tbuckley/cabot-search huggingface dataset:
Inhibition of Cyclooxygenase-2 Disrupts Tumor Vascular Mural Cell Recruitment and Survival Signaling
Authors: Alice Lee, Jason Frischer, Anna Serur, Jianzhong Huang, Jae-O Bae, Zev Noah Kornfield, Lucy Eljuga, Carrie J. Shawber, Nikki Feirt, Mahesh Mansukhani, Diana Stempak, Sylvain Baruchel, Julia Glade Bender, Jessica J. Kandel, Darrell J. Yamashiro
Journal: Cancer Research (2006)

Much evidence supports an important role for the inducible enzyme cyclooxygenase-2 (COX-2) in tumor angiogenesis. Previous studies have focused on the role of COX-2 in stimulating endothelial proliferation, with blockade of this enzyme impairing endothelial homeostasis. However, recent data suggest that COX-2 also regulates molecules implicated in endothelial trafficking with pericytes/vascular mural cells (VMC), an interaction crucial to vessel stability. We investigated the role of COX-2 in vascular assembly by testing the effect of the specific COX-2 inhibitor SC-236 in an orthotopic xenograft model of human Wilms' tumor. Tumor growth was significantly suppressed by SC-236 (78% at day 28, 55% at day 35). Perfusion studies and immunostaining showed a marked decrease in vasculature, particularly in small vessels. Specifically, SC-236 inhibited participation of VMC in xenograft vessels. SC-236-treated tumors developed segmentally dilated, architecturally erratic tumor vessels with decreased nascent pericytes and scant mature VMC. Although vascular endothelial growth factor expression was unchanged, expression of the chemokine receptor CXCR4 was decreased in tumor vessels, consistent with defective homing of vascular progenitor cells. Vascular expression of phosphorylated platelet-derived growth factor receptor-beta was also diminished, indicating impaired VMC-endothelial trafficking. Consistent with the key role of this interaction in vessel homeostasis, vascular cells in SC-236-treated tumors displayed markedly diminished phosphorylated Akt, indicating disrupted survival signaling. These results show that SC-236 causes defective vascular assembly by attenuating incorporation of VMC into tumor vessels, impairing endothelial survival, and raise the possibility that blockade of COX-2 may provide therapeutic synergies with antiangiogenic molecules that more selectively target endothelial cells.
Italy's health service faces new shake up
Authors: L Evans
Journal: BMJ (1994)

Italy's public sector health workers, including doctors, were planning a traditional Italian welcome for their new health minister, Raffaele Costa: a strike, on 1 July. The one day stoppage, with emergency and essential services ostensibly guaranteed, has been called over pay rather than in reaction to the new government. But it highlights the principal consideration facing Mr Costa as he prepares to apply to the health sector the free market remedies for which most Italians voted last March. At a general election that effectively buried the corruption stained parties that had ruled the country since the 1940s, voters handed victory to a rightist alliance formed by the television and property …
Assessment of skin barrier function in podoconiosis: measurement of stratum corneum hydration and transepidermal water loss
Authors: J.S. Ferguson, W. Yeshanehe, P. Matts, G. Davey, P. Mortimer, C. Fuller
Journal: British Journal of Dermatology (2013)

Podoconiosis is a common cause of lymphoedema in barefoot workers in Ethiopia and other countries. It has severe consequences for patients' physical function, quality of life and economic status.To investigate stratum corneum (SC) hydration and transepidermal water loss (TEWL) in patients with podoconiosis compared with controls.In total, 55 patients and 20 controls were recruited. For each study subject, SC and TEWL measurements were taken, along with foot and lower leg circumferences. Measurements were compared between the patient and control groups.Foot circumferences tended to be higher in patients with podoconiosis, with the mean foot:leg circumference ratio being 1·19 (95% confidence interval 1·11-1·28) times that for controls (P = 0·001). There was no detectable difference between patients and controls in TEWL values (P > 0·05); however, SC hydration was significantly lower in patients vs. controls for the foot (P = 0·004) and lower leg (P = 0·046) sites.Patients with podoconiosis have significantly lower SC hydration in the skin of their lower legs and feet than controls, which may lead to cracking and splitting, and increased risk of lymphoedema and infection.
The incidence of severe alpha-1-antitrypsin (AAT) deficiency alleles in COPD patients — Preliminary results from Central Eastern European (CEE) AAT NETWORK
Authors: Joanna Chorostowska-Wynimko, Anna Kubincova, Nikolay Yanev, Ruxandra Ulmeanu, Radoslaw Struniawski, Pavol Pobeha, Nikolay Kyuchukov, Oana Deleanu, Beata Poplawska, Ruzena Tkacova, Yavor Ivanov, Florin Dumitru Mihaltan, Arunas Valiulis
Journal: European Respiratory Journal (2013)

