tbuckley/cabot-search huggingface dataset:
A Galectin-3 Ligand Corrects the Impaired Function of Human CD4 and CD8 Tumor-Infiltrating Lymphocytes and Favors Tumor Rejection in Mice
Authors: Nathalie Demotte, Grégoire Wieërs, Patrick Van Der Smissen, Muriel Moser, Christopher Schmidt, Kris Thielemans, Jean-Luc Squifflet, Birgit Weynand, Javier Carrasco, Christophe Lurquin, Pierre J. Courtoy, Pierre van der Bruggen
Journal: Cancer Research (2010)

Abstract Human CD8+ tumor-infiltrating T lymphocytes (TIL), in contrast with CD8+ blood cells, show impaired IFN-γ secretion on ex vivo restimulation. We have attributed the impaired IFN-γ secretion to a decreased mobility of T-cell receptors on trapping in a lattice of glycoproteins clustered by extracellular galectin-3. Indeed, we have previously shown that treatment with N-acetyllactosamine, a galectin ligand, restored this secretion. We strengthened this hypothesis here by showing that CD8+ TIL treated with an anti–galectin-3 antibody had an increased IFN-γ secretion. Moreover, we found that GCS-100, a polysaccharide in clinical development, detached galectin-3 from TIL and boosted cytotoxicity and secretion of different cytokines. Importantly, we observed that not only CD8+ TIL but also CD4+ TIL treated with GCS-100 secreted more IFN-γ on ex vivo restimulation. In tumor-bearing mice vaccinated with a tumor antigen, injections of GCS-100 led to tumor rejection in half of the mice, whereas all control mice died. In nonvaccinated mice, GCS-100 had no effect by itself. These results suggest that a combination of galectin-3 ligands and therapeutic vaccination may induce more tumor regressions in cancer patients than vaccination alone. Cancer Res; 70(19); 7476–88. ©2010 AACR.
Trastuzumab Plus Anastrozole Versus Anastrozole Alone for the Treatment of Postmenopausal Women With Human Epidermal Growth Factor Receptor 2–Positive, Hormone Receptor–Positive Metastatic Breast Cancer: Results From the Randomized Phase III TAnDEM Study
Authors: Bella Kaufman, John R. Mackey, Michael R. Clemens, Poonamalle P. Bapsy, Ashok Vaid, Andrew Wardley, Sergei Tjulandin, Michaela Jahn, Michaela Lehle, Andrea Feyereislova, Cédric Révil, Alison Jones
Journal: Journal of Clinical Oncology (2009)

TAnDEM is the first randomized phase III study to combine a hormonal agent and trastuzumab without chemotherapy as treatment for human epidermal growth factor receptor 2 (HER2)/hormone receptor-copositive metastatic breast cancer (MBC).Postmenopausal women with HER2/hormone receptor-copositive MBC were randomly assigned to anastrozole (1 mg/d orally) with or without trastuzumab (4 mg/kg intravenous infusion on day 1, then 2 mg/kg every week) until progression. The primary end point was progression-free survival (PFS) in the intent-to-treat population. Results Overall, 103 patients received trastuzumab plus anastrozole; 104 received anastrozole alone. Patients in the trastuzumab plus anastrozole arm experienced significant improvements in PFS compared with patients receiving anastrozole alone (hazard ratio = 0.63; 95% CI, 0.47 to 0.84; median PFS, 4.8 v 2.4 months; log-rank P = .0016). In patients with centrally confirmed hormone receptor positivity (n = 150), median PFS was 5.6 and 3.8 months in the trastuzumab plus anastrozole and anastrozole alone arms, respectively (log-rank P = .006). Overall survival in the overall and centrally confirmed hormone receptor-positive populations showed no statistically significant treatment difference; however, 70% of patients in the anastrozole alone arm crossed over to receive trastuzumab after progression on anastrozole alone. Incidence of grade 3 and 4 adverse events was 23% and 5%, respectively, in the trastuzumab plus anastrozole arm, and 15% and 1%, respectively, in the anastrozole alone arm; one patient in the combination arm experienced New York Heart Association class II congestive heart failure.Trastuzumab plus anastrozole improves outcomes for patients with HER2/hormone receptor-copositive MBC compared with anastrozole alone, although adverse events and serious adverse events were more frequent with the combination.
Association between presence of HLA-B*5701, HLA-DR7 , and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir
Authors: S Mallal, D Nolan, C Witt, G Masel, AM Martin, C Moore, D Sayer, A Castley, C Mamotte, D Maxwell, I James, FT Christiansen
Journal: The Lancet (2002)
Identification of Volatile Biomarkers of Gastric Cancer Cells and Ultrasensitive Electrochemical Detection based on Sensing Interface of Au-Ag Alloy coated MWCNTs
Authors: Yixia Zhang, Guo Gao, Huijuan Liu, Hualin Fu, Jun Fan, Kan Wang, Yunsheng Chen, Baojie Li, Chunlei Zhang, Xiao Zhi, Lin He, Daxiang Cui
Journal: Theranostics (2014)

