tbuckley/cabot-search huggingface dataset:
Targeting OX40 by monoclonal antibody PF-04518600 to enhance T cell functions and inhibit tumor growth.
Authors: Hua Long, Ann L White, Brittany B Jiang, Reid Feldman, Danielle C Pappas, Aymen Al-Shamkhani, Changyu Wang, John Lin
Journal: Journal of Clinical Oncology (2016)

e14518 Background: T cell costimulation is an attractive strategy for cancer treatment in addition to check point inhibitors. Costimulatory molecule OX40 is a member of the TNF receptor superfamily that is transiently expressed on activated T cells. Activation of OX40 leads to enhanced T cell proliferation and cytokine secretion and in turn results in better anti-tumor efficacy as shown by multiple mouse syngeneic tumor models. Methods: PF-04518600 (PF-8600) is a fully human IgG2 agonist antibody to human OX40 with high affinity and specificity. We used in vitro and in vivo methods to evaluate the co-stimulatory functions of PF-8600. Results: PF-8600 demonstrated better agonist activity in a luciferase reporter cell line expressing OX40 and NFκB as compared to a human IgG1 antibody. In human primary T cells, plate bound PF-8600 dose dependently increased T cell proliferation and cytokine secretion in vitro. Furthermore in adoptive transfer experiments, PF-8600 in a mouse IgG1 framework (similar to human IgG2 in effector functions) increased the proliferation of OT1 cells that express human OX40 in vivo. In a mouse line expressing human OX40, PF-8600 inhibited EG7 tumor growth as compared to isotype control antibody, further confirming the mechanism of action as an OX40 agonist. As regulatory T cells are a major inhibitory population in the tumor microenvironment, their specific depletion in the tumor is highly desirable. In an in vitro assay using monocyte derived macrophages as effector cells, PF-8600 mediated the depletion of OX40 expressing cells similar to a human IgG1 antibody. Conclusions: Both in vitro and in vivo results demonstrated PF-8600 enhanced T cells functions and inhibited tumor growth in a mouse syngeneic tumor model. Based on the mechanism of action and robust anti-tumor efficacy in preclinical models, PF-8600 is currently in clinical development in a broad spectrum of malignancies.
Cyst Fluid Analysis in Pancreatic Intraductal Papillary Mucinous Neoplasms
Authors: Peter J. Allen, Christine A. Iacobuzio-Donahue, David S. Klimstra
Journal: Clinical Cancer Research (2016)

Pancreatic intraductal papillary mucinous neoplasms (IPMN) are surgically treatable cancer precursors, if high-risk features can be identified. Analysis of proteins and genes in cyst fluid helps diagnostically, but prior biomarkers had limited ability to detect high-risk cases. Cyst fluid telomerase activity may be a useful biomarker for high-risk IPMNs. Clin Cancer Res; 22(20); 4966-7. ©2016 AACRSee related article by Hata et al., p. 5141.
Periodontitis prevalence in adults ≥ 65 years of age, in the <scp>USA</scp>
Authors: Paul I. Eke, Liang Wei, Wenche S. Borgnakke, Gina Thornton‐Evans, Xingyou Zhang, Hua Lu, Lisa C. McGuire, Robert J. Genco
Journal: Periodontology 2000 (2016)

