tbuckley/cabot-search huggingface dataset:
Association of Variants in Candidate Genes with Lipid Profiles in Women with Early Breast Cancer on Adjuvant Aromatase Inhibitor Therapy
Authors: Cesar A. Santa-Maria, Amanda Blackford, Anne T. Nguyen, Todd C. Skaar, Santosh Philips, Steffi Oesterreich, James M. Rae, Zeruesenay Desta, Jason Robarge, Norah Lynn Henry, Anna M. Storniolo, Daniel F. Hayes, Roger S. Blumenthal, Pamela Ouyang, Wendy S. Post, David A. Flockhart, Vered Stearns
Journal: Clinical Cancer Research (2015)

Aromatase inhibitors can exert unfavorable effects on lipid profiles; however, previous studies have reported inconsistent results. We describe the association of single-nucleotide polymorphisms (SNP) in candidate genes with lipid profiles in women treated with adjuvant aromatase inhibitors.We conducted a prospective observational study to test the associations between SNPs in candidate genes in estrogen signaling and aromatase inhibitor metabolism pathways with fasting lipid profiles during the first 3 months of aromatase inhibitor therapy in postmenopausal women with early breast cancer randomized to adjuvant letrozole or exemestane. We performed genetic association analysis and multivariable linear regressions using dominant, recessive, and additive models.A total of 303 women had complete genetic and lipid data and were evaluable for analysis. In letrozole-treated patients, SNPs in CYP19A1, including rs4646, rs10046, rs700518, rs749292, rs2289106, rs3759811, and rs4775936 were significantly associated with decreases in triglycerides by 20.2 mg/dL and 39.3 mg/dL (P < 0.00053), respectively, and with variable changes in high-density lipoprotein (HDL-C) from decreases by 4.2 mg/dL to increases by 9.8 mg/dL (P < 0.00053).Variants in CYP19A1 are associated with decreases in triglycerides and variable changes in HDL-C in postmenopausal women on adjuvant aromatase inhibitors. Future studies are needed to validate these findings, and to identify breast cancer survivors who are at higher risk for cardiovascular disease with aromatase inhibitor therapy.
Abstract 20531: C-Abl Mediated Tyrosine Phosphorylation of Paxillin is Essential for LPS-Induced Endothelial Barrier Dysfunction and Acute Lung Injury
Authors: Panfeng Fu, Anne E Cress, Ting Wang, Joe G Garcia, Viswanathan Natarajan
Journal: Circulation (2014)

Paxillin, a multi-domain scaffold-adapter focal adhesion (FA) protein, plays an important role in facilitating protein networking and efficient signaling transduction. Paxillin is phosphorylated at multiple serine/threonine and tyrosine residues; however, the role of tyrosine phosphorylation of paxillin in endothelial barrier dysfunction and the acute respiratory distress syndrome (ARDS) remains unclear. In this study, we used paxillin-specific siRNA and site-specific non-phosphorylatable mutants of paxillin to abrogate the function of paxillin, both in vitro and in vivo, to determine its role in the regulation of lung endothelial permeability and ARDS. In vitro, lipopolysaccharide (LPS) challenge of human lung microvascular endothelial cells (ECs) resulted in paxillin accumulation at focal adhesions, enhanced tyrosine phosphorylation of paxillin at Y31 and Y118, and significant endothelial barrier dysfunction. However no significant changes in Y181 phosphorylation by LPS challenge was observed. Paxillin silencing (siRNA) attenuated LPS-induced endothelial barrier dysfunction and dissociation of VE-cadherin from adherens junctions. LPS-induced paxillin phosphorylation at Y31 and Y118 was mediated by c-Abl tyrosine kinase and not by Src or focal adhesion kinase (FAK) in human lung microvascular ECs. Furthermore, down-regulation of c-Abl (siRNA) significantly reduced LPS-mediated endothelial barrier dysfunction. Transfection of human lung microvascular ECs with paxillin Y31, Y118 and Y31/Y118 mutants mitigated LPS-induced barrier dysfunction and VE-cadherin destabilization at adherens junctions. In vivo, knockdown of paxillin with siRNA in mouse lungs ameliorated LPS-induced pulmonary protein leak and lung inflammation. Together, these results suggest that c-Abl-mediated tyrosine phosphorylation of paxillin at Y31 and Y118 regulates LPS-mediated pulmonary vascular permeability and injury.
Five types of skepticism
Authors: J. Aronson
Journal: BMJ (2015)

