tbuckley/cabot-search huggingface dataset:
Obeticholic acid, a Farensoid-X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats
Authors: Rajeshwar Mookerjee, Gautam Mehta, Rajiv Jalan
Journal: Hepatology (2014)

We read with interest the study by Verbeke et al., who demonstrate a beneficial effect of obeticholic acid (OCA) on portal hypertension in cirrhotic rats1 and proceed to characterize effects of OCA on the endothelial nitric oxide synthase (eNOS) inhibitor, asymmetric dimethylarginine (ADMA), and its metabolizing enzyme, dimethylarginine dimethylaminohydrolase (DDAH). However, several issues require clarification. First, the dose of OCA employed in the study; OCA has a median effective concentration in Hep G2 cells of 85-100 nanomolar, making it 100× more potent than the natural farnesoid X receptor (FXR) ligand, chenodeoxycholic acid, but with greater cytotoxicity.2 The dose of 30 mg/kg used by Verbeke et al. equates to a dose of >70 micromolar, that is, nearly 1,000 times the half maximal effective concentration, and thereby likely to produce toxicity, perhaps explaining the lack of stellate cell responses compared to earlier articles. Second, duration of in vivo therapy in the Verbeke et al. study is unprecedented, with two 30-mg/kg doses within 24 hours before hemodynamic assessment, contrasting with previous studies using 5-10 mg/kg in rodents over weeks.3 The data from pharmacokinetic studies in humans would suggest that optimal tissue levels of OCA are not reached until 5-7 days of therapy,2 and thus a 24-hour high-dose study is difficult to interpret. Finally, the interpretation of DDAH-2 being responsible for changes in eNOS function is likely erroneous. It is important to appreciate that there are two isoenzymes of DDAH: DDAH-1 predominantly in the liver and kidney accounting for over 80% of ADMA metabolism, and DDAH-2, located in the heart and vasculature with a role in promoting eNOS transcription, but little effect on ADMA.4 Therefore, the augmented DDAH-2 and improved ADMA metabolism post-OCA treatment in bile-duct–ligated (BDL) rats in the Verbeke et al. study is difficult to reconcile. Moreover, rodent models show increased hepatic DDAH-1 with FXR agonists, but there is no precedent for FXR agonism leading to increased hepatic DDAH-2 expression.5 In summary, whereas the Verbeke et al. study recapitulates important therapeutic effects of FXR agonists in portal hypertension, there are questions about study design and interpretation of mechanism pertaining to DDAH-2. Further studies are required to address concerns about the mechanism through which OCA reduces hepatic ADMA, and thereby portal pressure, in the BDL model. Rajeshwar Prosad Mookerjee, B.Sc., PH.D., FRCP Gautam Mehta, B.Sc., MRCP Rajiv Jalan, M.D., Ph.D., FRCP Liver Failure Group UCL Institute for Liver and Digestive Health The Royal Free Hospital London, United Kingdom
Whole-exome and targeted sequencing of angiosarcomas: Target identification and treatment implications.
Authors: Vinod Ravi, Naveen Ramesh, Madhavi Patnana, Anthony Paul Conley, Neeta Somaiah, Maria Alejandra Zarzour, Davis Ingram, Latasha Little, Alexei Protopopov, Alexander J. F. Lazar, Dejka M. Araujo, Keila E Torres, Shreyaskumar Patel, Jianhua Zhang, Siraj M. Ali, Vincent A. Miller, Philip J. Stephens, Robert S. Benjamin, Patrick Hwu, Andrew Futreal
Journal: Journal of Clinical Oncology (2014)

