tbuckley/cabot-search huggingface dataset:
Positron Emission Tomography Scans in the Evaluation of Postchemotherapy Residual Masses in Patients With Seminoma
Authors: Kristen N. Ganjoo, Rebecca J. Chan, Matt Sharma, Lawrence H. Einhorn
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To assess the ability of positron emission tomography (PET) scans in differentiating between necrosis and viable seminoma in postchemotherapy (PC) residual disease. PATIENTS AND METHODS: We conducted a prospective study of 29 patients with seminoma at Indiana University. All patients had PC residual disease. Computed tomography and PET scans were performed for 19 patients after primary chemotherapy (group A) and for 10 patients after salvage chemotherapy (group B). RESULTS: In group A, the PC masses were ≥ 3 cm in 14 patients, less than 3 cm in three patients, and not quantified in two patients. All of the patients in group A had negative PET scan results and have had stable or decreasing residual mass size (median follow-up duration, 11.5 months; range, 6 to 26 months). In group B, the PC masses were ≥ 3 cm in four patients, less than 3 cm in five patients, and not quantified in one patient. One patient had a positive PET scan result for a posterior mediastinal mass. Pathologic diagnosis of the PET-positive mass showed only necrotic tissue. The same patient had a negative PET scan of the retroperitoneal mass but relapsed in that area. Overall, of patients in group B, five have stable or decreasing mass (median follow-up duration, 8 months; range, 7 to 22 months), and five had relapsed disease. CONCLUSION: PET scans have no apparent benefit in PC evaluation of residual masses in bulky seminoma.
Hypofractionated Palliative Radiotherapy (17 Gy per two fractions) in Advanced Non–Small-Cell Lung Carcinoma Is Comparable to Standard Fractionation for Symptom Control and Survival: A National Phase III Trial
Authors: Stein Sundstrøm, Roy Bremnes, Ulf Aasebø, Steinar Aamdal, Reidulv Hatlevoll, Paal Brunsvig, Dag Clement Johannessen, Olbjørn Klepp, Peter M. Fayers, Stein Kaasa
Journal: Journal of Clinical Oncology (2004)

To investigate whether the effect of hypofractionated thoracic radiotherapy (TRT) is comparable to more standard fractionated radiotherapy (RT) in advanced non-small-cell lung cancer (NSCLC).A total of 421 patients with locally advanced stage III or stage IV NSCLC tumors were included. Inclusion criteria were inoperable, disease too advanced for curative radiotherapy, and chest symptoms or central tumor threatening the airways. Patients were randomly assigned to three arms: A, 17 Gy per two fractions (n = 146); B, 42 Gy per 15 fractions (n = 145); and C, 50 Gy per 25 fractions (n = 130). Four hundred seven patients were eligible for the study; 395 patients (97%) participated in the health-related quality-of-life (HRQOL) study. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and EORTC QLQ-lung cancer-specific module (LC13) were used to investigate airway symptom relief and changes in HRQOL. Assessments were performed before TRT and until week 54. Clinicians' assessments of symptom improvement were at 2, 6, and 14 weeks after completion of TRT. The patients were observed for a minimum of 3 years. Results Baseline prognostic data were equally distributed in the treatment groups. Patient compliance with respect to the HRQOL investigation was minimum 74%. HRQOL and symptom relief were equivalent in the treatment arms. No significant difference in survival among arms A, B, and C was found, with median survival 8.2, 7.0, and 6.8 months, respectively.Our data indicate that protracted palliative TRT renders no improvement in symptom relief, HRQOL, or survival when compared with short-term hypofractionated treatment in advanced NSCLC.
Validation of a parent-proxy quality of life questionnaire for paediatric chronic cough (PC-QOL)
Authors: P. A. Newcombe, J. K. Sheffield, E. F. Juniper, H. L. Petsky, C. Willis, A. B. Chang
Journal: Thorax (2010)

