tbuckley/cabot-search huggingface dataset:
A generic crystallopathic model for chronic kidney disease progression
Authors: Orson W. Moe
Journal: Journal of Clinical Investigation (2021)

Chronic kidney disease (CKD) has reached epidemic proportions globally. The natural course of chronic kidney disease is almost uniformly progressive, albeit at different rates in different individuals. The downhill course appears to pervade kidney diseases of all etiologies and seems to spiral down a self-perpetuating vortex, even if the original insult is ameliorated or controlled. In this issue of the JCI, Shiizaki, Tsubouchi, and colleagues proposed a model of renal tubule luminal calcium phosphate crystallopathy that accounts for renal function demise. Calcium phosphate crystals attached to TLR4 and underwent endocytosis at the brush border, triggering inflammation and fibrosis. This mechanism might operate in different kinds of kidney disease, with a theoretical phosphate concentration threshold in the proximal tubular lumen, beyond which is triggered undesirable downstream effects that eventuate in loss of renal function. If this model parallels human CKD, clinicians may focus efforts on determining phosphate exposure in the proximal tubular lumen.
Clinical and molecular predictors of fibrotic progression in essential thrombocythemia: A multicenter study involving 1607 patients
Authors: Giuseppe G. Loscocco, Paola Guglielmelli, Naseema Gangat, Elena Rossi, Carmela Mannarelli, Silvia Betti, Chiara Maccari, Francesco Ramundo, Yamna Jadoon, Francesca Gesullo, Sara Ceglie, Chiara Paoli, Animesh Pardanani, Valerio De Stefano, Ayalew Tefferi, Alessandro M. Vannucchi
Journal: American Journal of Hematology (2021)

The current retrospective study involving a total of 1607 patients was designed to identify clinical and molecular variables that were predictive of inferior myelofibrosis-free survival (MFS) in WHO-defined essential thrombocythemia (ET), utilizing three independent patient cohorts: University of Florence, Italy (n = 718); Mayo Clinic, USA (n = 479) and Policlinico Gemelli, Catholic University, Rome, Italy (n = 410). The Florence patient cohort was first examined to identify independent risk factors for MFS, which included age > 60 years (HR 2.5, 95% CI 1.3-4.9), male sex (2.1, 1.2-3.9), palpable splenomegaly (2.1, 1.2-3.9), CALR 1/1-like or MPL mutation (3.4, 1.9-6.1) and JAK2V617F variant allele frequency > 35% (4.2, 1.6-10.8). Subsequently, an operational molecular risk category was developed and validated in the other two cohorts from Mayo Clinic and Rome: "high molecular risk" category included patients with JAK2V617F VAF >35%, CALR type 1/1-like or MPL mutations; all other driver mutation profiles were assigned to "low molecular risk" category. The former, compared to the latter molecular risk category, displayed significantly higher risk of fibrotic transformation: Florence cohort with respective fibrotic transformation risk rates of 8% vs. 1.2% at 10 years and 33% vs. 8% at 20 years (p < 0.001; HR 6.1; 95% CI 3.2-11.7); Mayo Cohort, 16% vs. 7% at 10 years and 44% vs. 25% at 20 years (p < 0.001; HR 2.5; 95% CI 1.6-4.1); and Rome cohort 7.8% vs. 4.6% at 10 years and 31.2% vs. 7.1% at 20 years (p = 0.007, HR 2.7; 95% CI 1.3-5.8). The present study provides practically useful risk signals for fibrotic transformation in ET and facilitates identification of patients who require close monitoring and appropriate counseling.
Genetic analysis of dietary intake identifies new loci and functional links with metabolic traits
Authors: Jordi Merino, Hassan S. Dashti, Chloé Sarnowski, Jacqueline M. Lane, Petar V. Todorov, Miriam S. Udler, Yanwei Song, Heming Wang, Jaegil Kim, Chandler Tucker, John Campbell, Toshiko Tanaka, Audrey Y. Chu, Linus Tsai, Tune H. Pers, Daniel I. Chasman, Martin K. Rutter, Josée Dupuis, Jose C. Florez, Richa Saxena
Journal: Nature Human Behaviour (2021)
Imatinib augments standard malaria combination therapy without added toxicity
Authors: Huynh Dinh Chien, Antonella Pantaleo, Kristina R. Kesely, Panae Noomuna, Karson S. Putt, Tran Anh Tuan, Philip S. Low, Francesco M. Turrini
Journal: The Journal of Experimental Medicine (2021)

