tbuckley/cabot-search huggingface dataset:
In Vitro Analysis of<i>N</i>-Nitrosodimethylamine (NDMA) Formation From Ranitidine Under Simulated Gastrointestinal Conditions
Authors: Zongming Gao, Michael Karfunkle, Wei Ye, Tim Andres Marzan, Jingyue Yang, Timothy Lex, Cynthia Sommers, Jason D. Rodriguez, Xiaomei Han, Jeffry Florian, David G. Strauss, David A. Keire
Journal: JAMA Network Open (2021)

<h3>Importance</h3> A publication reported that<i>N</i>-nitrosodimethylamine (NDMA), a probable human carcinogen, was formed when ranitidine and nitrite were added to simulated gastric fluid. However, the nitrite concentrations used were greater than the range detected in acidic gastric fluid in prior clinical studies. <h3>Objective</h3> To characterize NDMA formation following the addition of ranitidine to simulated gastric fluid using combinations of fluid volume, pH levels, and nitrite concentrations, including physiologic levels. <h3>Design, Setting, and Participants</h3> One 150-mg ranitidine tablet was added to 50 or 250 mL of simulated gastric fluid with a range of nitrite concentrations from the upper range of physiologic (100 μmol/L) to higher concentrations (10 000 μmol/L) with a range of pH levels. NDMA amounts were assessed with a liquid chromatography–mass spectrometry method. <h3>Main Outcomes and Measures</h3> NDMA detected in simulated gastric fluid 2 hours after adding ranitidine. <h3>Results</h3> At a supraphysiologic nitrite concentration (ie, 10 000 μmol/L), the mean (SD) amount of NDMA detected in 50 mL simulated gastric fluid 2 hours after adding ranitidine increased from 222 (12) ng at pH 5 to 11 822 (434) ng at pH 1.2. Subsequent experiments with 50 mL of simulated gastric fluid at pH 1.2 with no added nitrite detected a mean (SD) of 22 (2) ng of NDMA, which is the background amount present in the ranitidine tablets. Similarly, at the upper range of physiologic nitrite (ie, 100 μmol/L) or at nitrite concentrations as much as 50-fold greater (1000 or 5000 μmol/L) only background mean (SD) amounts of NDMA were observed (21 [3] ng, 24 [2] ng, or 24 [3] ng, respectively). With 250 mL of simulated gastric fluid, no NDMA was detected at the upper physiologic range (100 μmol/L) or 10-fold physiologic (1000 μmol/L) nitrite concentrations, while NDMA was detected (mean [SD] level, 7353 [183] ng) at a 50-fold physiologic nitrite concentration (5000 μmol/L). <h3>Conclusions and Relevance</h3> In this in vitro study of ranitidine tablets added to simulated gastric fluid with different nitrite concentrations, ranitidine conversion to NDMA was not detected until nitrite was 5000 μmol/L, which is 50-fold greater than the upper range of physiologic gastric nitrite concentrations at acidic pH. These findings suggest that ranitidine is not converted to NDMA in gastric fluid at physiologic conditions.
Analyzing Genetic Differences Between Sporadic Primary and Secondary/Tertiary Hyperparathyroidism by Targeted Next-Generation Panel Sequencing
Authors: Yu Ah Hong, Ki Cheol Park, Bong Kyun Kim, Jina Lee, Woo Young Sun, Hae Joung Sul, Kyung-Ah Hwang, Won Jung Choi, Yoon-Kyung Chang, Suk Young Kim, Soyoung Shin, Joonhong Park
Journal: Endocrine Pathology (2021)
Evaluation and Comparison of Clinical and iLaboratory Characteristics of Patients With IgA Epidermolysis Bullosa Acquisita, Linear IgA Bullous Dermatosis, and IgG Epidermolysis Bullosa Acquisita
Authors: Mareike Becker, Nina Schumacher, Enno Schmidt, Detlef Zillikens, Christian D. Sadik
Journal: JAMA Dermatology (2021)

