tbuckley/cabot-search huggingface dataset:
New opportunities and challenges in the assessment of drugs for atopic diseases
Authors: T. Bieber, S. Vieths, K. Broich
Journal: Allergy (2016)

Abstract Atopic conditions (atopic dermatitis, rhinitis, and asthma) belong to the most common noncommunicable diseases and are driven by chronic inflammatory reactions. They have a strong impact on the quality of life and represent a substantial and growing socio‐economic burden. Interestingly, there is an increasing interest in the development of new therapeutic options with a number of biologics and small molecules targeting potential key mechanisms in atopic conditions. However, besides the safety issue, most of the new active substances are still evaluated according to the traditional efficacy paradigm focusing on the success in treating exacerbations and flares. Instead, the future approaches in drug development and assessment should rather concentrate on the long‐term control of these diseases and consider their potential as disease‐modifying strategies in the era of precision medicine. To reach this goal, a number of unsolved issues have to be addressed and consensually accepted by the stakeholders in this field. Thus, a successful and rapid development of new treatments requests a paradigm shift and a new way of thinking in the mind of physicians, pharmaceutical industry, regulators, and HTA s. This seems mandatory in order to optimize drug development and to facilitate the accessibility of new therapies to the growing population of patients suffering from atopic conditions on a global level.
National Institutes of Health Pathways to Prevention Workshop: Advancing Research to Prevent Youth Suicide
Authors: Todd D. Little, Kathleen M. Roche, Sy-Miin Chow, Anna P. Schenck, Leslie-Ann Byam
Journal: Annals of Internal Medicine (2016)

The National Institutes of Health (NIH) Pathways to Prevention Workshop "Advancing Research to Prevent Youth Suicide" was cosponsored by the NIH Office of Disease Prevention, National Institute of Mental Health, National Institute on Drug Abuse, and National Center for Complementary and Integrative Health. A multidisciplinary working group developed the agenda, and an evidence-based practice center prepared an evidence report that addressed data systems relevant to suicide prevention efforts through a contract with the Agency for Healthcare Research and Quality. During the workshop, experts discussed the evidence and participants commented during open forums. After considering the data from the evidence report, expert presentations, and public comments, an independent panel prepared a draft report that was posted on the NIH Office of Disease Prevention Web site for 5 weeks for public comment. This abridged version of the final report provides a road map for optimizing youth suicide prevention efforts by highlighting strategies for guiding the next decade of research in this area. These strategies include recommendations for improving data systems, enhancing data collection and analysis methods, and strengthening the research and practice community.
The relationship of K-ras mutations and EGFR gene copy number to outcome in patients treated with Erlotinib on National Cancer Institute of Canada Clinical Trials Group trial study PA.3
Authors: M. J. Moore, G. da Cunha Santos, S. Kamel-Reid, K. Chin, D. Tu, W. Parulekar, O. Ludkovski, J. Squire, F. Richardson, M. Tsao
Journal: Journal of Clinical Oncology (2007)

4521 Background: The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) PA.3 study compared treatment with the EGFR tyrosine kinase inhibitor erlotinib to placebo in patients with advanced stage pancreatic carcinoma who were receiving gemcitabine. This study demonstrated a significant advantage in survival [HR=0.82; P&lt;0.04] and in progression free survival [HR=0.77; P&lt;0.004] for patients who received erlotinib [Moore MJ et al, J Clin Oncol 2007]. While high-level expression of EGFR is common in pancreatic cancer, EGFR protein expression level as evaluated by immunohistochemistry did not predict which patients might benefit from erlotinib. In non- small cell lung cancer (NSCLC) where erlotinib has shown a survival benefit; the use of EGFR copy number measured by FISH is a better predictive factor for benefit, and patients whose tumor had a K-ras mutation do not respond nor benefit. Methods: The NCIC-CTG PA.3 trial had a sample size of 569 and NCIC.CTG has collected 280 archival formalin-fixed and paraffin embedded tumor biopsy or primary resection specimens from patients randomized on study. Many were fine needle aspirates and a total of 181 had sufficient tissue to allow molecular analysis. We performed a K-ras mutation analysis by PCR of exon 2 followed by sequencing, with negative results being validated by DHPLC. EGFR gene copy number was analysed by fluorescent in situ hybridization. Both methods were performed on all tumor samples adequate for analysis. Results: Overall 146 cases were suitable for K-ras mutation analysis and preliminary results have identified K-ras mutation in 90 patients [76%] and wild type KRAS in 29 patients; the remainder are pending. A total of 118 cases are suitable for EGFR FISH analysis, results have been obtained in 73 patients, and the remaining cases are pending. The correlations between K-ras mutational status and EGFR copy number, and outcomes [survival and disease control] in patients randomized to both erlotinib and placebo will be presented. [Table: see text]
Attenuation of carotid neointimal formation after direct delivery of a recombinant adenovirus expressing glucagon-like peptide-1 in diabetic rats
Authors: Soo Lim, Gha Young Lee, Ho Seon Park, Dong-Hwa Lee, Oh Tae Jung, Kim Kyoung Min, Young-Bum Kim, Hee-Sook Jun, Jang Hak Chul, Kyong Soo Park
Journal: Cardiovascular Research (2016)

