tbuckley/cabot-search huggingface dataset:
TrkC Is Essential for Nephron Function and Trans-Activates Igf1R Signaling
Authors: Carolin Lepa, Sascha Hoppe, Antje Stöber, Boris V. Skryabin, Laura Katharina Sievers, Barbara Heitplatz, Giuliano Ciarimboli, Ute Neugebauer, Maja T. Lindenmeyer, Clemens D. Cohen, Hannes C.A. Drexler, Peter Boor, Thomas Weide, Hermann Pavenstädt, Britta George
Journal: Journal of the American Society of Nephrology (2020)

Background Injury to kidney podocytes often results in chronic glomerular disease and consecutive nephron malfunction. For most glomerular diseases, targeted therapies are lacking. Thus, it is important to identify novel signaling pathways contributing to glomerular disease. Neurotrophic tyrosine kinase receptor 3 ( TrkC ) is expressed in podocytes and the protein transmits signals to the podocyte actin cytoskeleton. Methods Nephron-specific TrkC knockout ( TrkC-KO ) and nephron-specific TrkC -overexpressing ( TrkC-OE ) mice were generated to dissect the role of TrkC in nephron development and maintenance. Results Both TrkC-KO and TrkC-OE mice exhibited enlarged glomeruli, mesangial proliferation, basement membrane thickening, albuminuria, podocyte loss, and aspects of FSGS during aging. Igf1 receptor (Igf1R)–associated gene expression was dysregulated in TrkC-KO mouse glomeruli. Phosphoproteins associated with insulin, erb-b2 receptor tyrosine kinase (Erbb), and Toll-like receptor signaling were enriched in lysates of podocytes treated with the TrkC ligand neurotrophin-3 (Nt-3). Activation of TrkC by Nt-3 resulted in phosphorylation of the Igf1R on activating tyrosine residues in podocytes. Igf1R phosphorylation was increased in TrkC-OE mouse kidneys while it was decreased in TrkC-KO kidneys. Furthermore, TrkC expression was elevated in glomerular tissue of patients with diabetic kidney disease compared with control glomerular tissue. Conclusions Our results show that TrkC is essential for maintaining glomerular integrity. Furthermore, TrkC modulates Igf-related signaling in podocytes.
SAGE analysis of human metastatic and non-metastatic prostate cancer xenograft sublines from a single patient.
Authors: Akira Watahiki, Yuwei Wang, Hui Xue, Dong Lin, Lin Liu, Fang Zhang, Victor Ling, Y.Z. Wang
Journal: Cancer Research (2007)

4717  Malignant progression of prostate cancers results in metastasis, poor response to hormonal treatment and to chemotherapy. Identification of molecular markers predictive of malignant progression in primary prostate cancers is therefore of untmost importance for controlling this disease. We have previously reported the establishment of two transplantable prostate cancer tissue xenograft lines (a metastatic, PCa1-met, and a non-metastatic subline, PCa2) from a single patient’s primary tumor. In the present study we have subjected the two tumor sublines to Serial Analysis of Gene Expression (SAGE) with a view to identifying genes associated with metastatic and non-metastatic abilities. RNA was extracted from same generation and orthotopically grafted xenograft tissues. LongSAGE libraries were prepared and tags were sequenced, i.e. 132.163 tags (containing 35,186 unique tags) from the metastatic subline and 134,206 tags (containing 37,646 unique tags) from the non-metastatic subline. LongSAGE tags from the two libraries were annotated to cancer tissue (human) or stromal tissue (mouse), using human/mouse Genome and Unigene sequence data. A total of 28,567 unique tags were annotated in only human Genome sequences and 24,160 unique tags were annotated in only human Unigene sequences. The cancer (human) tags of the metastatic and non-metastatic sublines were then compared for identification of genes showing significant differences in expression. Various candidate genes were detected, including some not previously associated with prostate cancer. Some of these genes and their differential expressions were confirmed by real time PCR using various generations of the sublines. Xenografted tumor tissue sublines obtained from one patient appear to provide a good tool for screening genes that are responsible for a particular phenotype. This new approach, which avoids differences between individuals, overcomes the heterogeneity in patients’ tumor, could also be used for tumor-stroma specific expression pattern analysis. Supported by a Strategic Research Grant on Genomics and Proteomics of Metastatic Cancer from Cancer Research Society, Canada and a grant from the US Army Department of Defense, USAMRMC W81XWH-04-1-0290 (Y.Z.W.).
PTU-046 Developing anaesthetist-delivered propofol sedation for advanced endoscopy
Authors: I Smith, S Hebbar, K Lau, D Durkin
Journal: Gut (2017)