Immunoglobulin A (IgA) epidermolysis bullosa acquisita (EBA) is an autoimmune skin blistering disease with IgA autoantibodies directed against type VII collagen. There is debate whether it should be considered part of the clinical spectrum of linear IgA bullous dermatosis (LABD) or a separate disease entity.This cohort study aimed to define the clinical features and treatment responses of IgA EBA and anti-BP180-driven LABD, and to compare the prevalences of IgA EBA anti-BP180 LABD and classic IgG-mediated EBA in an autoimmune diagnostic laboratory database.This retrospective cohort study and case series study included demographic, immunopathologic, and serologic data from 300 patients diagnosed with IgA EBA, IgG EBA, or LABD. Furthermore, clinical features and treatment responses of IgA EBA were analyzed in a case series including 4 patients with IgA EBA. All patients from the database of the autoimmune diagnostic laboratory at the Department of Dermatology, University of Lübeck, Germany, who were diagnosed with IgA EBA, LABD, or IgG EBA between October 2010 and July 2019 were included. Four patients diagnosed with IgA EBA between October 2015 and January 2018 are described in detail.The clinical course of IgA EBA was observed before and during different treatments.The database search yielded 21 cases of IgA EBA (12 females [57%]/9 males [43%]), 222 cases of LABD (111 females [51%]/106 males [49]), and 57 cases of IgG EBA (29 females [50%]/28 males [48%]). The median (range) age of each cohort was 64 (4-81) years for IgA EBA, 56 (3-92) years for IgG EBA, and significantly older compared with IgG EBA (P = .002) for those with LAPD (median [range], 70 [1-94] years). The patients with IgA EBA exhibited heterogeneous clinical presentations that significantly differed from those of anti-BP180 LABD. All 4 patients with IgA EBA described in detail were first treated with dapsone, but only 1 responded to this treatment. The others required treatment with high-dose dexamethasone, rituximab, and/or intravenous immunoglobulins to achieve partial clinical remission.Overall, the findings of this cohort study and small case series suggest that IgA EBA may be more common than expected and may require more intensive systemic treatment than LABD, suggesting it should be considered a separate disease entity.
Outcomes of Unrelated Cord Blood Transplantation for Familial Hemophagocytic Lymphohistiocytosis: Risk Factors and Long Term Follow-up. an Analysis on Behalf of Eurocord, Cord Blood Committee of Cellular Therapy and Immunobiology Working Party of the EBMT and Inborn Errors Working Party of the EBMT
Authors: Juliana Montibeller Furtado E Silva, Annalisa Paviglianiti, Annalisa Ruggeri, Jaap Jan Boelens, Paul Veys, Ali Abdallah Ahmari, Franco Locatelli, Gerard Michel, Fernanda Volt, Chantal Kenzey, Petr Sedlacek, Kanchan Rao, Arjan Lankester, Eliane Gluckman, Vanderson Rocha
Journal: Blood (2017)
Global Burden of Cardiovascular Diseases
Authors: Salim Yusuf, Srinath Reddy, Stephanie Ôunpuu, Sonia Anand
Journal: Circulation (2001)

This two-part article provides an overview of the global burden of atherothrombotic cardiovascular disease. Part I initially discusses the epidemiological transition which has resulted in a decrease in deaths in childhood due to infections, with a concomitant increase in cardiovascular and other chronic diseases; and then provides estimates of the burden of cardiovascular (CV) diseases with specific focus on the developing countries. Next, we summarize key information on risk factors for cardiovascular disease (CVD) and indicate that their importance may have been underestimated. Then, we describe overarching factors influencing variations in CVD by ethnicity and region and the influence of urbanization. Part II of this article describes the burden of CV disease by specific region or ethnic group, the risk factors of importance, and possible strategies for prevention.
Sensing technologies and experimental platforms for the characterization of advanced oral drug delivery systems
Authors: Peter Ouma Okeyo, Sriram Thoppe Rajendran, Kinga Zór, Anja Boisen
Journal: Advanced Drug Delivery Reviews (2021)