<h3>Background</h3> Quality of life (QOL) measures are an important patient-relevant outcome measure for clinical studies. Currently there is no fully validated cough-specific QOL measure for paediatrics. The objective of this study was to validate a cough-specific QOL questionnaire for paediatric use. <h3>Method</h3> 43 children (28 males, 15 females; median age 29 months, IQR 20–41 months) newly referred for chronic cough participated. One parent of each child completed the 27-item Parent Cough-Specific QOL questionnaire (PC-QOL), and the generic child (Pediatric QOL Inventory 4.0 (PedsQL)) and parent QOL questionnaires (SF-12) and two cough-related measures (visual analogue score and verbal category descriptive score) on two occasions separated by 2–3 weeks. Cough counts were also objectively measured on both occasions. <h3>Results</h3> Internal consistency for both the domains and total PC-QOL at both test times was excellent (Cronbach alpha range 0.70–0.97). Evidence for repeatability and criterion validity was established, with significant correlations over time and significant relationships with the cough measures. The PC-QOL was sensitive to change across the test times and these changes were significantly related to changes in cough measures (PC-QOL with: verbal category descriptive score, r<sub>s</sub>=−0.37, p=0.016; visual analogue score, r<sub>s</sub>=−0.47, p=0.003). Significant correlations of the difference scores for the social domain of the PC-QOL and the domain and total scores of the PedsQL were also noted (r<sub>s</sub>=0.46, p=0.034). <h3>Conclusion</h3> The PC-QOL is a reliable and valid outcome measure that assesses QOL related to childhood cough at a given time point and measures changes in cough-specific QOL over time.
Decreased Survival of B Cells of HIV-viremic Patients Mediated by Altered Expression of Receptors of the TNF Superfamily
Authors: Susan Moir, Angela Malaspina, Oxana K. Pickeral, Eileen T. Donoghue, Joshua Vasquez, Natalie J. Miller, Surekha R. Krishnan, Marie A. Planta, John F. Turney, J. Shawn Justement, Shyamasundaran Kottilil, Mark Dybul, JoAnn M. Mican, Colin Kovacs, Tae-Wook Chun, Charles E. Birse, Anthony S. Fauci
Journal: The Journal of Experimental Medicine (2004)

Human immunodeficiency virus (HIV) infection leads to numerous perturbations of B cells through mechanisms that remain elusive. We performed DNA microarray, phenotypic, and functional analyses in an effort to elucidate mechanisms of B cell perturbation associated with ongoing HIV replication. 42 genes were up-regulated in B cells of HIV-viremic patients when compared with HIV-aviremic and HIV-negative patients, the majority of which were interferon (IFN)-stimulated or associated with terminal differentiation. Flow cytometry confirmed these increases and indicated that CD21low B cells, enhanced in HIV-viremic patients, were largely responsible for the changes. Increased expression of the tumor necrosis factor (TNF) superfamily (TNFSF) receptor CD95 correlated with increased susceptibility to CD95-mediated apoptosis of CD21low B cells, which, in turn, correlated with HIV plasma viremia. Increased expression of BCMA, a weak TNFSF receptor for B lymphocyte stimulator (BLyS), on CD21low B cells was associated with a concomitant reduction in the expression of the more potent BLyS receptor, BAFF-R, that resulted in reduced BLyS binding and BLyS-mediated survival. These findings demonstrate that altered expression of genes associated with IFN stimulation and terminal differentiation in B cells of HIV-viremic patients lead to an increased propensity to cell death, which may have substantial deleterious effects on B cell responsiveness to antigenic stimulation.
Chronic Kidney Disease after Nonrenal Solid-Organ Transplantation
Authors: Roy D. Bloom, Peter P. Reese
Journal: Journal of the American Society of Nephrology (2007)

Chronic kidney disease (CKD) is a common complication after nonrenal solid-organ transplantation. The risk for CKD is influenced by many factors, some of which have a direct impact on how such patients are treated in the pre-, peri-, and posttransplantation settings. This review describes hazards for acute and chronic kidney injury, with particular emphasis on calcineurin inhibitor-mediated nephrotoxicity. Rather than a detailed description of management issues that are common to the general CKD population, highlighted are aspects that are more specific to nonrenal solid-organ transplant recipients with a focus on liver, heart, and lung recipients. Strategies to minimize nephrotoxic insults and retard progressive renal injury are discussed, as are issues that are pertinent to dialysis and transplantation. Finally, future approaches to prevent and treat CKD without compromising function of the transplanted organ are addressed.
Cyclooxygenase-2 inhibition increases lipopolysaccharide-induced atherosclerosis in mice
Authors: J. M. Gitlin, C. D. Loftin
Journal: Cardiovascular Research (2008)

