tbuckley/cabot-search huggingface dataset:
Pharmacokinetics (pk) and tolerance of doxorubicin (dox) and etoposide (etop) during treatment of aggressive B-cell lymphomas indicate doses need not be routinely reduced for hepatic dysfunction
Authors: D. E. Cole, F. M. Balis, E. S. Lowe, N. D. Grant, T. White, K. Dunleavy, J. Janik, S. Xiao, W. J. Goodspeed, W. H. Wilson
Journal: Journal of Clinical Oncology (2005)

6573 Background: Hepatic and renal impairment by lymphoma may alter drug clearance (Cl) and routinely results in dose reductions which may compromise efficacy. We compared etop and dox pk during Dose-Adjusted-EPOCH in pts with normal (nl) and abnormal (abn) excretory organ function (eof). Methods: Plasma concentrations (conc) of dox, doxorubicinol (doxol), and total and non-protein bound (free) etop were measured in 55 pts with nl eof, 9 pts with elevated bilirubin (bili, median, 2.3 mg/dL; range, 1.3–12.1), and 1 pt with a serum creatinine of 18.9 mg/dL. Pts received DA-EPOCH (96 h infusion of dox, etop, vincristine; bolus cytoxan and oral prednisone). Doses were not reduced for abn eof. Doses of dox, etop and cytoxan were adjusted by 20% on subsequent cycles (cy) to achieve a nadir neutrophil count <500/μL. Dox and doxol were quantified by HPLC with fluorescence detection after solid phase extraction. Total etop was measured by HPLC with electrochemical detection after extraction into chloroform. Free etop was measured in plasma ultrafiltrates. Results: At cy 1, median (range) dox Cl was 393 (294–610) vs. 630 (262–1596) mL/min/m2 (p=0.006) and median (range) end of infusion plasma conc of doxol was 0.025 (0.008–0.052) vs. 0.009 (0.0025–0.021) μM (p=0.0027) in pts with elevated vs. nl bili. Median (range) free etop Cl was 665 (438–1413) vs. 663 (198–1148) mL/min/m2 and total etop Cl was 19.7 (13.1–38-6) vs. 27.7 (13.1–36.9) mL/min/m2 for pts with and without elevated bili, respectively. For the pt with renal dysfunction, Cl of dox, free etop and etop were 222, 338 and 16 mL/min/m2, respectively. 44% of pts with nl eof, but 1/9 pts with increased bili met the criteria for dose escalation between cy 1 and 2, and none required dose reduction. The pt with renal dysfunction required dose reduction. Conclusions: In pts with an elevated bili, the Cl of dox and doxol was lower but fell within the pk and tolerance range of pts with nl bili. Etop pk was unaffected by hepatic dysfunction. Cl of dox and free etop were impaired in a pt with severe renal dysfunction. Doses of dox and etop need not be routinely reduced for elevated bili with CHOP-based regimens. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech
RTOG 9802: Good Wines Need Aging
Authors: Martin J. van den Bent, Kurt Jaeckle, Brigitta Baumert, Wolfgang Wick
Journal: Journal of Clinical Oncology (2013)

