tbuckley/cabot-search huggingface dataset:
Predictive biomarkers for the efficacy of nivolumab as ≥ third-line therapy in patients with advanced gastric cancer (AGC): From a subset analysis of ATTRACTION-2 phase III trial.
Authors: Jwa Hoon Kim, Min-Hee Ryu, Young Soo Park, Jungeun Ma, Sun Young Lee, Deokhoon Kim, Yoon-Koo Kang
Journal: Journal of Clinical Oncology (2019)

152 Background: ATTRACTION-2 phase III trial proved the clinical efficacy of nivolumab (Nivo) in AGC patients (pts) treated with ≥ 2 previous chemotherapy regimens. However, the benefits of Nivo seem to be limited to a subset of pts and there is a need to identify predictive markers to select pts who would benefit from Nivo. Methods: Clinical data and tumor samples of AGC pts enrolled from Asan Medical Center in ATTRACTION-2 study were retrospectively analyzed. PD-L1 (+) was defined as combined positive score of ≥ 1%. EBV and MSI status were determined by EBV-encoded small RNA in situ hybridization and IHC for MLH-1, MSH-2, PMS-2, and MSH-6, respectively. Tumor mutation burden (TMB) was acquired by targeted next-generation sequencing using the NextSeq platform with OncoPanel. Results: A total of 45 pts (28/17 in Nivo/placebo arms) were eligible for the analysis. Baseline neutrophil-lymphocyte ratio (NLR) was median 2.9 and 7 pts had hyponatremia ( &lt; 135). In 36 pts with available tissues, there were PD-L1 (+) (N = 13, 36.1%), EBV (+) (N = 6, 16.7%), and no MSI-high. TMB data could be acquired in 29 pts and median TMB was 8.2/Mb (0.0-21.3). With a median follow-up of 28.3 months (mo) in surviving pts, objective response rate, median progression-free survival (PFS), and overall survival (OS) were 16.7%, 1.6 mo, and 8.1 mo in Nivo arm and 0%, 1.6 mo and 6.5 mo in placebo arm. In Nivo arm with measurable lesions, PD-L1 (+) pts had significantly higher disease control rate than PD-L1 (-) pts (87.5% vs. 20%, p = 0.015). In multivariate model adjusted for important factors (age, sex, Nivo vs. placebo, treatment line, NLR, Na, and PD-L1), NLR ≤ 2.9 and PD-L1 (+) were significant factors for PFS (Hazard Ratio [HR] 0.47, p = 0.037 and HR 0.32, p = 0.006, respectively) and PD-L1 (+) was a significant factor for OS (HR, 0.44, p = 0.012). With adjusting these factors with TMB, PD-L1 (+) remained favorable for PFS and OS. Pts with NLR ≤ 2.9 or PD-L1 (+) or Na &gt; 135 significantly favored Nivo compared to placebo in terms of PFS and OS. Conclusions: Baseline NLR and PD-L1 status may be relevant predictive markers to select pts with AGC who would benefit from Nivo.
Prevention of Prescription Opioid Misuse and Projected Overdose Deaths in the United States
Authors: Qiushi Chen, Marc R. Larochelle, Davis T. Weaver, Anna P. Lietz, Peter P. Mueller, Sarah Mercaldo, Sarah E. Wakeman, Kenneth A. Freedberg, Tiana J. Raphel, Amy B. Knudsen, Pari V. Pandharipande, Jagpreet Chhatwal
Journal: JAMA Network Open (2019)

