tbuckley/cabot-search huggingface dataset:
Effects of interval exercise on cigarette smoke-induced right ventricular dysfunction in mice
Authors: Erlend Hassel, Anne Marie Ormbostad, Ulrik Wisløff, Sigurd Steinshamn
Journal: European Respiratory Journal (2011)

Background:  Right ventricular heart failure in COPD is thought to be a result of pulmonary hypertension due to increased pulmonary vascular resistance. Exercise, and especially interval training has been shown to be effective in improving left ventricular function, but the same is not shown for right ventricular function in COPD. The goal of this study was to examine the effects of aerobic interval training on cigarette smoke-induced right ventricular heart dysfunction in a mouse model for COPD.   Methods:  42 female A/J-OlaHsd mice were exposed to either cigarette smoke (CS) or fresh air (FA), for 14 weeks, 6 hours/day, 5 days/week. For the next four weeks they were either kept sedate (Se) or put through interval treadmill running (IT) for 1 hour/day, 5 days/week. After this period the mice were sedated with light isoflurane anaesthesia and the heart function was evaluated with echocardiography. Tricuspid annular plane systolic excursion (TAPSE) was used as a measurement of right ventricular function.   Results:   Maximal oxygen uptake was higher for the IT groups compared to the Se groups (p   Conclusion:  Smoke exposure of A/J-OlaHsd mice causes a significant reduction in right ventricular function measured by echocardiographic TAPSE. This reduction seems to be normalized by intensive interval training.
Adjuvant Endocrine Therapy Compared With No Systemic Therapy for Elderly Women With Early Breast Cancer: 21-Year Results of International Breast Cancer Study Group Trial IV
Authors: Diana Crivellari, Karen Price, Richard D. Gelber, Monica Castiglione-Gertsch, Carl-Magnus Rudenstam, Jurij Lindtner, Martin F. Fey, Hans-Jörg Senn, Alan S. Coates, John Collins, Aron Goldhirsch
Journal: Journal of Clinical Oncology (2003)

Purpose: Increasing numbers of older women are affected by early breast cancer, because of prolonged life expectancy and the increasing incidence of breast cancer with age. The role of adjuvant therapy for this population is still a matter of debate. We reviewed the long-term outcome of a mature trial comparing endocrine treatment versus no adjuvant therapy in older women with node-positive breast cancer. Patients and Methods: From 1978 to 1981, 349 women 66 to 80 years of age with pathologically involved lymph nodes after total mastectomy and axillary clearance were randomly assigned to receive 12 months of adjuvant tamoxifen plus low-dose prednisone (p+T) or no adjuvant therapy. Three hundred twenty patients were eligible. Results: At 21 years’ median follow-up, 1 year of p+T significantly prolonged disease-free survival (DFS; P = .003) and overall survival (P = .05; 15-year DFS, 10% ± 3% v 19% ± 3%; hazard ratio, 0.71; 95% CI, 0.58 to 0.86). When comparing competing causes of failure (breast cancer recurrence and deaths before breast cancer recurrence), p+T was far superior in controlling breast cancer recurrence (P = .0003), but the improvement was seen mainly in soft tissue sites. Conversely, patients in the p+T group were more likely to die before a breast cancer recurrence (P = .03). Conclusion: This trial demonstrates that significant treatment benefits continue to be observed in older patients treated for 1 year with p+T. Despite issues relating to competing causes of failure, older breast cancer patients can benefit from treatment and should be considered for trials of adjuvant systemic therapy.
Combined Influence of Insulin Resistance, Overweight/Obesity, and Fatty Liver as Risk Factors for Type 2 Diabetes
Authors: Ki-Chul Sung, Woo-Shin Jeong, Sarah H. Wild, Christopher D. Byrne
Journal: Diabetes Care (2012)