Look here. The Greeks metathesised the hypothetical Indo-European root SPEK, to see or regard, into skopein, to look, see, watch, or regard, with its related deponent verb skeptesthai, “I consider,” and the adjective skeptikos, “thoughtful.” Hence skepticism, the earliest recorded spelling (or scepticism, as some spell it today). I recognise five types: philosophical, Voltairian, scientific, dogmatic, and nihilistic.

The Skeptics, an ancient Greek school of philosophers, founded by Pyrrho, asserted nothing positively and doubted the very possibility of knowledge, although they did not go so far as to assert its impossibility, because that would have been a positive assertion. Immanuel Kant adopted this extreme view in The Critique of Pure Reason (1781): “The skeptical method is the method of watching, or rather provoking, a conflict of assertions, not for the purpose of deciding in …
Cardiovascular Complications Of Thalassemia Patients In The Iron Chelation Therapy Era
Authors: Adisak Tantiworawit, Suebsakul Tapanya, Arintaya Phrommitikul, Lalita Norasetthada, Chatree Chai-adisaksopha, Ekarat Rattarittamrong, Sasinee Hantrakool, Sucharawee Taechacharn, Weerasak Nawarawong
Journal: Blood (2013)
Prothrombotic state in patients with severe and prednisolone-dependent asthma
Authors: Marlous M.S. Sneeboer, Christof J. Majoor, Anne de Kievit, Joost C.M. Meijers, Tom van der Poll, Pieter W. Kamphuisen, Elisabeth H. Bel
Journal: Journal of Allergy and Clinical Immunology (2015)
Cardiac Diseases Following Childhood Cancer Treatment
Authors: Nadia Haddy, Stéphanie Diallo, Chiraz El-Fayech, Boris Schwartz, François Pein, Mike Hawkins, Cristina Veres, Odile Oberlin, Catherine Guibout, Hélène Pacquement, Martine Munzer, Tan Dat N’Guyen, Pierre-Yves Bondiau, Delphine Berchery, Anne Laprie, Pierre-Yves Scarabin, Xavier Jouven, André Bridier, Serge Koscielny, Eric Deutsch, Ibrahima Diallo, Florent de Vathaire
Journal: Circulation (2015)

Cardiac disease (CD) is one of the major side effects of childhood cancer therapy, but until now little has been known about the relationship between the heart radiation dose (HRD) received during childhood and the risk of CD.The cohort comprised 3162 5-year survivors of childhood cancer. Chemotherapy information was collected and HRD was estimated. There were 347 CDs in 234 patients, 156 of them were rated grade ≥3. Cox and Poisson regression models were used. The cumulative incidence of any type of CD at 40 years of age was 11.0% (95% confidence interval [CI], 9.5-12.7) and 7·4% (95% CI, 6.2-8.9) when only the CDs of grade ≥3 were considered. In comparison with patients who received no anthracycline and either no radiotherapy or an HRD<0·1Gy, the risk was multiplied by 18·4 (95% CI, 7.1-48.0) in patients who had received anthracycline and no radiotherapy or a HRD <0.1Gy, by 60.4 (95% CI, 22.4-163.0) in those who had received no anthracycline and an HRD≥30Gy, and 61.5 (95% CI, 19.6-192.8) in those who had received both anthracycline and an HRD≥30Gy.Survivors of childhood cancers treated with radiotherapy and anthracycline run a high dose-dependent risk of developing CD. CDs develop earlier in patients treated with anthracycline than in those treated without it.
Gemcitabine, oxaliplatin and weekly high-dose 5-FU as a 24-hr-infusion in chemonaive patients with advanced or metastatic biliary tree adenocarcinoma: Preliminary results of a multicenter phase II study
Authors: A. D. Wagner, P. Buechner-Steudel, A. Wein, M. Moehler, H. Schmalenberg, J. Fahlke, O. Kuss, R. Behrens, G. Kleber, W. E. Fleig
Journal: Journal of Clinical Oncology (2005)

