tbuckley/cabot-search huggingface dataset:
Safety and Efficacy of Ixmyelocel-T
Authors: Timothy D. Henry, Jay H. Traverse, Baron L. Hammon, Cara A. East, Brian Bruckner, Ann E. Remmers, David Recker, David A. Bull, Amit N. Patel
Journal: Circulation Research (2014)

Ixmyelocel-T is associated with a wide range of biological activities relevant to tissue repair and regeneration.To evaluate the safety and efficacy of ixmyelocel-T in 2 prospective randomized phase 2A Trials administered via minithoracotomy or intramyocardial catheter injections in patients with dilated cardiomyopathy (DCM) stratified by ischemic or nonischemic status.In IMPACT-DCM, patients were randomized to either ixmyelocel-T or standard-of-care control in a 3:1 ratio (n=39); ixmyelocel-T was administered intramyocardially via minithoracotomy. In Catheter-DCM, patients were randomized to either ixmyelocel-T or standard of care control in a 2:1 ratio (n=22); ixmyelocel-T was administered intramyocardially using the NOGA Myostar catheter. Only patients randomized to ixmyelocel-T underwent bone marrow aspiration and injections. In the 2 studies, a total of 61 patients were randomized, and 59 were treated or received standard of care. Fewer ischemic patients treated with ixmyelocel-T experienced a major adverse cardiovascular event during follow-up when compared with control patients. A similar benefit was not seen in the nonischemic patients. Heart failure exacerbation was the most common major adverse cardiovascular event. Ixmyelocel-T treatment was associated with improved New York Heart Association class, 6-minute walk distance, and Minnesota Living with Heart Failure Questionnaire scores in the ischemic population relative to control; a similar trend was not observed in the nonischemic population.Intramyocardial injection with ixmyelocel-T reduces major adverse cardiovascular event and improves symptoms in patients with ischemic DCM but not in patients with nonischemic DCM.
How to optimize the treatment of early stage Parkinson’s disease
Authors: Fabrizio Stocchi, Laura Vacca, Fabiana G Radicati
Journal: Translational Neurodegeneration (2015)

The approach to early Parkinson's disease denotes the communication of the diagnosis and important decisions, such as when and how to start treatment. Evidence based medicine and guidelines indicate which drugs have robust evidence of efficacy and tolerability in this specific population. However, de-novo patients may show different characteristics and they may be in a different phase of their disease. In this review, we will give an insight into the appropriate time therapy should be started and the actual knowledge about disease modification therapies. Moreover, the drugs indicated for early treatment will be considered and an indication for the use of these drugs will be given with the support of the actual knowledge.
Interaction of CD31 with a heterophilic counterreceptor involved in downregulation of human T cell responses.
Authors: E Prager, R Sunder-Plassmann, C Hansmann, C Koch, W Holter, W Knapp, H Stockinger
Journal: The Journal of Experimental Medicine (1996)

