tbuckley/cabot-search huggingface dataset:
Multicenter phase I clinical trial of daily and weekly RAD001 in combination with weekly paclitaxel and trastuzumab in patients with HER2-overexpressing metastatic breast cancer with prior resistance to trastuzumab
Authors: F. André, M. Campone, S. A. Hurvitz, L. Vittori, I. Pylvaenaeinen, T. Sahmoud, R. M. O'Regan
Journal: Journal of Clinical Oncology (2008)

1003 Background: Loss of PTEN and AKT/mTOR activation have been reported to mediate resistance to trastuzumab. RAD001 (everolimus) is an oral inhibitor of the mTOR serine-threonine kinase, a downstream component of the PI3K/AKT signaling pathway. Preclinical models demonstrated that RAD001 enhances the efficacy of trastuzumab. Based on these data, we hypothesized that RAD001 could reverse resistance to trastuzumab in patients with HER2-overexpressing breast cancer. This phase I trial addresses the safety and efficacy of a combination between paclitaxel, trastuzumab and RAD001 in patients previously treated with trastuzumab and taxanes. Methods: Paclitaxel was administered at a dose of 80 mg/m2, IV over 60 min on days 1, 8 and 15 q4w. Trastuzumab 4 mg/kg loading dose was administered IV over 90 min on Day 1 (if pt was not already receiving trastuzumab), followed by weekly 2 mg/kg IV over 30 min. In the daily RAD001 arm, 2 cohorts were planned (5 and 10mg) and in the weekly RAD001 arm, 3 cohorts were planned (30, 50 and 70mg). Treatment continues until progression or unacceptable toxicity. Results: As of January 8, 2008, 13 heavily pretreated pts were enrolled; 6 pts to the 5mg daily and 7 pts to the 30mg weekly cohorts. All pts were resistant to trastuzumab and, except for one pt who progressed after bevacizumab-trastuzumab combination, all pts received prior taxane. Median number of prior chemotherapy regimens was 4 (range: 3–15). No DLT has been observed to date. Preliminary efficacy: Overall 7 patients were evaluated. All 3 pts in the daily arm had a PR. Of the 4 pts evaluated in the weekly arm, 2 pts had PR, 1 minor regression (-28% + PR of brain metastasis) and 1 SD. Eleven pts remain on treatment and none have progressed to date. The most commonly reported Aes are neutropenia and stomatitis. Recruitment continues. Sixty pts are planned. Conclusions: Initial findings show that RAD001 is well tolerated in combination with weekly paclitaxel and trastuzumab. The preliminary analysis of efficacy shows a high rate of unexpected tumor responses in a population of patients pretreated with trastuzumab and taxanes. Mature results and data on biomarkers will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Pharmaceuticals Novartis Pharmaceuticals Novartis Pharmaceuticals Genentech, Novartis Pharmaceuticals
Ultraviolet exposure from indoor tanning devices: a systematic review
Authors: L.T.N. Nilsen, M. Hannevik, M.B. Veierød
Journal: British Journal of Dermatology (2016)

Use of indoor tanning devices increases the risk of cutaneous melanoma and nonmelanoma skin cancer. Indoor tanning devices have become important sources of ultraviolet (UV) exposure, both UVB and UVA. This systematic review assessed UV measurements performed in indoor tanning devices related to irradiance level, wavelength distribution and similarities to natural sun. The study was performed in accordance with the MOOSE and PRISMA guidelines. We searched PubMed, Embase and Web of Science from inception to May 2015, and also examined the reference lists of the retrieved studies. Eighteen studies were included. Twelve studies examined the erythema-weighted UV irradiances of indoor tanning devices, 11 studies examined UVB and 13 studies studied UVA. Compliance with irradiance limits was reported in nine studies. Erythema-weighted irradiances were highest in the most recent studies. Most studies had mean values higher than from natural sun and with large variations between devices. All studies except two had mean unweighted UVB irradiances lower than from natural summer sun (at latitudes from 37°S to 35°N), while mean unweighted UVA irradiances were, with one exception, substantially higher than from natural sun. The high values of UVA exposure from modern tanning devices are alarming in light of the increased focus on UVA irradiance as a carcinogen, and as UVA exposure confers little protection against subsequent UV exposure.
A Case of Cushing’s Syndrome with Multiple Adrenocortical Adenomas Composed of Compact Cells and Clear Cells
Authors: Masahiro Asakawa, Takanobu Yoshimoto, Mitsutane Ota, Mitsuyuki Numasawa, Yuriko Sasahara, Takato Takeuchi, Yujiro Nakano, Norihiko Oohara, Masanori Murakami, Ryotaro Bouchi, Isao Minami, Kyoichiro Tsuchiya, Koshi Hashimoto, Hajime Izumiyama, Naoko Kawamura, Kazunori Kihara, Mariko Negi, Takumi Akashi, Yoshinobu Eishi, Hironobu Sasano, Yoshihiro Ogawa
Journal: Endocrine Pathology (2016)
Abstract 18763: Characteristics and Anti-Atherosclerotic Properties of (-)-Epigallocatechin Gallate Loaded Lipid Nanoparticles in vitro
Authors: Jia Zhang, Shufang Nie, Shu Wang
Journal: Circulation (2013)