4147 Background: Combinations of gemcitabine (GEM)/5-FU, GEM/oxaliplatin (LOHP) or 5-FU/LOHP work synergistically in pancreatic and/or colorectal malignancies, and have non-overlapping safety profiles. This phase II-study was designed to evaluate the efficacy and safety of the triple combination GEM/LOHP/5-FU in patients (pts) with advanced or metastatic biliary tree adenocarcinoma (BTC). Methods: Eligibility criteria: chemonaive pts with histologically proven advanced, recurrent or metastatic BTC (ECOG 0–1; expected survival >3 months; measurable disease; adequate renal, hepatic and bone marrow function). According to the results of our previous phase I-study (Proc ASCO 2003, p. 1298), pts were treated with GEM 900mg/m2 as a 30-min infusion, followed by LOHP (2-hr infusion) after a 30 min rest and 5-FU (24-hr-infusion) on d 1, 8, then every 3 weeks. The primary endpoint was tumor response, secondary endpoints were toxicity, median survival, one-year-survival rate, clinical benefit and quality of life. Results: At time of abstract submission, median follow-up of 38 enrolled pts is 9 months. Pt. characteristics: m/f: 17/21, median age 61 (range 36–75), ECOG 0/1/2: 23/14/1 (61/37/3%) pts, locally advanced/metastatic disease 9/28 (24/76%) pts. Analysis of response is still pending. 278 cycles in 38 pts are evaluable for toxicity (NCI-CTC). Grade III/ IV toxicities occurred in 50/10% of cycles and were neutropenia 7/2%, thrombocytopenia 1/2%, anemia 4/0%, nausea 4/1%, sensory neuropathy 2/0%, fatigue 1/0%, elevated bilirubin 4/5%, AP 5/0%, or SGOT/SGPT 5/0%, edema 4.7/0%, infection 3/0%, pruritus 1/0%, pain 3/0%. Grade III dyspnoe, diarrhea, emesis, flush, fever, constipation, dysphagia, palpitations and insomnia occurred in < 1% of cycles. Median survival of all pts is 10.0 (95% CI: 8.5–12.4) months, the one-year-survival-rate is 45 (95% CI: 28–62)%. Conclusions: GEM/LOHP/5-FU combination therapy is tolerated well. The promising survival data in BTC has to be confirmed in a phase III study. (Supported by grants from Eli Lilly and Company, Indianapolis, IN, USA and Sanofi-Synthelabo, Paris, France) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly, Sanofi-Synthelabo
Doctors should indeed cry, "Enough"
Authors: R. P Balfour
Journal: BMJ (1996)

has a protective function.It protects the vulnerable from misinformation due to mistakes by or the ignorance of the informer, from pressure by those with malintent, from economically driven judg- ments on their future, and from much more.It also protects us, as doctors, from ourselves: our ignorance or arrogance, any temptation to cover up medical mistakes, our difficulty in asking for help from a colleague, overinvolvement with a patient that colours our judgment, our fatigue, or personal prejudice or bias about clinical or social conditions.It protects us from undue pressure by relatives weary of caring or who stand to gain financially.Managers cannot put pressure on us to clear those who are dying from our beds rapidly, and purchas- ers cannot question why we strive to provide qual- ity care to patients with a poor prognosis.
Considerations in the Management of Gestational Diabetes Mellitus: “You Are What Your Mother Ate!”
Authors: Robert G. Moses, William T. Cefalu
Journal: Diabetes Care (2015)

