tbuckley/cabot-search huggingface dataset:
Relationship of oral glycine with radiation-induced HIF1-alpha and tumor growth delay in a prostate cancer xenograft.
Authors: Elizabeth Riley Kessler, Lih-Jen Su, Xiaoping Yang, Cem Altunbas, Thomas W. Flaig, Chuan-Yuan Li, Brian D. Kavanagh
Journal: Journal of Clinical Oncology (2013)

81 Background: Preclinical studies have shown that nitric oxide (NO) is produced by upregulation of inducible nitric oxide synthase (iNOS) in activated macrophages recruited to the site of cytotoxic injury from radiation or chemotherapy. NO stabilizes hypoxia-inducible factor 1-alpha (HIF1α), leading to increased vascular endothelial growth factor, thus promoting tumor angiogenesis as a recovery mechanism from the initial cytotoxic insult. Because glycine (G) suppresses macrophage activation, we hypothesized that dietary supplementation with G would inhibit HIF1α expression and enhance tumor growth delay by preventing recovery angiogenesis. Methods: PC3 cells were transfected with a HIF1α-inducible luciferase reporter and grown as nude mice xenografts. As tumors grew to 100mm 3 , mice were continued in 1 of 4 conditions: 1) control (C) diet ; 2) a 5%G diet; 3) C diet with ad libitum drinking water treated with L-NAME (500mg/L), an iNOS inhibitor; or 4) C diet with a single injection of carrageenan (2mg/500uL), a selective macrophagicidal agent. After 3 days tumors were irradiated with 0 Gy (sham) or 6 Gy using a 160kV source. Tumor growth and quantitative bioluminescence data were then collected (n = 4 mice/group). Results: HIF1α expression as assessed by bioluminescence increased more than two fold 4-6 days after 6 Gy (p&lt;0.05) in the C diet group but did not significantly increase in either the L-NAME, 5%G , or carrageenan groups. Tumor growth curves for the 6 Gy L-NAME and 5%G diet groups showed a corresponding statistically significant growth delay compared to 6 Gy C diet. No clear difference in bioluminescence or growth was noted in any 0 Gy cohort. Conclusions: The results support the hypothesis that radiation injury indirectly upregulates HIF1α via an iNOS dependent pathway. Inhibition of this pathway can enhance in vivo radiation-induced tumor growth delay and can be achieved via dietary supplementation with G. Thus, dietary G supplementation might have a clinical role for patients treated with radiotherapy for prostate cancer as a non-toxic means of achieving radiosensitization.
Boosting the Potency of T-cell Therapies
Authors: Alissa Poh
Journal: Cancer Discovery (2016)

Researchers in the adoptive T-cell therapy field are continuing to refine the ways in which the specificity of these immune cells can be redirected toward tumors. They've found that selecting the most persistent, proliferative T cells-and genetically manipulating only these defined subsets-ensures a potent therapeutic product that's effective even at minuscule doses.
Association between early PSA increase and clinical outcome in patients treated with enzalutamide for metastatic castration resistant prostate cancer.
Authors: Vincenza Conteduca, Simon J. Crabb, Emanuela Scarpi, Catherine Hanna, Francesca Maines, Helen Joyce, Paolo Fabbri, Lisa Derosa, Francesco Massari, Cristian Lolli, Sunnya Zarif, Robert J. Jones, Orazio Caffo, Tony Elliott, Ugo De Giorgi
Journal: Journal of Clinical Oncology (2016)

