tbuckley/cabot-search huggingface dataset:
Are There Groups of Patients Who Don't Benefit from Chemotherapy?
Authors: P. Ravdin
Journal: Cancer Research (2009)

Abstract The obvious answer to this question is: Yes. There are two reasons that a medical therapy would not be considered as of benefit to patients. The first of these is that the risks of toxicity or negative effects of a therapy outweigh the benefits. The second is that that therapy does not work: that it does not decrease the risk of negative outcome (for breast cancer that the risk of recurrence and/or death). Over the last 10 years there have been improvements in how we can assess patients for the appropriateness of chemotherapy: 1) We can better predict patients' prognoses without therapy, 2) in a modest way we can better assess their risk for toxicity and 3)we can better predict for individual patients the relative efficacy of a therapy. Over the last decade models to that integrate classical pathologic information to better predict the prognosis of patients have been refined. An advance beyond these models is the development of multi-gene assays either dependent on evaluation of mRNA or proteins that can stratify patients into prognostic groupings. These new methods can be integrated with classical pathologic information to evaluate prognosis. Work on predicting toxicity from chemotherapy has been more modest, but have important possible application. Models exist for some chemotherapeutic regimens for predicting the risk of clinically significant neutropenia or cardiac toxicity. In some instances the risk of particularly severe toxicity to specific agents such as 5FU can be tested for. Perhaps the greatest advance during this period is the better definition of predictors of response to chemotherapy. There has been a long recognition that the estrogen receptor status can stratify patients particularly likely to benefit from chemotherapy, but new predictors are able to identify patients within ER subgroups with particular chemosensitivity. The move toward more personalized therapy is taking place with improvements in prognostic assessment of patients, their risk of toxicity, and whether specific agents will (or will not) reduce the risk of recurrence or breast cancer related death. This review will show that there are certainly are patients who can be identified who do not benefit from chemotherapy, and will in its summary examine what current treatment guidelines say on this topic Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr CS1-1.
Specific incremental field test for aerobic fitness in tennis
Authors: O Girard, R Chevalier, F Leveque, J P Micallef, G P Millet
Journal: British Journal of Sports Medicine (2006)

Objectives: To compare metabolic and cardiorespiratory responses between subjects undergoing incremental treadmill (non-specific) and tennis field based (sport specific) tests. Methods: Nine junior competitive tennis players randomly performed two incremental protocols to exhaustion: a treadmill test (TT) and a tennis specific fitness test (FT). The FT consisted of repeated displacements replicating the game of tennis at increasing speed on a court. In both tests, ventilatory variables and heart rate (HR) were determined at the ventilatory threshold (VT), respiratory compensation point (RCP), and maximal loads (max). Blood lactate concentration was determined at the point of volitional fatigue. Results: Percentage (mean (SD)) maximal HR (83.6 (5.1) v 83.0 (2.8) and 92.1 (2.1) v 92.3 (2.1)%, respectively) and percentage maximal oxygen uptake (VO 2max ) (69.4 (8.1) v 73.5 (6.1) and 84.4 (6.5) v 85.5 (8.7)%, respectively) at the VT and RCP were not different between the FT and TT subjects, whereas VO 2max was higher in the FT than in the TT (63.8 (3.0) v 58.9 (5.3) ml/min/kg; p&lt;0.05). Blood lactate concentration (10.7 (3.0) v 10.6 (4.3) mmol/l) did not differ between the TT and FT. Conclusions: Although cardiorespiratory variables were not different at submaximal intensities between the two tests, VO 2max values derived from laboratory measurements were underestimated. Using field testing in addition to treadmill testing provides a better measurement of a player’s individual fitness level and may be routinely used to accurately prescribe appropriate aerobic exercise training.
Pioglitazone Inhibits Cell Growth and Reduces Matrix Production in Human Kidney Fibroblasts
Authors: Stephen Zafiriou, Scott R. Stanners, Sonia Saad, Tania S. Polhill, Philip Poronnik, Carol A. Pollock
Journal: Journal of the American Society of Nephrology (2005)

