tbuckley/cabot-search huggingface dataset:
TBCRC009: A Multicenter Phase II Clinical Trial of Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast Cancer
Authors: Steven J. Isakoff, Erica L. Mayer, Lei He, Tiffany A. Traina, Lisa A. Carey, Karen J. Krag, Hope S. Rugo, Minetta C. Liu, Vered Stearns, Steven E. Come, Kirsten M. Timms, Anne-Renee Hartman, Darrel R. Borger, Dianne M. Finkelstein, Judy E. Garber, Paula D. Ryan, Eric P. Winer, Paul E. Goss, Leif W. Ellisen
Journal: Journal of Clinical Oncology (2015)

The identification of patients with metastatic triple-negative breast cancer (mTNBC) who are expected to benefit from platinum-based chemotherapy is of interest. We conducted a single-arm phase II clinical trial of single-agent platinum for mTNBC with biomarker correlates.Patients with mTNBC received first- or second-line cisplatin (75 mg/m(2)) or carboplatin (area under the concentration-time curve 6) by physician's choice once every 3 weeks. Coprimary end points were objective response rate (RR) and response prediction by p63/p73 gene expression. Secondary and exploratory end points included toxicity assessment, RR in cisplatin versus carboplatin, and RR in molecularly defined subgroups, including BRCA1/2 mutation carriers.Patients (N = 86; 69 as first-line therapy) received cisplatin (n = 43) or carboplatin (n = 43). RR was 25.6% (95% CI, 16.8% to 36%) and was numerically higher with cisplatin (32.6%) than with carboplatin (18.7%). RR was 54.5% in patients with germline BRCA1/2 mutations (n = 11). In patients without BRCA1/2 mutations (n = 66), exploratory analyses showed that a BRCA-like genomic instability signature (n = 32) discriminated responding and nonresponding tumors (mean homologous recombination deficiency-loss of heterozygosity/homologous recombination deficiency-large-scale state transitions [HRD-LOH/HRD-LST] scores were 12.68 and 5.11, respectively), whereas predefined analysis by p63/p73 expression status (n = 61), p53 and PIK3CA mutation status (n = 53), or PAM50 gene expression subtype (n = 55) did not. Five of the six long-term responders alive at a median of 4.5 years lacked germline BRCA1/2 mutations, and two of them had increased tumor HRD-LOH/HRD-LST scores.Platinum agents are active in mTNBC, especially in patients with germline BRCA1/2 mutations. A measure of tumor DNA repair function may identify patients without mutations who could benefit from platinum therapy agents. Prospective controlled confirmatory trials are warranted.
Origins and Early Evolution of the Mevalonate Pathway of Isoprenoid Biosynthesis in the Three Domains of Life
Authors: J. Lombard, D. Moreira
Journal: Molecular Biology and Evolution (2010)

Isoprenoids are a very diverse family of organic compounds widespread in the three domains of life. Although they are produced from the condensation of the same precursors in all organisms (isopentenyl pyrophosphate and dimethylallyl diphosphate), the evolutionary origin of their biosynthesis remains controversial. Two independent nonhomologous metabolic pathways are known: the mevalonate (MVA) pathway in eukaryotes and archaea and the methylerythritol phosphate (MEP) pathway in bacteria and several photosynthetic eukaryotes. The MVA pathway is also found in a few bacteria, what has been explained in previous works by recent acquisition by horizontal gene transfer (HGT) from eukaryotic or archaeal donors. To reconsider the question of the evolutionary origin of the MVA pathway, we have studied the origin and the evolution of the enzymes of this pathway using phylogenomic analyses upon a taxon-rich sequence database. On the one hand, our results confirm the conservation in archaea of an MVA pathway partially different from eukaryotes. This implies that each domain of life possesses a characteristic major isoprenoid biosynthesis pathway: the classical MVA pathway in eukaryotes, a modified MVA pathway in archaea, and the MEP pathway in bacteria. On the other hand, despite the identification of several HGT events, our analyses support that the MVA pathway was ancestral not only in archaea and eukaryotes but also in bacteria, in contradiction with previous claims that the presence of this pathway in bacteria was due to HGT from other domains. Therefore, the MVA pathway is likely an ancestral metabolic route in all the three domains of life, and hence, it was probably present in the last common ancestor of all organisms (the cenancestor). These findings open the possibility that the cenancestor had membranes containing isoprenoids.
Necrotising myositis in Behcet's disease: characteristic features on magnetic resonance imaging and a review of the literature
Authors: H Sarui
Journal: Annals of the Rheumatic Diseases (2002)

Myositis is rarely associated with Behcet's disease. We report such a case with characteristic magnetic resonance imaging (MRI) findings, and review the literature.

