tbuckley/cabot-search huggingface dataset:
<i>Ex Vivo</i> PD-L1/PD-1 Pathway Blockade Reverses Dysfunction of Circulating CEA-Specific T Cells in Pancreatic Cancer Patients
Authors: Yuan Chen, Shao-An Xue, Shahriar Behboudi, Goran H. Mohammad, Stephen P. Pereira, Emma C. Morris
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Carcinoembryonic antigen (CEA) is a candidate target for cellular immunotherapy of pancreatic cancer. In this study, we have characterized the antigen-specific function of autologous cytotoxic T lymphocytes (CTL) specific for the HLA-A2–restricted peptide, pCEA691-699, isolated from the peripheral T-cell repertoire of pancreatic cancer patients and sought to determine if ex vivo PD-L1 and TIM-3 blockade could enhance CTL function. Experimental Design: CD8+ T-cell lines were generated from peripheral blood mononuclear cells of 18 HLA-A2+ patients with pancreatic cancer and from 15 healthy controls. In vitro peptide-specific responses were evaluated by flow cytometry after staining for intracellular cytokine production and carboxy fluorescein succinimydyl ester cytotoxicity assays using pancreatic cancer cell lines as targets. Results: Cytokine-secreting functional CEA691-specific CTL lines were successfully generated from 10 of 18 pancreatic cancer patients, with two CTL lines able to recognize and kill both CEA691 peptide–loaded T2 cells and CEA+ HLA-A2+ pancreatic cancer cell lines. In the presence of ex vivo PD-L1 blockade, functional CEA691-specific CD8+ T-cell responses, including IFNγ secretion and proliferation, were enhanced, and this effect was more pronounced on Ag-specific T cells isolated from tumor draining lymph nodes. Conclusions: These data demonstrate that CEA691-specific CTL can be readily expanded from the self-restricted T-cell repertoire of pancreatic cancer patients and that their function can be enhanced by PD-L1 blockade. Clin Cancer Res; 23(20); 6178–89. ©2017 AACR.
Defining the Immune Checkpoint Landscape in the Bone Marrow and Peripheral Blood of Patients with Chronic Lymphocytic Leukemia (CLL)
Authors: Nitin Jain, Sreyashi Basu, Beenu Thakral, Jan Burger, Philip A Thompson, Alessandra Ferrajoli, Zeev Estrov, Carlos E Bueso-Ramos, Francesco Stingo, Roland L Bassett, Naval Daver, Tapan M. Kadia, Jairo Matthews, Wilmer Flores, Narmeen Somani, Jorge Blando, Hagop M. Kantarjian, James Allison, Michael Keating, Padmanee Sharma, William G. Wierda
Journal: Blood (2016)
Tailor-made purified human platelet lysate concentrated in neurotrophins for treatment of Parkinson's disease
Authors: Ming-Li Chou, Joe-Wei Wu, Flore Gouel, Aurélie Jonneaux, Kelly Timmerman, Ting-Yi Renn, Charlotte Laloux, Hung-Ming Chang, Liang-Tzung Lin, Jean-Christophe Devedjian, David Devos, Thierry Burnouf
Journal: Biomaterials (2017)
The clinical impact of the Prognostic Nutritional Index (PNI) and Controlling Nutritional Status (CONUT) score on breast cancer patients survival.
Authors: Nami Yamashita, Yuka Inoue, Kimihiro Tanaka, Hiroshi Saeki, Eiji Oki, Eriko Tokunaga, Yoshihiko Maehara
Journal: Journal of Clinical Oncology (2017)