Abstract The older adult population is growing rapidly in the USA and it is expected that by 2040 the number of adults ≥ 65 years of age will have increased by about 50%. With the growth of this subpopulation, oral health status, and periodontal status in particular, becomes important in the quest to maintain an adequate quality of life. Poor oral health can have a major impact, leading to tooth loss, pain and discomfort, and may prevent older adults from chewing food properly, often leading to poor nutrition. Periodontitis is monitored in the USA at the national level as part of the Healthy People 2020 initiative. In this report, we provide estimates of the overall burden of periodontitis among adults ≥ 65 years of age and after stratification according to sociodemographic factors, modifiable risk factors (such as smoking status), the presence of other systemic conditions (such as diabetes) and access to dental care. We also estimated the burden of periodontitis within this age group at the state and local levels. Data from the National Health and Nutrition Examination Survey 2009/2010 and 2011/2012 cycles were analyzed. Periodontal measures from both survey cycles were based on a full‐mouth periodontal examination. Nineteen per cent of adults in this subpopulation were edentulous. The mean age was 73 years, 7% were current smokers, 8% lived below the 100% Federal Poverty Level and &lt; 40% had seen a dentist in the past year. Almost two‐thirds (62.3%) had one or more sites with ≥ 5 mm of clinical attachment loss and almost half had at least one site with probing pocket depth of ≥ 4 mm. We estimated the lowest prevalence of periodontitis in Utah (62.3%) and New Hampshire (62.6%) and the highest in New Mexico, Hawaii, and the District of Columbia each with a prevalence of higher than 70%. Overall, periodontitis is highly prevalent in this subpopulation, with two‐thirds of dentate older adults affected at any geographic level. These findings provide an opportunity to determine how the overall health‐care management of older adults should consider the improvement of their oral health conditions. Many older adults do not have dental insurance and are also likely to have some chronic conditions, which can adversely affect their oral health.
Changing Pathology of the Thoracic Aorta From Acute to Chronic Dissection
Authors: Sven Peterss, Ahmed M. Mansour, Julia A. Ross, Irena Vaitkeviciute, Paris Charilaou, Julia Dumfarth, Hai Fang, Bulat A. Ziganshin, John A. Rizzo, Adebowale J. Adeniran, John A. Elefteriades
Journal: Journal of the American College of Cardiology (2016)
A set of interesting sequoiatones stereoisomers from a wetland soil-derived fungus Talaromyces flavus
Authors: Tianyu Sun, Jian Zou, Guodong Chen, Dan Hu, Bin Wu, Xingzhong Liu, Xinsheng Yao, Hao Gao
Journal: Acta Pharmaceutica Sinica B (2016)

Four interesting sequoiatones stereoisomers (1-4) were isolated from a wetland soil-derived fungus Talaromyces flavus by chiral HPLC. On the basis of comprehensive NMR and mass analyses, their planar structures were elucidated as the same as that of sequoiatone B. Among them, 1 and 3 (or 2 and 4) were a pair of enantiomers, and 1 and 2 (or 3 and 4) were a pair of stereoisomers with epimerization at C-12, which indicated that sequoiatione-type metabolites exist as enantiomers rather than as optically pure compounds in some strains. With the quantum chemical ECD calculations, the absolute configurations of C-8 in 1-4 were determined, which is the first report to establish the absolute configuration of C-8 in sequoiatones. However, the absolute configurations of C-12 in sequoiatones are still unsolved.
<i>Notes from the Field</i>: Splenomegaly of<b>Unknown</b>Etiology in Congolese Refugees Applying for Resettlement to the United States — Uganda, 2015
Authors: Matthew Goers, Maurice O. Ope, Aaron Samuels, Natalia Gitu, Saul Akandwanaho, Gladys Nabwami, Raymond Nyoka, Martin S. Cetron, Warren Dalal, Andrea L. Conroy, Paul Cantey, Chandy John, Marwan Naoum, Michelle Weinberg, Nina Marano, William Stauffer
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Approximately 70,000-90,000 refugees are resettled to the United States each year, and during the next 5 years, 50,000 Congolese refugees are expected to arrive in the United States. The International Organization for Migration (IOM) performs refugee medical examinations overseas for the U.S. Refugee Resettlement Program. In 2014, IOM reported that a large number of U.S.-bound Congolese refugees from Uganda had spleens that were enlarged on examination. During two evaluations of refugee populations in western Uganda in March and July 2015, refugees with splenomegaly on physical examination were offered additional assessment and treatment, including abdominal ultrasonography and laboratory testing. Among 987 persons screened, 145 (14.7%) had splenomegaly and received further testing. Among the 145 patients with splenomegaly, 63.4% were aged 5-17 years (median = 14.8 years). There was some evidence of family clustering, with 33 (22.7%) of the 145 cases occurring in families.
P1148 : Long-term administration of ursodeoxycholic acid prevents recurrence of primary biliary cirrhosis after liver transplantation
Authors: A. Bosch, J. Dumortier, D. Maucor Boulch, F. Conti, I. Morard, L. Rubbia-Brandt, J.-Y. Scoazec, D. Wendum, B. Terris, O. Boillot, S. Radenne, O. Chazouillères, Y. Calmus, E. Giostra, C. Corpechot
Journal: Journal of Hepatology (2015)
Disease progression of metastatic breast cancer by first relapse site after definitive radiotherapy.
Authors: Kenshiro Shiraishi, Keiichiro Tada, Jiro Kawamori, Atsushi Fukuuchi, Tsunehiro Nishi
Journal: Journal of Clinical Oncology (2015)

