tbuckley/cabot-search huggingface dataset:
Patient and Physician Decision Styles and Breast Cancer Chemotherapy Use in Older Women: Cancer and Leukemia Group B Protocol 369901
Authors: Jeanne S. Mandelblatt, Leigh Anne Faul, George Luta, Solomon B. Makgoeng, Claudine Isaacs, Kathryn Taylor, Vanessa B. Sheppard, Michelle Tallarico, William T. Barry, Harvey J. Cohen
Journal: Journal of Clinical Oncology (2012)

Purpose Physician and patient decision styles may influence breast cancer care for patients ≥ 65 years (“older”) because there is uncertainty about chemotherapy benefits in this group. We evaluate associations between decision-making styles and actual treatment. Methods Data were collected from women treated outside of clinical trials for newly diagnosed stage I to III breast cancer (83% response) from January 2004 through April 2011 in 75 cooperative group sites. Physicians completed a one-time mailed survey (91% response), and clinical data were abstracted from charts. Patient decision style was measured on a five-point scale. Oncologists' preference for prescribing chemotherapy was based on standardized vignettes. Regression and multiple imputation were used to assess associations between chemotherapy and other variables. Results There were 1,174 women seen by 212 oncologists; 43% of women received chemotherapy. One-third of women preferred to make their own treatment decision. Patient and physician decision styles were independently associated with chemotherapy. Women who preferred less physician input had lower odds of chemotherapy than women who preferred more input (odds ratio [OR] = 0.79 per 1-point change; 95% CI, 0.65 to 0.97; P = .02) after considering covariates. Patients whose oncologists had a high chemotherapy preference had higher odds of receiving chemotherapy (OR = 2.65; 95% CI, 1.80 to 3.89; P &lt; .001) than those who saw oncologists with a low preference. Conclusion Physicians' and older patients' decision styles are each associated with breast cancer chemotherapy use. It will be important to re-evaluate the impact of decision styles when there is greater empirical evidence about the benefits and risks of chemotherapy in older patients.
Effects of strenuous exercise on haemostasis: Table 1
Authors: J E Smith
Journal: British Journal of Sports Medicine (2003)

To review the effects of exercise on haemostasis and examine the possible clinical sequelae of these changes.The search strategy included articles from 1966 to August 2002 using Medline and SportDiscus databases, and cross referencing the bibliographies of relevant papers.Exercise results in activation of both the coagulation and fibrinolytic cascades, as shown by a reduction in whole blood clotting time and activated partial thromboplastin time, an increase in the activity of several components of the cascades, and an increase in fibrin degradation products. In vitro tests suggest that coagulation remains activated after fibrinolysis has returned to baseline levels.Both the coagulation and fibrinolytic cascades are stimulated by strenuous exercise, but the temporal relation between the two and its clinical significance remains to be clarified. Doctors and athletes should be aware of the haemostatic changes induced by exercise, and further work is needed to clarify the possible role of these changes in sudden cardiac death.
Systemic IFN-β gene therapy results in long-term survival in mice with established colorectal liver metastases
Authors: Hiroomi Tada, David J. Maron, Eugene A. Choi, James Barsoum, Hanqin Lei, Qing Xie, Wenbiao Liu, Lee Ellis, A. David Moscioni, John Tazelaar, Stephen Fawell, Xiao Qin, Kathleen J. Propert, Alan Davis, Douglas L. Fraker, James M. Wilson, Francis R. Spitz
Journal: Journal of Clinical Investigation (2001)