It is clear that there remains a global crisis in the development and consequences of chronic diseases such as obesity and type 2 diabetes.These conditions lead to complications that increase morbidity and mortality, such as heart disease, stroke, amputations, and kidney disease.We have learned a great deal about the pathogenesis of these disorders and also about both treatment and preventive interventions.Clearly, there remains considerable progress to be made specifically in addressing these conditions and, more importantly, in preventing these conditions in resourcepoor areas.Over the recent past, there has been a startling new set of observations on the genesis of these conditions.There are data that certain processes observed in utero and in early childhood can certainly affect the risk of developing chronic diseases at a later age (1-3).This clearly provides a great opportunity to interdict on these pathophysiological processes when they may have the greatest effect.As such, there is a growing interest in learning more about epigenetic phenomena and how these events that can be observed in prenatal and early postnatal life can modulate the risk for the development of chronic diseases (i.e., obesity and type 2 diabetes) in adolescence and early adulthood.
Current screening programs for lung cancer – Are inclusion criteria too rigorous to identify asymptomatic patients?
Authors: Anders Bugge, Anne Naalsund, May Brit Lund
Journal: European Respiratory Journal (2011)

Background:  Preliminary results from the controlled National Lung Cancer Screening Trial (NLST) indicates a mortality reduction of > 20% in screened patients; high risk being defined as smokers (ex/current) > 55 years old with > 30 pack-years. Recent studies suggest that female smokers develop lung cancer at a younger age and following smaller amounts of tobacco consumption than males. In industrialized countries the incidence of lung cancer is falling in males, but increasing in females. We aimed to assess if the inclusion criteria used in NLST would have identified lung cancer in a cohort of asymptomatic subjects who underwent surgical resections at our tertiary university hospital.   Material and methods:  During the period 2002-10 clinical data from 1043 consecutive patients with lung cancer were prospectively registered. 626 patients (294 (47%) females, mean age 68 years, and 332 (53%) males, mean age 64 years), underwent surgery.   Results:  Of the 626 patients who underwent surgery, 267 (42%, 131 females, 136 males) had no clinical manifestations of lung disease at presentation, and chest x-rays had been performed for co-incidental conditions. In females, 30/131 (23%) were current or ex-smokers with > 30 pack-years. In males, the corresponding proportion was 65/136 (48%). Applying the NLST criteria, 77% of the females and 52% of the males would not have been admitted to the screening program.   Conclusion:  Less than one forth of asymptomatic females who underwent resection for lung cancer would have been included in NLST as their total consumption of tobacco in pack-years was too low. Also, half of symptom-free resected males would have been excluded from screening.
A phase I/II study of definitive chemoradiotherapy with docetaxel, nedaplatin, and 5-fluorouracil (DNF-R) for advanced esophageal cancer.
Authors: Yasushi Sato, Hiroyuki Ohnuma, Masahiro Hirakawa, Yutaka Okagawa, Takahiro Osuga, Kazuyuki Murase, Kohichi Takada, Yutaka Kawano, Satoshi Iyama, Tsuyoshi Hayashi, Tsutomu Sato, Koji Miyanishi, Rishu Takimoto, Masayoshi Kobune, Tamotsu Sagawa, Masakazu Hori, Masanori Someya, Koh-ichi Sakata, Tetsuji Takayama, Junji Kato
Journal: Journal of Clinical Oncology (2015)

