tbuckley/cabot-search huggingface dataset:
Hypothalamic C2-domain protein involved in MC4R trafficking and control of energy balance
Authors: Chaitanya K. Gavini, Tyler M. Cook, David J. Rademacher, Virginie Mansuy-Aubert
Journal: Metabolism (2019)

Rates of overweight and obesity epidemic have risen significantly in the past few decades, and 34% of adults and 15-20% of children and adolescents in the United States are now obese. Melanocortin receptor 4 (MC4R), contributes to appetite control in hypothalamic neurons and is a target for future anti-obesity treatments (such as setmelanotide) or novel drug development effort. Proper MC4R trafficking regulation in hypothalamic neurons is crucial for normal neural control of homeostasis and is altered in obesity and in presence of lipids. The mechanisms underlying altered MC4R trafficking in the context of obesity is still unclear. Here, we discovered that C2CD5 expressed in the hypothalamus is involved in the regulation of MC4R endocytosis. This study unmasked a novel trafficking protein nutritionally regulated in the hypothalamus providing a novel target for MC4R dependent pathways involved in bodyweight homeostasis and Obesity.To evaluate the expression of C2cd5, we first used in situ hybridization and RNAscope technology in combination with electronic microscopy. For in vivo, we characterized the energy balance of wild type (WT) and C2CD5 whole-body knockout (C2CD5KO) mice fed normal chow (NC) and/or western-diet (high-fat/high-sucrose/cholesterol) (WD). To this end, we performed comprehensive longitudinal assessment of bodyweight, energy balance (food intake, energy expenditure, locomotor activity using TSE metabolic cages), and glucose homeostasis. In addition, we evaluated the consequence of loss of C2CD5 on feeding behavior changes normally induced by MC4R agonist (Melanotan, MTII) injection in the paraventricular hypothalamus (PVH). For in vitro approach, we tease out the role of C2CD5 and its calcium sensing domain C2 in MC4R trafficking. We focused on endocytosis of MC4R using an antibody feeding experiment (in a neuronal cell line - Neuro2A (N2A) stably expressing HA-MC4R-GFP; against HA-tag and analyzed by flux cytometry).We found that 1) the expression of hypothalamic C2CD5 is decreased in diet-induced obesity models compared to controls, 2) mice lacking C2CD5 exhibit an increase in food intake compared to WT mice, 3) C2CD5 interacts with endocytosis machinery in hypothalamus, 4) loss of functional C2CD5 (lacking C2 domain) blunts MC4R endocytosis in vitro and increases MC4R at the surface that fails to respond to MC4R ligand, and, 5) C2CD5KO mice exhibit decreased acute responses to MTII injection into the PVH.Based on these, we conclude that hypothalamic C2CD5 is involved in MC4R endocytosis and regulate bodyweight homeostasis. These studies suggest that C2CD5 represents a new protein regulated by metabolic cues and involved in metabolic receptor endocytosis. C2CD5 represent a new target and pathway that could be targeted in Obesity.
Childhood pneumonia, pleurisy and lung function: a cohort study from the first to sixth decade of life
Authors: Jennifer L Perret, Caroline J Lodge, Adrian J Lowe, David P Johns, Bruce R Thompson, Dinh S Bui, Lyle C Gurrin, Melanie C Matheson, Christine F McDonald, Richard Wood-Baker, Cecilie Svanes, Paul S Thomas, Graham G Giles, Anne B Chang, Michael J Abramson, E Haydn Walters, Shyamali C Dharmage
Journal: Thorax (2019)