Successful development of novel electrochemical biosensing interface for ultrasensitive detection of volatile biomarkers of gastric cancer cells is a challenging task.Herein we reported to screen out novel volatile biomarkers associated with gastric cancer cells and develop a novel Au-Ag alloy composites-coated MWCNTs as sensing interface for ultrasensitive detection of volatile biomarkers.MGC-803 gastric cancer cells and GES-1 gastric mucous cells were cultured in serum-free media.The sample preparation approaches and HS-SPME conditions were optimized for screening volatile biomarkers.Volatiles emitted from the headspace of the cells/medium culture were identified using GC-MS.The Au-Ag nanoparticles-coated multiwalled carbon nanotubes were prepared as a sensing interface for detection of volatile biomarkers.Results showed that eight different volatile metabolites were screened out between MGC-803 cells and GES-1 cells.Two compounds such as 3-octanone and butanone were specifically present in the headspace of the MGC-803 cells.Three volatiles such as 4-isopropoxybutanol, nonanol and 4-butoxy 1-butanol coexisted in the headspace of both the MGC-803 cells and the GES-1 cells, their concentrations in the headspace of the GES-1cells were markedly higher than those in the MGC-803 cells, three volatiles such as formic acid propyl ester, 1.4-butanediol and 2, 6, 11-trimethyl dodecane solely existed in the headspace of the GES-1 cells.The nanocomposites of MWNTs loaded with Au-Ag nanoparticles were prepared as a electrochemical sensing interface for detection of two volatile biomarkers, cyclic voltammetry studies showed that the fabricated sensor could detect 3-octanone in the range of 0~0.0025% (v/v) and with a detection limitation of 0.3 ppb, could detect butanone in the range of 0 ~ 0.055% (v/v), and with a detection limitation of 0.5 ppb, and exhibited good selectivity.The novel electrochemical biosensor combined with volatile biomarkers of gastric cancer owns great potential in applications such as early diagnosis and the prognosis of gastric cancer in near future.
Comparison of Survival Outcomes Among Cancer Patients Treated In and Out of Clinical Trials
Authors: Joseph M. Unger, William E. Barlow, Diane P. Martin, Scott D. Ramsey, Michael LeBlanc, Ruth Etzioni, Dawn L. Hershman
Journal: JNCI Journal of the National Cancer Institute (2014)

Clinical trials test the efficacy of a treatment in a select patient population. We examined whether cancer clinical trial patients were similar to nontrial, "real-world" patients with respect to presenting characteristics and survival.We reviewed the SWOG national clinical trials consortium database to identify candidate trials. Demographic factors, stage, and overall survival for patients in the standard arms were compared with nontrial control subjects selected from the Surveillance, Epidemiology, and End Results program. Multivariable survival analyses using Cox regression were conducted. The survival functions from aggregate data across all studies were compared separately by prognosis (≥50% vs <50% average 2-year survival). All statistical tests were two-sided.We analyzed 21 SWOG studies (11 good prognosis and 10 poor prognosis) comprising 5190 patients enrolled from 1987 to 2007. Trial patients were younger than nontrial patients (P < .001). In multivariable analysis, trial participation was not associated with improved overall survival for all 11 good-prognosis studies but was associated with better survival for nine of 10 poor-prognosis studies (P < .001). The impact of trial participation on overall survival endured for only 1 year.Trial participation was associated with better survival in the first year after diagnosis, likely because of eligibility criteria that excluded higher comorbidity patients from trials. Similar survival patterns between trial and nontrial patients after the first year suggest that trial standard arm outcomes are generalizable over the long term and may improve confidence that trial treatment effects will translate to the real-world setting. Reducing eligibility criteria would improve access to clinical trials.
Aspergillus fumigatus during stable state and exacerbations of COPD
Authors: Mona Bafadhel, Susan Mckenna, Joshua Agbetile, Abbie Fairs, Dhananjay Desai, Vijay Mistry, Joseph P. Morley, Mitesh Pancholi, Ian D. Pavord, Andrew J. Wardlaw, Catherine H. Pashley, Christopher E. Brightling
Journal: European Respiratory Journal (2013)

