tbuckley/cabot-search huggingface dataset:
Case Study: Kidney Transplant Patient with COVID-19: Impact of Viral Infection on Background Cell-Free DNA in a Donor-Derived Cell-Free DNA Rejection Assay
Authors: Suphamai Bunnapradist, Joanna Schaenman, Erik L. Lum, Philippe M. Gauthier, Ebad Ahmed, Paul R. Billings
Journal: Journal of the American Society of Nephrology (2020)

Introduction: Donor-derived cell-free DNA (dd-cfDNA) assays are clinically validated to detect kidney transplant injury, reporting the donor fraction as a percentage of the total, or background, cfDNA  Various clinical factors can cause a significant increase in recipient cfDNA, contributing to higher background cfDNA and lower donor fraction, which may result in a false negative test result  Case Description: A 50+ year old woman with end-stage renal disease secondary to polycystic kidney disease presented with 4 days (d) of diffuse muscle pain at 11 months post-kidney transplant  In the emergency department she had a fever to 101°F, bilateral infiltrates on chest x-ray, and a positive COVID-19 (SARS-CoV-2) test  She remained febrile for 3d before developing acute respiratory distress requiring oxygen supplementation;her creatinine level was 3 mg/dL  Due to worsening of her respiratory status, she was intubated and started empirically on vancomycin, meropenem, and azithromycin;mycophenolate mofetil was discontinued  She rapidly progressed to septic shock requiring vasopressor therapy  Her renal function deteriorated, and she was started on continuous renal replacement therapy on hospital d7  She received leronlimab on hospital d7 and d14 and convalescent plasma on hospital d11  Tacrolimus was discontinued on hospital d10 and she continued prednisone at 5 mg/d  Dd-cfDNA testing to assess allograft injury and to rule out active rejection was performed  At hospital d20, her dd-cfDNA was 0 07% with an elevated background cfDNA of 28,569 arbitrary units (AU, ∼57X median value)  At the second blood draw at hospital d25, her dd-cfDNA was 0 25% with a background cfDNA level reduced to 7,503 AU (∼15X median value)  Discussion: In this case, infection with the SARS-CoV-2 virus was associated with a very elevated background cfDNA level, likely due to cellular apoptosis due to the immune process and/or tissue ischemia due to sepsis-associated hypoperfusion  Although this patient was not known to have active rejection of her allograft, the very high background levels complicate the interpretation of results, especially when donor fraction were reported
Preclinical modeling of chronic inhibition of the Parkinson’s disease associated kinase LRRK2 reveals altered function of the endolysosomal system in vivo
Authors: Jillian H. Kluss, Melissa Conti Mazza, Yan Li, Claudia Manzoni, Patrick A. Lewis, Mark R. Cookson, Adamantios Mamais
Journal: Molecular Neurodegeneration (2021)

Abstract The most common mutation in the Leucine-rich repeat kinase 2 gene (LRRK2), G2019S, causes familial Parkinson’s Disease (PD) and renders the encoded protein kinase hyperactive. While targeting LRRK2 activity is currently being tested in clinical trials as a therapeutic avenue for PD, to date, the molecular effects of chronic LRRK2 inhibition have not yet been examined in vivo. We evaluated the utility of newly available phospho-antibodies for Rab substrates and LRRK2 autophosphorylation to examine the pharmacodynamic response to treatment with the potent and specific LRRK2 inhibitor, MLi-2, in brain and peripheral tissue in G2019S LRRK2 knock-in mice. We report higher sensitivity of LRRK2 autophosphorylation to MLi-2 treatment and slower recovery in washout conditions compared to Rab GTPases phosphorylation, and we identify pS106 Rab12 as a robust readout of downstream LRRK2 activity across tissues. The downstream effects of long-term chronic LRRK2 inhibition in vivo were evaluated in G2019S LRRK2 knock-in mice by phospho- and total proteomic analyses following an in-diet administration of MLi-2 for 10 weeks. We observed significant alterations in endolysosomal and trafficking pathways in the kidney that were sensitive to MLi-2 treatment and were validated biochemically. Furthermore, a subtle but distinct biochemical signature affecting mitochondrial proteins was observed in brain tissue in the same animals that, again, was reverted by kinase inhibition. Proteomic analysis in the lung did not detect any major pathway of dysregulation that would be indicative of pulmonary impairment. This is the first study to examine the molecular underpinnings of chronic LRRK2 inhibition in a preclinical in vivo PD model and highlights cellular processes that may be influenced by therapeutic strategies aimed at restoring LRRK2 physiological activity in PD patients.
GP was negligent in failing to suspect TB in teenage girl, High Court rules
Authors: Clare Dyer
Journal: BMJ (2020)

A GP partner in Newham, east London, was negligent in failing to ask a teenage patient the questions that would have led him to suspect that she had tuberculosis (TB), the High Court has ruled.