231 Background: Prostate specific antigen (PSA) decline by 50% from the baseline to 12 weeks (PSA50w12) is currently used to predict response to treatment and clinical outcome of patients with metastatic castration resistant prostate cancer (mCRPC). However, in clinical practice, PSA changes are monitored monthly in several centers. We evaluated the association between PSA changes at 4 weeks and clinical outcome. Methods: We retrospectively evaluated mCRPC patients treated with enzalutamide after docetaxel. Early PSA increase was defined as a PSA level at 4 weeks ≥ 20% (PSA+20w4) from baseline. Early PSA decline was defined as a PSA response at 4 weeks ≥ 30% (PSA30w4) and ≥ 50% (PSA50w4) from baseline.Progression-free survival (PFS), overall survival (OS) and their 95% Confidence Interval (95% CI) were evaluated by the Kaplan-Meier method and compared with the log-rank test. A multivariate analysis was performed including the following variables: PSA+20w4, PSA30w4, PSA50w4 and PSA50w12, baseline PSA, performance status, LDH values, sites of metastases, age. Results: We assessed 193 patients with median age of 73.1 years (range, 42.8 to 90.7). The median follow-up was 11.7 months. PSA+20w4 was associated with shorter PFS (median PFS 2.0 vs. 6.1 months; HR 4.03; 95% CI 2.62-6.19; p &lt; 0.0001) and shorter OS (median OS 5.9 vs. 15.6 months; HR 3.48; 95% CI 2.12-5.69; p &lt; 0.0001). At multivariate analysis, PSA+20w4 remained predictive of both PFS and OS [HR 4.03 (95% CI 0.2.62-6.19; p &lt; 0.0001) and HR 3.48 (95% CI 2.12-5.69; p &lt; 0.0001), respectively], whereas PSA30w4 and PSA50w4 predicted only PFS [HR 0.37 (95% CI 0.21-0.67; p = 0.0009) and HR 0.34 (95% CI 0.19-0.60; p = 0.0003), respectively]. No cases of PSA flare were reported. Conclusions: An early PSA increase, defined as a PSA level at 4 weeks ≥ 20% (PSA+20w4), could be useful to identify patients unlikely to benefit from enzalutamide. Larger studies are needed to confirm PSA+20W4 as an early and cheap biomarker of primary resistance to enzalutamide.
Self-Reported Quality-of-Life Impairment and Productivity Loss in Patients with Polycythemia Vera: Early Patient-Reported Outcomes Assessment from the REVEAL Study
Authors: Ruben A. Mesa, Ralph V. Boccia, Alison Moliterno, Ahmad B. Naim, Joseph A. Cordaro, Wei Peng, Hao Sun, Shreekant V. Parasuraman, Brady Stein
Journal: Blood (2015)
Giancarlo (Gianni) Berni
Authors: Caroline White
Journal: BMJ (2016)

Emergency medicine specialist who “taught Italy how to do first aid”



Giancarlo (Gianni) Berni, who has died just a few months short of his 80th birthday, is credited with bringing emergency and intensive care to the Italian region of Tuscany, where he was born, grew up, and spent his working life.

His methods have since been widely adopted across Italy. As Antonio Panti, president of the Florentine Order of Doctors, observed in a tribute published in Corriere Fiorentino after the professor’s death, “He taught Italy how to do first aid.”

Before Berni came up with the idea of creating a 24 hour acute care unit that incorporated different strands of specialist internal medicine expertise and diagnostics, “the concept of emergency and critical care didn’t really exist in Tuscany,” says Berni’s colleague Luigi Tonelli, a retired medical director.

Urgent cases were consigned to the care of doctors without the requisite emergency medicine skills, whose task was …
Use of standardised patients to assess antibiotic dispensing for tuberculosis by pharmacies in urban India: a cross-sectional study
Authors: Srinath Satyanarayana, Ada Kwan, Benjamin Daniels, Ramnath Subbaraman, Andrew McDowell, Sofi Bergkvist, Ranendra K Das, Veena Das, Jishnu Das, Madhukar Pai
Journal: The Lancet Infectious Diseases (2016)

