tbuckley/cabot-search huggingface dataset:
A NKG2D-based CAR-T therapy in a multinational phase I dose escalation and expansion study targeting multiple solid and hematologic tumor types.
Authors: Bikash Verma, Philippe Georges Aftimos, Ahmad Awada, Jean-Pascal H. Machiels, Jason B. Brayer, David A Sallman, Tessa Kerre, Kunle Odunsi, Caroline Lonez, David Edward Gilham, Frederic Lehmann
Journal: Journal of Clinical Oncology (2017)

TPS3093 Background: Chimeric Antigen Receptor (CAR)-T therapy has potentially serious limitations related to target antigen loss, toxicity due to pre-conditioning regimen, and lack of activity in many tumor types. To overcome these limitations, we have developed a novel CAR-T, called NKR-2, incorporating the full-length human natural killer receptor NKG2D fused with the human CD3 zeta signaling domain. When expressed in T-cells, the naturally-expressed DAP10 provides co-stimulatory signals to NKR-2 to produce cytokines and selectively target tumor cells upon recognition of up to 8 different stress-induced NKG2D ligands expressed in many solid and hematologic malignancies. In preclinical studies, NKR-2 demonstrated long-term anti-tumor activity towards a breadth of tumor indications, in the absence of pre-conditioning, whilst simultaneously targeting tumor cells and cells from the local tumor neo-vasculature and suppressive immune environment. In our recently completed First-in-Human Phase 1 study (NCT02203825) in hematologic cancers, a single administration of autologous NKR-2 was safe with initial signs of clinical benefit. Methods: Exploiting the multiple ligand targeting capability and unique mode of action of NKR-2, the THINK trial (THerapeutic Immunotherapy with NKR-2) is an open-label Phase I study that will assess the safety and clinical activity of multiple infusion NKR-2 treatment (every 2 weeks x 3 infusions) in relapse/refractory patients with metastatic or locally advanced CRC, urothelial carcinoma, TNBC, pancreatic cancer, recurrent epithelial ovarian and fallopian tube carcinoma, AML/MDS and MM, post standard treatment. The study contains two consecutive segments. The dose escalation segment will enroll 18 patients in two separate hematologic and solid malignancy arms, and will evaluate 3 dose levels of NKR-2 (3x10 8 , 1x10 9 and 3x10 9 per injection) following a 3+3 design. The expansion segment will then enroll 96 additional patients in 7 separate cohorts for each indication with 3 steps of statistical analysis (overall futility, cohort futility and final evaluation). The study is open for recruitment in both EU and US. Clinical trial information: NCT03018405.
Physiological genomics identifies genetic modifiers of long QT syndrome type 2 severity
Authors: Sam Chai, Xiaoping Wan, Angelina Ramirez-Navarro, Paul J. Tesar, Elizabeth S. Kaufman, Eckhard Ficker, Alfred L. George, Isabelle Deschênes
Journal: Journal of Clinical Investigation (2018)

Congenital long QT syndrome (LQTS) is an inherited channelopathy associated with life-threatening arrhythmias. LQTS type 2 (LQT2) is caused by mutations in KCNH2, which encodes the potassium channel hERG. We hypothesized that modifier genes are partly responsible for the variable phenotype severity observed in some LQT2 families. Here, we identified contributors to variable expressivity in an LQT2 family by using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and whole exome sequencing in a synergistic manner. We found that iPSC-CMs recapitulated the clinical genotype-phenotype discordance in vitro. Importantly, iPSC-CMs derived from the severely affected LQT2 patients displayed prolonged action potentials compared with cells from mildly affected first-degree relatives. The iPSC-CMs derived from all patients with hERG R752W mutation displayed lower IKr amplitude. Interestingly, iPSC-CMs from severely affected mutation-positive individuals exhibited greater L-type Ca2+ current. Whole exome sequencing identified variants of KCNK17 and the GTP-binding protein REM2, providing biologically plausible explanations for this variable expressivity. Genome editing to correct a REM2 variant reversed the enhanced L-type Ca2+ current and prolonged action potential observed in iPSC-CMs from severely affected individuals. Thus, our findings showcase the power of combining complementary physiological and genomic analyses to identify genetic modifiers and potential therapeutic targets of a monogenic disorder. Furthermore, we propose that this strategy can be deployed to unravel myriad confounding pathologies displaying variable expressivity.
Endoscopic removal of a proximally migrated pancreatic stent
Authors: Shawn Shah, Enad Dawod, Michel Kahaleh
Journal: Endoscopy (2018)