Data concerning the prevalence of AAT deficiency in general population or respiratory patients in CEE countries are limited or non-existent. The overwhelming majority of individuals with AAT deficiency remains undiagnosed. We present preliminary data from the CEE A1AT Network, recently established within the LPP Leonardo da Vinci EU program (2011-1-PL-LEO04-197151)“Introducing standards of the best medical practice for the patients with inherited Alpha-1 Antitrypsin Deficiency in Central Eastern Europe”

DBS samples were collected from 328 COPD patients between October 2012-January 2013 in Poland (n=198), Bulgaria (n=44), Romania (n=26) and Slovakia (n=60). AAT serum concentration in DBS was measured by nephelometry and PI-phenotype identified by real-time PCR. The PI*S and PI*Z alleles were confirmed by isoelectrofocusing; rare phenotypes were identified by sequencing.

Results: PI*S or PI*Z deficiency alleles were observed respectively in 14 (4,27%) and 30 (9,14 %) patients. There were 6 patients with rare AAT mutations: FM-3, IM-2, Mzbristol-1. In total, any AAT mutation was diagnosed in 48 COPD patients (14,63%). The calculated frequency for PI*Z and PI*S alleles in overall tested population was 46,1 (95% CI: 31,1-60,9) and 15,8 (95% CI: 6,92-24,6), respectively. The AAT gene prevalence calculated by Hardy-Weinberg equilibrium was: 1/1.15 for MM, 1/34 for MS, 1/4011 for SS, 1/12 for MZ, 1/688 for SZ and 1/471 for ZZ.

Conclusion: Our results confirm the relatively high frequency of AAT deficiency in COPD patients from CEE. This is the very first attempted to establish the diagnostic and scientific collaboration for AATD in CEE.
Aging and antimicrobial immunity. Lowered efficiency of protective T cells as a contributing factor for the decreased resistance of senescent mice to listeriosis.
Authors: P J Patel
Journal: The Journal of Experimental Medicine (1982)

Experimental murine listeriosis was used as a model to investigate the immunological basis for the age-associated decline in antimicrobial immunity. The reduced capacity of protective T cells from Listeria-immune senescent mice to adoptively immunize normal syngeneic recipients could not be attributed to inhibition of their activity by suppressor cells. Radiolabeled enriched splenic T cells from Listeria-immune young or senescent donors exhibited an identical distribution pattern after an intravenous infusion into young recipients. Moreover, cells from Listeria-immune young donors showed markedly greater protective capacity than cells from senescent immune donors whether the cells were transferred to young or senescent recipients. Dose-response analysis of protective T cells revealed that in response to immunizing infection (a) senescent mice generated 10-fold fewer protective T cells, and (b) protective T cells from senescent mice were 100-fold less efficient than cells from young mice.
Leukemia-Specific T-Cell Reactivity Induced by Leukemic Dendritic Cells Is Augmented by 4-1BB Targeting
Authors: Ilse Houtenbos, Theresia M. Westers, Annemiek Dijkhuis, Tanja D. de Gruijl, Gert J. Ossenkoppele, Arjan A. van de Loosdrecht
Journal: Clinical Cancer Research (2006)

Acute myelogenous leukemia (AML) blasts are able to differentiate into leukemia-derived dendritic cells (AML-DC), thereby enabling efficient presentation of known and unknown leukemic antigens. Advances in culture techniques and AML-DC characterization justify clinical application. However, additional measures are likely needed to potentiate vaccines and overcome the intrinsic tolerant state of the patients' immune system. Engagement of the costimulatory molecule 4-1BB can break immunologic tolerance and increase CTL responses. In this study, we examined the role of the 4-1BB ligand (4-1BBL) on T-cell responses induced by AML-DC.In allogeneic and autologous cocultures of T cells and AML-DC, the effect of the addition of 4-1BBL on T-cell proliferation, T-cell subpopulations, and T-cell function was determined.Addition of 4-1BBL to cocultures of AML-DC and T cells induced a preferential increase in the proliferation of CD8(+) T cells. Increased differentiation into effector and central memory populations was observed in both CD4(+) and CD8(+) T cells in the presence of 4-1BBL. AML-DC induce a T helper 1 response, characterized by high IFN-gamma production, which is significantly increased by targeting 4-1BB. T cells primed in the presence of 4-1BBL show specificity for the leukemia-associated antigen Wilms' tumor 1, whereas cytotoxicity assays with leukemic blast targets showed the cytolytic potential of T cells primed in the presence of 4-1BBL.We conclude that 4-1BBL is an effective adjuvant to enhance T-cell responses elicited by AML-DC.
Benefits from aerobic exercise in patients with major depression: a pilot study
Authors: F Dimeo, M Bauer, I Varahram, G Proest, U Halter
Journal: British Journal of Sports Medicine (2001)