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists are increasingly used in patients with diabetes, and small studies have suggested a beneficial effect on renal function, but their effects on extracellular matrix (ECM) turnover are unknown. The aims of this study were to investigate the effects of the PPAR-gamma agonist pioglitazone on growth and matrix production in human cortical fibroblasts (CF). Cell growth and ECM production and turnover were measured in human CF in the presence and absence of 1 and 3 muM pioglitazone. Exposure of CF to pioglitazone caused an antiproliferative (P < 0.0001) and hypertrophic (P < 0.0001) effect; reduced type IV collagen secretion (P < 0.01), fibronectin secretion (P < 0.0001), and proline incorporation (P < 0.0001); decreased MMP-9 activity (P < 0.05); and reduced tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 secretion (P < 0.001 and P < 0.0001, respectively). These effects were independent of TGF-beta1. A reduction in ECM production was similarly observed when CF were exposed to a selective PPAR-gamma agonist (L-805645) in concentrations that caused no toxicity, confirming the antifibrotic effects of pioglitazone were mediated through a PPAR-gamma-dependent mechanism. Exposure of CF to high glucose conditions induced an increase in the expression of collagen IV (P < 0.05), which was reversed both in the presence of pioglitazone (1 and 3 muM) and by L-805645. In summary, exposure of human CF to pioglitazone causes an antiproliferative effect and reduces ECM production through mechanisms that include reducing TIMP activity, independent of TGF-beta1. These studies suggest that the PPAR-gamma agonists may have a specific role in ameliorating the course of progressive tubulointerstitial fibrosis under both normoglycemic and hyperglycemic states.
Modulation of the Startle Response and Startle Laterality in Relatives of Schizophrenic Patients and in Subjects With Schizotypal Personality Disorder: Evidence of Inhibitory Deficits
Authors: Kristin S. Cadenhead, Neal R. Swerdlow, Kathleen M. Shafer, Martha Diaz, David L. Braff
Journal: American Journal of Psychiatry (2000)

Patients with schizophrenia spectrum disorders have been shown to have deficits in sensorimotor gating as assessed by prepulse inhibition of the startle response. The authors hypothesized that nonschizophrenic relatives of patients with schizophrenia would also have prepulse inhibition deficits, thereby reflecting a genetically transmitted susceptibility to sensorimotor gating deficits.Twenty-five comparison subjects, 23 patients with schizophrenia, 34 relatives of the schizophrenic patients, and 11 subjects with schizotypal personality disorder were assessed in an acoustic startle paradigm. The eye-blink component of the startle response was assessed bilaterally by using electromyographic recordings of orbicularis oculi.The patients with schizophrenia, their relatives, and subjects with schizotypal personality disorder all had reduced prepulse inhibition relative to comparison subjects, and these deficits were more evident in measures of right eye-blink prepulse inhibition. Comparison subjects demonstrated greater right versus left eye-blink prepulse inhibition, whereas the probands, their relatives, and subjects with schizotypal personality disorder showed less asymmetry of prepulse inhibition.These data suggest a genetically transmitted deficit in prepulse inhibition (sensorimotor gating) in patients with schizophrenia spectrum disorders, including subjects with schizotypal personality disorder and relatives of patients with schizophrenia.
Compartmental analysis of steady-state taurocholate transport kinetics by isolated rat hepatocytes
Authors: Thierry Coche, Xavier Deroubaix, Eric Depiereux, Ernest Feytmans
Journal: Hepatology (1991)

We used compartmental modeling to describe taurocholate transport by isolated rat liver cells in suspension. Cells are preincubated in the presence of unlabeled taurocholate. When a steady-state for taurocholate is reached, radiolabeled taurocholate is added to the medium and its exchange kinetics between the medium and the cells are followed over time. Because the studies are performed under steady-state conditions, the kinetics can be described by linear compartmental models. We found a closed two-compartment model sufficient to describe the steady-state transport data. Simulations reveal that if the pools of free and bound intracellular taurocholate exchange rapidly, the cells will behave as a single, kinetically homogeneous compartment and intracellular events will not influence the exchange kinetics of taurocholate between the medium and the cells. The two-compartment model was used to study the concentration dependence of taurocholate transport by isolated cells. Steady-state transport rates and taurocholate concentrations in the medium and the cells were calculated using the model equations. Taurocholate influx, accumulation and efflux processes were studied simultaneously by examining the relationship between appropriate combinations of these variables. Application of this approach to study the inhibition of taurocholate transport by taurochenodeoxycholate is illustrated. In conclusion, this method provides a complementary approach to initial rate studies, which are generally used to investigate bile acid transport by isolated cells.
Targeting HSP90 in ovarian cancers with multiple receptor tyrosine kinase coactivation
Authors: Yisheng Jiao, Wenbin Ou, Fanguo Meng, Haimeng Zhou, Aiyuan Wang
Journal: Molecular Cancer (2011)