Bacteria are often isolated in stable chronic obstructive pulmonary disease (COPD). Whether fungi are also commonly present and associated with clinical and pathological features of disease is uncertain. We investigated the frequency of filamentous fungal culture and IgE sensitisation to Aspergillus fumigatus and the relationship to clinical outcomes in COPD subjects. COPD subjects were recruited to enter a 1-year observational study. Assessments of lung function, allergen testing and sputum analysis for inflammation, bacteria and fungus were undertaken in COPD subjects and healthy smoking and nonsmoking controls. Filamentous fungi were cultured at baseline in 49% (63 out of 128) of COPD subjects, of which 75% (47 out of 63) were A. fumigatus . Fungus was cultured in three out of 22 controls (two were A. fumigatus ). The total sputum cell count and inhaled corticosteroid dosage were significantly increased in COPD patients with a positive filamentous fungal culture at baseline (p&lt;0.05). Sensitisation to A. fumigatus was present in 13% of COPD subjects and was associated with worse lung function (forced expiratory volume in 1 s 39% predicted versus 51% predicted; p=0.01), but not related to filamentous fungal culture. A. fumigatus sensitisation is related to poor lung function. Positive filamentous fungal culture is a common feature of COPD. The clinical significance of this remains uncertain.
Non-tuberculous mycobacteria: a retrospective review of Scottish isolates from 2000 to 2010: Table 1
Authors: Clark D Russell, Pauline Claxton, Christine Doig, Amie-Louise Seagar, Alan Rayner, Ian F Laurenson
Journal: Thorax (2013)

There is growing recognition of the clinical importance of non-tuberculous mycobacteria (NTM), a group of versatile opportunistic bacterial pathogens. We describe the characteristics of NTM isolates in Scotland over an 11-year period using data held by the Scottish Mycobacteria Reference Laboratory. American Thoracic Society microbiological criteria were used to evaluate the clinical significance of isolates. Data presented include analysis of trends across time, species/body site associations, gender and age differences, geographical variations and the association between cystic fibrosis and <i>Mycobacterium abscessus</i>. We emphasise the need for standardised reporting criteria for NTM isolates to ensure optimal surveillance of NTM disease.
Liver dysfunction related to hepatitis B and C in patients with inflammatory bowel disease treated with immunosuppressive therapy
Authors: C. Loras, J. P. Gisbert, M. Minguez, O. Merino, L. Bujanda, C. Saro, E. Domenech, J. Barrio, M. Andreu, I. Ordas, L. Vida, G. Bastida, F. Gonzalez-Huix, M. Piqueras, D. Ginard, X. Calvet, A. Gutierrez, A. Abad, M. Torres, J. Panes, M. Chaparro, I. Pascual, M. Rodriguez-Carballeira, F. Fernandez-Banares, J. M. Viver, M. Esteve
Journal: Gut (2010)

<h3>Background</h3> There is no information about the frequency of liver dysfunction in patients with inflammatory bowel disease (IBD) treated with immunosuppressants and infected with hepatitis B (HBV) and/or C virus (HCV). <h3>Aim</h3> To assess the influence of immunosuppressants on the course of HBV and HCV infection in IBD. <h3>Methods</h3> Patients with IBD with HBV and/or HCV infection from 19 Spanish hospitals were included. Clinical records were reviewed for the type of immunosuppressant used, treatment duration, liver function tests and viral markers before, during and after each immunosuppressant. Logistic and Cox regression analysis were used to identify predictors of outcome. <h3>Results</h3> 162 patients were included; 104 had HBV markers (25 HBsAg positive) and 74 had HCV markers (51 HCV-RNA positive), and 16 patients had markers of both infections. Liver dysfunction was observed in 9 of 25 HBsAg positive patients (36%), 6 of whom developed hepatic failure. Liver dysfunction in HCV was observed in 8 of 51 HCV-RNA positive patients (15.7%), and only one developed hepatic failure. The frequency and severity of liver dysfunction was significantly higher in HBV-infected patients than in HCV-infected patients (p=0.045 and p=0.049, respectively). Treatment with ≥2 immunosuppressants was an independent predictor of HBV reactivation (OR 8.75; 95% CI 1.16 to 65.66). The majority of patients without reactivation received only one immunosuppressant for a short period and/or prophylactic antiviral treatment. No definite HBV reactivations were found in anti-HBc positive patients lacking HBsAg. <h3>Conclusion</h3> Liver dysfunction in patients with IBD treated with immunosuppressants is more frequent and severe in those with HBV than in HCV carriers and is associated with combined immunosuppression.
Adam10 Mediates the Choice between Principal Cells and Intercalated Cells in the Kidney
Authors: Qiusha Guo, Yinqiu Wang, Piyush Tripathi, Kalyan R. Manda, Malini Mukherjee, Malay Chaklader, Paul F. Austin, Kameswaran Surendran, Feng Chen
Journal: Journal of the American Society of Nephrology (2014)