The risk of adverse cardiovascular events in humans is increased with chronic use of cyclooxygenase-2 (COX-2) inhibitors. However, the role of COX-2 in animal models of cardiovascular disease has been controversial. In humans and animal models, cardiovascular disease is increased by bacterial infection of the supporting tissue of the teeth, a condition known as periodontal disease. Periodontal disease may result in chronic exposure to pro-inflammatory mediators, such as bacterial lipopolysaccharide (LPS), thereby producing a systemic inflammatory response. The current study examined the role of COX-2 in atherosclerosis induced by LPS derived from the periodontal disease pathogen Porphyromonas gingivalis (P. gingivalis).Porphyromonas gingivalis LPS was administered by chronic infusion for 28 days and atherosclerosis development was examined in the aortic root of ApoE (apolipoprotein E)-deficient mice. The extent of atherosclerosis was compared between mice receiving control diet or diet containing the COX-2 inhibitor celecoxib. The role of COX-2 in P. gingivalis LPS-induced inflammatory cell activation was examined in peritoneal macrophages. Porphyromonas gingivalis LPS infusion significantly increased atherosclerosis development. In mice infused with P. gingivalis LPS, administration of the COX-2 inhibitor celecoxib further increased the extent of atherosclerotic lesion area. In peritoneal macrophages, P. gingivalis LPS increased the expression of COX-2 mRNA (messenger ribonucleic acid) and the production of prostaglandin (PG) E(2) (PGE(2)), the latter of which was inhibited by celecoxib. Porphyromonas gingivalis LPS-induced expression of tumour necrosis factor alpha (TNFalpha) was enhanced by inactivation of COX-2 and was attenuated by treatment with PGE(2).The inhibition of COX-2-derived PGE(2) may enhance P. gingivalis LPS-induced atherosclerosis by increasing macrophage production of TNFalpha.
Distribution and three-dimensional structure of intercellular junctions in canine myocardium.
Authors: R H Hoyt, M L Cohen, J E Saffitz
Journal: Circulation Research (1989)

Electrotonic coupling of cardiac myocytes at gap junctions may influence patterns of conduction in myocardium. To delineate the three-dimensional structure and distribution of intercellular junctions, we analyzed serial ultrathin sections of canine myocardium with transmission electron microscopy and disaggregated myocytes with scanning electron microscopy. Morphometric analysis of left ventricular myocardium sectioned in three orthogonal planes revealed that 80% of total gap junctional membrane occurred in large, ribbon-like gap junctions oriented transversely at cell end processes. The remaining 20% of gap junctional membrane was contained in small gap junctions located within plicate segments (interdigitating regions of cell-to-cell adhesion) of intercalated disks. In serial ultrathin sections, all gap junctions were contiguous with plicate segments. Thus, true "lateral" gap junctions do not exist in working ventricular myocytes and would not likely be able to withstand shear forces created by laterally sliding cells. Examination of serial plastic sections with light microscopy revealed complex overlapping of myocytes such that individual myocytes were connected at intercalated disks to an average of 9.1 +/- 2.2 other myocytes. These observations provide an improved understanding of the extent and distribution of cell junctions and should facilitate experimental and model studies of conduction in myocardium.
Government says no to lowering drink driving limit in UK
Authors: S. Mayor
Journal: BMJ (2011)

The government has decided against lowering the legal drink driving limit for alcohol in the United Kingdom, despite a recommendation from an independent report, which showed that this could save more than 300 lives a year.

The transport secretary, Philip Hammond, announced a package of measures on driving, alcohol, and drugs on 21 March, in response to the report by the legal scholar Peter North on drink and drug driving, which recommended reducing the limit from 80 mg to 50 mg of alcohol per 100 ml of blood ( BMJ 2010;340:c3315, doi:10.1136/bmj.c3315). 