BackgroundIndia's total antibiotic use is the highest of any country. Patients often receive prescription-only drugs directly from pharmacies. Here we aimed to assess the medical advice and drug dispensing practices of pharmacies for standardised patients with presumed and confirmed tuberculosis in India.MethodsIn this cross-sectional study in the three Indian cities Delhi, Mumbai, and Patna, we developed two standardised patient cases: first, a patient presenting with 2–3 weeks of pulmonary tuberculosis symptoms (Case 1); and second, a patient with microbiologically confirmed pulmonary tuberculosis (Case 2). Standardised patients were scheduled to present each case once to sampled pharmacies. We defined ideal management for both cases a priori as referral to a health-care provider without dispensing antibiotics or steroids or both.FindingsBetween April 1, 2014, and Nov 29, 2015, we sampled 622 pharmacies in Delhi, Mumbai, and Patna. Standardised patients completed 1200 (96%) of 1244 interactions. We recorded ideal management (defined as referrals without the use of antibiotics or steroids) in 80 (13%) of 599 Case 1 interactions (95% CI 11–16) and 372 (62%) of 601 Case 2 interactions (95% CI 58–66). Antibiotic use was significantly lower in Case 2 interactions (98 [16%] of 601, 95% CI 13–19) than in Case 1 (221 [37%] of 599, 95% CI 33–41). First-line anti-tuberculosis drugs were not dispensed in any city. The differences in antibiotic or steroid use and number of medicines dispensed between Case 1 and Case 2 were almost entirely attributable to the difference in referral behaviour.InterpretationOnly some urban Indian pharmacies correctly managed patients with presumed tuberculosis, but most correctly managed a case of confirmed tuberculosis. No pharmacy dispensed anti-tuberculosis drugs for either case. Absence of a confirmed diagnosis is a key driver of antibiotic misuse and could inform antimicrobial stewardship interventions.FundingGrand Challenges Canada, Bill & Melinda Gates Foundation, Knowledge for Change Program, and World Bank Development Research Group.
Patient-Reported Quality of Life (QoL) in Elderly, Newly Diagnosed Multiple Myeloma (MM) Patients Receiving Bortezomib-Based Combinations: Results From All Randomized Patients in the Community-Based, Phase 3b UPFRONT Study
Authors: Ruben Niesvizky, Ian W. Flinn, Robert Rifkin, Nashat Gabrail, Veena Charu, Billy Clowney, Yousuf Gaffar, Thomas A. Warr, Rachel Neuwirth, Hui Huang, Sanggyu Choi, Deyanira Corzo
Journal: Blood (2011)
Functional profiling of signal transduction pathway proteins in gastric cancer (GC) patients.
Authors: J. Lee, P. Kim, X. Liu, J. Park, S. Ng, T. Lee, H. Lim, S. Singh, S. Kim, W. Kang
Journal: Journal of Clinical Oncology (2010)