1560 Background: Recent reports show that the preoperative immunonutritional status correlate with the survival rate in cancer patients. The Prognostic Nutritional Index (PNI) and Controlling Nutritional Status (CONUT) score are used as screening tools for immunonutritional status and reported to be a predictor of postoperative recurrence in patients with various gastrointestinal cancers. However, the clinical importance of the PNI and CONUT in breast cancer has not been elucidated. The aim of this study is to investigate the clinical impact of preoperative PNI and CONUT on long-term survival of breast cancer patients. Methods: We retrospectively analyzed 653 consecutive stage I-III breast cancer patients who were treated from January 2002 to December 2013. The PNI score was calculated as 10 x serum albumin (g/dl) + 0.005 x total lymphocyte count (per mm 3 ). The CONUT score is calculated from three parameters, serum albumin, cholesterol, and total lymphocytes count. The patients were divided into two groups according to the PNI and CONUT score. The uni- and multivariate Cox regression analyses were performed to evaluate the prognositic value of the PNI and CONUT in breast cancer. Results: The malnutritional status was observed in 170 (26%) and 131 (20%) patients as low-PNI and high-CONUT, respectively. The relapse-free survival (RFS) and overall survival (OS) rates were significantly lower in the low-PNI group (RFS: p &lt; 0.0001, OS: p &lt; 0.0001) and high-CONUT group (RFS: p = 0.0009, OS: p = 0.0018). In the multivariate analysis, low-PNI was independent prognostic factors for both RFS and OS (RFS: HR2.33, p = 0.032, OS: HR5.01, p = 0.0009). In the subset analysis, the low-PNI group showed poor prognosis especially in the postmenopausal, hormone receptor negative patients. The low-PNI also had poorer prognosis in post-recurrence survival. Conclusions: The preoperative PNI is a strong independent predictor of long-term survival among breast cancer patients.
Updated antitumor activity and safety of FPA144, an ADCC-enhanced, FGFR2b isoform-specific monoclonal antibody, in patients with FGFR2b+ gastric cancer.
Authors: Daniel V.T. Catenacci, Sun Young Rha, Yung-Jue Bang, Zev A. Wainberg, Joseph Chao, Keun Wook Lee, Wolfgang Michael Korn, Yeul Hong Kim, Eun-Kee Song, Chang-Fang Chiu, Chia-Jui Yen, Jordan Berlin, Jin-Soo Kim, Robert S. Sikorski, Helen Collins, Lee Clark, Sandeep P. Inamdar, Charlie Zhang, Jeeyun Lee
Journal: Journal of Clinical Oncology (2017)

4067 Background: FGFR2b-overexpressing gastric cancer is characterized by poor prognosis. FPA144, a humanized monoclonal IgG1 antibody that specifically binds to and blocks FGFR2b, has been engineered for enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). FPA144-001 is a two-part Phase 1 study of FPA144 monotherapy in patients with advanced solid tumors, including gastric and gastroesophageal cancers (GEJ cancers). Methods: Part 1A was a 3+3 design to assess safety and PK and to establish a recommended dose (RD) of FPA144. Patients with gastric cancer were enrolled in Part 1B to assess PK in gastric cancer. Part 2 includes 4 cohorts of gastric cancer patients with either high, moderate, low or no FGFR2b overexpression based on a centralized immunohistochemistry (IHC) assay. Here, we describe results of gastric cancer patients that highly overexpress FGFR2b (FGFR2b+ High) enrolled in Parts 1 and 2 of the study. Results: As of October 28, 2016, 18 FGFR2b+ High (IHC 3+ ≥10% tumor membrane staining) patients were enrolled in the study. 12 of these patients received the RD of 15 mg/kg every 2 weeks. Enrolled patients received a median of 3 prior treatment regimens. Fatigue (22.2%, none ≥ gr 3) and infusion reaction (16.7%, 5.6% gr 3) were the most common treatment-related AEs. Treatment-related SAEs were reported in 2 patients: Grade 2 ulcerative keratitis and Grade 3 infusion reaction. There were 5 PRs, 4 confirmed and 1 unconfirmed. Disease control (PR+SD) was 55.6%, including a confirmed ORR of 22% with median DOR of 15.4 weeks. ctDNA analysis of a responding patient revealed baseline elevated FGFR2 gene copy (165 copies in the blood, mutation allele burden 66%) that decreased after monotherapy (nadir 75 copies, mutation allele burden 38.5%) corresponding with clinical response, serum tumor markers and near complete response on PET imaging. Conclusions: The demonstration of activity and an acceptable safety profile supports further development of FPA144 in patients with FGFR2b+ tumors. FGFR2 gene amplification detected in ctDNA may provide a non-invasive diagnostic test for patient selection. Updated data will be presented. Clinical trial information: NCT02318329.
MicroRNA-532 protects the heart in acute myocardial infarction, and represses prss23, a positive regulator of endothelial-to-mesenchymal transition
Authors: Ahmed S. Bayoumi, Jian-Peng Teoh, Tatsuya Aonuma, Zhize Yuan, Xiaofen Ruan, Yaoliang Tang, Huabo Su, Neal L. Weintraub, Il-Man Kim
Journal: Cardiovascular Research (2017)