In his report Sir Peter had …
Suppression of Graft Coronary Artery Disease by a Brief Treatment With a Selective εPKC Activator and a δPKC Inhibitor in Murine Cardiac Allografts
Authors: Masashi Tanaka, Raya D. Terry, Golnaz K. Mokhtari, Koichi Inagaki, Tomoyoshi Koyanagi, Theo Kofidis, Daria Mochly-Rosen, Robert C. Robbins
Journal: Circulation (2004)

Inhibiting delta protein kinase C (deltaPKC) during reperfusion and activating epsilon PKC (epsilonPKC) before ischemia each limits cardiac ischemic injury. Here, we examined whether limiting ischemia-reperfusion injury inhibits graft coronary artery disease (GCAD) and improves murine cardiac allografting.Hearts of FVB mice (H-2q) were transplanted into C57BL/6 mice (H-2b). epsilonPKC activator (psiepsilonRACK) was injected intraperitoneally (20 nmol) into donor mice 20 minutes before procurement. Hearts were then perfused with psiepsilonRACK (1.5 nmol) through the inferior vena cava (IVC) and subsequently submerged in psiepsilonRACK (0.5 micromol/L) for 20 minutes at 4 degrees C. Before reperfusion, the peritoneal cavity of recipients was irrigated with deltaPKC inhibitor (deltaV1-1, 300 nmol); control animals were treated with normal saline. The total ischemic time to the organ was 50 minutes. Two hours after transplantation, production of inflammatory cytokines and adhesion molecules, cardiomyocyte apoptosis, and caspase-3 and caspase-9 (but not caspase-8) activities were significantly reduced in the PKC regulator-treated group. Fas ligand levels (but not Fas) were also significantly reduced in this group. Importantly, GCAD indices, production of inflammatory cytokines, and adhesion molecules were significantly decreased and cardiac allograft function was significantly better as measured up to 30 days after transplantation.An epsilonPKC activator and a deltaPKC inhibitor together reduced GCAD. Clinically, these PKC isozyme regulators may be useful for organ preservation and prevention of ischemia-reperfusion injury and graft coronary artery disease in cardiac transplantation.
2-Deoxyglucose Induces Noxa-Dependent Apoptosis in Alveolar Rhabdomyosarcoma
Authors: Silvia Ramírez-Peinado, Fermín Alcázar-Limones, Laura Lagares-Tena, Nadia El Mjiyad, Alfredo Caro-Maldonado, Oscar M. Tirado, Cristina Muñoz-Pinedo
Journal: Cancer Research (2011)

Alveolar and embryonal rhabdomyosarcomas are childhood tumors that do not respond well to current chemotherapies. Here, we report that the glycolytic inhibitor 2-deoxyglucose (2-DG) can efficiently promote cell death in alveolar, but not embryonal, rhabdomyosarcoma cell lines. Notably, 2-DG also induced cell differentiation accompanied by downregulation of PAX3/FOXO1a, the chromosome translocation-encoded fusion protein that is a central oncogenic driver in this disease. Cell death triggered by 2-DG was associated with its ability to activate Bax and Bak. Overexpression of the antiapoptotic Bcl-2 homologues Bcl-x(L) and Mcl-1 prevented apoptosis, indicating that cell death proceeds through the mitochondrial pathway. Mechanistic investigations indicated that Mcl-1 downregulation and Noxa upregulation were critical for 2-DG-induced apoptosis. In addition, 2-DG promoted eIF2α phosphorylation and inactivation of the mTOR pathway. Mcl-1 loss and cell death were prevented by downregulation of the endoplasmic reticulum (ER) stress-induced protein ATF4 and by incubating cells in the presence of mannose, which reverted 2-DG-induced ER stress but not ATP depletion. Thus, energetic stresses created by 2-DG were not the primary cause of cell death. Together, our findings suggest that glycolysis inhibitors such as 2-DG may be highly effective in treating alveolar rhabdomyosarcoma and that Noxa could offer a prognostic marker to monitor the efficacy of such agents.
Urinary transforming growth factor-beta1 and alpha1-microglobulin in children and adolescents with type 1 diabetes.
Authors: E Korpinen, A M Teppo, L Hukkanen, H K Akerblom, C Grönhagen-Riska, O Vaarala
Journal: Diabetes Care (2000)