BACKGROUND: Atherosclerotic cardiovascular disease is the leading cause of death and disability in the United States and other developed countries. Macrophages are major cells responsible for atherosclerotic lesion development. (-)-Epigallocatechin gallate (EGCG), a natural compound found in green tea, is valuable to prevent atherosclerosis. But EGCG’s low level of stability, bioavailability and targeting specificity in the body makes administering it in therapeutic doses unrealistic. METHODS AND RESULTS: We have successfully synthesized EGCG loaded lipid nanoparticles (ENP), which are composed of biocompatible and biodegradable lipids, surfactants and EGCG. The size of nanoparticles was less than 100 nm in diameter measured using a dynamic light scattering method and a transmission electron microscope. The encapsulation efficiency was around 90%. As compared to native EGCG, ENP significantly increased EGCG stability and macrophage EGCG content at 37°C. Remarkably, ENP significantly decreased human macrophage cholesteryl ester content measured using a high performance liquid chromatography (HPLC) system. ENP also significantly lowered both gene expression and protein secretion of monocyte chemoattractant protein 1 (MCP-1) in/from human macrophages measured using real-time PCR and ELISA assays, respectively. We also incorporated target ligands on the surface of ENP. The target ligands further increased the binding and uptake of those nanoparticles in human macrophages. CONCLUSIONS: ENP significantly enhanced EGCG stability, increased its cellular bioavailability, decreased cholesteryl ester content and MCP-1 expression in macrophages. Target ligands increased the target specificity of those nanoparticles to human macrophages. ENP with target ligands have a potential for preventing atherosclerotic lesion development through enhancing EGCG uptake by macrophages and decreasing macrophage cholesterol accumulation and inflammatory responses. Funding support: The project described was supported by Grant Number R15AT007013 from NIH NCCAM.
A Point Mutation Thr799Met on the 2 Integrin Leads to the Formation of New Human Platelet Alloantigen Sita and Affects Collagen-Induced Aggregation
Authors: Sentot Santoso, Julia Amrhein, Heiko A. Hofmann, Ulrich J.H. Sachs, Matthias M. Walka, Hartmut Kroll, Volker Kiefel
Journal: Blood (1999)
Targeting BET proteins in melanoma: A novel treatment approach.
Authors: Luca Paoluzzi, Miguel F. Segura, Barbara Fontanals-Cirera, Avital Gaziel-Sovran, Maria V Guijarro, Douglas Hanniford, Pilar Gonzales-Gomez, Weijia Zhang, Guantao Zhang, Farbod Darvishian, Michael Ohlmeyer, Iman Osman, Ming-Ming Zhou, Eva Hernando
Journal: Journal of Clinical Oncology (2013)