Complex and miniaturized oral drug delivery systems are being developed rapidly for targeted, controlled drug release and improved bioavailability. Standard analytical techniques are widely used to characterize i) drug carrier and active pharmaceutical ingredients before loading into a delivery device (to ensure the solid form), and ii) the entire drug delivery system during the development process. However, in light of the complexity and the size of some of these systems, standard techniques as well as novel sensing technologies and experimental platforms need to be used in tandem. These technologies and platforms are discussed in this review, with a special focus on passive delivery systems in size range from a few 100 µm to a few mm. Challenges associated with characterizing these systems and evaluating their effect on oral drug delivery in the preclinical phase are also discussed.
AAV-mediated in vivo CAR gene therapy for targeting human T-cell leukemia
Authors: Waqas Nawaz, Bilian Huang, Shijie Xu, Yanlei Li, Linjing Zhu, Hu Yiqiao, Zhiwei Wu, Xilin Wu
Journal: Blood Cancer Journal (2021)

Chimeric antigen receptor (CAR) T-cell therapy is the most active field in immuno-oncology and brings substantial benefit to patients with B cell malignancies. However, the complex procedure for CAR T-cell generation hampers its widespread applications. Here, we describe a novel approach in which human CAR T cells can be generated within the host upon injecting an Adeno-associated virus (AAV) vector carrying the CAR gene, which we call AAV delivering CAR gene therapy (ACG). Upon single infusion into a humanized NOD.Cg-Prkdcscid Il2rgem26/Nju tumor mouse model of human T-cell leukemia, AAV generates sufficient numbers of potent in vivo CAR cells, resulting in tumor regression; these in vivo-generated CAR cells produce antitumor immunological characteristics. This instantaneous generation of in vivo CAR T cells may bypass the need for patient lymphodepletion, as well as the β processes of traditional CAR T-cell production, which may make CAR therapy simpler and less expensive. It may allow the development of intricate, individualized treatments in the form of on-demand and diverse therapies.
Abstract 281: Sigma-1 Receptor Dependent Pathway for a Protective Endoplasmic Reticulum Stress Response in Cardiomyocytes
Authors: Shafiul Alam, A. Wayne Orr, Christopher B. Pattillo, Md. Shenuarin Bhuiyan
Journal: Circulation Research (2016)

Rationale: We recently reported that Sigma 1 receptor (Sigmar1) is a molecular chaperone protein highly expressed in the heart. Studies involving different cancer and neuronal cell lines indicated Sigmar1 resides in the mitochondrion-associated ER membrane (MAM). However, the subcellular localization of Sigmar1 and the molecular function in ER-stress remains unknown in cardiomyocytes. Here we describe a function for Sigmar1 as an effector of an adaptive ER stress response. Objective: The objective of this study was to elucidate functional roles of Simgar1 in ER-stress in cardiomyocytes. Methods and Results: Subcellular fractionation of the mouse heart showed extensive localization of Sigmar1 in the MAM and mitochondrial fraction. To define the function in an ER-stress response, we used small interfering RNA-mediated Sigmar1 knockdown and adenovirus-mediated overexpression in cultured neonatal rat ventricular cardiomyocytes. We treated with tunicamycin to induce ER stress. In cardiomyocytes, tunicamycin increased C/EBP-homologous protein (CHOP) expression; Sigmar1 overexpression significantly decreased the CHOP expression. We found that Sigmar1 overexpression was sufficient to activate the nuclear transport of spliced X-box binding protein 1 (Xbp1s) with minimal effects in other adaptive ER stress proteins. Sigmar1 knockdown decreased the nuclear transport of Xbp1s, increased the expression of nuclear CHOP and significantly increased LDH release. We also observed significant Sigmar1 expression dependent increases in mitochondrial respiration in cardiomyocytes under ER stress. Hence, Sigmar1 can function inside the cell during disease remodeling to augment ER function and protect through a mechanism involving regulation of Xbp1s. Conclusions: Sigmar1 is an essential component of the adaptive ER stress response in cardiomyocytes. Sigmar1 can regulate ER-stress induced CHOP expression by activating XBP1s signaling in cardiomyocytes. Therefore, Sigmar1 residing at the ER-mitochondrion interface serves as an important subcellular entity in the regulation of cellular survival by enhancing the stress-response signaling between the ER and mitochondria.
Genetic correlation and causal relationships between cardio-metabolic traits and lung function impairment
Authors: Matthias Wielscher, Andre F. S. Amaral, Diana van der Plaat, Louise V. Wain, Sylvain Sebert, David Mosen-Ansorena, Juha Auvinen, Karl-Heinz Herzig, Abbas Dehghan, Debbie L. Jarvis, Marjo-Riitta Jarvelin
Journal: Genome Medicine (2021)

