tbuckley/cabot-search huggingface dataset:
A Phase I Trial of the Oral, Multikinase Inhibitor Sorafenib in Combination with Carboplatin and Paclitaxel
Authors: Keith T. Flaherty, Joan Schiller, Lynn M. Schuchter, Glenn Liu, David A. Tuveson, Maryann Redlinger, Chetan Lathia, Chenghua Xia, Oana Petrenciuc, Sunil R. Hingorani, Michael A. Jacobetz, Patricia A. Van Belle, David Elder, Marcia S. Brose, Barbara L. Weber, Mark R. Albertini, Peter J. O'Dwyer
Journal: Clinical Cancer Research (2008)

Abstract Purpose: This study evaluated the safety, maximum tolerated dose, pharmacokinetics, and antitumor activity of sorafenib, a multikinase inhibitor, combined with paclitaxel and carboplatin in patients with solid tumors. Patients and Methods: Thirty-nine patients with advanced cancer (24 with melanoma) received oral sorafenib 100, 200, or 400 mg twice daily on days 2 to 19 of a 21-day cycle. All patients received carboplatin corresponding to AUC6 and 225 mg/m2 paclitaxel on day 1. Pharmacokinetic analyses were done for sorafenib on days 2 and 19 of cycle 1 and for paclitaxel on day 1 of cycles 1 and 2. Pretreatment tumor samples from 17 melanoma patients were analyzed for BRAF mutations. Results: Sorafenib was well tolerated at the doses evaluated. The most frequent severe adverse events were hematologic toxicities (grade 3 or 4 in 33 patients, 85%). Twenty-seven (69%) patients had sorafenib-related adverse events, the most frequent of which were dermatologic events (26 patients, 67%). Exposure to paclitaxel was not altered by intervening treatment with sorafenib. Treatment with sorafenib, paclitaxel, and carboplatin resulted in one complete response and nine partial responses, all among patients with melanoma. There was no correlation between BRAF mutational status and treatment responses in patients with melanoma. Conclusions: The recommended phase II doses are oral 400 mg twice daily sorafenib, carboplatin at an AUC6 dose, and 225 mg/m2 paclitaxel. The tumor responses observed with this combined regimen in patients with melanoma warrant further investigation.
Phase III Trial of Carboplatin Plus Paclitaxel With or Without Gemcitabine in First-Line Treatment of Epithelial Ovarian Cancer
Authors: Andreas du Bois, Jørn Herrstedt, Anne-Claire Hardy-Bessard, Hans-Helge Müller, Philipp Harter, Gunnar Kristensen, Florence Joly, Jens Huober, Elisabeth Åvall-Lundqvist, Béatrice Weber, Christian Kurzeder, Svetislav Jelic, Eric Pujade-Lauraine, Alexander Burges, Jacobus Pfisterer, Martina Gropp, Anne Staehle, Pauline Wimberger, Christian Jackisch, Jalid Sehouli
Journal: Journal of Clinical Oncology (2010)

One attempt to improve long-term survival in patients with advanced ovarian cancer was thought to be the addition of more non-cross-resistant drugs to platinum-paclitaxel combination regimens. Gemcitabine was among the candidates for a third drug.We performed a prospective, randomized, phase III, intergroup trial to compare carboplatin plus paclitaxel (TC; area under the curve [AUC] 5 and 175 mg/m(2), respectively) with the same combination and additional gemcitabine 800 mg/m(2) on days 1 and 8 (TCG) in previously untreated patients with advanced epithelial ovarian cancer. TC was administered intravenously (IV) on day 1 every 21 days for a planned minimum of six courses. Gemcitabine was administered by IV on days 1 and 8 of each cycle in the TCG arm.Between 2002 and 2004, 1,742 patients were randomly assigned; 882 and 860 patients received TC and TCG, respectively. Grades 3 to 4 hematologic toxicity and fatigue occurred more frequently in the TCG arm. Accordingly, quality-of-life analysis during chemotherapy showed a disadvantage in the TCG arm. Although objective response was slightly higher in the TCG arm, this did not translate into improved progression-free survival (PFS) or overall survival (OS). Median PFS was 17.8 months for the TCG arm and 19.3 months for the TC arm (hazard ratio [HR], 1.18; 95% CI, 1.06 to 1.32; P = .0044). Median OS was 49.5 for the TCG arm and 51.5 months for the TC arm (HR, 1.05; 95% CI, 0.91 to 1.20; P = .5106).The addition of gemcitabine to carboplatin plus paclitaxel increased treatment burden, reduced PFS time, and did not improve OS in patients with advanced epithelial ovarian cancer. Therefore, we recommend no additional clinical use of TCG in this population.
Duodenal Infusion of Donor Feces for Recurrent<i>Clostridium difficile</i>
Authors: Els van Nood, Anne Vrieze, Max Nieuwdorp, Susana Fuentes, Erwin G. Zoetendal, Willem M. de Vos, Caroline E. Visser, Ed J. Kuijper, Joep F.W.M. Bartelsman, Jan G.P. Tijssen, Peter Speelman, Marcel G.W. Dijkgraaf, Josbert J. Keller
Journal: New England Journal of Medicine (2013)