36 Background: Bone metastasis as initial distant relapse is commonly considered to have better prognosis than other sites in metastatic breast cancer. To elucidate true clinical course of metastatic disease, it is essential that we prospectively manage patients since primary setting. Methods: Overall, 3,417 patients with breast cancer treated with mastectomy (n = 379, 11.1%) or breast-conserving surgery (n = 3,029, 88.6%) followed by definitive radiotherapy at two institutions in Center of Tokyo between 1980 and 2014 were included in the study. Information on all patients was prospectively collected and rigorously-controlled. Initial metastatic relapse sites included bone, brain, and other (mainly visceral). Intrinsic subtypes of tumor were classified as luminal A, luminal-human epidermal growth factor receptor 2 (HER2), luminal B, triple negative, and HER2 identified by routine immunohistochemistry and histological grade. Cumulative incidence rates of overall survival (OS) for each affected site after metastatic relapse were estimated according to Kaplan-Meier method. Results: Median follow-up time for living patients was 113 months. A total of 370 patients experienced metastatic progression as first relapse event. Median duration of OS after initial metastatic relapse was 69 month in all subtypes. No difference was seen in OS among five subtypes after initial bone or brain relapse. Meanwhile, OS of luminal subtypes after initial other-site relapse was better than that of triple negative and HER2 subtypes (P = .003). Notably, OS rates of bone and non-bone/brain metastasis groups as initial relapse site were almost identical (P= .626). Conclusions: We find no difference in mortality after metastatic relapse between bone and other site except for brain metastasis as initial relapse in breast cancer patients following definitive radiotherapy in our cohort without primary metastatic setting. Careful consideration is needed for initial distant relapse regardless of which site is involved. However, prognosis of metastatic breast cancer after definitive radiotherapy is favorable based on real world data, attributable mainly to improved systemic therapy and modern multidisciplinary approach.
Phase I trial of 19-28z chimeric antigen receptor modified T cells (19-28z CAR-T) post-high dose therapy and autologous stem cell transplant (HDT-ASCT) for relapsed and refractory (rel/ref) aggressive B-cell non-Hodgkin lymphoma (B-NHL).
Authors: Craig Steven Sauter, Isabelle Riviere, Yvette Bernal, Xiuyan Wang, Terence Purdon, Sarah Yoo, Craig H. Moskowitz, Sergio Giralt, Matthew J. Matasar, Kevin Joseph Curran, Jae Hong Park, Michel Sadelain, Renier J. Brentjens
Journal: Journal of Clinical Oncology (2015)

8515 Background: HDT-ASCT is the standard of care for patients with rel/ref diffuse large B-cell lymphoma (DLBCL). Herein, we report safety data on the first 8 patients of our phase I clinical trial of 19-28z CAR-T post HDT-ASCT for poor-risk rel/ref aggressive B-NHL (NCT01840566). Methods: Eligibility for this study includes rel/ref aggressive B-NHL chemosensitive to salvage therapy with: 1) FDG-PET (+) following 2 cycles of salvage therapy or 2) bone marrow involvement of B-NHL. T cells were retroviral transduced with anti-CD19 scFV linked to CD28 and CD3ζ signaling domains. Patients underwent BEAM conditioned HDT-ASCT and 19-28z CAR-T were administered on days +2 and +3. Results: See table for patient characteristics and results. Seven patients were treated at dose level #1 (5 x106 19-28z CAR-T/kg) with one dose-limiting toxicity (DLT) of prolonged grade III-IV cytopenias and non-relapse mortality (NRM) of mucormycosis pneumonia. One patient treated at dose-level #2, 1 x107 CAR-T/kg, experienced a DLT related to severe cytokine-release syndrome (CRS) and fully recovered. Fifty percent of the patients experienced CRS effectively treated with tocilizumab +/- corticosteroids. All patients engrafted neutrophils post-HDT-ASCT. Five of eight remain alive and progression-free at the time of this analysis. Conclusions: This is the first study of 19-28z CAR-T cells following consolidative HDT-ASCT for poor-risk rel/ref aggressive B-NHL. The use of 19-28z CAR T cells is a promising approach in poor-risk PET+ B-NHL patients undergoing HDT-ASCT with manageable CRS. Clinical trial information: NCT01840566. Patient Age Disease Disease at HDT-ASCT Dose Level CRS Peak CRP (mg/dL) Status Post- HDT-ASCT 1 34 transformed follicular lymphoma (tFL) PET(+ )PR 1 Yes 27.3 CR/18 mo 2 68 DLBCL PET(+) PR 1 No 16.5 CR/17 mo 3 56 transformed marginal zone lymphoma PET(+) PR, bone marrow (BM) involved 1 No 17.6 CR/11 mo 4 59 tFL/double-hit (DHL) PET(+) PR 2 Yes 43.1 CR/10 mo 5 66 DLBCL PET(+) PR 1 No 5 CR/11mo 6 64 CD5+ DLBCL PET(+) PR 1 No 7.9 POD/6 mo 7 65 Burkitt lymphoma PET(+) PR BM involved 1 Yes 11.8 POD/2 mo 8 56 DLBCL/DHL PET (+) PR 1 Yes 18.1 NRM/d38
inv(16) and NPM1mut AMLs engraft human cytokine knock-in mice
Authors: Jana M. Ellegast, Philipp J. Rauch, Larisa V. Kovtonyuk, Rouven Müller, Ulrich Wagner, Yasuyuki Saito, Nicole Wildner-Verhey van Wijk, Christine Fritz, Anahita Rafiei, Veronika Lysenko, Ewa Dudkiewicz, Alexandre P. Theocharides, Davide Soldini, Jeroen S. Goede, Richard A. Flavell, Markus G. Manz
Journal: Blood (2016)
Discordant Interpretations of Breast Biopsy Specimens by Pathologists—Reply
Authors: Joann G. Elmore, Margaret S. Pepe, Donald L. Weaver
Journal: JAMA (2015)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Planar cell polarity genes Celsr1 and Vangl2 are necessary for kidney growth, differentiation, and rostrocaudal patterning
Authors: Hortensja Ł. Brzóska, Angela M. d’Esposito, Maria Kolatsi-Joannou, Vishal Patel, Peter Igarashi, Yunping Lei, Richard H. Finnell, Mark F. Lythgoe, Adrian S. Woolf, Eugenia Papakrivopoulou, David A. Long
Journal: Kidney International (2016)

