tbuckley/cabot-search huggingface dataset:
John “Brian” Cocking
Authors: Alexander Marshall
Journal: BMJ (2021)

After a stroke and being in hospital for five weeks, John “Brian” Cocking sadly died in the Queen Elizabeth the Queen Mother Hospital (QUQM), Margate, Kent, where he had served as the consultant in general medicine and gastroenterology since 1973, and as medical director in 1993-97. He retired in 1999.

In reviewing his papers and speaking with friends and former colleagues, various themes became apparent about Brian—his modesty, ability, loyalty, duty, collaboration, tenacity, humour, and history.

Brian was born in Morecambe on 24 September 1936 and attended Lancaster Royal Grammar School from 1947, achieving success in academic and sporting subjects (rowing, athletics, and rugby) and leaving with a Lancashire County Major Scholarship in 1955, to read medicine at Emmanuel College Cambridge.

He immersed himself wholeheartedly into college life and, as Emmanuel’s rowing captain, was instrumental in introducing a coaching system that is now considered normal in elite sport, one of holistic performance management by in bringing teams of specialist coaches, including ex-Olympians, to train the college rowers with great success. Brian’s coxless four were nicknamed “Emma’s Famous Four” and were once described by Peter Haig-Thomas, the veteran rowing champion, as “the first crew he’d seen rowing properly since 1934.” The application of meticulous and specialist technical review to improve performance became a theme through …
I Have Chronic Pelvic Pain: What Should I Know?
Authors: Saundra Nguyen, Elizabeth Harleman
Journal: JAMA Internal Medicine (2021)

What Is Chronic Pelvic Pain?Chronic pelvic pain (CPP) is pain below the belly button that lasts for at least 6 months and can affect quality of life in many areas, including emotional, sexual, and economic well-being.It is a common condition that most often affects women, but it can affect people across the gender spectrum.
Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors in clinical trials for cancer immunotherapy
Authors: Kai Tang, Ya-Hong Wu, Yihui Song, Bin Yu
Journal: Journal of Hematology & Oncology (2021)

Abstract Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme enzyme that catalyzes the oxidation of L -tryptophan. Functionally, IDO1 has played a pivotal role in cancer immune escape via catalyzing the initial step of the kynurenine pathway, and overexpression of IDO1 is also associated with poor prognosis in various cancers. Currently, several small-molecule candidates and peptide vaccines are currently being assessed in clinical trials. Furthermore, the “proteolysis targeting chimera” (PROTAC) technology has also been successfully used in the development of IDO1 degraders, providing novel therapeutics for cancers. Herein, we review the biological functions of IDO1, structural biology and also extensively summarize medicinal chemistry strategies for the development of IDO1 inhibitors in clinical trials. The emerging PROTAC-based IDO1 degraders are also highlighted. This review may provide a comprehensive and updated overview on IDO1 inhibitors and their therapeutic potentials.
Data-Driven multi-Contrast spectral microstructure imaging with InSpect: INtegrated SPECTral component estimation and mapping
Authors: Paddy J. Slator, Jana Hutter, Razvan V. Marinescu, Marco Palombo, Laurence H. Jackson, Alison Ho, Lucy C. Chappell, Mary Rutherford, Joseph V. Hajnal, Daniel C. Alexander
Journal: Medical Image Analysis (2021)

We introduce and demonstrate an unsupervised machine learning technique for spectroscopic analysis of quantitative MRI experiments. Our algorithm supports estimation of one-dimensional spectra from single-contrast data, and multidimensional correlation spectra from simultaneous multi-contrast data. These spectrum-based approaches allow model-free investigation of tissue properties, but require regularised inversion of a Laplace transform or Fredholm integral, which is an ill-posed calculation. Here we present a method that addresses this limitation in a data-driven way. The algorithm simultaneously estimates a canonical basis of spectral components and voxelwise maps of their weightings, thereby pooling information across whole images to regularise the ill-posed problem. We show in simulations that our algorithm substantially outperforms current voxelwise spectral approaches. We demonstrate the method on multi-contrast diffusion-relaxometry placental MRI scans, revealing anatomically-relevant sub-structures, and identifying dysfunctional placentas. Our algorithm vastly reduces the data required to reliably estimate spectra, opening up the possibility of quantitative MRI spectroscopy in a wide range of new applications. Our InSpect code is available at github.com/paddyslator/inspect.
Abstract #1427: Over 1,600 genomic hot spots are associated with CML progression from chronic phase to blast crisis
Authors: Colin Grace, Diana Brazma, Julie Howard-Reeves, Elisabeth Nacheva
Journal: Cancer Research (2009)

