tbuckley/cabot-search huggingface dataset:
Optimization of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells for Improved Anti-tumor Efficacy against Glioblastoma
Authors: Christine E. Brown, Brenda Aguilar, Renate Starr, Xin Yang, Wen-Chung Chang, Lihong Weng, Brenda Chang, Aniee Sarkissian, Alfonso Brito, James F. Sanchez, Julie R. Ostberg, Massimo D’Apuzzo, Behnam Badie, Michael E. Barish, Stephen J. Forman
Journal: Molecular Therapy (2017)

T cell immunotherapy is emerging as a powerful strategy to treat cancer and may improve outcomes for patients with glioblastoma (GBM). We have developed a chimeric antigen receptor (CAR) T cell immunotherapy targeting IL-13 receptor α2 (IL13Rα2) for the treatment of GBM. Here, we describe the optimization of IL13Rα2-targeted CAR T cells, including the design of a 4-1BB (CD137) co-stimulatory CAR (IL13BBζ) and a manufacturing platform using enriched central memory T cells. Utilizing orthotopic human GBM models with patient-derived tumor sphere lines in NSG mice, we found that IL13BBζ-CAR T cells improved anti-tumor activity and T cell persistence as compared to first-generation IL13ζ-CAR CD8+ T cells that had shown evidence for bioactivity in patients. Investigating the impact of corticosteroids, given their frequent use in the clinical management of GBM, we demonstrate that low-dose dexamethasone does not diminish CAR T cell anti-tumor activity in vivo. Furthermore, we found that local intracranial delivery of CAR T cells elicits superior anti-tumor efficacy as compared to intravenous administration, with intraventricular infusions exhibiting possible benefit over intracranial tumor infusions in a multifocal disease model. Overall, these findings help define parameters for the clinical translation of CAR T cell therapy for the treatment of brain tumors. T cell immunotherapy is emerging as a powerful strategy to treat cancer and may improve outcomes for patients with glioblastoma (GBM). We have developed a chimeric antigen receptor (CAR) T cell immunotherapy targeting IL-13 receptor α2 (IL13Rα2) for the treatment of GBM. Here, we describe the optimization of IL13Rα2-targeted CAR T cells, including the design of a 4-1BB (CD137) co-stimulatory CAR (IL13BBζ) and a manufacturing platform using enriched central memory T cells. Utilizing orthotopic human GBM models with patient-derived tumor sphere lines in NSG mice, we found that IL13BBζ-CAR T cells improved anti-tumor activity and T cell persistence as compared to first-generation IL13ζ-CAR CD8+ T cells that had shown evidence for bioactivity in patients. Investigating the impact of corticosteroids, given their frequent use in the clinical management of GBM, we demonstrate that low-dose dexamethasone does not diminish CAR T cell anti-tumor activity in vivo. Furthermore, we found that local intracranial delivery of CAR T cells elicits superior anti-tumor efficacy as compared to intravenous administration, with intraventricular infusions exhibiting possible benefit over intracranial tumor infusions in a multifocal disease model. Overall, these findings help define parameters for the clinical translation of CAR T cell therapy for the treatment of brain tumors.
Ciprofloxacin treatment for cryptogenic Klebsiella pneumoniae liver abscesses
Authors: Se Yoon Park, Taeeun Kim, Min-Chul Kim, Heungsup Sung, Mi-Na Kim, Sung-Han Kim, Sang-Oh Lee, Sang-Ho Choi, Jun Hee Woo, Yang Soo Kim, Yong Pil Chong
Journal: Journal of Infection (2017)
Abstract 3703: The Effect of Naringenin and Antiarrhythmic Drugs on IKr Inhibition
Authors: Congrong Lin, Xiaogang Ke, Vasant Ranade, John Somberg
Journal: Circulation (2006)