123 Background: Deﬁnitive chemoradiotherapy is one of the options for advanced esophageal cancer (AEC). However, AEC patient survival remains unsatisfactory. To investigate a regimen of definitive chemoradiotherapy that exerts good local control of AEC, we performed a phase I/II study to assess the safety and efficacy of triple-drug chemoradiotherapy with docetaxel, 5-fluorouracil, and nedaplatin (DNF-R) that has less adverse events than cisplatin. Methods: Eligible patients had stage II-IVA AEC. Patients received 2 cycles of docetaxel (20, 30, or 40 mg/m 2 for dose levels 1, 2, or 3) and nedaplatin (50 mg/m 2 ) on days 1 and 8, and a continuous infusion of 5-fluorouracil (400 mg/m 2 /day) on days 1-5 and 8-12, with concurrent radiotherapy (on days 1-5, 8-12, and 15-19, total 60 Gy) every 5 weeks. After DNF-R, patients received at least 2 more cycles of DNF. The recommended dose (RD) was determined with a 3 + 3 design. Results: Thirty-one patients were enrolled from July 2010 to April 2013. In the phase I study, the dose-limiting toxicity (DLT) was grade 4 neutropenia, which was observed in all 3 patients at dose level 2.Thus, the RD schedule was level 1. In the phase II study, the 25 eligibles had a median age of 64 (range 56-78; male/female: 21/4), with PS0/1/2 of 13/10/2 and cStage II/III/IVA of 6/10/9. Grade 3/4 acute toxicity included neutropenia (46%), leukopenia (43%), febrile neutropenia (11%), thrombocytopenia (18%), esophagitis (18%), and nausea (11%) during CRT. Grade3/4 late radiotoxicity included 2 cases of esophagostenosis (7%), but they improved by dilatation. Of the 28 patients treated at the RD level 1, including 3 patients of the RD phase I portion, all of them showed response including 23 (82%) CR and 5 PR. The protocol completion rate was 96.4% (27/28). No treatment-related death was observed. The median PFS (1-year PFS: 67.6% and 3-year PFS: 44.8%) and OS were 21 months and 33.2 months, respectively. The 3-year survival rate was 62.5%. Conclusions: DNF-R showed good tolerability and achieved a high CR rate, suggesting that it is a potentially effective therapeutic regimen for AEC. Clinical trial information: UMIN000005446.
Abstract 16859: Acute Hyperglycemia, but not Hemoglobin A1c, is Associated With Poor Outcome in Patients With Acute Myocardial Infarction
Authors: Masashi Fujino, Masaharu Ishihara, Takafumi Yamane, Toshihisa Nagai, Tadayoshi Miyagi, Tomoaki Kanaya, Leon Kumasaka, Yasuhide Asaumi, Tetsuo Arakawa, Michio Nakanishi, Hiroki Sakamoto, Teruo Noguchi, Kengo Kusano, Toshihisa Anzai, Yoichi Goto, Satoshi Yasuda, Hisao Ogawa
Journal: Circulation (2013)

Background: Elevation of plasma glucose (PG) adversely influences outcomes of patients with acute myocardial infarction (AMI). Admission hyperglycemia and hemoglobin A1c (HbA1c) represent acute and...
A Randomised Comparison Evaluating Changes in Bone Mineral Density in Advanced Prostate Cancer: Luteinising Hormone-releasing Hormone Agonists Versus Transdermal Oestradiol
Authors: Ruth E. Langley, Howard G. Kynaston, Abdulla A. Alhasso, Trinh Duong, Edgar M. Paez, Gordana Jovic, Christopher D. Scrase, Andrew Robertson, Fay Cafferty, Andrew Welland, Robin Carpenter, Lesley Honeyfield, Richard L. Abel, Michael Stone, Mahesh K.B. Parmar, Paul D. Abel
Journal: European Urology (2015)

Luteinising hormone-releasing hormone agonists (LHRHa), used as androgen deprivation therapy (ADT) in prostate cancer (PCa) management, reduce serum oestradiol as well as testosterone, causing bone mineral density (BMD) loss. Transdermal oestradiol is a potential alternative to LHRHa. To compare BMD change in men receiving either LHRHa or oestradiol patches (OP). Men with locally advanced or metastatic PCa participating in the randomised UK Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) trial (allocation ratio of 1:2 for LHRHa:OP, 2006–2011; 1:1, thereafter) were recruited into a BMD study (2006–2012). Dual-energy x-ray absorptiometry scans were performed at baseline, 1 yr, and 2 yr. LHRHa as per local practice, OP (FemSeven 100 μg/24 h patches). The primary outcome was 1-yr change in lumbar spine (LS) BMD from baseline compared between randomised arms using analysis of covariance. A total of 74 eligible men (LHRHa 28, OP 46) participated from seven centres. Baseline clinical characteristics and 3-mo castration rates (testosterone ≤1.7 nmol/l, LHRHa 96% [26 of 27], OP 96% [43 of 45]) were similar between arms. Mean 1-yr change in LS BMD was −0.021 g/cm3 for patients randomised to the LHRHa arm (mean percentage change −1.4%) and +0.069 g/cm3 for the OP arm (+6.0%; p < 0.001). Similar patterns were seen in hip and total body measurements. The largest difference between arms was at 2 yr for those remaining on allocated treatment only: LS BMD mean percentage change LHRHa −3.0% and OP +7.9% (p < 0.001). Transdermal oestradiol as a single agent produces castration levels of testosterone while mitigating BMD loss. These early data provide further supporting evidence for the ongoing phase 3 trial. This study found that prostate cancer patients treated with transdermal oestradiol for hormonal therapy did not experience the loss in bone mineral density seen with luteinising hormone-releasing hormone agonists. Other clinical outcomes for this treatment approach are being evaluated in the ongoing PATCH trial. ISRCTN70406718, PATCH trial (ClinicalTrials.gov NCT00303784).
Diversity in Clinical and Biomedical Research: A Promise Yet to Be Fulfilled
Authors: Sam S. Oh, Joshua Galanter, Neeta Thakur, Maria Pino-Yanes, Nicolas E. Barcelo, Marquitta J. White, Danielle M. de Bruin, Ruth M. Greenblatt, Kirsten Bibbins-Domingo, Alan H. B. Wu, Luisa N. Borrell, Chris Gunter, Neil R. Powe, Esteban G. Burchard
Journal: PLoS Medicine (2015)