Acute myocardial infarction (MI) leads to cardiac remodelling and development of heart failure. Insufficient myocardial capillary density after MI is considered a critical determinant of this process. MicroRNAs (miRs), negative regulators of gene expression, have emerged as important players in MI. We previously showed that miR-532-5p (miR-532) is up-regulated by the β-arrestin-biased β-adrenergic receptor antagonist (β-blocker) carvedilol, which activates protective pathways in the heart independent of G protein-mediated second messenger signalling. Here, we hypothesize that β2-adrenergic receptor/β-arrestin-responsive miR-532 confers cardioprotection against MI.Using cultured cardiac endothelial cell (CEC) and in vivo approaches, we show that CECs lacking miR-532 exhibit increased transition to a fibroblast-like phenotype via endothelial-to-mesenchymal transition (EndMT), while CECs over-expressing miR-532 display decreased EndMT. We also demonstrate that knockdown of miR-532 in mice causes abnormalities in cardiac structure and function as well as reduces CEC proliferation and cardiac vascularization after MI. Mechanistically, cardioprotection elicited by miR-532 is in part attributed to direct repression of a positive regulator of maladaptive EndMT, prss23 (a protease serine 23) in CECs.In conclusion, these findings reveal a pivotal role for miR-532-prss23 axis in regulating CEC function after MI, and this novel axis could be suitable for therapeutic intervention in ischemic heart disease.
German doctors condemn internet TV series depicting teenage suicide
Authors: Ned Stafford
Journal: BMJ (2017)

Two psychiatric societies and a paediatrics association in Germany have condemned a new internet television series about a 17 year old girl who dies by suicide, saying that the series could trigger so called copycat suicides among troubled young viewers.

Although the societies are only “urgently advising” vulnerable young people to avoid viewing the series, Germany’s Professional Association of Paediatricians (BVKJ) has called for the “immediate cancellation” of the series.

A member of the association’s board, the paediatric cardiologist Josef Kahl, said that “adolescents contemplating suicide will probably be influenced in that direction by the series.” He added, “As the series shows how a suicide can be done successfully, we demand that the series be banned.”

The 13 part series, called 13 Reasons Why , was …
Erythrocyte membrane-encapsulated celecoxib improves the cognitive decline of Alzheimer's disease by concurrently inducing neurogenesis and reducing apoptosis in APP/PS1 transgenic mice
Authors: Jing-Wen Guo, Pei-Pei Guan, Wei-Yan Ding, Si-Ling Wang, Xue-Shi Huang, Zhan-You Wang, Pu Wang
Journal: Biomaterials (2017)
Imatinib failure-free survival (IFS) in patients with localized gastrointestinal stromal tumors (GIST) treated with adjuvant imatinib (IM): The EORTC/AGITG/FSG/GEIS/ISG randomized controlled phase III trial.
Authors: Paolo Giovanni Casali, Axel Le Cesne, Andres Poveda Velasco, Dusan Kotasek, Piotr Rutkowski, Peter Hohenberger, Elena Fumagalli, Ian Robert Judson, Antoine Italiano, Javier Martin Broto, Alessandro Gronchi, Angelo Paolo Dei Tos, Sandrine Marreaud, Winette T.A. Van Der Graaf, John Raymond Zalcberg, Saskia Litière, Jean-Yves Blay
Journal: Journal of Clinical Oncology (2013)