A disintegrin and metalloproteinase domain 10 (Adam10), a member of the ADAM family of cell membrane–anchored proteins, has been linked to the regulation of the Notch, EGF, E-cadherin, and other signaling pathways. However, it is unclear what role Adam10 has in the kidney in vivo. In this study, we showed that Adam10 deficiency in ureteric bud (UB) derivatives leads to a decrease in urinary concentrating ability, polyuria, and hydronephrosis in mice. Furthermore, Adam10 deficiency led to a reduction in the percentage of aquaporin 2 (Aqp2)+ principal cells (PCs) in the collecting ducts that was accompanied by a proportional increase in the percentage of intercalated cells (ICs). This increase was more prominent in type A ICs than in type B ICs. Foxi1, a transcription factor important for the differentiation of ICs, was upregulated in the Adam10 mutants. The observed reduction of Notch activity in Adam10 mutant collecting duct epithelium and the similar reduction of PC/IC ratios in the collecting ducts in mice deficient for mindbomb E3 ubiquitin protein ligase 1, a key regulator of the Notch and Wnt/receptor-like tyrosine kinase signaling pathways, suggest that Adam10 regulates cell fate determination through the activation of Notch signaling, probably through the regulation of Foxi1 expression. However, phenotypic differences between the Adam10 mutants, the Mib1 mutants, and the Foxi1 mutants suggest that the functions of Adam10 in determining the fate of collecting duct cells are more complex than those of a simple upstream factor in a linear pathway involving Notch and Foxi1.
Mammalian Target of Rapamycin Inhibitors as Possible Adjuvant Therapy for Microscopic Residual Disease in Head and Neck Squamous Cell Cancer
Authors: Cherie-Ann O. Nathan, Nazanin Amirghahari, Xiaohua Rong, Tony Giordano, Don Sibley, Mary Nordberg, Jonathan Glass, Anshul Agarwal, Gloria Caldito
Journal: Cancer Research (2007)

Abstract Molecular therapeutics identifies an aberration in tumors to select patients that benefit from molecular targeted therapy. Overexpression of eIF4E in histologically “tumor-free” surgical margins of head and neck squamous cell cancer (HNSCC) patients is an independent predictor of recurrence and is functionally activated through the Akt/mammalian target of rapamycin (mTOR) pathway. Although mTOR inhibitors are cytostatic agents, best used in combination therapy, we hypothesize that they can be used as long-term single agents in an HNSCC model of minimal residual disease (MRD). CCI-779, an mTOR inhibitor, arrested growth of a phosphatase and tensin homologue deleted on chromosome 10 (PTEN) abnormal HNSCC cell line FaDu, inhibiting phosphorylation of 4E-binding protein 1, resulting in increased association with eIF4E and inhibition of basic fibroblast growth factor and vascular endothelial growth factor. Fluorescence in situ hybridization detected PTEN abnormalities in 68% of patient tumors and 35% of tumor-free margins. CCI-779 inhibited growth of established tumors in nude mice. However, in the MRD model, there were significant differences in the tumor-free rate between the control (4%) and the treatment group (50%), and the median tumor-free time was 7 versus 18 days, respectively (P &amp;lt; 0.0001). In those animals that formed tumors, CCI-779 caused a significant decrease in the tumor volume. The Kaplan-Meier curve showed that CCI-779 significantly increased survival (P &amp;lt; 0.0001). The mTOR pathway was inhibited in peripheral blood mononuclear cells potential surrogate markers of response to therapy. Stable transfection of FaDu with luciferase allowed us to monitor the effects of CCI-779 with bioluminescence imaging in the MRD model. These results pave the way for a clinical trial using targeted molecular therapy with CCI-779 as a single agent for mTOR-activated residual cells. [Cancer Res 2007;67(5):2160–8]
Sympathetic neural mechanisms in obstructive sleep apnea.
Authors: V K Somers, M E Dyken, M P Clary, F M Abboud
Journal: Journal of Clinical Investigation (1995)

