tbuckley/cabot-search huggingface dataset:
Chronic Manganese Exposure and the Enteric Nervous System: An <i>in Vitro</i> and Mouse <i>in Vivo</i> Study
Authors: Shivani Ghaisas, Dilshan S. Harischandra, Bharathi Palanisamy, Alexandra Proctor, Huajun Jin, Somak Dutta, Souvarish Sarkar, Monica Langley, Gary Zenitsky, Vellareddy Anantharam, Arthi Kanthasamy, Gregory J. Phillips, Anumantha Kanthasamy
Journal: Environmental Health Perspectives (2021)

Background: Chronic environmental exposure to manganese (Mn) can cause debilitating damage to the central nervous system. However, its potential toxic effects on the enteric nervous system (ENS) have yet to be assessed. Objective: We examined the effect of Mn on the ENS using both cell and animal models. Method: Rat enteric glial cells (EGCs) and mouse primary enteric cultures were exposed to increasing concentrations of Mn and cell viability and mitochondrial health were assessed using various morphological and functional assays. C57BL/6 mice were exposed daily to a sublethal dose of Mn (15mg/kg/d) for 30 d. Gut peristalsis, enteric inflammation, gut microbiome profile, and fecal metabolite composition were assessed at the end of exposure. Results: EGC mitochondria were highly susceptible to Mn neurotoxicity, as evidenced by lower mitochondrial mass, adenosine triphosphate–linked respiration, and aconitase activity as well as higher mitochondrial superoxide, upon Mn exposure. Minor differences were seen in the mouse model: specifically, longer intestinal transit times and higher levels of colonic inflammation. Conclusion: Based on our findings from this study, Mn preferentially induced mitochondrial dysfunction in a rat EGC line and in vivo resulted in inflammation in the ENS. https://doi.org/10.1289/EHP7877
27376 Speed of clinical response and improvement in psoriasis with bimekizumab: Pooled results from the multicenter, randomized, double-blinded phase 3 BE VIVID, BE READY and BE SURE trials
Authors: Mark Lebwohl, Philip Hampton, Akimichi Morita, Kristian Reich, Jo Lambert, Eva Cullen, Christopher Cioffi, Maggie Wang, Cynthia Madden, Richard Langley
Journal: Journal of the American Academy of Dermatology (2021)
Silencing of ceramide synthase 2 in hepatocytes modulates plasma ceramide biomarkers predictive of cardiovascular death
Authors: Steffen Schmidt, Sandra F. Gallego, Iris Daphne Zelnik, Sergey Kovalchuk, Nanna Albæk, Richard R. Sprenger, Charlotte Øverup, Yael Pewzner-Jung, Anthony H. Futerman, Marie W. Lindholm, Ole N. Jensen, Christer S. Ejsing
Journal: Molecular Therapy (2021)