Ovarian cancer has the highest mortality rate of all gynecologic malignancy. The receptor tyrosine kinases (RTKs), including EGFR, ERBB2, PDGFR, VEGFR and MET, are activated in subsets of ovarian cancer, suggesting that these kinases might represent novel therapeutic targets. However, clinical trials have not or just partially shown benefit to ovarian cancers treated with EGFR, ERBB2, or PDGFR inhibitors. Despite multiple RTK activation in ovarian cancer pathogenesis, it is unclear whether transforming activity is dependent on an individual kinase oncoprotein or the coordinated activity of multiple kinases. We hypothesized that a coordinated network of multi-RTK activation is important for the tumorigenesis of ovarian cancers. Herein, we demonstrate co-activation of multiple RTKs (EGFR, ERBB2, ERBB4, MET and/or AXL) in individual ovarian cancer cell lines and primary tumors. We also show that coordinate inhibition of this multi-kinase signaling has substantially greater effect on ovarian cancer proliferation and survival, compared to inhibition of individual activated kinases. The inhibition of this multi-RTK signaling by HSP90 suppression results in profound pro-apoptotic and anti-proliferative effects, and is associated with the inactivation of RTK downstream PI3-K/AKT/mTOR and RAF/MAPK signaling. These studies suggest that anti-multiple RTK strategy could be useful in the treatment of ovarian cancer.
FK 506 ameliorates the hepatic injury associated with ischemia and reperfusion in rats
Authors: Mahmoud F. Sakr, Giorgio M. Zetti, Tarek I. Hassanein, Hassan Farghali, Michael A. Nalesnik, Judith S. Gavaler, Thomas E. Starzl, David H. Van Thiel
Journal: Hepatology (1991)

The effect of FK 506 on regeneration of the liver was studied in rats after a two-thirds partial hepatectomy after 60 min of ischemia of the unresected liver. The animals were divided into three distinct groups of 10 rats each. Group 1 (controls) received 0.5 ml saline solution intravenously 30 min after the induction of ischemia. Groups 2 and 3 were injected with FK 506 (0.3 mg/kg) intravenously 30 min after and 24 min before the induction of hepatic ischemia, respectively. The hepatic content of ATP and serum levels of ALT and lactate dehydrogenase were determined on each animal. In addition, the histological appearance and mitotic activity of the remnant liver was determined at regular 24-hr intervals after hepatic ischemia. All 10 control animals died within 72 hr. Treatment with FK 506 resulted in improved survival in groups 2 and 3 (30% and 80%, respectively). The improved survival seen in the FK 506-treated animals was reflected by a restoration of hepatic ATP content, a reduction in the serum levels of ALT and lactate dehydrogenase, an amelioration of hepatic necrosis and neutrophilic infiltration and an increase in the mitotic activity of the liver. These results suggest that FK 506 ameliorates the hepatic injury associated with ischemia/reperfusion and has a potent stimulatory effect on liver cell regeneration that may make it valuable as a hepatoprotective agent when administered to organ donors before graft harvesting.
Cell Carriers for Oncolytic Viruses: Fed Ex for Cancer Therapy
Authors: Candice Willmon, Kevin Harrington, Timothy Kottke, Robin Prestwich, Alan Melcher, Richard Vile
Journal: Molecular Therapy (2009)

Oncolytic viruses delivered directly into the circulation face many hazards that impede their localization to, and infection of, metastatic tumors. Such barriers to systemic delivery could be overcome if couriers, which confer both protection, and tumor localization, to their viral cargoes, could be found. Several preclincal studies have shown that viruses can be loaded into, or onto, different types of cells without losing the biological activity of either virus or cell carrier. Importantly, such loading can significantly protect the viruses from immune-mediated virus-neutralizing activities, including antiviral antibody. Moreover, an impressive portfolio of cellular vehicles, which have some degree of tropism for tumor cells themselves, or for the biological properties associated with the tumor stroma, is already available. Therefore, it will soon be possible to initiate clinical protocols to test the hypopthesis that cell-mediated delivery can permit efficient shipping of oncolytic viruses from the loading bay (the production laboratory) directly to the tumor in immune-competent patients with metastatic disease.
Seasonal Influenza Vaccine Provides Priming for A/H1N1 Immunization
Authors: Giuseppe Del Giudice, Koert J. Stittelaar, Geert van Amerongen, James Simon, Albert D. M. E. Osterhaus, Klaus Stöhr, Rino Rappuoli
Journal: Science Translational Medicine (2009)