Blood pressure, heart rate, sympathetic nerve activity, and polysomnography were recorded during wakefulness and sleep in 10 patients with obstructive sleep apnea. Measurements were also obtained after treatment with continuous positive airway pressure (CPAP) in four patients. Awake sympathetic activity was also measured in 10 age- and sex-matched control subjects and in 5 obese subjects without a history of sleep apnea. Patients with sleep apnea had high levels of nerve activity even when awake (P < 0.001). Blood pressure and sympathetic nerve activity did not fall during any stage of sleep. Mean blood pressure was 92 +/- 4.5 mmHg when awake and reached peak levels of 116 +/- 5 and 127 +/- 7 mmHg during stage II sleep (n = 10) and rapid eye movement (REM) sleep (n = 5), respectively (P < 0.001). Sympathetic activity increased during sleep (P = 0.01) especially during stage II (133 +/- 9% above wakefulness; P = 0.006) and REM (141 +/- 13%; P = 0.007). Peak sympathetic activity (measured over the last 10 s of each apneic event) increased to 299 +/- 96% during stage II sleep and to 246 +/- 36% during REM sleep (both P < 0.001). CPAP decreased sympathetic activity and blood pressure during sleep (P < 0.03). We conclude that patients with obstructive sleep apnea have high sympathetic activity when awake, with further increases in blood pressure and sympathetic activity during sleep. These increases are attenuated by treatment with CPAP.
Cardiomyocyte Stiffness in Diastolic Heart Failure
Authors: Attila Borbély, Jolanda van der Velden, Zoltán Papp, Jean G.F. Bronzwaer, Istvan Edes, Ger J.M. Stienen, Walter J. Paulus
Journal: Circulation (2005)

Heart failure with preserved left ventricular (LV) ejection fraction (EF) is increasingly recognized and usually referred to as diastolic heart failure (DHF). Its pathogenetic mechanism remains unclear, partly because of a lack of myocardial biopsy material. Endomyocardial biopsy samples obtained from DHF patients were therefore analyzed for collagen volume fraction (CVF) and sarcomeric protein composition and compared with control samples. Single cardiomyocytes were isolated from these biopsy samples to assess cellular contractile performance.DHF patients (n=12) had an LVEF of 71+/-11%, an LV end-diastolic pressure (LVEDP) of 28+/-4 mm Hg, and no significant coronary artery stenoses. DHF patients had higher CVFs (7.5+/-4.0%, P<0.05) than did controls (n=8, 3.8+/-2.0%), and no conspicuous changes in sarcomeric protein composition were detected. Cardiomyocytes, mechanically isolated and treated with Triton X-100 to remove all membranes, were stretched to a sarcomere length of 2.2 microm and activated with solutions containing varying [Ca2+]. Compared with cardiomyocytes of controls, cardiomyocytes of DHF patients developed a similar total isometric force at maximal [Ca2+], but their resting tension (F(passive)) in the absence of Ca2+ was almost twice as high (6.6+/-3.0 versus 3.5+/-1.7 kN/m2, P<0.001). F(passive) and CVF combined yielded stronger correlations with LVEDP than did either alone. Administration of protein kinase A (PKA) to DHF cardiomyocytes lowered F(passive) to control values.DHF patients had stiffer cardiomyocytes, as evident from a higher F(passive) at the same sarcomere length. Together with CVF, F(passive) determined in vivo diastolic LV dysfunction. Correction of this high F(passive) by PKA suggests that reduced phosphorylation of sarcomeric proteins is involved in DHF.
Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus
Authors: Eric J. Yager, Mushtaq Ahmed, Kathleen Lanzer, Troy D. Randall, David L. Woodland, Marcia A. Blackman
Journal: The Journal of Experimental Medicine (2008)

A diverse T cell repertoire is essential for a vigorous immune response to new infections, and decreasing repertoire diversity has been implicated in the age-associated decline in CD8 T cell immunity. In this study, using the well-characterized mouse influenza virus model, we show that although comparable numbers of CD8 T cells are elicited in the lung and lung airways of young and aged mice after de novo infection, a majority of aged mice exhibit profound shifts in epitope immunodominance and restricted diversity in the TCR repertoire of responding cells. A preferential decline in reactivity to viral epitopes with a low naive precursor frequency was observed, in some cases leading to “holes” in the T cell repertoire. These effects were also seen in young thymectomized mice, consistent with the role of the thymus in maintaining naive repertoire diversity. Furthermore, a decline in repertoire diversity generally correlated with impaired responses to heterosubtypic challenge. This study formally demonstrates in a mouse infection model that naturally occurring contraction of the naive T cell repertoire can result in impaired CD8 T cell responses to known immunodominant epitopes and decline in heterosubtypic immunity. These observations have important implications for the design of vaccine strategies for the elderly.