A 64-year-old woman with choledocholithiasis underwent endoscopic retrograde cholangiopancreatography (ERCP) with stone extraction and biliary and pancreatic duct (PD) stent placement. She subsequently presented with postprandial abdominal distension of a few weeks' duration. The patient had undergone a laparoscopic cholecystectomy following the ERCP; however, a repeat ERCP nearly 2 months after her initial endoscopy revealed a proximally migrated PD stent that could not be retrieved, prompting transfer to our center.
Sargramostim Accelerates Leukocyte Recovery and Improves Mortality Rate at Day 60 in a Non-Human Primate Model of Hematopoietic Acute Radiation Syndrome When Administered 48 h after Total Body Irradiation
Authors: Nicholas P. Clayton, Eric J.J. Charpentier, Emily R. LaCasse, Richard C. Khan-Malek, Joan M. Keutzer
Journal: Blood (2016)
Phosphatidylinositol 3-Kinase α–Selective Inhibition With Alpelisib (BYL719) in <i>PIK3CA</i>-Altered Solid Tumors: Results From the First-in-Human Study
Authors: Dejan Juric, Jordi Rodon, Josep Tabernero, Filip Janku, Howard A. Burris, Jan H.M. Schellens, Mark R. Middleton, Jordan Berlin, Martin Schuler, Marta Gil-Martin, Hope S. Rugo, Ruth Seggewiss-Bernhardt, Alan Huang, Douglas Bootle, David Demanse, Lars Blumenstein, Christina Coughlin, Cornelia Quadt, José Baselga
Journal: Journal of Clinical Oncology (2018)

Purpose We report the first-in-human phase Ia study to our knowledge ( ClinicalTrials.gov identifier: NCT01219699) identifying the maximum tolerated dose and assessing safety and preliminary efficacy of single-agent alpelisib (BYL719), an oral phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor. Patients and Methods In the dose-escalation phase, patients with PIK3CA-altered advanced solid tumors received once-daily or twice-daily oral alpelisib on a continuous schedule. In the dose-expansion phase, patients with PIK3CA-altered solid tumors and PIK3CA-wild-type, estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer received alpelisib 400 mg once daily. Results One hundred thirty-four patients received treatment. Alpelisib maximum tolerated doses were established as 400 mg once daily and 150 mg twice daily. Nine patients (13.2%) in the dose-escalation phase had dose-limiting toxicities of hyperglycemia (n = 6), nausea (n = 2), and both hyperglycemia and hypophosphatemia (n = 1). Frequent all-grade, treatment-related adverse events included hyperglycemia (51.5%), nausea (50.0%), decreased appetite (41.8%), diarrhea (40.3%), and vomiting (31.3%). Alpelisib was rapidly absorbed; half-life was 7.6 hours at 400 mg once daily with minimal accumulation. Objective tumor responses were observed at doses ≥ 270 mg once daily; overall response rate was 6.0% (n = 8; one patient with endometrial cancer had a complete response, and seven patients with cervical, breast, endometrial, colon, and rectal cancers had partial responses). Stable disease was achieved in 70 (52.2%) patients and was maintained > 24 weeks in 13 (9.7%) patients; disease control rate (complete and partial responses and stable disease) was 58.2%. In patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, median progression-free survival was 5.5 months. Frequently mutated genes (≥ 10% tumors) included TP53 (51.3%), APC (23.7%), KRAS (22.4%), ARID1A (13.2%), and FBXW7 (10.5%). Conclusion Alpelisib demonstrated a tolerable safety profile and encouraging preliminary activity in patients with PIK3CA-altered solid tumors, supporting the rationale for selective PI3Kα inhibition in combination with other agents for the treatment of PIK3CA-mutant tumors.
AOM)誘発アゾキシメタン結腸異常陰窩巣(ACF)の形成を調整するPPARガンマリガンドおよびPPARガンマヘテロノックアウト(HKO)トランスジェニックマウス
Authors: Osawa E, Nakajima A, Sekihara H, Matsuhashi N, Ochiai I, Nakagama H
Journal: Clinical Cancer Research (2001)
Proteomic Profiling Reveals the Transglutaminase-2 Externalization Pathway in Kidneys after Unilateral Ureteric Obstruction
Authors: Giulia Furini, Nina Schroeder, Linghong Huang, David Boocock, Alessandra Scarpellini, Clare Coveney, Elisa Tonoli, Raghavendran Ramaswamy, Graham Ball, Claudia Verderio, Timothy S. Johnson, Elisabetta A.M. Verderio
Journal: Journal of the American Society of Nephrology (2018)