The discovery of the BCR/ABL1 fusion within the Philadelphia chromosome in 1985 marked the start of new era in the understanding of the molecular basis of hematological malignancies. It has not only provided a tool for leukemia diagnosis, risk stratification, and monitoring of response to therapy, but also the rationale for a novel therapeutic approach: the use of small molecules designed to inhibit the tyrosine kinase activity of the BCR/ABL1 oncoprotein. However, cardinal questions regarding the production of the fusion gene and the events underlying the disease progression, remain poorly understood. The identification of cryptic deletions at der(9)t(9;22) fuelled expectations that submicroscopic lesions may mark disease evolution. We screened 83 CML samples, including 40 derived from patients in blast crisis (BC), for genome imbalances using array comparative genome hybridization (aCGH) with the Agilent 105k oligonucleotide chip at a resolution of 35Kb. We identified over 1,600 loci in blast crisis samples that displayed fluorescent ratios well in excess of expectations (SD > 4) in 3 or more samples (Hot Spots). As many as 60 Hot Spots unique to the advanced stage of the disease, were identified in 25 % or more cases. Comparison with chronic phase and 14 controls showed that the main bulk of the hot spots are associated with disease progression, whilst a few are reported as polymorphic genome features (copy number variations, CNVs). Many, though not all, of the genome loci specifically affected in blast phase samples were associated with known genes, most of which belong to Focal Adhesion (COL1A1, COL5A1, ITGB3, PRKCA, PTK2, RAC3), MAPK signaling (FGF11, MAP3K3, MAP2K6, MINK1, CACN1) and cell cycle control (p16, E2F5, ANAOC2, FZR1) pathways. Notably, the Hot Spots were found to be associated with the phenotype of the blast cells in advanced disease. Genes such as p16, PAX5, Ikaros, MLLT3 and HOXB7, were found exclusively in lymphoid blast transformation samples. The deletions of these loci, housed by the short arms of chromosomes 7 and 9, are seen only in samples that also carry imbalances consistent with rearrangements of both IgH and TCR genes. In contrast, the 45% of the known genes in myeloid BC samples were located at 17q11-qter, a further 40% shared equally by sequences at 8q21-qter, 9q34-qter, 17p11-pter and 19p13. In addition, a set of Hot Spots that coincided with known CNVs, such as NME7 (37/40), PPP1R12B (20/40) and RNF38 (38/40), were identified at frequencies well in excess of figures reported for occurrence in the disease free population and in our controls. In conclusion, these novel findings provide new insights into the genome aberrations associated with disease progression in BCR/ABL1 harbouring cells.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1427.
The H+-linked monocarboxylate transporter (MCT1/SLC16A1): A potential target in neuroblastoma
Authors: Jun Fang, Zhaoxi Zhong, Michael J. Morowitz, Qun Wang, Frank Sivo, John M. Maris, Miriam L. Wahl
Journal: Cancer Research (2004)

2719  Neuroblastoma (NB) is the most common extracranial solid tumor in children and is fatal in up to 50% of cases. In this work, we have demonstrated that NB cells have upregulated the H+-linked monocarboxylate transporter (MCT1/SLC16A1) when grown chronically at low pH to mimic the microenvironment of the tumor. The MCTs move lactate and protons out of the cell, so it was predicted that inhibition of this transporter could impact upon intracellular pH. Since extracellular pH is typically low in tumors, and this transporter is activated when extracellular pH is below 7.0, there should be some specificity for MCT inhibitors in targeting the tumor microenvironment as well, which has an average extracellular pH of 6.7. NB cells were grown at an extracellular pH of 7.3, then extracellular pH was lowered with and without a specific MCT1 inhibitor added. There were marked decreases in intracellular pH in a dose-dependent manner and as a function of degree of extracellular pH lowering. The effect on intracellular pH was tightly correlated with effects on viability, as determined by the MTT assay, and is correlated with tumor cell line aggressiveness and overexpression of MYCN. Myc is a regulator of lactate dehydrogenase, thus these findings likely have a direct relationship to one another. In order to determine the clinical relevance of these observations, we measured MCT1 mRNA expression in 101 diagnostic primary NBs by Affymetrix oligonucleotide DNA microarray hybridizations and quantitative RT-PCR. MCT1 was differentially expressed with high expression strongly associated with metastatic disease, MYCN oncogene amplification and decreased survival probability (P
Abstract 14887: Look Beyond the Coronaries: A Rare Cause of Acute Papillary Muscle Rupture
Authors: Calvin M Kagan, Benjamin Kenigsberg, Gaby WEISSMAN, Mark Hofmeyer, Samer S Najjar, Jayashree Krishnan, Christopher Barnett
Journal: Circulation (2020)