CD31 is a 130-kD glycoprotein of the immunoglobulin (Ig) superfamily expressed on the surface of endothelial cells, platelets, and several leukocyte subsets. Previous reports indicated that CD31 can mediate intercellular adhesion via both homophilic and heterophilic interaction mechanisms. Using a soluble recombinant CD31-Ig fusion protein (CD31 receptor globulin [Rg]), we demonstrate here that human CD31- T lymphocytes and CD4+CD31- T cell clones express a heterophilic CD31 ligand that is upregulated 18 h after activation. Interaction of CD31Rg with CD31- T helper cell (Th) clones was divalent cation independent but could be blocked by heparin, thus indicating that the CD31 counterreceptor on T cells can be distinguished from the ligands identified on other cell types. Moreover, a single chain protein of 120 kD was precipitated by CD31Rg from the lysates of CD31- Th clones. CD31Rg completely downregulated the proliferative response and cytokine production (interleukin-4, interferon-gamma, and tumor necrosis factor-alpha) of CD31- Th clones when the cells were maximally stimulated via immobilized CD3 monoclonal antibody. These results suggest that interaction of CD31 with a heterophilic counterreceptor on T lymphocytes can interfere with a positive regulatory pathway of T cell activation, or directly signal T cells to downregulate immune function.
HLA Tetramer–Based Artificial Antigen-Presenting Cells Efficiently Stimulate CTLs Specific for Malignant Glioma
Authors: Xiaobing Jiang, Xiaoling Lu, Ruen Liu, Fangcheng Zhang, Hongyang Zhao
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The interleukin-13 receptor α2 (IL-13Rα2) is a glioma-restricted cell-surface epitope not otherwise detected within the central nervous system. Here, we report a novel approach for targeting malignant glioma with IL-13Rα2–specific CTLs. Experimental Design: Artificial antigen-presenting cells (aAPC) were made by coating human leukocyte antigen (HLA)-A2/pIL-13Rα2345-354 tetrameric complexes, anti-CD28 antibody, and CD83 molecules to cell-sized latex beads, and used to stimulate IL-13Rα2–specific CTLs from the peripheral blood mononuclear cells of HLA-A2+ healthy donors. After multiple stimulations, the induced CTLs were analyzed for tetramer staining, IFN-γ production, and CTL reactivity. Results: Tetramer staining assay showed that the induced CTLs specifically bound HLA-A2/pIL-13Rα2345-354 tetramers. The CTLs specifically produced IFN-γ in response to the HLA-A2/pIL-13Rα2345-354-aAPCs and exhibited specific lysis against T2 cells pulsed with the peptide pIL-13Rα2345-354 and HLA-A2+ glioma cells expressing IL-13Rα2345-354, whereas HLA-A2− glioma cell lines that express IL-13Rα2345-354 could not be recognized by the CTLs. The peptide-specific activity was inhibited by anti–HLA class I monoclonal antibody. Conclusion: The induced CTLs specific for IL-13Rα2345-354 peptide could be a potential target of specific immunotherapy for HLA-A2+ patients with malignant glioma.
Efficacy and safety of golimumab as add-on therapy to disease-modifying antirheumatic drugs: results of the GO-MORE study
Authors: Bernard Combe, Bhaskar Dasgupta, Ingrid Louw, Sarvajeet Pal, Jürgen Wollenhaupt, Cristiano A F Zerbini, Andre D Beaulieu, Hendrik Schulze-Koops, Patrick Durez, Ruji Yao, Nathan Vastesaeger, Haoling H Weng
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To evaluate the efficacy and safety of subcutaneous golimumab as add-on therapy in patients with active rheumatoid arthritis (RA) despite disease-modifying antirheumatic drug (DMARD) treatment. To evaluate an intravenous plus subcutaneous (IV+SC) golimumab strategy in patients who had not attained remission. <h3>Methods</h3> GO-MORE was an open-label, multinational, prospective study in patients with active RA in typical clinical practice settings. In part 1, patients received add-on monthly 50-mg subcutaneous golimumab for 6 months. The percentage of patients with good/moderate European League Against Rheumatism (EULAR) 28-joint disease activity score (DAS28)–erythrocyte sedimentation rate (ESR) response was compared in patient subgroups with various concurrent or previous DMARD treatments. In part 2, patients with EULAR responses but not remission were randomly assigned to receive IV+SC or subcutaneous golimumab to month 12; DAS28–ESR remission was measured. <h3>Results</h3> 3366 patients were enrolled. At baseline of part 1, 3280 efficacy-evaluable patients had mean disease duration of 7.6 years and mean DAS28–ESR of 5.97 (SD=1.095). At month 6, 82.1% achieved good/moderate EULAR responses and 23.9% attained remission. When EULAR responses were analysed by the number of previously failed DMARD or the concomitant methotrexate dose, DMARD type, or corticosteroid use, no statistically significant differences were observed. Part 2 patients (N=490) who received IV+SC or subcutaneous golimumab achieved similar remission rates (∼25%). Adverse events were consistent with previous reports of golimumab and other tumour necrosis antagonists in this population. <h3>Conclusions</h3> Add-on monthly subcutaneous golimumab resulted in good/moderate EULAR response in most patients; 25% achieved remission after 6 more months of golimumab, but an IV+SC regimen provided no additional efficacy over the subcutaneous regimen.
The Excitability Cycle of the Dog's Left Ventricle Determined by Anodal, Cathodal, and Bipolar Stimulation
Authors: R. TH. VAN DAM, D. DURRER, J. STRACKEE, L. H. VAN DER TWEEL
Journal: Circulation Research (1956)

