tbuckley/cabot-search huggingface dataset:
Lowering Blood Pressure Reduces Renal Events in Type 2 Diabetes
Authors: Bastiaan E. de Galan, Vlado Perkovic, Toshiharu Ninomiya, Avinesh Pillai, Anushka Patel, Alan Cass, Bruce Neal, Neil Poulter, Stephen Harrap, Carl-Erik Mogensen, Mark Cooper, Michel Marre, Bryan Williams, Pavel Hamet, Giuseppe Mancia, Mark Woodward, Paul Glasziou, Diederick E. Grobbee, Stephen MacMahon, John Chalmers
Journal: Journal of the American Society of Nephrology (2009)

BP is an important determinant of kidney disease among patients with diabetes. The recommended thresholds to initiate treatment to lower BP are 130/80 and 125/75 mmHg for people with diabetes and nephropathy, respectively. We sought to determine the effects of lowering BP below these currently recommended thresholds on renal outcomes among 11,140 patients who had type 2 diabetes and participated in the Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study. Patients were randomly assigned to fixed combination perindopril-indapamide or placebo, regardless of their BP at entry. During a mean follow-up of 4.3 yr, active treatment reduced the risk for renal events by 21% (P < 0.0001), which was driven by reduced risks for developing microalbuminuria and macroalbuminuria (both P < 0.003). Effects of active treatment were consistent across subgroups defined by baseline systolic or diastolic BP. Lower systolic BP levels during follow-up, even to <110 mmHg, was associated with progressively lower rates of renal events. In conclusion, BP-lowering treatment with perindopril-indapamide administered routinely to individuals with type 2 diabetes provides important renoprotection, even among those with initial BP <120/70 mmHg. We could not identify a BP threshold below which renal benefit is lost.
OBSERVATIONS ON THE PATHOLOGY OF BARCOO ROT (VELD SORE?): WITH SUGGESTIONS AS TO TREATMENT
Authors: C. J. Martin
Journal: BMJ (1917)

By the middle of the summer of 1916 a nulmiber of men of the Anzac Mounted Division, which had been operating in the desert east of the Suez Canal for uipwards of six months, suffered from spreading superficial ulcers on the back of the hands, extensor surface of the forearms, and, to a less extent, on the back of the feet and on the slhins.The ulceration resembles that met witlh amongst buslhmen in the back-blocks of Australia, and is known locally as barcoo rot.It was recognized by the men as the same disease they had seen or experienced in Australia.Superficial ulcers were also troublesome during the Boer war.They affected troops kept on trek on the high veld, and the disease was labelled" veld sore."A slhort descrip- tion of veld sore and its pathology was given by Ogston
Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies
Authors: N Sarwar, M S Sandhu, S L Ricketts, A S Butterworth, E Di Angelantonio, S M Boekholdt, W Ouwehand, H Watkins, N J Samani, D Saleheen, D Lawlor, M P Reilly, A D Hingorani, P J Talmud, J Danesh
Journal: The Lancet (2010)
Bionic Technology Revitalizes Native Baroreflex Function in Rats With Baroreflex Failure
Authors: Takayuki Sato, Toru Kawada, Masaru Sugimachi, Kenji Sunagawa
Journal: Circulation (2002)