e14555 Background: With the advent of molecularly targeted therapy in cancer care, identification of target population for target drug is of utmost importance. Gastric cancer has not been extensively profiled for transduction pathway proteins. Here we report the prevalence of HER1, HER2, p95HER2, HER3, IGF1-R, c-MET, PI3K, Shc, VEGFR, panCK, and other signal transduction pathway protein expression and their levels of activation in GC patients. Methods: From 2004 to 2006, 500 GC surgical specimens were procured at Samsung Medical Center. All of the specimens were collected during gastrectomy and were appropriately frozen at – 80 °C. All of the specimens were analyzed at Prometheus, CA, USA. We applied COPIA to investigate the levels of expression and activation of signaling proteins in frozen tissues collected from GC patients. The Collaborative Proximity Immunoassay (COPIA) is a multiplexed protein microarray platform that utilizes the formation of a unique immuno-complex requiring co-localization of two detector-antibodies. The detector-antibodies are conjugated with corresponding channeling-enzymes, glucose oxidase (GO) and horseradish peroxidase (HRP). Once target proteins are bound by the capture antibodies, the channeling events between GO and HRP in proximity enables the profiling of the target proteins with extreme sensitivity. COPIA delivers extremely high analytical specificity as it requires multiple entities within target specific proximity for the signal generation/amplification. COPIA can also be configured for each specific target protein to allow differential detection of truncated targets (i.e., p95HER2) from their normal counter parts (i.e., HER2). Results: We will be reporting on the prevalence of HER1, HER2, p95HER2, HER3, IGF1-R, c-MET, PI3K, Shc, VEGFR, panCK, and other signal transduction pathway protein expression and their levels of activation in 500 GC patients. Conclusions: The treatment of recurrent or metastatic GC may be optimized by functional profiling of GC. In addition, the incidence of alteration in transduction pathway proteins may guide oncologists for further clinical development of targeted therapies or combined therapies. No significant financial relationships to disclose.
CRISPR/Cas9-Mediated <i>Trp53</i> and <i>Brca2</i> Knockout to Generate Improved Murine Models of Ovarian High-Grade Serous Carcinoma
Authors: Josephine Walton, Julianna Blagih, Darren Ennis, Elaine Leung, Suzanne Dowson, Malcolm Farquharson, Laura A. Tookman, Clare Orange, Dimitris Athineos, Susan Mason, David Stevenson, Karen Blyth, Douglas Strathdee, Frances R. Balkwill, Karen Vousden, Michelle Lockley, Iain A. McNeish
Journal: Cancer Research (2016)

There is a need for transplantable murine models of ovarian high-grade serous carcinoma (HGSC) with regard to mutations in the human disease to assist investigations of the relationships between tumor genotype, chemotherapy response, and immune microenvironment. In addressing this need, we performed whole-exome sequencing of ID8, the most widely used transplantable model of ovarian cancer, covering 194,000 exomes at a mean depth of 400× with 90% exons sequenced >50×. We found no functional mutations in genes characteristic of HGSC (Trp53, Brca1, Brca2, Nf1, and Rb1), and p53 remained transcriptionally active. Homologous recombination in ID8 remained intact in functional assays. Further, we found no mutations typical of clear cell carcinoma (Arid1a, Pik3ca), low-grade serous carcinoma (Braf), endometrioid (Ctnnb1), or mucinous (Kras) carcinomas. Using CRISPR/Cas9 gene editing, we modeled HGSC by generating novel ID8 derivatives that harbored single (Trp53
Development of a multi-target peptide for potentiating chemotherapy by modulating tumor microenvironment
Authors: Xu Song, Zhuoya Wan, Tijia Chen, Yao Fu, Kejun Jiang, Xiaoli Yi, Huan Ke, Jianxia Dong, Liuqing Yang, Lin Li, Xun Sun, Tao Gong, Zhirong Zhang
Journal: Biomaterials (2016)
The US Food and Drug Administration and the Future of Cardiovascular Medicine
Authors: Mona Fiuzat, Robert M. Califf
Journal: JAMA Cardiology (2016)

Cardiovascular medicine has led the drive for creativity and innovation with a culture that has been at the forefront of evidence generation. However, we are functioning at only a fraction of our evidence generation capacity. Despite the leadership of cardiovascular medicine, very few guideline recommendations are supported by high levels of evidence, and the proportion of recommendations for which there is no conclusive evidence is substantial. Clinical research has proven to be too slow, unreliable, and expensive as conducted in the past. In the current era, a new model of unlimited information, better access to care, and better payer coverage has the potential to change our evidence base to support clinical guidelines. We now have the opportunity to use volumes of data to support US Food and Drug Administration labeling and practice guidelines. The electronic health record can be used to feed decisions and provide an information feedback loop. In addition, learning health systems can contribute to providing networks and registries for information sharing. In this Special Communication, we summarize opportunities of the cardiovascular community to build on its pioneering leadership in evidence-based medicine through major initiatives now under way. By joining in broad efforts to create an efficient national evidence generation system, larger proportions of clinical practice can be guided by high-quality evidence; clinicians and their practice organizations will be increasingly able to focus on interpreting, applying, and communicating research findings to improve outcomes; and patients and consumers will be increasingly informed and empowered to play active roles in managing their own health and health care.
Personalized adjuvant chemotherapy for colorectal cancer based on an individual 50% inhibitory area under the concentration curve using collagen gel droplet embedded culture-drug sensitivity test.
Authors: T. Ochiai, K. Nishimura, T. Watanabe, M. Kitajima, T. Hashiguchi, A. Nakatani, A. Muraki, N. Sakuyama, S. Futagawa, I. Nagaoka
Journal: Journal of Clinical Oncology (2010)