A 29 year old man was first admitted to Matsunami General Hospital because of high fever and muscle pain of both lower legs, finally resulting in him being unable to walk. Painful multiple subcutaneous nodules of both lower legs and the left arm were seen. There was no history of trauma. Total leucocytes, erythrocyte sedimentation rate, and C reactive protein were raised. The serum creatine kinase value was normal. An MRI study of the lower legs (fig 1) showed a focal mass-like lesion, about 3 cm in diameter, in the left gastrocnemius muscle with a decreased intensity on a T1 weighted image compared with that for normal muscle. Gadolinium enhanced T1 weighted images showed a well defined …
Effects of an Acute Care for Elders Unit on Costs and 30-Day Readmissions
Authors: Kellie L. Flood, Paul A. MacLennan, Deborah McGrew, Darlene Green, Cindy Dodd, Cynthia J. Brown
Journal: JAMA Internal Medicine (2013)

Providing high-quality care while containing cost is essential for the economic stability of our health care system. The United States is experiencing a rapidly growing elderly population. The Acute Care for Elders (ACE) unit interdisciplinary team model of care has been shown to improve outcomes in hospitalized older adults. The University of Alabama at Birmingham ACE unit incorporates evidence-based care processes. We hypothesized that the ACE model would also reduce costs.To examine variable direct costs from an interdisciplinary ACE compared with a multidisciplinary usual care (UC) unit.Retrospective cohort study.Tertiary care academic medical center.Hospitalists' patients aged 70 years or older spending the entirety of their hospitalization in either the ACE or UC unit in fiscal year 2010.Using administrative data, we analyzed variable direct costs for ACE and UC patients. We also conducted a subset analysis restricted to the 25 most common diagnosis related groups (DRGs) shared by ACE and UC patients. Generalized linear regression was used to estimate cost ratios and 95% confidence intervals adjusted for age, sex, comorbidity score, and case mix index (CMI).A total of 818 hospitalists' patients met inclusion criteria: 428 from the ACE and 390 from the UC unit. For this study group (all DRGs), the mean (SD) variable direct cost per patient was $2109 ($1870) for ACE and $2480 ($2113) for UC (P = .009). Adjusted cost ratios revealed significant cost savings for patients with low (0.82; 95% CI, 0.72-0.94) or moderate (0.74; 95% CI, 0.62-0.89) CMI scores; care was cost neutral for patients with high CMI scores (1.13; 95% CI, 0.93-1.37). Significantly fewer ACE patients than UC patients were readmitted within 30 days of discharge (7.9% vs 12.8%; P = .02). Subset analysis of the 25 most common DRGs revealed a significantly reduced mean (SD) variable direct cost per patient for ACE compared with UC patients ($1693 [$1063] vs $2138 [$1431]; P < .001); cost ratios for total (0.78; 95% CI, 0.70-0.87) and daily (0.89; 95% CI, 0.85-0.94) variable direct costs remained significant after adjustment.The ACE unit team model reduces costs and 30-day readmissions. In an era when improving care processes while reducing costs is a vital objective for the Medicare program and our nation as a whole, the ACE model meets these goals.
Emerin and the Nuclear Lamina in Muscle and Cardiac Disease
Authors: James M. Holaska
Journal: Circulation Research (2008)

The human genome is contained within the nucleus and is separated from the cytoplasm by the nuclear envelope. Mutations in the nuclear envelope proteins emerin and lamin A cause a number of diseases including premature aging syndromes, muscular dystrophy, and cardiomyopathy. Emerin and lamin A are implicated in regulating muscle- and heart-specific gene expression and nuclear architecture. For example, lamin A regulates the expression and localization of gap junction and intercalated disc components. Additionally, emerin and lamin A are also required to maintain nuclear envelope integrity. Demonstrating the importance of maintaining nuclear integrity in heart disease, atrioventricular node cells lacking lamin A exhibit increased nuclear deformation and apoptosis. This review highlights the present understanding of lamin A and emerin function in regulating nuclear architecture, gene expression, and cell signaling and discusses putative mechanisms for how specific mutations in lamin A and emerin cause cardiac- or muscle-specific disease.
Safety and Efficacy of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis
Authors: Animesh Pardanani, Jason R. Gotlib, Catriona Jamieson, Jorge E. Cortes, Moshe Talpaz, Richard M. Stone, Michael H. Silverman, D. Gary Gilliland, Jolene Shorr, Ayalew Tefferi
Journal: Journal of Clinical Oncology (2011)

Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients frequently harbor JAK-STAT activating mutations that are sensitive to TG101348, a selective small-molecule Janus kinase 2 (JAK2) inhibitor.In a multicenter phase I trial, oral TG101348 was administered once a day to patients with high- or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia myelofibrosis.Fifty-nine patients were treated, including 28 in the dose-escalation phase. The maximum-tolerated dose was 680 mg/d, and dose-limiting toxicity was a reversible and asymptomatic increase in the serum amylase level. Forty-three patients (73%) continued treatment beyond six cycles; the median cumulative exposure to TG101348 was 380 days. Adverse events included nausea, vomiting, diarrhea, anemia, and thrombocytopenia; corresponding grades 3 to 4 incidence rates were 3%, 3%, 10%, 35%, and 24%. TG101348 treatment had modest effect on serum cytokine levels, but greater than half of the patients with early satiety, night sweats, fatigue, pruritus, and cough achieved rapid and durable improvement in these symptoms. By six and 12 cycles of treatment, 39% and 47% of patients, respectively, had achieved a spleen response per International Working Group criteria. The majority of patients with leukocytosis or thrombocytosis at baseline (n = 28 and n = 10, respectively) achieved normalization of blood counts after six (57% and 90%, respectively) and 12 (56% and 88%, respectively) cycles. A significant decrease in JAK2 V617F allele burden was observed at 6 months in mutation-positive patients (n = 51; P = .04), particularly in the subgroup with allele burden greater than 20% (n = 23; P < .01); the decrease was durable at 12 months.TG101348 is well tolerated and produces significant reduction in disease burden and durable clinical benefit in patients with myelofibrosis.
Neonatal Thyroid Function in Seveso 25 Years after Maternal Exposure to Dioxin
Authors: Andrea Baccarelli, Sara M Giacomini, Carlo Corbetta, Maria Teresa Landi, Matteo Bonzini, Dario Consonni, Paolo Grillo, Donald G Patterson, Angela C Pesatori, Pier Alberto Bertazzi
Journal: PLoS Medicine (2008)

Neonatal hypothyroidism has been associated in animal models with maternal exposure to several environmental contaminants; however, evidence for such an association in humans is inconsistent. We evaluated whether maternal exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a persistent and widespread toxic environmental contaminant, is associated with modified neonatal thyroid function in a large, highly exposed population in Seveso, Italy.Between 1994 and 2005, in individuals exposed to TCDD after the 1976 Seveso accident we conducted: (i) a residence-based population study on 1,014 children born to the 1,772 women of reproductive age in the most contaminated zones (A, very high contamination; B, high contamination), and 1,772 age-matched women from the surrounding noncontaminated area (reference); (ii) a biomarker study on 51 mother-child pairs for whom recent maternal plasma dioxin measurements were available. Neonatal blood thyroid-stimulating hormone (b-TSH) was measured on all children. We performed crude and multivariate analyses adjusting for gender, birth weight, birth order, maternal age, hospital, and type of delivery. Mean neonatal b-TSH was 0.98 microU/ml (95% confidence interval [CI] 0.90-1.08) in the reference area (n = 533), 1.35 microU/ml (95% CI 1.22-1.49) in zone B (n = 425), and 1.66 microU/ml (95% CI 1.19-2.31) in zone A (n = 56) (p < 0.001). The proportion of children with b-TSH > 5 microU/ml was 2.8% in the reference area, 4.9% in zone B, and 16.1% in zone A (p < 0.001). Neonatal b-TSH was correlated with current maternal plasma TCDD (n = 51, beta = 0.47, p < 0.001) and plasma toxic equivalents of coplanar dioxin-like compounds (n = 51, beta = 0.45, p = 0.005).Our data indicate that environmental contaminants such as dioxins have a long-lasting capability to modify neonatal thyroid function after the initial exposure.
The Risks and Benefits of Indacaterol — The FDA's Review
Authors: Badrul A Chowdhury, Sally M Seymour, Theresa M Michele, Anthony G Durmowicz, Dongmei Liu, Curtis J Rosebraugh
Journal: New England Journal of Medicine (2011)