Recurrent Clostridium difficile infection is difficult to treat, and failure rates for antibiotic therapy are high. We studied the effect of duodenal infusion of donor feces in patients with recurrent C. difficile infection.
Efficacy of Sertraline in a 12-Week Trial for Generalized Anxiety Disorder
Authors: Christer Allgulander, Alv A. Dahl, Carol Austin, Philip L.P. Morris, Jesper A. Sogaard, Rana Fayyad, Stan P. Kutcher, Cathryn M. Clary
Journal: American Journal of Psychiatry (2004)

Sertraline's efficacy and tolerability in treating generalized anxiety disorder were evaluated.Adult outpatients with DSM-IV generalized anxiety disorder and a total score of 18 or higher on the Hamilton Anxiety Rating Scale were eligible. After a 1-week single-blind placebo lead-in, patients were randomly assigned to 12 weeks of double-blind treatment with placebo (N=188, mean baseline anxiety score=25) or flexible doses (50-150 mg/day) of sertraline (N=182, mean anxiety score=25). The primary outcome measure was baseline-to-endpoint change in the Hamilton anxiety scale total score. A secondary efficacy measure was the Clinical Global Impression (CGI) improvement score; response was defined as a score of 2 or less.Sertraline patients had significantly greater improvement than placebo patients on all efficacy measures at week 4. Analysis of covariance of the intent-to-treat group at endpoint (with the last observation carried forward) showed a significant difference in the decrease from baseline of the least-square mean total score on the Hamilton anxiety scale between sertraline (mean=11.7) and placebo (mean=8.0). Significantly greater endpoint improvement with sertraline than placebo was obtained for mean scores on the Hamilton anxiety scale psychic factor (6.7 versus 4.1) and somatic factor (5.0 versus 3.9). The rate of responders, based on CGI improvement and last observation carried forward, was significantly higher for sertraline (63%) than placebo (37%). Sertraline was well tolerated; 8% of patients versus 10% for placebo dropped out because of adverse events.Sertraline appears to be efficacious and well tolerated in the treatment of generalized anxiety disorder.
Hepatic histological findings in suspected drug‐induced liver injury: Systematic evaluation and clinical associations
Authors: David E. Kleiner, Naga P. Chalasani, William M. Lee, Robert J. Fontana, Herbert L. Bonkovsky, Paul B. Watkins, Paul H. Hayashi, Timothy J. Davern, Victor Navarro, Rajender Reddy, Jayant A. Talwalkar, Andrew Stolz, Jiezhun Gu, Huiman Barnhart, Jay H. Hoofnagle
Journal: Hepatology (2013)

Drug-induced liver injury (DILI) is considered to be a diagnosis of exclusion. Liver biopsy may contribute to diagnostic accuracy, but the histological features of DILI and their relationship to biochemical parameters and outcomes are not well defined. We have classified the pathological pattern of liver injury and systematically evaluated histological changes in liver biopsies obtained from 249 patients with suspected DILI enrolled in the prospective, observational study conducted by the Drug Induced Liver Injury Network. Histological features were analyzed for their frequency within different clinical phenotypes of liver injury and to identify associations between clinical and laboratory findings and histological features. The most common histological patterns were acute (21%) and chronic hepatitis (14%), acute (9%) and chronic cholestasis (10%), and cholestatic hepatitis (29%). Liver histology from 128 patients presenting with hepatocellular injury had more severe inflammation, necrosis, and apoptosis and more frequently demonstrated lobular disarray, rosette formation, and hemorrhage than those with cholestasis. Conversely, histology of the 73 patients with cholestatic injury more often demonstrated bile plugs and duct paucity. Severe or fatal hepatic injury in 46 patients was associated with higher degrees of necrosis, fibrosis stage, microvesicular steatosis, and ductular reaction among other findings, whereas eosinophils and granulomas were found more often in those with milder injury. Conclusion : We describe an approach for evaluating liver histology in DILI and demonstrate numerous associations between pathological findings and clinical presentations that may serve as a foundation for future studies correlating DILI pathology with its causality and outcome. (Hepatology 2014;59:661–670)
Receptor activator NF-kappaB ligand (RANKL) expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathy, osteoarthritis, and from normal patients: semiquantitative and quantitative analysis
Authors: T N Crotti
Journal: Annals of the Rheumatic Diseases (2002)