Health disparities persist across race/
The effects of distance from primary treatment centers on survival among patients with multiple myeloma.
Authors: R E Lenhard, J P Enterline, J Crowley, G Y Ho
Journal: Journal of Clinical Oncology (1987)

Twenty-one comprehensive cancer centers participated in a national reporting system of common data items, recording information on all patients seen between 1977 and 1982. There were 240,531 patients who had data abstracted. This report describes 1,479 patients with multiple myeloma. Parameters that may effect the type of treatment given during the initial episode of therapy in the center and the effect of these characteristics on survival were studied. In the univariate analysis, age, treatment, and distance traveled to the center were statistically associated with survival. In a multivariate analysis adjusting for potentially confounding covariates, blacks survive better than whites and the effects of sex and socioeconomic status (SES) on survival approach significance. Survival consistently improved with increasing distance traveled to treatment centers. This may be a serious confounding variable in assessing the results by both single and multiinstitution clinical trials.
Density of immunogenic antigens does not explain presence or absence of the T cell-inflamed tumor microenvironment in metastatic melanoma
Authors: Yuanyuan Zha, Stefani Spranger, Kyle M Hernandez, Yan Li, Riyue Bao, Peter Alexieff, Jorge Andrade, Jason J Luke, Thomas F Gajewski
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Immune checkpoints blockade inhibitors, such as anti-CTLA-4 and anti-PD-1, are now proven effective cancer treatments. In melanoma, the patients who experience clinical benefits usually have T cell-inflamed tumor microenvironment. Understanding the molecular mechanism explaining
PIK3CA mutation, aspirin use after diagnosis and survival of colorectal cancer. A systematic review and meta-analysis of epidemiological studies
Authors: L. Paleari, M. Puntoni, M. Clavarezza, D. Corradengo, E. Campazzi, S. Caviglia, N. Provinciali, J. Cuzick, A. DeCensi
Journal: Annals of Oncology (2015)
Clinical Characteristics and Outcomes of Young and Very Young Adults With Heart Failure
Authors: Chih M. Wong, Nathaniel M. Hawkins, Pardeep S. Jhund, Michael R. MacDonald, Scott D. Solomon, Christopher B. Granger, Salim Yusuf, Marc A. Pfeffer, Karl Swedberg, Mark C. Petrie, John J.V. McMurray
Journal: Journal of the American College of Cardiology (2013)
Detecting Plasma Tumor DNA in Early-Stage Breast Cancer—Letter
Authors: Annette R. Kodahl, Niels Pallisgaard, Anne Marie B. Jylling, Søren Cold, Ann S. Knoop, Henrik J. Ditzel
Journal: Clinical Cancer Research (2015)

Beaver and colleagues ([1][1]) reported that the detection of mutant PIK3CA circulating tumor DNA (ctDNA) in early-stage breast cancer patients before and after surgery could improve selection of systemic postsurgical therapies. They reported that 14 of 15 patients with PIK3CA mutations in the