IMPORTANCEDeaths due to opioid overdose have tripled in the last decade.Efforts to curb this trend have focused on restricting the prescription opioid supply; however, the near-term effects of such efforts are unknown.OBJECTIVE To project effects of interventions to lower prescription opioid misuse on opioid overdose deaths from 2016 to 2025.DESIGN, SETTING, AND PARTICIPANTS This system dynamics (mathematical) model of the US opioid epidemic projected outcomes of simulated individuals who engage in nonmedical prescription or illicit opioid use from 2016 to 2025.The analysis was performed in 2018 by retrospectively calibrating the model from 2002 to 2015 data from the National Survey on Drug Use and Health and the Centers for Disease Control and Prevention.INTERVENTIONS Comparison of interventions that would lower the incidence of prescription opioid misuse from 2016 to 2025 based on historical trends (a 7.5% reduction per year) and 50% faster than historical trends (an 11.3% reduction per year), vs a circumstance in which the incidence of misuse remained constant after 2015.MAIN OUTCOMES AND MEASURES Opioid overdose deaths from prescription and illicit opioids from 2016 to 2025 under each intervention.RESULTS Under the status quo, the annual number of opioid overdose deaths is projected to increase from 33 100 in 2015 to 81 700 (95% uncertainty interval [UI], 63 600-101 700) in 2025 (a 147% increase from 2015).From 2016 to 2025, 700 400 (95% UI, 590 200-817 100) individuals in the United States are projected to die from opioid overdose, with 80% of the deaths attributable to illicit opioids.The number of individuals using illicit opioids is projected to increase by 61%-from 0.93 million (95% UI, 0.83-1.03million) in 2015 to 1.50 million (95% UI, 0.98-2.22 million) by 2025.Across all interventions tested, further lowering the incidence of prescription opioid misuse from 2015 levels is projected to decrease overdose deaths by only 3.0% to 5.3%.CONCLUSIONS AND RELEVANCE This study's findings suggest that interventions targeting prescription opioid misuse such as prescription monitoring programs may have a modest effect, at best, on the number of opioid overdose deaths in the near future.Additional policy interventions are urgently needed to change the course of the epidemic.
Retraction notice to: "Biomechanical and biocompatibility characteristics of electrospun polymeric tracheal scaffolds "[BIOMATERIALS 35/20 (2014) 5307-5315]
Authors: Fatemeh Ajalloueian, Mei Ling Lim, Greg Lemon, Johannes C. Haag, Ylva Gustafsson, Sebastian Sjöqvist, Antonio Beltrán-Rodríguez, Costantino Del Gaudio, Silvia Baiguera, Alessandra Bianco, Philipp Jungebluth, Paolo Macchiarini
Journal: Biomaterials (2019)
FoxP3 and Ezh2 regulate Tfr cell suppressive function and transcriptional program
Authors: Shenda Hou, Rachel L. Clement, Alos Diallo, Bruce R. Blazar, Alexander Y. Rudensky, Arlene H. Sharpe, Peter T. Sage
Journal: The Journal of Experimental Medicine (2019)

Follicular regulatory T (Tfr) cells are a regulatory T cell subset that controls antibody production by inhibiting T follicular helper (Tfh)–mediated help to B cells. Tfh and Tfr cells possess opposing functions suggesting unique programming. Here we elucidated the transcriptional program controlling Tfr suppressive function. We found that Tfr cells have a program for suppressive function fine-tuned by tissue microenvironment. The transcription factor FoxP3 and chromatin-modifying enzyme EZH2 are essential for this transcriptional program but regulate the program in distinct ways. FoxP3 modifies the Tfh program to induce a Tfr-like functional state, demonstrating that Tfr cells coopt the Tfh program for suppression. Importantly, we identified a Tfr cell population that loses the Tfr program to become “ex-Tfr” cells with altered functionality. These dysfunctional ex-Tfr cells may have roles in modulating pathogenic antibody responses. Taken together, our studies reveal mechanisms controlling the Tfr transcriptional program and how failure of these mechanisms leads to dysfunctional Tfr cells.
Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma
Authors: Kurt A. Schalper, Maria E. Rodriguez-Ruiz, Ricardo Diez-Valle, Alvaro López-Janeiro, Angelo Porciuncula, Miguel A. Idoate, Susana Inogés, Carlos de Andrea, Ascensión López-Diaz de Cerio, Sonia Tejada, Pedro Berraondo, Franz Villarroel-Espindola, Jungmin Choi, Alfonso Gúrpide, Miriam Giraldez, Iosune Goicoechea, Jaime Gallego Perez-Larraya, Miguel F. Sanmamed, Jose L. Perez-Gracia, Ignacio Melero
Journal: Nature Medicine (2019)
Therapeutic Plasma Exchange Practices in Immune Thrombocytopenic Purpura Related Hospitalizations: Real World Practices for a Category III Apheresis Indication
Authors: Sarah Makhani, Joseph Schwartz, Aaron Tobian, Saurav Chopra, Ljiljana V. Vasovic, Robert Andrew Desimone, Patricia Shi, Shipra Kaicker, Cassandra D Josephson, James B. Bussel, Ruchika Goel
Journal: Blood (2018)
Conventional DCs sample and present myelin antigens in the healthy CNS and allow parenchymal T cell entry to initiate neuroinflammation
Authors: Sarah Mundt, Dunja Mrdjen, Sebastian G. Utz, Melanie Greter, Bettina Schreiner, Burkhard Becher
Journal: Science Immunology (2019)