3582 Background: Tumor cell drug sensitivity is important in developing personalized chemotherapy. We approximated growth inhibition rate (IR) and area under the concentration curve (AUC) of 5-FU to a logarithmic curve using the collagen gel droplet embedded culture-drug sensitivity test (CD-DST) (ASCO 2003, #1283) and showed that achieving an individual 50% inhibitory AUC (AUCIR50) from the AUC-IR curve in 5-FU chemotherapy correlated with prognosis (ASCO 2006, #13560; ASCO 2007, #14553). In this study, the importance of achieving an individual AUCIR50 in 5-FU-based chemotherapy was evaluated based on recurrence and 5-year disease-free survival (DFS) to determine criteria for establishing personalized adjuvant chemotherapy. Methods: Between 2001 and 2009, surgical specimens were obtained from 79 resectable colorectal cancer patients with no preoperative chemotherapy. 5-FU-based adjuvant chemotherapy was administered in all patients. The CD-DST was performed under 4-9 different conditions. The individual AUCIR50 was obtained from each AUC-IR curve. In patient cohort I, total administered AUC was greater than the AUCIR50; in cohort II, total administered AUC was less than the AUCIR50. Recurrence and 5-year DFS were evaluated between the cohorts using the X2 test, t-test and Kaplan-Meier method. Results: No significant bias in patient characteristics was observed between cohorts. Recurrence rates in cohort I and II were 10.3% (6/58) and 33.3% (7/21), respectively. Five-year DFS rates in cohort I and II were 85.0 and 65.0%, respectively. Significant differences were observed between cohorts. Conclusions: Cohort I showed a statistically significant better prognosis. The results suggest that achieving an individual AUCIR50is important in personalized 5-FU-based adjuvant chemotherapy. No significant financial relationships to disclose.
Accuracy of Hair Mineral Analysis
Authors: Mitchell V. Kaminski, Jr
Journal: JAMA (2001)

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Pre‐eclampsia and risk of infantile haemangioma
Authors: N. Auger, W.D. Fraser, L. Arbour, J. Healy‐Profitós, B.A. Drolet
Journal: British Journal of Dermatology (2016)