Background — We developed a bionic technology for the treatment of baroreflex failure and tested its efficacy in restoration of arterial pressure against head-up tilt (HUT) in rats with baroreflex failure. Methods and Results — The bionic baroreflex system (BBS) was a negative feedback system controlled by a computer, the artificial vasomotor center. It sensed systemic arterial pressure (SAP) through a micromanometer placed in the aortic arch and automatically computed the frequency of a pulse train to stimulate sympathetic efferent nerves. We selected the celiac ganglion as the sympathetic vasomotor interface. To make this system bionic, the operational rule of the artificial vasomotor center (H BRP→STM ; BRP indicates baroreceptor pressure; STM, electrical stimulation) was actively matched to that of the native center. First, we identified the open-loop transfer functions of the native baroreflex control of SAP (H Native ) and the response of SAP to electrical stimulation of the celiac ganglion (H STM→SAP ). We computed H BRP→STM from H Native /H STM→SAP and transplanted the operational rule into the computer. In 10 rats with baroreflex failure, we evaluated the performance of the BBS during rapid hypotension induced by HUT. Abrupt HUT dropped SAP by 34±6 mm Hg in 2 seconds and by 52±5 mm Hg in 10 seconds. During real-time execution of the BBS, on the other hand, the fall in SAP was 21±5 mm Hg at 2 seconds and 15±6 mm Hg at 10 seconds after HUT. These arterial responses controlled by the BBS were indistinguishable from those by the native baroreflex. Conclusions — We concluded that the BBS revitalized the native baroreflex function in rats with baroreflex failure.
Allogeneic Granulocyte Macrophage Colony-Stimulating Factor–Secreting Tumor Immunotherapy Alone or in Sequence with Cyclophosphamide for Metastatic Pancreatic Cancer: A Pilot Study of Safety, Feasibility, and Immune Activation
Authors: Dan Laheru, Eric Lutz, James Burke, Barbara Biedrzycki, Sara Solt, Beth Onners, Irena Tartakovsky, John Nemunaitis, Dung Le, Elizabeth Sugar, Kristen Hege, Elizabeth Jaffee
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The combination of chemotherapy and immunotherapy has not been examined in patients with advanced pancreatic cancer. We conducted a study of two granulocyte macrophage colony-stimulating factor–secreting pancreatic cancer cell lines (CG8020/CG2505) as immunotherapy administered alone or in sequence with cyclophosphamide in patients with advanced pancreatic cancer. Experimental Design: This was an open-label study with two cohorts: cohort A, 30 patients administered a maximum of six doses of CG8020/CG2505 at 21-day intervals; and cohort B, 20 patients administered 250 mg/m2 of cyclophosphamide i.v. 1 day before the same immunotherapy given as in cohort A. The primary objective was to evaluate safety and duration of immunity. Secondary objectives included time to disease progression and median overall survival. Results: The administration of CG8020/CG2505 alone or in sequence with cyclophosphamide showed minimal treatment-related toxicity. Median survival values in cohort A and cohort B were 2.3 and 4.3 months, respectively. CD8+ T-cell responses to HLA class I–restricted mesothelin epitopes were identified predominantly in patients treated with cyclophosphamide + CG8020/CG2505 immunotherapy. Conclusion: Granulocyte macrophage colony-stimulating factor–secreting pancreatic cancer cell lines CG8020/CG2505 alone or in sequence with cyclophosphamide showed minimal treatment-related toxicity in patients with advanced pancreatic cancer. Also, mesothelin-specific T-cell responses were detected/enhanced in some patients treated with CG8020/CG2505 immunotherapy. In addition, cyclophosphamide-modulated immunotherapy resulted in median survival in a gemcitabine-resistant population similar to chemotherapy alone. These findings support additional investigation of cyclophosphamide with CG8020/CG2505 immunotherapy in patients with advanced pancreatic cancer.
Harnessing the Intestinal Microbiome for Optimal Therapeutic Immunomodulation
Authors: S. Viaud, R. Daillère, I.G. Boneca, P. Lepage, M.J. Pittet, F. Ghiringhelli, G. Trinchieri, R. Goldszmid, L. Zitvogel
Journal: Cancer Research (2014)

Abstract Distinct cytotoxic agents currently used in the oncological armamentarium mediate their clinical benefit by influencing, directly or indirectly, the immune system in such a way that innate and adaptive immunity contributes to the tumoricidal activity. Now, we bring up evidence that both arms of anticancer immunity can be triggered through the intervention of the intestinal microbiota. Alkylating agents, such as cyclophosphamide, set up the stage for enhanced permeability of the small intestine, facilitating the translocation of selected arrays of Gram-positive bacteria against which the host mounts effector pTh17 cells and memory Th1 responses. In addition, gut commensals, through lipopolysaccharide and other bacterial components, switch the tumor microenvironment, in particular the redox equilibrium and the TNF production of intratumoral myeloid cells during therapies with platinum salts or intratumoral TLR9 agonists combined with systemic anti-IL10R Ab respectively. Consequently, antibiotics can compromise the efficacy of certain chemotherapeutic or immunomodulatory regimens. Cancer Res; 74(16); 4217–21. ©2014 AACR.
Changes at peptide residues buried in the major histocompatibility complex (MHC) class I binding cleft influence T cell recognition: a possible role for indirect conformational alterations in the MHC class I or bound peptide in determining T cell recognition.
Authors: W Chen, J McCluskey, S Rodda, F R Carbone
Journal: The Journal of Experimental Medicine (1993)

