tbuckley/cabot-search huggingface dataset:
Phase 3 KEYNOTE-426 trial: Pembrolizumab (pembro) plus axitinib versus sunitinib alone in treatment-naive advanced/metastatic renal cell carcinoma (mRCC).
Authors: Brian I. Rini, Thomas Powles, Mei Chen, Markus Puhlmann, Michael B. Atkins
Journal: Journal of Clinical Oncology (2017)

TPS4597 Background: Antiangiogenic agents, including sunitinib and axitinib, have shown clinically significant efficacy in patients (pts) with mRCC. Results from a phase 1b study in 52 pts suggest first-line pembro, an anti–programmed death 1 antibody, in combination with axitinib, has substantial antitumor activity in mRCC (objective response rate [ORR], 71%) and manageable toxicity. The phase 3, multicenter, open-label, randomized KEYNOTE-426 study (NCT02853331) is designed to evaluate the efficacy and safety of pembro plus axitinib versus sunitinib alone in pts with treatment-naive mRCC. Methods: Key eligibility criteria include age ≥18 years, histologically confirmed mRCC with clear cell component (with or without sarcomatoid features), measurable disease (RECIST v1.1, investigator review), no prior systemic therapy for advanced disease, Karnofsky performance status ≥70%, and provision of a tumor sample for biomarker analyses. Before randomization, pts will be stratified by International Metastatic RCC Database Consortium risk category and geographic region. 840 pts will be randomly assigned 1:1 to receive pembro 200 mg every 3 wk + axitinib 5 mg twice daily or sunitinib 50 mg once daily for 4 wk followed by 2 wk off. Treatment will continue until progressive disease, unacceptable adverse events (AEs), or withdrawal of consent. Pts in the pembro arm may receive up to 35 doses of pembro, after which axitinib-only treatment may continue. Imaging will be performed at wk 12, then every 6 wk for the first year, and every 12 wk thereafter. Bone scans will be performed at baseline, and if positive, repeated at wk 18, 30, 42, and 54, and every 24 wk thereafter. AEs will be monitored throughout and graded per National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4.0. Primary end points are to compare progression-free survival (RECIST v1.1, central review) and overall survival between treatment arms. Secondary end points include the comparison of ORR, duration of response, disease control rate, safety, and patient-reported outcomes between arms. Enrollment is ongoing. Clinical trial information: NCT02853331.
An RNA interference screen identifies druggable regulators of MeCP2 stability
Authors: Laura M. Lombardi, Manar Zaghlula, Yehezkel Sztainberg, Steven A. Baker, Tiemo J. Klisch, Amy A. Tang, Eric J. Huang, Huda Y. Zoghbi
Journal: Science Translational Medicine (2017)

Alterations in gene dosage due to copy number variation are associated with autism spectrum disorder, intellectual disability (ID), and other psychiatric disorders. The nervous system is so acutely sensitive to the dose of methyl-CpG-binding protein 2 (MeCP2) that even a twofold change in MeCP2 protein-either increased or decreased-results in distinct disorders with overlapping features including ID, autistic behavior, and severe motor dysfunction. Rett syndrome is caused by loss-of-function mutations in MECP2, whereas duplications spanning the MECP2 locus result in MECP2 duplication syndrome (MDS), which accounts for ~1% of X-linked ID. Despite evidence from mouse models that restoring MeCP2 can reverse the course of disease, there are currently no U.S. Food and Drug Administration-approved therapies available to clinically modulate MeCP2 abundance. We used a forward genetic screen against all known human kinases and phosphatases to identify druggable regulators of MeCP2 stability. Two putative modulators of MeCP2, HIPK2 (homeodomain-interacting protein kinase 2) and PP2A (protein phosphatase 2A), were validated as stabilizers of MeCP2 in vivo. Further, pharmacological inhibition of PP2A in vivo reduced MeCP2 in the nervous system and rescued both overexpression and motor abnormalities in a mouse model of MDS. Our findings reveal potential therapeutic targets for treating disorders of altered MECP2 dosage.
The DNA Methylcytosine Dioxygenase Tet2 Sustains Immunosuppressive Function of Tumor-Infiltrating Myeloid Cells to Promote Melanoma Progression
Authors: Wen Pan, Shu Zhu, Kun Qu, Katrina Meeth, Jijun Cheng, Kaixin He, Hongdi Ma, Yan Liao, Xizhi Wen, Christine Roden, Zuzana Tobiasova, Zheng Wei, Jun Zhao, Jun Liu, Ji Zheng, Bo Guo, Sajid A. Khan, Marcus Bosenberg, Richard A. Flavell, Jun Lu
Journal: Immunity (2017)
Bioactive flavonoids in medicinal plants: Structure, activity and biological fate
Authors: Tian-yang Wang, Qing Li, Kai-shun Bi
Journal: Asian Journal of Pharmaceutical Sciences (2017)