Most patients succumbing to colorectal cancer fail with liver-predominant metastases. To make a clinical impact in this disease, a systemic or whole-liver therapy may be required, whereas most cancer gene therapy approaches are limited in their ability to treat beyond local disease. As a preclinical model for cancer gene therapy, recombinant adenovirus containing the human IFN-β (hIFN-β) cDNA was delivered systemically in nude mouse xenograft models of human colorectal cancer liver metastases. The vector targeted hepatocytes that produced high levels of hIFN-β in the liver, resulting in a profound apoptotic response in the tumors and significant tumor regression. hIFN-β gene therapy not only resulted in improved survival and long-term cure in a micrometastatic model, but provided similar benefits in a clinically relevant gross disease model. A similar recombinant adenovirus containing the murine IFN-β (mIFN-β) cDNA also resulted in a therapeutic response and improved survival in syngeneic mouse models of colorectal cancer liver metastases. Depletion studies demonstrate a contribution of natural killer cells to this therapeutic response. The toxicity of an adenoviral vector expressing murine IFN-β in a syngeneic model is also presented. These encouraging results warrant further investigation of the use of cancer gene therapy for targeting metastatic disease.
Brief Report: Excitatory and Inhibitory Brain Metabolites as Targets of Motor Cortex Transcranial Direct Current Stimulation Therapy and Predictors of Its Efficacy in Fibromyalgia
Authors: Bradley R. Foerster, Thiago D. Nascimento, Misty DeBoer, Marycatherine A. Bender, Indie C. Rice, Dennis Q. Truong, Marom Bikson, Daniel J. Clauw, Jon‐Kar Zubieta, Richard E. Harris, Alexandre F. DaSilva
Journal: Arthritis & Rheumatology (2014)

Objective Transcranial direct current stimulation (tDCS) has been shown to improve pain symptoms in fibromyalgia (FM), a central pain syndrome whose underlying mechanisms are not well understood. This study was undertaken to explore the neurochemical action of tDCS in the brain of patients with FM, using proton magnetic resonance spectroscopy ( 1 H‐MRS). Methods Twelve patients with FM underwent sham tDCS over the left motor cortex (anode placement) and contralateral supraorbital cortex (cathode placement) for 5 consecutive days, followed by a 7‐day washout period and then active tDCS for 5 consecutive days. Clinical pain assessment and 1 H‐MRS testing were performed at baseline, the week following the sham tDCS trial, and the week following the active tDCS trial. Results Clinical pain scores decreased significantly between the baseline and active tDCS time points ( P = 0.04). Levels of glutamate + glutamine (Glx) in the anterior cingulate were significantly lower at the post–active tDCS assessment compared with the post–sham tDCS assessment ( P = 0.013), and the decrease in Glx levels in the thalami between these time points approached significance ( P = 0.056). From baseline to the post–sham tDCS assessment, levels of N ‐acetylaspartate (NAA) in the posterior insula increased significantly ( P = 0.015). There was a trend toward increased levels of γ‐aminobutyric acid (GABA) in the anterior insula after active tDCS, compared with baseline ( P = 0.064). Baseline anterior cingulate Glx levels correlated significantly with changes in pain score, both for the time period from baseline to sham tDCS (β 1 = 1.31, P &lt; 0.001) and for the time period from baseline to active tDCS (β 1 = 1.87, P &lt; 0.001). Conclusion The present findings suggest that GABA, Glx, and NAA play an important role in the pathophysiology of FM and its modulation by tDCS.
Variations in laser energy outputs over a series of simulated treatments
Authors: T.S. Lister, M.P. Brewin
Journal: British Journal of Dermatology (2014)

Test patches are routinely employed to determine the likely efficacy and the risk of adverse effects from cutaneous laser treatments. However, the degree to which these represent a full treatment has not been investigated in detail.This study aimed to determine the variability in pulse-to-pulse output energy from a representative selection of cutaneous laser systems in order to assess the value of laser test patches.The output energies of each pulse from seven cutaneous laser systems were measured using a pyroelectric measurement head over a 2-h period, employing a regime of 10-min simulated treatments followed by a 5-min rest period (between patients).Each laser system appeared to demonstrate a different pattern of variation in output energy per pulse over the period measured.The output energies from a range of cutaneous laser systems have been shown to vary considerably between a representative test patch and a full treatment, and over the course of an entire simulated clinic list.
Pitfalls in Management of Patients With Germ Cell Tumors and Slight Elevation of Serum α-Fetoprotein
Authors: Costantine Albany, Lawrence Einhorn
Journal: Journal of Clinical Oncology (2014)