There is dissociation between insulin resistance, overweight/obesity, and fatty liver as risk factors for type 2 diabetes, suggesting that different mechanisms are involved. Our aim was to 1) quantify risk of incident diabetes at follow-up with different combinations of these risk factors at baseline and 2) determine whether each is an independent risk factor for diabetes.We examined 12,853 subjects without diabetes from a South Korean occupational cohort, and insulin resistance (IR) (homeostasis model assessment-IR ≥75th centile, ≥2.0), fatty liver (defined by standard ultrasound criteria), and overweight/obesity (BMI ≥25 kg/m(2)) identified at baseline. Odds ratios (ORs) and 95% confidence intervals (CIs) for incident diabetes at 5-year follow-up were estimated using logistic regression.We identified 223 incident cases of diabetes from which 26 subjects had none of the three risk factors, 37 had one, 56 had two, and 104 had three. In the fully adjusted model, the OR and CI for diabetes were 3.92 (2.86-5.37) for IR, 1.62 (1.17-2.24) for overweight/obesity, and 2.42 (1.74-3.36) for fatty liver. The OR for the presence of all three factors in a fully adjusted model was 14.13 (8.99-22.21).The clustering of IR, overweight/obesity, and fatty liver is common and markedly increases the odds of developing type 2 diabetes, but these factors also have effects independently of each other and of confounding factors. The data suggest that treatment for each factor is needed to decrease risk of type 2 diabetes.
Phase II Clinical Trial of Ixabepilone (BMS-247550), an Epothilone B Analog, in Metastatic and Locally Advanced Breast Cancer
Authors: Jennifer A. Low, Suparna B. Wedam, James J. Lee, Arlene W. Berman, Adam Brufsky, Sherry X. Yang, Marianne S. Poruchynsky, Seth M. Steinberg, Nitin Mannan, Tito Fojo, Sandra M. Swain
Journal: Journal of Clinical Oncology (2005)

Purpose Ixabepilone (BMS-247550) is an epothilone B analog that stabilizes microtubules and has antitumor activity in taxane-refractory patients in phase I studies. In a phase II trial, we evaluated the efficacy and safety of ixabepilone in women with metastatic and locally advanced breast cancer. Patients and Methods Breast cancer patients with measurable disease who had paclitaxel and/or docetaxel as prior neoadjuvant, adjuvant, or metastatic therapy were treated with ixabepilone at 6 mg/m 2 /d intravenously on days 1 through 5 every 3 weeks. Levels of glutamate (glu) -terminated and acetylated α-tubulin, markers of microtubule stabilization, were detected by Western blot and by immunohistochemistry in a subset of matched pre- and post-treatment tumor biopsies. Results Thirty-seven patients received 153 cycles of ixabepilone. The best responses were a complete response in one patient (3%), partial responses in seven patients (19%), and stable disease in 13 patients (35%). Grade 3 and 4 toxicities included neutropenia (35%), febrile neutropenia (14%), fatigue (14%), diarrhea (11%), nausea/vomiting (5%), myalgia/arthralgia (3%), and sensory neuropathy (3%). Two patients were removed from study because of prolonged grade 2 or 3 neurotoxicity, and three patients were removed from study for other grade 3 and 4 nonhematologic toxicities. Compared with baseline levels, levels of both glu-terminated and acetylated α-tubulin were increased in tumor biopsies performed after ixabepilone therapy. Conclusion An objective response was seen in 22% of the patients in a population who had been previously treated with a taxane. Sensory neuropathy was mild with grade 3 neurotoxicity rarely seen. Microtubule stabilization occurred in tumor biopsies after treatment with ixabepilone.
Home Environment Related to Respiratory and Allergic Diseases in Children Taking Into Account Early Exposure
Authors: C. Pénard-Morand, C. Raherison, D. Moreau, C. Kopferschmitt, F. Lavaud, D. Caillaud, D. Charpin, I. Annesi-Maesano
Journal: Journal of Allergy and Clinical Immunology (2006)
GATA-3 in Human T Cell Helper Type 2 Development
Authors: Alla Skapenko, Jan Leipe, Uwe Niesner, Koen Devriendt, Rolf Beetz, Andreas Radbruch, Joachim R. Kalden, Peter E. Lipsky, Hendrik Schulze-Koops
Journal: The Journal of Experimental Medicine (2004)

The delineation of the in vivo role of GATA-3 in human T cell differentiation is a critical step in the understanding of molecular mechanisms directing human immune responses. We examined T cell differentiation and T cell–mediated effector functions in individuals lacking one functional GATA-3 allele. CD4 T cells from GATA-3+/− individuals expressed significantly reduced levels of GATA-3, associated with markedly decreased T helper cell (Th)2 frequencies in vivo and in vitro. Moreover, Th2 cell–mediated effector functions, as assessed by serum levels of Th2-dependent immunoglobulins (Igs; IgG4, IgE), were dramatically decreased, whereas the Th1-dependent IgG1 was elevated compared with GATA-3+/+ controls. Concordant with these data, silencing of GATA-3 in GATA-3+/+ CD4 T cells with small interfering RNA significantly reduced Th2 cell differentiation. Moreover, GATA-3 mRNA levels increased under Th2-inducing conditions and decreased under Th1-inducing conditions. Taken together, the data strongly suggest that GATA-3 is an important transcription factor in regulating human Th2 cell differentiation in vivo.
Hyper-CVAD and rituximab therapy in HIV-Negative Burkitt (BL) or Burkitt-like (BLL) leukemia/lymphoma and mature B-cell acute lymphocytic leukemia (B-ALL)
Authors: D. A. Thomas, J. Cortes, S. Faderl, S. O’Brien, F. J. Giles, S. Pierce, H. M. Kantarjian
Journal: Journal of Clinical Oncology (2005)