10512 Background: Angiosarcoma (AS) is a rare, aggressive tumor with vascular differentiation. Mutational landscape of AS is largely unknown. Utility of inhibition of targets/pathways identified by sequencing has not been investigated in AS. Methods: Study population included 20 patients with AS with tissue available for sequencing. 6 patients with fresh frozen paired normal and tumor samples underwent whole exome sequencing (WES) to identify somatic mutations. 14 patients with formalin fixed paraffin embedded (FFPE) tumor tissue underwent targeted sequencing of select cancer associated genes at high coverage. These data were filtered for germline SNPs utilizing publicly available databases and the remaining variants were classified on the basis of their being previously reported in the COSMIC database. Retrospective chart review was used to determine utilization of targeted therapies and clinical outcomes. Results: Study population (N=20) was predominantly Caucasian (80%), median age 64 years, with localized AS in 15%, nodal involvement in 40%, distant metastases in 45%. 60% of patients had cutaneous AS and 65% had previous history of radiation exposure prior to diagnosis. 65% of patients were alive at last follow-up. WES of patients with normal/tumor paired samples (n=6) showed a total of 485 alterations in 371 genes (range: 4-189 alterations/patient). Alterations were observed in the angiogenesis associated genes PTPRB (2/6 patients) PLCG1 (2/6) as well as TP53 (1/6) in addition to other alterations. Targeted sequencing of FFPE samples (n=14) showed 27 alterations in 10/14 patients that were either mutations described in COSMIC or structural variants. These included MYC & KDR amplifications and mutations in TP53, MDM2, KDR, FLT4 & PIK3CA. 9 patients received 1 or more targeted agents creating 18 episodes of treatment. Clinical benefit rate was 45% when target was absent compared to 71% when target was present. Conclusions: Identification of genetic alterations specific to AS using WES should be utilized to construct targeted sequencing panels of select genes that help identify actionable targets and potential prognostic and predictive markers in patients with AS.
HIGH BASELINE VALVULOARTERIAL IMPEDENCE PREDICTS WORSE 1-YEAR OUTCOMES AFTER TRANSCATHETER AORTIC VALVE REPLACEMENT
Authors: Cheng-Han Chen, Matthew Brinkman, Omar Khalique, Tamim Nazif, Torsten Vahl, Isaac George, Amisha Patel, Pablo Codner, Remi Kouz, Juan Terre, Jennifer Jantz, Ming Liao, Martin Leon, Susheel Kodali, Rebecca Hahn
Journal: Journal of the American College of Cardiology (2017)
Contents Vol. 75, 2006
Authors: Chiara Brombin, Ernesto Caffo, J. Wiltink, P. Bech, H.V. Hansen, L.V. Kessing, C. Faravelli, C. Ravaldi, E. Truglia, T. Zucchi, F. Cosci, V. Ricca, Johann F. Kinzl, Katharina Hauer, Christian Traweger, Ingrid Kiefer, Chiara Ruini, Carlotta Belaise, A. Dippel, M. Szczepanski, R. Thiede, Yi-Ching Lu, M.E. Beutel, Giovanni A. Fava, Silvana Grandi, Stefania Fabbri, Naike Panattoni, Elisabetta Gonnella, Isaac Marks, Nina Rieckmann, Matthew M. Burg, William Gerin, William F. Chaplin, Lynn Clemow, Karina W. Davidson, Johan Denollet, Jacqueline J. Strik, Richel Lousberg, Adriaan Honig, Bih-Ching Shu, Yong-Yuan Chang, For-Wey Lung, Boudewijn van Houdenhove, Victor I. Spoormaker, Jan van den Bout
Journal: Psychotherapy and Psychosomatics (2006)
Genetic polymorphisms of SCNA9 as predictive markers of oxaliplatin-induced neuropathy.
Authors: Maria Sereno, Gerardo Gutierrez-Gutierrez, Cristina Rodriguez-Antona, Lara Sanchez, Cesar gomez Lopez, Miriam Lopez Gomez, Francisco Zambrana Tevar, Maria Merino, Ambrosio Miralles, Enrique Casado
Journal: Journal of Clinical Oncology (2012)