Flavonoids, a class of polyphenol secondary metabolites, are presented broadly in plants and diets. They are believed to have various bioactive effects including anti-viral, anti-inflammatory, cardioprotective, anti-diabetic, anti-cancer, anti-aging, etc. Their basic structures consist of C6-C3-C6 rings with different substitution patterns to produce a series of subclass compounds, and correlations between chemical structures and bioactivities have been studied before. Given their poor bioavailability, however, information about associations between structure and biological fate is limited and urgently needed. This review therefore attempts to bring some order into relationships between structure, activity as well as pharmacokinetics of bioactive flavonoids.
Dasatinib Reversibly Disrupts Endothelial Vascular Integrity by Increasing Non-Muscle Myosin II Contractility in a ROCK-Dependent Manner
Authors: Anna Kreutzman, Beatriz Colom-Fernández, Ana Marcos Jiménez, Mette Ilander, Carlos Cuesta-Mateos, Yaiza Pérez-García, Cristina Delgado Arévalo, Oscar Brück, Henna Hakanen, Jani Saarela, Alvaro Ortega-Carrión, Ana de Rosendo, Alba Juanes-García, Juan Luis Steegmann, Satu Mustjoki, Miguel Vicente-Manzanares, Cecilia Muñoz-Calleja
Journal: Clinical Cancer Research (2017)