Infantile haemangioma is the most common tumour of infancy, but the association with pre‐eclampsia is poorly understood. We determined the relationship between variants of pre‐eclampsia and risk of infantile haemangioma. We carried out a retrospective cohort study of hospital data for all live births between 1989 and 2013 in Quebec, Canada. We identified 14 240 neonates with, and 1 930 564 without haemangioma before discharge, and determined whether early‐ or late‐onset pre‐eclampsia was documented on the maternal chart. We used log‐binomial regression to compute prevalence ratios (PRs) and 95% confidence intervals (CIs) for the association between pre‐eclampsia and infantile haemangioma, adjusted for maternal characteristics. The prevalence of any haemangioma was higher for pre‐eclampsia than for no pre‐eclampsia (81·3 vs. 72·9 per 10 000), with a PR of 1·15 (95% CI 1·06–1·25) after adjustment for maternal characteristics. Pre‐eclampsia with onset before 34 weeks’ gestation was associated with cutaneous (PR 2·32, 95% CI 1·68–3·21), noncutaneous (PR 3·66, 95% CI 2·49–5·37) and unspecified haemangioma (PR 2·49, 95% CI 1·77–3·49). However, the association between early‐onset pre‐eclampsia and haemangioma was attenuated once long neonatal length of hospital stays was accounted for. There was no association with late‐onset pre‐eclampsia after 34 weeks, and associations were weaker for other variants including severe pre‐eclampsia and pre‐eclampsia with low birthweight. Early‐onset pre‐eclampsia is associated with increased risk of haemangioma at birth, but detection bias due to longer hospital stays and closer follow‐up may be part of the reason.
Overall survival benefit and safety profile of radium-223 chloride, a first-in-class alpha-pharmaceutical: Results from a phase III randomized trial (ALSYMPCA) in patients with castration-resistant prostate cancer (CRPC) with bone metastases.
Authors: Chris Parker, Daniel Heinrich, Joe M. O'Sullivan, Sophie D. Fossa, Ales Chodacki, Tomasz Demkow, John P. Logue, Mihalj Seke, Anders Widmark, Dag Clement Johannessen, Sten Nilsson, Peter Hoskin, Arne Solberg, Nicholas David James, Isabel Syndikus, Andrew Cross, C. Gillies O'Bryan-Tear, Jose E. Garcia-Vargas, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2012)

8 Background: Radium-223 chloride (Ra-223) is a first-in-class alpha-pharmaceutical targeting bone metastases (mets) with high-energy alpha-particles of extremely short range (&lt;100 μm). ALSYMPCA, a phase III, double-blind, randomized, multinational study, compared efficacy, in terms of overall survival (OS), and safety of Ra-223 plus best standard of care (BSC) vs placebo plus BSC in patients (pts) with bone mets in CRPC. Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving BSC; and either previously received docetaxel, were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to receive 6 injections of Ra‐223 (50 kBq/kg IV) q4 wks or matching placebo and stratified by prior docetaxel use, baseline alkaline phosphatase level, and current bisphosphonate use. A planned interim analysis (IA) was conducted to assess the effect of Ra-223 on the primary endpoint (OS) using a predefined threshold. Survival data were compared using a stratified log-rank test. Results: 922 pts (Ra-223, n = 615; placebo, n = 307) were randomized from 6/2008-2/2011. 445 (58%) of 809 pts in the IA data set received prior treatment with docetaxel. Ra-223 significantly improved OS in pts with CRPC with bone mets vs placebo (two-sided P = 0.00185; HR = 0.695; 95% CI, 0.552-0.875; median OS 14.0 mo vs 11.2 mo, respectively). Safety and tolerability of Ra-223 were highly favorable and showed low incidence of myelosuppression (eg, grades 3/4 neutropenia in 1.8% and 0.8% and thrombocytopenia in 4% and 2% of the Ra-223 and placebo groups, respectively). Conclusions: Ra-223 is an effective therapy that improved OS with a highly favorable safety profile, and may provide a new standard of care for the treatment of CRPC pts with bone mets. [Table: see text]
Percutaneous Intervention for Myocardial Infarction After Noncardiac Surgery
Authors: Akhil Parashar, Shikhar Agarwal, Amar Krishnaswamy, Karan Sud, Kanhaiya L. Poddar, Mehak Bassi, Stephen Ellis, E. Murat Tuzcu, Venu Menon, Samir R. Kapadia
Journal: Journal of the American College of Cardiology (2016)
Conventional and Pretargeted Radioimmunotherapy Using an Anti-Murine CD45 Monoclonal Antibody in a Syngeneic, Disseminated Murine Leukemia Model.
Authors: John M. Pagel, Nathan Hedin, Lacey Drouet, Anastasia Pantelias, Yukang Lin, Don Hamlin, Darrell Fisher, D. Scott Wilbur, Ajay K. Gopal, Damian Green, Frederick R. Appelbaum, Oliver W. Press
Journal: Blood (2006)