9073 Background: Oxaliplatin (OXL) is an active drug in digestive tumors. Oxaliplatin induced peripheral neuropathy (OIN) is the main dose limiting toxicity. Around 60-80% of patients developed a mild cold-induced neurotoxicity that used to disappear few days after but in 15% became a persistent neuropathy. The pathophysiology of oxaliplatin-induced neuropathy (OIN) remains unclear, preclinical studies suggest involvement of voltage Na channels. SCN9A gene codifies to Na channels α subunit highly expressed in nociceptive neurons. Mutations in SCN9A are involved in alterations in neuropatic pain perception. This study tried to identify if variants in SCN9A could be associated to a higher risk to OIN. Methods: Serum were obtained from 100 patients with digestive cancer (colorectal, gastric, pancreatic and bile duct) treated with OXL (adjuvant or advanced setting) in Infanta Sofía University Hospital. No diabetes or hypotiroidism were detected. Patients were divided in two groups according to the development of OIN: Arm A 50 patients diagnosed of grade 2-3 OIN after 6 courses and Arm B 50 with no OIN. The evaluation of severity of the OIN by a neurologist included a classification according to NCI-CTC and OSNS scales and conduction studies. Genomic DNA was isolated from serum and variants of SCN9A were analyzed by PCR-RFLP. The relation between SCN9A genotype and the development of severe OIN was the primary aim Results: One hundred patients were enrolled between May 2010-November 2011. 56 (56%) females and 44 (44%) males; mean age was 62; mean ECOG was 1; primary tumor were colorectal 81 pts (81%), gastric 10 (10%); 8 (8%) pancreto-biliar and anus 1(1%). Stage were classified in localized 65 (65%) and advanced (35%). The chemotherapy regimen included: 94 (94%) XELOX, 1 (1%) XELOX-Herceptin and 5 (5%) EOX regimen. The mean of cycles were 7 (1-14). Mean OXL dose intensity was 100mg/m2.The mean PFS was 23 months. High expression of SCN9A variants were detected in patients 26/50, 52% arm A and in 5/50, 10% arm B patients, suggesting a possible relationship beetwen the development of OIN and SCN9A genotype (p=0.04). Conclusions: SCN9A polimorphysms may help to identify those patients with a higher risk to develop oxaliplatin induced neuropathy.
Oral chronic graft-versus-host disease symptom experience and cytokine correlates in survivors after transplantation for hematologic malignancies
Authors: J. M. Fall-Dickson, E. S. Ramsay, M. Imanguli, J. Guadagnini, J. Odom, N. Atlam, S. Pavletic
Journal: Journal of Clinical Oncology (2007)