When 16 year old Naziyah Ismail consulted GP Ciaran Joyce on 10 August 2011, his notes recorded that she had had a cough for three weeks, was fasting for Ramadan, and was “sweaty at night.” He diagnosed an upper respiratory tract infection and prescribed an antibiotic.

Her condition worsened and she went to the walk in centre at Whipps Cross Hospital on …
Food Insecurity During COVID-19 in Children with ESKD: The Second Wave?
Authors: Melvin Chan, Amy C. Wilson, Neha D. Pottanat, Michelle C. Starr
Journal: Journal of the American Society of Nephrology (2020)

Journal of the American Society of Nephrology 31(10S):p 699, October 2020. | DOI: 10.1681/ASN.20203110S1699b
Fibroblast Activation Protein Inhibitor PET/CT
Authors: Punit Sharma, Shashank Shekhar Singh, Shankaramurthy Gayana
Journal: Clinical Nuclear Medicine (2020)

Purpose Fibroblast activation protein (FAP) is a cell membrane–bound serine peptidase, overexpressed in cancer-associated fibroblasts and activated fibroblasts at wound healing/inflammatory sites. Recently, molecular PET/CT imaging with radiolabeled FAP inhibitor (FAPI) has been evaluated in different diseases. We aimed to assess its potential role based on the available literature. Patients and Methods We conducted a comprehensive review of the available preclinical and clinical data on FAPI PET/CT in an attempt to summarize its current status and potential future role. Based on that, we have discussed the pathophysiology behind FAP-based imaging, followed by a discussion of FAPI radiopharmaceuticals including their synthesis, biodistribution, and dosimetry. Next, we have discussed studies evaluating FAPI PET/CT in different oncological and nononcological pathologies. The potential of FAPI PET/CT in theranostics has also been addressed. Results Based on the early scientific evidence available, including preclinical and clinical studies, FAPI PET/CT seems to be a promising molecular imaging tool, especially in oncology. It can be used for imaging different types of cancers and outperforms 18 F-FDG PET/CT in some of these. Its potential as a theranostic tool warrants special attention. Conclusions Fibroblast activation protein inhibitor PET/CT has the potential to emerge as a powerful molecular imaging tool in the future. However, as of yet, the available evidence is limited, warranting further research and trials in this field.
Rhabdomyolysis in SARS-CoV-2 Infection
Authors: Zhabiz Solhjou, Ignacio A. Portales Castillo, Bassem Mikhael, Nicholas Chedid, Ebrahim Barkoudah, Alice M. Sheridan
Journal: Journal of the American Society of Nephrology (2020)

Introduction: Acute kidney injury (AKI) is a common complication of SARSCoV- 2 infection  Multiple mechanisms have been proposed including acute tubular necrosis (ATN) due to shock, cytokine release syndrome, hypoxia or vascular injury and thrombosis  Direct viral injury to tubular epithelial cells and podocytes has also been described  Rhabdomyolysis has been reported in infection with SARS-CoV, Respiratory Syncytial Virus and Influenza A  Although mild CK elevation was reported in cohorts of patients with COVID-19 and there is a single case report of late onset rhabdomyolysis, overt rhabdomyolysis on presentation has not been described  To our knowledge this is the first patient who presented with signs and symptoms of severe rhabdomyolysis and AKI that was likely secondary to SARS-CoV-2 infection  Case Description: A 51 year-old male with hypertension and diabetes, presented with 2 days of diffuse myalgia and mild dry cough without shortness of breath  He denied trauma, new medications, changes in diet, strenuous exercise or illicit drug use  Physical exam notable for fever and mild tachypnea, but no hypoxia  Lungs were clear and all muscles groups were soft and non-tender  Polymerase chain reaction was positive for SARS-CoV-2  Serum creatinine was 2 4 mg/dL (baseline 1 3 mg/dL), Urinalysis showed 3+ blood, 2+protein and 1-2 RBC per high power field  Initial serum creatinine kinase was 340,000 U/L and peaked at 464,000 U/L on day 4  Serum and urine myoglobin levels were elevated at 15,175 mg/L and >5000 mcg/L respectively on day 5  He received isotonic intravascular (IV) fluids but developed oliguria on day 2, requiring diuresis to maintain urine output  BUN and creatinine increased to 130 and 19 mg/dL respectively by day 8 and hemodialysis was initiated  Renal clearance and urine output then slowly improved, and dialysis was discontinued by day 15  Discussion: Myalgia and fatigue are common symptoms of COVID-19 infection  In addition, dipstick hematuria is reported in up to 10% of patients  Thus diagnosis of rhabdomyolysis and myoglobinuria requires a high index of suspicion  Early consideration and timely diagnosis of rhabdomyolysis and the treatment of myoglobinuria with intravenous fluids is critically important to prevent ATN  However, administration of IV fluids may be challenging in COVID-19 patients at risk of hypoxia and acute respiratory distress syndrome
FGF-23 from erythroblasts promotes hematopoietic progenitor mobilization
Authors: Shinichi Ishii, Tomohide Suzuki, Kanako Wakahashi, Noboru Asada, Yuko Kawano, Hiroki Kawano, Akiko Sada, Kentaro Minagawa, Yukio Nakamura, Seiya Mizuno, Satoru Takahashi, Toshimitsu Matsui, Yoshio Katayama
Journal: Blood (2020)
TFEB Links MYC Signaling to Epigenetic Control of Myeloid Differentiation and Acute Myeloid Leukemia
Authors: Seongseok Yun, Nicole D. Vincelette, Xiaoqing Yu, Gregory W. Watson, Mario R. Fernandez, Chunying Yang, Taro Hitosugi, Chia-Ho Cheng, Audrey R. Freischel, Ling Zhang, Weimin Li, Hsinan Hou, Franz X. Schaub, Alexis R. Vedder, Ling Cen, Kathy L. McGraw, Jungwon Moon, Daniel J. Murphy, Andrea Ballabio, Scott H. Kaufmann, Anders E. Berglund, John L. Cleveland
Journal: Blood Cancer Discovery (2020)