Introduction  Following recommendations from the Royal College of Anaesthetists (RCA) and British Society of Gastroenterology (BSG)1 we report our results of propofol sedation for complex endoscopic procedures delivered by a single consultant anaesthetist over a four year period.  Method  A service level agreement was used to deliver an average of one session per week to which were scheduled procedures which were complex or could previously not be completed successfully due to inadequate sedation or extreme patient anxiety. Deep sedation was provided by intermittent bolus doses of propofol, supplemented with fentanyl where necessary, titrated to clinical effect. Patients were usually in the semi-prone or lateral position and spontaneously breathed air supplemented with nasal oxygen. Service evaluation included patient recall, endoscopist satisfaction with conditions, procedural success and adverse outcomes.  Results  Over four years we completed 811 procedures, 44% of which were for endoscopic retrograde cholangiopancreatography (ERCP) with the remainder comprising a diverse range of endoscopic procedures of 3–156 min duration. These included endoscopic mucosal resection (EMR) polypectomies (54), endoscopic ultrasound (55), oesophageal dilatation (37) and percutaneous endoscopic gastrostomy (PEG) insertion (31). 654 procedures were completed with propofol only while 157 received 25–100 µg fentanyl, mainly due to anticipated post-procedural pain. Procedural conditions were excellent in 80.9% of cases and very good (14.9%) or good in the remainder. 209 procedures were completed which had been previously abandoned, 195 patients (24%) had a better experience than previously and none recalled any part of their procedure. Only 30 procedures were unable to be completed, mostly for technical reasons. Three patients required transient bag and mask ventilation and nasal airways were used in nine patients. Most patients required no airway support, 22.7% required occasional chin support and 4.4% required almost continuous chin support. No patients required tracheal intubation or vasopressor support.  Conclusion  These guidelines facilitated a propofol sedation service with considerable benefits for patients and endoscopists. Although established to facilitate ERCP, the service rapidly expanded to meet demands, due to complexity or patient anxiety, of other endoscopic procedures, which ultimately comprised more than half the caseload. Provision of deep propofol sedation by a consultant anaesthetist in patients undergoing endoscopy with an unsecured airway appears practical, effective and efficient. Small adjustments to the airway were fairly common but the incidence of adverse events and requirement for airway instrumentation was low.  Reference  . RCA/BSG joint working party. Guidance for the use of propofol sedation for adult patients undergoing ERCP and other complex upper GI endoscopic procedures, 2011.  Disclosure of Interest  None Declared
A case of severe thrombocytopenia in a patient with COVID-19 receiving continuous venovenous hemodialysis
Authors: B. S. F. Chang, R. Parikh, R. Wanchoo, V. Bijol, K. D. Jhaveri
Journal: Journal of the American Society of Nephrology (2020)

Introduction: We describe a patient with COVID-19 and clinically significant kidney biopsy proven TMA Case Description: 69-year-old Caucasian female with medical history of asthma came to the ED with productive cough, fever and dyspnea for 2 weeks  She was afebrile, tachypneic and hypoxic  Initial laboratories showed a normal WBC, hemoglobin level and platelet count  Inflammatory markers were elevated  SARS-CoV-2 infection was confirmed by PCR assay  CXR showed bilateral diffuse patchy opacities  Treated with hydroxychloroquine, enoxaparin and oxygen was started  Patient received anakinra and tocilizumab  On day 12, the patient developed thrombocytopenia, anemia and worsening kidney function concerning for microangiopathic hemolytic anemia  Due to worsening hypoxemia, patient received convalescent plasma  On day 17, she was intubated due to worsening respiratory failure  Findings suggestive of hemolysis were present  Urinalysis showed hematuria and proteinuria  Patient's kidney function worsened requiring initiation of CRRT  On day 20, the patient underwent a kidney biopsy that revealed severe acute TMA with cortical necrosis  Beta 2 glycoprotein-1 IgM levels were elevated, antiphospholipid antibodies were absent  A disintegrin and ADAMTS13 level were not low  C3,C4 were in normal range  Heparin induced antibody testing was negative  Coagulation parameters were normal  Kidney doppler was unremarkable  No other systemic findings of macro thrombi were found  Low factor H complement antigen, elevated plasma CBb complement and plasma SC5b-9 complement levels suggesting an activation of the alternative complement pathway were found  Genetic testing was not done  Plasma exchange was not performed, but received a single dose of eculizumab on day 21  Unfortunately, she died on day 23  Discussion: Coagulopathy associated with SARS-CoV-2 has been widely reported  Profound hypoxia, inflammation, disseminated intravascular coagulation(DIC) have all been implicated as potential causes, but were not present in our patient  To the best of our knowledge, we report the first case of TMA associated with SARS-CoV-2 with presence of diffuse cortical necrosis and widespread microthrombi in kidney biopsy  It is not clear if the virus played a direct pathogenic role or unmasked a latent complement defect leading to widespread endothelial damage and micro thrombi
Re: Marcus J. Drake, Amanda L. Lewis, Grace J. Young, et al. Diagnostic Assessment of Lower Urinary Tract Symptoms in Men Considering Prostate Surgery: A Noninferiority Randomised Controlled Trial of Urodynamics in 26 Hospitals. Eur Urol 2020;78:701–10
Authors: Satoshi Funada, Takashi Yoshioka, Yan Luo
Journal: European Urology (2020)
Growth factor delivery using extracellular matrix-mimicking substrates for musculoskeletal tissue engineering and repair
Authors: Robert C.H. Gresham, Chelsea S. Bahney, J. Kent Leach
Journal: Bioactive Materials (2020)