19510 Background: Oral chronic graft-versus-host-disease (cGVHD) is a frequent, clinically significant sequela of hematopoietic stem cell transplant (HSCT). No optimal treatment exists; molecular pathogenesis remains unclear. This descriptive study assessed stomatitis, oral pain, and dry mouth severity, and correlations with proinflammatory cytokine levels in stimulated submandibular saliva samples from cGVHD patients. Methods: Subjects were enrolled in the NCI sponsored cGVHD natural history protocol. Stomatitis severity was assessed with the Oral Mucositis Rating Scale (OMRS) (0–103); oral pain and dryness were self-reported via VAS (0–10). Saliva samples were collected on ice, stored at -80°C, centrifuged at 4000xg for 10 minutes at 4°C, and supernatant retained. Salivary TNFa, IL1a, and IL6 concentrations were measured by enzyme-linked immunosorbent assay (ELISA) (R &amp; D Systems, Minneapolis, MN). Results: Adult male and female subjects (N = 42) with cGVHD after HSCT primarily for hematologic malignancies were prescribed systemic (n = 34) and/or topical (n = 4) immunosuppressive agents, and opioids (n = 19). All subjects had mild to moderate stomatitis (OMRS mean = 18.38; range = 2.0 to 46) with erythema (n = 40), lichenoid (n = 32), and ulceration (n = 25). Mild to severe oral dryness (43%) (mean = 2.56; range 0 to 10) was more clinically significant than oral pain (8%) (mean = .13). Salivary cytokine concentrations were: TNFa (n = 32; mean = .31 pg/mL; range 0 to 2.8); IL1a (n = 29; mean = 85.23 pg/mL; range = 13 to 250), and IL6 (n = 29; mean = 2.48 pg/mL; range 0.100 to 10.00). Significant associations by Pearson Product Moment correlation were: TNFa and erythema (r = .34; p &lt; .05); IL1a and oral dryness (r = .40; p &lt; .05); IL6 and OMRS (r = .49; p &lt; .01), erythema (r = .63; p &lt; .001), and ulceration (r = .38; p &lt; .05). Conclusions: Paucity of oral pain may be related to appropriate management. Moderate to strong correlations between salivary TNFa and IL6 and oral cGVHD severity, and IL1a and oral dryness suggest utility as correlates of disease severity and symptom, and monitors of therapeutic response to investigational agents. No significant financial relationships to disclose.
MITRAL VALVE PHASE CONTRAST IMAGING IS A MORE REPRODUCIBLE METHOD OF DETERMINING CARDIAC REST PERIODS FOR WHOLE-HEART CORONARY MAGNETIC RESONANCE ANGIOGRAPHY IN CONGENITAL HEART DISEASE THAN 4 CHAMBER CINE
Authors: Maria Batsis, Gerald Greil, Animesh Tandon, Tarique Hussain
Journal: Journal of the American College of Cardiology (2017)
RENAL FUNCTION-BASED CONTRAST DOSING TO DEFINE “PROGNOSTIC” CONTRAST DOSE LIMITS FOR PERCUTANEOUS CORONARY INTERVENTION – THE PROGNOSTIC IMPLICATION OF THE CONTRAST VOLUME: GLOMERULAR FILTRATION RATIO IN 44,082 PATIENTS FROM THE BRITISH COLUMBIA CARDIAC REGISTRY
Authors: Navin Chandra, Imad Nadra, Sean Hardiman, Lillian Ding, Anthony Fung, Eve Aymong, Albert Chan, Stephen Hodge, Simon Robinson, Anthony Della Siega, Bilal Iqbal
Journal: Journal of the American College of Cardiology (2017)
Impact of Anti-CD20 Antibodies on the Incidence of Secondary Cancers in Patients Treated for Chronic Lymphocytic Leukemia
Authors: Stéphanie Guidez, Hélène Demarquette, Morgane Nudel, Charline Le Grand, Eileen Boyle, Charles Herbaux, Thierry Facon, Bruno Cazin, Franck Morschhauser
Journal: Blood (2015)
Serotonin Reuptake Inhibitor Use During Pregnancy
Authors: Sonya Rasminsky, Vivien K. Burt
Journal: JAMA Psychiatry (2017)

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EVALUACION DE LA TASA DE RECURRENCIA A LARGO PLAZO DE COLECCIONES LÍQUIDAS PANCREÁTICAS (CLP) DRENADAS POR ECOENDOSCOPIA MEDIANTE PRÓTESIS METÁLICAS DE APOSICIÓN LUMINAL (PMAL)
Authors: C De La Serna, I Peñas, R Sánchez-Ocaña, P Gil, H Núñez, P Diez, M Pérez-Miranda
Journal: Endoscopy (2015)

El drenaje de colecciones líquidas pancreáticas (pseudoquistes -PP- y necrosis pancreática organizada- NPO- con componente líquido) mediante prótesis plásticas se asocia a altas tasas de recidiva (Arvanitakis, GIE 2007). El empleo de prótesis metálicas de aposición luminal (PMAL) durante periodos prolongados podría reducir las tasas de recurrencia postretirada.
A Call for Fertility Preservation Coverage for Breast Cancer Patients: The Cost of Consistency
Authors: Jessica R. Walter, Shuai Xu, Teresa K. Woodruff
Journal: JNCI Journal of the National Cancer Institute (2017)