Enhancement of glucagon-like peptide-1 (GLP-1) reduces glucose levels and preserves pancreatic β-cell function, but its effect against restenosis is unknown.We investigated the effect of subcutaneous injection of exenatide or local delivery of a recombinant adenovirus expressing GLP-1 (rAd-GLP-1) into carotid artery, in reducing the occurrence of restenosis following balloon injury. As a control, we inserted β-galactosidase cDNA in the same vector (rAd-βGAL). Otsuka Long-Evans Tokushima rats were assigned to three groups (n = 12 each): (1) normal saline plus rAd-βGAL delivery (NS + rAd-βGAL), (2) exenatide plus rAd-βGAL delivery (Exenatide + rAd-βGAL), and (3) normal saline plus rAd-GLP-1 delivery (NS + rAd-GLP-1). Normal saline or exenatide were administered subcutaneously from 1 week before to 2 weeks after carotid injury. After 3 weeks, the NS + rAd-βGAL group showed the highest intima-media ratio (IMR; 3.73 ± 0.90), the exenatide + rAd-βGAL treatment was the next highest (2.80 ± 0.51), and NS + rAd-GLP-1 treatment showed the lowest IMR (1.58 ± 0.48, P < 0.05 vs. others). The proliferation and migration of vascular smooth muscle cells and monocyte adhesion were decreased significantly after rAd-GLP-1 treatment, showing the same overall patterns as the IMR. In injured vessels, the apoptosis was greater and MMP2 expression was less in the NS + rAd-GLP-1 than in the exenatide or rAd-βGAL groups. In vitro expressions of matrix metalloproteinases-2 and monocyte chemoattractant protein-1 and nuclear factor-kappa-B-p65 translocation were decreased more in the NS + rAd-GLP-1 group than in the other two groups (all P < 0.05).Direct GLP-1 overexpression showed better protection against restenosis after balloon injury via suppression of vascular smooth muscle cell migration, increased apoptosis, and decreased inflammatory processes than systemic exenatide treatment. This has potential therapeutic implications for treating macrovascular complications in diabetes.
Electrophilic nitro-fatty acids suppress allergic contact dermatitis in mice
Authors: A. R. Mathers, C. D. Carey, M. E. Killeen, J. A. Diaz-Perez, S. R. Salvatore, F. J. Schopfer, B. A. Freeman, L. D. Falo
Journal: Allergy (2016)

Reactions between nitric oxide (NO), nitrite (NO2-), and unsaturated fatty acids give rise to electrophilic nitro-fatty acids (NO2 -FAs), such as nitro oleic acid (OA-NO2 ) and nitro linoleic acid (LNO2 ). Endogenous electrophilic fatty acids (EFAs) mediate anti-inflammatory responses by modulating metabolic and inflammatory signal transduction reactions. Hence, there is considerable interest in employing NO2 -FAs and other EFAs for the prevention and treatment of inflammatory disorders. Thus, we sought to determine whether OA-NO2 , an exemplary nitro-fatty acid, has the capacity to inhibit cutaneous inflammation.We evaluated the effect of OA-NO2 on allergic contact dermatitis (ACD) using an established model of contact hypersensitivity in C57Bl/6 mice utilizing 2,4-dinitrofluorobenzene as the hapten.We found that subcutaneous (SC) OA-NO2 injections administered 18 h prior to sensitization and elicitation suppresses ACD in both preventative and therapeutic models. In vivo SC OA-NO2 significantly inhibits pathways that lead to inflammatory cell infiltration and the production of inflammatory cytokines in the skin. Moreover, OA-NO2 is capable of enhancing regulatory T-cell activity. Thus, OA-NO2 treatment results in anti-inflammatory effects capable of inhibiting ACD by inducing immunosuppressive responses.Overall, these results support the development of OA-NO2 as a promising therapeutic for ACD and provides new insights into the role of electrophilic fatty acids in the control of cutaneous immune responses potentially relevant to a broad range of allergic and inflammatory skin diseases.
Pharmacogenomics of Drug Metabolizing Enzymes and Transporters: Relevance to Precision Medicine
Authors: Shabbir Ahmed, Zhan Zhou, Jie Zhou, Shu-Qing Chen
Journal: Genomics Proteomics & Bioinformatics (2016)