Increased export of transglutaminase-2 (TG2) by tubular epithelial cells (TECs) into the surrounding interstitium modifies the extracellular homeostatic balance, leading to fibrotic membrane expansion. Although silencing of extracellular TG2 ameliorates progressive kidney scarring in animal models of CKD, the pathway through which TG2 is secreted from TECs and contributes to disease progression has not been elucidated. In this study, we developed a global proteomic approach to identify binding partners of TG2 responsible for TG2 externalization in kidneys subjected to unilateral ureteric obstruction (UUO) using TG2 knockout kidneys as negative controls. We report a robust and unbiased analysis of the membrane interactome of TG2 in fibrotic kidneys relative to the entire proteome after UUO, detected by SWATH mass spectrometry. The data have been deposited to the ProteomeXchange with identifier PXD008173. Clusters of exosomal proteins in the TG2 interactome supported the hypothesis that TG2 is secreted by extracellular membrane vesicles during fibrosis progression. In established TEC lines, we found TG2 in vesicles of both endosomal (exosomes) and plasma membrane origin (microvesicles/ectosomes), and TGF- β 1 stimulated TG2 secretion. Knockout of syndecan-4 (SDC4) greatly impaired TG2 exosomal secretion. TG2 coprecipitated with SDC4 from exosome lysate but not ectosome lysate. Ex vivo , EGFP-tagged TG2 accumulated in globular elements (blebs) protruding/retracting from the plasma membrane of primary cortical TECs, and SDC4 knockout impaired bleb formation, affecting TG2 release. Through this combined in vivo and in vitro approach, we have dissected the pathway through which TG2 is secreted from TECs in CKD.
Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums
Authors: Steven E. Arnold, Zoe Arvanitakis, Shannon L. Macauley-Rambach, Aaron M. Koenig, Hoau-Yan Wang, Rexford S. Ahima, Suzanne Craft, Sam Gandy, Christoph Buettner, Luke E. Stoeckel, David M. Holtzman, David M. Nathan
Journal: Nature Reviews Neurology (2018)
Histomorphological Responses after Therapy with Pegylated Interferon Alpha-2a in Patients with Essential Thrombocythemia (ET) and Polycythemia Vera (PV)
Authors: Lucia Masarova, C. Cameron Yin, Jorge E. Cortes, Marina Konopleva, Gautam Borthakur, Kate J Newberry, Hagop M. Kantarjian, Carlos E Bueso-Ramos, Srdan Verstovsek
Journal: Blood (2016)
Second consensus on the assessment of sublingual microcirculation in critically ill patients: results from a task force of the European Society of Intensive Care Medicine
Authors: Can Ince, E. Christiaan Boerma, Maurizio Cecconi, Daniel De Backer, Nathan I. Shapiro, Jacques Duranteau, Michael R. Pinsky, Antonio Artigas, Jean-Louis Teboul, Irwin K. M. Reiss, Cesar Aldecoa, Sam D. Hutchings, Abele Donati, Marco Maggiorini, Fabio S. Taccone, Glenn Hernandez, Didier Payen, Dick Tibboel, Daniel S. Martin, Alexander Zarbock, Xavier Monnet, Arnaldo Dubin, Jan Bakker, Jean-Louis Vincent, Thomas W. L. Scheeren
Journal: Intensive Care Medicine (2018)
Human natural killer cell IFN-gamma production: Inhibition by TGF-beta involves SMAD-mediated downregulation of T-BET expression
Authors: Jianhua Yu, Brian Becknell, Rossana Trotta, Shujun Liu, Min Wei, Darshna Bhatt, Michael Jaung, Tiffany Hughes, Guido Marcucci, Michael A. Caligiuri
Journal: Cancer Research (2005)