Introduction Adult spirometry following community-acquired childhood pneumonia has variably been reported as showing obstructive or non-obstructive deficits. We analysed associations between doctor-diagnosed childhood pneumonia/pleurisy and more comprehensive lung function in a middle-aged general population cohort born in 1961. Methods Data were from the prospective population-based Tasmanian Longitudinal Health Study cohort. Analysed lung function was from ages 7 years (prebronchodilator spirometry only, n=7097), 45 years (postbronchodilator spirometry, carbon monoxide transfer factor and static lung volumes, n=1220) and 53 years (postbronchodilator spirometry and transfer factor, n=2485). Parent-recalled histories of doctor-diagnosed childhood pneumonia and/or pleurisy were recorded at age 7. Multivariable linear and logistic regression were used. Results At age 7, compared with no episodes, childhood pneumonia/pleurisy-ever was associated with reduced FEV 1 :FVC for only those with current asthma (beta-coefficient or change in z-score=−0.20 SD, 95% CI −0.38 to –0.02, p=0.028, p interaction=0.036). At age 45, for all participants, childhood pneumonia/pleurisy-ever was associated with a restrictive pattern: OR 3.02 (1.5 to 6.0), p=0.002 for spirometric restriction (FVC less than the lower limit of normal plus FEV 1 :FVC greater than the lower limit of normal); total lung capacity z-score −0.26 SD (95% CI −0.38 to –0.13), p&lt;0.001; functional residual capacity −0.16 SD (−0.34 to –0.08), p=0.001; and residual volume −0.18 SD (−0.31 to –0.05), p=0.008. Reduced lung volumes were accompanied by increased carbon monoxide transfer coefficient at both time points (z-score +0.29 SD (0.11 to 0.49), p=0.001 and +0.17 SD (0.04 to 0.29), p=0.008, respectively). Discussion For this community-based population, doctor-diagnosed childhood pneumonia and/or pleurisy were associated with obstructed lung function at age 7 for children who had current asthma symptoms, but with evidence of ‘smaller lungs’ when in middle age.
68Ga–Prostate-Specific Membrane Antigen-11 PET/CT
Authors: Jolanta Kunikowska, Radosław Kuliński, Kristoff Muylle, Henryk Koziara, Leszek Królicki
Journal: Clinical Nuclear Medicine (2019)

Background Glioblastoma multiforme (GBM) is the most common and most aggressive primary tumor of the brain. After initial therapy and total resection of GBM, 80% to 90% of recurrences occur at the surgical margins. Currently, limited data are available in the literature on the possible use of 68 Ga–prostate-specific membrane antigen (PSMA-11) for diagnosis of recurrence in GBM patients. The aim was to assess the feasibility and potential of 68 Ga-PSMA-11 PET/CT as a diagnostic procedure in patients with histologically confirmed of GBM and suspected recurrent disease on MRI. Results No radiopharmaceutical-related adverse events were noted. Characterization of recurrent disease with MRI included T2-weighted fast spin-echo images, fluid-attenuated inversion recovery and diffusion-weighted imaging sequences, and gadolinium enhanced T1-weighted images. Visual interpretation of PET showed increased accumulation of 68 Ga-PSMA-11 in recurrent lesion detected by T1 contrast enhanced and diffusion-weighted imaging images in all patients with a median SUVmax of the tumor of 6.5 and an SUVmean of 3.5. The median tumor-to-background brain ratio and tumor-to-liver ratio obtained from 68 Ga-PSMA-11 PET/CT were 96.7 and 0.8, respectively. Conclusions The extremely low background uptake in normal brain tissue and consequently high tumor-to-brain ratio make 68 Ga-PSMA-11 PET/CT highly promising for diagnosis of recurrent disease in GBM patients. Although PSMA expression in recurrent GBM also opens a potential way for targeted peptide therapy with α/β-emitters as well as for prediction of treatment with antiangiogenic agents, the low tumor-to-liver ratio observed in the majority of patients in this study suggests a limited role of radiolabeled PSMA ligands for targeted radionuclide therapy of recurrent GBM.
Blood Pressure Normalization–Independent Cardioprotective Effects of Endogenous, Physical Activity–Induced αCGRP (α Calcitonin Gene-Related Peptide) in Chronically Hypertensive Mice
Authors: Tom Skaria, Katharyn Jean Mitchell, Olga Vogel, Thomas Wälchli, Max Gassmann, Johannes Vogel
Journal: Circulation Research (2019)