<b>Objectives:</b> To compare receptor activator of NF-κB ligand (RANKL) production in the synovial tissue from patients with active rheumatoid arthritis (RA), inactive RA, spondyloarthropathies (SpA), osteoarthritis, and from normal subjects. In addition, to establish the cell lineages expressing RANKL in these tissues. <b>Methods:</b> Immunohistological analysis of frozen synovial tissue biopsy specimens was performed using a monoclonal antibody (mAb) to detect RANKL. Sections were evaluated by computer assisted image analysis and semiquantitative analysis to compare RANKL expression between groups. Dual and sequential labelling with mAb RANKL and cell lineage specific monoclonal antibodies were used to determine the types of cells expressing RANKL. <b>Results:</b> Higher levels of RANKL were expressed in tissues from patients with active RA and SpA than in tissues from patients with inactive RA, osteoarthritis, and from normal subjects. RANKL protein was associated with CD3 antigen-positive lymphocytes and some macrophages. RANKL was predominantly associated with activated, memory T cells (CD45Ro positive cells) in patients with active RA and spondyloarthropathy (SpA). <b>Conclusions:</b> The highest levels of RANKL were detected in patients with RA with active synovitis and in some patients with SpA. An increase in RANKL in the inflamed joint of patients with RA, produced by infiltrating activated T cells and macrophages, is likely to be an important cause of joint erosions in RA.
Expression of Stress Response Protein Grp78 Is Associated with the Development of Castration-Resistant Prostate Cancer
Authors: Llana Pootrakul, Ram H. Datar, Shan-Rong Shi, Jie Cai, Debra Hawes, Susan G. Groshen, Amy S. Lee, Richard J. Cote
Journal: Clinical Cancer Research (2006)

Abstract Background: Induction of molecular chaperone Grp78 (78-kDa glucose-regulated protein) occurs in stress conditions that often characterize tumor microenvironments. We investigated the role of Grp78 in prostate cancer progression and the development of castration resistance, where cancer cells continue to survive despite the stress of an androgen-starved environment. Experimental Design: Immunohistochemistry was done to examine Grp78 expression in 219 prostate cancers from patients with pathologic stage T3N0M0 disease [androgen ablation naive (untreated) and androgen ablation exposed (treated)] and castration-resistant prostate cancer. Classification of tumors was based on intensity of Grp78 cytoplasmic immunoreactivity and percentage of immunoreactive tumor cells. The associations of Grp78 expression with prostate cancer recurrence (clinical and/or serum prostate-specific antigen) and survival were examined in the untreated stage T3N0M0 group. Grp78 expression was also analyzed in the androgen-dependent LNCaP and castration-resistant C42B cell lines. Results: The percentage of tumor cells expressing Grp78 was strongly associated with castration-resistant status (P = 0.005). Increased Grp78 expression was consistently associated with greater risk of prostate cancer recurrence and worse overall survival in patients who had not undergone prior hormonal manipulation. Grp78 expression was also increased in the castration-resistant LNCaP-derived cell line C42B and in LNCaP cells grown in androgen-deprived conditions compared with LNCaP cells grown in androgen-rich media. Conclusion: Our findings show that up-regulation of Grp78 is associated with the development of castration resistance, possibly in part by augmenting cell survival as previously suggested, and may serve as an important prognostic indicator of recurrence in a subset of patients with T3N0M0 disease.
Malpractice. The problem in perspective
Authors: J. M. Vaccarino
Journal: JAMA (1977)

Malpractice, for all intents and purposes, is ordinary negligence or carelessness. By legal definition, it is an unintentional act; that is, you cannot form the intent to commit an act of ordinary negligence. You may be intentionally careless, but such act would not come within the definition of ordinary negligence or malpractice. Rather, it would be categorized as willful and reckless misconduct, and I can assure you that this distinction is more than a paper one if for no other reason than the substantially greater amount of monetary damages awarded in the latter case. If you cannot form the intent to commit an act of ordinary negligence then, conversely, it is logical and correct to postulate that you cannot, by an act of the will, prevent ordinary negligent conduct. The act of ordinary negligence which will occur with statistical surety in a random fashion in all our daily lives can only be prevented by diligent conduct—by the practice of good medicine. You assure yourself that good medicine is practiced by participating in ongoing medical education programs and continuous association with those persons and practices which will maintain your intellectual capacity. Worrying about the occurrence of acts of negligence is of no value and is often harmful.
Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo
Authors: H Aurich, M Sgodda, P Kaltwasser, M Vetter, A Weise, T Liehr, M Brulport, J G Hengstler, M M Dollinger, W E Fleig, B Christ
Journal: Gut (2008)