Therapeutic approaches for musculoskeletal tissue regeneration commonly employ growth factors (GFs) to influence neighboring cells and promote migration, proliferation, or differentiation. Despite promising results in preclinical models, the use of inductive biomacromolecules has achieved limited success in translation to the clinic. The field has yet to sufficiently overcome substantial hurdles such as poor spatiotemporal control and supraphysiological dosages, which commonly result in detrimental side effects. Physiological presentation and retention of biomacromolecules is regulated by the extracellular matrix (ECM), which acts as a reservoir for GFs via electrostatic interactions. Advances in the manipulation of extracellular proteins, decellularized tissues, and synthetic ECM-mimetic applications across a range of biomaterials have increased the ability to direct the presentation of GFs. Successful application of biomaterial technologies utilizing ECM mimetics increases tissue regeneration without the reliance on supraphysiological doses of inductive biomacromolecules. This review describes recent strategies to manage GF presentation using ECM-mimetic substrates for the regeneration of bone, cartilage, and muscle.
Successful Recovery of COVID-19 Pneumonia in a Kidney Transplant Recipient with a Regimen Consisting of Favipiravir, Azithromycin, Nafamostat Mesylate (NM), and Intravenous Immunoglobulin (IVIg)
Authors: Sumi Hidaka, Kunihiro Ishioka, Hidekazu Moriya, Yasuhiro Mochida, Hiroyuki Suzuki, Takayasu Ohtake, Shuzo Kobayashi
Journal: Journal of the American Society of Nephrology (2020)

Hidaka, Sumi; Ishioka, Kunihiro; Moriya, Hidekazu; Mochida, Yasuhiro; Suzuki, Hiroyuki; Ohtake, Takayasu; Kobayashi, Shuzo Author Information
Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis
Authors: Jun Li, Mercedes A. Duran, Ninjit Dhanota, Walid K. Chatila, Sarah E. Bettigole, John Kwon, Roshan K. Sriram, Matthew P. Humphries, Manuel Salto-Tellez, Jacqueline A. James, Matthew G. Hanna, Johannes C. Melms, Sreeram Vallabhaneni, Kevin Litchfield, Ieva Usaite, Dhruva Biswas, Rohan Bareja, Hao Wei Li, Maria Laura Martin, Princesca Dorsaint, Julie-Ann Cavallo, Peng Li, Chantal Pauli, Lee Gottesdiener, Benjamin J. DiPardo, Travis J. Hollmann, Taha Merghoub, Hannah Y. Wen, Jorge S. Reis-Filho, Nadeem Riaz, Shin-San Michael Su, Anusha Kalbasi, Neil Vasan, Simon N. Powell, Jedd D. Wolchok, Olivier Elemento, Charles Swanton, Alexander N. Shoushtari, Eileen E. Parkes, Benjamin Izar, Samuel F. Bakhoum
Journal: Cancer Discovery (2020)

Abstract Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS–STING innate immune pathway. How tumors co-opt inflammatory signaling while evading immune surveillance remains unknown. Here, we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune-stimulatory metabolite whose breakdown products include the immune suppressor adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wild-type ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti–PD-1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune-suppressive pathway. Significance: Chromosomal instability promotes metastasis by generating chronic tumor inflammation. ENPP1 facilitates metastasis and enables tumor cells to tolerate inflammation by hydrolyzing the immunotransmitter cGAMP, preventing its transfer from cancer cells to immune cells. This article is highlighted in the In This Issue feature, p. 995
The BMJ wins libel case brought by gynaecologist
Authors: Zosia Kmietowicz
Journal: BMJ (2020)

A High Court judge has dismissed a claim from a gynaecologist who sought damages from The BMJ for defamation after his fitness to practise case was reported in the journal.