Investigations are reported in which the excitability cycle of the dog's heart was tested successively by unipolar anodal and cathodal square wave shocks as well as by bipolar stimulation. The classical view that excitability decreases smoothly during the relative refractory phase was substantiated. The excitability for anodal stimulation reached its maximum of the cardiac cycle immediately after the absolute refractory period and exceeded cathodal excitability at that moment. Evidence is presented that the dip phenomenon described by Orias, Brooks and their associates is due to their arrangement of driving and testing electrodes. The coincidence of the dip phenomenon with the vulnerable period may be related to simultaneous spreading of two fronts of activation from cathode and anode of bipolar electrodes which would create favorable conditions for reentry.
Molecular Pathophysiology of Myelodysplastic Syndromes
Authors: R. Coleman Lindsley, Benjamin L. Ebert
Journal: Annual Review of Pathology Mechanisms of Disease (2011)

The clinicopathologic heterogeneity of myelodysplastic syndromes (MDS) is driven by diverse, somatically acquired genetic abnormalities. Recent technological advances have enabled the identification of many new mutations, which have implicated novel pathways in MDS pathogenesis, including RNA splicing and epigenetic regulation of gene expression. Molecular abnormalities, either somatic point mutations or chromosomal lesions, can be identified in the vast majority of MDS cases and underlie specific disease phenotypes. As the full array of molecular abnormalities is characterized, genetic variables are likely to complement standard morphologic evaluation in future MDS classification schemes and risk models.
Sorafenib: A glimmer of hope for unresectable hepatocellular carcinoma?
Authors: Andrew Scanga, Kris Kowdley, Kris Kowdley, Geoffrey McCaughan, Christian Trautwein
Journal: Hepatology (2008)

Background: No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. Methods: In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. Results: At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P < 0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P < 0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand–foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. Conclusions: In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo. (ClinicalTrials.gov number, NCT00105443 http://clinicaltrials.gov.)
Racial Differences in Clinical Outcomes From Metastatic Breast Cancer: A Pooled Analysis of CALGB 9342 and 9840—Cancer and Leukemia Group B
Authors: Blase N. Polite, Constance Cirrincione, Gini F. Fleming, Donald A. Berry, Andrew Seidman, Hyman Muss, Larry Norton, Charles Shapiro, Kamal Bakri, Kelly Marcom, Diana Lake, Joel H. Schwartz, Clifford Hudis, Eric P. Winer
Journal: Journal of Clinical Oncology (2008)

African American women are more likely to be diagnosed with metastatic breast cancer at the time of presentation than whites, and have shorter survival once diagnosed. This study examines racial differences in clinical outcomes in the setting of two large cooperative group randomized clinical trials.
Long-Term Inhalable Particles and Other Air Pollutants Related to Mortality in Nonsmokers
Authors: DAVID E. ABBEY, NAOMI NISHINO, WILLIAM F. McDONNELL, RAOUL J. BURCHETTE, SYNNØVE F. KNUTSEN, W. LAWRENCE BEESON, JIE X. YANG
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Long-term ambient concentrations of inhalable particles less than 10 μ m in diameter (PM10) (1973– 1992) and other air pollutants—total suspended sulfates, sulfur dioxide, ozone (O3), and nitrogen dioxide—were related to 1977–1992 mortality in a cohort of 6,338 nonsmoking California Seventh-day Adventists. In both sexes, PM10 showed a strong association with mortality for any mention of nonmalignant respiratory disease on the death certificate, adjusting for a wide range of potentially confounding factors, including occupational and indoor sources of air pollutants. The adjusted relative risk (RR) for this cause of death as associated with an interquartile range (IQR) difference of 43 d/yr when PM10 exceeded 100 μ g/m3 was 1.18 (95% confidence interval [CI]: 1.02, 1.36). In males, PM10 showed a strong association with lung cancer deaths—RR for an IQR was 2.38 (95% CI: 1.42, 3.97). Ozone showed an even stronger association with lung cancer mortality for males with an RR of 4.19 (95% CI: 1.81, 9.69) for the IQR difference of 551 h/yr when O3 exceeded 100 parts per billion. Sulfur dioxide showed strong associations with lung cancer mortality for both sexes. Other pollutants showed weak or no association with mortality.
Pulmonary and critical care medicine: a peculiarly American hybrid?
Authors: M. J TOBIN, E. HINES
Journal: Thorax (1999)