Abstract MYC oncoproteins regulate transcription of genes directing cell proliferation, metabolism, and tumorigenesis. A variety of alterations drive MYC expression in acute myeloid leukemia (AML), and enforced MYC expression in hematopoietic progenitors is sufficient to induce AML. Here we report that AML and myeloid progenitor cell growth and survival rely on MYC-directed suppression of Transcription Factor EB (TFEB), a master regulator of the autophagy–lysosome pathway. Notably, although originally identified as an oncogene, TFEB functions as a tumor suppressor in AML, where it provokes AML cell differentiation and death. These responses reflect TFEB control of myeloid epigenetic programs by inducing expression of isocitrate dehydrogenase-1 (IDH1) and IDH2, resulting in global hydroxylation of 5-methycytosine. Finally, activating the TFEB–IDH1/IDH2–TET2 axis is revealed as a targetable vulnerability in AML. Thus, epigenetic control by an MYC–TFEB circuit dictates myeloid cell fate and is essential for maintenance of AML. Significance: Alterations in epigenetic control are a hallmark of AML. This study establishes that a MYC–TFEB circuit controls AML differentiation and epigenetic programs by inducing IDH1/IDH2 and hydroxylation of 5-methylcytosine, that TFEB functions as a tumor suppressor in AML, and that this circuit is a targetable vulnerability in AML. See related commentary by Wu and Eisenman, p. 116.
Studying Proteinuria in COVID-19 to Define Markers of Severity and New Treatments
Authors: Yask Gupta, Juntao Ke, Jeremiah Martino, Qingxue Liu, Byum hee Kil, Tze Yin Lim, Gina Ying Jin, Dina Ahram, Nicholas J. Steers, Simone Sanna-Cherchi
Journal: Journal of the American Society of Nephrology (2020)

Gupta, Yask; Ke, Juntao; Martino, Jeremiah; Liu, Qingxue; Kil, Byum hee; Lim, Tze Yin; Jin, Gina Ying; Ahram, Dina; Steers, Nicholas J.; Sanna-Cherchi, Simone Author Information
Abstract 16365: The Nature and Number of Unreported Events Identified by the Clinical Event Adjudication Process in the AEGIS-1 Trial
Authors: Aldo L Schenone, Vidyasagar Kalahasti, Kimberly Brown, Crissy Shaffer, C Michael Gibson, Denise M D’Andrea, John H Alexander, Mathew Dey, A Michael Lincoff, Roxana Mehran, J.J.P. Kastelein, Venu Menon
Journal: Circulation (2017)

