tbuckley/cabot-search huggingface dataset:
Inhibition of EphB4–Ephrin-B2 Signaling Reprograms the Tumor Immune Microenvironment in Head and Neck Cancers
Authors: Shilpa Bhatia, Ayman Oweida, Shelby Lennon, Laurel B. Darragh, Dallin Milner, Andy V. Phan, Adam C. Mueller, Benjamin Van Court, David Raben, Natalie J. Serkova, Xiao-Jing Wang, Antonio Jimeno, Eric T. Clambey, Elena B. Pasquale, Sana D. Karam
Journal: Cancer Research (2019)

Abstract Identifying targets present in the tumor microenvironment that contribute to immune evasion has become an important area of research. In this study, we identified EphB4–ephrin-B2 signaling as a regulator of both innate and adaptive components of the immune system. EphB4 belongs to receptor tyrosine kinase family that interacts with ephrin-B2 ligand at sites of cell–cell contact, resulting in bidirectional signaling. We found that EphB4–ephrin-B2 inhibition alone or in combination with radiation (RT) reduced intratumoral regulatory T cells (Tregs) and increased activation of both CD8+ and CD4+Foxp3− T cells compared with the control group in an orthotopic head and neck squamous cell carcinoma (HNSCC) model. We also compared the effect of EphB4–ephrin-B2 inhibition combined with RT with combined anti-PDL1 and RT and observed similar tumor growth suppression, particularly at early time-points. A patient-derived xenograft model showed reduction of tumor-associated M2 macrophages and favored polarization towards an antitumoral M1 phenotype following EphB4–ephrin-B2 inhibition with RT. In vitro, EphB4 signaling inhibition decreased Ki67-expressing Tregs and Treg activation compared with the control group. Overall, our study is the first to implicate the role of EphB4–ephrin-B2 in tumor immune response. Moreover, our findings suggest that EphB4–ephrin-B2 inhibition combined with RT represents a potential alternative for patients with HNSCC and could be particularly beneficial for patients who are ineligible to receive or cannot tolerate anti-PDL1 therapy. Significance: These findings present EphB4–ephrin-B2 inhibition as an alternative to anti-PDL1 therapeutics that can be used in combination with radiation to induce an effective antitumor immune response in patients with HNSCC.
Sorafenib: Experience and Better Manage­ment of Side Effects Improve Overall Survival in Hepatocellular Carcinoma Patients: A Real-Life Retrospective Analysis
Authors: Jean-Luc Raoul, Xavier Adhoute, Guillaume Penaranda, Hervé Perrier, Paul Castellani, Valérie Oules, Marc Bourlière
Journal: Liver Cancer (2019)

Sorafenib is the first-line treatment for advanced hepatocellular carcinoma (HCC). The management of its side effects is improving. This study aimed to assess, in real life, if this translates into a better prognosis.This was a retrospective study of advanced HCC patients treated with sorafenib between 2007 and 2017.188 advanced HCC patients received > 4 weeks of sorafenib. Median treatment duration was 5.4 months and median overall survival (mOS) 10 months (95% confidence interval 15-27). Sorafenib was initiated in 65 patients in 2007-2012 and 123 in 2013-2017. Both groups were comparable except for Barcelona Clinic liver cancer class. Tumor progression, disease control (DC) rate, and incidence of toxicity were similar in the 2 periods, but the duration of treatment (4.3 vs. 5.9 months; p < 0.01) and mOS (8 vs. 12 months; p < 0.002) differed. Among progressive disease patients, mOS was similar (7 months) but for those who had DC at 8 weeks, mOS was longer in the recent period (13 vs. 27 months; p < 0.0001). In the univariate analysis of OS, the period of treatment had a prognostic value.When comparing 2 periods of treatment in advanced HCC patients under sorafenib, duration of treatment and mOS were higher in the recent period. While mOS did not differ for patients who progressed, it was 2-fold higher in the recent period for those who had tumor control. Improvements in the use of sorafenib seem to be associated with better outcomes limited to patients with DC.
How Confident Should We Be About Recommendations Based on Network Meta-analyses?
Authors: Jesse A. Berlin
Journal: Annals of Internal Medicine (2019)