The mammalian kidney contains nephrons comprising glomeruli and tubules joined to ureteric bud-derived collecting ducts. It has a characteristic bean-like shape, with near-complete rostrocaudal symmetry around the hilum. Here we show that Celsr1, a planar cell polarity (PCP) gene implicated in neural tube morphogenesis, is required for ureteric tree growth in early development and later in gestation prevents tubule overgrowth. We also found an interaction between Celsr1 and Vangl2 (another PCP gene) in ureteric tree growth, most marked in the caudal compartment of the kidneys from compound heterozygous mutant mice with a stunted rump. Furthermore, these genes together are required for the maturation of glomeruli. Interestingly, we demonstrated patients with CELSR1 mutations and spina bifida can have significant renal malformations. Thus, PCP genes are important in mammalian kidney development and have an unexpected role in rostrocaudal patterning during organogenesis.
Early oral exposure to house dust mite allergen through breast milk: A potential risk factor for allergic sensitization and respiratory allergies in children
Authors: Nour Baïz, Patricia Macchiaverni, Meri K. Tulic, Akila Rekima, Isabella Annesi-Maesano, Valérie Verhasselt, I. Annesi-Maesano, J.Y. Bernard, J. Botton, M.A. Charles, P. Dargent-Molina, B. de Lauzon-Guillain, P. Ducimetière, M. de Agostini, B. Foliguet, A. Forhan, X. Fritel, A. Germa, V. Goua, R. Hankard, B. Heude, M. Kaminski, B. Larroque, N. Lelong, J. Lepeule, G. Magnin, F. Pierre, L. Marchand, C. Nabet, R. Slama, M.J. Saurel-Cubizolles, M. Schweitzer, O. Thiebaugeorges
Journal: Journal of Allergy and Clinical Immunology (2016)
Keeping Kate Granger’s legacy alive
Authors: Narinder Kapur
Journal: BMJ (2016)

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 Keeping Kate Granger’s legacy alive Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
A phase I trial of MK-0752 in children with recurrent or refractory CNS malignancies: A Pediatric Brain Tumor Consortium study.
Authors: M. Fouladi, J. Olson, C. F. Stewart, M. Kocak, A. J. Gajjar, T. Demuth, S. Goldman, L. E. Kun, J. M. Boyett, R. J. Gilbertson
Journal: Journal of Clinical Oncology (2010)