In vivo reactivation of myelin-reactive T cells requires conventional DCs but not other brain-resident antigen-presenting cells.
Delayed Response (Partial Remission) 3 Years After Peptide Receptor Radionuclide Therapy in a Patient Participating in the NETTER-1 Trial
Authors: Jingjing Zhang, Harshad R. Kulkarni, Aviral Singh, Richard P. Baum
Journal: Clinical Nuclear Medicine (2019)

Abstract Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues has been shown to be highly efficacious concerning progression-free survival and response rates in patients with advanced, progressive, well-differentiated, somatostatin-receptor–positive neuroendocrine neoplasm. We report here delayed response of a midgut neuroendocrine neoplasm patient, who had stable disease after 4 cycles of PRRT and over a long period of 5 restaging admissions with excellent quality of life (full working hours), persisting for 3 years of follow-up, and presented as further partial remission according to both Response Evaluation Criteria in Solid Tumors and EORTC criteria, respectively, 36 months after the last PRRT cycle.
Incidence of Inhibitors in a Previously Untreated Patients with Severe Hemophilia Α Cohort Treated with a Single Third-Generation Recombinant Factor VIII Concentrate
Authors: Alessandra N L Prezotti, Monica H Cerqueira, Marilia Renni, Clarissa Ferreira, Ieda S. Pinto, Maria do Rosário Roberti, Rosangela Ribeiro, Paula Ribeiro Villaça, Maria P S V Orletti, Carolina Costa-Lima, Gabriela G Yamaguti-Hayakawa, Samuel S Medina, Margareth C Ozelo
Journal: Blood (2018)
Liquid biopsy in central nervous system metastases: a RANO review and proposals for clinical applications
Authors: Adrienne Boire, Dieta Brandsma, Priscilla K Brastianos, Emilie Le Rhun, Manmeet Ahluwalia, Larry Junck, Michael Glantz, Morris D Groves, Eudocia Q Lee, Nancy Lin, Jeffrey Raizer, Roberta Rudà, Michael Weller, Martin J Van den Bent, Michael A Vogelbaum, Susan Chang, Patrick Y Wen, Riccardo Soffietti
Journal: Neuro-Oncology (2019)

Liquid biopsies collect and analyze tumor components in body fluids, and there is an increasing interest in the investigation of liquid biopsies as a surrogate for tumor tissue in the management of both primary and secondary brain tumors. Herein we critically review available literature on spinal fluid and plasma circulating tumor cells (CTCs) and cell-free tumor (ctDNA) for diagnosis and monitoring of leptomeningeal and parenchymal brain metastases. We discuss technical issues and propose several potential applications of liquid biopsies in different clinical settings (ie, for initial diagnosis, for assessment during treatment, and for guidance of treatment decisions). Last, ongoing clinical studies on CNS metastases that include liquid biopsies are summarized, and recommendations for future clinical studies are provided.
Comprehensive Genomic Analysis of Primary Mediastinal B-Cell Lymphoma
Authors: Bjoern Chapuy, Chip Stewart, Andrew Dunford, Jaegil Kim, Kirsty Wienand, Atanas Kamburov, Gabriel Kenneth Griffin, Claire McEwen Cote, Matthew D. Ducar, Aaron R. Thorner, Scott J Rodig, Gad Getz, Margaret A. Shipp
Journal: Blood (2018)
Inhibition of S-Adenosylhomocysteine Hydrolase Induces Endothelial Dysfunction via Epigenetic Regulation of p66shc-Mediated Oxidative Stress Pathway
Authors: Yunjun Xiao, Junjie Xia, Jinquan Cheng, Haiyan Huang, Yani Zhou, Xifei Yang, Xuefen Su, Yuebin Ke, Wenhua Ling
Journal: Circulation (2019)