10500 Background: In 2004 we launched an open-label randomized trial with adjuvant IM for 2 yrs in localized, surgically resected, high/intermediate-risk GIST. Methods: Pts were randomized between 2 yrs of IM, 400 mg daily, and no further therapy after surgery. The primary end-point was OS, while RFS, RFI and toxicity were secondary end-points. Main eligibility criteria were: age &gt;18 yrs, PS 0-2, localized CD117-positive GIST, intermediate or high risk according to the 2002 Consensus classification, R0 or R1 surgical margins, no previous medical therapy. Pts were stratified by risk, tumor site and margins. An accrual of 400 pts was planned, then escalated to 900. Given the prognostic improvement of advanced GIST pts, in 2009 the study IDMC authorized to change the primary end-point into IFS, whose failure was defined as the time when a different tyrosine kinase inhibitor (TKI) is started. We report on a planned interim analysis carried out after 115 events according to the new primary end-point, with a significance level of 1.5%. Hazard ratios (HR) and p-values were adjusted for stratification factors. Results: 908 pts were randomized between 2005 and 2008, 454 to IM and 454 to observation arm; 835 pts were eligible. 17% of pts treated with IM stopped early due to toxicity or refusal. With a median follow-up of 4.7 yrs, 5-yr IFS was 87% in the IM-arm vs 84% in the control arm (HR=0.80, 98.5% CI [0.51; 1.26], p=0.23); RFS was 84% vs 66% at 3 yrs, and 69% vs 63% at 5 yrs (p&lt;0.001); 5-yr OS was 100% vs 99%. Among 528 pts with high-risk GIST by local pathology, 5-yr IFS was 79% vs 73% (p=0.11), and 77% vs 73% (p=0.44) amongst 336 high-risk GIST pts by centrally reviewed pathology. Conclusions: This study confirms that adjuvant IM has an overt impact on short-term freedom from relapse. In the high-risk subgroup, a non-statistically significant trend in favor of the adjuvant arm was observed in terms of IFS. This new end-point for the adjuvant setting, i.e. survival free from any failure of the first employed TKI, was designed to incorporate secondary resistance, i.e. the currently main factor adversely affecting prognosis of advanced GIST pts. Clinical trial information: NCT00103168.
Abstract P060: VDAC2 and 3, but Not VDAC1, Are Required for HK2-Mediated Protection Against Cell Death
Authors: Kyle S McCommis, Christopher P Baines
Journal: Circulation Research (2011)

The glycolytic enzyme hexokinase-2 (HK2) has been shown to protect several cell types including cardiomyocytes against death. However, the mechanisms of this HK2-mediated protection have not been elucidated. HK2 is normally associated with the mitochondrial voltage-dependent anion channels (VDACs) on the outer mitochondrial membrane, but it is unknown if association with VDACs is required for HK2’s protective functions. In addition, Akt has been shown to phosphorylate HK2, resulting in its translocation to the outer mitochondrial membrane. The purpose of this study was to investigate the role of the three VDAC isoforms, as well as Akt signaling, on HK2-mediated protection. Studies were conducted using cultured murine embryonic fibroblasts (MEFs) from wildtype (WT), VDAC1-/-, and VDAC3-/- mice. WT MEFs were also transfected with a VDAC2 siRNA to reduce VDAC2 protein expression. Murine HK2 was overexpressed by infection with adenovirus. Akt signaling was inhibited by 2 μM Akt Inhibitor VIII. Cell death was induced by 500 μM H2O2 for 4 hours, and cells were stained by Sytox green to identify dead cells and Bis-Benzimide to label all cell nuclei. Protein expression as well as subcellular localization was determined by Western Blot. The HK2 adenovirus resulted in 50-60% increased HK2 expression. In WT MEFs, HK2 overexpression resulted in roughly 50% less death compared to control transfected cells. Surprisingly, although VDAC1 appears to bind the greatest percentage of HK2, cells lacking VDAC1 were still protected by HK2 to a similar degree as WT cells. However, cells with reduced levels of VDAC2, or cells lacking VDAC3 were no longer protected from cell death by HK2. Additionally, HK2 overexpression remained protective in cells treated with the Akt inhibitor. In conclusion, association with the less abundant VDAC2 and VDAC3 isoforms, not the more abundant VDAC1 isoform, appears to be central to HK2-mediated cytoprotection. It also appears that active Akt is not essential to HK2-mediated protection against cell death.
A phase I study of convection enhanced delivery (CED) of <sup>124</sup>I-8H9 radio-labeled monoclonal antibody in children with diffuse intrinsic pontine glioma (DIPG).
Authors: Mark M. Souweidane, Kim Kramer, Neeta Pandit-Taskar, Pat Zanzonico, Zhiping Zhou, Maria Donzelli, Serge K. Lyashchenko, Sofia Haque, Sunitha B Thakur, Nai-Kong V. Cheung, Steven M. Larson, Ira J. Dunkel
Journal: Journal of Clinical Oncology (2017)