In December 2016 The BMJ reported1 that Joseph Onwude, a consultant gynaecologist, was struck off by a medical practitioners tribunal for dishonesty and misconduct that was incompatible with registration.

Onwude, who qualified in Nigeria in 1981 and trained in Dublin and Leeds before becoming a fellow of the Royal College of Obstetricians and Gynaecologists, appealed against the tribunal’s decision.

In May 2017 a High Court judge ruled that the tribunal in the case had reached a conclusion that “no reasonable tribunal could conceivably have reached,” and the decision to erase him was quashed, including the most serious …
Abstract 12540: Neural Crest Cell-derived Wnt5a Regulates Planar Cell Polarity in Cranial Second Heart Field Progenitor Cells
Authors: Omar Toubat, Prashan De Zoysa, Jongkyu Choi, Drayton Harvey, Henry Sucov, Ram Kumar Subramanyan
Journal: Circulation (2020)

Introduction: Wnt5a is a known regulator of planar cell polarity (PCP) signaling in second heart field (SHF) progenitor cells. It is generally believed that Wnt5a ligands are secreted by the SHF; however, SHF-specific conditional deletion of Wnt5a does not recapitulate outflow tract (OFT) defects observed in global Wnt5a mutants. Hypothesis: Given the proximity and interaction between neural crest cells (NCC) and cranial SHF that contributes to the developing OFT, we hypothesize that NCC may serve as an additional source of Wnt5a for SHF progenitors. Methods: Wnt5a was conditionally deleted in the neural crest using transgenic Wnt1-cre mice. Embryos were harvested from control and mutant litter mates and immunofluoresence, in situ hybridization, and hematoxylin-eosin stains were performed on histologic sections using standard techniques. India ink injections were performed to evaluate pharyngeal arch artery and outflow tract morphology in whole mount embryos. Results: Wnt1-cre driven conditional deletion of Wnt5a in NCC did not impact NCC survival or migration into the developing OFT. However, SHF cells in mutant E10.5 embryos showed altered PCP signaling with reduced phalloidin and laminin expression. The resulting loss in polarized directional movement of the SHF led to reduced incorporation into and elongation of the developing OFT. The shortened OFT was mal-aligned resulting in fully penetrant double outlet right ventricle (DORV) at E14.5. In addition, maturation of pharyngeal arch arteries was also impaired such that all mutants express pharyngeal arch artery defects, including aortic arch abnormalities and aberrant right subclavian artery. In contrast, there was no observed effect on PCP in the more caudal SHF cells, and none of the mutant embryos had inflow tract or venous pole defects. Conclusions: Our results demonstrate that NCC are a novel source of Wnt5a. NCC-derived Wnt5a is critically required to regulate PCP signals in the most cranial SHF regulating the development of the OFT and pharyngeal arch arteries.
Efficacy of Pazopanib With or Without Gemcitabine in Patients With Anthracycline- and/or Ifosfamide-Refractory Soft Tissue Sarcoma
Authors: Hans-Joachim Schmoll, Lars H. Lindner, Peter Reichardt, Klaus Heißner, Hans-Georg Kopp, Torsten Kessler, Regine Mayer-Steinacker, Jörn Rüssel, Gerlinde Egerer, Martina Crysandt, Bernd Kasper, Dietger Niederwieser, Annegret Kunitz, Ekkehard Eigendorff, Iver Petersen, Jörg Steighardt, Franziska Cygon, Fabian Meinert, Alexander Stein
Journal: JAMA Oncology (2020)