αCGRP (α calcitonin gene-related peptide), one of the strongest vasodilators, is cardioprotective in hypertension by reducing the elevated blood pressure.However, we hypothesize that endogenous, physical activity-induced αCGRP has blood pressure-independent cardioprotective effects in chronic hypertension.Chronically hypertensive (one-kidney-one-clip surgery) wild-type and αCGRP-/- sedentary or voluntary wheel running mice were treated with vehicle, αCGRP, or the αCGRP receptor antagonist CGRP8-37. Cardiac function and myocardial phenotype were evaluated echocardiographically and by molecular, cellular, and histological analysis, respectively. Blood pressure was similar among all hypertensive experimental groups. Endogenous αCGRP limited pathological remodeling and heart failure in sedentary, chronically hypertensive wild-type mice. In these mice, voluntary wheel running significantly improved myocardial phenotype and function, which was abolished by CGRP8-37 treatment. In αCGRP-/- mice, αCGRP treatment, in contrast to voluntary wheel running, improved myocardial phenotype and function. Specific inhibition of proliferation and myofibroblast differentiation of primary, murine cardiac fibroblasts by αCGRP suggests involvement of these cells in αCGRP-dependent blunting of pathological cardiac remodeling.Endogenous, physical activity-induced αCGRP has blood pressure-independent cardioprotective effects and is crucial for maintaining cardiac function in chronic hypertension. Consequently, inhibiting endogenous αCGRP signaling, as currently approved for migraine prophylaxis, could endanger patients with hypertension.
Legionnaires’ Disease: State of the Art Knowledge of Pathogenesis Mechanisms of <i>Legionella</i>
Authors: Sonia Mondino, Silke Schmidt, Monica Rolando, Pedro Escoll, Laura Gomez-Valero, Carmen Buchrieser
Journal: Annual Review of Pathology Mechanisms of Disease (2019)

Legionella species are environmental gram-negative bacteria able to cause a severe form of pneumonia in humans known as Legionnaires' disease. Since the identification of Legionella pneumophila in 1977, four decades of research on Legionella biology and Legionnaires' disease have brought important insights into the biology of the bacteria and the molecular mechanisms that these intracellular pathogens use to cause disease in humans. Nowadays, Legionella species constitute a remarkable model of bacterial adaptation, with a genus genome shaped by their close coevolution with amoebae and an ability to exploit many hosts and signaling pathways through the secretion of a myriad of effector proteins, many of which have a eukaryotic origin. This review aims to discuss current knowledge of Legionella infection mechanisms and future research directions to be taken that might answer the many remaining open questions. This research will without a doubt be a terrific scientific journey worth taking.
HRT: GPs raise concern about “threatening and unprofessional” template letter for patients “refused” treatment
Authors: Elisabeth Mahase
Journal: BMJ (2019)

A template letter for patients who have been “refused” hormone replacement therapy to send to their GP warning of “litigation” has been criticised for being confrontational and inappropriate.

The GP and menopause specialist Louise Newson, who runs a private menopause clinic, posted the template letter for patients to send to “GPs who refuse to prescribe HRT” on the website she runs for patients called “My menopause doctor.”1

The letter, which was co-created with a medical negligence lawyer, was posted with a message telling patients that all they had to do was “copy and paste the letter . . . and edit to add your own information.”

GPs raised concerns about the “threatening and unprofessional” letter after Newson spoke at the annual conference of the Royal College of General Practitioners in Liverpool on 24 October, in a session entitled “Simple and safe prescribing of HRT for primary care.” In the session Newson discussed patients’ difficulties in getting HRT.

While many GPs praised …
PD01.11 Artificial Intelligence Can Detect Lung Cancer From High Resolution Microscopic Images of Conditioned Peripheral Blood
Authors: D. Akolkar, R. Patil, C. Sims, D. Patil, P. Fulmali, S. Patil, S. Patel, A. Adhav, V. Datta, P. Fulmali, S. Khan, A. Ranade, A. Srinivasan, R. Datar
Journal: Journal of Thoracic Oncology (2019)
Gene expression profiling of glioblastoma cell lines using cDNA microarrays: Association with response to chemotherapeutic drugs
Authors: Wilfried Roth, Darek Kedra, Kutbuddin Doctor, Andrei Osterman, Michael Weller, John C. Reed
Journal: Cancer Research (2004)