OBJECTIVE: Transforming growth factor (TGF)-beta1 is an important mediator in the pathogenesis of diabetic nephropathy. Urinary TGF-beta1 reflects TGF-beta1 production in the kidney, and alpha1-microglobulin tubular dysfunction. These 2 markers were studied in the early phases of type 1 diabetes. RESEARCH DESIGN AND METHODS: There were 113 type 1 diabetic children and adolescents (mean +/- SD: age 14.1 +/- 2.9 years, and diabetes duration 7.4 +/- 2.9 years, HbA1c 9.3 +/- 1.5%) and 39 healthy subjects (age 13.8 +/- 2.8 years) who participated in the study. Of the diabetic patients, 105 were normoalbuminuric (2-3 consecutive overnight urinary albumin excretion rates [AERs] &amp;lt;20 microg/min) and 8 had microalbuminuria (at least 2 AERs 20-200 microg/min). Overnight urinary TGF-beta1 and alpha1-microglobulin levels were measured and the results expressed as the ratio to urinary creatinine concentration. RESULTS: Data are medians (range). Diabetic patients had higher urinary TGF-beta1 levels than those of control subjects: 0.9 ng/mg (0.05-122.3) vs. 0.3 ng/mg (0.05-2.2) creatinine, respectively (P = 0.003). Urinary TGF-beta1 levels correlated with urinary glucose (r = 0.2, P = 0.03) and alpha1-microglobulin (r = 0.2, P = 0.02) levels, but not with HbA1c, AER, age, or duration of diabetes. In 43 patients with urinary TGF-beta1 above the control levels, urinary TGF-beta1 levels correlated with urinary glucose (r = 0.6, P &amp;lt; 0.001) and alpha1-microglobulin (r = 0.6, P &amp;lt; 0.001) levels. Diabetic patients had higher urinary alpha1-microglobulin levels than those of control subjects: 4.8 microg/mg (0.6-48.8) vs. 2.7 microg/mg (0.8-11.6) creatinine, respectively (P &amp;lt; 0.001). Alpha1-microglobulin levels correlated with AER (r = 0.2, P = 0.02), HbA1c (r = 0.3, P = 0.001), urinary glucose (r = 0.5, P &amp;lt; 0.001), and urinary TGF-beta1 levels. CONCLUSIONS: An early rise in urinary TGF-beta1 levels was observed in young type 1 diabetic patients. Urinary TGF-beta1 is associated with 2 interrelated tubular markers, alpha1-microglobulin and urinary glucose.
The Importance of Caloric Restriction in the Early Improvements in Insulin Sensitivity After Roux-en-Y Gastric Bypass Surgery
Authors: James M. Isbell, Robyn A. Tamboli, Erik N. Hansen, Jabbar Saliba, Julia P. Dunn, Sharon E. Phillips, Pamela A. Marks-Shulman, Naji N. Abumrad
Journal: Diabetes Care (2010)