Purpose: Dasatinib is a short-acting dual ABL/SRC family tyrosine kinase inhibitor (TKI), which is frequently used to treat chronic myeloid leukemia. Although very effective, patients taking dasatinib often display severe adverse effects, including pleural effusions and increased risk of bleeding primarily in the gastrointestinal tract. The actual causes of these side effects are currently undetermined. We hypothesize that endothelial cells (ECs) that line the inner walls of blood vessels and control the traffic to the underlying tissues might be involved.Experimental Design: The effects of TKIs on ECs were studied by various assays, such as real-time cell impedance measurements, live-cell microscopy, wound healing, Western blot, and an in vivo model.Results: Dasatinib uniquely causes a profound, dose-dependent disorganization of the EC monolayers. Dasatinib promoted the disassembly of cell-cell contacts, altered cell-matrix contacts, and further altered the wound healing. A key observation is that this effect is fully reversible after drug washout. In line with these in vitro observations, intraperitoneal administration of dasatinib to mice caused significant vascular leakage in the intestine. The underlying molecular mechanism of dasatinib-induced reorganization of the actin involves ROCK activation, which increases the amount of the phosphorylation of myosin light chain and consequently activates the non-muscle myosin II.Conclusions: Our data are consistent with a scenario in which dasatinib triggers a transient increase in vascular leakage that probably contributes to adverse effects such as bleeding diathesis and pleural effusions. Clin Cancer Res; 23(21); 6697-707. ©2017 AACR.
SAT0594 The effect of radİal extracorporeal shock wave therapy (RESWT) İn the treatment of trİgger fİnger
Authors: M Dogru, S Narin, M Erduran
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Trigger finger is a stenotic tendovaginitis characterized by hand pain and dysfunction, commonly encountered and easily recognizable (1). RESWT is frequently used in the treatment of soft tissue pathologies such as lateral epicondylitis, plantar fasciitis and calcific rotator cuff tendinitis (2–3). However, there is no study examining whether RESWT is effective on the trigger finger or not. <h3>Objectives</h3> The aim of this study was to investigate the effect of Radial Extracorporeal Shock Wave Therapy (RESWT) in the Treatment of Trigger Finger. <h3>Methods</h3> This study was carried out on 16 patients (18 patient hand) who had been diagnosed with trigger finger that grade 1,2,3 according to quinnel classification. Patients were carried out as a single group. 16 patients (18 patient hand) with trigger fingers were applied to ten-sessions,twice a week of RESWT (2000 impulses, 2 bar, 10 Hz). Pain scores (Numeric Pain Rating Scale - NRS), general funtional capasities (The Disabilities of the Arm, Shoulder and Hand Score (Quick-DASH)), range of motion, grip strength (GS) and pinch strenght (PS) were assessed at every week for five weeks during treatment and 3 months after treatment. <h3>Results</h3> 13 female and 3 male patients over 18 years of age were evaluated. In the evaluations performed every week during 10 sessions of RESWT treatment and 3 months after treatment, decrease in pain levels and increase in general functional capacity, range of motion, grip strength and pinch strength were observed in the patients treated (p&lt;0.001) (tablo 1). <h3>Conclusions</h3> According to our results; RESWT might be an effective method to decrease pain severity, improve general functional capacity, range of motion, grip strength and pinch strength in patients with trigger finger. <h3>References</h3> Canale ST. Beaty JH. Canale &amp; Beaty: Campbell9s Operative Orthopaedics, (CD-ROM) 11th Edition. 2008. Philadelphia, Pennsylvania. Ogden JA, Toth-Kischkat A, Schultheiss R. Principles of shock wave therapy. Clin Orthop Relat Res 2001; 387: 8–17. Okay B, Mustafa E. Ortopedi ve travmatolojideekstrakorporeal şok dalga tedavisi uygulamaları. C. Ü. Tıp Fakültesi Dergisi. 2002; 24(3):161–164. <h3>Acknowledgements</h3> The authors declare that they have no conflict of interest. <h3>Disclosure of Interest</h3> None declared
The Rest of Them
Authors: Roger Sippl
Journal: JAMA Oncology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Comprehensive Intrametastatic Immune Quantification and Major Impact of Immunoscore on Survival
Authors: Bernhard Mlecnik, Marc Van den Eynde, Gabriela Bindea, Sarah E Church, Angela Vasaturo, Tessa Fredriksen, Lucie Lafontaine, Nacilla Haicheur, Florence Marliot, Daphné Debetancourt, Géraldine Pairet, Anne Jouret-Mourin, Jean-Francois Gigot, Catherine Hubert, Etienne Danse, Cristina Dragean, Javier Carrasco, Yves Humblet, Viia Valge-Archer, Anne Berger, Franck Pagès, Jean-Pascal Machiels, Jérôme Galon
Journal: JNCI Journal of the National Cancer Institute (2017)