Elevated levels of S-adenosylhomocysteine (SAH), the precursor of homocysteine, are positively associated with the risk of cardiovascular disease and with the development and progression of atherosclerosis. However, the role of SAH in endothelial dysfunction is unclear.Apolipoprotein E-deficient ( apoE-/-) mice received dietary supplementation with the SAH hydrolase (SAHH) inhibitor adenosine dialdehyde or were intravenously injected with a retrovirus expressing SAHH shRNA. These 2 approaches, along with the heterozygous SAHH gene knockout ( SAHH+/-) mouse model, were used to elevate plasma SAH levels and to examine the role of SAH in aortic endothelial dysfunction. The relationship between plasma SAH levels and endothelial dysfunction was also investigated in human patients with coronary artery disease and healthy control subjects.Plasma SAH levels were increased in SAHH+/- mice and in apoE-/- mice after dietary administration of adenosine dialdehyde or intravenous injection with SAHH shRNA. SAHH+/- mice or apoE-/- mice with SAHH inhibition showed impaired endothelium-dependent vascular relaxation and decreased nitric oxide bioavailability after treatment with acetylcholine; this was completely abolished by the administration of the endothelial nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester. Furthermore, SAHH inhibition induced production of reactive oxygen species and p66shc expression in the mouse aorta and human aortic endothelial cells. Antioxidants and p66shc siRNA prevented SAHH inhibition-induced generation of reactive oxygen species and attenuated the impaired endothelial vasomotor responses in high-SAH mice. Moreover, inhibition of SAHH induced hypomethylation in the p66shc gene promoter and inhibited expression of DNA methyltransferase 1. Overexpression of DNA methyltransferase 1, induced by transduction of an adenovirus, was sufficient to abrogate SAHH inhibition-induced upregulation of p66shc expression. Finally, plasma SAH levels were inversely associated with flow-mediated dilation and hypomethylation of the p66shc gene promoter and positively associated with oxidative stress levels in patients with coronary artery disease and healthy control subjects.Our findings indicate that inhibition of SAHH results in elevated plasma SAH levels and induces endothelial dysfunction via epigenetic upregulation of the p66shc-mediated oxidative stress pathway. Our study provides novel molecular insight into mechanisms of SAH-associated endothelial injury that may contribute to the development of atherosclerosis.URL: https://www.clinicaltrials.gov . Unique identifier: NCT03345927.
Enhancement of the efficacy of radiofrequency ablation by neoadjuvant oncolytic virus therapy via antitumor immunity and the booster effect of immune checkpoint inhibitors.
Authors: Tomoharu Yamada, Yasushi Inou, Miwako Iwai, Ryosuke Tateishi, Kazuhiko Koike, Tomoki Todo
Journal: Journal of Clinical Oncology (2019)