Mass vaccination against the 2009 A/H1N1 influenza virus, with different vaccine formulations, is being implemented globally. Because of the urgency with which the vaccine has been prepared, little information has been gathered on variables that influence the effectiveness of the vaccine. Specifically, it is not clear whether priming by previous infection with or vaccination against seasonal influenza affects the response to the vaccine. Similarly, the role of vaccine adjuvants in vaccine response is not known. To address these questions, we injected ferrets with seasonal influenza vaccine and then vaccinated with 2009 A/H1N1 vaccine with or without the oil-in-water adjuvant MF59. The results show that the seasonal flu vaccine, although it did not induce functional antibodies against the 2009 A/H1N1 virus, provided immunological priming and allowed production of protective antibodies to 2009 A/H1N1 after one dose of 2009 A/H1N1 vaccine. The vaccine given without adjuvant significantly reduced viral load in the lungs but did not protect from infection. Only the vaccine with adjuvant completely prevented both pulmonary and nasal infection.
Evidence‐based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group
Authors: M. Cicardi, K. Bork, T. Caballero, T. Craig, H. H. Li, H. Longhurst, A. Reshef, B. Zuraw
Journal: Allergy (2011)

To cite this article: Cicardi M, Bork K, Caballero T, Craig T, Li HH, Longhurst H, Reshef A, Zuraw B on behalf of HAWK ( H ereditary A ngioedema International W or k ing Group). Evidence‐based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy 2012; 67 : 147–157. Abstract Angioedema owing to hereditary deficiency of C1 inhibitor (HAE) is a rare, life‐threatening, disabling disease. In the last 2 years, the results of well‐designed and controlled trials with existing and new therapies for this condition have been published, and new treatments reached the market. Current guidelines for the treatment for HAE were released before the new trials and before the new treatments became available and were essentially based on observational studies and expert opinion. To provide evidence‐based HAE treatment guidelines supported by the new studies, a conference was held in Gargnano del Garda, Italy, from September 26 to 29, 2010. The meeting hosted 58 experienced HAE expert physicians, representatives of pharmaceutical companies and representatives of HAE patients’ associations. Here, we report the topics discussed during the meeting and evidence‐based consensus about management approaches for HAE in adult/adolescent patients.
Comparative epidemiology of human infections with avian influenza A H7N9 and H5N1 viruses in China: a population-based study of laboratory-confirmed cases
Authors: Benjamin J Cowling, Lianmei Jin, Eric HY Lau, Qiaohong Liao, Peng Wu, Hui Jiang, Tim K Tsang, Jiandong Zheng, Vicky J Fang, Zhaorui Chang, Michael Y Ni, Qian Zhang, Dennis KM Ip, Jianxing Yu, Yu Li, Liping Wang, Wenxiao Tu, Ling Meng, Joseph T Wu, Huiming Luo, Qun Li, Yuelong Shu, Zhongjie Li, Zijian Feng, Weizhong Yang, Yu Wang, Gabriel M Leung, Hongjie Yu
Journal: The Lancet (2013)
A public T cell clonotype within a heterogeneous autoreactive repertoire is dominant in driving EAE
Authors: Juscilene S. Menezes, Peter van den Elzen, Jordan Thornes, Donald Huffman, Nathalie M. Droin, Emanual Maverakis, Eli E. Sercarz
Journal: Journal of Clinical Investigation (2007)