This study assesses how the metastatic immune landscape is impacting the response to treatment and the outcome of colorectal cancer (CRC) patients. Complete curative resection of metastases (n = 441) was performed for two patient cohorts (n = 153). Immune densities were quantified in the center and invasive margin of all metastases. Immunoscore and T and B cell (TB) score were analyzed in relation to radiological and pathological responses and patient’s disease-free (DFS) and overall survival (OS) using multivariable Cox proportional hazards models. All statistical tests were two-sided. The spatial distribution of immune cells within metastases was nonuniform. Patients, as well as metastases of the same patient, had variable immune infiltrates and response to therapy. A beneficial response was statistically significantly associated with increased immune densities. Among all metastases, Immunoscore (I) and TB score evaluated in the least immune-infiltrated metastases were the strongest predictors for DFS and OS (five-year follow-up, Immunoscore: I 3–4: DFS rate = 27.9%, 95% CI = 15.2 to 51.3; vs I 0–1–2: DFS rate = 12.3%, 95% CI = 4.9 to 30.6; HR = 0.45, 95% CI = 0.28 to 0.70, P = .02; I 3–4: OS rate = 64.6%, 95% CI = 46.6 to 89.6; vs I 0–1–2: OS rate = 32.5%, 95% CI = 17.2 to 61.4; HR = 0.32, 95% CI = 0.15 to 0.66, P = .001, C-index = 65.9%; five-year follow-up, TB score: TB 3–4: DFS rate = 25.7%, 95% CI = 14.2 to 46.6; vs TB 0–1–2: DFS rate = 5.0%, 95% CI = 0.8 to 32.4; HR = 0.36, 95% CI = 0.22 to 0.57, P < .001; TB 3–4: OS rate = 63.7%, 95% CI = 46.4 to 87.5; vs TB 0–1–2: OS rate: 21.4%, 95% CI = 9.2 to 49.8; HR = 0.25, 95% CI = 0.12 to 0.51, P < .001, C-index = 67.8%). High TB score and Immunoscore patients had a median survival of 70.5 months, while low patients survived only 25.1 to 38.3 months. Nonresponding patients with high-immune infiltrates had prolonged DFS (HR = 0.28, 95% CI = 0.15 to 0.52, P = .001) and OS (HR = 0.25, 95% CI = 0.1 to 0.62, P = .001). The immune parameters remained the only statistically significant prognostic factor associated with DFS and OS in multivariable analysis (P < .001), while response to treatment was not. Response to treatment and prolonged survival of metastatic CRC patients were statistically significantly associated with high-immune densities quantified into the least immune-infiltrated metastasis.
Next-generation sequencing (NGS) of cell-free circulating tumor DNA and tumor tissue in patients with advanced urothelial cancer: a pilot assessment of concordance
Authors: P.C. Barata, V.S. Koshkin, P. Funchain, D. Sohal, A. Pritchard, S. Klek, T. Adamowicz, D. Gopalakrishnan, J. Garcia, B. Rini, P. Grivas
Journal: Annals of Oncology (2017)
Injectable nanomedicine hydrogel for local chemotherapy of glioblastoma after surgical resection
Authors: C. Bastiancich, J. Bianco, K. Vanvarenberg, B. Ucakar, N. Joudiou, B. Gallez, G. Bastiat, F. Lagarce, V. Préat, F. Danhier
Journal: Journal of Controlled Release (2017)
Activity of lurbinectedin (PM01183) as single agent and in combination in patients with endometrial cancer.
Authors: Martin David Forster, Victor Moreno, Valentina Boni, Eva Guerra, Andres Poveda, Rebecca Kristeleit, Carmen Maria Kahatt, Pilar Lardelli, Jose Antonio Lopez Vilarino, Nazly M Cuevas, Arturo Soto-Matos, Emiliano Calvo
Journal: Journal of Clinical Oncology (2017)

5586 Background: Lurbinectedin (L) is a new anticancer drug that blocks trans-activated transcription, induces DNA double-strand breaks and modulates the tumor microenvironment. Advanced endometrial cancer (EC) is an unmet medical need. Methods: Activity in EC patients was reviewed in 3 trials: a phase IB study of lurbinectedin combined with doxorubicin (L+DOX), a phase I study of PM combined with paclitaxel (L+TAX) and a phase II single-agent basket trial (L). Baseline characteristics, safety and efficacy were analyzed. Results: 97 patients were evaluated: 34 (2 cohorts) with L+DOX, 11 with L+TAX and 52 with L. Median age was similar in the 3 studies. Endometrioid was the most frequent histology. Median (range) of prior chemotherapy lines for advanced disease was: L+DOX, 1(0-2); L+TAX, 2(1-3); L, 1(0-2). Responses were observed in the 3 studies (see table). Main adverse event was myelosuppression (grade 3-4 neutropenia/thrombocytopenia/febrile neutropenia: L+DOX Cohort A, 94%/26%/40%; L+DOX Cohort B, 79%/10%/16%; L+TAX, 54%/0%/0%; L, 33%/6%/6%). Non-hematological toxicity was mostly grade 1-2: fatigue, nausea and vomiting, and transaminase increase. Conclusions: Lurbinectedin is active as single agent and in combination in patients with advanced EC, with remarkable activity in terms of response rate, duration of response and PFS when combined with doxorubicin. Safety was acceptable in L+DOX Cohort B, L+TAX and L, and myelosuppression was well managed. Clinical trial information: NCT01970540. [Table: see text]
Comparison and interpretability of the available urticaria activity scores
Authors: T. Hawro, T. Ohanyan, N. Schoepke, M. Metz, A. Peveling‐Oberhag, P. Staubach, M. Maurer, K. Weller
Journal: Allergy (2017)