599  Glioblastoma multiforme is the most common brain tumor in adult life. Only 25% of patients with glioblastoma respond to chemotherapy, and the reasons why some patients benefit from chemotherapy and some do not remain unclear. The molecular basis of glioma cell resistance are mutations or amplifications affecting the expression or functional activity of tumor suppressor genes and oncogenes. Genome-wide expression analysis is a promising tool for identifying the precise genetic causes and molecular mechanisms of chemoresistance. The aim of this study was to identify genes, gene clusters, and signalling pathways that determine the sensitivity of glioblastoma cells to chemotherapeutic drugs. Thus, we used a cDNA microarray representing 5,800 human genes to analyze expression profiles in a panel of 12 human malignant glioma cell lines (A172, D247MG, LN-18, LN-229, LN-308, LN-319, LN-428, T98G, U87MG, U138MG, U251MG, U373MG). Using a bioinformatics approach, the gene expression data of the glioma cell lines were then compared with their responsiveness to 25 anticancer drugs. Cluster and gene expression correlation analysis identified subsets of genes whose expression levels exhibited significant associations with the drug sensitivity profiles. This integrated database of expression profiles and pharmacological profiles might be helpful to predict glioma cell resistance by determining the expression levels of a limited number of genes. Moreover, this approach could potentially contribute to the identification of novel drug targets for combating brain tumors.
Nanotopography-based lymphatic delivery for improved anti-tumor responses to checkpoint blockade immunotherapy
Authors: Sunkuk Kwon, Fred Christian Velasquez, John C. Rasmussen, Matthew R. Greives, Kelly D. Turner, John R. Morrow, Wen-Jen Hwu, Russell F. Ross, Songlin Zhang, Eva M. Sevick-Muraca
Journal: Theranostics (2019)

Rationale: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a co-inhibitory checkpoint receptor that is expressed by naïve T-cells in lymph nodes (LNs) to inhibit activation against "self" antigens (Ags).In cancer, anti-CTLA-4 blocks inhibitory action, enabling robust activation of T-cells against tumor Ags presented in tumor draining LNs (TDLNs).However, anti-CTLA-4 is administered intravenously with limited exposure within TDLNs and immune related adverse events (irAEs) are associated with over-stimulation of the immune system.Methods: Herein, we first deliver anti-CTLA-4 in an orthotopic mammary carcinoma murine model using a nanotopographical microneedle-array device to compare its anti-tumor response to that from systemic administration.Additionally, to demonstrate the feasibility of lymphatic delivery in humans using the device, we use near-infrared fluorescence imaging to image delivery of ICG to LNs.Results: Our data show that lymphatic infusion results in more effective tumor growth inhibition, arrest of metastases, increased tumor infiltrating lymphocytes and complete responses when compared to conventional systemic administration.In clinical studies, we demonstrate for the first time that nanotopographic infusion can deliver ICG through the lymphatics directly to the axilla and inguinal LNs of healthy human volunteers.Conclusion: Taken together, these results suggest that regional delivery using a nanotopography-based microneedle array could revolutionize checkpoint blockade immunotherapy by reducing systemic drug exposure and maximizing drug delivery to TDLNs where tumor Ags present.Future work is needed to determine whether lymphatic delivery of anti-CTLA-4 can alleviate irAEs that occur with systemic dosing.
Sixty seconds on . . . ageing
Authors: Abi Rimmer
Journal: BMJ (2019)

True, but research by the independent think tank the Resolution Foundation has found that some parts of the UK are ageing faster than others.1

Not quite, the researchers found that the youngest region was London, where the typical (average) age is 35.3. By contrast, the south-west, the oldest region, has a typical age of 43.9. …
43 Serial transient elastography readings indicate progression of untreated fibrosis among patients attending opioid substitution treatment clinic in south county dublin
Authors: J Moloney, G Hawthorn, AP McCormick, E Feeney, D Houlihan, S Keating, C Murphy, T McHugh, JS Lambert
Journal: Gut (2017)

Background  Injecting drug use (IDU) is a major driver of the hepatitis c virus (HCV) epidemic. Opioid substitution treatment clinics (OST) are the main provider of care for these individuals.  Aim  To assess the prevalence of significant liver disease and progression in patients attending an OST clinic and evaluate the effectiveness of opportunistic Transient Elastography (TE) service in this setting.  Method  Unselected serial TE readings were carried out on patients in the OST clinic in 2008 and 2016. Mortality in the 2008 group was related to TE readings and progression of TE readings from 2008 to 2016 was recorded.  Results  In 2008, 84 patients were scanned. Of these 77% were HCV Ab positive and 58% of this group were HCV viraemic. By 2016, all of the 2008 patients with TE scores>13 Kilopascal (Kpa) had died (a total of 13 patients) and 11 of these patients died as a result of liver failure associated with hepatitis c viraemia and alcohol. In 2016 105 scans were carried out on surviving patients from 2008 who still attended the clinic and on new patients attending the clinic. 16 patients (15%) of the 2016 population had TE scores>13 Kpa, the previous threshold for death at eight years.  Conclusions  This longitudinal data demonstrates universal mortality at 8 years among OST patients with a TE reading of 13 Kpa or greater. Among surviving patients it demonstrated widespread progression of TE readings to levels indicating a requirement for early DAA treatment, and to levels previously associated with high mortality.
Inquiry into eminent psychologist failed to list many unsafe papers, biographer claims
Authors: Nigel Hawkes
Journal: BMJ (2019)

A report from King’s College London that listed 26 papers coauthored by the eminent psychologist Hans Eysenck as “unsafe” fell well short of the true target, Eysenck’s biographer has said.