The hepatic integration of human adipose tissue derived mesenchymal stem cells (hAT-MSCs) in vivo with or without prior differentiation to hepatocyte-like cells in vitro was investigated.Cells, isolated either from peritoneal or subcutaneous adipose tissue, expressed mesenchymal stem cell surface markers and featured multiple lineage differentiation. Under conditions favouring hepatocyte differentiation, hAT-MSCs gained hepatocytic functions in vitro including urea formation, glycogen synthesis, cytochrome P450 enzyme activity, and expression of hepatocyte-specific transcripts of carbamoylphosphate synthetase, albumin and cytochrome P450 type 3A4 (CYP3A4). Transgenic expression of green fluorescent protein emerged upon hepatocyte differentiation when driven by the hepatocyte-specific promoter of the cytosolic phosphoenolpyruvate carboxykinase gene but was constitutive from the ubiquitin gene promoter. Human AT-MSCs were transplanted into livers of immunodeficient Pfp/Rag2-/- mice with or without prior hepatocyte differentiation in vitro. Donor-derived human cells engrafted in the mouse host liver predominantly in the periportal region of the liver lobule. They expressed HepPar1 and albumin, typical features of differentiated human hepatocytes, in the otherwise negative mouse liver background. Engraftment was significantly more efficient using hAT-MSCs pre-differentiated to hepatocyte-like cells in vitro as compared with undifferentiated cells.Pre-differentiation of human MSCs from adipose tissue into hepatocyte-like cells in vitro facilitates long term functional hepatic integration in vivo.
Chronic dermatophyte infections. I. Clinical and mycological features
Authors: R.J. HAY
Journal: British Journal of Dermatology (1982)

One hundred and six patients with chronic dermatophytosis unresponsive to griseofulvin were studied. Trichophyton rubrum was the causative organism in 93% of cases. Chronic dermatophyte infections caused by organisms other than T. rubrum occurred predominantly, but not exclusively, in patients with underlying diseases. Forty-nine percent of the patients had a personal or family history of atopy but other abnormalities included disorders of keratinization, collagen vascular disease and systemic steroid therapy. The commonest sites of infection were the palms and soles, as opposed to toe webs or groins in control patients with griseofulvin-res-ponsive dermatophyte infections. A significant proportion of chronically infected patients had raised IgE levels. Only 11% of the chronically infected group showed delayed hypersensitivity responses to intradermal trichophytin but 58% showed immediate hypersensitivity responses to trichophytin as well as other fungal and non-fungal allergens.
Increased Activity of cGMP-Specific Phosphodiesterase (PDE5) Contributes to Resistance to Atrial Natriuretic Peptide Natriuresis in the Pregnant Rat
Authors: Xi-Ping Ni, Massy Safai, Rahul Rishi, Chris Baylis, Michael H. Humphreys
Journal: Journal of the American Society of Nephrology (2004)

Increased cGMP-specific phosphodiesterase (PDE5) activity in renal inner medullary collecting duct (IMCD) cells contributes to resistance to atrial natriuretic peptide (ANP) and the excessive sodium retention seen in experimental nephrotic syndrome and liver cirrhosis. Normal pregnancy is also accompanied by sodium retention and plasma volume expansion, and pregnant rats are resistant to the natriuretic action of ANP. The authors investigated a possible role of increased renal PDE5 activity in the physiologic sodium retention of normal rat pregnancy. The natriuresis and increased urinary cGMP excretion (U(cGMP)V) evoked by acute volume expansion (a measure of renal responsiveness to endogeneous ANP) was blunted in 16-d pregnant versus virgin rats, despite equivalent increases in circulating ANP in pregnants and virgins. The ANP-dependent cGMP accumulation in isolated IMCD cells from pregnants was blunted versus virgins and restored by the PDE5-selective antagonist DMPPO (10(-7) mol/L). PDE5 activity in vitro and PDE5 protein abundance in IMCD were greater in pregnants. Four days postpartum, volume expansion natriuresis, U(cGMP)V, and PDE5 protein levels in IMCD cell homogenates had returned to virgin values. These results demonstrate that normal rat pregnancy leads to in vivo and in vitro renal resistance to ANP, in association with heightened activity of the cGMP-specific PDE5 in IMCD. This may contribute to the physiologic sodium retention of normal pregnancy.
Prognostic Significance of Immune Subset Measurement in Individuals With AIDS-Associated Kaposi's Sarcoma
Authors: Justin Stebbing, Adam Sanitt, Alastair Teague, Tom Powles, Mark Nelson, Brian Gazzard, Mark Bower
Journal: Journal of Clinical Oncology (2007)