The urticaria activity score (UAS) is the gold standard for assessing disease activity in patients with chronic spontaneous urticaria (CSU). Two different versions, the UAS7 and UAS7TD , are currently used in clinical trials and routine care. To compare both versions and to obtain data on their interpretability, 130 CSU patients applied both versions and globally rated their disease activity as none, mild, moderate, or severe. UAS7 and UAS7TD values correlated strongly (r = .90, P < .001). Interquartile ranges for UAS7 and UAS7TD values for mild, moderate, and severe CSU were 11-20 and 10-24, 16-30 and 16-32, and 27-37 and 28-40. UAS7 values were slightly, but significantly lower as compared to UAS7TD values (mean difference: 1.6 ± 4.6, P < .001). This difference was driven by lower wheal subscores (2.1 ± 3.5, P < .001) and was most pronounced in patients with severe CSU (2.5 ± 5.6, P < .01). The UAS7/UAS7TD ratio was 0.96 ± 0.21 and did not differ significantly between mild, moderate, and severe CSU. Since the results of both UAS versions are comparable, we recommend the use of the UAS7, which is less burdensome in administration and scoring.
LRRK2 promotes the activation of NLRC4 inflammasome during <i>Salmonella</i> Typhimurium infection
Authors: Weiwei Liu, Xia’nan Liu, Yu Li, Junjie Zhao, Zhenshan Liu, Zhuqin Hu, Ying Wang, Yufeng Yao, Aaron W. Miller, Bing Su, Mark R. Cookson, Xiaoxia Li, Zizhen Kang
Journal: The Journal of Experimental Medicine (2017)

Although genetic polymorphisms in the LRRK2 gene are associated with a variety of diseases, the physiological function of LRRK2 remains poorly understood. In this study, we report a crucial role for LRRK2 in the activation of the NLRC4 inflammasome during host defense against Salmonella enteric serovar Typhimurium infection. LRRK2 deficiency reduced caspase-1 activation and IL-1β secretion in response to NLRC4 inflammasome activators in macrophages. Lrrk2−/− mice exhibited impaired clearance of pathogens after acute S. Typhimurium infection. Mechanistically, LRRK2 formed a complex with NLRC4 in the macrophages, and the formation of the LRRK2–NLRC4 complex led to the phosphorylation of NLRC4 at Ser533. Importantly, the kinase activity of LRRK2 is required for optimal NLRC4 inflammasome activation. Collectively, our study reveals an important role for LRRK2 in the host defense by promoting NLRC4 inflammasome activation.
Peanut immunotherapy provides long lasting suppression of allergy, finds study
Authors: Susan Mayor
Journal: BMJ (2017)

Probiotic and peanut oral immunotherapy provides long lasting suppression of peanut allergy in children that continues for at least four years after stopping treatment, reports a long term follow-up study that investigated this approach.1

“Combined probiotic and peanut oral immunotherapy was associated with long lasting peanut tolerance four years after stopping treatment,” said the researchers, led by Mimi Tang, from the Royal Children’s Hospital in Melbourne, Australia.