Editorials16 April 2019How Confident Should We Be About Recommendations Based on Network Meta-analyses?Jesse A. Berlin, ScDJesse A. Berlin, ScDJohnson & Johnson, Titusville, New Jersey (J.A.B.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M19-0754 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail The current article by Phillippo and colleagues (1) presents an insightful approach to the challenges of evaluating the robustness of guideline recommendations. The authors, admirably, leave the technical details for those who are interested. At a high level, their approach is intuitive and appeals to common sense. Focusing specifically on network meta-analysis (NMA), they ask how much the data supporting a guideline would have to differ before the recommendations based on those data would change. Here, data can mean results of a specific pairwise meta-analysis, or study-specific results, making the authors' method flexible and easily adapted to many decision-making contexts. ...References1. Phillippo DM, Dias S, Welton NJ, Caldwell DM, Taske N, Ades AE. Threshold analysis as an alternative to GRADE for assessing confidence in guideline recommendations based on network meta-analyses. Ann Intern Med. 2019;170:538-46. doi:10.7326/M18-3542. LinkGoogle Scholar2. Institute of Medicine. Clinical Practice Guidelines We Can Trust. Washington, DC: National Academies Pr; 2011. Google Scholar3. Institute of Medicine. Finding What Works in Health Care: Standards for Systematic Reviews. Washington, DC: National Academies Pr; 2011. Google Scholar Author, Article, and Disclosure InformationAffiliations: Johnson & Johnson, Titusville, New Jersey (J.A.B.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-0754.Corresponding Author: Jesse A. Berlin, ScD, Johnson & Johnson, 1125 Trenton-Harbourton Road, K3 Zone 1, Titusville, NJ 08560; e-mail, [email protected]jnj.com.This article was published at Annals.org on 26 March 2019. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoThreshold Analysis as an Alternative to GRADE for Assessing Confidence in Guideline Recommendations Based on Network Meta-analyses David M. Phillippo , Sofia Dias , Nicky J. Welton , Deborah M. Caldwell , Nichole Taske , and A.E. Ades Metrics 16 April 2019Volume 170, Issue 8Page: 571-572KeywordsDisclosureGrading of Recommendations Assessment Development and EvaluationHeadachesHealth careNetwork analysisRacial and ethnic issuesRelative riskStatistical dataSystematic reviewsTreatment guidelines ePublished: 26 March 2019 Issue Published: 16 April 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy
Authors: Israel Hernandez, Gabriel Luna, Jennifer N. Rauch, Surya A. Reis, Michel Giroux, Celeste M. Karch, Daniel Boctor, Youssef E. Sibih, Nadia J. Storm, Antonio Diaz, Susmita Kaushik, Cezary Zekanowski, Alexander A. Kang, Cassidy R. Hinman, Vesna Cerovac, Elmer Guzman, Honjun Zhou, Stephen J. Haggarty, Alison M. Goate, Steven K. Fisher, Ana M. Cuervo, Kenneth S. Kosik
Journal: Science Translational Medicine (2019)

Tau inclusions are a shared feature of many neurodegenerative diseases, among them frontotemporal dementia caused by tau mutations. Treatment approaches for these conditions include targeting posttranslational modifications of tau proteins, maintaining a steady-state amount of tau, and preventing its tendency to aggregate. We discovered a new regulatory pathway for tau degradation that operates through the farnesylated protein, Rhes, a GTPase in the Ras family. Here, we show that treatment with the farnesyltransferase inhibitor lonafarnib reduced Rhes and decreased brain atrophy, tau inclusions, tau sumoylation, and tau ubiquitination in the rTg4510 mouse model of tauopathy. In addition, lonafarnib treatment attenuated behavioral abnormalities in rTg4510 mice and reduced microgliosis in mouse brain. Direct reduction of Rhes in the rTg4510 mouse by siRNA reproduced the results observed with lonafarnib treatment. The mechanism of lonafarnib action mediated by Rhes to reduce tau pathology was shown to operate through activation of lysosomes. We finally showed in mouse brain and in human induced pluripotent stem cell-derived neurons a normal developmental increase in Rhes that was initially suppressed by tau mutations. The known safety of lonafarnib revealed in human clinical trials for cancer suggests that this drug could be repurposed for treating tauopathies.
CCN3/NOV as a functional driver and prognostic biomarker of prostate cancer bone metastasis.
Authors: VéRonique Ouellet, Matthew Dankner, Laudine Desreumaux-Communal, Estelle Schmitt, Dru Perkins, Matthew G Annis, Veronique Barres, Christine Caron, Anne-Marie Mes-Masson, Fred Saad, Peter Siegel
Journal: Journal of Clinical Oncology (2019)