To egress from its erythrocyte host, the malaria parasite, Plasmodium falciparum, must destabilize the erythrocyte membrane by activating an erythrocyte tyrosine kinase. Because imatinib inhibits erythrocyte tyrosine kinases and because imatinib has a good safety profile, we elected to determine whether coadministration of imatinib with standard of care (SOC) might be both well tolerated and therapeutically efficacious in malaria patients. Patients with uncomplicated P. falciparum malaria from a region in Vietnam where one third of patients experience delayed parasite clearance (DPC; continued parasitemia after 3 d of therapy) were treated for 3 d with either the region's SOC (40 mg dihydroartemisinin + 320 mg piperaquine/d) or imatinib (400 mg/d) + SOC. Imatinib + SOC-treated participants exhibited no increase in number or severity of adverse events, a significantly accelerated decline in parasite density and pyrexia, and no DPC. Surprisingly, these improvements were most pronounced in patients with the highest parasite density, where serious complications and death are most frequent. Imatinib therefore appears to improve SOC therapy, with no obvious drug-related toxicities.
Efficacy and Safety of Abrocitinib in Combination With Topical Therapy in Adolescents With Moderate-to-Severe Atopic Dermatitis
Authors: Lawrence F. Eichenfield, Carsten Flohr, Robert Sidbury, Elaine Siegfried, Zsuzsanna Szalai, Ryszard Galus, Zhirong Yao, Hidetoshi Takahashi, Sébastien Barbarot, Claire Feeney, Fan Zhang, Marco DiBonaventura, Ricardo Rojo, Hernan Valdez, Gary Chan
Journal: JAMA Dermatology (2021)

Dupilumab subcutaneous injection is approved for treating moderate-to-severe atopic dermatitis (AD) in adolescents, but there has been too little research on an efficacious systemic oral treatment with a favorable benefit-risk profile for adolescents with moderate-to-severe AD.To investigate the efficacy and safety of oral abrocitinib plus topical therapy in adolescents with moderate-to-severe AD.The phase 3, randomized, double-blind, placebo-controlled study JADE TEEN was conducted in countries of the Asia-Pacific region, Europe, and North America in patients aged 12 to 17 years with moderate-to-severe AD and an inadequate response to 4 consecutive weeks or longer of topical medication or a need for systemic therapy for AD. The study was conducted between February 18, 2019, and April 8, 2020. The data were analyzed after study completion.Patients were randomly assigned 1:1:1 to receive once-daily oral abrocitinib, 200 mg or 100 mg, or placebo for 12 weeks in combination with topical therapy.Coprimary end points were achievement of an Investigator's Global Assessment (IGA) response of clear (0) or almost clear (1) with improvement of 2 or more grades from baseline (IGA 0/1) and 75% or greater improvement from baseline in Eczema Area and Severity Index (EASI-75) response at week 12. Key secondary end points included 4-point or greater improvement in Peak Pruritus Numerical Rating Scale (PP-NRS4) at week 12. Adverse events (AEs) were monitored.This study included 285 adolescents with moderate-to-severe AD (145 boys [50.9%] and 140 girls [49.1%]), of whom 160 (56.1%) were White and 94 (33.0%) were Asian; the median age was 15 years (interquartile range 13-17 years). Substantially more patients treated with abrocitinib (200 mg or 100 mg) vs placebo achieved an IGA response of 0/1 (46.2%; 41.6% vs 24.5%; P < .05 for both), EASI-75 (72.0%; 68.5% vs 41.5%; P < .05 for both), and PP-NRS4 (55.4%; 52.6% vs 29.8%; P < .01 for 200 mg vs placebo) at week 12. Adverse events were reported for 59 (62.8%), 54 (56.8%), and 50 (52.1%) patients in the 200 mg, 100 mg, and placebo groups, respectively; nausea was more common with abrocitinib, 200 mg (17 [18.1%]) and 100 mg (7 [7.4%]). Herpes-related AEs were infrequent; 1 (1.1%), 0, and 2 (2.1%) patients had serious AEs.This randomized clinical trial found that oral abrocitinib combined with topical therapy was significantly more effective than placebo with topical therapy in adolescents with moderate-to-severe AD, with an acceptable safety profile.ClinicalTrials.gov identifier: NCT03796676.
Dose schedule modulates the pharmacodynamic response to ANA773, a prodrug of a toll-like receptor (TLR)-7 selective-agonist
Authors: Joyce Tan, Simon Fletcher, Tim Harding, Wei Li, Gregory Haley, Erik Rueden, James Appleman
Journal: Cancer Research (2008)