In contrast, our study, 2 cited by the authors, that found that a delay had no impact on prognosis, included only patients with endometrial endometrioid carcinoma.4][5] Indeed we reported 6 a prolonged survival in a small series of untreated patients with endometrial endometrioid cancer and patients with a prolonged treatment delay.This seems to indicate that the natural progression course, even in untreated patients, may be slow in endometrial endometrioid carcinoma with favorable prognostic factors.
Glycosylation of Circulating IgA in Patients with IgA Nephropathy Modulates Proliferation and Apoptosis of Mesangial Cells
Authors: ALESSANDRO AMORE, PAOLA CIRINA, GIOVANNI CONTI, PAOLA BRUSA, LICIA PERUZZI, ROSANNA COPPO
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Abnormalities in circulating IgA1 have been demonstrated in patients with IgA nephropathy (IgAN). This study addresses the question of the functional significance of this alteration in creating mesangial injury. Biologic effects of selected IgA glycoforms isolated from serum of IgAN patients and controls and in vitro deglycosylated normal IgA were tested on cultured human mesangial cells (MC). IgA glycoforms, ranging from 250 to 500 kD molecular weight, were isolated by lectin affinity chromatography followed by HPLC. IgA and IgG content was measured by enzyme-linked immunosorbent assay. HPLC fractions were incubated with MC to evaluate proliferation and apoptosis rates and nitric oxide synthesis. Moreover, MC were conditioned with in vitro desialylated and degalactosylated normal IgA. Patients with IgAN displayed increased levels of IgA glycoforms exposing sialic acid in α2,6 linkage with N-acetylgalactosamine (Neu5Acα2,6GalNAc) (P < 0.02) and GalNAc (P < 0.05), indicating truncation of O-linked glycans of IgA1. Moreover, IgA glycoforms with increased exposure of mannose were observed (P < 0.03), suggesting a defective N-linked glycosylation. No modification in IgG glycosylation was detected. When incubated with MC, the IgA glycoforms isolated from patients with increased exposure of GalNAc, Neu5Acα2,6GalNAc, or mannose, significantly depressed the proliferation and increased the apoptotic rate and nitric oxide synthesis activity of cultured MC, in comparison with fractions isolated from controls. Similarly, in vitro desialylated and degalactosylated IgAs significantly depressed the proliferation and enhanced the apoptosis rates of MC. In conclusion, a significant modulation of several human MC functions exerted by serum IgA with increased exposure of GalNAc, Neu5Acα2,6GalNAc, and mannose residues isolated from IgAN patients is reported for the first time.
Abstract 3777: Combining VELIPARIB (ABT-888) with temozolomide shows strong synergy when treating temozolomide-resistant and recurrent GBM cell lines
Authors: Kerrie McDonald, Kyoko Nozue-Okada, Mustafa Khasraw
Journal: Cancer Research (2014)

Abstract Introduction: The survival trends for glioblastoma (GBM) patients have remained largely static, reflecting lack of improvement in the therapeutic options for patients. Less than 5% of newly diagnosed GBM survive more than 5 years. Standard treatment for GBM comprises of radiotherapy and temozolomide (TMZ) chemotherapy (chemoradiotherapy). Methylation of the promoter region of MGMT has been shown to be predictive of response to chemoradiotherapy. Approximately 30% of GBM are MGMT methylated. ABT-888 (Veliparib; Abbvie) is a Poly (ADP-ribose) polymerase (PARP) inhibitor that has been shown to enhance response of GBM to chemoradiotherapy in MGMT methylated patients. However, despite response (and lack of response in the case of MGMT unmethylated patients), recurrent GBM is refractory to treatment, occurring 2-3cm from the original resection and patient die within few months after recurrence. Herein we demonstrate the use of ABT-888 might be effective in patients who have recurrent GBM. Methods: We tested ABT-888 alone and in combination with TMZ on low passage patient derived cell lines cultured from patients with recurrent GBM. We have used low passage patient derived cells including BAH and HW that are MGMT methylated. We also used U87, U251 and LN229 that are immortalized cells that are MGMT methylated. Of these lines, only U251 harbors a mutation in the binding domain of TP53. We also tested MGMT methylated low passage patient derived cell lines where TMZ resistance was selected for through continuous TMZ treatment of the cell line. Results: Consistent with previous studies, monotherapy with ABT-888 was largely ineffective on all of the cell lines. We combined a low dose of ABT-888 (5μM) with a range of TMZ concentrations. Combination treatment was highly efficacious with sensitivity to TMZ improved by 30-70% when tested in 5 recurrent cell lines. All cell lines were MGMT unmethylated. We continuously treated 3 cell lines (2 MGMT methylated and 1 MGMT unmethylated) with TMZ until resistance was achieved. We found a response to the ABT-888/ TMZ combination was dramatic. Cells were 75% more sensitive to ABT-888/TMZ compared to retreatment with TMZ. Conclusion: This novel strategy of combining ABT-888 with TMZ demonstrated synergistic antitumor activity for the treatment of relapsed and/or “chemo-resistant” GBM cell lines. Further investigation of this synergy has potential for rapid translation into clinical studies. Citation Format: Kerrie McDonald, Kyoko Nozue-Okada, Mustafa Khasraw. Combining VELIPARIB (ABT-888) with temozolomide shows strong synergy when treating temozolomide-resistant and recurrent GBM cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3777. doi:10.1158/1538-7445.AM2014-3777
MicroRNAs: novel regulators in cardiac development and disease
Authors: T. Thum, D. Catalucci, J. Bauersachs
Journal: Cardiovascular Research (2008)