6531 Background: Prognosis has improved for BL/BLL, particularly with short, intensive, multi-agent chemotherapy. Outcome of 26 non-HIV BL/BLL patients (pts) treated with hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) showed CR rate of 81% with induction mortality 19% owing to systemic fungal infections in pts aged 60 years (yrs) and older [Thomas et al, JCO 17:2461, 1999]. Older age was an adverse feature predicting relapse with shorter 3-yr survival compared with younger pts (17% vs 77%). Methods: The program was modified with the induction course given in laminar air flow rooms for older pts. Rituximab was added for high CD20 expression. From November 1999 to April 2004, 31 pts with newly diagnosed BL (n=15) or BLL (n=16) were treated (HIV-positive pts reported separately). The median age was 46 yrs (range, 17–77) with 29% aged 60 yrs or older. Ann Arbor stage was III/IV in 80% (7% had CNS involvement). Rituximab 375 mg/m2 was given days 1 and 11 of courses 1 & 3 with hyper-CVAD and days 1 and 8 of courses 2 & 4 with methotrexate (MTX) and ara-C. A total of 8 courses was planned with 2 intrathecal (IT) prophylactic treatments of MTX and ara-C per course (total 16 ITs). Results: The overall complete response rate in 23 evaluable pts (2 too early, 6 with CR at start with 1 course of prior therapy or resected disease) was 91%, with no difference between BL or BLL or B-ALL. CR rate for pts less than 60 yrs old was 86%; all 9 pts 60 yrs or older achieved CR. No induction deaths were observed. After a median follow up of 18 months (range, 3 - 50+ months), 2 relapses occurred. Seventeen of 31 pts have been followed over 1 yr from start of therapy without disease recurrence. One pt died in CR related to co-morbid conditions. Compared with 48 historical BL/BLL or B-ALL pts treated with hyper-CVAD alone, the 2-yr comparison rates for survival were: overall (89% vs 58%, p<.001), age < 60 yrs (88% vs 77%, p=.31) and age 60 yrs or older (89% vs 19%, p<.01) were superior for hyper-CVAD and rituximab. Toxicity profile was similar to hyper-CVAD alone. Conclusions: Rituximab added to the hyper-CVAD regimen appears to improve outcome in BL/BLL and B-ALL, particularly for elderly pts. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Amgen, Genentech
Synergistic Effect of Urotensin II With Mildly Oxidized LDL on DNA Synthesis in Vascular Smooth Muscle Cells
Authors: Takuya Watanabe, Rajbabu Pakala, Takashi Katagiri, Claude R. Benedict
Journal: Circulation (2001)

The urotensin II (UII) found in coronary atheroma is the most potent vasoconstrictor known to date. Mildly oxidized LDL (moxLDL) contributes to atherogenesis and plaque formation. We assessed the effect of UII and its interaction with moxLDL and the oxidative components of moxLDL on vascular smooth muscle cell (VSMC) proliferation. Methods and Results-Growth-arrested VSMCs were incubated in serum-free medium with different concentrations of LDL, moxLDL, oxLDL, hydrogen peroxide, lysophosphatidylcholine, or 4-hydroxy-2-nonenal, with or without UII. [(3)H]Thymidine incorporation into DNA was measured as an index of VSMC proliferation. UII stimulated [(3)H]thymidine incorporation in a dose-dependent manner, with a maximal effect at a concentration of 50 nmol/L (161%). Low concentrations of UII potentiated the mitogenic effect of LDL (108% to 242%), oxLDL (129% to 302%), moxLDL (120% to 337%), hydrogen peroxide (177% to 226%), lysophosphatidylcholine (115% to 332%), and 4-hydroxy-2-nonenal (142% to 299%). The synergistic interaction between UII and moxLDL was partially inhibited by anti-Gq/11alpha antibody, the epidermal growth factor receptor tyrosine kinase inhibitor erbstatin A (10 micromol/L), and the intracellular free radical scavenger N-acetylcysteine (400 micromol/L) and was completely inhibited by the c-Src tyrosine kinase inhibitor radicicol (10 micromol/L), the protein kinase C (PKC) inhibitor Ro31-8220 (0.1 micromol/L), and the mitogen-activated protein kinase (MAPK) kinase inhibitor PD098059 (10 micromol/L).Our results suggest that UII acts synergistically with moxLDL in inducing VSMC proliferation via the c-Src/PKC/MAPK pathway, which may explain the relatively rapid progression of atherosclerosis in patients with hypertension and hypercholesterolemia.
Genomic Profiling Defines Subtypes of Prostate Cancer with the Potential for Therapeutic Stratification
Authors: Jamie R. Schoenborn, Pete Nelson, Min Fang
Journal: Clinical Cancer Research (2013)