Two thirds of the study participants who were given probiotic and peanut immunotherapy were able to continue eating peanut products regularly, with more than half eating …
PETとCherenkovイメージングを用いた肺遺伝子導入のための分解性ナノ粒子のin vivoでの運命追跡【Powered by NICT】
Authors: C L Black Kvar, Ibricevic Aida, P Gunsten Sean, A Flores Jeniree, P Gustafson Tiffany, E Raymond Jeffery, Samarajeewa Sandani, Shrestha Ritu, E Felder Simcha, Cai Tianyi, Shen Yuefei, Lobs Ann-Kathrin, Zhegalova Natalia, H Sultan Deborah, Berezin Mikhail, L Wooley Karen, Liu Yongjian, L Brody Steven
Journal: Biomaterials (2016)
神経膠芽腫の治療のためのPEG化スクアレノイルゲムシタビンナノ粒子【Powered by NICT】
Authors: Gaudin Alice, Song Eric, R King Amanda, K Saucier-Sawyer Jennifer, Bindra Ranjit, Desmaeele Didier, Couvreur Patrick, Saltzman W. Mark
Journal: Biomaterials (2016)
Herpes Zoster and Tofacitinib: Clinical Outcomes and the Risk of Concomitant Therapy
Authors: Kevin L. Winthrop, Jeffrey R. Curtis, Stephen Lindsey, Yoshiya Tanaka, Kunihiro Yamaoka, Hernan Valdez, Tomohiro Hirose, Chudy I. Nduaka, Lisy Wang, Alan M. Mendelsohn, Haiyun Fan, Connie Chen, Eustratios Bananis
Journal: Arthritis & Rheumatology (2017)

Objective Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster (HZ), and the risk appears to be increased in patients treated with tofacitinib. The aim of this study was to evaluate whether concomitant treatment with conventional synthetic disease‐modifying antirheumatic drugs (csDMARDs) or glucocorticoids (GCs) contributes to the increased risk of HZ in RA patients treated with tofacitinib. Methods HZ cases were identified from the databases of 2 phase I, 9 phase II, 6 phase III, and 2 long‐term extension studies of tofacitinib in RA patients. Crude incidence rates (IRs) of all HZ events (serious and nonserious) per 100 patient‐years (with 95% confidence intervals [95% CIs]) were calculated for unique patients. Within phase III studies, we described HZ rates according to concomitant csDMARD treatment and baseline GC use. A multivariable Cox proportional hazards regression model was used to evaluate HZ risk factors across studies. Results Across all studies (6,192 patients; 16,839 patient‐years), HZ was reported in 636 tofacitinib‐treated patients (IR 4.0, 95% CI 3.7–4.4). In most cases (93%), HZ was classified as nonserious, and the majority of patients (94%) had involvement of only 1 dermatome. HZ IRs varied across regions, from 2.4 (95% CI 2.0–2.9) in Eastern Europe to 8.0 (95% CI 6.6–9.6) in Japan and 8.4 (95% CI 6.4–10.9) in Korea. Within phase III studies, HZ IRs varied according to tofacitinib dose, background csDMARD treatment, and baseline use of GCs. The IRs were numerically lowest for monotherapy with tofacitinib 5 mg twice daily without GCs (IR 0.56 [95% CI 0.07–2.01]) and highest for tofacitinib 10 mg twice daily with csDMARDs and GCs (IR 5.44 [95% CI 3.72–7.68]). Age, GC use, tofacitinib dose, and enrollment within Asia were independent risk factors for HZ. Conclusion Patients receiving treatment with tofacitinib and GCs appear to have a greater risk of developing HZ compared with patients receiving tofacitinib monotherapy without GCs.
Natural NS5A inhibitor resistance associated substitutions in hepatitis C virus genotype 1 infected patients from Italy
Authors: C. Caudai, A. Materazzi, F. Saladini, S. Di Giambenedetto, C. Torti, B. Ricciardi, B. Rossetti, P. Almi, A. De Luca, M. Zazzi
Journal: Clinical Microbiology and Infection (2017)