253 Background: A third generation oncolytic herpes simplex virus type 1, G47Δ, destroys tumor cells selectively and induces antitumor immune responses. Radiofrequency ablation (RFA) is a standard local therapy for hepatocellular carcinoma (HCC). Here, we examined the efficacy of G47Δ used in combination with RFA and evaluated the antitumor immune responses. Methods: In A/J mice harboring bilateral poorly immunogenic Neuro2a subcutaneous tumors, tumors on one side were treated with intratumoral injections with G47Δ (2×10 6 pfu) on days 0, 2 and 4 followed by RFA treatment on day 6, which results in complete regression of the treated tumors. We further treated with an immune checkpoint inhibitor (ICI) in combination. Tumor infiltrating lymphocytes in contralateral tumors were analyzed with flow cytometric analysis. To examine the contribution of CD8 + T cells, CD8 + T cells were depleted by treatment with anti-CD8 monoclonal antibody. To mimic a remote recurrence, unilateral subcutaneous tumors were treated with G47Δ and RFA, and Neuro2a cells were implanted on the same day of RFA. In a separate experiment without rechallenge, antitumor immunity was evaluated using ELISpot assay on day 20. Results: The G47Δ+RFA treatment caused smaller volumes of contralateral tumors and increased infiltration of CD8 + /CD45 + T cells within the tumor, compared with RFA or G47Δ monotherapy. Without CD8 + T cells, the antitumor effect on the contralateral tumors was completely abolished. When mice were rechallenged, those cured by G47Δ+RFA rejected the Neuro2a more frequently than those cured by RFA alone. ELISpot assay revealed that the number of Neuro2a reactive splenocytes was significantly greater in the G47Δ+RFA group than the RFA group. The G47Δ+RFA+anti-PD-L1 treatment caused smaller volumes of contralateral tumors compared with G47Δ+RFA treatment, whereas anti-PD-L1 alone showed no effect. Conclusions: Intratumoral administration of G47Δ prior to RFA would enhance systemic antitumor immunity that is further enhanced by ICI.
Complex formulations, simple techniques: Can 3D printing technology be the Midas touch in pharmaceutical industry?
Authors: Shrawani Lamichhane, Santosh Bashyal, Taekwang Keum, Gyubin Noh, Jo Eun Seo, Rakesh Bastola, Jaewoong Choi, Dong Hwan Sohn, Sangkil Lee
Journal: Asian Journal of Pharmaceutical Sciences (2019)

3D printing is a method of rapid prototyping and manufacturing in which materials are deposited onto one another in layers to produce a three-dimensional object. Although 3D printing was developed in the 1980s and the technology has found widespread industrial applications for production from automotive parts to machine tools, its application in pharmaceutical area is still limited. However, the potential of 3D printing in the pharmaceutical industry is now being recognized. The ability of 3D printing to produce medications to exact specifications tailored to the needs of individual patients has indicated the possibility of developing personalized medicines. The technology allows dosage forms to be precisely printed in various shapes, sizes and textures that are difficult to produce using traditional techniques. However, there are various challenges associated with the proper application of 3D printing in the pharmaceutical sector which should be overcome to exploit the scope of this technology. In this review, an overview is provided on the various 3D printing technologies used in fabrication of complex dosage forms along with their feasibility and limitations.
T cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapy
Authors: Tori N. Yamamoto, Ping-Hsien Lee, Suman K. Vodnala, Devikala Gurusamy, Rigel J. Kishton, Zhiya Yu, Arash Eidizadeh, Robert Eil, Jessica Fioravanti, Luca Gattinoni, James N. Kochenderfer, Terry J. Fry, Bulent Arman Aksoy, Jeffrey E. Hammerbacher, Anthony C. Cruz, Richard M. Siegel, Nicholas P. Restifo, Christopher A. Klebanoff
Journal: Journal of Clinical Investigation (2019)