Grapefruit juice has been reported to cause significant QT prolongation in healthy volunteers. Naringenin (N), the principal flavonoid in grapefruit juice, has been identified as the most potent HERG channel blocker among several dietary flavonoids. We evaluated the effect of combining N with IKr inhibiting antiarrhythmic drugs on the cardiac IKr channel. The effect of N combined with quinidine (Q), dofetilide (D) and amiodarone (A) were studied in an oocyte system with heterogeneously expressed human-ether-a-go-go-related gene (HERG) employing two electrodes voltage clamp technique for recording. The recording solution contained 96mM Na Cl, 5.0mM KCl, 2.0mM CaCl2, and 1.0mM MgCl2, 5mM HEPES and the pH of solution was adjusted with NaOH to 7.4. The experiments were performed at room temperature. N 100uM was found to inhibit HERG current by 31±6% and Q at 1 and 10uM cause 10±1 and 26±3% inhibition of HERG. N 100uM plus 1uM Q caused a 48±5% current inhibition. N 100uM plus 10uM Q caused a 58±6% block in HERG current. N 100uM combined with 1uM D and N 100uM combined with 10uM D caused 56±5 and 90±2% inhibition in HERG current, while D 1 and 10uM alone inhibited current 22±4 and 69±4% respectively. A 1uM decreased current by 20±2% and by 38±8% when combined with 100uM N. A 10uM alone caused 43±4% inhibition and the inhibition increased to 53±9% with the combination of 100uM N. N inhibits IKr and there is an additive inhibitory effect on IKr when N is combined with other IKr blocking antiarrhythmic drugs (Q, D and A). The additive IKr inhibition could pose an increased health risk by increasing repolarization delay and that could give rise to cardiac arrhythmias.
A nationwide genomic screening project for small cell lung cancer in Japan (LC-SCRUM-Japan)
Authors: Haruko Daga, Shigeki Umemura, Yuichiro Ohe, Tetsuhiro Shiota, Masaki Fujita, Naoki Furuya, Takeshi Tsuda, Masahiro Morise, Shingo Matsumoto, Koichi Goto
Journal: Annals of Oncology (2017)
Population-based analysis of ocular Chlamydia trachomatis in trachoma-endemic West African communities identifies genomic markers of disease severity
Authors: A. R. Last, H. Pickering, C. h. Roberts, F. Coll, J. Phelan, S. E. Burr, E. Cassama, M. Nabicassa, H. M. B. Seth-Smith, J. Hadfield, L. T. Cutcliffe, I. N. Clarke, D. C. W. Mabey, R. L. Bailey, T. G. Clark, N. R. Thomson, M. J. Holland
Journal: Genome Medicine (2018)

Chlamydia trachomatis (Ct) is the most common infectious cause of blindness and bacterial sexually transmitted infection worldwide. Ct strain-specific differences in clinical trachoma suggest that genetic polymorphisms in Ct may contribute to the observed variability in severity of clinical disease. Using Ct whole genome sequences obtained directly from conjunctival swabs, we studied Ct genomic diversity and associations between Ct genetic polymorphisms with ocular localization and disease severity in a treatment-naïve trachoma-endemic population in Guinea-Bissau, West Africa. All Ct sequences fall within the T2 ocular clade phylogenetically. This is consistent with the presence of the characteristic deletion in trpA resulting in a truncated non-functional protein and the ocular tyrosine repeat regions present in tarP associated with ocular tissue localization. We have identified 21 Ct non-synonymous single nucleotide polymorphisms (SNPs) associated with ocular localization, including SNPs within pmpD (odds ratio, OR = 4.07, p* = 0.001) and tarP (OR = 0.34, p* = 0.009). Eight synonymous SNPs associated with disease severity were found in yjfH (rlmB) (OR = 0.13, p* = 0.037), CTA0273 (OR = 0.12, p* = 0.027), trmD (OR = 0.12, p* = 0.032), CTA0744 (OR = 0.12, p* = 0.041), glgA (OR = 0.10, p* = 0.026), alaS (OR = 0.10, p* = 0.032), pmpE (OR = 0.08, p* = 0.001) and the intergenic region CTA0744–CTA0745 (OR = 0.13, p* = 0.043). This study demonstrates the extent of genomic diversity within a naturally circulating population of ocular Ct and is the first to describe novel genomic associations with disease severity. These findings direct investigation of host-pathogen interactions that may be important in ocular Ct pathogenesis and disease transmission.
Circulating Tumor Cells from Different Vascular Sites Exhibit Spatial Heterogeneity in Epithelial and Mesenchymal Composition and Distinct Clinical Significance in Hepatocellular Carcinoma
Authors: Yun-Fan Sun, Wei Guo, Yang Xu, Yin-Hong Shi, Zi-Jun Gong, Yuan Ji, Min Du, Xin Zhang, Bo Hu, Ao Huang, George G. Chen, Paul B.S. Lai, Ya Cao, Shuang-Jian Qiu, Jian Zhou, Xin-Rong Yang, Jia Fan
Journal: Clinical Cancer Research (2017)