Abstract The remarkable variation in prostate cancer clinical behavior represents an opportunity to identify and understand molecular features that can be used to stratify patients into clinical subgroups for more precise outcome prediction and treatment selection. Significant progress has been made in recent years in establishing the composition of genomic and epigenetic alterations in localized and advanced prostate cancers using array-based technologies and next-generation sequencing approaches. The results of these efforts shed new light on our understanding of this disease and point to subclasses of prostate cancer that exhibit distinct vulnerabilities to therapeutics. The goal of this review is to categorize the genomic data and, where available, corresponding expression, functional, or related therapeutic information, from recent large-scale and in-depth studies that show a new appreciation for the molecular complexity of this disease. We focus on how these results inform our growing understanding of the mechanisms that promote genetic instability, as well as routes by which specific genes and biologic pathways may serve as biomarkers or potential targets for new therapies. We summarize data that indicate the presence of genetic subgroups of prostate cancers and show the high level of intra- and intertumoral heterogeneity, as well as updated information on disseminated and circulating tumor cells. The integrated analysis of all types of genetic alterations that culminate in altering critical biologic pathways may serve as the impetus for developing new therapeutics, repurposing agents used currently for treating other malignancies, and stratifying early and advanced prostate cancers for appropriate interventions. Clin Cancer Res; 19(15); 4058–66. ©2013 AACR.
Sulforaphane Increases Drug-mediated Cytotoxicity Toward Cancer Stem-like Cells of Pancreas and Prostate
Authors: Georgios Kallifatidis, Sabrina Labsch, Vanessa Rausch, Juergen Mattern, Jury Gladkich, Gerhard Moldenhauer, Markus W. Büchler, Alexei V. Salnikov, Ingrid Herr
Journal: Molecular Therapy (2010)

Despite intense efforts to develop treatments against pancreatic cancer, agents that cure this highly resistant and metastasizing disease are not available. Considerable attention has focused on broccoli compound sulforaphane (SF), which is suggested as combination therapy for targeting of pancreatic cancer stem cells (CSCs). However, there are concerns that antioxidative properties of SF may interfere with cytotoxic drugs-as suggested, e.g., for vitamins. Therefore we investigated a combination therapy using established pancreatic CSCs. Although cisplatin (CIS), gemcitabine (GEM), doxorubicin, 5-flurouracil, or SF effectively induced apoptosis and prevented viability, combination of a drug with SF increased toxicity. Similarly, SF potentiated the drug effect in established prostate CSCs revealing that SF enhances drug cytotoxicity also in other tumor entities. Most importantly, combined treatment intensified inhibition of clonogenicity and spheroid formation and aldehyde dehydrogenase 1 (ALDH1) activity along with Notch-1 and c-Rel expression indicating that CSC characteristics are targeted. In vivo, combination treatment was most effective and totally abolished growth of CSC xenografts and tumor-initiating potential. No pronounced side effects were observed in normal cells or mice. Our data suggest that SF increases the effectiveness of various cytotoxic drugs against CSCs without inducing additional toxicity in mice.
MetAMOS: a modular and open source metagenomic assembly and analysis pipeline
Authors: Todd J Treangen, Sergey Koren, Daniel D Sommer, Bo Liu, Irina Astrovskaya, Brian Ondov, Aaron E Darling, Adam M Phillippy, Mihai Pop
Journal: Genome biology (2013)

Abstract We describe MetAMOS, an open source and modular metagenomic assembly and analysis pipeline. MetAMOS represents an important step towards fully automated metagenomic analysis, starting with next-generation sequencing reads and producing genomic scaffolds, open-reading frames and taxonomic or functional annotations. MetAMOS can aid in reducing assembly errors, commonly encountered when assembling metagenomic samples, and improves taxonomic assignment accuracy while also reducing computational cost. MetAMOS can be downloaded from: https://github.com/treangen/MetAMOS .
Repair of severed brachial plexus
Authors: L. O. Nahai F Vasonez
Journal: JAMA (1976)