The evolution of pulmonary medicine over the last 15 years has differed in the United States from that in other countries. Today, most fellow applicants to a pulmonary training programme seek combined training in pulmonary medicine and critical care medicine. Programmes that offer fellowship training in pulmonary medicine alone, without critical care training, are decreasing in number. Of the 2019 fellows trained in pulmonary medicine in the United States over the last five years, 79% obtained their training in a three year combined pulmonary and critical care medicine programme; this number increases to 88% if programmes in New York are excluded.1 Applicants to fellowship programmes that offer training in critical care medicine alone have concurrently decreased. As such, the majority of newly certified pulmonary physicians in the United States also obtain certification in critical care medicine, and vice versa. This experience is very different from that of pulmonary medicine in Europe, and even from that in Canada.

Critical care medicine is one of the most recent disciplines in medicine. The crucible for its development was the polio epidemic in Copenhagen in 1952. An anaesthesiologist, Bjorn Ibsen, found that the combination of careful airway management and positive pressure ventilation—skills previously confined to the operating theatre—resulted in a dramatic reduction in mortality of patients presenting with respiratory paralysis.2 With the focus on airway care and ventilator management, it is not surprising that anaesthesiologists led the way in the introduction of intensive care units (ICUs) and the development of the new discipline of critical care medicine.3 4 In the 1960s and 1970s technological advances pioneered for aerospace research were directly incorporated into intensive care monitoring.5 These technological advances, especially in cardiopulmonary monitoring and treatment, combined with the considerable growth in knowledge of …
The Ketogenic Diet and Brain Metabolism of Amino Acids: Relationship to the Anticonvulsant Effect
Authors: Marc Yudkoff, Yevgeny Daikhin, Torun Margareta Melø, Ilana Nissim, Ursula Sonnewald, Itzhak Nissim
Journal: Annual Review of Nutrition (2007)

In many epileptic patients, anticonvulsant drugs either fail adequately to control seizures or they cause serious side effects. An important adjunct to pharmacologic therapy is the ketogenic diet, which often improves seizure control, even in patients who respond poorly to medications. The mechanisms that explain the therapeutic effect are incompletely understood. Evidence points to an effect on brain handling of amino acids, especially glutamic acid, the major excitatory neurotransmitter of the central nervous system. The diet may limit the availability of oxaloacetate to the aspartate aminotransferase reaction, an important route of brain glutamate handling. As a result, more glutamate becomes accessible to the glutamate decarboxylase reaction to yield gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter and an important antiseizure agent. In addition, the ketogenic diet appears to favor the synthesis of glutamine, an essential precursor to GABA. This occurs both because ketone body carbon is metabolized to glutamine and because in ketosis there is increased consumption of acetate, which astrocytes in the brain quickly convert to glutamine. The ketogenic diet also may facilitate mechanisms by which the brain exports to blood compounds such as glutamine and alanine, in the process favoring the removal of glutamate carbon and nitrogen.
BCMab1, A Monoclonal Antibody against Aberrantly Glycosylated Integrin α3β1, Has Potent Antitumor Activity of Bladder Cancer <i>In Vivo</i>
Authors: Chong Li, Zhao Yang, Ying Du, Haidong Tang, Jun Chen, Deqing Hu, Zusen Fan
Journal: Clinical Cancer Research (2014)