In July, the FDA approved Arcapta Neohaler (indacaterol maleate powder), a long-acting beta-agonist, at a daily dose of 75 μg for chronic obstructive pulmonary disease. Why was this dose selected, after the European Medicines Agency approved 150-μg and 300-μg doses?
Phase II Multicenter Study of the Antiepidermal Growth Factor Receptor Monoclonal Antibody Cetuximab in Combination With Platinum-Based Chemotherapy in Patients With Platinum-Refractory Metastatic and/or Recurrent Squamous Cell Carcinoma of the Head and Neck
Authors: José Baselga, José M. Trigo, Jean Bourhis, Jacques Tortochaux, Hernán Cortés-Funes, Ricardo Hitt, Pere Gascón, Nadia Amellal, Andreas Harstrick, André Eckardt
Journal: Journal of Clinical Oncology (2005)

To evaluate the efficacy and safety of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN).Ninety-six eligible patients received cetuximab (initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2) followed by platinum chemotherapy at the same dose and schedule at which progressive disease was documented before entry onto the study.The response rate, based on an independently read assessment, in the intent-to-treat population was 10%, with a disease control rate (complete response, partial response [PR], and stable disease) of 53%. The median time to progression and overall survival were 85 and 183 days, respectively; both were longest in patients achieving a PR (median, 203.5 and 294 days, respectively). Treatment was well tolerated. The most common cetuximab-related adverse events were skin reactions, particularly an acne-like rash.The combination of cetuximab and platinum chemotherapy is an active and well-tolerated approach to the treatment of this poor-prognosis patient population with platinum-refractory recurrent or metastatic SCCHN for whom there are no recommended standard therapeutic options.
Physicians and Domestic Violence
Authors: Oscar W. Clark
Journal: JAMA (1992)

DOMESTIC violence, spouse abuse, and battering all refer to the victimization of a person with whom the abuser has or has had an intimate/romantic relationship.<sup>1,2</sup>These three terms are used interchangeably throughout this article. Domestic violence may take the form of physical, sexual, and psychological abuse, is generally repeated, and often escalates within relationships.<sup>3-7</sup> Most evidence indicates that domestic violence is predominantly perpetrated by men against women.<sup>8-11</sup>Some evidence suggests that women are as likely to use violence against male partners as men are against female partners.<sup>12</sup>However, these research findings have been criticized on various counts as misleading.<sup>13(p312),14(pp181-183),15</sup>In particular, it is clear that the impact on the health of female victims of domestic violence is generally much more severe than the impact on the health of male victims.<sup>3,14,16</sup>Battering is also known to occur in gay and lesbian relationships, but there has
Chemokines in the gastric mucosa in <i>Helicobacter pylori</i> infection
Authors: Y Yamaoka, M Kita, T Kodama, N Sawai, T Tanahashi, K Kashima, J Imanishi
Journal: Gut (1998)

Although chemokines have been suggested to play an important role in Helicobacter pylori associated gastritis, few studies have investigated the role of chemokines other than interleukin 8 (IL-8) in gastric mucosa.To investigate the expression and production patterns of various chemokines using gastric biopsy specimens.In 192 patients, expression patterns of C-X-C chemokines (IL-8 and growth regulated alpha (GRO alpha)) and C-C chemokines (regulated on activation, normal T cell expressed and presumably secreted (RANTES), monocyte chemotactic and activating factor (MCAF), macrophage inflammatory protein 1 alpha (MIP-1 alpha), and MIP-1 beta) were examined using reverse transcription polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA). cagA gene was identified using PCR.H pylori infection was associated with increased rates of expression of mRNA for IL-8, GRO alpha, RANTES, and MIP-1 alpha and with increased levels of mucosal IL-8 and GRO alpha. IL-8 and GRO alpha levels correlated with the density of H pylori in both the antrum and corpus. The levels of these chemokines correlated with cellular infiltration in the antrum but not the corpus. cagA gene positive H pylori infection was associated with increased rates of expression of mRNA for IL-8 and GRO alpha and with increased levels of these chemokines.H pylori infection is associated with increased expression rates and production of C-X-C chemokines (IL-8 and GRO alpha), but not with increased production of C-C chemokines. Although H pylori infection is associated with increased C-X-C chemokines in the antrum and corpus, there is a difference in the inflammatory response between these two areas of the stomach.
Induction therapy with adalimumab plus methotrexate for 24 weeks followed by methotrexate monotherapy up to week 48 versus methotrexate therapy alone for DMARD-naïve patients with early rheumatoid arthritis: HIT HARD, an investigator-initiated study
Authors: Jacqueline Detert, Hans Bastian, Joachim Listing, Anja Weiß, Siegfried Wassenberg, Anke Liebhaber, Karin Rockwitz, Rieke Alten, Klaus Krüger, Rolf Rau, Christina Simon, Eva Gremmelsbacher, Tanja Braun, Bettina Marsmann, Vera Höhne-Zimmer, Karl Egerer, Frank Buttgereit, Gerd-R Burmester
Journal: Annals of the Rheumatic Diseases (2012)