Emerging clinical data show that three ceramide molecules, Cer d18:1/16:0, Cer d18:1/24:1, and Cer d18:1/24:0, are biomarkers of a fatal outcome in patients with cardiovascular disease. This finding raises basic questions about their metabolic origin, their contribution to disease pathogenesis, and the utility of targeting the underlying enzymatic machinery for treatment of cardiometabolic disorders. Here, we outline the development of a potent N-acetylgalactosamine-conjugated antisense oligonucleotide engineered to silence ceramide synthase 2 specifically in hepatocytes in vivo. We demonstrate that this compound reduces the ceramide synthase 2 mRNA level and that this translates into efficient lowering of protein expression and activity as well as Cer d18:1/24:1 and Cer d18:1/24:0 levels in liver. Intriguingly, we discover that the hepatocyte-specific antisense oligonucleotide also triggers a parallel modulation of blood plasma ceramides, revealing that the biomarkers predictive of cardiovascular death are governed by ceramide biosynthesis in hepatocytes. Our work showcases a generic therapeutic framework for targeting components of the ceramide enzymatic machinery to disentangle their roles in disease causality and to explore their utility for treatment of cardiometabolic disorders. Emerging clinical data show that three ceramide molecules, Cer d18:1/16:0, Cer d18:1/24:1, and Cer d18:1/24:0, are biomarkers of a fatal outcome in patients with cardiovascular disease. This finding raises basic questions about their metabolic origin, their contribution to disease pathogenesis, and the utility of targeting the underlying enzymatic machinery for treatment of cardiometabolic disorders. Here, we outline the development of a potent N-acetylgalactosamine-conjugated antisense oligonucleotide engineered to silence ceramide synthase 2 specifically in hepatocytes in vivo. We demonstrate that this compound reduces the ceramide synthase 2 mRNA level and that this translates into efficient lowering of protein expression and activity as well as Cer d18:1/24:1 and Cer d18:1/24:0 levels in liver. Intriguingly, we discover that the hepatocyte-specific antisense oligonucleotide also triggers a parallel modulation of blood plasma ceramides, revealing that the biomarkers predictive of cardiovascular death are governed by ceramide biosynthesis in hepatocytes. Our work showcases a generic therapeutic framework for targeting components of the ceramide enzymatic machinery to disentangle their roles in disease causality and to explore their utility for treatment of cardiometabolic disorders.
SARS-CoV-2 Neutralizing Antibodies for COVID-19 Prevention and Treatment
Authors: Dapeng Li, Gregory D. Sempowski, Kevin O. Saunders, Priyamvada Acharya, Barton F. Haynes
Journal: Annual Review of Medicine (2021)

Prophylactic and therapeutic drugs are urgently needed to combat coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Over the past year, SARS-CoV-2 neutralizing antibodies have been developed for preventive or therapeutic uses. While neutralizing antibodies target the spike protein, their neutralization potency and breadth vary according to recognition epitopes. Several potent SARS-CoV-2 antibodies have shown degrees of success in preclinical or clinical trials, and the US Food and Drug Administration has issued emergency use authorization for two neutralizing antibody cocktails.Nevertheless, antibody therapy for SARS-CoV-2 still faces potential challenges, including emerging viral variants of concern that have antibody-escape mutations and the potential for antibody-mediated enhancement of infection or inflammation. This review summarizes representative SARS-CoV-2 neutralizing antibodies that have been reported and discusses prospects and challenges for the development of the next generation of COVID-19 preventive or therapeutic antibodies.
SO-15 Quality of life and physical functioning in older patients with metastatic colorectal cancer receiving palliative chemotherapy: The randomized NORDIC9-study
Authors: G. Liposits, H. Eshoj, S. Möller, S. Winther, H. Skuladottir, R. Jesper, E. Hofsli, L. Poulsen, C. Shah, Å. Berglund, C. Qvortrup, P. Osterlund, B. Glimelius, H. Sorbye, P. Pfeiffer
Journal: Annals of Oncology (2021)
Minimally invasive co-injection of modular micro-muscular and micro-vascular tissues improves in situ skeletal muscle regeneration
Authors: Ying Wang, Ranjith Kumar Kankala, Yuan-Yuan Cai, Han-Xiao Tang, Kai Zhu, Jian-Ting Zhang, Da-Yun Yang, Shi-Bin Wang, Yu Shrike Zhang, Ai-Zheng Chen
Journal: Biomaterials (2021)
Blocking α <sub>4</sub> β <sub>7</sub> integrin delays viral rebound in SHIV <sub>SF162P3</sub> -infected macaques treated with anti-HIV broadly neutralizing antibodies
Authors: Ines Frank, Mariasole Cigoli, Muhammad S. Arif, Marissa D. Fahlberg, Stephanie Maldonado, Giulia Calenda, Amarendra Pegu, Eun Sung Yang, Reda Rawi, Gwo-Yu Chuang, Hui Geng, Cuiping Liu, Tongqing Zhou, Peter D. Kwong, James Arthos, Claudia Cicala, Brooke F. Grasperge, James L. Blanchard, Agegnehu Gettie, Christine M. Fennessey, Brandon F. Keele, Monica Vaccari, Thomas J. Hope, Anthony S. Fauci, John R. Mascola, Elena Martinelli
Journal: Science Translational Medicine (2021)