9502 Background: The NOTCH pathway plays a central role in normal neural stem cell regulation and maintenance. Recent data indicate that most brain tumors including gliomas, medulloblastoma, and ependymoma are maintained by rare fractions of stem cell-like cancer cells. NOTCH signaling is important in medulloblastoma pathogenesis; NOTCH amplification has been identified in a subgroup of posterior fossa ependymomas, and high-levels of NOTCH ligand expression (Delta 1, Jagged 1 and 2) have been identified in high-grade gliomas. MK-0752 is an orally active inhibitor of gamma secretase which inhibits the cleavage of Notch with an IC50 of 55 nM. A phase I trial of MK0752 was conducted in children with recurrent or refractory CNS malignancies to estimate the maximum tolerated dose (MTD), dose limiting toxicities (DLT), and pharmacokinetics (PK). We also assessed expression of NOTCH and HES proteins in peripheral blood mononuclear cells (PBMCs) prior to and following treatment with MK-0752. Methods: MK0752 was administered once daily for 3 consecutive days of every 7 days at dose levels of (1) 200 mg/m2/dose and (2) 260 mg/m2/dose. A course was 28 days in duration. PK analysis was performed during the first course. Results: We enrolled 23 eligible patients: 10 males, median age 8.1 years (range 2.6-17.7) with diagnoses of brain stem glioma (n=6), ependymoma (n=8), medulloblastoma (n=2), PNET (n=2), GBM (n=2), ATRT (n=1), astrocytic glioma (n=1), and nonspecific malignant CNS neoplasm, (n=1).17 patients were fully evaluable for toxicity. No DLTs occurred in the 3 patients enrolled at 200 mg/m2/dose. At 260 mg/m2/dose, DLT occurred in 2 patients: ALT [n=2], AST ( n=2). There were no Grade 4 toxicities; non-dose limiting grade 3 toxicities included elevated hypokalemia and lymphopenia. The population pharmacokinetic values (%CV) were: apparent oral clearance, 0.444 (38%) L/hr/m2; apparent volume of distribution, 7.36 (24%) L/m2; and ka, 0.358 (99%) hr−1. Conclusions: MK 0752 is well-tolerated in children with recurrent CNS malignancies. The recommended phase II dose is 260 mg/m2/dose once daily, for 3 consecutive days of every 7 days. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Merck Merck
Association Between Distance From Home to Tobacco Outlet and Smoking Cessation and Relapse
Authors: Anna Pulakka, Jaana I. Halonen, Ichiro Kawachi, Jaana Pentti, Sari Stenholm, Markus Jokela, Ilkka Kaate, Markku Koskenvuo, Jussi Vahtera, Mika Kivimäki
Journal: JAMA Internal Medicine (2016)

<h3>Importance</h3> Reduced availability of tobacco outlets is hypothesized to reduce smoking, but longitudinal evidence on this issue is scarce. <h3>Objective</h3> To examine whether changes in distance from home to tobacco outlet are associated with changes in smoking behaviors. <h3>Design, Setting, and Participants</h3> The data from 2 prospective cohort studies included geocoded residential addresses, addresses of tobacco outlets, and responses to smoking surveys in 2008 and 2012 (the Finnish Public Sector [FPS] study, n = 53 755) or 2003 and 2012 (the Health and Social Support [HeSSup] study, n = 11 924). All participants were smokers or ex-smokers at baseline. We used logistic regression in between-individual analyses and conditional logistic regression in case-crossover design analyses to examine change in walking distance from home to the nearest tobacco outlet as a predictor of quitting smoking in smokers and smoking relapse in ex-smokers. Study-specific estimates were pooled using fixed-effect meta-analysis. <h3>Exposures</h3> Walking distance from home to the nearest tobacco outlet. <h3>Main Outcomes and Measures</h3> Quitting smoking and smoking relapse as indicated by self-reported current and previous smoking at baseline and follow-up. <h3>Results</h3> Overall, 20 729 men and women (age range 18-75 years) were recruited. Of the 6259 and 2090 baseline current smokers, 1744 (28%) and 818 (39%) quit, and of the 8959 and 3421 baseline ex-smokers, 617 (7%) and 205 (6%) relapsed in the FPS and HeSSup studies, respectively. Among the baseline smokers, a 500-m increase in distance from home to the nearest tobacco outlet was associated with a 16% increase in odds of quitting smoking in the between-individual analysis (pooled odds ratio, 1.16; 95% CI, 1.05-1.28) and 57% increase in within-individual analysis (pooled odds ratio, 1.57; 95% CI, 1.32-1.86), after adjusting for changes in self-reported marital and working status, substantial worsening of financial situation, illness in the family, and own health status. Increase in distance to the nearest tobacco outlet was not associated with smoking relapse among the ex-smokers. <h3>Conclusions and Relevance</h3> These data suggest that increase in distance from home to the nearest tobacco outlet may increase quitting among smokers. No effect of change in distance on relapse in ex-smokers was observed.