In 1998, the passage of the Women’s Health and Cancer Rights Act required insurance health plans nationwide covering breast cancer treatments to also reimburse for subsequent breast reconstructive surgery and prostheses. In response to low utilization of breast reconstructive services, particularly among racial minorities, plastic surgery interest groups successfully advocated for the passage of the Breast Cancer Patient Education Act, which provides a timely opportunity to reconsider patient accessibility to other equally important quality of life issues for cancer survivors. Currently, the potential threat of infertility as a consequence of cancer therapy does not meet preexisting definitions of infertility, making preemptive fertility preservation elective. Ultimately, cost remains the largest barrier to the pursuit of fertility preservation. In this Commentary, we estimate the potential additive cost of providing fertility preservation coverage for approximately 19 000 eligible women of reproductive age diagnosed with breast cancer based on previously published prevalence and cost data. We determine an upper limit of yearly cost of $126.6 million US dollars assuming 100% participation. Legislation providing mandatory insurance coverage of breast reconstruction surgeries in all 50 states following cancer treatment represents a powerful policy commitment to address existing health disparities in reproductive health services and ensures comprehensive cancer survivorship care. Extending coverage for fertility preservation in the setting of fertility-threatening treatment offers a consistent stance for insurance coverage of iatrogenic sequelae of cancer therapy at a fraction of the cost of breast reconstruction.
CHARACTERISTICS AND OUTCOMES OF PATIENTS WITH CLINICALLY SILENT PERI-PROCEDURAL HEMOGLOBIN DROPS AS COMPARED TO PATIENTS WITH OVERT BLEEDING FOLLOWING PERCUTANEOUS CORONARY INTERVENTION
Authors: Ahmed Farawi, Paula D. Strassle, Rahul Jaswaney, Christopher End, George Stouffer, Prashant Kaul, John Vavalle
Journal: Journal of the American College of Cardiology (2017)
THE IMPACT OF PREOPERATIVE RENAL DYSFUNCTION ON THE OUTCOMES OF PATIENTS UNDERGOING SURGICAL VERSUS TRANSCATHETER AORTIC VALVE REPLACEMENT: AN ANALYSIS FROM THE COREVALVE US PIVOTAL HIGH RISK TRIAL
Authors: Andres M. Pineda Maldonado, Nirat Beohar, J. Kevin Harrison, Neal Kleiman, Michael Reardon, John Conte, Daniel O'Hair, Stanley Chetcuti, Steven Yakubov, Jeffrey Popma
Journal: Journal of the American College of Cardiology (2017)
High tau-protein expression may predict taxane resistance in breast cancer patients
Authors: Piotr Wysocki, Konstanty Korski, Anna Malicka
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

242 

Aim: The aim of this study is to find correlation between tau-protein expression in breast cancer patients and their response to taxane treatment. Materials and methods: We selected the group of 12 patients with breast cancer treated in Wielkopolska Cancer Ctr. in the years 1995-2004. The patients underwent total mastectomy with the lymph node dissection. Despite the adjuvant therapy based on taxane regiment they showed clinical progression of the disease. From the archives of the Pathology Department we retrieved paraffin blocks containing tumor samples obtained from the patients and used immunohistochemistry to asses tau-protein, ER, PR and HER2 expression. Tau-protein expression was considered high in tumor cells when the expression intesivity was equal or higher than one observed in the normal breast epithelium. Results: Eight out of 12 tumors (66%) showed high tau-protein expression. Two of the eight (25%) tau-positive tumors showed positive ER expression, four of them (50%) were PR positive and three (37%) were HER2 positive. Conclusion: High tau-protein expression may be considered as a predictive marker of the resistance to the taxane-based adjuvant therapy in breast cancer patients. To validate these data we need further studies based on the larger population with the comparison of tau-protein expression in breast cancer patients who show clinical response to this kind of treatment.
A randomised phase II study of interferon alpha alone or in combination with thalidomide in metastatic renal cancer
Authors: S. Madhusudan, A. Protheroe, P. Vasey, P. Patel, P. Selby, D. Altman, K. Christodoulos, A. L. Harris
Journal: Journal of Clinical Oncology (2004)