2079  The immune response elicited by TLR7 agonism is believed to have potential benefit in the treatment of cancer. ANA773 is an oral prodrug of a selective TLR7 agonist, one of several receptors within the TLR family. Activation of TLR7 by the biologically active metabolite of ANA773 initiates a cascade of immune stimulatory events that includes the secretion of cytokines and chemokines and the activation of the cellular immune response. This immune induction is likely responsible for the tumor growth inhibition observed in mice with the active metabolite of ANA773. To further elucidate the effects of ANA773 on immune activation, a number of pharmacodynamic studies were performed in cynomolgus monkeys to investigate whether different ANA773 dosing schedules affects the type, magnitude, and duration of the immune response.  Methods: Three different repeat dose schedules were explored, A) alternate day dosing spanning either 14 or 28 days followed by 7 days of recovery (QOD), B) dosing daily for 7 consecutive days followed by 7 days of recovery (7 on 7 off), and C) daily dosing for 3 consecutive days followed by 4 days of recovery (3 on 4 off). The 3 on 4 off dose schedule was repeated over 3 treatment courses. Immune parameters measured included cytokine and chemokine secretion, neopterin production, and cellular responses.  Results: A) The 14 and 28 day QOD regimens elicited minimal to moderate levels of cytokine, chemokine, neopterin and cellular responses that, for the most part, did not build with repeated doses, producing the most stable level of immune enhancement observed with the various dosing schedules. B)The 7 on 7 off dose schedule elicited cytokine, chemokine, and neopterin responses that built during the first 3-4 days, but then diminished after the fourth dose, prior to the end of the 7-day dosing period. The cellular response was induced subsequent to the cytokine and chemokine response and declined during the non-dosing period.C) The 3 on 4 off schedule also promoted cytokine, chemokine, and neopterin responses that built with 3 repeated doses of ANA773 and declined during the non-dosing period from days 4 to 7. The cytokine and chemokine responses were re-induced with repeated courses of 3 on 4 off dosing, which suggest that a 4-day off-period is sufficient to re-set these responses between courses. The 3 on 4 off schedule elicited T cell, NK cell and B cell activation that was either amplified or sustained with repeated courses, demonstrating that this dosing regimen, along with the 7 on 7 off regimen, strongly promotes the cellular response.  The results from these repeat dose schedule studies demonstrate that immunostimulatory responses to ANA773 can be effectively modulated in vivo by dose schedule.
S‐adenosylmethionine inhibits la ribonucleoprotein domain family member 1 in murine liver and human liver cancer cells
Authors: Komal Ramani, Aaron E. Robinson, Joshua Berlind, Wei Fan, Aushinie Abeynayake, Aleksandra Binek, Lucía Barbier‐Torres, Mazen Noureddin, Nicholas N. Nissen, Zehra Yildirim, Ebru Erbay, José M. Mato, Jennifer E. Van Eyk, Shelly C. Lu
Journal: Hepatology (2021)