biopsy or subtotal resection, no or mild pretreatment neurologic deficit, or age older than 40 years. 1 The expansive RTOG definition of high-risk LGG includes all but those tumors completely excised in patients younger than age 40 years and, consequently, the majority of patients with newly diagnosed LGG.Currently there are no published randomized trials that prospectively examined the effect of extent of resectiononriskofrecurrence.Itisthereforedifficulttoreconcilethesequite differing definitions (EORTC v RTOG) of high-risk LGG that consequently determine the need for the up-front RT that is generally prescribed for these tumors at risk for early recurrence. 1,5This difference in what constitutes high-risk LGG may in part account for the failure to demonstrate a survival difference in the two treatment arms.Perhaps most challenging in the interpretation of the current RTOG trial is the apparent premature reporting of trial results.If the trial intent was to demonstrate a survival advantage in patients treated with RT plus PCV (prespecified primary end point) and thereby change practice (given that the majority of these patients would be offered the equiefficacious treatment of observation with deferred RT or up-front RT), early reporting of results when only 30% of patients who were treated with combined modality treatment (RT plus PCV) experienced progression seems counterproductive.Why not instead permit trial results to mature so that a more definitive outcome can be reported?7][8] Notwithstanding completion of the EORTC trial that compared up-front RT to temozolomide in high-risk LGG (defined as by Pignatti et al 5 and differing significantly from the definition used in the RTOG trial), how does early reporting of the current trial impact therapy or management of these patients?Are patients better served by these initial and incomplete results?In addition, does the current RTOG definition of high-risk LGG change practice by including these newly defined patients in this category and consequently recommend up-front RT as opposed to deferred RT after initial resection?Thesecommentsarenotmeanttodiminishtheresultsofthiselegant study.2][3][4] LGG is often a chronic disease, unlike high-grade glioma, and therefore the long-term effects of treatment are particularly relevant to any discussion that changes patterns of care, including the introduction of up-front RT to a newly defined and large population of patients with these tumors.
Modeling precision treatment of breast cancer
Authors: Anneleen Daemen, Obi L Griffith, Laura M Heiser, Nicholas J Wang, Oana M Enache, Zachary Sanborn, Francois Pepin, Steffen Durinck, James E Korkola, Malachi Griffith, Joe S Hur, Nam Huh, Jongsuk Chung, Leslie Cope, Mary Fackler, Christopher Umbricht, Saraswati Sukumar, Pankaj Seth, Vikas P Sukhatme, Lakshmi R Jakkula, Yiling Lu, Gordon B Mills, Raymond J Cho, Eric A Collisson, Laura J van’t Veer, Paul T Spellman, Joe W Gray
Journal: Genome biology (2013)

First-generation molecular profiles for human breast cancers have enabled the identification of features that can predict therapeutic response; however, little is known about how the various data types can best be combined to yield optimal predictors. Collections of breast cancer cell lines mirror many aspects of breast cancer molecular pathobiology, and measurements of their omic and biological therapeutic responses are well-suited for development of strategies to identify the most predictive molecular feature sets. We used least squares-support vector machines and random forest algorithms to identify molecular features associated with responses of a collection of 70 breast cancer cell lines to 90 experimental or approved therapeutic agents. The datasets analyzed included measurements of copy number aberrations, mutations, gene and isoform expression, promoter methylation and protein expression. Transcriptional subtype contributed strongly to response predictors for 25% of compounds, and adding other molecular data types improved prediction for 65%. No single molecular dataset consistently out-performed the others, suggesting that therapeutic response is mediated at multiple levels in the genome. Response predictors were developed and applied to TCGA data, and were found to be present in subsets of those patient samples. These results suggest that matching patients to treatments based on transcriptional subtype will improve response rates, and inclusion of additional features from other profiling data types may provide additional benefit. Further, we suggest a systems biology strategy for guiding clinical trials so that patient cohorts most likely to respond to new therapies may be more efficiently identified.
Genetic and Demographic Implications of the Bantu Expansion: Insights from Human Paternal Lineages
Authors: G. Berniell-Lee, F. Calafell, E. Bosch, E. Heyer, L. Sica, P. Mouguiama-Daouda, L. van der Veen, J.-M. Hombert, L. Quintana-Murci, D. Comas
Journal: Molecular Biology and Evolution (2009)

The expansion of Bantu languages, which started around 5,000 years before present in west/central Africa and spread all throughout sub-Saharan Africa, may represent one of the major and most rapid demographic movements in the history of the human species. Although the genetic footprints of this expansion have been unmasked through the analyses of the maternally inherited mitochondrial DNA lineages, information on the genetic impact of this massive movement and on the genetic composition of pre-Bantu populations is still scarce. Here, we analyze an extensive collection of Y-chromosome markers—41 single nucleotide polymorphisms and 18 short tandem repeats—in 883 individuals from 22 Bantu-speaking agriculturalist populations and 3 Pygmy hunter-gatherer populations from Gabon and Cameroon. Our data reveal a recent origin for most paternal lineages in west Central African populations most likely resulting from the expansion of Bantu-speaking farmers that erased the more ancient Y-chromosome diversity found in this area. However, some traces of ancient paternal lineages are observed in these populations, mainly among hunter-gatherers. These results are at odds with those obtained from mtDNA analyses, where high frequencies of ancient maternal lineages are observed, and substantial maternal gene flow from hunter-gatherers to Bantu farmers has been suggested. These differences are most likely explained by sociocultural factors such as patrilocality. We also find the intriguing presence of paternal lineages belonging to Eurasian haplogroup R1b1*, which might represent footprints of demographic expansions in central Africa not directly related to the Bantu expansion.
Nonalcoholic Fatty Liver Disease Is Independently Associated With an Increased Incidence of Chronic Kidney Disease in Patients With Type 1 Diabetes
Authors: Giovanni Targher, Alessandro Mantovani, Isabella Pichiri, Lucia Mingolla, Valentina Cavalieri, William Mantovani, Serena Pancheri, Maddalena Trombetta, Giacomo Zoppini, Michel Chonchol, Christopher D. Byrne, Enzo Bonora
Journal: Diabetes Care (2014)