Pazopanib and gemcitabine have shown good tolerability, albeit modest single-agent activity in pretreated soft tissue sarcoma. A combined regimen to improve outcomes is required.To determine the efficacy of gemcitabine and pazopanib compared with pazopanib alone.This multicenter, randomized phase 2 clinical trial was conducted in Germany from September 2011 to July 2014 and included patients with an Eastern Cooperative Oncology Group performance status score of 0 to 2, adequate organ function, measurable lesion, and progression after at least 1 prior treatment with anthracyclines and/or ifosfamide. Data analysis was performed during 2019 and 2020.Patients were randomized to pazopanib with gemcitabine (A) or without gemcitabine (B).The primary end point was progression-free survival rate (PFSR) at 12 weeks; secondary end points included toxicity, quality of life, overall survival, and response rates.A total of 90 patients were randomized, and 86 eligible patients (43 women [50%]) were evaluable, with a median age of 57 (range, 22-84) years and Eastern Cooperative Oncology Group performance status score of 0/1 in 77 participants (90%). The predominant histological subtypes were leiomyosarcoma (22 [26%]) and liposarcoma (16 [19%]). After a median follow-up of 12.4 (range, 1-48) months, the primary end point was met, with a PFSR at 12 weeks of 74% (A) vs 47% (B) (hazard ratio [HR], 1.60; 90% CI, 1.15-2.23; P = .01). In the combination arm, PFSR was significantly longer, with a median of 5.6 vs 2.0 months (HR, 0.58; 95% CI, 0.36-0.92; P = .02) compared with single-agent pazopanib, whereas overall survival was similar, with 13.1 vs 11.2 months (HR, 0.98; 95% CI, 0.60-1.58; P = .83). The objective response rate was overall low, with 11% (A) vs 5% (B) (P = .10). The toxicity of the combination of pazopanib and gemcitabine was increased, but it was manageable and mainly hematological.This phase 2 randomized clinical trial of patients with soft tissue sarcoma found that the addition of gemcitabine to pazopanib was tolerable, and PFSR at 12 weeks was significantly higher compared with pazopanib alone. These results suggest clinical activity of the combination, but they should be confirmed in a phase 3 trial in a more homogeneous population (eg, leiomyosarcoma).German Clinical Trials Identifier: DRKS00003139.
Secular Clinical Ethicists Should Not Be Neutral Toward All Religious Beliefs: An Argument for a Moral-Metaphysical Proceduralism
Authors: Abram L. Brummett
Journal: The American Journal of Bioethics (2020)

Secular clinical ethics has responded to the problem of moral pluralism with a procedural approach. However, defining this term stirs debate: H. Tristram Engelhardt Jr. has championed a contentless proceduralism (P1), while others, conversely, argue for a proceduralism that permits some content in the form of moral claims (P2). This paper argues that the content P2 permits ought to be expanded to include some metaphysical commitments, in an approach referred to as P2+. The need for P2+ is demonstrated by analyzing and rejecting three standards (the best interest or harm principle, internal reasonability, and the child’s right to an open future) used by P2 to justify overriding religiously motivated refusals of treatment for children. These approaches fail because each maintains a neutral stance regarding the truth of religious belief. This paper drives at the broader thesis that the proceduralism of secular clinical ethics requires some moral and metaphysical commitments.
Screening for SARS-CoV-2 (COVID) Infection in Chronic Dialysis Patients: A Nonprofit Provider’s Experience
Authors: Harold J. Manley, Karen M. Majchrzak, Ronald Sanders, Serena Cumber, Gideon N. Aweh, Vladimir Ladik, Carol Stewart, Doug Johnson, Antonia Harford, Eduardo K. Lacson
Journal: Journal of the American Society of Nephrology (2020)

Background: Acute kidney injury (AKI) is emerging as an important sequela of COVID-19 infection  Existing data on the incidence and clinical features of AKI in patients with COVID-19 are mainly limited to single-center studies  Given the high incidence of severe AKI among patients with COVID-19 and its strong association with mortality in other settings, we conducted a multicenter nationally representative cohort study to examine the incidence, clinical features, risk factors, and outcomes of AKI in critically ill patients with COVID-19  Methods: We used data from a multicenter observational study that collected granular, patient-level data from >3,000 critically ill adults with laboratory-confirmed COVID-19 admitted to participating ICUs from 67 centers across the United States  Using multivariable logistic regression, we examined risk factors for the primary composite outcome, AKI requiring renal replacement therapy or death (RRT/death) in the 14 days following ICU admission  Results: Among 3099 patients, 1205 (38 9%) developed the primary outcome of RRT/death (n=637 required RRT, n=792 died within 14 days, and n=224 both required RRT and died within 14 days)  Independent risk factors for RRT/death included chronic kidney disease (odds ratio [OR], 5 02;95% CI, 3 55-7 10 for eGFR<30 vs  ≥60;OR 1 90;95% CI, 1 55-2 33 for eGFR 30-59 vs  ≥60), as well as older age, male sex, higher body mass index, and greater severity of hypoxemia on ICU admission (Figure)  Patients admitted to hospitals with higher degrees of strain also had a greater risk of RRT/death (OR 1 49;95% CI, 1 06-2 06 for highest versus lowest quintile of hospital strain)  Conclusions: This multicenter study identifies several key insights into the risk factors for RRT/death in critically ill patients with COVID-19  (Figure Presented)