182 Background: Prostate cancer commonly metastasizes to the bone, resulting in pathological fractures and poor prognosis. CCN3/NOV (Nephroblastoma overexpressed) has been implicated in promoting the formation of osteolytic prostate cancer (PC) bone metastases. The C-terminal domain of CCN3 binds growth factors, heparin sulfate proteoglycans, activates Notch signaling and promotes dimerization of CCN family members. We hypothesize that the CCN3 CT domain is required to promote osteolytic PC bone metastasis and that CCN3 represents a prognostic biomarker in primary PC tumors to predict recurrence to bone. Methods: CCN3 WT and CCN3 ∆CT were overexpressed in LNCaP C4-2 cells. The role of CCN3 was assessed with in vitro proliferation, migration and invasion assays, and in vivo through intracardiac injection in male Nude mice (Nu/Nu). Ex vivo µCT scans were performed on bone specimens. CCN3 expression was assessed in two unique tissue microarrays (TMA) comprising over 1,500 primary prostate tumor using different anti-CCN3 antibodies with immunohistochemistry and immunohistofluorescnece, respectively. Results: While CCN3 WT and CCN3 ∆CT had little effect in vitro on cell proliferation, migration or invasion, intracardiac injection of CCN3 WT resulted in increased incidence of bone metastasis compared to empty vector control and CCN3 ∆CT . Ex vivo µCT revealed decreased bone mineral density in bones from mice injected with CCN3 WT cells compared to control and CCN3 ∆CT expressing cells. In both TMAs studied, high CCN3 expression in tumor epithelium correlated with increased risk of biochemical relapse and bone metastasis at 5 years and 15 years post-resection, respectively. Conclusions: CCN3 requires its C-terminal domain for its bone metastatic function, and CCN3 is correlated with aggressive disease biology in prostate cancer. These findings point to CCN3 as a biomarker that can be useful to predict prostate cancer aggressiveness, while providing clarity on its role as a functional mediator of prostate cancer bone metastasis.
Michael Wilks: campaigner who helped found the Sick Doctors Trust after his own experience with alcoholism
Authors: Matt Limb
Journal: BMJ (2019)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following Michael Wilks: campaigner who helped found the Sick Doctors Trust after his own experience with alcoholism Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
BPI19-020: A New Protecting Method for the Inferior Parathyroid Gland in situ: The Meticulous Thyrothymic Ligament Dissection Technique
Authors: Yan Si, Jingsheng Cai, Hao Zhang, Haisheng Fang, Meiping Shen
Journal: Journal of the National Comprehensive Cancer Network (2019)

Objective: To explore the anatomic features and the dissection technique of thyrothymic ligament (TTL) and to explore the clinical significance of protecting the inferior parathyroid gland (IPTG) with this structure. Method: Dissect the TTL of patients who receive initial thyroid surgery in our center, describe the structural features of TTL, and investigate the positional relationship of TTL and IPTG. Results: TTL is a kind of adipose connective tissue that is wide at the bottom and narrow at the top, accompanying with the inferior thyroid vein, from the thymus to the thyroid. Over 70% TTL are attached to the lower pole and the lower one-third dorsal of thyroid, containing fat and vessels. About 121 patients have undergone this dissection, totally dissected 194 sides, 143 sides had TTL (73.7%). About 63.4% IPTGs are located in the thymus-thyrothymic ligament-IPTG complex (TLIC), and nearly 70.6% IPTG can be proactively identified and located by the TTL during the operation. The incidence rate of postsurgical hypoparathyroidism is 14.9%. According to whether the dissection is successful, the IPTG can be described into 2 types, the ligament type (L) and the non-ligament type (N), and each type can be described into different subtypes.
Activation of naïve CD4+ T cells re-tunes STAT1 signaling to deliver unique cytokine responses in memory CD4+ T cells
Authors: Jason P. Twohig, Ana Cardus Figueras, Robert Andrews, Florian Wiede, Benjamin C. Cossins, Alicia Derrac Soria, Myles J. Lewis, Michael J. Townsend, David Millrine, Jasmine Li, David G. Hill, Javier Uceda Fernandez, Xiao Liu, Barbara Szomolay, Christopher J. Pepper, Philip R. Taylor, Costantino Pitzalis, Tony Tiganis, Nigel M. Williams, Gareth W. Jones, Simon A. Jones
Journal: Nature Immunology (2019)
Melanoma-Induced Reprogramming of Schwann Cell Signaling Aids Tumor Growth
Authors: Galina V. Shurin, Oleg Kruglov, Fei Ding, Yan Lin, Xingxing Hao, Anton A. Keskinov, Zhaoyang You, Anna E. Lokshin, William A. LaFramboise, Louis D. Falo, Michael R. Shurin, Yuri L. Bunimovich
Journal: Cancer Research (2019)