Abstract The interindividual genetic variations in drug metabolizing enzymes and transporters influence the efficacy and toxicity of numerous drugs. As a fundamental element in precision medicine, pharmacogenomics, the study of responses of individuals to medication based on their genomic information, enables the evaluation of some specific genetic variants responsible for an individual’s particular drug response. In this article, we review the contributions of genetic polymorphisms to major individual variations in drug pharmacotherapy, focusing specifically on the pharmacogenomics of phase-I drug metabolizing enzymes and transporters. Substantial frequency differences in key variants of drug metabolizing enzymes and transporters, as well as their possible functional consequences, have also been discussed across geographic regions. The current effort illustrates the common presence of variability in drug responses among individuals and across all geographic regions. This information will aid health-care professionals in prescribing the most appropriate treatment aimed at achieving the best possible beneficial outcomes while avoiding unwanted effects for a particular patient.
Risk factors for central nervous system (CNS) metastases in patients with stage I-III breast cancer.
Authors: S. P. Neciosup, H. L. Gomez, W. R. Cruz, F. F. Doimi, J. A. Pinto, J. M. Cotrina, J. F. Suazo, V. E. Carlos, L. Mauricio, C. Vallejos Sologuren
Journal: Journal of Clinical Oncology (2010)

1063 Background: Some subpopulations of breast cancer patients have an increased risk of developing CNS metastases. The aim of this study is to identify risk factors for developing CNS metastases in stage I-III breast cancer patients. Methods: A retrospective review of 1,232 stage I-III breast cancer patients who had undergone chemotherapy, surgery, and/or radiotherapy, was performed. Estrogen/progesterone receptor (ER, PR) and HER2 status was determined by immunohistochemistry. The endpoint was CNS metastases-free survival. Tumor phenotypes were classified as luminal A (ER+ and/or PR+, HER2-); luminal B (ER+ and/or PR+, HER2+); triple- negative (ER-, PR-, HER2-); HER2/neu (ER-, PR-, HER2+). The association between histologic features and occurrence of CNS metastases was evaluated with univariate and multivariate analyses. Results: Median follow-up was 7.6 years, 416 (34%) patients had local, regional, or distant metastatic disease, 62 (5%) of whom had CNS metastases at any time before last follow-up, and 36 (39%) patients had CNS metastases as site of first recurrence. Comparison of median time to diagnosis of CNS metastases showed significant differences by molecular subtype (p=0.04). Triple-negative and HER2 subtypes had the shortest time to recurrence (21.9 and 29.7 months, respectively) versus luminal A and B subtypes (48.7 and 30.4 months, respectively). Main univariate predictive factors for CNS recurrence were: negative hormone receptor (7.8% of CNS metastases), positive nodal status (8.4% of CNS metastases >3 N+), molecular subtype HER2 (8.2%), p<0.001 for all. Main multivariate predictive factor was molecular subtype (p<0.001), using luminal A as reference, other molecular subtypes were expressed by hazard ratios (HR); luminal B (HR=3.4, 95%CI; 1.6 – 7.2), triple-negative (HR=4.0, 95%CI; 1.9–8.4), HER2 (HR=4.3, 95%CI; 2.0–9.1). Conclusions: Molecular subtype is the strongest risk factor for developing CNS metastases in stage I-III breast cancer. Time to diagnosis of CNS metastases Molecular subtype N N pt CNS metastases Median time (mo) P (Kruskal Wallis) Luminal A 577 12 (2.1%) 48.3 0.04 Luminal B 207 15 (7.2%) 30.4 Triple-negative 254 19 (7.5%) 21.9 HER2 194 16 (8.2%) 29.7 No significant financial relationships to disclose.
Assessment of prognosis in hepatocellular carcinoma (HCC) using biomarkers and serum measurements.
Authors: Mabel Joey Teng, Ravindhi Lakmalee Nathavitharana, Richard Fox, Sarah Berhane, Anna Skowronska, Philip James Johnson
Journal: Journal of Clinical Oncology (2013)