Abstract Purpose: To identify a novel biomarker for bladder cancer targeting therapy. Experimental Design: The human bladder cancer cell line T24 cells were used as immunogen to generate mouse monoclonal antibodies. We screened and identified a specific antibody BCMab1 against bladder cancer. We examined BCMab1 antigen expression in the patients with bladder cancer through immunohistochemical staining and investigated the BCMab1 antigen association with clinical severity. We detected the antitumor activity of BCMab1 antibody and investigated its therapeutic efficacy by subcutaneous and orthotopic bladder cancer models. Results: We developed a new monoclonal antibody BCMab1 against bladder cancer that specifically recognized the aberrantly glycosylated Integrin α3β1 epitope on bladder cancer cells. Expression of the BCMab1 antigen was consistent with clinical severity and prognosis of bladder cancer. The glycosyltransferase GALNT1 could contribute to aberrant glycosylation of Integrin α3. The aberrant glycosylation of integrin α3–activated integrin signaling to initiate FAK activation. BCMab1 could block Integrin engagement to inhibit its signaling leading to cell-cycle arrest. In addition, BCMab1 enhanced FcγR-dependent antitumor activity in vivo. Conclusions: BCMab1 antigen is a new biomarker for bladder cancer. BCMab1 antibody exhibited potent antitumor activity against bladder cancer in vivo. Clin Cancer Res; 20(15); 4001–13. ©2014 AACR.
Sorafenib for Treatment of Renal Cell Carcinoma: Final Efficacy and Safety Results of the Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial
Authors: Bernard Escudier, Tim Eisen, Walter M. Stadler, Cezary Szczylik, Stéphane Oudard, Michael Staehler, Sylvie Negrier, Christine Chevreau, Apurva A. Desai, Frédéric Rolland, Tomasz Demkow, Thomas E. Hutson, Martin Gore, Sibyl Anderson, Gloria Hofilena, Minghua Shan, Carol Pena, Chetan Lathia, Ronald M. Bukowski
Journal: Journal of Clinical Oncology (2009)

Mature survival data and evaluation of vascular endothelial growth factor (VEGF) as a prognostic biomarker from the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) study in patients with renal cell carcinoma (RCC) are reported.Nine hundred three previously treated patients were randomly assigned to receive sorafenib versus placebo. On demonstration of progression-free survival (PFS) benefit with sorafenib, patients assigned to placebo were offered sorafenib. Overall survival (OS) was determined at two planned interim analyses and one final analysis, with a secondary OS analysis conducted by censoring placebo patients who crossed over to sorafenib. The relationships between baseline VEGF level and prognosis and efficacy were evaluated.The final OS of patients receiving sorafenib was comparable with that of patients receiving placebo (17.8 v 15.2 months, respectively; hazard ratio [HR] = 0.88; P = .146); however, when post-cross-over placebo survival data were censored, the difference became significant (17.8 v 14.3 months, respectively; HR = 0.78; P = .029). Adverse events at 16 months after cross over were similar to those previously reported. Baseline VEGF levels correlated with Eastern Cooperative Oncology Group performance status (P < .0001), Memorial Sloan-Kettering Cancer Center score (P < .0001), and PFS and OS in univariate (PFS, P = .0013; OS, P = .0009) and multivariate (PFS, P = .0231; OS, P = .0416) analyses of placebo patients and with short OS by multivariate analysis of patients receiving sorafenib (P = .0145). Both high-VEGF (P < .01) and low-VEGF (P < .01) groups benefited from sorafenib.Although an OS benefit was not seen on a primary intent-to-treat analysis, results of a secondary OS analysis censoring placebo patients demonstrated a survival advantage for those receiving sorafenib, suggesting an important cross-over effect. VEGF levels are prognostic for PFS and OS in RCC. The results of TARGET establish the efficacy and safety of sorafenib in advanced RCC.
Obesity and colorectal cancer risk: the role of oxidative stress
Authors: Alphons J M Vermorken, Jingjing Zhu, Emmanuel Andrès
Journal: Gut (2013)

We read the very interesting and informative article by Bardou et al. 1 The authors reviewed important findings on obesity and colorectal cancer (CRC). The mechanisms linking obesity to CRC are still uncertain—metabolic syndrome, insulin resistance (IR) and adipocytokines play a role. Two questions related to prevention of CRC in obesity were formulated. Should preventive strategies specifically target obese patients? Is the risk of cancer great enough to propose prophylactic bariatric surgery in certain patients with obesity? While these questions are valid, research on the interaction between nutrition, adipose tissue and immune cells strongly suggests that it is not obesity per se …