Anti-HIV broadly neutralizing antibodies (bNAbs) may favor development of antiviral immunity by engaging the immune system during immunotherapy. Targeting integrin α4β7 with an anti-α4β7 monoclonal antibody (Rh-α4β7) affects immune responses in SIV/SHIV-infected macaques. To explore the therapeutic potential of combining bNAbs with α4β7 integrin blockade, SHIVSF162P3-infected, viremic rhesus macaques were treated with bNAbs only (VRC07-523LS and PGT128 anti-HIV antibodies) or a combination of bNAbs and Rh-α4β7 or were left untreated as a control. Treatment with bNAbs alone decreased viremia below 200 copies/ml in all macaques, but seven of eight macaques (87.5%) in the bNAbs-only group rebounded within a median of 3 weeks (95% CI: 2 to 9). In contrast, three of six macaques treated with a combination of Rh-α4β7 and bNAbs (50%) maintained a viremia below 200 copies/ml until the end of the follow-up period; viremia in the other three macaques rebounded within a median of 6 weeks (95% CI: 5 to 11). Thus, there was a modest delay in viral rebound in the macaques treated with the combination antibody therapy compared to bNAbs alone. Our study suggests that α4β7 integrin blockade may prolong virologic control by bNAbs in SHIVSF162P3-infected macaques.
In vivo synergy between oncolytic reovirus and gemcitibane in ras-mutated human HCT116 xenografts
Authors: Maureen Lane, Jeanne Fahey, Christen Besanceney, Nancy Hamel, Bo Yu, Brad Thompson, Matt Coffey, Scott Wadler
Journal: Cancer Research (2007)

4812  Reolysin, a type 3 reovirus, is a ubiquitous double-stranded RNA virus that exhibits selective oncolytic activity in ras-activated tumor cells and is non-pathogenic in humans. Our laboratory has previously demonstrated that Reolysin is synergistic when used in combination with gemcitabine and other commonly used cytotoxic agents against human colon carcinoma cells in vitro. To determine whether the combination of gemcitabine and Reolysin is synergistic in vivo, we injected HCT116 cells, a human colon carcinoma cell line, into the flanks of nude mice. Resulting tumors were treated every 6 days upon reaching 0.5 cm2 with DPBS (n=5), gemcitabine (n=5), Reolysin (n=5) , or a combination of Reolysin (5X108 pfu, i.t.) and gemcitabine (83.3 mg/kg, i.p.) (n=5). Tumors treated with the drug combination exhibited a significant decrease in tumor area compared to controls and single agent therapy within 2 weeks of receiving treatment. Within 1 month, all treatment regimens exhibited a decrease in tumor area, with the combination of gemcitabine and Reolysin being the most efficacious. Statistical tests performed on raw data area measurements 30 days post treatment demonstrated a significant decrease in tumor area for gemcitabine v. control (p
Abstract 749: Efficiacy and Safety of Gabapentin on the Treatment of Non-Ischaemic Chest Pain and Paresthesia in Patients Undergoing Heart Surgery with Sternotomy Technique
Authors: Ismail Biyik, Oktay Ergene, Nezih Tayyar
Journal: Circulation (2008)

Post-sternotomy chest pain and paresthesia are frequently seen and reduce the quality of life. We aimed to demonstrate the efficacy and safety of gabapentin compared with diclofenac on the treatmen...
Trifunctional Graphene Quantum Dot@LDH Integrated Nanoprobes for Visualization Therapy of Gastric Cancer (Adv. Healthcare Mater. 16/2021)
Authors: Bin Wu, Kun Li, Feiyue Sun, Jintong Niu, Rongrong Zhu, Yechang Qian, Shilong Wang
Journal: Advanced Healthcare Materials (2021)