Associations of low lung function with features of poor cardio-metabolic health have been reported. It is, however, unclear whether these co-morbidities reflect causal associations, shared genetic heritability or are confounded by environmental factors.We performed three analyses: (1) cardio-metabolic health to lung function association tests in Northern Finland Birth cohort 1966, (2) cross-trait linkage disequilibrium score regression (LDSC) to compare genetic backgrounds and (3) Mendelian randomisation (MR) analysis to assess the causal effect of cardio-metabolic traits and disease on lung function, and vice versa (bidirectional MR). Genetic associations were obtained from the UK Biobank data or published large-scale genome-wide association studies (N > 82,000).We observed a negative genetic correlation between lung function and cardio-metabolic traits and diseases. In Mendelian Randomisation analysis (MR), we found associations between type 2 diabetes (T2D) instruments and forced vital capacity (FVC) as well as FEV1/FVC. Body mass index (BMI) instruments were associated to all lung function traits and C-reactive protein (CRP) instruments to FVC. These genetic associations provide evidence for a causal effect of cardio-metabolic traits on lung function. Multivariable MR suggested independence of these causal effects from other tested cardio-metabolic traits and diseases. Analysis of lung function specific SNPs revealed a potential causal effect of FEV1/FVC on blood pressure.The present study overcomes many limitations of observational studies by using Mendelian Randomisation. We provide evidence for an independent causal effect of T2D, CRP and BMI on lung function with some of the T2D effect on lung function being attributed to inflammatory mechanisms. Furthermore, this analysis suggests a potential causal effect of FEV1/FVC on blood pressure. Our detailed analysis of the interplay between cardio-metabolic traits and impaired lung function provides the opportunity to improve the quality of existing intervention strategies.
Museomics Dissects the Genetic Basis for Adaptive Seasonal Coloration in the Least Weasel
Authors: Inês Miranda, Iwona Giska, Liliana Farelo, João Pimenta, Marketa Zimova, Jarosław Bryk, Love Dalén, L Scott Mills, Karol Zub, José Melo-Ferreira
Journal: Molecular Biology and Evolution (2021)

Abstract Dissecting the link between genetic variation and adaptive phenotypes provides outstanding opportunities to understand fundamental evolutionary processes. Here, we use a museomics approach to investigate the genetic basis and evolution of winter coat coloration morphs in least weasels (Mustela nivalis), a repeated adaptation for camouflage in mammals with seasonal pelage color moults across regions with varying winter snow. Whole-genome sequence data were obtained from biological collections and mapped onto a newly assembled reference genome for the species. Sampling represented two replicate transition zones between nivalis and vulgaris coloration morphs in Europe, which typically develop white or brown winter coats, respectively. Population analyses showed that the morph distribution across transition zones is not a by-product of historical structure. Association scans linked a 200-kb genomic region to coloration morph, which was validated by genotyping museum specimens from intermorph experimental crosses. Genotyping the wild populations narrowed down the association to pigmentation gene MC1R and pinpointed a candidate amino acid change cosegregating with coloration morph. This polymorphism replaces an ancestral leucine residue by lysine at the start of the first extracellular loop of the protein in the vulgaris morph. A selective sweep signature overlapped the association region in vulgaris, suggesting that past adaptation favored winter-brown morphs and can anchor future adaptive responses to decreasing winter snow. Using biological collections as valuable resources to study natural adaptations, our study showed a new evolutionary route generating winter color variation in mammals and that seasonal camouflage can be modulated by changes at single key genes.
Why ‘best practice’ is not always best in sport
Authors: Will Greenberg, Jo Clubb
Journal: British Journal of Sports Medicine (2021)