To the Editor.—  The case report by Drs Amine and Sugar in Repair of Severed Brachial Plexus: A Plea to Emergency Room Physicians (235: 1039, 1976), while outlining some established principles for the acute care of nerve injuries, does not take into account any of the recent developments in the management of nerve gaps. Specifically, we refer to the work of Millesi et al1,2and suggest interfascicular nerve grafting as an alternative approach in such cases.  They refer to  mobilization of distal nerves and 90° flexion of the elbow to overcome a 9-cm gap. The deleterious effect of such extensive mobilization on the vascular supply of nerves has been demonstrated to by Smith.3,4Millesi and co-workers have shown the superiority of results with an interfascicular graft as compared to direct epineural suture under tension.1,2We believe that despite extensive mobilization, substantial tension must exist at the
Protecting the tuberculosis drug pipeline: stating the case for the rational use of fluoroquinolones
Authors: Giovanni Battista Migliori, Miranda W. Langendam, Lia D'Ambrosio, Rosella Centis, Francesco Blasi, Emma Huitric, Davide Manissero, Marieke J. van der Werf
Journal: European Respiratory Journal (2012)

The use of fluoroquinolones (FQs) to treat lower respiratory tract infections (LTRI) other than tuberculosis (TB) allows selection of FQ-resistant TB when TB is misdiagnosed. This study maps national guidelines on the use of FQs for LRTI in Europe and determines the risk of FQ-resistant TB upon FQ treatment before TB diagnosis. A questionnaire was developed to map existing national LRTI and community-acquired pneumonia (CAP) guidelines. A systematic review and meta-analysis were performed to determine the risk of FQ-resistant TB if prescribed FQs prior to TB diagnosis. 15 (80%) out of 24 responding European Respiratory Society national delegates reported having national LRTI management guidelines, seven including recommendations on FQ use and one recommending FQs as the first-choice drug. 18 out of 24 countries had national CAP management guidelines, two recommending FQ as the drug of choice. Six studies investigating FQ exposure and the risk of FQ-resistant TB were analysed. TB patients had a three-fold higher risk of having FQ-resistant TB when prescribed FQs before TB diagnosis, compared to non FQ-exposed patients (OR 2.81, 95% CI 1.47–5.39). Although the majority of European countries hold national LRTI/CAP guidelines, our results suggest that a risk of developing FQ resistance exists. Further strengthening of, and adherence to, guidelines is needed to ensure rational use of FQs.
Molecular Target Class Is Predictive of <i>In vitro</i> Response Profile
Authors: Joel Greshock, Kurtis E. Bachman, Yan Y. Degenhardt, Junping Jing, Yuan H. Wen, Stephen Eastman, Elizabeth McNeil, Christopher Moy, Ronald Wegrzyn, Kurt Auger, Mary Ann Hardwicke, Richard Wooster
Journal: Cancer Research (2010)

Preclinical cellular response profiling of tumor models has become a cornerstone in the development of novel cancer therapeutics. As efforts to predict clinical efficacy using cohorts of in vitro tumor models have been successful, expansive panels of tumor-derived cell lines can recapitulate an "all comers" efficacy trial, thereby identifying which tumors are most likely to benefit from treatment. The response profile of a therapy is most often studied in isolation; however, drug treatment effect patterns in tumor models across a diverse panel of compounds can help determine the value of unique molecular target classes in specific tumor cohorts. To this end, a panel of 19 compounds was evaluated against a diverse group of cancer cell lines (n = 311). The primary oncogenic targets were a key determinant of concentration-dependent proliferation response, as a total of five of six, four of four, and five of five phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, insulin-like growth factor-I receptor (IGF-IR), and mitotic inhibitors, respectively, clustered with others of that common target class. In addition, molecular target class was correlated with increased responsiveness in certain histologies. A cohort of PI3K/AKT/mTOR inhibitors was more efficacious in breast cancers compared with other tumor types, whereas IGF-IR inhibitors more selectively inhibited growth in colon cancer lines. Finally, specific phenotypes play an important role in cellular response profiles. For example, luminal breast cancer cells (nine of nine; 100%) segregated from basal cells (six of seven; 86%). The convergence of a common cellular response profile for different molecules targeting the same oncogenic pathway substantiates a rational clinical path for patient populations most likely to benefit from treatment. Cancer Res; 70(9); 3677-86. (c)2010 AACR.