MicroRNAs (miRNAs) are endogenous, small ribonucleotides regulating the translation of target messenger RNAs that have been shown to be involved in orchestrating growth, development, function, and stress responses of various organs, including the heart. Muscle miRNAs are mainly controlled by a network of myogenic transcription factors, and throughout cardiac development they fine-tune regulatory protein levels in a spatiotemporal manner. Recent profiling studies revealed that miRNA expression patterns are derailed in both human cardiac disease and animal models of cardiac hypertrophy and failure. Modulation of miRNA expression in vitro as well as in vivo has revealed an important role of miRNAs in regulating heart function, particularly cardiac growth and conductance. Here, we overview the recent findings on miRNAs in cardiac development and disease and report the latest advances in the identification and validation of miRNA targets, which are important for a comprehensive understanding of cardiac miRNA function. Finally, we focus on the development and use of miRNA antagonists (antagomirs) to target miRNAs in vivo, which may translate into novel therapeutic strategies for heart disease in the future.
Vinculin network–mediated cytoskeletal remodeling regulates contractile function in the aging heart
Authors: Gaurav Kaushik, Alice Spenlehauer, Ayla O. Sessions, Adriana S. Trujillo, Alexander Fuhrmann, Zongming Fu, Vidya Venkatraman, Danielle Pohl, Jeremy Tuler, Mingyi Wang, Edward G. Lakatta, Karen Ocorr, Rolf Bodmer, Sanford I. Bernstein, Jennifer E. Van Eyk, Anthony Cammarato, Adam J. Engler
Journal: Science Translational Medicine (2015)

The human heart is capable of functioning for decades despite minimal cell turnover or regeneration, suggesting that molecular alterations help sustain heart function with age. However, identification of compensatory remodeling events in the aging heart remains elusive. We present the cardiac proteomes of young and old rhesus monkeys and rats, from which we show that certain age-associated remodeling events within the cardiomyocyte cytoskeleton are highly conserved and beneficial rather than deleterious. Targeted transcriptomic analysis in Drosophila confirmed conservation and implicated vinculin as a unique molecular regulator of cardiac function during aging. Cardiac-restricted vinculin overexpression reinforced the cortical cytoskeleton and enhanced myofilament organization, leading to improved contractility and hemodynamic stress tolerance in healthy and myosin-deficient fly hearts. Moreover, cardiac-specific vinculin overexpression increased median life span by more than 150% in flies. A broad array of potential therapeutic targets and regulators of age-associated modifications, specifically for vinculin, are presented. These findings suggest that the heart has molecular mechanisms to sustain performance and promote longevity, which may be assisted by therapeutic intervention to ameliorate the decline of function in aging patient hearts.
Recombinant Glycoprotein Vaccine for the Prevention of Genital HSV-2 Infection
Authors: Lawrence Corey, Andria G. M. Langenberg, Rhoda Ashley, Rose E. Sekulovich, Allen E. Izu, John M. Douglas, Jr, H. Hunter Handsfield, Terri Warren, Lisa Marr, Stephen Tyring, Richard DiCarlo, Adaora A. Adimora, Peter Leone, Cornelia L. Dekker, Rae Lyn Burke, Wai Ping Leong, Stephen E. Straus, None for the Chiron HSV Vaccine Study Group
Journal: JAMA (1999)