Introduction: The primary role of the Clinical Events Adjudication Committee (CEAC) is to standardize event adjudication during the conduct of a clinical trial. However, the cost and complexity of ...
Integrin αvβ6–TGFβ–SOX4 Pathway Drives Immune Evasion in Triple-Negative Breast Cancer
Authors: Archis Bagati, Sushil Kumar, Peng Jiang, Jason Pyrdol, Angela E. Zou, Anze Godicelj, Nathan D. Mathewson, Adam N.R. Cartwright, Paloma Cejas, Myles Brown, Anita Giobbie-Hurder, Deborah Dillon, Judith Agudo, Elizabeth A. Mittendorf, X. Shirley Liu, Kai W. Wucherpfennig
Journal: Cancer Cell (2020)
Early use of nitazoxanide in mild COVID-19 disease: randomised, placebo-controlled trial
Authors: Patricia R.M. Rocco, Pedro L. Silva, Fernanda F. Cruz, Marco Antonio C. Melo-Junior, Paulo F.G.M.M. Tierno, Marcos A. Moura, Luís Frederico G. De Oliveira, Cristiano C. Lima, Ezequiel A. Dos Santos, Walter F. Junior, Ana Paula S.M. Fernandes, Kleber G. Franchini, Erick Magri, Nara F. de Moraes, José Mário J. Gonçalves, Melanie N. Carbonieri, Ivonise S. Dos Santos, Natália F. Paes, Paula V.M. Maciel, Raissa P. Rocha, Alex F. de Carvalho, Pedro Augusto Alves, José Luiz Proença-Módena, Artur T. Cordeiro, Daniela B.B. Trivella, Rafael E. Marques, Ronir R. Luiz, Paolo Pelosi, Jose Roberto Lapa e Silva
Journal: European Respiratory Journal (2020)

Nitazoxanide is widely available and exerts broad-spectrum antiviral activity in vitro. However, there is no evidence of its impact on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.In a multicentre, randomised, double-blind, placebo-controlled trial, adult patients presenting up to 3 days after onset of coronavirus disease 2019 (COVID-19) symptoms (dry cough, fever and/or fatigue) were enrolled. After confirmation of SARS-CoV-2 infection using reverse transcriptase PCR on a nasopharyngeal swab, patients were randomised 1:1 to receive either nitazoxanide (500 mg) or placebo, three times daily, for 5 days. The primary outcome was complete resolution of symptoms. Secondary outcomes were viral load, laboratory tests, serum biomarkers of inflammation and hospitalisation rate. Adverse events were also assessed.From June 8 to August 20, 2020, 1575 patients were screened. Of these, 392 (198 placebo, 194 nitazoxanide) were analysed. Median (interquartile range) time from symptom onset to first dose of study drug was 5 (4-5) days. At the 5-day study visit, symptom resolution did not differ between the nitazoxanide and placebo arms. Swabs collected were negative for SARS-CoV-2 in 29.9% of patients in the nitazoxanide arm versus 18.2% in the placebo arm (p=0.009). Viral load was reduced after nitazoxanide compared to placebo (p=0.006). The percentage viral load reduction from onset to end of therapy was higher with nitazoxanide (55%) than placebo (45%) (p=0.013). Other secondary outcomes were not significantly different. No serious adverse events were observed.In patients with mild COVID-19, symptom resolution did not differ between nitazoxanide and placebo groups after 5 days of therapy. However, early nitazoxanide therapy was safe and reduced viral load significantly.
Antineutrophil Cytoplasmic Antibody (ANCA) Vasculitis with Glomerulonephritis in COVID-19
Authors: Yuriy Khanin, Vanesa Bijol, Kenar D. Jhaveri, Nupur N. Uppal
Journal: Journal of the American Society of Nephrology (2020)

Journal of the American Society of Nephrology 31(10S):p 291, October 2020. | DOI: 10.1681/ASN.20203110S1291d
Metabolic syndrome and its factors are associated with noncalcified coronary burden in psoriasis: An observational cohort study
Authors: Meron Teklu, Wunan Zhou, Promita Kapoor, Nidhi Patel, Amit K. Dey, Alexander V. Sorokin, Grigory A. Manyak, Heather L. Teague, Julie A. Erb-Alvarez, Aparna Sajja, Khaled M. Abdelrahman, Aarthi S. Reddy, Domingo E. Uceda, Sundus S. Lateef, Sujata M. Shanbhag, Colin Scott, Nina Prakash, Maryia Svirydava, Philip Parel, Justin A. Rodante, Andrew Keel, Evan L. Siegel, Marcus Y. Chen, David A. Bluemke, Martin P. Playford, Joel M. Gelfand, Nehal N. Mehta
Journal: Journal of the American Academy of Dermatology (2021)
Plasma Exchange in Critically Ill COVID-19 Patients
Authors: Christian Morath, Markus A. Weigand, Martin G. Zeier, Claudius Speer, Theresa Hippchen, Shilpa Tiwari-Heckler, Uta Merle
Journal: Journal of the American Society of Nephrology (2020)