Abstract Purpose: The spatial heterogeneity of phenotypic and molecular characteristics of CTCs within the circulatory system remains unclear. Herein, we mapped the distribution and characterized biological features of CTCs along the transportation route in hepatocellular carcinoma (HCC). Experimental Design: In 73 localized HCC patients, blood was drawn from peripheral vein (PV), peripheral artery (PA), hepatic veins (HV), infrahepatic inferior vena cava (IHIVC), and portal vein (PoV) before tumor resection. Epithelial and mesenchymal transition (EMT) phenotype in CTCs were analyzed by a 4-channel immunofluorescence CellSearch assay and microfluidic quantitative RT-PCR. The clinical significance of CTCs from different vascular sites was evaluated. Results: The CTC number and size gradient between tumor efferent vessels and postpulmonary peripheral vessels was marked. Tracking the fate of CTC clusters revealed that CTCs displayed an aggregated–singular-aggregated manner of spreading. Single-cell characterization demonstrated that EMT status of CTCs was heterogeneous across different vascular compartments. CTCs were predominantly epithelial at release, but switched to EMT-activated phenotype during hematogeneous transit via Smad2 and β-catenin related signaling pathways. EMT activation in primary tumor correlated with total CTC number at HV, rather than epithelial or EMT-activated subsets of CTCs. Follow-up analysis suggested that CTC and circulating tumor microemboli burden in hepatic veins and peripheral circulation prognosticated postoperative lung metastasis and intrahepatic recurrence, respectively. Conclusions: The current data suggested that a profound spatial heterogeneity in cellular distribution and biological features existed among CTCs during circulation. Multivascular measurement of CTCs could help to reveal novel mechanisms of metastasis and facilitate prediction of postoperative relapse or metastasis pattern in HCC. Clin Cancer Res; 24(3); 547–59. ©2017 AACR.
A genetically inactivated two-component acellular pertussis vaccine, alone or combined with tetanus and reduced-dose diphtheria vaccines, in adolescents: a phase 2/3, randomised controlled non-inferiority trial
Authors: Sirintip Sricharoenchai, Chukiat Sirivichayakul, Kulkanya Chokephaibulkit, Punnee Pitisuttithum, Jittima Dhitavat, Arom Pitisuthitham, Wanatpreeya Phongsamart, Kobporn Boonnak, Keswadee Lapphra, Yupa Sabmee, Orasri Wittawatmongkol, Pailinrut Chinwangso, Indrajeet Kumar Poredi, Jean Petre, Pham Hong Thai, Simonetta Viviani
Journal: The Lancet Infectious Diseases (2017)
PrLZ increases prostate cancer docetaxel resistance by inhibiting LKB1/AMPK-mediated autophagy
Authors: Jin Zeng, Wei Liu, Yi-Zeng Fan, Da-Lin He, Lei Li
Journal: Theranostics (2017)

Rationale: Docetaxel-mediated chemotherapy is the first-line standard approach and has been determined to show a survival advantage for metastatic castration-resistant prostate cancer (mCRPC) patients.However, a substantial proportion of patients eventually becomes refractory due to drug resistance.The detailed mechanisms remain unclear.We have previously reported that Prostate Leucine Zipper (PrLZ), a specific oncogene of prostate cancer (PCa), promotes PCa cell growth at the castration-resistant stage, thus suggesting a vital role of PrLZ in the progression of CRPC.In this study, we aimed to investigate the role of PrLZ in docetaxel resistance in PCa, focusing on PrLZ-regulating autophagy pathway.Methods: Human PCa PC3, LNCaP and C4-2 cell lines were used as the model system in vitro and PCa xenografts and PrLZ-knockout mice were used as the model system in vivo.Docetaxel-induced cell death and apoptosis in PCa were determined by MTT and flow cytometry assay.The role of PrLZ on the regulation of autophagy and liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) signaling pathway was analyzed using immunoblotting, immunoprecipitation, siRNA silencing and plasmid overexpression.Results: PrLZ increased docetaxel-mediated drug resistance both in vitro and in vivo.Mechanistic dissection revealed that PrLZ interacted with LKB1 and further inhibited the activation of LKB1/AMPK signals, which negatively contributed to the induction of autophagy.Moreover, PrLZ/LKB1-mediated autophagy conferred resistance to docetaxel-induced cell death and apoptosis both in vitro and in vivo.Conclusion: These findings identify a novel role of PrLZ in autophagy manipulation and provide new insight into docetaxel chemoresistance in PCa, suggesting a new strategy for treating mCRPC by targeting this newly identified signaling pathway.
Neutrophils drive alveolar macrophage IL-1β release during respiratory viral infection
Authors: Teresa Peiró, Dhiren F Patel, Samia Akthar, Lisa G Gregory, Chloe J Pyle, James A Harker, Mark A Birrell, Clare M Lloyd, Robert J Snelgrove
Journal: Thorax (2017)