A 63-year-old male with numerous cardiac risk factors presented with two hours of rapidly progressing chest pain and shortness of breath. Exam was notable for respiratory distress requiring non-invasive mechanical ventilation and a holosystolic apical murmur radiating to the axilla. He had an elevated troponin and an electrocardiogram with anteroseptal ST depressions. He was diagnosed with a non-ST segment elevation acute coronary syndrome and taken for cardiac catheterization. Surprisingly, no occlusive epicardial disease was discovered. Left ventriculogram revealed engorgement of the left atrium and pulmonary arteries suggestive of severe mitral regurgitation. The mechanism of mitral regurgitation was unclear until transesophageal echocardiography showed a ruptured posteromedial papillary muscle with flail mitral valve, a picture classically caused by myocardial infarction. Cardiac MRI demonstrated preserved LV function with minor inferior apical hypokinesis, nonspecific endocardial late gadolinium enhancement in the inferior segments, and a small LV thrombus. An embolic myocardial infarction targeting a small territory involving posteromedial papillary muscle was thought most probable. The patient then underwent an uneventful mitral valve replacement and recovery. However, he returned two months later with severe biventricular dysfunction and cardiogenic shock with peripheral eosinophilia. Myocardial biopsy confirmed the diagnosis of eosinophilic myocarditis. An exhaustive workup for the etiology of his eosinophilia proved unrevealing; he was consequently diagnosed with the idiopathic subtype. The case highlights a rare but important clinical entity that has a varied phenotype. Our patient presented atypically with an acute papillary muscle rupture that mimicked an acute myocardial infarction, ultimately delaying diagnosis. As evidenced by our case, clinical suspicion of myocarditis should be high in all patients presenting with typical anginal symptoms with mechanical or circulatory compromise in the absence of acute coronary occlusion.
Targeting long noncoding RNA PMIF facilitates osteoprogenitor cells migrating to bone formation surface to promote bone formation during aging
Authors: Dijie Li, Jin Liu, Chaofei Yang, Ye Tian, Chong Yin, Lifang Hu, Zhihao Chen, Fan Zhao, Ru Zhang, Aiping Lu, Ge Zhang, Airong Qian
Journal: Theranostics (2021)

Rationale: The migration of mesenchymal osteoprogenitor cells (OPCs) to bone formation surface is the initial step of osteoblastogenesis before they undergo osteoblast differentiation and maturation for governing bone formation. However, whether the migration capacity of OPCs is compromised during aging and how it contributes to the aging-related bone formation reduction remain unexplored. In the present study, we identified a migration inhibitory factor (i.e., long noncoding RNA PMIF) and examined whether targeting lnc-PMIF could facilitate osteoprogenitor cells migrating to bone formation surface to promote bone formation during aging. Methods: Primary OPCs from young (6-momth-old) and aged (18-momth-old) C57BL/6 mice and stable lnc-PMIF knockdown/overexpression cell lines were used for in vitro and in vivo cell migration assay (i.e., wound healing assay, transwell assay and cell intratibial injection assay). RNA pulldown-MS/WB and RIP-qPCR were performed to identify the RNA binding proteins (RBPs) of lnc-PMIF. Truncations of lnc-PMIF and the identified RBP were engaged to determine the interaction motif between them by RNA pulldown-WB and EMSA. By cell-based therapy approach and by pharmacological approach, small interfering RNA (siRNA)-mediated lnc-PMIF knockdown were used in aged mice. The cell migration ability was evaluated by transwell assay and cell intratibial injection assay. The bone formation was evaluated by microCT analysis and bone morphometry analysis. Results: We reported that the decreased bone formation was accompanied by the reduced migration capacity of the bone marrow mesenchymal stem cells (BMSCs, the unique source of OPCs in bone marrow) in aged mice. We further identified that the long non-coding RNA PMIF (postulated migration inhibitory factor) (i.e., lnc-PMIF) was highly expressed in BMSCs from aged mice and responsible for the reduced migration capacity of aged OPCs to bone formation surface. Mechanistically, we found that lnc-PMIF could bind to human antigen R (HuR) for interrupting the HuR-β-actin mRNA interaction, therefore inhibit the expression of β-actin for suppressing the migration of aged OPCs. We also authenticated a functionally conserved human lncRNA ortholog of the murine lnc-PMIF. By cell-based therapy approach, we demonstrated that replenishing the aged BMSCs with small interfering RNA (siRNA)-mediated lnc-PMIF knockdown could promote bone formation in aged mice. By pharmacological approach, we showed that targeted delivery of lnc-PMIF siRNA approaching the OPCs around the bone formation surface could also promote bone formation in aged mice. Conclusion: Toward translational medicine, this study hints that targeting lnc-PMIF to facilitate aged OPCs migrating to bone formation surface could be a brand-new anabolic strategy for aging-related osteoporosis.
Endotypes of chronic rhinosinusitis: Relationships to disease phenotypes, pathogenesis, clinical findings, and treatment approaches
Authors: Atsushi Kato, Anju T. Peters, Whitney W. Stevens, Robert P. Schleimer, Bruce K. Tan, Robert C. Kern
Journal: Allergy (2021)