Recent crystallographic studies on two peptide complexes with the mouse Kb molecule have shown that peptide binding appears to alter the conformation of the class I alpha-helical regions that flank the antigen binding cleft. Given that this study also showed that much of the foreign peptide is buried within the class I binding cleft with only a small portion accessible for direct interaction with the components of the T cell receptor, this finding suggests that at least some component of T cell specificity may arise as a consequence of peptide-induced conformational changes in the class I structure. To assess this possibility, we have made systematic substitutions at residues within the Kb-restricted determinant from ovalbumin (OVA257-264) that are thought to be buried on binding to the class I molecule. We have found that changes in this determinant at the completely buried second residue (P2) can influence T cell recognition without affecting binding to Kb, suggesting that the substitutions may indirectly determine T cell recognition by altering the conformation of the class I molecule or the bound peptide.
Strongly Binding Myosin Crossbridges Regulate Loaded Shortening and Power Output in Cardiac Myocytes
Authors: Kerry S. McDonald, Richard L. Moss
Journal: Circulation Research (2000)

Abstract —This study investigated the possible roles of strongly binding myosin crossbridges in determining loaded shortening and power output in cardiac myocytes. Single skinned cardiac myocytes were attached between a force transducer and position motor, and shortening velocities were measured over a range of loads during varying levels of Ca 2+ activation. Lowering the [Ca 2+ ] slowed shortening velocities, decreased relative power output, and increased the curvature of length traces. We tested the hypothesis that Ca 2+ activation dependence of loaded shortening is determined primarily by strongly binding crossbridges or by [Ca 2+ ] per se, which was done by measuring loaded shortening before and after addition of N -ethylmaleimide–conjugated myosin subfragment-1 (NEM-S1), a strongly binding myosin analogue that cooperatively enhances thin filament activation. At fixed [Ca 2+ ], NEM-S1 reduced the curvature of length traces and sped loaded shortening velocities. Even when [Ca 2+ ] was adjusted so that force was equal with and without NEM-S1, myocyte shortening was faster and exhibited less curvature with NEM-S1. In the presence of NEM-S1, peak relative power output was also significantly greater during activations either at the same [Ca 2+ ] or when [Ca 2+ ] was adjusted to achieve the same force. Consequently, NEM-S1 eliminated any Ca 2+ dependence of relative power output that is normally observed in cardiac myocytes. These results indicate that strongly binding crossbridges play a significant role in determining loaded shortening and power output and suggest that previously observed Ca 2+ dependence of power output is mediated by alterations in numbers of crossbridges bound to the thin filament.
Exchange Protein Directly Activated by Cyclic AMP Increases Melanoma Cell Migration by a Ca2+-Dependent Mechanism
Authors: Erdene Baljinnyam, Mariana S. De Lorenzo, Lai-Hua Xie, Mizuka Iwatsubo, Suzie Chen, James S. Goydos, Martha C. Nowycky, Kousaku Iwatsubo
Journal: Cancer Research (2010)

Melanoma has a poor prognosis due to its strong metastatic ability. Although Ca(2+) plays a major role in cell migration, little is known about the role of Ca(2+) in melanoma cell migration. We recently found that the exchange protein directly activated by cyclic AMP (Epac) increases melanoma cell migration via a heparan sulfate-related mechanism. In addition to this mechanism, we also found that Epac regulates melanoma cell migration by a Ca(2+)-dependent mechanism. An Epac agonist increased Ca(2+) in several different melanoma cell lines but not in melanocytes. Ablation of Epac1 with short hairpin RNA inhibited the Epac agonist-induced Ca(2+) elevation, suggesting the critical role of Epac1 in Ca(2+) homeostasis in melanoma cells. Epac-induced Ca(2+) elevation was negated by the inhibition of phospholipase C (PLC) and inositol triphosphate (IP(3)) receptor. Furthermore, Epac-induced cell migration was reduced by the inhibition of PLC or IP(3) receptor. These data suggest that Epac activates Ca(2+) release from the endoplasmic reticulum via the PLC/IP(3) receptor pathway, and this Ca(2+) elevation is involved in Epac-induced cell migration. Actin assembly was increased by Epac-induced Ca(2+), suggesting the involvement of actin in Epac-induced cell migration. In human melanoma specimens, mRNA expression of Epac1 was higher in metastatic melanoma than in primary melanoma, suggesting a role for Epac1 in melanoma metastasis. In conclusion, our findings reveal that Epac is a potential target for the suppression of melanoma cell migration, and, thus, the development of metastasis.
Anti-interleukin 2 receptor monoclonal antibodies spare phenotypically distinct T suppressor cells in vivo and exert synergistic biological effects.
Authors: R Di Stefano, A Mouzaki, D Araneda, T Diamantstein, N L Tilney, J W Kupiec-Weglinski
Journal: The Journal of Experimental Medicine (1988)