Morath, Christian; Weigand, Markus A.; Zeier, Martin G.; Speer, Claudius; Hippchen, Theresa; Tiwari-Heckler, Shilpa; Merle, Uta Author Information
Design and Testing of a Cabotegravir Implant for HIV Prevention
Authors: Dipu Karunakaran, Solange M. Simpson, Jonathan T. Su, Ewa Bryndza-Tfaily, Thomas J. Hope, Ronald Veazey, Georgina Dobek, Jiang Qiu, David Watrous, Samuel Sung, Jorge E. Chacon, Patrick F. Kiser
Journal: Journal of Controlled Release (2020)
Tumor heterogeneity and the potential role of liquid biopsy in bladder cancer
Authors: Hai‐Ming Huang, Hai‐Xia Li
Journal: Cancer Communications (2020)

Abstract Bladder cancer (BC) is a heterogeneous disease that characterized by genomic instability and a high mutation rate. Heterogeneity in tumor may partially explain the diversity of responses to targeted therapies and the various clinical outcomes. A combination of cytology and cystoscopy is the standard methodology for BC diagnosis, prognosis, and disease surveillance. However, genomics analyses of single tumor‐biopsy specimens may underestimate the mutational burden of heterogeneous tumors. Liquid biopsy, as a promising technology, enables analysis of tumor components in the bodily fluids, such as blood and urine, at multiple time points and provides a minimally invasive approach that can track the evolutionary dynamics and monitor tumor heterogeneity. In this review, we describe the multiple faces of BC heterogeneity at the genomic and transcriptional levels and how they affect clinical care and outcomes. We also summarize the outcomes of liquid biopsy in BC, which plays a potential role in revealing tumor heterogeneity. Finally, we discuss the challenges that must be addressed before liquid biopsy can be widely used in clinical treatment.
Long-Term Cause-Specific Mortality in Hodgkin Lymphoma Patients
Authors: Simone de Vries, Michael Schaapveld, Cécile P M Janus, Laurien A Daniëls, Eefke J Petersen, Richard W M van der Maazen, Josée M Zijlstra, Max Beijert, Marten R Nijziel, Karijn M S Verschueren, Leontien C M Kremer, Anna M van Eggermond, Pieternella J Lugtenburg, Augustinus D G Krol, Judith M Roesink, Wouter J Plattel, Dick Johan van Spronsen, Gustaaf W van Imhoff, Jan Paul de Boer, Berthe M P Aleman, Flora E van Leeuwen
Journal: JNCI Journal of the National Cancer Institute (2020)

Few studies have examined the impact of treatment-related morbidity on long-term, cause-specific mortality in Hodgkin lymphoma (HL) patients.This multicenter cohort included 4919 HL patients, treated before age 51 years between 1965 and 2000, with a median follow-up of 20.2 years. Standardized mortality ratios, absolute excess mortality (AEM) per 10 000 person-years, and cause-specific cumulative mortality by stage and primary treatment, accounting for competing risks, were calculated.HL patients experienced a 5.1-fold (AEM = 123 excess deaths per 10 000 person-years) higher risk of death due to causes other than HL. This risk remained increased in 40-year survivors (standardized mortality ratio = 5.2, 95% confidence interval [CI] = 4.2 to 6.5, AEM = 619). At age 54 years, HL survivors experienced similar cumulative mortality (20.0%) from causes other than HL to 71-year-old individuals from the general population. Whereas HL mortality statistically significantly decreased over the calendar period (P < .001), solid tumor mortality did not change in the most recent treatment era. Patients treated in 1989-2000 had lower 25-year cardiovascular disease mortality than patients treated in 1965-1976 (4.3% vs 5.7%; subdistribution hazard ratio = 0.65, 95% CI = 0.46 to 0.93). Infectious disease mortality was not only increased after splenectomy but also after spleen irradiation (hazard ratio = 2.81, 95% CI = 1.55 to 5.07). For stage I-II, primary treatment with chemotherapy (CT) alone was associated with statistically significantly higher HL mortality (P < .001 for CT vs radiotherapy [RT]; P = .04 for CT vs RT+CT) but lower 30-year mortality from causes other than HL (15.8%, 95% CI = 9.7% to 23.3%) compared with RT alone (36.9%, 95% CI = 34.0% to 39.8%, P = .001) and RT and CT combined (29.8%, 95% CI = 26.8% to 32.9%, P = .02).Compared with the general population, HL survivors have a substantially reduced life expectancy. Optimal selection of patients for primary CT is crucial, weighing risks of HL relapse and long-term toxicity.