OBJECTIVE There is no information about the role of nonalcoholic fatty liver disease (NAFLD) in predicting the development of chronic kidney disease (CKD) in type 1 diabetes. RESEARCH DESIGN AND METHODS We studied 261 type 1 diabetic adults with preserved kidney function and with no macroalbuminuria at baseline, who were followed for a mean period of 5.2 years for the occurrence of incident CKD (defined as estimated glomerular filtration rate [eGFR] &amp;lt;60 mL/min/1.73 m2 and/or macroalbuminuria). NAFLD was diagnosed by ultrasonography. RESULTS At baseline, patients had a mean eGFR of 92 ± 23 mL/min/1.73 m2; 234 (89.7%) of them had normoalbuminuria and 27 (10.3%) microalbuminuria. NAFLD was present in 131 (50.2%) patients. During follow-up, 61 subjects developed incident CKD. NAFLD was associated with an increased risk of incident CKD (hazard ratio [HR] 2.85 [95% CI 1.59–5.10]; P &amp;lt; 0.001). Adjustments for age, sex, duration of diabetes, hypertension, A1C, and baseline eGFR did not appreciably attenuate this association (adjusted HR 2.03 [1.10–3.77], P &amp;lt; 0.01). Results remained unchanged after excluding those who had microalbuminuria at baseline (adjusted HR 1.85 [1.03–3.27]; P &amp;lt; 0.05). Addition of NAFLD to traditional risk factors for CKD significantly improved the discriminatory capability of the regression models for predicting CKD (e.g., with NAFLD c statistic 0.79 [95% CI 0.73–0.86] vs. 0.76 [0.71–0.84] without NAFLD, P = 0.002). CONCLUSIONS This is the first study to demonstrate that NAFLD is strongly associated with an increased incidence of CKD. Measurement of NAFLD improves risk prediction for CKD, independently of traditional cardio-renal risk factors, in patients with type 1 diabetes.
Ursocholic acid: bile acid and bile lipid dose response and clinical studies in patients with gall stones.
Authors: P J Howard, D Gleeson, G M Murphy, R H Dowling
Journal: Gut (1989)

The biliary bile acid and bile lipid responses to six weeks treatment with approximately 5, 10, and 15 mg/kg/day of ursocholic acid (UCA) were studied in 11 gall stone patients. Maximum enrichment of bile with UCA (24 (SE) 4.9%) occurred with 15 mg UCA/kg/day. The maximum reduction in biliary cholesterol saturation was seen with the 10 mg/kg/day dose when the moles % cholesterol fell from 14 (2.4)% before treatment to 5.6 (0.83)% (p less than 0.02) and the saturation index fell from 1.4 (0.23) to 0.77 (0.13) (p less than 0.05). Clinical studies of the safety and efficacy of UCA in dissolving gall stones were carried out in 13 patients treated for up to two years with a dose of approximately 10 mg/kg/day. Diarrhoea caused withdrawal of treatment in three patients. There were no significant changes in liver function or haematology tests but fasting serum cholesterol tended to rise during treatment. Of nine patients treated for greater than 6 months, only one showed complete gall stone dissolution. As UCA may cause diarrhoea and hypercholesterolaemia, has only a modest effect on biliary cholesterol saturation and low gall stone dissolution efficacy, it is unlikely to replace existing forms of gall stone dissolution therapy.
Skin immunosenescence: decreased receptor for activated C kinase-1 expression correlates with defective tumour necrosis factor-α production in epidermal cells
Authors: E. Corsini, M. Racchi, L. Lucchi, E. Donetti, M. Bedoni, B. Viviani, C.L. Galli, M. Marinovich
Journal: British Journal of Dermatology (2008)