2431  Transforming growth factor (TGF)-β plays an important role in the negative regulation of interferon (IFN)-γ production by natural killer (NK) cells and T cells, but the mechanism is unclear. Here we first show that retroviral expression of dominant negative T-BET in the human NK cell line NK-92 impairs IFN-γ production in response to monokine stimulation. In NK-92 and primary human NK cells, TGF-β1 inhibits T-BET expression, and this inhibition correlates with the suppression of monokine-activated IFN-γ production by TGF-β1. Moreover, transfection of SMAD2, SMAD3 and SMAD4, mediators of TGF-β signaling, into 293T cells represses T-BET promoter activity. We mapped the TBET promoter responsible for SMAD-mediated repression to the 100bp proximal region. We then performed chromatin immunoprecipitation assay and showed that SMAD2 is increased on the proximal T-BET promoter following TGF-β1 treatment. Although we did not find any SMAD binding sites in the100bp promoter of T-BET, we found at least six Sp1 binding sites within the 100bp region, and there is evidence that Sp1 physically associates with SMAD proteins (Feng et al., EMBO J 19, 5178-5193, 2000). We therefore hypothesized that following TGF-β signaling, Sp1 recruits SMAD proteins onto proximal promoter of T-BET to repress its transcription. To support our hypothesis, we performed an electrophoretic mobility shift assay and found Sp1 binds to the T-BET promoter. Collectively, our results suggest that T-BET is a positive regulator of IFN-γ production in human NK cells. Furthermore, T-BET expression is suppressed by TGF-β signaling, and this inhibition likely contributes to inhibition of NK cell IFN-γ production by TGF-β. Our preliminary evidence suggests that the SMAD transcription factors are recruited by Sp1 onto the T-BET promoter and act as negative regulators to suppress the transcription of IFN-γ in human NK cells.
Protein corona–mediated targeting of nanocarriers to B cells allows redirection of allergic immune responses
Authors: Limei Shen, Stefan Tenzer, Wiebke Storck, Dominika Hobernik, Verena Katherina Raker, Karl Fischer, Sandra Decker, Andrzej Dzionek, Susanne Krauthäuser, Mustafa Diken, Alexej Nikolaev, Joachim Maxeiner, Petra Schuster, Cinja Kappel, Admar Verschoor, Hansjörg Schild, Stephan Grabbe, Matthias Bros
Journal: Journal of Allergy and Clinical Immunology (2018)

