tbuckley/cabot-search huggingface dataset:
Safety and Pharmacodynamics of the PDE4 Inhibitor Roflumilast in Advanced B-cell Malignancies
Authors: Kevin Kelly, Alex Mejia, Avvaru N. Suhasini, An-Ping Lin, John Kuhn, Anand B. Karnad, Steven Weitman, Ricardo C.T. Aguiar
Journal: Clinical Cancer Research (2016)

Purpose: In this study, we aimed to validate our extensive preclinical data on phosphodiesterase 4 (PDE4) as actionable target in B-cell malignancies. Our specific objectives were to determine the safety, pharmacokinetics, and pharmacodynamics (PI3K/AKT activity), as well as to capture any potential antitumor activity of the PDE4 inhibitor roflumilast in combination with prednisone in patients with advanced B-cell malignancies.Experimental Design: Single-center, exploratory phase Ib open-label, nonrandomized study. Roflumilast (500 mcg PO) was given daily for 21 days with prednisone on days 8 to 14. Additional 21-day cycles were started if patients tolerated cycle 1 and had at least stable disease.Results: Ten patients, median age 65 years with an average of three prior therapies, were enrolled. The median number of cycles administered was 4 (range, 1-13). Treatment was well tolerated; the most common ≥grade 2 treatment-related adverse events were fatigue, anorexia (≥25%), and transient ≥ grade 2 neutropenia (30%). Treatment with roflumilast as a single agent significantly suppressed PI3K activity in the 77% of patients evaluated; on average, patients with PI3K/AKT suppression stayed in trial for 156 days (49-315) versus 91 days (28-139 days) for those without this biomarker response. Six of the nine evaluable patients (66%) had partial response or stable disease. The median number of days in trial was 105 days (range, 28-315).Conclusions: Repurposing the PDE4 inhibitor roflumilast for treatment of B-cell malignancies is safe, suppresses the oncogenic PI3K/AKT kinases, and may be clinically active. Clin Cancer Res; 23(5); 1186-92. ©2016 AACR.
Health must be embedded across all government policy, MPs say
Authors: Ingrid Torjesen
Journal: BMJ (2016)

A new Cabinet Office minister post should be created to take responsibility for embedding health across all areas of government policy to ensure that health inequalities were tackled promptly and nationally, a committee of MPs has said.

This minister is needed, said a House of Commons Health Committee report on public health,1 because “tackling health inequalities and improving public health will not primarily happen in hospitals, even though hospitals receive the lion’s share of health funding. Rather, it requires a whole life course approach, tackling the wider determinants of health in local communities, and through joined-up policy making at a national level.”

The report said that cuts to public health and its frontline services in England were a false economy, because …
The Expert-Icu Study: a French Multicenter Study of Icu Physician-Based Determinants of Life-Sustaining Therapy During Night and Week-End Shifts
Authors: M. Ben-Rehouma, J-F Timsit, S. Ruckly, M. Darmon, C. Clec'h, C. Adrie, A. Tabah, L. Azoulay, M. Garrouste-Orgeas
Journal: Intensive Care Medicine (2013)
Extended Dual Antiplatelet Therapy in Patients With Prior Myocardial Infarction
Authors: John A. Bittl, Eric R. Bates, Sanjay Kaul
Journal: JAMA Cardiology (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
Anemia, Shortened Erythrocyte Lifespan and Stomatocytosis In a Flippase Mutant Mouse Strain
Authors: Coupland Lucy, Mehmet Yabas, Deborah Cromer, Markus Winterberg, Narcissus Teoh, Kiaran Kirk, Stefan Broer, Christopher Parish, Anselm Enders
Journal: Blood (2013)
Body Mass Index and All-Cause Mortality—Reply
Authors: Shoaib Afzal, Børge G. Nordestgaard
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Evaluation of Drug Utilization Review Programs
Authors: Robert Berringer, Ellen Friedla, Karen Rich
Journal: JAMA (2004)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Standards of Medical Care in Diabetes—2013
Journal: Diabetes Care (2012)