9091 Background: Manipulation of key epigenetic regulators in melanoma proliferation is emerging as a new therapeutic strategy. Bromodomain-containing proteins such as the extraterminal domain (BET) family are components of transcription factor complexes and determinants of epigenetic memory. We investigated the expression of BRD4, a BET family member in melanoma cell lines and tissues, and the effects of its inhibition with the small molecule compounds MS436 and MS417 in in vitro and in vivo models of melanoma. Methods: BRD2 and BRD4 expression were analyzed by immunohistochemistry. We tested the effects of pharmacological or RNAi-mediated inhibition of BRD4 in melanoma cells using crystal violet-based assays for proliferation/colony formation and flow-cytometry for cell cycle analysis. The molecular effects of BRD4 suppression were examined using RNA sequencing, Real-Time quantitative PCR and western blots for p27, p21, MYC, ERK1 and SKP2. In the in vivo xenograft experiments NOD/SCID/IL2γR-/-mice were injected with melanoma cells and treated with MS417. Statistical significance was determined by unpaired t-test (GraphPad). Results: BRD4 was found significantly upregulated in primary and metastatic melanoma tissues compared to melanocytes and nevi (p&lt;0.001). Treatment with BET inhibitors impaired melanoma cell proliferation in vitro and tumor growth and metastatic behavior in vivo, effects that were mostly recapitulated by individual silencing of BRD4. Rapidly after BET displacement, key cell cycle genes (SKP2, ERK1 and c-MYC) were downregulated concomitantly with the accumulation of CDK inhibitors (p21, p27), followed by melanoma cell cycle arrest. BET inhibitor efficacy was not influenced by BRAF or NRAS mutational status. Conclusions: Our results demonstrate for the first time a role for BRD4 in melanoma maintenance and support the role of BET proteins as novel targets in melanoma. Further investigation in the clinical setting is warranted.
MPs criticise government for complacency over GP crisis
Authors: Gareth Iacobucci
Journal: BMJ (2016)

MPs have criticised the Department of Health for England and NHS England for being “complacent” about the rising levels of demand in general practice over the past decade and for failing to act quickly enough to tackle staffing shortages.

Demand for general practice services had outstripped capacity throughout the past 10 years, and national leaders had been too slow to realise the severity of the situation, said the House of Commons Public Accounts Committee in a new report.1

The report urged government bodies to report back to the committee by December 2016 setting out how they plan to …
Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann–Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease
Authors: Tobias Schwerd, Sumeet Pandey, Huei-Ting Yang, Katrin Bagola, Elisabeth Jameson, Jonathan Jung, Robin H Lachmann, Neil Shah, Smita Y Patel, Claire Booth, Heiko Runz, Gesche Düker, Ruth Bettels, Marianne Rohrbach, Subra Kugathasan, Helen Chapel, Satish Keshav, Abdul Elkadri, Nick Platt, Alexio M Muise, Sibylle Koletzko, Ramnik J Xavier, Thorsten Marquardt, Fiona Powrie, James E Wraith, Mads Gyrd-Hansen, Frances M Platt, Holm H Uhlig
Journal: Gut (2016)

<h3>Objective</h3> Patients with Niemann–Pick disease type C1 (NPC1), a lysosomal lipid storage disorder that causes neurodegeneration and liver damage, can present with IBD, but neither the significance nor the functional mechanism of this association is clear. We studied bacterial handling and antibacterial autophagy in patients with NPC1. <h3>Design</h3> We characterised intestinal inflammation in 14 patients with NPC1 who developed IBD. We investigated bacterial handling and cytokine production of NPC1 monocytes or macrophages in vitro and compared NPC1-associated functional defects to those caused by IBD-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) variants or mutations in X-linked inhibitor of apoptosis (XIAP). <h3>Results</h3> Patients with the lysosomal lipid storage disorder NPC1 have increased susceptibility to early-onset fistulising colitis with granuloma formation, reminiscent of Crohn9s disease (CD). Mutations in NPC1 cause impaired autophagy due to defective autophagosome function that abolishes NOD2-mediated bacterial handling in vitro similar to variants in NOD2 or XIAP deficiency. In contrast to genetic NOD2 and XIAP variants, NPC1 mutations do not impair NOD2-receptor-interacting kinase 2 (RIPK2)-XIAP-dependent cytokine production. Pharmacological activation of autophagy can rescue bacterial clearance in macrophages in vitro by increasing the autophagic flux and bypassing defects in NPC1. <h3>Conclusions</h3> NPC1 confers increased risk of early-onset severe CD. Our data support the concept that genetic defects at different checkpoints of selective autophagy cause a shared outcome of CD-like immunopathology linking monogenic and polygenic forms of IBD. Muramyl dipeptide-driven cytokine responses and antibacterial autophagy induction are parallel and independent signalling cascades downstream of the NOD2-RIPK2-XIAP complex.
Cord blood leptin levels in relation to child growth trajectories
Authors: Polyxeni Karakosta, Theano Roumeliotaki, Georgia Chalkiadaki, Katerina Sarri, Maria Vassilaki, Maria Venihaki, Niki Malliaraki, Marilena Kampa, Elias Castanas, Manolis Kogevinas, Christos Mantzoros, Leda Chatzi
Journal: Metabolism (2016)
A Cytomegalovirus Peptide-Specific Antibody Alters Natural Killer Cell Homeostasis and Is Shared in Several Autoimmune Diseases
Authors: Yu Liu, Rong Mu, Ya-Ping Gao, Jie Dong, Lei Zhu, Yuyuan Ma, Yu-Hui Li, He-Qiu Zhang, Dong Han, Yu Zhang, Iain B. McInnes, Jingang Zhang, Beifen Shen, Guang Yang, Zhan-Guo Li
Journal: Cell Host & Microbe (2016)
Safety and Efficacy of Ruxolitinib in Patients with Low Platelets Enrolled in a Phase 3b Expanded-Access Study in Myelofibrosis (MF)
Authors: Martin Griesshammer, Alessandro M. Vannucchi, Philipp le Coutre, Renato S Tavares, Haifa Kathrin Al-Ali, Pia Raanani, Vikas Gupta, Lynda M Foltz, Pilar Giraldo, Catherine Bouard, Julian Perez Ronco, Jagannath Ghosh, Bruno Martino
Journal: Blood (2014)
NCCN Work Group Report: Emerging Issues in Tissue Allocation
Authors: Jessica K. DeMartino
Journal: Journal of the National Comprehensive Cancer Network (2016)