2010 Background: Diffuse intrinsic pontine glioma (DIPG) represents one of the most deadly central nervous system tumors of childhood with a median survival of less than 12 months. Convection-enhanced delivery (CED) has been recently hypothesized as a means for augmenting distribution of therapeutic agents within the brain stem. We conducted this study to evaluate CED in children with DIPG. Methods: We performed a standard 3+3 phase I, open-label, dose escalation study in patients with non-progressive DIPG 4 to 14 weeks post-completion or radiation therapy. Seven dose levels of a single injection of 124 I-8H9 (range 0.25 to 4.0 mCi, 250 to 4000 mcl) were studied. Results: 25 children were treated. The average age at enrollment 8 years old (range 3-17). There was no dose limiting toxicity (DLT) and adverse events were limited to grade 1 or 2 (CTCAE v4.0). Estimations of distribution volumes were dose dependent and ranged from 1.5 to 20.1 cm 3 . The mean volume of distribution/volume of infusion (Vd/Vi) was 3.4 (SD 1.2). The mean lesion absorbed dose was 1527 rad/mCi. The mean tumor coverage on dose level 7 was 107%. Conclusions: CED in the brain stem of children with DIPG who were previously irradiated is a safe therapeutic strategy. Up to 4 mCi of 124 I-8H9 was well tolerated. An infusion volume of 4000 mcl appears to be a reasonable single dose for good tumor coverage. PET-based dosimetry validates the conceptual basis for direct drug delivery. Based on our finding CED merits further exploration in early phase clinical trials for children with DIPG. Clinical trial information: NCT01502917.
The Best We Can Be
Authors: Neil Skolnik
Journal: Circulation (2017)

ow we treat ourselves has profound effects on the way we treat our patients.I learned this seeing Ted once a year for 10 years as he slowly put on weight while his triglycerides and glucose began to rise.To perform at our highest level, we need to examine our attitudes and behaviors as what we believe is conveyed to patients in our every gesture and intonation.Each year I would discuss diet and exercise and nod as he smiled and said, "I hear you, Doc."He worked hard and had little time for exercise.He loved watching football and enjoyed tossing a ball with his 2 boys.Around the same time, I began to ignore changes in my own body.I had been gaining a few pounds each year and clearly wasn't listening to my own advice.Then one day while walking through the Philadelphia airport to go to Chicago, I noticed I was short of breath and sweating.When we landed, I took a taxi to the hotel, went over my lecture notes, and lied down.I woke the next morning and looked in the mirror.I appeared tired and sluggish.The idea of 500 people watching me lecture about diabetes mellitus made me feel like a hypocrite.I turned from the mirror and refocused on my lecture materials.My lecture went well.I should have been satisfied, but I left the stage disturbed.After boarding the plane, I leaned against the window and fell asleep.When I awoke, the rain on the wings was creating a reflection of orange and blue in the setting sun.I resolved to implement for myself the advice I had been telling my patients for years.The next day, I bought an elliptical machine and planned to run for a half hour a day.It turned out that I could only exercise for 7 minutes.That was 7 years ago.I slowly increased my endurance over time, have continued to exercise 4 to 5 times a week, lost substantial weight, think and feel better, and am now able to walk through an airport without feeling short of breath.When Ted next came to our office, his triglycerides were >400, and his A1c was mildly elevated.We sat and talked about life choices.I told him if we started medications, his laboratory values would improve.I explained that he would probably continue to gain weight, and over a few years we would likely add medicines for diabetes mellitus.Another option was that he could make changes to his diet, commit to an exercise program, and together we would chart out a plan toward a healthier life.I explained that I understood how difficult it was to make these changes.I then listened to his thoughts.I asked him what he wanted to do.In the past, I would have told him what he needed to do.This patient-centered approach is described in the literature as motivational interviewing.Its effectiveness for behavioral change is supported by evidence.
Heads up on concussion in para sport
Authors: Nick Webborn, Cheri A Blauwet, Wayne Derman, Guzel Idrisova, Jan Lexell, Jaap Stomphorst, Yetsa A Tuakli-Wosornu, James Kissick
Journal: British Journal of Sports Medicine (2017)

Concussions to high-profile professional athletes and the $1 billion court settlement between the NFL in the USA and thousands of former NFL players have brought sports concussion to the top of news headlines.1 The crux of the NFL case centred around retired players’ allegation that the NFL did not warn them about the potential long-term health impact of concussions. Cases such as these alert sport governing bodies to the medicolegal importance of this issue and their responsibility for player safety. For the Para athlete, the International Paralympic Committee’s (IPC) term for a sportsperson with an impairment, the concussion debate struggles to garner attention. This is partly because funding for epidemiological research in this area is limited. But athletes with a variety of impairments due to a range of medical issues face the risks and consequences of concussive brain injury in Para sports: it is time for paralympic medical and sporting communities to address this important issue.

Recommendations from the International Conferences on Concussion in Sport mandate that all potential cases of concussion undergo medical assessment, including a comprehensive history and detailed neurological …