4742 Background: Interferon alpha is the standard treatment for patients with metastatic kidney cancer. Single agent thalidomide may have some activity in renal cancer. To investigate whether the combination of Interferon alpha (INF) and thalidomide is feasible and more efficacious than interferon alone as the first line therapy we initiated an ongoing phase II randomised study. Methods: The main aims were to assess safety, toxicity, therapeutic efficacy and biological activity of the combination compared to INF alone. Patients were randomised [interferon arm; INF 9 MIU subcutaneously thrice a week, INF + Thalidomide arm: INF as above and thalidomide 100 mgs once daily then 200 mgs once daily after two weeks] and stratified by prognostic groups. Toxicity analysis and QOL assessments were performed every 3 weeks. Disease response evaluation was performed 12 weekly. Results: A total of 34 patients have been recruited so far (males: 22, females: 12). Median age 57 years (range 44–76). 16 patients were randomised to receive INF and 18 patients received INF + thalidomide. 20 patients who received >= 12 weeks of therapy were evaluable for disease response: INF arm; [complete response 1, stable disease (SD) 9, progressive disease (PD) 2 and in INF + thalidomide arm; partial response (1), SD (2), PD (5)]. All others received < 12 weeks of therapy due to toxicity or early PD. A total of 13 patients came off therapy due to toxicity [INF (5), INF + thalidomide arm (8)]. The common grade III or IV toxicities were: INF arm; anorexia (1), fatigue (6), vomiting (1), nausea (1), flu like symptom (1), thrombocytopenia (1), neutropenia (2) and in INF + thalidomide arm: anorexia (1), fatigue (2), dizziness (2), drowsiness (1), skin rash (2), anaemia (4) and neutropenia (2). Conclusions: Interferon + thalidomide combination therapy is safe. The toxicity is comparable with INF alone though dizziness, drowsiness, skin rash and anaemia were more severe in the combination arm. Preliminary analysis suggests no significant advantage in the combination arm with regards to disease response. No significant financial relationships to disclose.
REST MYOCARDIAL PERFUSION IMAGING IN THE MANAGEMENT OF CHEST PAIN: A FEASIBLE AND SECURE PROTOCOL IN A BRAZILIAN EMERGENCY DEPARTMENT
Authors: Lucas Cronemberger Maia Mendes, Sebastiao L.L. Filho, Heleno R. Reis, Ludmilla R.A. Silva, Edmur C. Araujo, Carlos J.D.G. Barbosa
Journal: Journal of the American College of Cardiology (2017)
Glycemic Control During Continuous Subcutaneous Insulin Infusion Versus Multiple Daily Insulin Injections in Type 2 Diabetes: Individual Patient Data Meta-analysis and Meta-regression of Randomized Controlled Trials
Authors: John C. Pickup, Yves Reznik, Alex J. Sutton
Journal: Diabetes Care (2017)

OBJECTIVE To compare glycemic control during continuous subcutaneous insulin infusion (CSII) and multiple daily insulin injections (MDI) in people with type 2 diabetes to identify patient characteristics that determine those best treated by CSII. RESEARCH DESIGN AND METHODS Randomized controlled trials were selected comparing HbA1c during CSII versus MDI in people with type 2 diabetes. Data sources included Cochrane database and Ovid Medline. We explored patient-level determinants of final HbA1c level and insulin dose using Bayesian meta-regression models of individual patient data and summary effects using two-step meta-analysis. Hypoglycemia data were unavailable. RESULTS Five trials were identified, with 287 patients randomized to receive MDI and 303 to receive CSII. Baseline HbA1c was the best determinant of final HbA1c: HbA1c difference (%) = 1.575 − (0.216 [95% credible interval 0.371–0.043] × baseline HbA1c) for all trials, but with largest effect in the trial with prerandomization optimization of control. Baseline insulin dose was best predictor of final insulin dose: insulin dose difference (units/kg) = 0.1245 − (0.382 [0.510–0.254] × baseline insulin dose). Overall HbA1c difference was −0.40% (−0.86 to 0.05 [−4.4 mmol/mol (−9.4 to 0.6)]). Overall insulin dose was reduced by −0.25 units/kg (−0.31 to −0.19) (26% reduction on CSII), and by −24.0 units/day (−30.6 to −17.5). Mean weight did not differ between treatments (0.08 kg [−0.33 to 0.48]). CONCLUSIONS CSII achieves better glycemic control than MDI in people with poorly controlled type 2 diabetes, with ∼26% reduction in insulin requirements and no weight change. The best effect is in those worst controlled and with the highest insulin dose at baseline.