The real total should be at least 88, said Rod Buchanan, an Australian writer and teacher whose 2010 biography of Eysenck is the most comprehensive study of the controversial figure whose personality and ideas dominated British psychology for so long.1

Eysenck’s critics have been calling for decades for the retraction of a series of papers he wrote that used data collected by the German sociologist Ronald Grossarth-Maticek. The King’s College report, compiled by an anonymous group at the college’s Institute of Psychiatry, Psychology and Neuroscience, singled out 26 papers coauthored by the two men, agreeing that …
Correction to: CircMYO10 promotes osteosarcoma progression by regulating miR-370-3p/RUVBL1 axis to enhance the transcriptional activity of β-catenin/LEF1 complex via effects on chromatin remodeling
Authors: Junxin Chen, Gang Liu, Yizheng Wu, Jianjun Ma, Hongfei Wu, Ziang Xie, Shuai Chen, Yute Yang, Shengyu Wang, Panyang Shen, Yifan Fang, Shunwu Fan, Shuying Shen, Xiangqian Fang
Journal: Molecular Cancer (2020)

Following the publication of the original paper [1], one corresponding author was inadvertently missed.
Tumor suppressive BTB/POZ zinc-finger protein ZBTB28 inhibits oncogenic BCL6/ZBTB27 signaling to maintain p53 transcription in multiple carcinogenesis
Authors: Tingxiu Xiang, Jun Tang, Lili Li, Weiyan Peng, Zhenfang Du, Xiangyu Wang, Qianqian Li, Hongying Xu, Lei Xiong, Can Xu, Xin Le, Xufu Wei, Fang Yu, Shuman Li, Qian Xiao, Bing Luo, Xinni Xiang, Ailong Huang, Yong Lin, Guosheng Ren, Qian Tao
Journal: Theranostics (2019)

Zinc-finger and BTB/POZ domain-containing family proteins (ZBTB) are important transcription factors functioning as tumor suppressors or oncogenes, such as BCL6/ZBTB27 as a key oncoprotein for anti-cancer therapy.Through epigenome study, we identified ZBTB28/BCL6B/BAZF, a BTB/POZ domain protein highly homologous to BCL6, as a methylated target in multiple tumors.However, the functions and mechanism of ZBTB28 in carcinogenesis remain unclear.Methods: ZBTB28 expression and methylation were examined by reverse-transcription PCR and methylation-specific PCR.The effects and mechanisms of ectopic ZBTB28 expression on tumor cells were assessed with molecular biological and cellular approaches in vitro and in vivo.Results: Albeit broadly expressed in multiple normal tissues, ZBTB28 is frequently downregulated in aeroand digestive carcinoma cell lines and primary tumors, and correlated with its promoter CpG methylation status.Further gain-of-function study showed that ZBTB28 functions as a tumor suppressor inhibiting carcinoma cell growth in vitro and in vivo, through inducing cell cycle arrest and apoptosis of tumor cells.ZBTB28 suppresses cell migration and invasion by reversing EMT and cell stemness.ZBTB28 transactivates TP53 expression, through binding to the p53 promoter in competition with BCL6, while BCL6 itself was also found to be a direct target repressed by ZBTB28. Conclusion:Our results demonstrate that ZBTB28 functions as a tumor suppressor through competing with BCL6 for targeting p53 regulation.This newly identified ZBTB28/BCL6/p53 regulatory axis provides further molecular insight into carcinogenesis mechanisms and has implications in further improving BCL6-based anticancer therapy.
Tyrosine modified irinotecan-loaded liposomes capable of simultaneously targeting LAT1 and ATB0,+ for efficient tumor therapy
Authors: Zhenjie Wang, Dongxu Chi, Xingchen Wu, Yingli Wang, Xinxin Lin, Zhaochu Xu, Hongzhuo Liu, Jin Sun, Zhonggui He, Yongjun Wang
Journal: Journal of Controlled Release (2019)