Across clinical trials, T cell expansion and persistence following adoptive cell transfer (ACT) have correlated with superior patient outcomes. Herein, we undertook a pan-cancer analysis to identify actionable ligand-receptor pairs capable of compromising T cell durability following ACT. We discovered that FASLG, the gene encoding the apoptosis-inducing ligand FasL, is overexpressed within the majority of human tumor microenvironments (TMEs). Further, we uncovered that Fas, the receptor for FasL, is highly expressed on patient-derived T cells used for clinical ACT. We hypothesized that a cognate Fas-FasL interaction within the TME might limit both T cell persistence and antitumor efficacy. We discovered that genetic engineering of Fas variants impaired in the ability to bind FADD functioned as dominant negative receptors (DNRs), preventing FasL-induced apoptosis in Fas-competent T cells. T cells coengineered with a Fas DNR and either a T cell receptor or chimeric antigen receptor exhibited enhanced persistence following ACT, resulting in superior antitumor efficacy against established solid and hematologic cancers. Despite increased longevity, Fas DNR-engineered T cells did not undergo aberrant expansion or mediate autoimmunity. Thus, T cell-intrinsic disruption of Fas signaling through genetic engineering represents a potentially universal strategy to enhance ACT efficacy across a broad range of human malignancies.
Frequency And Potential Risks Factors For Systemic Reactions (SRs) During Subcutaneous Immunotherapy (SCIT) In A Puerto Rican Cohort.
Authors: Yanira Arce-Ayala, Giannina Coppola Fasick, Jorge J. Cruz-Cruz, Sylvette Nazario, Cristina J. Ramos-Romey
Journal: Journal of Allergy and Clinical Immunology (2019)
Impact of Early Switching to Nilotinib As Second Line TKI in Patients with Chronic Myeloid Leukemia Who Were Intolerant to, Suboptimal to and Failed Imatinib: The Thai Multi-Centered Study
Authors: Pongtep Viboonjuntra, Arnuparp Lekhakula, Kanchana Chansung, Chittima Sirijerachai, Pimjai Niparuck, Teeraya Pauvilai, Tontanai Numbenjapon, Udomsak Bunworasate, Weerasak Nawarawong, Adisak Tantiworawit, Tawatchai Suwanban, Saengsuree Jootar
Journal: Blood (2018)
How we diagnose and manage altered oxygen affinity hemoglobin variants
Authors: Jovana Yudin, Madeleine Verhovsek
Journal: American Journal of Hematology (2019)

Altered oxygen affinity variant hemoglobins (Hbs) are caused by mutations of the globin genes. Changes in Hb oxygen affinity shift the oxygen dissociation curve, and can be identified by abnormal p50 measurements of patient red blood cells. Variants are categorized as either low oxygen affinity (high p50) or high oxygen affinity (low p50). Accurate diagnosis requires recognition of typical clinical and laboratory findings. In this case‐based review, we present two patients with altered oxygen affinity variants, illustrating barriers to prompt and accurate diagnosis, and issues in management. We then review pathophysiology, diagnostic tests, clinical features, and management strategies.
Contaminated Bypass Equipment
Authors: Bridget Kuehn
Journal: JAMA (2019)

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Description of Subjects Reporting Reactions to Mammalian Meat Who Test Negative for IgE to Galactose-α-1,3-galactose (α-Gal)
Authors: Monica Gupta, Lisa Workman, Alexander J. Schuyler, Scott P. Commins, Thomas A.E. Platts-Mills, Jeffrey M. Wilson
Journal: Journal of Allergy and Clinical Immunology (2019)
Resistance of Natural Killer and T Cells to Venetoclax Allows for Combination Treatment with Cancer Immunotherapy Agents
Authors: Elisabeth A Lasater, An D Do, Luciana Burton, Yijin Li, Erin Williams, Jason Oeh, Luciana Molinero, Elicia Penuel, Deepak Sampath, Monique Dail, Marcia Belvin, Teiko Sumiyoshi, Elizabeth A Punnoose, Jeffrey Venstrom, Aparna Raval
Journal: Blood (2018)
Arsenic Trioxide Induces Apoptosis and Regulatory Functions of Plasmacytoid Dendritic Cells
Authors: Yishan Ye, Laure Ricard, Nicolas Stocker, Baptiste Lamarthée, Frédéric De Vassoigne, Eolia Brissot, Arsène Mekinian, Mohamad Mohty, Béatrice Gaugler, Florent Malard
Journal: Blood (2018)
Why I decided to provide assisted dying: it is truly patient centred care
Authors: Sandy Buchman
Journal: BMJ (2019)

As the Royal College of Physicians polls its members in the UK this February, <b>Sandy Buchman</b>, the Canadian Medical Association9s president elect, explains how accepting terminally ill patients' autonomy led him to provide medical assistance in dying. See www.bmj.com/content/assisted-dying for more opinions—for, against, and neutral