AClear evidence from well-conducted, generalizable RCTs that are adequately powered, including: c Evidence from a well-conducted multicenter trial c Evidence from a meta-analysis that incorporated quality ratings in the analysis Compelling nonexperimental evidence, i.e., "all or none" rule developed by the Centre for Evidence-Based Medicine at the University of Oxford Supportive evidence from well-conducted RCTs that are adequately powered, including:c Evidence from a well-conducted trial at one or more institutions c Evidence from a meta-analysis that incorporated quality ratings in the analysis B Supportive evidence from well-conducted cohort studies c Evidence from a well-conducted prospective cohort study or registry c Evidence from a well-conducted meta-analysis of cohort studies Supportive evidence from a well-conducted case-control study C Supportive evidence from poorly controlled or uncontrolled studies c Evidence from randomized clinical trials with one or more major or three or more minor methodological flaws that could invalidate the results c Evidence from observational studies with high potential for bias (such as case series with comparison with historical controls) c Evidence from case series or case reports Conflicting evidence with the weight of evidence supporting the recommendation E Expert consensus or clinical experience S12
High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells
Authors: Sina Oppermann, Jarkko Ylanko, Yonghong Shi, Santosh Hariharan, Christopher C. Oakes, Patrick M. Brauer, Juan C. Zúñiga-Pflücker, Brian Leber, David E. Spaner, David W. Andrews
Journal: Blood (2016)
Final Results of a Frontline Phase 1/2 Study of Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone (CRd) in Multiple Myeloma (MM)
Authors: Andrzej J Jakubowiak, Dominik Dytfeld, Sundar Jagannath, David H. Vesole, Tara B. Anderson, Brian K. Nordgren, Kristen Detweiler-Short, Daniel Lebovic, Keith E. Stockerl-Goldstein, Kent A. Griffith, Terri L. Jobkar, Diane E Durecki, Sandra M. Wear, Robert F Ott, Ammar Al-Zoubi, Melissa A Mietzel, M Hussein, Daniel Couriel, Joseph A Leveque, Ravi Vij
Journal: Blood (2011)
Human Trafficking: The Role of Medicine in Interrupting the Cycle of Abuse and Violence
Authors: Wendy Macias-Konstantopoulos
Journal: Annals of Internal Medicine (2016)

Human trafficking, a form of modern slavery, is an egregious violation of human rights with profound personal and public health implications. It includes forced labor and sexual exploitation of both U.S. and non-U.S. citizens and has been reported in all 50 states. Victims of human trafficking are currently among the most abused and disenfranchised persons in society, and they face a wide range of negative health outcomes resulting from their subjugation and exploitation. Medicine has an important role to play in mitigating the devastating effects of human trafficking on individuals and society. Victims are cared for in emergency departments, primary care offices, urgent care centers, community health clinics, and reproductive health clinics. In addition, they are unknowingly being treated in hospital inpatient units. Injuries and illnesses requiring medical attention thus represent unique windows of opportunity for trafficked persons to receive assistance from trusted health care professionals. With education and training, health care providers can recognize signs and symptoms of trafficking, provide trauma-informed care to this vulnerable population, and respond to exploited persons who are interested and ready to receive assistance. Multidisciplinary response protocols, research, and policy advocacy can enhance the impact of antitrafficking health care efforts to interrupt the cycle of abuse and violence for these victims.
Genomic diversity in established melanoma cell lines and human melanoma tumors.
Authors: Polina Shindiapina, Chery A Whipple, Jan L Fisher, Thomas H Hampton, Mary Jo Turk, David W. Mullins, Craig R Tomlinson, Camilo E. Fadul, Marc S. Ernstoff
Journal: Journal of Clinical Oncology (2016)

e13001 Background: Melanoma progression is often associated with a mutation in the BRAF oncogene that promotes constitutive activation of the MAPK signaling cascade. Analysis of malignant transformation of melanocytes and melanoma progression frequently utilizes immortalized melanoma cell lines that propagated in the laboratory. We studied the diversity of genetic mutations in the MAPK pathway in established melanoma cell lines and compared it to that of human melanoma tissue samples. Methods: We screened 30 well-established human melanoma cell lines, the majority of which were derived from melanoma metastases at dermal or nodal locations, for 85 mutations found within the AKT1, BRAF, KIT, KRAS, HRAS, NRAS, PIK3CA and PTEN genes by RT-PCR. We then interrogated 263 melanoma genomes available in the TCGA (The Cancer Genome Atlas) skin cutaneous melanoma dataset for the presence and frequency of these mutations. Mutational frequencies were determined by sorting the data in MS Excel. Results: BRAF was mutated in 39% of TCGA melanoma genomes and 53% of cell line genomes. NRAS genes were mutated in 26% of TCGA samples and 13% of cell lines. Cell lines were 34 times more likely to bear a KIT mutation than TCGA samples. Mutations in each of the 8 tested genes except PTEN were found in TCGA genome samples, while cell lines contained mutations in BRAF, KIT, NRAS, PTEN, and lacked any of the tested mutations in AKT1, KRAS, HRAS, PIK3CA. Cell lines exhibited a higher frequency of unique mutational combinations. Both BRAF and KIT were mutated in 13% of cell lines, and each of NRAS and KIT; NRAS and PTEN; and NRAS, BRAF and PTEN in 3.3% of cell lines; all these combinations were absent in TCGA melanoma genomes. Mutations in PIK3CA combined with either BRAF or NRAS were found in 1% of TCGA samples but absent from cell lines. Conclusions: These data indicate that mutational status and frequency of individual mutations and mutation combinations found in melanoma cell lines can diverge from that observed in clinical tissue specimens. Additional changes observed in cell lines may provide insight into evolutionary mutations in progressive melanoma. Understanding of genetic profiles of cell lines may provide additional information in their sensitivity to pathway inhibitors.
Climate Change and Future Pollen Allergy in Europe
Authors: Iain R. Lake, Natalia R. Jones, Maureen Agnew, Clare M. Goodess, Filippo Giorgi, Lynda Hamaoui-Laguel, Mikhail A. Semenov, Fabien Solomon, Jonathan Storkey, Robert Vautard, Michelle M. Epstein
Journal: Environmental Health Perspectives (2016)