The therapeutic efficacies of ART-18, ART-65, and OX-39, mouse antibodies of IgG1 isotype recognizing distinct epitopes of the p55 beta chain of the rat IL-2-R molecule, were probed in LEW rat recipients of (LEW X BN)F1 heterotopic cardiac allografts (acute rejection in untreated hosts occurs within 8 d). A 10-d course with ART-18 prolongs graft survival to approximately 21 d (p less than 0.001). Therapy with ART-65, but not with OX-39, was effective (graft survival approximately 16 and 8 d, respectively). Anti-IL-2-R mAb treatment selectively spared T cells with donor-specific suppressor functions; the CD8+ (OX8+ W3/25-) fraction from ART-18-modified recipients, and primarily the CD4+ (W3/25+ OX8-) subset from ART-65-treated hosts conferred unresponsiveness to naive syngeneic rats after adoptive transfer, increasing test graft survival to approximately 16 and 45 d, respectively. Concomitant administration of ART-18 and ART-65 to recipient animals in relatively low doses exerted a strikingly synergistic effect, with 30% of the transplants surviving indefinitely and 50% undergoing late rejection over 50 d. These studies provide evidence that anti-IL-2-R mAbs selectively spare phenotypically distinct T cells with suppressor functions. The data also suggest that in vivo targeting of functionally different IL-2-R epitopes may produce synergistic biological effects.
Mature bone marrow erythroid burst-forming units do not require T cells for induction of erythropoietin-dependent differentiation.
Authors: J M Lipton, E L Reinherz, M Kudisch, P L Jackson, S F Schlossman, D G Nathan
Journal: The Journal of Experimental Medicine (1980)

Cell-cell interactions between mature T cells and peripheral blood null cells induce erythropoietin-stimulated differentiation of peripheral blood-derived erythroid progenitors. By the use of complement-fixing cytolytic murine hybridoma and antibody uniquely reactive with mature T lymphocytes, this dependence of immature peripheral blood erythroid burst-forming unit (BFU-E) differentiation upon mature T cells or a T cell conditioned medium is confirmed. By using the same antibody, it is demonstrated that the differentiation of mature bone marrow BFU-E does not require either mature T cells or lymphocyte mitogenic factor. These findings do not preclude the presence in the bone marrow of other cells, perhaps even immature T cells, that influence erythropoietin-dependent erythroid differentiation of mature marrow BFU-E.
Changes in Circulating Postprandial Proinflammatory Cytokine Concentrations in Diet-Controlled Type 2 Diabetes and the Effect of Ingested Fat
Authors: Patrick J. Manning, Wayne H. Sutherland, Gavin Hendry, Sylvia A. de Jong, Michelle McGrath, Sheila M. Williams
Journal: Diabetes Care (2004)

The proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α are thought to impair insulin signaling (1,2), and abnormally high levels of them are associated with insulin resistance (3,4) and type 2 diabetes (3,5). In patients with type 2 diabetes, a meal rich in fat, mainly in the form of sausages and butter, increases postprandial plasma concentrations of IL-6 and TNF-α, whereas a meal rich in carbohydrates has less effect (5). Current dietary recommendations for diabetic patients prescribe replacement of saturated fatty acids (SAFAs) with monounsaturated fatty acids (MUFAs) in the diet (6). There is little information available on the effect of ingesting MUFAs on postprandial plasma IL-6 and TNF-α concentrations in patients with type 2 diabetes. We therefore tested the effect of meals consisting of starch with or without added olive oil (MUFA) and cream (SAFA) on postprandial concentrations of plasma IL-6 and TNF-α in patients whose type 2 diabetes was controlled by diet alone.

Eighteen patients (7 men and 11 women) with type 2 diabetes who had good glycemic control by diet alone, did not smoke cigarettes or use antioxidant supplements, and did not have hepatic or renal diseases or a history …
Association between Rectal Optical Signatures and Colonic Neoplasia: Potential Applications for Screening
Authors: Hemant K. Roy, Vladimir Turzhitsky, Young Kim, Michael J. Goldberg, Patrice Watson, Jeremy D. Rogers, Andrew J. Gomes, Alexey Kromine, Randall E. Brand, Mohammed Jameel, Andrej Bogovejic, Prabhakar Pradhan, Vadim Backman
Journal: Cancer Research (2009)