A prognostic index for AIDS-associated Kaposi's sarcoma (KS) diagnosed in the era of highly active antiretroviral therapy (HAART) was based on routine clinical and laboratory characteristics. Because immune subset measurement is often performed in HIV-positive individuals, we examined whether these were predictive of mortality independently of the prognostic index, or could predict time to progression of KS.We performed univariate and multivariate Cox regression analyses on a data set of 326 individuals with AIDS-associated KS to identify immune subset covariates predictive of overall survival and time to progression. Adaptive (CD8 T cell and CD19 B cell) and innate (CD16/56 natural-killer cell) immune parameters were studied by flow cytometry.In univariate analyses, all three immune subsets had significant effects on overall survival (P < .025). In multivariate analyses including the prognostic index, only CD8 counts remained significant (P = .026), although its effect on the overall prognostic index is small. An increase of 100 cells/mm3 in the CD8 count confers a 5% improvement in overall survival. Individuals with a higher CD8 count did not have an increased time to progression. Patients who were already on HAART at the time of KS diagnosis did not have a shorter time to progression than those who were antiretroviral naïve at KS diagnosis.The CD8 count appears to provide independent prognostic information in individuals with AIDS-associated KS. Measurement of the CD8 count is clinically useful in patients with KS.
HMGB1 in Cancer: Good, Bad, or Both?
Authors: Rui Kang, Qiuhong Zhang, Herbert J. Zeh, Michael T. Lotze, Daolin Tang
Journal: Clinical Cancer Research (2013)

Abstract Forty years ago, high mobility group box 1 (HMGB1) was discovered in calf thymus and named according to its electrophoretic mobility in polyacrylamide gels. Now, we know that HMGB1 performs dual functions. Inside the cell, HMGB1 is a highly conserved chromosomal protein acting as a DNA chaperone. Outside of the cell, HMGB1 is a prototypical damage-associated molecular pattern, acting with cytokines, chemokines, and growth factors. During tumor development and in cancer therapy, HMGB1 has been reported to play paradoxical roles in promoting both cell survival and death by regulating multiple signaling pathways, including inflammation, immunity, genome stability, proliferation, metastasis, metabolism, apoptosis, and autophagy. Here, we review the current knowledge of both HMGB1′s oncogenic and tumor-suppressive roles and the potential strategies that target HMGB1 for the prevention and treatment of cancer. Clin Cancer Res; 19(15); 4046–57. ©2013 AACR.
Drug-grapefruit juice interactions
Authors: M. Pirmohamed
Journal: BMJ (2013)

<h3>ABSTRACT</h3> Countries finance health care using a combination of 3 main functions: raising resources for health, pooling resources, and purchasing health services. In this paper, we examine how digital health technologies can be used to enhance these health financing functions in low- and middle-income countries and can thus contribute to progress toward universal health coverage. We illustrate our points by presenting some recent innovations in digital technologies for financing health care, identifying their contributions and their limits. Some examples include a mobile-health wallet application used in Kenya that encourages households to put money aside for future health expenses; an online software platform developed by a startup in Tanzania in partnership with a private insurance provider to give individuals and families the opportunity to choose among different health coverage options; and digital maps by a number of startups that bring together data on health facility locations and capacity, including equipment, staff, and types of services offered. We also sketch an agenda for future research and action for digital strategies for health financing. The development and adoption of effective solutions that align well with the universal health coverage agenda will require strong partnerships between stakeholders and enough proactive stewardship by authorities.
Ultrasound treatment for treating the carpal tunnel syndrome: randomised "sham" controlled trial
Authors: G. R Ebenbichler, K. L Resch, P. Nicolakis, G. F Wiesinger, F. Uhl, A.-H. Ghanem, V. Fialka
Journal: BMJ (1998)

To assess the efficacy of ultrasound treatment for mild to moderate idiopathic carpal tunnel syndrome.
Symptom-onset-to-balloon time and mortality in patients with acute myocardial infarction treated by primary angioplasty
Authors: Giuseppe De Luca, Harry Suryapranata, Felix Zijlstra, Arnoud W.J van't Hof, Jan C.A Hoorntje, A.T.Marcel Gosselink, Jan-Henk Dambrink, Menko-Jan de Boer
Journal: Journal of the American College of Cardiology (2003)