Globally, pollen allergy is a major public health problem, but a fundamental unknown is the likely impact of climate change. To our knowledge, this is the first study to quantify the consequences of climate change upon pollen allergy in humans.
Complement-Regulatory Proteins CFHR1 and CFHR3 and Patient Response to Anti-CD20 Monoclonal Antibody Therapy
Authors: Laura M. Rogers, Sarah L. Mott, Brian J. Smith, Brian K. Link, Deniz Sahin, George J. Weiner
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Anti-CD20 mAb therapies, including rituximab and obinutuzumab (GA101), are common treatments for follicular lymphoma. In an effort to better understand the role of complement in mAb action, we recently performed germline SNP profiling on 142 follicular lymphoma patients and found rs3766404 genotype correlated with patient response to rituximab. To assess the role of three SNP-associated complement-regulatory proteins (CFH, CFHR1, and CFHR3) in clinical response to anti-CD20 mAb, we studied two cohorts of patients treated with anti-CD20 mAb. Experimental Design: Cohorts included the Iowa/Mayo Lymphoma SPORE observational cohort of subjects with a new diagnosis of follicular lymphoma treated with rituximab and the GAUSS prospective randomized trial cohort of follicular lymphoma subjects randomized to receive single-agent rituximab or obinutuzumab. Circulating protein expression was measured for CFH, CFHR1, and CFHR3 and correlated to clinical outcome. Results: rs3766404 genotype correlated with expression of the related downstream genes CFHR1 and CFHR3. Loss of CFHR1 expression correlated with inferior patient outcome in the observational cohort, but not in the GAUSS cohort. Loss of CFHR3 correlated with superior event-free survival in GAUSS subjects treated with obinutuzumab, but not rituximab. Conclusions: We conclude that the relationship between complement-regulatory proteins CFHR1 and CFHR3 and response to anti-CD20 mAb therapy varies based on the specific anti-CD20 mAb used. We propose that CFHR3 is a candidate biomarker for obinutuzumab response. Further studies are needed to validate these findings and to better understand how complement pathways and complement-regulatory proteins impact on the efficacy of anti-CD20 mAb therapy. Clin Cancer Res; 23(4); 954–61. ©2016 AACR.
Evidence for change in prognostic stratification of breast tumor subtypes.
Authors: S. S. Dawood, A. Buzdar, T. A. Buchholz, G. N. Hortobagyi, A. M. Gonzalez-Angulo
Journal: Journal of Clinical Oncology (2010)