e15093 Background: Factors that influence prognosis in HCC are well-recognised. They include tumour size and number, the severity of liver dysfunction and the symptomology. Several staging systems combining a number of these factors offer an estimate of prognosis. Some concerned that these staging systems encompass factors that are inherently subjective, e.g. the extent of HCC in CLIP or the use of performance status in BCLC. This have led to the development BALAD score by Toyoda et al, using serum Bilirubin and Albumin and three biomarkers: alpha-fetoprotein-L3 (L3), Alpha-fetoprotein (AFP) and Des-gamma-carboxy prothrombin (DCP). This system was developed in a Japanese population which has mainly HCV-related HCC. Our aim was to develop an objective staging system using the three biomarkers for a western population and compared it to BALAD to assess its performance. Methods: 317 subjects with HCC were recruited from Birmingham, UK between 2007 and 2011. Blood samples were collected at the time of diagnosis. Liver, renal functions plus AFP, L3 and DCP were measured. L3 and DCP were measured by microchip capillary electrophoresis and liquid-phase binding assay on a uTASWako i30 auto analyzer (Wako Pure Chemical Industries Ltd, Japan). Results: Univariable and multivariable regression analyses were performed. Our scoring system (CRCTU score) was developed based on a flexible baseline hazard functions fitted using restricted cubic splines. Suitable fractional polynomials (FP) were used to explain relationship between the outcome and covariates. The level of discrimination achieved using the risk groups was assess by Harrell’s–C statistic. The CRCTU score permitted identification of 4 clearly distinct subgroups as indicated both graphically and by Harrell’s-C values. Both the CRCTU and BALAD scores return Harrell’s-C values of 0.7. Conclusions: We have shown that it is possible to use entirely objective markers to predict prognosis of HCC in a western population. Our model is comparable to the BALAD with the same variables included. However, our treatment of variables with FP is much more robust statistical technique for continuous variable as compared to having artificial categories that were seen in the BALAD system.
Phase II study of PEG-Intron in combination with chemotherapy for the treatment of first line patients with follicular lymphoma who need to be treated
Authors: C. E. Saba, P. Brice, C. Haioun, P. Feugier, F. Bauduer, B. Salles, C. Du Manoir-Baumgarten, M. Blanc, C. Kulekci, B. Coiffier
Journal: Journal of Clinical Oncology (2004)

6571 Background & Methods: This phase II study combined PEG-Intron to CHVP in place of interferon alfa-2b in untreated patients with follicular lymphoma and high-risk criteria (B symptoms, poor PS, high LDH or β2-microglobulin levels, or high tumor burden defined as disseminated lymph nodes >3 cm, one lymph node >7 cm, pleura or ascites, splenomegaly, or organ compression). Treatment comprised 12 cycles of CHVP (cyclophosphamide 600 mg/m2, doxorubicin 25 mg/m2, VP16 100 mg/m2, and prednisone 40 mg/m2 x 5 days) plus PEG-Intron 35 μg (or 50 μg for pts >70 kg) once a week over the 18 months. PEG-Intron is a pegylated derivative of Intron A with a longer half-life that may be administered once a week. The objective of the study was to evaluate the efficacy and tolerability of PEG-Intron by historical comparison with patients treated with Intron A in the GELF-94 study. Results: 79 patients have been included: 9% had bulky stage II, 12% stage III, and 79% stage IV. 25% had B symptoms, 15% poor performance status, 19% high LDH level, 45% high beta-2-microglobulin level, and 53% had a high tumor mass. Median age was 52 years (27–75 y). At the end of the 18-month treatment, 66% of the patients reached a CR, 13% a PR and 81% progressed during the treatment or changed of treatment because of response less than PR. With a median follow-up of 2 years, 10% of responding patients had a progression and 2 of them died. Median time to progression is 32 months. The only frequent toxicity was neutropenia which was observed in 20 to 25% of the patients during cycles 1 to 6 but less frequently thereafter. It was not associated to increased infectious event (only 1 patient with grade >2 infection) but let to transitory or definitive decrease of PEG-Intron dose in 39% of the patients and to premature stop in 15% of them. Conclusions: Compared to results observed with Intron A in the GELF-94 study, these results are superposable for response to treatment, time to progression and safety. PEG-Intron (50 μg/week) seems to have the same efficacy that Intron A in the treatment of patients with follicular lymphoma and was easier to administer (only 1 injection per week). Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough
A multicenter phase II study of primary systemic therapy epirubicin/cyclophosphamide followed by docetaxel plus concurrent trastuzumab for HER2-positive advanced breast cancer.
Authors: T. Saeki, K. Aogi, S. Nakamura, M. Kashiwaba, N. Sato, N. Masuda, Y. Rai, S. Ohno, K. Miyakoda, T. Ikeda
Journal: Journal of Clinical Oncology (2010)