Background Alveolar macrophages are sentinels of the airways that must exhibit immune restraint to innocuous antigens but elicit a robust inflammatory response to pathogenic threats. How distinction between these dichotomous functions is controlled is poorly defined. Neutrophils are the first responders to infection, and we hypothesised that they may free alveolar macrophages from their hyporesponsive state, promoting their activation. Activation of the inflammasome and interleukin (IL)-1β release is a key early inflammatory event that must be tightly regulated. Thus, the role of neutrophils in defining inflammasome activation in the alveolar macrophage was assessed. Methods Mice were infected with the X31 strain of influenza virus and the role of neutrophils in alveolar macrophage activation established through administration of a neutrophil-depleting (1A8) antibody. Results Influenza elicited a robust IL-1β release that correlated (r=0.6849; p&lt;0.001) with neutrophil infiltrate and was ablated by neutrophil depletion. Alveolar macrophages were shown to be the prominent source of IL-1β during influenza infection, and virus triggered the expression of Nod-like receptor protein 3 (NLRP3) inflammasome and pro-IL-1β in these cells. However, subsequent activation of the inflammasome complex and release of mature IL-1β from alveolar macrophages were critically dependent on the provision of a secondary signal, in the form of antimicrobial peptide mCRAMP, from infiltrating neutrophils. Conclusions Neutrophils are critical for the activation of the NLRP3 inflammasome in alveolar macrophages during respiratory viral infection. Accordingly, we rationalise that neutrophils are recruited to the lung to confront a viable pathogenic threat and subsequently commit alveolar macrophages to a pro-inflammatory phenotype to combat infection.
Efficacy of anti-PD-1/PD-L1 antibody after discontinuation of antibody due to non-progressive disease in NSCLC Patients
Authors: Takako Inoue, Motoko Tachihara, Motohiro Tamiya, Yuki Akazawa, Ken Uenami, Yoshiko Urata, Yoshihiro Hattori, Chiyuki Okuda, Nobuyuki Katakami, Shunichi Negoro
Journal: Annals of Oncology (2017)
Authors’ reply. Virological analysis of fatal influenza cases in the United Kingdom during the early wave of influenza in winter 2010/11
Authors: J Ellis, M Galiano, R Pebody, A Lackenby, CI Thompson, A Bermingham, E McLean, H Zhao, S Bolotin, O Dar, J  M Watson, M Zambon
Journal: Eurosurveillance (2011)

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Association Between Appendectomy Outcomes and Surgeons’ Seniority
Authors: Jiong-Jie Yu, Xin-Fei Xu, Tian Yang
Journal: JAMA Surgery (2017)

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TCT-858 Long-Term Prognostic Value of Invasive and Non-Invasive Measures Early after Heart Transplantation
Authors: Yukari Kobayashi, Yuhei Kobayashi, Helen Luikart, Takeshi Nishi, Dong-Hyun Choi, Ingela Schnittger, William Fearon
Journal: Journal of the American College of Cardiology (2017)
Reply
Authors: Cory A. Perugino, John H. Stone
Journal: Arthritis & Rheumatology (2017)

We thank Dr. Karim and colleagues for their thoughtful comment on our paper [1], including their mention of a patient with longstanding IgG4-related disease (IgG4-RD) who developed secondary (AA) amyloidosis, presumably as a consequence of longstanding, untreated inflammation [2].

This article is protected by copyright. All rights reserved.
Accumulation of Antigen‐Driven Lymphoproliferations in Complement Receptor 2/ <scp>CD</scp> 21 <sup>−/low</sup> B Cells From Patients With Sjögren's Syndrome
Authors: Salomé Glauzy, Marco Boccitto, Jason M. Bannock, Fabien R. Delmotte, David Saadoun, Patrice Cacoub, John A. Ice, Kathy L. Sivils, Judith A. James, Sandra L. Wolin, Eric Meffre
Journal: Arthritis & Rheumatology (2017)