Many of the metabolic benefits of Roux-en-Y gastric bypass (RYGB) occur before weight loss. In this study we investigated the influence of caloric restriction on the improvements in the metabolic responses that occur within the 1st week after RYGB. RESEARCH METHODS AND DESIGN: A mixed meal was administered to nine subjects before and after RYGB (average 4 +/- 0.5 days) and to nine matched, obese subjects before and after 4 days of the post-RYGB diet.Weight loss in both groups was minimal; the RYGB subjects lost 1.4 +/- 5.3 kg (P = 0.46) vs. 2.2 +/- 1.0 kg (P = 0.004) in the calorically restricted group. Insulin resistance (homeostasis model assessment of insulin resistance) improved with both RYGB (5.0 +/- 3.1 to 3.3 +/- 2.1; P = 0.03) and caloric restriction (4.8 +/- 4.1 to 3.6 +/- 4.1; P = 0.004). The insulin response to a mixed meal was blunted in both the RYGB and caloric restriction groups (113 +/- 67 to 65 +/- 33 and 85 +/- 59 to 65 +/- 56 nmol x l(-1) x min(-1), respectively; P < 0.05) without a change in the glucose response. Glucagon-like peptide 1 levels increased (9.2 +/- 8.6 to 12.2 +/- 5.5 pg x l(-1) x min(-1); P = 0.04) and peaked higher (45.2 +/- 37.3 to 84.8 +/- 33.0 pg/ml; P = 0.01) in response to a mixed meal after RYGB, but incretin responses were not altered after caloric restriction.These data suggest that an improvement in insulin resistance in the 1st week after RYGB is primarily due to caloric restriction, and the enhanced incretin response after RYGB does not improve postprandial glucose homeostasis during this time.
Phospholipase A2 Receptor (PLA2R1) Sequence Variants in Idiopathic Membranous Nephropathy
Authors: Marieke J.H. Coenen, Julia M. Hofstra, Hanna Debiec, Horia C. Stanescu, Alan J. Medlar, Bénédicte Stengel, Anne Boland-Augé, Johanne M. Groothuismink, Detlef Bockenhauer, Steve H. Powis, Peter W. Mathieson, Paul E. Brenchley, Robert Kleta, Jack F.M. Wetzels, Pierre Ronco
Journal: Journal of the American Society of Nephrology (2013)

The M-type receptor for phospholipase A2 (PLA2R1) is the major target antigen in idiopathic membranous nephropathy (iMN). Our recent genome-wide association study showed that genetic variants in an HLA-DQA1 and phospholipase A2 receptor (PLA2R1) allele associate most significantly with biopsy-proven iMN, suggesting that rare genetic variants within the coding region of the PLA2R1 gene may contribute to antibody formation. Here, we sequenced PLA2R1 in a cohort of 95 white patients with biopsy-proven iMN and assessed all 30 exons of PLA2R1, including canonical (GT-AG) splice sites, by Sanger sequencing. Sixty patients had anti-PLA2R1 in serum or detectable PLA2R1 antigen in kidney tissue. We identified 18 sequence variants, comprising 2 not previously described, 7 reported as rare variants (<1%) in the Single Nucleotide Polymorphism Database or the 1000 Genomes project, and 9 known to be common polymorphisms. Although we confirmed significant associations among 6 of the identified common variants and iMN, only 9 patients had the private or rare variants, and only 4 of these patients were among the 60 who were PLA2R positive. In conclusion, rare variants in the coding sequence of PLA2R1, including splice sites, are unlikely to explain the pathogenesis of iMN.
Complement regulation in murine and human hypercholesterolemia and role in the control of macrophage and smooth muscle cell proliferation
Authors: F VERDEGUER, C CASTRO, M KUBICEK, D PLA, M VILACABALLER, A VINUE, F CIVEIRA, M POCOVI, J CALVETE, V ANDRES
Journal: Cardiovascular Research (2007)

Objective Mounting evidence suggests that activation of complement, an important constituent of innate immunity, contributes to atherosclerosis. Here we investigated the expression of complement components (CCs) in the setting of experimental and clinical hypercholesterolemia, a major risk factor for atherosclerosis, their effects on vascular smooth muscle cell (VSMC) and macrophage proliferation, and the underlying molecular mechanisms.
Induction of death receptor ligand-independent apoptosis by endogeneous TIMP3 in mesenchymal cells
Authors: C Wunrau, D Wendholt, N Pundt, T Pap, B Dankbar
Journal: Annals of the Rheumatic Diseases (2010)

The matrix metalloproteinases (MMPs) and their endogenous regulators, the tissue inhibitors of MMPs (TIMPs 1–4) are responsible for the physiological remodelling of the extracellular matrix (ECM) by maintaining the balance between matrix destruction and formation. An imbalance between MMPs and TIMPs leads to excess MMP activity and is associated with ECM destruction in various inflammatory conditions such as rheumatoid arthritis and malignant tumours. Among all TIMPs, TIMP3 appears to play …