Expanding research interests in molecular profiling over the past several years have led researchers in academia and pharmaceutical and biotechnology companies to significantly increase their need for access to tissue specimens collected through clinical care and clinical trials. As a result, tissue allocation has become a growing issue for many clinical and translational investigators. High-quality biospecimens are needed by all stakeholders in order to have scientifically accurate studies and results. At the center of the process are the patients, who have increasingly become active partners in the clinical research enterprise as individuals and through highly sophisticated patient advocacy organizations. All stakeholders must recognize that human specimens, including tissue, represent a valuable and unique resource that must have proper acquisition, handling, custodianship, and consent for use in accordance with best practices for biospecimen resources.
A phase I/II study of combination therapy of S-1 and irinotecan in patients with previously untreated metastatic or recurrent colorectal cancer
Authors: Y. Choi, T. Kim, S. Lee, J. Lee, H. Chang, H. Kim, J. Shin, J. Lee, Y. Kang
Journal: Journal of Clinical Oncology (2009)

e15023 Background: To investigate S-1 and irinotecan (CPT-11) combination as an alternative to infusional 5- fluorouracil/leucovorin plus CPT-11, we performed a phase I/II trial to determine maximum tolerated dose (MTD), efficacy and toxicity in metastatic or recurrent colorectal cancer. In addition, we evaluated the association between genotypes of candidate genes and phenotypes. Methods: S-1 was administered orally at a dose of 70 mg/m 2 (level I-III) or 80 (IV and V) from day 1 to 14. CPT-11 was given i.v. on day 1, stepping up to 175 (level I), 200 (II), 225 (III and IV) or 250 (V) mg/m 2 . The treatment was repeated every 3 weeks. The association of the UGT1A1 genotypes (*6, *28, and *60) and CYP2A6 genotypes (*4, *7, and *9) with toxicities or efficacy were analyzed in patients who participated in phase II portion. Results: Twenty-three patients entered the phase I and 30 enrolled in phase II study. The MTD of S-1 and CPT-11 was considered to be 80 mg/m 2 and 250 mg/m 2 , respectively. The dose-limiting toxicities (DLTs) were diarrhea and neutropenia. The recommended dose (RD) was determined at a S-1 dose of 80 mg/m 2 and a CPT- 11 dose of 225 mg/m 2 . The overall response rate was 66.7% (95% CI, 48.7–84.6) at the RD level. Median time to progression was 7.6 months (95 % CI, 5.7–9.5). Median survival time was not reached. Grade3–4 neutropenia was observed in 53.4% of the patients. Grade 3–4 nonhematologic toxicities were diarrhea (16.7%) and asthenia (6.7%). The frequencies of UGT1A1*60, *28, and *6 allele were 25.8%, 10.3%, and 15.5%, respectively. Homozygous for *28 or *6 were not observed. All three double heterozygous for *28 and *6 experienced grade 3–4 neutropenia. The allele frequencies of CYP2A6*4, *7, and *9 were 15.5%, 8.6%, and 29.3%, respectively. There were no association between CYP2A6 genotypes and response rates or toxicities. Conclusions: The combination of S-1 and CPT-11 was effective and had manageable toxicities in patients with metastatic or recurrent colorectal cancer. [Table: see text] No significant financial relationships to disclose.
Hematopoietic stem cell transplantation in chronic lymphocytic leukemia: A report of 12 patients from a single institution
Authors: J. Esteve, N. Villamor, D. Colomer, F. Bosch, A. López-Guillermo, M. Rovira, A. Urbano-Ispizua, J. Sierra, E. Carreras, E. Montserrat
Journal: Annals of Oncology (1998)
Discretionary Interpretations of Accountable Care Organization Data—Reply
Authors: Aaron L. Schwartz, Bruce E. Landon, J. Michael McWilliams
Journal: JAMA Internal Medicine (2016)