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis. Immunization of B10.PL mice with the Ac1-9 peptide, the immunodominant determinant of myelin basic protein (MBP), produced a single episode of EAE followed by recovery and resistance to reinduction of disease. Using the CDR3 length spectratyping technique, we characterized the clonal composition of the Ac1-9-specific T cell repertoire from induction through onset and resolution of disease. Two clonally restricted subsets within a heterogeneous self-reactive repertoire were found in mouse lymph nodes, spleen, and spinal cord soon after immunization, before any sign of EAE. These clonotypes, designated BV8S2/BJ2S7 and BV16/BJ2S5, were present in all mice examined and thus considered public. BV8S2/BJ2S7 was found in far greater excess; was exclusively Th1 polarized; disappeared from the spinal cord, spleen, and lymph nodes concomitantly with recovery; and transferred disease to naive recipients. In contrast, BV16/BJ2S5 and numerous private clonotypes were either Th1 or Th2 and persisted following recovery. These results are consistent with the hypothesis that the public clonotype BV8S2/BJ2S7 is a driver of disease and necessary for its propagation.
Allergies and Adult Gliomas: Cohort Results Strengthen Evidence for a Causal Association
Authors: F. G. Davis, U. Al-Alem
Journal: JNCI Journal of the National Cancer Institute (2011)

The evidence for an association between a history of allergies and a reduced risk of glioma has been emerging (1). In this issue of the Journal, Calboli et al. (2) analyze associations between prediagnostic plasma immunoglobulin E (IgE) levels and the risk of adult glioma by combining data from four large prospective cohort studies. The pooled data resulted in a modest number of 169 glioma cases, but for a rare disease, this is a substantial contribution to the literature. A statistically significant protective association with borderline elevated levels of total IgE (25–100 kU/L) relative to clinically normal levels ( 100 kU/L) was not observed. The findings are somewhat perplexing, but further our understanding of the biological underpinnings of the protection that allergies appear to provide in the development of brain tumors. The results of Calboli et al. (2) are consistent with one other cohort study that reported a statistically significant inverse associ ation between risk of glioma and borderline elevated levels of IgE, but inconsistent associations with elevated IgE levels (3). This study (2) estimated an odds ratio (OR) near unity at elevated total IgE levels, whereas Schlehofer et al. (3) reported a protective association with elevated levels of respiratory allergen–specific IgE. They observed that the higher the level of respiratory allergen– specific IgE, the stronger was the association, and an increased association was statistically significant in patients with high grade glioma (3). Together, these studies point to an association between prediagnosis IgE level and risk of glioma, but the biological mechanism underlying this association is still unclear. The suggestion that allergies may be associated with a reduced risk of developing of brain tumors was made in the early 1990s (4). Since then, 10 case–control and two cohort studies have investigated this association using self-reported data on the history of allergic conditions. Results showed an inverse association of glioma risk with any allergic conditions compared with nonallergic conditions (pooled estimated OR = 0.60, 95% confidence interval [CI] = 0.52 to 0.69) (1). The association was statistically significant when limited to asthma, eczema, and hay fever as a group, and the association remained when consideration of proxy reporting was introduced in the analysis (1). These estimates based on self-report of allergies are similar to that observed by Calboli et al. (2) (total IgE 25–100 vs <25 kU/L, OR = 0.63, 95% CI = 0.42 to 0.93).
Incidence and outcome of weaning from mechanical ventilation according to new categories
Authors: G-C. Funk, S. Anders, M-K. Breyer, O. C. Burghuber, G. Edelmann, W. Heindl, G. Hinterholzer, R. Kohansal, R. Schuster, A. Schwarzmaier-D'Assie, A. Valentin, S. Hartl
Journal: European Respiratory Journal (2009)

Weaning from mechanical ventilation was categorised as simple, difficult or prolonged by an international task force of the American Thoracic Society/European Respiratory Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine/Sociéte de Réanimation de Langue Française in 2007. This new classification has not been tested in clinical practice. The objective of the present study was to determine the incidence and outcome of weaning according to the new categories. We included medical and surgical patients who required mechanical ventilation in a prospective, multicentre, 6-month cohort study. From an initial cohort of 510 patients, 257 intubated patients started weaning. Of these patients, the cumulative incidences of simple, difficult, and prolonged weaning were 152 (59%), 68 (26%) and 37 (14%), respectively. Hospital mortality was increased in patients with prolonged (32%) but not difficult (9%) weaning in comparison with those with simple weaning (13%), overall p = 0.0205. In a multivariate logistic regression model, prolonged but not difficult weaning was associated with an increased risk of death. Ventilator-free days and intensive care unit (ICU)-free days were decreased in both difficult and prolonged weaning. In conclusion, the new weaning category prolonged weaning is associated with increased mortality and morbidity in the ICU. The new category difficult to wean was associated with increased morbidity, but not mortality.