFpEF group without surgery (HR 2.05, 95% CI 1.38-3.02, P < 0.001). Results remained consistent after adjustment for clinical and imaging risk factors and when using the established HFA-PEFF risk score for HFpEF diagnosis. Notably, only 12.5% of HFpEF patients after surgery were diagnosed with HF despite regular follow-up visits by board-certified cardiologists. In contrast, 92.1% of HFmrEF/HFrEF patients after surgery were diagnosed correctly.Heart failure with preserved ejection fraction following left-sided valve surgery is highly prevalent, associated with unfavourable outcomes, but rarely recognized.