681 Background: The position of trastuzumab (T) treatment for operable patients with HER2-positive locally advanced and metastatic breast cancer has been discussed. We conducted a multicenter, prospective phase II study of primary systemic therapy including T to evaluate the efficacy and safety of epirubicin/cyclophosphamide (EC) followed by docetaxel (D) with concurrent use of T. Methods: Stage IIIB/IIIC/IV pts with HER2-positive disease (IHC 3+ or FISH +) were eligible. All patients should receive 4 cycles of EC (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2, q3w) followed by 4 cycles of D (75 mg/m2, q3w), with 12 cycles of concurrent T (loading dose 4 mg/kg followed by 2 mg/kg, qw). For the patients with stage IV disease, salvage mastectomy will be considered as a local control treatment with patients' request. The primary endpoint was pathological complete response (pCR) excluding intraductal component in the tumor by central pathological review. The secondary endpoints were clinical response rate (cRR), pCR rate in the ipsilateral axillary lymph node, disease free survival (DFS), overall survival (OS) and toxicity. Results: Between January 2006 and December 2008, 38 patients were enrolled (stage IIIB, 63.2%; IIIC, 23.7%; IV, 13.2%; ER and/or PR+, 52.6%). The intent to treat pCR rate in the primary tumor was 16.2% (6/37 pts) in total: stage IIIB, 8.3%; IIIC, 33.3%; IV, 25.0%; ER and/or PR+, 5.9%; ER and PR-, 25.0%. Among 37pts, 27 received the planned treatment. Of 27pts, 6 demonstrated pCR (22.2%). The cRR was 67.6% (25/37; cCR, 13.5%; cPR, 54.1%). The pCR rate in the ipsilateral axillary lymph node was 51.4% (19/37). No CHF was reported, however more than 10% decrease of left ventricular ejection fraction without symptom occurred in 3 patients. Conclusions: The PST including concurrent use of T combined with D is effective and safe in HER2-positive advanced breast cancer patients, even who need mastectomy for local control. The results of DFS and OS in the study will be available in the future. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chugai Pharma
Long-Term Health Outcomes in Women With Silicone Gel Breast Implants
Authors: Ethan M. Balk, Gowri Raman
Journal: Annals of Internal Medicine (2016)

Letters4 October 2016Long-Term Health Outcomes in Women With Silicone Gel Breast ImplantsEthan M. Balk, MD, MPH and Gowri Raman, MD, MSEthan M. Balk, MD, MPHFrom Center for Evidence-Based Medicine, Brown University School of Public Health, Providence, Rhode Island, and Center for Clinical Evidence Synthesis, Tufts Medical Center, Boston, Massachusetts.Search for more papers by this author and Gowri Raman, MD, MSFrom Center for Evidence-Based Medicine, Brown University School of Public Health, Providence, Rhode Island, and Center for Clinical Evidence Synthesis, Tufts Medical Center, Boston, Massachusetts.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L16-0196 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:We believe that Dr. Brown has overinterpreted the purpose, methodology, and conclusions of our review. We evaluated the narrow question of whether comparative observational study data are sufficient to support (or refute) any putative associations between silicone gel implants and long-term adverse health outcomes. Future reviews would need to assess the evidence on associations between environmental silicone exposure and health outcomes. If we assess the totality of evidence on breast implants, the answer is, in brief, no—the examined evidence is inadequate to make conclusions about the long-term safety of silicone gel implants. This conclusion in no way supports ... Author, Article, and Disclosure InformationAffiliations: From Center for Evidence-Based Medicine, Brown University School of Public Health, Providence, Rhode Island, and Center for Clinical Evidence Synthesis, Tufts Medical Center, Boston, Massachusetts.Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-1169. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoLong-Term Health Outcomes in Women With Silicone Gel Breast Implants Ethan M. Balk , Amy Earley , Esther A. Avendano , and Gowri Raman Long-Term Health Outcomes in Women With Silicone Gel Breast Implants Tim Brown Metrics Cited byBreast Implant Illness (BII): Real Syndrome or a Social Media Phenomenon? A Narrative Review of the LiteratureCommentary on: The Prevalence of Self-Reported Health Complaints and Health-Related Quality of Life in Women With Breast ImplantsSilicone Implant IllnessCommentary on “The new opt-out Dutch national breast implant registry – Lessons learnt from the road to implementation” 4 October 2016Volume 165, Issue 7Page: 527-528KeywordsDisclosureEnvironmental healthForecastingObservational studiesSafety ePublished: 4 October 2016 Issue Published: 4 October 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...