Nanoprobes In article number 2100512 by Yechang Qian, Shilong Wang, and co-workers, trifunctional LDH@SGQD-VP16 integrated nanoprobes are composed of layered double hydroxides (LDHs), sulfur-doped graphene quantum dots (SGQDs) with stable fluorescence, and etoposide (VP16). Which can simultaneously achieve targeted aggregation, fluorescence visualization, and chemotherapy. This work provides a theoretical and experimental basis for LDH@SGQD-VP16 as a potential multifunctional agent for visualization therapy of gastric cancer.
Epigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition
Authors: Raghav Sundar, Kie-Kyon Huang, Vikrant Kumar, Kalpana Ramnarayanan, Deniz Demircioglu, Zhisheng Her, Xuewen Ong, Zul Fazreen Bin Adam Isa, Manjie Xing, Angie Lay-Keng Tan, David Wai Meng Tai, Su Pin Choo, Weiwei Zhai, Jia Qi Lim, Meghna Das Thakur, Luciana Molinero, Edward Cha, Marcella Fasso, Monica Niger, Filippo Pietrantonio, Jeeyun Lee, Anand D Jeyasekharan, Aditi Qamra, Radhika Patnala, Arne Fabritius, Mark De Simone, Joe Yeong, Cedric Chuan Young Ng, Sun Young Rha, Yukiya Narita, Kei Muro, Yu Amanda Guo, Anders Jacobsen Skanderup, Jimmy Bok Yan So, Wei Peng Yong, Qingfeng Chen, Jonathan Göke, Patrick Tan
Journal: Gut (2021)

Objectives Epigenomic alterations in cancer interact with the immune microenvironment to dictate tumour evolution and therapeutic response. We aimed to study the regulation of the tumour immune microenvironment through epigenetic alternate promoter use in gastric cancer and to expand our findings to other gastrointestinal tumours. Design Alternate promoter burden (APB) was quantified using a novel bioinformatic algorithm ( proActiv ) to infer promoter activity from short-read RNA sequencing and samples categorised into APB high , APB int and APB low. Single-cell RNA sequencing was performed to analyse the intratumour immune microenvironment. A humanised mouse cancer in vivo model was used to explore dynamic temporal interactions between tumour kinetics, alternate promoter usage and the human immune system. Multiple cohorts of gastrointestinal tumours treated with immunotherapy were assessed for correlation between APB and treatment outcomes. Results APB high gastric cancer tumours expressed decreased levels of T-cell cytolytic activity and exhibited signatures of immune depletion. Single-cell RNAsequencing analysis confirmed distinct immunological populations and lower T-cell proportions in APB high tumours. Functional in vivo studies using ‘humanised mice’ harbouring an active human immune system revealed distinct temporal relationships between APB and tumour growth, with APB high tumours having almost no human T-cell infiltration. Analysis of immunotherapy-treated patients with GI cancer confirmed resistance of APB high tumours to immune checkpoint inhibition. APB high gastric cancer exhibited significantly poorer progression-free survival compared with APB low (median 55 days vs 121 days, HR 0.40, 95% CI 0.18 to 0.93, p=0.032). Conclusion These findings demonstrate an association between alternate promoter use and the tumour microenvironment, leading to immune evasion and immunotherapy resistance.
Ranasinhage Dayaratna Samaratunga
Authors: Mary Samaratunga
Journal: BMJ (2021)