Background —Several reports indicate that physical activity can reduce the severity of symptoms in depressed patients. Some data suggest that even a single exercise bout may result in a substantial mood improvement. Objective —To evaluate the short term effects of a training programme on patients with moderate to severe major depression. Methods —Twelve patients (mean (SD) age 49 (10) years; five men, seven women) with a major depressive episode according to the Diagnostic and Statistical Manual of the American Society of Psychiatry (DSM IV) criteria participated. The mean (SD) duration of the depressive episode was 35 (21) weeks (range 12–96). Training consisted of walking on a treadmill following an interval training pattern and was carried out for 30 minutes a day for 10 days. Results —At the end of the training programme, there was a clinically relevant and statistically significant reduction in depression scores (Hamilton Rating Scale for Depression: before, 19.5 (3.3); after, 13 (5.5); p = 0.002. Self assessed intensity of symptoms: before, 23.2 (7); after, 17.7 (8.1); p = 0.006. Values are mean (SD)). Subjective and objective changes in depression scores correlated strongly ( r = 0.66, p = 0.01). Conclusions —Aerobic exercise can produce substantial improvement in mood in patients with major depressive disorders in a short time.
Agricultural task and exposure to organophosphate pesticides among farmworkers.
Authors: Gloria D Coronado, Beti Thompson, Larki Strong, William C Griffith, Ilda Islas
Journal: Environmental Health Perspectives (2003)

Little is known about pesticide exposure among farmworkers, and even less is known about the exposure associated with performing specific farm tasks. Using a random sample of 213 farmworkers in 24 communities and labor camps in eastern Washington State, we examined the association between occupational task and organophosphate (OP) pesticide residues in dust and OP metabolite concentrations in urine samples of adult farmworkers and their children. The data are from a larger study that sought to test a culturally appropriate intervention to break the take-home pathway of pesticide exposure. Commonly reported farm tasks were harvesting or picking (79.2%), thinning (64.2%), loading plants or produce (42.2%), planting or transplanting (37.6%), and pruning (37.2%). Mixing, loading, or applying pesticide formulations was reported by 20% of our sample. Workers who thinned were more likely than those who did not to have detectable levels of azinphos-methyl in their house dust (92.1% vs. 72.7%; p = 0.001) and vehicle dust (92.6% vs. 76.5%; p = 0.002). Thinning was associated with higher urinary pesticide metabolite concentrations in children (91.9% detectable vs. 81.3%; p = 0.02) but not in adults. Contrary to expectation, workers who reported mixing, loading, or applying pesticide formulations had lower detectable levels of pesticide residues in their house or vehicle dust, compared with those who did not perform these job tasks, though the differences were not significant. Future research should evaluate workplace protective practices of fieldworkers and the adequacy of reentry intervals for pesticides used during thinning.
Epidermal Growth Factor Receptor Gene Copy Number and Clinical Outcome of Metastatic Colorectal Cancer Treated With Panitumumab
Authors: Andrea Sartore-Bianchi, Mauro Moroni, Silvio Veronese, Carlo Carnaghi, Emilio Bajetta, Gabriele Luppi, Alberto Sobrero, Carlo Barone, Stefano Cascinu, Giuseppe Colucci, Enrico Cortesi, Michele Nichelatti, Marcello Gambacorta, Salvatore Siena
Journal: Journal of Clinical Oncology (2007)