Objective Patients with Sjögren's syndrome ( SS ) are prone to develop malignant lymphomas, and a correlation has been established between the lymphoproliferations occurring in these disorders and the presence in patients’ blood of an unusual B cell population that down‐regulates complement receptor 2/ CD 21. This study was undertaken to identify the B cell compartment from which these lymphoproliferations emerge and determine the mechanisms that promote clonal B cell expansion in patients with SS . Methods The reactivity of antibodies expressed by CD19+CD10−CD27−IgM+CD21 −/low cells isolated from the blood of patients with SS was tested using a polymerase chain reaction–based approach that allows us to clone and express, in vitro, recombinant antibodies produced by single B cells. Results Clonal expansions were identified in CD 21 −/low B cells isolated from the peripheral blood of 3 patients with SS . These lymphoproliferations expressed B cell receptors ( BCR s) that displayed somatic hypermutation lineage trees characteristic of a strong selection by antigens; one of these antigens was identified as a ribosomal self antigen. When the mutated BCR sequences expressed by the expanded CD 21 −/low B cell clones from patients with SS were reverted in vitro to their germline counterparts, one clone remained autoreactive. Conclusion Clonal lymphoproliferations in patients with SS preferentially accumulate in the autoreactive CD 21 −/low B cell compartment often expanded in these subjects, and recognition of self antigens may drive the clonal B cell expansion while further refining BCR self‐reactivity.
The spectrum of manifestations in desmoplakin gene ( DSP ) spectrin repeat 6 domain mutations: Immunophenotyping and response to ustekinumab
Authors: Amy S. Paller, Tali Czarnowicki, Yael Renert-Yuval, Kristen Holland, Thy Huynh, Muriel Sadlier, Maeve A. McAleer, Gary Tran, Gabrielle C. Geddes, Alan D. Irvine, Emma Guttman-Yassky
Journal: Journal of the American Academy of Dermatology (2017)
TCT-64 Procedural success of pulmonary balloon angioplasty in patients with chronic thromboembolic pulmonary hypertension – a German single-centre, two-year experience
Authors: Christoph Liebetrau, Christoph Wiedenroth, Andreas Breithecker, Moritz Haas, Steffen Kriechbaum, Stefan Guth, Christian Hamm, Eckhard Mayer
Journal: Journal of the American College of Cardiology (2017)
Hepatitis B virus sensitivity to interferon‐α in hepatocytes is more associated with cellular interferon response than with viral genotype
Authors: Fang Shen, Yaming Li, Yang Wang, Vitina Sozzi, Peter A. Revill, Jiangxia Liu, Lu Gao, Guang Yang, Mengji Lu, Kathrin Sutter, Ulf Dittmer, Jieliang Chen, Zhenghong Yuan
Journal: Hepatology (2017)

Interferon-α (IFN-α) is used to treat chronic hepatitis B virus (HBV) infection, but only 20%-40% of patients respond well. Clinical observations have suggested that HBV genotype is associated with the response to IFN therapy; however, its role in viral responsiveness to IFN in HBV-infected hepatocytes remains unclear. Here, we produced infectious virions of HBV genotypes A to D to infect three well-recognized cell-culture-based HBV infection systems, including primary human hepatocytes (PHH), differentiated HepaRG (dHepaRG), and HepG2-NTCP cells to quantitatively compare the antiviral effect of IFN-α on HBV across genotypes and cell models. The efficacy of IFN-α against HBV in hepatocytes was generally similar across genotypes A2, B5, C2, and D3; however, it was significantly different among the infection models given that the half maximal inhibitory concentration value of IFN-α for inhibition of viral DNA replication in PHH (<20 U/mL) and dHepaRG cells were much lower than that in HepG2-NTCP cells (>500 U/mL). Notably, even in PHH, IFN-α did not reduce HBV covalently closed circular DNA at the concentrations for which viral antigens and DNA replication intermediates were strongly reduced. The three cell-culture models exhibited differential cellular response to IFN-α. The genes reported to be associated with responsiveness to IFN-α in patients were robustly induced in PHH while weakly induced in HepG2-NTCP cells upon IFN-α treatment. Reduction or promotion of IFN response in PHH or HepG2-NTCP cells significantly attenuated or improved the inhibitory capacity of IFN-α on HBV replication, respectively.In the cell-culture-based HBV infection models, the sensitivity of HBV to IFN-α in hepatocytes is determined more by the cell-intrinsic IFN response than by viral genotype, and improvement of the IFN response in HepG2-NTCP cells promotes the efficacy of IFN-α against HBV. (Hepatology 2018;67:1237-1252).