Born in Sri Lanka, Ranasinhage Dayaratna Samaratunga studied medicine at the General Hospital Colombo and met his future wife, Mary, then a student nurse, in 1954. He passed his exams in 1957 and over the next 16 years, he …
<i>Notes from the Field</i>: Illicit Benzodiazepines Detected in Patients Evaluated in Emergency Departments for Suspected Opioid Overdose — Four States, October 6, 2020–March 9, 2021
Authors: Kim Aldy, Desiree Mustaquim, Sharan Campleman, Alison Meyn, Stephanie Abston, Alex Krotulski, Barry Logan, Matthew R. Gladden, Adrienne Hughes, Alexandra Amaducci, Joshua Shulman, Evan Schwarz, Paul Wax, Jeffrey Brent, Alex Manini
Journal: MMWR Morbidity and Mortality Weekly Report (2021)
Intravenous bamlanivimab use associates with reduced hospitalization in high-risk patients with mild to moderate COVID-19
Authors: Ravindra Ganesh, Colin F. Pawlowski, John C. O’Horo, Lori L. Arndt, Richard F. Arndt, Sarah J. Bell, Dennis M. Bierle, Molly Destro Borgen, Sara N. Hanson, Alexander Heyliger, Jennifer J. Larsen, Patrick J. Lenehan, Robert Orenstein, Arjun Puranik, Leigh L. Speicher, Sidna M. Tulledge-Scheitel, A.J. Venkatakrishnan, Caroline G. Wilker, Andrew D. Badley, Raymund R. Razonable
Journal: Journal of Clinical Investigation (2021)

BACKGROUND. Clinical data to support the use of bamlanivimab for the treatment of outpatients with mild to moderate coronavirus disease-19 (COVID-19) are needed.
26043 In vitro evaluation of anti-inflammatory properties of a multifunctional sunscreen
Authors: Francine Papaiordanou, Gabriela Pacheco de Oliveira, Jéssica Parolina Salvador, Flavia Cardoso Males, Antonio Carlos Amedeo Vatimo, Douglas Costa Morais, Stevin Zung
Journal: Journal of the American Academy of Dermatology (2021)
Assessment of the Diagnostic Efficiency of a Liquid Biopsy Assay for Early Detection of Gastric Cancer
Authors: Daisuke Izumi, Zhongxu Zhu, Yuetong Chen, Shusuke Toden, Xinying Huo, Mitsuro Kanda, Takatsugu Ishimoto, Dongying Gu, Miaomiao Tan, Yasuhiro Kodera, Hideo Baba, Wei Li, Jinfei Chen, Xin Wang, Ajay Goel
Journal: JAMA Network Open (2021)

Noninvasive detection of early-stage disease is a key strategy for reducing gastric cancer (GC)-associated patient mortality.To establish a novel, noninvasive, microRNA (miRNA)-based signature for the early detection of GC using a comprehensive biomarker discovery approach with retrospective and prospective validation.This diagnostic study was conducted in 4 phases using publicly available genome sequences and tissue samples from patients at an academic medical center in Japan, and validated with retrospective multicenter cohorts of patients with GC. Three tissue miRNA data sets were used to identify a miRNA signature that discriminated GC vs normal tissues. The robustness of this signature was assessed in serum from 2 retrospective cohorts of patients with GC. A risk-scoring model was derived, then the performance of the miRNA signature was evaluated in a prospective cohort of patients with GC. The robustness of the miRNA signature was compared with current blood-based markers, and a cost-effectiveness analysis of the miRNA signature against the current practice of endoscopy was performed. All clinical samples used for this study were collected and data analyzed between April 1997 and March 2018.Assessment of diagnostic efficiency on the basis of area under the curve (AUC), specificity, and sensitivity.The data sets for the genome-wide expression profiling analysis stage included 598 total patient samples (284 [55.4%] from men; mean [SE] patient age, 65.7 [0.5] years). The resulting 10-miRNA signature was validated in 2 retrospective GC serum cohorts (586 patients; 348 [59.4%] men, mean [SE] age, 66.0 [0.7] years), which led to the establishment of a 5-miRNA signature (AUC, 0.90; 95% CI, 0.85-0.94) that also exhibited high levels of diagnostic performance in patients with stage I disease (AUC, 0.89; 95% CI, 0.83-0.94). A risk-scoring model was derived and the assay was optimized to a minimal number of miRNAs. The performance of the resulting 3-miRNA signature was then validated in a prospective cohort of patients with GC (349 patients; 124 [70.5%] men, median [range] age, 66.0 [0.66] years). The final 3-miRNA signature (miR-18a, miR-181b, and miR-335) exhibited high diagnostic accuracy in all stages of patients (AUC, 0.86; 95% CI 0.83-0.90), including in patients with stage I disease (AUC, 0.85; 95% CI, 0.79-0.91). Furthermore, this miRNA signature was superior to currently used blood markers and outperformed the endoscopic screening in a cost-effectiveness analysis (incremental cost-effectiveness ratio, CNY ¥16162.5 per quality-adjusted life-year [USD $2304.80 per quality-adjusted life-year]).These results suggest the potential clinical significance of the 3-miRNA signature as a noninvasive, cost-effective, and facile assay for the early detection of GC.
PSYCHOPHYSIOLOGICAL STUDY OF MENTALLY ILL PATIENTS
Authors: DANIEL FUNKENSTEIN, MILTON GREENBLATT, STEVEN ROOT, HARRY C. SOLOMON
Journal: American Journal of Psychiatry (1949)