Abstract Chronic rhinosinusitis (CRS) is a common clinical syndrome that produces significant morbidity and costs to our health system. The study of CRS has progressed from an era focused on phenotype to include endotype‐based information. Phenotypic classification has identified clinical heterogeneity in CRS based on endoscopically observed features such as presence of nasal polyps, presence of comorbid or systemic diseases, and timing of disease onset. More recently, laboratory‐based findings have established CRS endotype based upon specific mechanisms or molecular biomarkers. Understanding the basis of widespread heterogeneity in the manifestations of CRS is advanced by findings that the three main endotypes, Type 1, 2, and 3, orchestrate the expression of three distinct large sets of genes. The development and use of improved methods of endotyping disease in the clinic are ushering in an expansion of the use of biological therapies targeting Type 2 inflammation now and perhaps other inflammatory endotypes in the near future. The purpose of this review is to discuss the phenotypic and endotypic heterogeneity of CRS from the perspective of advancing the understanding of the pathogenesis and improvement of treatment approaches and outcomes.
SARS-CoV-2 as a superantigen in multisystem inflammatory syndrome in children
Authors: Theodore Kouo, Worarat Chaisawangwong
Journal: Journal of Clinical Investigation (2021)

Multisystem inflammatory syndrome in children (MIS-C) is a rare but deadly new disease in children that rapidly progresses to hyperinflammation and shock, and can lead to multiple organ failure if unrecognized. It has been found to be temporally associated with the COVID-19 pandemic and is often associated with SARS-CoV-2 exposure in children. In this issue of the JCI, Porritt, Paschold, et al. identify restricted T cell receptor (TCR) β-chain variable domain (Vβ) usage in patients with severe MIS-C, indicating a potential role for SARS-CoV-2 as a superantigen. These findings suggest that a blood test that determines the presence of specific TCRβ variable gene (TRBV) segments may identify patients at risk for severe MIS-C.
Two for one: endoscopic drainage of a large pyogenic liver abscess at the time of ERCP
Authors: Arvind J. Trindade, Nichol Martinez, Petros C. Benias, Larry Miller
Journal: Endoscopy (2021)

An 84-year-old man with chronic lung disease on home oxygen, coronary artery disease with coronary stents, and diabetes, presented with right upper quadrant pain and fever. Magnetic resonance imaging was performed that showed choledocholithiasis in a dilated bile duct. Additionally, a large 7-cm fluid-filled cavity was seen in the left lobe of the liver abutting the stomach, consistent with an abscess ([Fig. 1]). Given the choledocholithiasis and lack of travel history, the presumptive diagnosis was pyogenic liver abscess.
<i>Cis</i>-epistasis at the <i>LPA</i> locus and risk of cardiovascular diseases
Authors: Lingyao Zeng, Sylvain Moser, Nazanin Mirza-Schreiber, Claudia Lamina, Stefan Coassin, Christopher P Nelson, Tarmo Annilo, Oscar Franzén, Marcus E Kleber, Salome Mack, Till F M Andlauer, Beibei Jiang, Barbara Stiller, Ling Li, Christina Willenborg, Matthias Munz, Thorsten Kessler, Adnan Kastrati, Karl-Ludwig Laugwitz, Jeanette Erdmann, Susanne Moebus, Markus M Nöthen, Annette Peters, Konstantin Strauch, Martina Müller-Nurasyid, Christian Gieger, Thomas Meitinger, Elisabeth Steinhagen-Thiessen, Winfried März, Andres Metspalu, Johan L M Björkegren, Nilesh J Samani, Florian Kronenberg, Bertram Müller-Myhsok, Heribert Schunkert
Journal: Cardiovascular Research (2021)