In a previous cohort study, we proposed that responsiveness of metastatic colorectal cancer (mCRC) to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies has a genetic basis, being associated with increased EGFR gene copy number (GCN) as measured by fluorescence in situ hybridization (FISH) in individual tumors. The present study was aimed at assessing the predictive role of EGFR GCN, in terms of clinical outcome, in patients treated with panitumumab.Patients with mCRC refractory to standard therapies were a subset of patients from a phase III trial of panitumumab plus best supportive care (BSC; n = 58) versus BSC alone (n = 34) who were selected on the basis of availability of tumor samples adequate for FISH.In patients treated with panitumumab, a mean EGFR GCN of less than 2.5/nucleus or less than 40% of tumor cells displaying chromosome 7 polysomy within the tumor predicted for shorter progression-free survival (PFS; P = .039 and P = .029, respectively) and overall survival (P = .015 and P = .014, respectively). None of the treated patients with mean EGFR GCN of less than 2.47/nucleus or less than 43% of tumor cells displaying chromosome 7 polysomy obtained objective response compared with six of 20 and six of 19 patients with values greater than these cutoff limits, respectively (P = .0009 and P = .0007, respectively). Evaluation of BSC-treated patients showed no correlation between EGFR GCN or chromosome 7 polysomy status and PFS.In a larger and more homogeneous series than in previous studies, present exploratory data suggest that mCRC patients with tumors distinguishable by FISH analysis of EGFR as homogenously disomic or with low chromosome 7 polysomy have a reduced likelihood of response to panitumumab.
Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure
Authors: T. Hansotia, A. Maida, G. Flock, Y. Yamada, K. Tsukiyama, Y. Seino, Daniel. J. Drucker
Journal: Journal of Clinical Investigation (2006)

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) control glucose homeostasis through well-defined actions on the islet beta cell via stimulation of insulin secretion and preservation and expansion of beta cell mass. We examined the importance of endogenous incretin receptors for control of glucose homeostasis through analysis of Glp1r(-/-), Gipr(-/-), and double incretin receptor knockout (DIRKO) mice fed a high-fat (HF) diet. DIRKO mice failed to upregulate levels of plasma insulin, pancreatic insulin mRNA transcripts, and insulin content following several months of HF feeding. Both single incretin receptor knockout and DIRKO mice exhibited resistance to diet-induced obesity, preservation of insulin sensitivity, and increased energy expenditure associated with increased locomotor activity. Moreover, plasma levels of plasminogen activator inhibitor-1 and resistin failed to increase significantly in DIRKO mice after HF feeding, and the GIP receptor agonist [D-Ala(2)]GIP, but not the GLP-1 receptor agonist exendin-4, increased the levels of plasma resistin in studies of both acute and chronic administration. These findings extend our understanding of how endogenous incretin circuits regulate glucose homeostasis independent of the beta cell via control of adipokine secretion and energy expenditure.
P21-Activated Kinase 1 Regulation of Estrogen Receptor-α Activation Involves Serine 305 Activation Linked with Serine 118 Phosphorylation
Authors: Suresh K. Rayala, Amjad H. Talukder, Seetharaman Balasenthil, Robbin Tharakan, Christopher J. Barnes, Rui-An Wang, Marcelo Aldaz, Sohaib Khan, Rakesh Kumar
Journal: Cancer Research (2006)