Abstract The tumor microenvironment has been compared with a nonhealing wound involving a complex interaction between multiple cell types. Schwann cells, the key regulators of peripheral nerve repair, have recently been shown to directly affect nonneural wound healing. Their role in cancer progression, however, has been largely limited to neuropathic pain and perineural invasion. In this study, we showed that melanoma activated otherwise dormant functions of Schwann cells aimed at nerve regeneration and wound healing. Such reprogramming of Schwann cells into repair-like cells occurred during the destruction and displacement of neurons as the tumor expanded and via direct signaling from melanoma cells to Schwann cells, resulting in activation of the nerve injury response. Melanoma-activated Schwann cells significantly altered the microenvironment through their modulation of the immune system and the extracellular matrix in a way that promoted melanoma growth in vitro and in vivo. Local inhibition of Schwann cell activity following cutaneous sensory nerve transection in melanoma orthotopic models significantly decreased the rate of tumor growth. Tumor-associated Schwann cells, therefore, can have a significant protumorigenic effect and may present a novel target for cancer therapy. Significance: These findings reveal a role of the nerve injury response, particularly through functions of activated Schwann cells, in promoting melanoma growth.
Effectiveness of an mHealth-Based Electronic Decision Support System for Integrated Management of Chronic Conditions in Primary Care
Authors: Dorairaj Prabhakaran, Dilip Jha, David Prieto-Merino, Ambuj Roy, Kavita Singh, Vamadevan S. Ajay, Devraj Jindal, Priti Gupta, Dimple Kondal, Shifalika Goenka, Pramod Jacob, Rekha Singh, B. G. Prakash Kumar, Pablo Perel, Nikhil Tandon, Vikram Patel, C. Venkat, S. Ram, Sudhir Saxena, K. Venugopal, Lars Gredsted, Vikram Sheel Kumar, Shirshendu Mukherjee, K. Srinath Reddy, Nitish Naik, S.N. Dwivedi, A.G. Unnikrishnan, Meenakshi Sharma
Journal: Circulation (2019)

The burden of noncommunicable diseases and their risk factors has rapidly increased worldwide, including in India. Innovative management strategies with electronic decision support and task sharing have been assessed for hypertension, diabetes mellitus, and depression individually, but an integrated package for multiple chronic condition management in primary care has not been evaluated.In a prospective, multicenter, open-label, cluster-randomized controlled trial involving 40 community health centers, using hypertension and diabetes mellitus as entry points, we evaluated the effectiveness of mWellcare, an mHealth system consisting of electronic health record storage and an electronic decision support for the integrated management of 5 chronic conditions (hypertension, diabetes mellitus, current tobacco and alcohol use, and depression) versus enhanced usual care among patients with hypertension and diabetes mellitus in India. At trial end (12-month follow-up), using intention-to-treat analysis, we examined the mean difference between arms in change in systolic blood pressure and glycated hemoglobin as primary outcomes and fasting blood glucose, total cholesterol, predicted 10-year risk of cardiovascular disease, depression score, and proportions reporting tobacco and alcohol use as secondary outcomes. Mixed-effects regression models were used to account for clustering and other confounding variables.Among 3698 enrolled participants across 40 clusters (mean age, 55.1 years; SD, 11 years; 55.2% men), 3324 completed the trial. There was no evidence of difference between the 2 arms for systolic blood pressure (Δ=-0.98; 95% CI, -4.64 to 2.67) and glycated hemoglobin (Δ=0.11; 95% CI, -0.24 to 0.45) even after adjustment of several key variables (adjusted differences for systolic blood pressure: - 0.31 [95% CI, -3.91 to 3.29]; for glycated hemoglobin: 0.08 [95% CI, -0.27 to 0.44]). The mean within-group changes in systolic blood pressure in mWellcare and enhanced usual care were -13.65 mm Hg versus -12.66 mm Hg, respectively, and for glycated hemoglobin were -0.48% and -0.58%, respectively. Similarly, there were no differences in the changes between the 2 groups for tobacco and alcohol use or other secondary outcomes.We did not find an incremental benefit of mWellcare over enhanced usual care in the management of the chronic conditions studied.URL: https://www.gov. Unique identifier: NCT02480062.
Venetoclax Combined With Low-Dose Cytarabine for Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase Ib/II Study
Authors: Andrew H. Wei, Stephen A. Strickland, Jing-Zhou Hou, Walter Fiedler, Tara L. Lin, Roland B. Walter, Anoop Enjeti, Ing Soo Tiong, Michael Savona, Sangmin Lee, Brenda Chyla, Relja Popovic, Ahmed Hamed Salem, Suresh Agarwal, Tu Xu, Kaffa M. Fakouhi, Rod Humerickhouse, Wan-Jen Hong, John Hayslip, Gail J. Roboz
Journal: Journal of Clinical Oncology (2019)

Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. An international phase Ib/II study evaluated the safety and preliminary efficacy of venetoclax, a selective B-cell leukemia/lymphoma-2 inhibitor, together with low-dose cytarabine (LDAC) in older adults with AML.Adults 60 years or older with previously untreated AML ineligible for intensive chemotherapy were enrolled. Prior treatment of myelodysplastic syndrome, including hypomethylating agents (HMA), was permitted. Eighty-two patients were treated at the recommended phase II dose: venetoclax 600 mg per day orally in 28-day cycles, with LDAC (20 mg/m2 per day) administered subcutaneously on days 1 to 10. Key end points were tolerability, safety, response rates, duration of response (DOR), and overall survival (OS).Median age was 74 years (range, 63 to 90 years), 49% had secondary AML, 29% had prior HMA treatment, and 32% had poor-risk cytogenetic features. Common grade 3 or greater adverse events were febrile neutropenia (42%), thrombocytopenia (38%), and WBC count decreased (34%). Early (30-day) mortality was 6%. Fifty-four percent achieved complete remission (CR)/CR with incomplete blood count recovery (median time to first response, 1.4 months). The median OS was 10.1 months (95% CI, 5.7 to 14.2), and median DOR was 8.1 months (95% CI, 5.3 to 14.9 months). Among patients without prior HMA exposure, CR/CR with incomplete blood count recovery was achieved in 62%, median DOR was 14.8 months (95% CI, 5.5 months to not reached), and median OS was 13.5 months (95% CI, 7.0 to 18.4 months).Venetoclax plus LDAC has a manageable safety profile, producing rapid and durable remissions in older adults with AML ineligible for intensive chemotherapy. High remission rate and low early mortality combined with rapid and durable remission make venetoclax and LDAC an attractive and novel treatment for older adults not suitable for intensive chemotherapy.
CLO19-056: Scalp Cooling Proved to be Successful in the Prevention of Alopecia in >7,000 Patients With Solid Tumors
Authors: Corina van den Hurk, Wouter Dercksen, Birgit Vriens, Wim Breed
Journal: Journal of the National Comprehensive Cancer Network (2019)

Introduction: Hair loss is a frequently occurring and stigmatizing side effect of chemotherapy. Worldwide scalp cooling is being introduced to prevent chemotherapy-induced alopecia (CIA). In the Netherlands scalp cooling is implemented in many hospitals since 2005. Methods: From 2006–2017, data have been collected in a prospective, longitudinal registry. Patients with all types of solid tumors, with all stages of disease, from all ages and both sexes could participate, if they received a chemotherapy that induced severe hair loss. The hospitals were free to offer scalp cooling to their patients according to their local protocols on cooling and infusion time of the drugs. Patients were eligible for evaluation of hair loss after they received at least 2 cycles of chemotherapy or if they ceased scalp cooling because of severe hair loss after the first cycle. Data will be presented using descriptive statistics and multivariate regression analysis to explore determinants of scalp cooling efficacy. Results: Preliminary results show data of 7,378 patients from 68 hospital locations of whom 75% had breast and 8% prostate cancer. Most patients (61%) were treated in the adjuvant setting. In general, preinfusion cooling time was 30 minutes and postinfusion cooling time 90 minutes. An exception was for docetaxel, for which 20 minutes postinfusion cooling time was used in recent years. Scalp cooling efficacy varied from above 80% for taxanes monotherapy to below 10% for the combination of docetaxel, doxorubicin, and cyclophosphamide (TAC). Results from the regression analyses will be presented at the conference. Conclusion: Scalp cooling proved to be successful for most types of chemotherapy causing CIA.