Nanoparticle (NP)-based vaccines are attractive immunotherapy tools because of their capability to codeliver antigen and adjuvant to antigen-presenting cells. Their cellular distribution and serum protein interaction ("protein corona") after systemic administration and their effect on the functional properties of NPs is poorly understood.We analyzed the relevance of the protein corona on cell type-selective uptake of dextran-coated NPs and determined the outcome of vaccination with NPs that codeliver antigen and adjuvant in disease models of allergy.The role of protein corona constituents for cellular binding/uptake of dextran-coated ferrous nanoparticles (DEX-NPs) was analyzed both in vitro and in vivo. DEX-NPs conjugated with the model antigen ovalbumin (OVA) and immunostimulatory CpG-rich oligodeoxynucleotides were administered to monitor the induction of cellular and humoral immune responses. Therapeutic effects of this DEX-NP vaccine in mouse models of OVA-induced anaphylaxis and allergic asthma were assessed.DEX-NPs triggered lectin-induced complement activation, yielding deposition of activated complement factor 3 on the DEX-NP surface. In the spleen DEX-NPs targeted predominantly B cells through complement receptors 1 and 2. The DEX-NP vaccine elicited much stronger OVA-specific IgG2a production than coadministered soluble OVA plus CpG oligodeoxynucleotides. B-cell binding of the DEX-NP vaccine was critical for IgG2a production. Treatment of OVA-sensitized mice with the DEX-NP vaccine prevented induction of anaphylactic shock and allergic asthma accompanied by IgE inhibition.Opsonization of lectin-coated NPs by activated complement components results in selective B-cell targeting. The intrinsic B-cell targeting property of lectin-coated NPs can be exploited for treatment of allergic immune responses.
What’s coming for health science and policy in 2018? Global experts look ahead in their field
Authors: Soumya Swaminathan, Robin S. Room, Louise C. Ivers, Graham Hillis, Rebecca F. Grais, Zulfiqar A. Bhutta, Peter Byass
Journal: PLoS Medicine (2018)

PLOS Medicine's commitment to bringing research and commentary on urgent, grievous, and underaddressed health needs to an open-access platform has never felt more relevant than in 2017.A study [1] quantifying police activity-related deaths in the United States, published in October, received more than 100,000 views within a few weeks of publication, and our Special Issue on Advances in HIV Research led November to a journal record for number of articles published in a single month.Meanwhile, requirements for sharing data, which PLOS launched in 2014, expanded across medical publishers [2], indicating that globally important findings in health research, and the ability to further analyze these, will become increasingly accessible in coming years.In 2018, we plan a Special Issue on cardiovascular disease in the context of comorbid conditions and another probing the interaction between climate change and health.What further priorities must research and policy address?For our first editorial of 2018, we asked editorial board members and other leading researchers to share their hopes, pleas, concerns, and expectations for medical research and policy related to global health in 2018.
Transcriptional Regulation of the Warburg Effect in Cancer by SIX1
Authors: Ling Li, Yingchun Liang, Lei Kang, Yang Liu, Shan Gao, Siyu Chen, Ying Li, Wenye You, Qian Dong, Tian Hong, Zhifeng Yan, Shuai Jin, Tao Wang, Wei Zhao, Haixing Mai, Jun Huang, Xiao Han, Quanbo Ji, Qi Song, Chao Yang, Shixin Zhao, Xiaojie Xu, Qinong Ye
Journal: Cancer Cell (2018)
Significant correlation between interleukin-10 expression and progression of non-small cell lung cancer through heme oxygenase
Authors: Piera Boschetto, Elena Zeni, Lucia Mazzetti, P Maestrelli, B Murer, Patrizia Querzoli, Massimo Pedriali, Deborah Miotto, Edoardo De Rosa, Lm Fabbri, Cristina Mapp
Journal: European Respiratory Journal (2005)
A Schwannoma of the Small Bowel
Authors: Yugo Iwaya, Catherine Streutker, Norman Marcon
Journal: Clinical Gastroenterology and Hepatology (2018)

An 83-year-old woman presented to our hospital with abdominal pain, loose stools, and bright red blood per rectum. Computed tomography (CT) abdomen showed thickening of sigmoid colon that was consistent with ischemic colitis. Incidentally, CT also revealed a 12-mm enhancing polypoid lesion in the ileum. We performed video capsule endoscopy, which showed a mobile submucosal polyp in the distal small bowel (Figure A). Retrograde double balloon enteroscopy was carried out, which demonstrated a 15-mm smooth and firm submucosal polypoid lesion located approximately 70 cm proximal to the ileocecal valve (Figure B). Multiple biopsies were obtained; however, they did not show any submucosal lesion and the patient underwent laparoscopic small bowel resection. Macroscopic examination revealed a single, yellow, firm polypoid submucosal lesion. Microscopic examination showed a submucosal spindle cell lesion (Figure C). On immunostaining, the lesion stained strongly with S100, and was negative for desmin, CD117, CD34, and DOG1. The features and immunohistochemical staining pattern were consistent with small bowel schwannoma, which is an extremely rare condition. This tumor was considered an incidental finding, as pathologically there were no erosive ulcerations in this lesion and the patient’s presenting complaints were consistent with ischemic colitis.
Macrophages and neutrophils: dynamic duo or partners in crime?
Authors: Karl J Staples
Journal: Thorax (2018)