Field carcinogenesis detection represents a promising means for colorectal cancer (CRC) screening, although current techniques (e.g., flexible sigmoidoscopy) lack the requisite sensitivity. The novel optical technology low-coherence enhanced backscattering (LEBS) spectroscopy, allows identification of microscale architectural consequences of the field carcinogenesis in preclinical CRC models with unprecedented accuracy. To investigate the potential clinical translatability of this approach, we obtained biopsies from the normal-appearing rectal mucosa from patients undergoing colonoscopy (n = 219). LEBS signals were recorded through a bench-top instrument. Four parameters characterizing LEBS signal were linearly combined into a single marker. We found that LEBS signal parameters generally mirrored neoplasia progression from patients with no neoplasia, to 5 to 9 mm adenoma and to advanced adenomas. The composite LEBS marker calculated from the LEBS signal paralleled this risk status (ANOVA P < 0.001). Moreover, this was independent of CRC risk factors, benign colonic findings, or clinically unimportant lesions (diminutive adenomas, hyperplastic polyps). For advanced adenomas, the LEBS marker had a sensitivity of 100%, specificity of 80%, and area under the receiver operator characteristic curve of 0.895. Leave-one-out cross-validation and an independent data set (n = 51) supported the robustness of these findings. In conclusion, we provide the first demonstration that LEBS-detectable alterations in the endoscopically normal rectum were associated with the presence of neoplasia located elsewhere in the colon. This study provides the proof of concept that rectal LEBS analysis may potentially provide a minimally intrusive CRC screening technique. Further studies with an endoscopically compatible fiber optic probe are under way for multicenter clinical validation.
Torsades de pointes: electrophysiologic studies in patients without transient pharmacologic or metabolic abnormalities.
Authors: L N Horowitz, A M Greenspan, S R Spielman, M E Josephson
Journal: Circulation (1981)

Electrophysiologic studies were performed in 21 patients who had torsades de pointes. This ventricular tachyarrhythmia, characterized by rapid (200-250 beats/min) and irregular paroxysms and progressively varying QRS amplitude and polarity, occurred in the absence of electrolyte disturbance, antiarrhythmic drug therapy or acute ischemia. The QTc interval was prolonged in seven of 21 patients. Electrophysiologic study included ventricular pacing with the introduction of one to three extrastimuli and rapid ventricular pacing. The effect of i.v. procainamide or quinidine in these patients was also studied. Torsades de pointes was inducible n 19 of 21 patients. Induced episodes closely resembled spontaneous episodes. Torsades de pointes spontaneously progressed to ventricular tachycardia with a uniform morphology in three patients and to ventricular fibrillation in four. In eight patients, procainamide or quinidine converted torsades de pointes into typical reentrant ventricular tachycardia. Our data suggest that torsades de pointes in this setting may be a rapid reentrant ventricular tachycardia closely related to recurrent sustained ventricular tachycardia and a precursor to ventricular fibrillation and sudden death.
Interval Carcinomas in the European Randomized Study of Screening for Prostate Cancer (ERSPC)-Rotterdam
Authors: I. W. van der Cruijsen-Koeter
Journal: JNCI Journal of the National Cancer Institute (2003)

Background: The interval cancer rate is an important parameter for determining the sensitivity of a screening procedure and the screening interval. We evaluated the time and mechanism of detection and the stage distribution of interval prostate cancers diagnosed during a 4-year screening interval. Methods: We determined the rate of interval cancers and the sensitivity of the screening protocol (involving prostate-specific antigen, digital rectal and transrectal ultrasound examinations) in a cohort of 17 226 men (8350 on the screened arm, 8876 on the control arm) enrolled consecutively on the European Randomized Study of Screening for Prostate Cancer–Rotterdam. Men on the screened arm received a first screen between October 1993 and December 1996 and a scheduled second screen 4 years later. Prostate cancers detected in men enrolled on the control arm over the same 4-year period and, between screens, in men on the screened arm, were identified by linkage to the Dutch national cancer registry. Results: During the first screen, 412 prostate cancers were detected. During the subsequent 4-year period, 135 cancers were diagnosed in men in the control arm and 25 cancers were diagnosed in men in the screened arm. Seven of the 25 cancers were diagnosed in men who had refused a recommended biopsy at their initial screen. Of the remaining 18 cancers, all were classified as stage T1A–C or T2A and none were poorly differentiated or metastatic. The rate of interval cancers relative to the number of cancers in the control group was 18.5% (25/135), or 13.3% (18/135), if the seven who refused an initial biopsy were excluded. The sensitivity of the screening protocol was 79.8% when considering all 25 interval cancers and 85.5% when considering 18 interval cancers. Conclusion: The interval cancer rate with a 4-year screening interval was low, confirming that the screening procedure has a high sensitivity and that the 4-year screening interval is reasonable.