Abstract Here, we investigated the role of P21-activated kinase 1 (Pak1) signaling in the function of estrogen receptor-α (ER-α) as assessed by serine 305 (S305) activation and transactivation activity of ER. We found that Pak1 overexpression interfered with the antiestrogenic action of tamoxifen upon the ER transactivation function in hormone-sensitive cells. In addition, tamoxifen stimulation led to up-regulation of ER target genes in breast cancer cells with increased Pak1 expression. Tamoxifen also increased Pak1-ER interaction in tamoxifen-resistant but not in tamoxifen-sensitive cells. Results from the mutational studies discovered a role of ER-S305 phosphorylation in triggering a subsequent phosphorylation of serine 118 (S118), and these effects were further potentiated by tamoxifen treatment. We found that S305 activation-linked ER transactivation function requires a functional S118, and active Pak1 signaling is required for a sustaining S118 phosphorylation of the endogenous ER. All of these events were positively influenced by tamoxifen and thus may contribute toward the loss of antiestrogenic effect of tamoxifen. These findings suggest that Pak1 signaling-dependent activation of ER-S305 leads to an enhanced S118 phosphorylation presumably due to a conformational change, and such structural modifications may participate in the development of tamoxifen resistance. (Cancer Res 2006; 66(3): 1694-701)
tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia
Authors: Birgit S Budde, Yasmin Namavar, Peter G Barth, Bwee Tien Poll-The, Gudrun Nürnberg, Christian Becker, Fred van Ruissen, Marian A J Weterman, Kees Fluiter, Erik T te Beek, Eleonora Aronica, Marjo S van der Knaap, Wolfgang Höhne, Mohammad Reza Toliat, Yanick J Crow, Maja Steinlin, Thomas Voit, Filip Roelens, Wim Brussel, Knut Brockmann, Marten Kyllerman, Eugen Boltshauser, Gerhard Hammersen, Michèl Willemsen, Lina Basel-Vanagaite, Ingeborg Krägeloh-Mann, Linda S de Vries, Laszlo Sztriha, Francesco Muntoni, Colin D Ferrie, Roberta Battini, Raoul C M Hennekam, Eugenio Grillo, Frits A Beemer, Loes M E Stoets, Bernd Wollnik, Peter Nürnberg, Frank Baas
Journal: Nature Genetics (2008)
Characterization of Functional Excision Repair Cross-Complementation Group 1 Variants and Their Association with Lung Cancer Risk and Prognosis
Authors: Dianke Yu, Xuemei Zhang, Ju Liu, Peng Yuan, Wen Tan, Yongli Guo, Tong Sun, Dan Zhao, Ming Yang, Junniao Liu, Binghe Xu, Dongxin Lin
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The excision repair cross-complementation group 1 (ERCC1) plays a pivotal role in DNA repair and has been linked to protection against carcinogenesis and resistance to platinum-based anticancer drugs. We tested whether genetic variants in the ERCC1 gene are associated with susceptibility to lung cancer and efficacy of platinum-chemotherapy in patients with small cell lung cancer (SCLC). Experimental Design: Thirty individual DNA samples were sequenced to search for single-nucleotide polymorphisms, and the functions of the variants were investigated by a series of biochemical assays. A case-control study was done in 988 patients with lung cancer and 986 control subjects. According to the genotypes, a comparison of chemotherapy outcome in 162 SCLC patients was executed. Overall survival was computed by Cox model adjusted for clinical factors. Results: We identified two functional variants in the ERCC1 5′-flanking region, −433T&amp;gt;C and 262G&amp;gt;T, which cooperatively influence transcriptional regulation of ERCC1. The 262G allele had significantly lower affinity to bind nuclear protein(s) and was associated with decreased ERCC1 RNA expression. The case-control analysis showed that the −433C and 262G alleles are associated with an increased susceptibility to lung cancer, alone and in a gene-smoking joint effect manner. In contrast, the analysis of chemotherapy outcome of SCLC patients revealed that the 262G allele is associated with better drug response and longer survival time compared with the 262T allele. Conclusions: These findings are consistent with the notion that DNA repair is a double-edged sword in cancer and suggest that functional single-nucleotide polymorphisms in ERCC1 might serve as simple and less invasive biomarkers for personalized chemotherapy of platinum-based anticancer drugs.
Connexins and Atrial Fibrillation
Authors: Takeshi Kato, Yu-ki Iwasaki, Stanley Nattel
Journal: Circulation (2011)

A trial fibrillation (AF) is an extremely common arrhyth- mia with important consequences and presently suboptimal therapeutic options. 1 A great deal of research has been performed to understand the detailed mechanisms of AF, with the hope that a better appreciation of the fundamental determinants of arrhythmogenesis will lead to the development of novel, more successful treatment possibilities.
Comment on Guest et al. Clinical Outcomes and Cost-effectiveness of Continuous Positive Airway Pressure to Manage Obstructive Sleep Apnea in Patients With Type 2 Diabetes in the U.K. Diabetes Care 2014;37:1263–1271
Authors: Abd A. Tahrani
Journal: Diabetes Care (2014)

The article by Guest et al. (1) addresses a hotly debated topic. While many studies have examined the impact of obstructive sleep apnea (OSA) on glucose metabolism and cardiovascular disease in patients without diabetes, little is known about the impact of OSA on clinical outcomes in patients with type 2 diabetes—hence the importance of the findings by Guest et al. The importance of this area is further emphasized by the high prevalence of OSA in patients with type 2 diabetes (2,3).

The impact of continuous positive airway pressure (CPAP) on glycemic measures is unclear. Although uncontrolled studies have shown that CPAP improved glycemic control in patients with type 2 diabetes, the only randomized controlled trial has not shown such benefit (2, …