As spring emerges from the shadows of a cold, dark winter, we are again left to reflect on the ravages of another influenza season. Based on the emergent data from Australia,1 the 2017–2018 outbreak in the Northern Hemisphere was predicted to be particularly severe and so it proved to be. Disease severity can be driven by a number of factors, including shifts in the viral genome, but host innate immune responses also play a role, most notably in the lethal cytokine storm response to avian influenza strains.2

Macrophages are the predominant innate immune cell in the human airway and critical for an appropriate protective response to bacterial, fungal and viral infections. These cells enhance viral clearance, being essential for both viral antigen presentation to mucosal T cells3 and the development of neutralising antibodies.4 Furthermore, when macrophages are depleted, there is increased lung pathology5 in response to viral infection demonstrating the central role of macrophages in ensuring that virus control does not compromise host survival. In the majority of cases, such mechanisms ensure that lung inflammation is kept to a minimum so that pneumonias do not develop. However, it is known that influenza infection can lead to both primary and secondary bacterial pneumonias,6 although whether as a result of virus or host factors is unclear. Pneumonias are primarily associated with massive neutrophil influx into the lung leading to compromised gas exchange but there are conflicting reports as to whether the role of the neutrophil in viral infections is protective or pathological.7 The study by Peiro et al 8 has provided further insight into the complex interplay between macrophages and neutrophils in a mouse model of influenza infection.

Peiro and colleagues first demonstrated that the pleiotropic proinflammatory cytokine, interleukin 1-beta (IL-1β), is induced by influenza …
Indoxyl Sulfate Upregulates Liver P-Glycoprotein Expression and Activity through Aryl Hydrocarbon Receptor Signaling
Authors: Tacy Santana Machado, Stéphane Poitevin, Pascale Paul, Nathalie McKay, Noémie Jourde-Chiche, Tristan Legris, Annick Mouly-Bandini, Françoise Dignat-George, Philippe Brunet, Rosalinde Masereeuw, Stéphane Burtey, Claire Cerini
Journal: Journal of the American Society of Nephrology (2017)

Export In patients with CKD, not only renal but also, nonrenal clearance of drugs is altered. Uremic toxins could modify the expression and/or activity of drug transporters in the liver. We tested whether the uremic toxin indoxyl sulfate (IS), an endogenous ligand of the transcription factor aryl hydrocarbon receptor, could change the expression of the following liver transporters involved in drug clearance: SLC10A1, SLC22A1, SLC22A7, SLC47A1, SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCB11, ABCC2, ABCC3, ABCC4, ABCC6, and ABCG2. We showed that IS increases the expression and activity of the efflux transporter P-glycoprotein (P-gp) encoded by ABCB1 in human hepatoma cells (HepG2) without modifying the expression of the other transporters. This effect depended on the aryl hydrocarbon receptor pathway. Presence of human albumin at physiologic concentration in the culture medium did not abolish the effect of IS. In two mouse models of CKD, the decline in renal function associated with the accumulation of IS in serum and the specific upregulation of Abcb1a in the liver. Additionally, among 109 heart or kidney transplant recipients with CKD, those with higher serum levels of IS needed higher doses of cyclosporin, a P-gp substrate, to obtain the cyclosporin target blood concentration. This need associated with serum levels of IS independent of renal function. These findings suggest that increased activity of P-gp could be responsible for increased hepatic cyclosporin clearance. Altogether, these results suggest that uremic toxins, such as IS, through effects on drug transporters, may modify the nonrenal clearance of drugs in patients with CKD.