Background Skin immunosenescence accounts for increased susceptibility in the elderly to cutaneous infections and malignancies, and decreased contact hypersensitivity and response to vaccination. We have recently shown in immune cells that decreased expression of the receptor for activated C kinase (RACK)-1 underlies defective protein kinase C (PKC) activation and functional immune impairment with ageing. Objectives This study was designed to determine if an age-related decline in skin RACK-1 expression was present and whether it correlated with defective tumour necrosis factor (TNF)-α production. Methods PKC isoforms and RACK-1 expression were evaluated by Western blot analysis and by immunofluorescence in skin obtained from Sprague-Dawley rats of different ages. TNF-α release by epidermal cells induced by lipopolysaccharide, 12-O-tetradecanoyl-phorbol-13-acetate and the contact allergen dinitrochlorobenzene was assessed by the L929 biological assay. Results Skin obtained from old rats (> 18 months) showed decreased RACK-1 immunoreactivity if compared with young rats (< 3 months). RACK-1 preferentially interacts with PKC β. Despite a similar total skin content of this isoform, the reduced expression of RACK-1 was associated with a decreased translocation of PKC β in the membrane compartment. The defective PKC β translocation associated with ageing correlated with decreased TNF-α release from epidermal cells following treatment with different inflammatory stimuli. Conclusions Overall, we demonstrated for the first time a decrease in RACK-1 expression, defective PKC β translocation and reduced TNF-α release in epidermal cells with ageing. These alterations might be mechanistically significant, and provide a new understanding of the consequences of ageing on skin immunology.
Assessing the prevalence of hand osteoarthritis in epidemiological studies. The reliability of a radiological hand scale
Authors: S Kessler, P Dieppe, J Fuchs, T Stürmer, K P Günther
Journal: Annals of the Rheumatic Diseases (2000)

The hands are often involved in the osteoarthritic disease process. A radiological grading scale is presented, derived from a published atlas, to assess the prevalence of hand osteoarthritis (OA) involvement in clinical and epidemiological studies and its reproducibility is studied.This hand scale is based on the radiological feature "joint space narrowing", which represents the macromorphological process of cartilage loss. Osteophytes and sclerosis are less important unless seen in conjuction with joint space narrowing. Nine individual joints per hand (four proximal interphalangeal joints (PIP), four distal interphalangeal joints (DIP), first carpometacarpal joint (CMC-1)) are scored dichotomously for the presence of OA. To save time and to increase reliability a severity grading of radiological features is not performed. To determine inter-rater and intra-rater reliability of the individual joints and the presence of OA in two separate joint groups (>/= 2 PIP or DIP and at least one CMC-1, used to define "generalised OA" in the ongoing Ulm Osteoarthritis Study) 50 pairs of anteroposterior hand radiographs were read by two investigators twice within one month. The kappa coefficient was calculated to quantify the strength of associations.On average five minutes were needed to score one hand radiograph. Both raters were able to reproduce their own readings in all individual joints and for the presence of OA in two separate joint groups after one month. Reliability was highest for the PIP joints (kappa: 0.56-1. 00) it was slightly lower for the DIP joints (0.38-0.87), for the CMC-1 joints (0.58-0.69) and for OA in two separate joint groups (0. 54). The values for inter-rater agreement were good as well, kappa coefficients ranged from 0.52 to 0.92.This grading scale was shown to be reliable within and between readers for all the individual joints as well as for the presence of OA in two separate joint groups. Scoring a limited number of joints dichotomously makes this scale efficient and therefore useful for clinical and epidemiological trials, when dealing with large patient samples.
Vascular Endothelial Growth Factor Expression in Ovarian Cancer: A Model for Targeted Use of Novel Therapies?
Authors: Timothy J. Duncan, Ahmad Al-Attar, Phil Rolland, Ian V. Scott, Suha Deen, David T.Y. Liu, Ian Spendlove, Lindy G. Durrant
Journal: Clinical Cancer Research (2008)