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 Internal Medicine 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 Internal Medicine journal
Enjoying Opera, Dermatology Style
Authors: Abigail L. Alexander, Leonard J. Hoenig
Journal: JAMA Dermatology (2016)

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 Dermatology 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 Dermatology journal
Junior doctors' hours
Authors: C. Wong
Journal: BMJ (1995)

EDITOR,--I am sick to death of hearing about reducing hours, the intensity of work, and periods of rest. I cannot see how the Junior Doctors Committee has the nerve to recommend, in its annual report for 1995, eight hours of rest during night duty on an on call rota.1 I would then get more sleep while on call than when I am at home and, better still, would be paid for it.

All the talk about intensity of …
Abstract 16928: Critical Role of Endoplasmic Reticulum Stress-Regulated CXCL10/CXCR3 Axis in the Ischemia-Reperfusion Injured Tissue
Authors: Yonju Ha, Hua Liu, Zhimin Xu, Harumasa Yokota, Tahira Lemtalsi, Sylvia B Smith, Robert W Caldwell, Massoud Motamedi, Ruth B Caldwell, Wenbo Zhang
Journal: Circulation (2013)

Ischemic stroke is caused by neurologic dysfunction in the brain, spinal cord and retina by blocking blood flow. Mechanisms of neuronal injury caused by ischemia-reperfusion (IR) remain to be defin...
Prolonged Inhibition of Mouse Epidermal DNA Synthesis by Dexamethasone&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: T J Slaga, S Thompson, E A Smuckler
Journal: JNCI Journal of the National Cancer Institute (1975)

The effect of dexamethasone, an anti-inflammatory agent that inhibits skin carcinogenesis, on DNA, RNA, and protein synthesis in mouse epidermis was investigated. Within 1 hour after the topical application of 75 mug dexamethasone to the skin of mice, epidermal DNA synthesis was inhibited drastically and lasted for approximately 5 days, followed by a biphasic stimulation at 7 and 10 days after treatment. Histologically, the skin after dexamethasone treatment revealed only subtle quantitative changes. The dermis was not altered. The epidermal thickness was unchanged, but the nuclei of the epidermal cells were more densely stained and the chromatin was more densely clumped. These changes were present by 12 hours and persisted for 10 days. Both epidermal RNA and protein syntheses were stimulated early, reached a peak of around 180% of controls at 1 hour, but returned to control levels by 3 hours. They were slightly inhibited between 3 and 12 hours after treatment and then returned to control levels. This prolonged inhibition of DNA synthesis by dexamethasone may be related to its anticarcinogenic effect.
A Mechanistic Role For Mir-126, a Hematopoietic Stem Cell Microrna, In Acute Leukemias
Authors: Alice Giustacchini, Silvia Nucera, Eric R. Lechman, Cristiana Fanciullo, Francesco E Boccalatte, Tiziana Plati, Anna Ranghetti, Luca Vago, Massimo Bernardi, Maurilio Ponzoni, John E. Dick, Luigi Naldini, Bernhard Gentner
Journal: Blood (2013)
A Long-Term Phenotype Analysis Of 51 Patients With Upshaw–Schulman Syndrome In Japan, With Special References To Pregnancy and Renal Failure That Requires Hemodialysis
Authors: Yoshihiro Fujimura, Yumi Yoshii, Masanori Matsumoto, Ayami Isonishi, Masaki Hayakawa, Yoko Yoshida, Hideo Yagi, Koichi Kokame, Toshiyuki Miyata
Journal: Blood (2013)
Cultural evolution need not imply group selection
Authors: Dorsa Amir, Matthew R Jordan, David G Rand
Journal: Behavioral and Brain Sciences (2016)

Abstract Richerson et al. make a compelling case for cultural evolution. In focusing on cultural group selection, however, they neglect important individual-level accounts of cultural evolution. While scientific discourse typically links cultural evolution to group selection and genetic evolution to individual selection, this association is due to historical accident only. We thus call for more consideration of individual-level cultural evolution.