As sport and exercise medicine clinicians, we are constantly faced with challenging decisions. We contend with a diverse range of physical and psychological ailments, how to optimise rehabilitation, clear players to return to play and even the advancement of training to improve performance. Accordingly, clinicians often seek to provide evidence-based ‘best practice’.1 Monocausal thinking may drive the adoption of so-called ‘best practice’.2 However, while evidence-based solutions can provide a foundation for decision making, the quest for ‘best practice’ may often be misplaced given the complexity of both sports performance and injury manifestations.3 4 

Problems arise in different contexts, requiring different responses. We may use the process of sense-making—defined as ‘how we make sense of the world so we can act in it’5—to understand and respond to such injury and performance dilemmas. A decision support framework from this field can benefit clinicians by guiding appropriate styles of thinking and responses to the array of problems faced.6 

Cynefin (pronounced ku- nev -in) is a conceptual framework used in industry, government and academia that aids decision making. It offers four principal decision-making domains that …
Characterization of the HLA-Class-II (HLAcII)/Therapeutic Factor VIII (FVIII)-Derived Peptidome By FVIII Domain and HLAcII Isomer
Authors: Marcio Almeida, Vincent P. Diego, Bernadette W. Luu, Marco Hofmann, Jose Antonio G. Hernandez, Juan Peralta, Joanne Curran, Miguel A Escobar, Rajalingam Raja, LV Dinh, Jerry S. Powell, Sarah Williams-Blangero, John Blangero, Eugene Maraskovsky, Tom Howard
Journal: Blood (2017)
Tissue engineering and 3D printing of bioartificial pancreas for regenerative medicine in diabetes
Authors: Andreas Alvin Purnomo Soetedjo, Jia Min Lee, Hwee Hui Lau, Guo Liang Goh, Jia An, Yexin Koh, Wai Yee Yeong, Adrian Kee Keong Teo
Journal: Trends in Endocrinology and Metabolism (2021)
Differential seeding and propagating efficiency of α-synuclein strains generated in different conditions
Authors: Di Liu, Jian-Jun Guo, Ji-Hui Su, Alexander Svanbergsson, Lin Yuan, Caroline Haikal, Wen Li, Gunnar Gouras, Jia-Yi Li
Journal: Translational Neurodegeneration (2021)