(1) The physiological and psychological response to intravenous epinephrine and intramuscular mecholyl of 24 neuropsychiatric patients was studied before and after a series of electric shock treatments. Special attention was given to the curves of systolic blood pressure following the injection of the drugs. (2) Over-all effects of electric shock were: (a) A lowering of the resting blood pressure level. (b) An increase in the systolic blood pressure response after intravenous epinephrine. (c) A lessened systolic blood pressure response after intramuscular mecholyl. These changes were usually accompanied by clinical improvement. (3) Those patients who before shock treatment experienced an anxiety attack or a frank chill after injection of mecholyl showed a dramatic clinical response to electric shock treatment. Not only was their clinical condition greatly improved after a few electric shock treatments, but it was no longer possible to precipitate an anxiety attack or a chill by intramuscular mecholyl. (4) Those patients with pretreatment high response to intravenous epinephrine (80 mm. Hg. or more) or with anxiety attacks precipitable by epinephrine showed no clinical improvement after electric shock. Anxiety was made worse. (5) Several patients failed to show any change in pattern of response to autonomic drugs after electric shock treatment and these patients failed to show any sustained improvement in clinical condition.
Respiratory epithelial cell responses to SARS-CoV-2 in COVID-19
Authors: James P Bridges, Eszter K Vladar, Hua Huang, Robert J Mason
Journal: Thorax (2021)

COVID-19 has different clinical stages, and effective therapy depends on the location and extent of the infection. The purpose of this review is to provide a background for understanding the progression of the disease throughout the pulmonary epithelium and discuss therapeutic options. The prime sites for infection that will be contrasted in this review are the conducting airways and the gas exchange portions of the lung. These two sites are characterised by distinct cellular composition and innate immune responses, which suggests the use of distinct therapeutic agents. In the nose, ciliated cells are the primary target cells for SARS-CoV-2 viral infection, replication and release. Infected cells shed their cilia, which disables mucociliary clearance. Evidence further points to a suppressed or incompletely activated innate immune response to SARS-CoV-2 infection in the upper airways. Asymptomatic individuals can still have a productive viral infection and infect others. In the gas exchange portion of the lung, the alveolar type II epithelial cell is the main target cell type. Cell death and marked innate immune response during infection likely contribute to alveolar damage and resultant acute respiratory distress syndrome. Alveolar infection can precipitate a hyperinflammatory state, which is the target of many therapies in severe COVID-19. Disease resolution in the lung is variable and may include scaring and long-term sequalae because the alveolar type II cells are also progenitor cells for the alveolar epithelium.
Helen Salisbury: Lifelong lessons in learning
Authors: Helen Salisbury
Journal: BMJ (2021)

When I first became a GP registrar (having made a happy escape from a hospital specialty), I found my new colleagues' willingness to own up to the gaps in their knowledge very refreshing.The contrast between this and the fiercely competitive environment of academic grand rounds-where no one would dream of admitting ignorance-was crystallised one morning when a senior GP fished a paper result from his pigeonhole at coffee time, read it aloud, and asked, "Does anyone know what on earth this means?"Early in our careers it can be hard to admit ignorance but, for me, the licence not to know was one of the attractions of general practice.One cannot be expert in every area of medicine, so my role is often to look things up or to ask a specialist