Methionine adenosyltransferase 1A (MAT1A) is responsible for S-adenosylmethionine (SAMe) biosynthesis in the liver. Mice lacking Mat1a have hepatic SAMe depletion and develop NASH and HCC spontaneously. Several kinases are activated in Mat1a knockout (KO) mice livers. However, characterizing the phospho-proteome and determining whether they contribute to liver pathology remain open for study. Our study aimed to provide this knowledge.We performed phospho-proteomics in Mat1a KO mice livers with and without SAMe treatment to identify SAMe-dependent changes that may contribute to liver pathology. Our studies used Mat1a KO mice at different ages treated with and without SAMe, cell lines, in vitro translation and kinase assays, and human liver specimens. We found that the most striking change was hyperphosphorylation and increased content of La-related protein 1 (LARP1), which, in the unphosphorylated form, negatively regulates translation of 5'-terminal oligopyrimidine (TOP)-containing mRNAs. Consistently, multiple TOP proteins are induced in KO livers. Translation of TOP mRNAs ribosomal protein S3 and ribosomal protein L18 was enhanced by LARP1 overexpression in liver cancer cells. We identified LARP1-T449 as a SAMe-sensitive phospho-site of cyclin-dependent kinase 2 (CDK2). Knocking down CDK2 lowered LARP1 phosphorylation and prevented LARP1-overexpression-mediated increase in translation. LARP1-T449 phosphorylation induced global translation, cell growth, migration, invasion, and expression of oncogenic TOP-ribosomal proteins in HCC cells. LARP1 expression is increased in human NASH and HCC.Our results reveal a SAMe-sensitive mechanism of LARP1 phosphorylation that may be involved in the progression of NASH to HCC.
25334 Primary cutaneous EBV-positive diffuse large B-cell lymphoma masquerading as periorbital cellulitis
Authors: Zaydi Javeed, L. Kevin Heard, Kerry Hennessy, Adel Haque, Vidhi Shah, Lucia Seminario-Vidal, Wei-Shen Chen, Pei-Ling Chen
Journal: Journal of the American Academy of Dermatology (2021)
Protracted, Intermittent Outbreak of <i>Salmonella</i> Mbandaka Linked to a Restaurant — Michigan, 2008–2019
Authors: William D. Nettleton, Bethany Reimink, Katherine D. Arends, Douglas Potter, Justin J. Henderson, Stephen Dietrich, Mary Franks
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

In 2018, Michigan public health officials determined that a single restaurant in southwest Michigan was the source for a protracted, intermittent outbreak of Salmonella enterica serotype Mbandaka infections occurring since 2008. Isolates from 36 infected persons shared two highly related pulsed-field gel electrophoresis (PFGE) patterns and highly related whole genome sequencing (WGS) subtypes. The initial focus of the local public health investigation on food items rather than food sources (i.e., restaurants) through a questionnaire, difficulty in food history recollection among ill persons, and sporadic case identification over periods from months to years contributed to delayed source identification. The Kalamazoo County Health and Community Services Department (KHCSD) and the Michigan Department of Health and Human Services (MDHHS) collected clinical specimens, performed multiple rounds of environmental testing, and conducted multiple regulatory visits, and based on accumulated findings over 10 years, identified the restaurant source. A 2018 investigation by KCHCSD and MDHHS found that environmental samples and stool specimens from asymptomatic restaurant employees tested positive for the Salmonella Mbandaka outbreak strain. A complex association between the restaurant environment and employees resulted in patron illnesses. Environmental health interventions, facility renovation, asymptomatic employee exclusions, employee health monitoring, and recurrent facility environmental sampling measures were implemented. As a result of ongoing cases and environmental persistence of Salmonella Mbandaka, the restaurant closed permanently in 2018. Restaurant employee stool testing and environmental sampling for Salmonella early during the investigation of confirmed Salmonella cases linked to a restaurant enhances source identification. Exclusion or restriction of asymptomatic food workers with stool-positive nontyphoidal Salmonella should be considered part of restaurant outbreak mitigation.
Abstract 15924: Interstage Monitoring is Associated With Greater Weight Gain and Oxygen Saturation Over Time: A Longitudinal Analysis of National Pediatric Cardiology-Quality Improvement Collaborative Phase 1 Data
Authors: James M Meza, Eugene H Blackstone, Jeevanantham Jajeswaran, Nicholas D Andersen, Holly LoTurco, Brian W McCrindle, Kristine J Guleserian, Tara Karamlou, Garick D Hill, Joseph W Turek
Journal: Circulation (2019)