Accumulation of alpha-synuclein (α-syn) is a main pathological hallmark of Parkinson's and related diseases, which are collectively known as synucleinopathies. Growing evidence has supported that the same protein can induce remarkably distinct pathological progresses and disease phenotypes, suggesting the existence of strain difference among α-syn fibrils. Previous studies have shown that α-syn pathology can propagate from the peripheral nervous system (PNS) to the central nervous system (CNS) in a "prion-like" manner. However, the difference of the propagation potency from the periphery to CNS among different α-syn strains remains unknown and the effect of different generation processes of these strains on the potency of seeding and propagation remains to be revealed in more detail.Three strains of preformed α-syn fibrils (PFFs) were generated in different buffer conditions which varied in pH and ionic concentrations. The α-syn PFFs were intramuscularly (IM) injected into a novel bacterial artificial chromosome (BAC) transgenic mouse line that expresses wild-type human α-syn, and the efficiency of seeding and propagation of these PFFs from the PNS to the CNS was evaluated.The three strains of α-syn PFFs triggered distinct propagation patterns. The fibrils generated in mildly acidic buffer led to the most severe α-syn pathology, degeneration of motor neurons and microgliosis in the spinal cord.The different α-syn conformers generated in different conditions exhibited strain-specific pathology and propagation patterns from the periphery to the CNS, which further supports the view that α-syn strains may be responsible for the heterogeneity of pathological features and disease progresses among synucleinopathies.
COVID-19 in Patients Receiving CD20-depleting Immunochemotherapy for B-cell Lymphoma
Authors: Erik Gaitzsch, Verena Passerini, Elham Khatamzas, Carolin D. Strobl, Maximilian Muenchhoff, Clemens Scherer, Andreas Osterman, Michael Heide, Anna Reischer, Marion Subklewe, Alexandra Leutbecher, Benjamin Tast, Adrian Ruhle, Tobias Weiglein, Stephanie-Susanne Stecher, Hans J. Stemmler, Martin Dreyling, Philipp Girl, Enrico Georgi, Roman Wölfel, Laura Mateyka, Elvira D’Ippolito, Kilian Schober, Dirk H. Busch, Juliane Kager, Christoph D. Spinner, Matthias Treiber, Sebastian Rasch, Tobias Lahmer, Roman Iakoubov, Jochen Schneider, Ulrike Protzer, Christof Winter, Jürgen Ruland, Michael Quante, Oliver T. Keppler, Michael von Bergwelt-Baildon, Johannes Hellmuth, Oliver Weigert
Journal: HemaSphere (2021)

The clinical and immunological impact of B-cell depletion in the context of coronavirus disease 2019 (COVID-19) is unclear. We conducted a prospectively planned analysis of COVID-19 in patients who received B-cell depleting anti-CD20 antibodies and chemotherapy for B-cell lymphomas. The control cohort consisted of age- and sex-matched patients without lymphoma who were hospitalized because of COVID-19. We performed detailed clinical analyses, in-depth cellular and molecular immune profiling, and comprehensive virological studies in 12 patients with available biospecimens. B-cell depleted lymphoma patients had more severe and protracted clinical course (median hospitalization 88 versus 17 d). All patients actively receiving immunochemotherapy (n = 5) required ICU support including long-term mechanical ventilation. Neutrophil recovery following granulocyte colony stimulating factor stimulation coincided with hyperinflammation and clinical deterioration in 4 of the 5 patients. Immune cell profiling and gene expression analysis of peripheral blood mononuclear cells revealed early activation of monocytes/macrophages, neutrophils, and the complement system in B-cell depleted lymphoma patients, with subsequent exacerbation of the inflammatory response and dysfunctional interferon signaling at the time of clinical deterioration of COVID-19. Longitudinal immune cell profiling and functional in vitro assays showed SARS-CoV-2-specific CD8 + and CD4 + T-effector cell responses. Finally, we observed long-term detection of SARS-CoV-2 in respiratory specimens (median 84 versus 12 d) and an inability to mount lasting SARS-CoV-2 antibody responses in B-cell depleted lymphoma patients. In summary, we identified clinically relevant particularities of COVID-19 in lymphoma patients receiving B-cell depleting immunochemotherapies.
Sublingual Buprenorphine-Naloxone Compared With Injection Naltrexone for Opioid Use Disorder: Potential Utility of Patient Characteristics in Guiding Choice of Treatment
Authors: Edward V. Nunes, Jennifer M. Scodes, Martina Pavlicova, Joshua D. Lee, Patricia Novo, Aimee N.C. Campbell, John Rotrosen
Journal: American Journal of Psychiatry (2021)

Sublingual buprenorphine-naloxone and extended-release injection naltrexone are effective treatments, with distinct mechanisms, for opioid use disorder. The authors examined whether patients' demographic and clinical characteristics were associated with better response to one medication or the other.