Coronary artery disease (CAD) has a strong genetic predisposition. However, despite substantial discoveries made by genome-wide association studies (GWAS), a large proportion of heritability awaits identification. Non-additive genetic effects might be responsible for part of the unaccounted genetic variance. Here, we attempted a proof-of-concept study to identify non-additive genetic effects, namely epistatic interactions, associated with CAD.
IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 lungs and inflammatory diseases with tissue inflammation
Authors: Fan Zhang, Joseph R. Mears, Lorien Shakib, Jessica I. Beynor, Sara Shanaj, Ilya Korsunsky, Aparna Nathan, Laura T. Donlin, Soumya Raychaudhuri
Journal: Genome Medicine (2021)

Abstract Background Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. Methods To identify cellular phenotypes that may be shared across tissues affected by disparate inflammatory diseases, we developed a meta-analysis and integration pipeline that models and removes the effects of technology, tissue of origin, and donor that confound cell-type identification. Using this approach, we integrated &gt; 300,000 single-cell transcriptomic profiles from COVID-19-affected lungs and tissues from healthy subjects and patients with five inflammatory diseases: rheumatoid arthritis (RA), Crohn’s disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), and interstitial lung disease. We tested the association of shared immune states with severe/inflamed status compared to healthy control using mixed-effects modeling. To define environmental factors within these tissues that shape shared macrophage phenotypes, we stimulated human blood-derived macrophages with defined combinations of inflammatory factors, emphasizing in particular antiviral interferons IFN-beta (IFN-β) and IFN-gamma (IFN-γ), and pro-inflammatory cytokines such as TNF. Results We built an immune cell reference consisting of &gt; 300,000 single-cell profiles from 125 healthy or disease-affected donors from COVID-19 and five inflammatory diseases. We observed a CXCL10+ CCL2+ inflammatory macrophage state that is shared and strikingly abundant in severe COVID-19 bronchoalveolar lavage samples, inflamed RA synovium, inflamed CD ileum, and UC colon. These cells exhibited a distinct arrangement of pro-inflammatory and interferon response genes, including elevated levels of CXCL10 , CXCL9 , CCL2 , CCL3 , GBP1, STAT1 , and IL1B . Further, we found this macrophage phenotype is induced upon co-stimulation by IFN-γ and TNF-α. Conclusions Our integrative analysis identified immune cell states shared across inflamed tissues affected by inflammatory diseases and COVID-19. Our study supports a key role for IFN-γ together with TNF-α in driving an abundant inflammatory macrophage phenotype in severe COVID-19-affected lungs, as well as inflamed RA synovium, CD ileum, and UC colon, which may be targeted by existing immunomodulatory therapies.
Multivalent Aptamer‐Functionalized Single‐Strand RNA Origami as Effective, Target‐Specific Anticoagulants with Corresponding Reversal Agents
Authors: Abhichart Krissanaprasit, Carson M. Key, Kristen Froehlich, Sahil Pontula, Emily Mihalko, Daniel M. Dupont, Ebbe S. Andersen, Jørgen Kjems, Ashley C. Brown, Thomas H. LaBean
Journal: Advanced Healthcare Materials (2021)

Abstract Anticoagulants are commonly utilized during surgeries and to treat thrombotic diseases like stroke and deep vein thrombosis. However, conventional anticoagulants have serious side‐effects, narrow therapeutic windows, and lack safe reversal agents (antidotes). Here, an alternative RNA origami displaying RNA aptamers as target‐specific anticoagulant is described. Improved design and construction techniques for self‐folding, single‐molecule RNA origami as a platform for displaying pre‐selected RNA aptamers with precise orientational and spatial control are reported. Nuclease resistance is added using 2′‐fluoro‐modified pyrimidines during in vitro transcription. When four aptamers are displayed on the RNA origami platform, the measured thrombin inhibition and anticoagulation activity is higher than observed for free aptamers, ssRNA‐linked RNA aptamers, and RNA origami displaying fewer aptamers. Importantly, thrombin inhibition is immediately switched off by addition of specific reversal agents. Results for single‐stranded DNA (ssDNA) and single‐stranded peptide nucleic acid (PNA) antidotes show restoration of 63% and 95% coagulation activity, respectively. To demonstrate potential for practical, long‐term storage for clinical use, RNA origami is freeze‐dried, and stored at room temperature. Freshly produced and freeze‐dried RNA show identical levels of activity in coagulation assays. Compared to current commercial intravenous anticoagulants, RNA origami‐based molecules show promise as safer alternatives with rapid activity switching for future therapeutic applications.