To investigate the long-term effects of induction therapy with adalimumab (ADA) plus methotrexate (MTX) in comparison with placebo (PBO) plus MTX in DMARD-naïve patients with active early rheumatoid arthritis (RA).Patients with active early RA (disease duration of ≤12 months) were randomly assigned to receive 40 mg ADA subcutaneously every other week (eow) plus MTX 15 mg/week subcutaneously or PBO plus MTX subcutaneously at 15 mg/week over 24 weeks. Thereafter, all patients received MTX monotherapy up to week 48. The primary outcome was the Disease Activity Score 28 (DAS28) at week 48. Secondary outcomes included proportions of patients in remission (DAS28<2.6), ACR responses, Health Assessment Questionnaire (HAQ) score and radiographic progression.87 patients were assigned to ADA/MTX and 85 patients to PBO/MTX. At baseline, DAS28 was 6.2±0.8 in the ADA/MTX and 6.3±0.9 in the PBO/MTX groups. At week 24, treatment with ADA/MTX compared with PBO/MTX resulted in a greater reduction in DAS28 (3.0±1.2 vs 3.6±1.4; p=0.009) and other secondary outcomes such as DAS28 remission rate (47.9% vs 29.5%; p=0.021) and HAQ (0.49±0.6 vs 0.72±0.6; p=0.0014). At week 48, the difference in clinical outcomes between groups was not statistically significant (DAS28: 3.2±1.4 vs 3.4±1.6; p=0.41). Radiographic progression at week 48 was significantly greater in patients administered PBO/MTX (Sharp/van der Heijde score: ADA/MTX 2.6 vs PBO/MTX 6.4; p=0.03, Ratingen score: 1.7 vs 4.2; p=0.01).A greater reduction in radiographic progression after initial combination therapy with ADA and MTX was seen at week 48, even after discontinuation of ADA treatment at week 24. This sustained effect was not found at the primary endpoint (DAS28 reduction).
A New Era in Understanding Diabetes Disparities Among U.S. Latinos—All Are Not Equal
Authors: Lenny López, Sherita Hill Golden
Journal: Diabetes Care (2014)

Latinos currently comprise 15% of the U.S. population. It is estimated that by 2050, 1 out of 3 U.S. residents will be Latino (1). The Latino population is a heterogeneous mix of people born in and outside the U.S., with different social, cultural, and behavioral attitudes that may affect health. The prevalence of diabetes in adults over the age of 20 years is higher among Latinos compared with non-Hispanic whites (2). However, the differences in diabetes and obesity prevalence among Latino subgroups are masked when all individuals are combined into a single group. Specifically, the higher overall diabetes prevalence is driven by Puerto Rican and Mexican Americans, while Cuban, Central, and South Americans have similar prevalence to non-Hispanic whites (2,3). The Endocrine Society’s Scientific Statement on Health Disparities in Endocrine Disorders identified that “a major gap in our current understanding of race/ethnic disparities in endocrine disorders is a failure of most studies to specify Hispanic-American and Asian-American subgroups” and recommended that “future studies accurately identify ethnic subgroups” (2). The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is the first U.S. population-based study to address this knowledge gap with 16,415 Latino women and men (3,4). Prior to the creation of this cohort, the Centers for Disease Control and Prevention was unable to estimate the total prevalence of diabetes among Latinos (5). In this issue, two articles published from the HCHS/SOL fill in this void in diabetes epidemiology (5,6).

Both articles demonstrate high prevalence of diabetes and the metabolic syndrome among Latinos, and their major strength is highlighting the heterogeneity in prevalence among U.S. Latinos of diverse origins. …
Biopsy and selective recall compared with immediate large loop excision in management of women with low grade abnormal cervical cytology referred for colposcopy: multicentre randomised controlled trial
Authors: Linda Sharp, Maggie Cruickshank, Julian Little, Seonaidh Cotton, Kirsten Harrild, Claire Cochran, Ian Duncan, Nicola Gray, Rob Hammond, Louise Smart, Alison Thornton, Norman Waugh, Claire Woolley
Journal: BMJ (2009)

Objectives To compare the effectiveness of punch biopsy and selective recall for treatment versus a policy of immediate treatment by large loop excision in the management of women with low grade abnormal cervical cytology referred for colposcopy.