Angiogenesis has a vital role in tumor growth and metastasis, and vascular endothelial growth factor (VEGF) represents a potent cytokine in this process. However, the influence of VEGF in ovarian cancer remains controversial. Interest has focused on the use of antiangiogenic drugs in ovarian cancer. This study aims to establish the pattern of expression and effect on prognosis of VEGF in a large population of ovarian cancer patients and to potentially identify a cohort in whom antiangiogenic therapy is appropriate.Using a tissue microarray of 339 primary ovarian cancers, the expression of VEGF was assessed immunohistochemically. Coupled to a comprehensive database of clinicopathologic variables, its effect on these factors and survival was studied.Tumors expressing high levels of VEGF had significantly poorer survival (P = 0.04). Factors shown to predict prognosis independently of each other were age, International Federation of Gynecologists and Obstetricians stage, and the absence of macroscopic disease after surgery. VEGF was independently predictive of prognosis on multivariate analysis (P = 0.02). There was no correlation between VEGF and any clinicopathologic variable. High expression of VEGF was seen in only 7% of the tumors, suggesting that the role of antiangiogenic drugs may be limited to a small subset of patients.High VEGF expression occurs in a small proportion of ovarian cancers, and this independently predicts poor prognosis. The small percentage of tumors with high levels of VEGF activity suggests that the role of bevacizumab may potentially be limited to a few patients; these patients could be targeted by molecular profiling.
Effects of Conjugated Equine Estrogen on Stroke in the Women’s Health Initiative
Authors: Susan L. Hendrix, Sylvia Wassertheil-Smoller, Karen C. Johnson, Barbara V. Howard, Charles Kooperberg, Jacques E. Rossouw, Maurizio Trevisan, Aaron Aragaki, Alison E. Baird, Paul F. Bray, Julie E. Buring, Michael H. Criqui, David Herrington, John K. Lynch, Stephen R. Rapp, James Torner
Journal: Circulation (2006)

Background— The Women’s Health Initiative (WHI) Estrogen Alone trial assessed the balance of benefits and risks of hormone use in healthy postmenopausal women. The trial was stopped prematurely because there was no benefit for coronary heart disease and an increased risk of stroke. This report provides a thorough analysis of the stroke finding using the final results from the completed trial database. Methods and Results— The WHI Estrogen Alone hormone trial is a multicenter, double-blind, placebo-controlled, randomized clinical trial in 10 739 women aged 50 to 79 years who were given daily conjugated equine estrogen (CEE; 0.625 mg; n=5310) or placebo (n=5429). During an average follow-up of 7.1 years, there were 168 strokes in the CEE group and 127 in the placebo group; 80.3% of strokes were ischemic. For all stroke the intention-to-treat hazard ratio [HR] (95% CI) for CEE versus placebo was 1.37 (1.09 to 1.73). The HR (95% CI) was 1.55 (1.19 to 2.01) for ischemic stroke and 0.64 (0.35, 1.18) for hemorrhagic stroke. The HRs indicate excess risk of ischemic stroke was apparent in all categories of baseline stroke risk, including younger and more recently menopausal women and in women with prior or current use of statins or aspirin. Conclusions— CEE increases the risk of ischemic stroke in generally healthy postmenopausal women. The excess risk appeared to be present in all subgroups of women examined, including younger and more recently menopausal women. There was no convincing evidence to suggest that CEE had an effect on the risk of hemorrhagic stroke.
Medical Communication Companies and Industry Grants
Authors: Sheila M. Rothman, Karen F. Brudney, Whitney Adair, David J. Rothman
Journal: JAMA (2013)

<h3>Importance</h3> Medical communication companies (MCCs) are among the most significant health care stakeholders, supported mainly by drug and device companies. How MCCs share or protect physicians' personal data requires greater transparency. <h3>Objective</h3> To explore the financial relationships between MCCs and drug and device companies, to describe the characteristics of the large MCCs, and to explore whether they accurately represent themselves to physicians. <h3>Design</h3> We combined data from the 2010 grant registries of 14 pharmaceutical and device companies; grouped recipients into categories such as MCCs, academic medical centers, disease-targeted advocacy organizations, and professional associations; and created a master list of 19 272 grants. <h3>Main Outcomes and Measures</h3> Determine the distribution of funds from drug and device companies to various entities and assess the characteristics of large MCCs. <h3>Results</h3> Of the 6493 recipients of more than $657 million grant awards from drug and device companies, 18 of 363 MCCs received 26%, academic medical centers received 21%, and disease-targeted organizations received 15%. For-profit MCCs received 77% of funds (208 of 363). Among the top 5% of MCCs, 14 of 18 were for-profit. All 18 offered continuing medical education: 14 offered live and 17 offered online CME courses. All required physicians to provide personal data. Ten stated that they shared information with unnamed third parties. Eight stated they did not share information, but almost all added exceptions. None required explicit physician consent to their sharing policies. <h3>Conclusions and Relevance</h3> Medical communication companies receive substantial support from drug and device companies. Physicians who interact with MCCs should be aware that all require personal data from the physician and some share these data with unnamed third parties.