ContextIn the last 3 decades, herpes simplex virus type 2 (HSV-2) infection seroprevalence and neonatal herpes have increased substantially. An effective vaccine for the prevention of genital herpes could help control this epidemic.ObjectiveTo evaluate the efficacy of a vaccine for prevention of HSV-2 infection.DesignTwo randomized, double-blind, placebo-controlled multicenter trials of a recombinant subunit vaccine containing 30 µg each of 2 major HSV-2 surface glycoproteins (gB2 and gD2) against which neutralizing antibodies are directed, administered at months 0, 1, and 6. Control subjects were given a citrate buffer vehicle. Participants were followed up for 1 year after the third immunization.Setting and ParticipantsWe enrolled 2393 persons from December 10, 1993, to April 4, 1995, who were HSV-2 and human immunodeficiency virus seronegative. One trial with 18 centers enrolled 531 HSV-2–seronegative partners of HSV-2–infected persons; the other, with 22 centers, enrolled 1862 persons attending sexually transmitted disease clinics. A total of 2268 (94.8%) met inclusion criteria and were included in the analysis with 1135 randomized to placebo and 2012 to vaccine.Main Outcome MeasureTime to acquisition of HSV-2 infection, defined by seroconversion or isolation of HSV-2 in culture during the study period by randomization group.ResultsTime-to-event curves indicated a 50% lower acquisition rate among vaccine vs placebo recipients during the initial 5 months of the trial; however, overall vaccine efficacy was 9% (95% confidence interval,−29% to 36%). Acquisition rates of HSV-2 were 4.6 and 4.2 per 100 patient-years in the placebo and vaccine recipients, respectively (P=.58). Follow-up of vaccine recipients acquiring HSV-2 infection showed vaccination had no significant influence on duration of clinical first genital HSV-2 episodes (vaccine, median of 7.1 days; placebo, 6.5 days; P&gt;.10) or subsequent frequency of reactivation (median monthly recurrence rate with vaccine, 0.2; with placebo, 0.3; P&gt;.10). The vaccine induced high levels of HSV-2–specific neutralizing antibodies in vaccinated persons who did and did not develop genital herpes.ConclusionsEfficient and sustained protection from sexual acquisition of HSV-2 infection will require more than high titers of specific neutralizing antibodies. Protection against sexually transmitted viruses involving exposure over a prolonged period will require a higher degree of vaccine efficacy than that achieved in this study.
Gene Expression Profiles of Estrogen Receptor–Positive and Estrogen Receptor–Negative Breast Cancers Are Detectable in Histologically Normal Breast Epithelium
Authors: Kelly Graham, Xijin Ge, Antonio de las Morenas, Anusri Tripathi, Carol L. Rosenberg
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Previously, we found that gene expression in histologically normal breast epithelium (NlEpi) from women at high breast cancer risk can resemble gene expression in NlEpi from cancer-containing breasts. Therefore, we hypothesized that gene expression characteristic of a cancer subtype might be seen in NlEpi of breasts containing that subtype. Experimental Design: We examined gene expression in 46 cases of microdissected NlEpi from untreated women undergoing breast cancer surgery. From 30 age-matched cases [15 estrogen receptor (ER)+, 15 ER−] we used Affymetryix U133A arrays. From 16 independent cases (9 ER+, 7 ER−), we validated selected genes using quantitative real-time PCR (qPCR). We then compared gene expression between NlEpi and invasive breast cancer using four publicly available data sets. Results: We identified 198 genes that are differentially expressed between NlEpi from breasts with ER+ (NlEpiER+) compared with ER− cancers (NlEpiER−). These include genes characteristic of ER+ and ER− cancers (e.g., ESR1, GATA3, and CX3CL1, FABP7). qPCR validated the microarray results in both the 30 original cases and the 16 independent cases. Gene expression in NlEpiER+ and NlEpiER− resembled gene expression in ER+ and ER− cancers, respectively: 25% to 53% of the genes or probes examined in four external data sets overlapped between NlEpi and the corresponding cancer subtype. Conclusions: Gene expression differs in NlEpi of breasts containing ER+ compared with ER− breast cancers. These differences echo differences in ER+ and ER− invasive cancers. NlEpi gene expression may help elucidate subtype-specific risk signatures, identify early genomic events in cancer development, and locate targets for prevention and therapy. Clin Cancer Res; 17(2); 236–46. ©2010 AACR.