Introduction: Post-Norwood, interstage monitoring programs (ISM) track an infant’s weight and oxygen saturation (SaO2). Clinical decisions are made based upon changes in these values. Their traject...
26633 The role research gap-years play in a successful dermatology match
Authors: Collin M. Costello, Jamison A. Harvey, Jake G. Besch-Stokes, Puneet Bhullar, Elisabeth S. Lim, Katie L. Kunze, Megha M. Tollefson, Leila M. Tolaymat, Shari A. Ochoa
Journal: Journal of the American Academy of Dermatology (2021)
26094 A randomized, evaluator-blinded, comparator-controlled, study to evaluate safety and effectiveness of HARC for cheek augmentation and correction of midface contour deficiencies
Authors: Derek Jones, Leslie Baumann, Amir Moradi, Sachin Shridharani, Melanie Palm, Craig Teller, Mark Taylor, Theda Kontis, Anne Chapas, Michael S. Kaminer, David Bank
Journal: Journal of the American Academy of Dermatology (2021)
25851 Efficacy of secukinumab in managing axial manifestations and nail psoriasis in patients with psoriatic arthritis: Results from the MAXIMISE trial
Authors: Alice B. Gottlieb, Xenofon Baraliakos, Laura C. Coates, Effie Pournara, Michael Rissler, Dermot Whyms, Chiara Perella, Kristian Reich, Dafna D. Gladman, Maher Aassi
Journal: Journal of the American Academy of Dermatology (2021)
Lung Cancer in Vietnam
Authors: Huong T.T. Tran, Sang Nguyen, Kiem K. Nguyen, Dung X. Pham, Uoc H. Nguyen, Anh T. Le, Giang H. Nguyen, Dung V. Tran, Son D.H. Phung, Hung M. Do, Thuan V. Tran, Xiao-Ou Shu, Raymond U. Osarogiagbon
Journal: Journal of Thoracic Oncology (2021)
GAB1 SCAFFOLDING ADAPTOR PROTEIN PROTECTS FROM LIVER FIBROSIS DURING CHRONIC LIVER INJURY IN MICE
Authors: Takehara T, Kiso S, Ezaki H, Tsubakio M, Hamano M, Chatani N, Kamada Y, Furuta K, Takemura T, Yoshida Y, Kizu T
Journal: Hepatology (2011)
Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma
Authors: Toni K. Choueiri, Piotr Tomczak, Se Hoon Park, Balaji Venugopal, Thomas Ferguson, Yen-Hwa Chang, Jaroslav Hajek, Stefan N. Symeonides, Jae Lyun Lee, Naveed Sarwar, Antoine Thiery-Vuillemin, Marine Gross-Goupil, Mauricio Mahave, Naomi B. Haas, Piotr Sawrycki, Howard Gurney, Christine Chevreau, Bohuslav Melichar, Evgeniy Kopyltsov, Ajjai Alva, John M. Burke, Gurjyot Doshi, Delphine Topart, Stephane Oudard, Hans Hammers, Hiroshi Kitamura, Jens Bedke, Rodolfo F. Perini, Pingye Zhang, Kentaro Imai, Jaqueline Willemann-Rogerio, David I. Quinn, Thomas Powles
Journal: New England Journal of Medicine (2021)

Patients with renal-cell carcinoma who undergo nephrectomy have no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence.
Endoscopic ultrasound-guided hepaticoduodenostomy with anterograde stenting for recurrent hepatic hilar obstruction
Authors: Shota Harai, Susumu Hijioka, Yuta Maruki, Akihiro Ohba, Yoshikuni Nagashio, Takuji Okusaka, Yutaka Saito
Journal: Endoscopy (2021)