602 Background: Before the introduction of trastuzumab the prognosis associated with molecular subtypes of breast cancer, using surrogates of hormone receptor (HR) and HER2 receptors, were ranked, in order of decreasing distant disease free survival (DDFS) rates, as luminal A (HR+/HER2-), luminal B (HR+/HER2+), HER2 (HR-/HER2+), and triple-negative (TN) (HR-/HER2-). The objective of this study was to determine whether trastuzumab has altered the prognostic stratification of breast tumor subtypes among women with stage I-III breast cancer. Methods: 5,019 women with stage I-III breast cancer and known HR and HER2 status diagnosed between 1998-2007 were identified from a single-institution prospective database. All women with HER2 positive disease received adjuvant trastuzumab. DDFS was estimated using the Kaplan-Meier product limit methods and compared across groups using log rank statistic. Cox proportional hazards models were then used to determine the association of DDFS and breast tumor subtype after adjusting for patient/tumor characteristics. Results: 3,010 (59.9%) women had luminal A tumors, 161 (3.2%) had luminal B tumors, 279 (5.6%) had HER2 tumors and 1569 had TN tumors. Median follow-up was 41 months. 5-year DDFS rates among women with luminal A, luminal B, HER2 and TN tumors was 80%, 90%, 72%, and 59% respectively (p < 0.0001). In the multivariable model, compared to women with luminal A tumors those with luminal B tumors had a decreased risk of distant recurrence (HR = 0.39, 95%CI 0.19-0.78, p = 0.0081) and those with HER2 tumors (HR = 1.32, 95%CI0.97-1.79, p = 0.07) and TN tumors (HR = 2.15, 95%CI 1.89-2.45, p < 0.001) had an increased risk of distant recurrence. Conclusions: Our results indicate that with the introduction of adjuvant trastuzumab, the prognostic stratification of breast cancer subtypes has changed, with patients with luminal B tumors having the best prognosis, followed in order by those with luminal A, HER2 disease and TN disease. Our results further show that hormone receptor status still plays an important role in the prognostic stratification of breast tumors regardless of HER2 status. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche
Surgeon, Scientist, and Entrepreneur: One Man’s Fight Against Cancer
Authors: Aria Razmaria
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Targeted sequencing informs the evaluation of normal karyotype cytopenic patients for low-grade myelodysplastic syndrome
Authors: E J Duncavage, J O'Brien, K Vij, C A Miller, G S Chang, J Shao, M A Jacoby, S Heath, M R Janke, K Elliott, R S Fulton, C Fronick, M O'Laughlin, P Westervelt, T J Ley, R K Wilson, M J Walter
Journal: Leukemia (2016)
BIIB021, an oral, synthetic non-ansamycin Hsp90 inhibitor: Phase I experience
Authors: A. Elfiky, M. W. Saif, M. Beeram, S. O' Brien, N. Lammanna, J. E. Castro, J. Woodworth, R. Perea, C. Storgard, D. D. Von Hoff
Journal: Journal of Clinical Oncology (2008)

2503 Background: BIIB021 is an oral fully synthetic Hsp90 inhibitor that is being developed for both solid and hematologic tumors. BIIB021 selectively and potently inhibits the molecular chaperone Hsp90 thereby inhibiting the proper assembly of multiple oncogenic proteins involved in tumor growth and survival. Phase I studies assessing various dosing regimens have been initiated to determine safety, MTD, tolerability, and pharmacokinetics (PK) of BIIB021 in patients (pts) with advanced solid tumors (ST) or chronic lymphocytic leukemia (CLL). Methods: Three to 6 pts were enrolled into sequential dose cohorts of BIIB021 po daily for 3 weeks followed by 1 week off (CLL) or twice weekly for 3 weeks followed by 1 week off (ST). Pts remained on study until tumor progression or unacceptable toxicities occurred. Results: Of 23 pts administered BIIB021 (5 in CLL; 18 in ST), 14 were men (3 in CLL and 11 in ST); median age was 66 (45, 79) yrs in CLL and 59.5 (35, 81) in ST. Two DLTs (Gr3 syncope, Gr3 dizziness) were reported in pts receiving 800 mg po twice weekly. Gr 3 or 4 AEs in ST were fatigue, hyponatremia and hypoglycemia; in CLL 1 pt experienced Gr3 abnormal LFT. AEs in CLL in >1 pts were: abdominal pain and diarrhea (n=2 each). AEs in ST in >2 pts were: fatigue (n=6); nausea, vomiting, hot flush (n=5 each), dry mouth (n=4), flushing (n=3). BIIB021 demonstrated dose-linear kinetics with a T1/2 of ∼1h and no evidence of accumulation with multiple dosing. PD assessments indicate significant induction of Hsp70 and inhibition of the biomarker Her 2/neu extracellular domain (ECD) in the ST trial. Efficacy: One pt with CLL (25 mg) had a 39% reduction in lymph node size. In ST, 11 of 16 (68%) evaluable subjects reported stable disease. Conclusions: BIIB021 appears to be generally well tolerated. 800 mg BIIB021 twice weekly exceeds the safe and tolerated dose. Biologic activity has been confirmed with elevations of serum and intracellular Hsp70 and a dose-related decrease in serum Her-2 ECD. Further studies evaluating BIIB021 without a drug holiday and in combination with chemotherapy and targeted agents are planned. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Biogen Idec Biogen Idec Biogen Idec