We present the case of a 52-year-old woman who underwent endoscopic ultrasound-guided hepaticoduodenostomy (EUS-HDS) with anterograde stenting. She had undergone side-by-side stent drainage (the left hepatic and anterior bile ducts) for Bismuth type II hilar bile duct obstruction (HBO) caused by intrahepatic cholangiocarcinoma. She was diagnosed with cholangitis in the posterior bile duct (B6) due to stent occlusion 2 months later. Endoscopic retrograde cholangiopancreatography was performed, but the catheter could not be inserted into B6 ([Fig. 1]). Although balloon dilation of the stent mesh was performed, even the thinnest (5.7 Fr) uncovered self-expandable metal stent (UCSEMS) could not be inserted. Therefore, we performed anterograde stenting via EUS-HDS.
Differential Immune-Related Microenvironment Determines Programmed Cell Death Protein-1/Programmed Death-Ligand 1 Blockade Efficacy in Patients With Advanced NSCLC
Authors: Masayuki Shirasawa, Tatsuya Yoshida, Yukiko Shimoda, Daisuke Takayanagi, Kouya Shiraishi, Takashi Kubo, Sachiyo Mitani, Yuji Matsumoto, Ken Masuda, Yuki Shinno, Yusuke Okuma, Yasushi Goto, Hidehito Horinouchi, Hitoshi Ichikawa, Takashi Kohno, Noboru Yamamoto, Shingo Matsumoto, Koichi Goto, Shun-ichi Watanabe, Yuichiro Ohe, Noriko Motoi
Journal: Journal of Thoracic Oncology (2021)
Thioredoxin Reductase Inhibition for Cancer Therapy
Authors: Radosveta Gencheva, Elias S.J. Arnér
Journal: The Annual Review of Pharmacology and Toxicology (2021)

The cytosolic selenoprotein thioredoxin reductase 1 (TrxR1, TXNRD1), and to some extent mitochondrial TrxR2 (TXNRD2), can be inhibited by a wide range of electrophilic compounds. Many such compounds also yield cytotoxicity toward cancer cells in culture or in mouse models, and most compounds are likely to irreversibly modify the easily accessible selenocysteine residue in TrxR1, thereby inhibiting its normal activity to reduce cytosolic thioredoxin (Trx1, TXN) and other substrates of the enzyme. This leads to an oxidative challenge. In some cases, the inhibited forms of TrxR1 are not catalytically inert and are instead converted to prooxidant NADPH oxidases, named SecTRAPs, thus further aggravating the oxidative stress, particularly in cells expressing higher levels of the enzyme. In this review, the possible molecular and cellular consequences of these effects are discussed in relation to cancer therapy, with a focus on outstanding questions that should be addressed if targeted TrxR1 inhibition is to be further developed for therapeutic use.
Clonal myelopoiesis promotes adverse outcomes in chronic kidney disease
Authors: Ahmed A. Z. Dawoud, Rodney D. Gilbert, William J. Tapper, Nicholas C. P. Cross
Journal: Leukemia (2021)

Abstract We sought to determine the relationship between age-related clonal hematopoiesis (CH) and chronic kidney disease (CKD). CH, defined as mosaic chromosome abnormalities (mCA) and/or driver mutations was identified in 5449 (2.9%) eligible UK Biobank participants ( n = 190,487 median age = 58 years). CH was negatively associated with glomerular filtration rate estimated from cystatin-C (eGFR.cys; β = −0.75, P = 2.37 × 10 –4 ), but not with eGFR estimated from creatinine, and was specifically associated with CKD defined by eGFR.cys &lt; 60 (OR = 1.02, P = 8.44 × 10 –8 ). In participants without prevalent myeloid neoplasms, eGFR.cys was associated with myeloid mCA ( n = 148, β = −3.36, P = 0.01) and somatic driver mutations ( n = 3241, β = −1.08, P = 6.25 × 10 –5 ) associated with myeloid neoplasia (myeloid CH), specifically mutations in CBL , TET2 , JAK2 , PPM1D and GNB1 but not DNMT3A or ASXL1 . In participants with no history of cardiovascular disease or myeloid neoplasms, myeloid CH increased the risk of adverse outcomes in CKD (HR = 1.6, P = 0.002) compared to those without myeloid CH. Mendelian randomisation analysis provided suggestive evidence for a causal relationship between CH and CKD ( P = 0.03). We conclude that CH, and specifically myeloid CH, is associated with CKD defined by eGFR.cys. Myeloid CH promotes adverse outcomes in CKD, highlighting the importance of the interaction between intrinsic and extrinsic factors to define the health risk associated with CH.