tbuckley/cabot-search huggingface dataset:
Age and Sex May Significantly Interact With Diabetes on the Risks of Lower-Extremity Amputation and Peripheral Revascularization Procedures
Authors: Hua-Fen Chen, Ching-An Ho, Chung-Yi Li
Journal: Diabetes Care (2006)

Using the National Health Insurance claim data, we prospectively investigated the age- and sex-specific incidence density and relative hazards of nontraumatic lower-extremity amputation (LEA) and peripheral revascularization procedure (PRP) of the diabetic population in Taiwan.A total of 500,868 diabetic patients and 500,248 age- and sex-matched control subjects, selected from the ambulatory care claim (1997) and the registry for beneficiaries, respectively, were linked to inpatient claims (1997-2002) to identify hospitalizations due to nontraumatic LEA and PRP. Incidence density was calculated under the Poisson assumption, and the Kaplan-Meier analysis was used to assess the cumulative event rates over a 6-year follow-up period. We also evaluated the age- and sex-specific relative hazards of nontraumatic LEA and PRP in relation to diabetes with Cox proportional hazard regression model adjusted for demographics and regional areas.The estimated incidence density of nontraumatic LEA and PRP for diabetic men was 410.3 and 317.0 per 100,000 patient-years, respectively. The corresponding data for diabetic women were relatively low at 115.2 and 86.0 per 100,000 patient-years. Compared with control subjects with the same age and sex, diabetic patients consistently suffered from significantly elevated relative hazards of nontraumatic LEA. Young and female patients were especially vulnerable to experience increased risks of nontraumatic LEA, but such effect modification by age and sex was less apparent for PRP.Multidisciplinary diabetes foot care systems, including the provision of revascularization procedures, should be further enforced to reduce subsequent risks of nontraumatic LEA, especially in young and female diabetic patients.
Loss of Androgen Receptor Expression Promotes a Stem-like Cell Phenotype in Prostate Cancer through STAT3 Signaling
Authors: Anne Schroeder, Andreas Herrmann, Gregory Cherryholmes, Claudia Kowolik, Ralf Buettner, Sumanta Pal, Hua Yu, Gerhard Müller-Newen, Richard Jove
Journal: Cancer Research (2013)

Androgen receptor (AR) signaling is important for prostate cancer progression. However, androgen-deprivation and/or AR targeting-based therapies often lead to resistance. Here, we demonstrate that loss of AR expression results in STAT3 activation in prostate cancer cells. AR downregulation further leads to development of prostate cancer stem-like cells (CSC), which requires STAT3. In human prostate tumor tissues, elevated cancer stem-like cell markers coincide with those cells exhibiting high STAT3 activity and low AR expression. AR downregulation-induced STAT3 activation is mediated through increased interleukin (IL)-6 expression. Treating mice with soluble IL-6 receptor fusion protein or silencing STAT3 in tumor cells significantly reduced prostate tumor growth and CSCs. Together, these findings indicate an opposing role of AR and STAT3 in prostate CSC development.
TNFα sensitizes neuroblastoma cells to FasL-, cisplatin- and etoposide-induced cell death by NF-κB-mediated expression of Fas
Authors: Koen MO Galenkamp, Paulina Carriba, Jorge Urresti, Laura Planells-Ferrer, Elena Coccia, Joaquín Lopez-Soriano, Bruna Barneda-Zahonero, Rana S Moubarak, Miguel F Segura, Joan X Comella
Journal: Molecular Cancer (2015)

Patients with high-risk neuroblastoma (NBL) tumors have a high mortality rate. Consequently, there is an urgent need for the development of new treatments for this condition. Targeting death receptor signaling has been proposed as an alternative to standard chemo- and radio-therapies in various tumors. In NBL, this therapeutic strategy has been largely disregarded, possibly because ~50-70% of all human NBLs are characterized by caspase-8 silencing. However, the expression of caspase-8 is detected in a significant group of NBL patients, and they could therefore benefit from treatments that induce cell death through death receptor activation. Given that cytokines, such as TNFα, are able to upregulate Fas expression, we sought to address the therapeutic relevance of co-treatment with TNFα and FasL in NBL.For the purpose of the study we used a set of eight NBL cell lines. Here we explore the cell death induced by TNFα, FasL, cisplatin, and etoposide, or a combination thereof by Hoechst staining and calcein viability assay. Further assessment of the signaling pathways involved was performed by caspase activity assays and Western blot experiments. Characterization of Fas expression levels was achieved by qRT-PCR, cell surface biotinylation assays, and cytometry.We have found that TNFα is able to increase FasL-induced cell death by a mechanism that involves the NF-κB-mediated induction of the Fas receptor. Moreover, TNFα sensitized NBL cells to DNA-damaging agents (i.e. cisplatin and etoposide) that induce the expression of FasL. Priming to FasL-, cisplatin-, and etoposide-induced cell death could only be achieved in NBLs that display TNFα-induced upregulation of Fas. Further analysis denotes that the high degree of heterogeneity between NBLs is also manifested in Fas expression and modulation thereof by TNFα.In summary, our findings reveal that TNFα sensitizes NBL cells to FasL-induced cell death by NF-κB-mediated upregulation of Fas and unveil a new mechanism through which TNFα enhances the efficacy of currently used NBL treatments, cisplatin and etoposide.
Gender variations regarding long term effect of CPAP on blood pressure in hypertensive patients with obstructive sleep apnea. A prospective study
Authors: Oana Claudia Deleanu, Andra Elena Malaut, Anca Donoaica, Miruna Micheu, Florin Dumitru Mihaltan
Journal: European Respiratory Journal (2013)

RATIONALE:  The reduction of blood pressure(BP) values under CPAP treatment in obstructive sleep apnea(OSA) patients is controversial, without long term follow up and most of the studies used sphygmomanometer(SM) measurements.   AIM:  We studied variation of BP after 3 and 6 months of CPAP, measured by SM and ambulatory blood pressure monitoring(ABPM) concomitant, in OSA patients with treated hypertension(HT), men vs. women.   METHOD:  We applied exclusion criteria (hypoventilation syndromes, respiratory dysfunctions, other secondary HT, modifying treatment during study, noncompliant patients) to 96 patients (SPSS 17.0: Chi test, T-test).   RESULTS:  We studied 30 remaining patients: 9 women(30%), 21 men(70%) without significant differences regarding age, body mass index, Epworth score and apnea-hypopnea index. BP measured by SM in men had a decrease of systolic(SBP) and diastolic(DBP) values only at 3 months (SBP: from 142.0±8.9 to 128.7±11.7 mmHg, p=0.005, DBP: from 82.0±11.9 to 69.1± 6.6 mmHg, p=0.040); in women BP did not have any modification at 3 and 6 months. On the contrary, regarding ABPM measurements: men did not have any modification, women had a significant increase in maximal value of DBP at 6 months: 24h DBP from 104.0±13.4 to 169.5±27.5 mmHg, p=0.034, diurnal DBP from 100.0±14.1 to 166.0±32.5 mmHg, p=0.046. There was no modification regarding the dipper pattern at 3 or 6 months in both groups.   CONCLUSION : We have shown a difference in BP decrease under long term CPAP regarding gender only measured by SM. It is important to determine in OSA patients which measurement (SM or ABPM) is more reliable in terms of cardiovascular risk.
Detection of maternal-fetal microchimerism in the inflammatory lesions of patients with Sjogren's syndrome
Authors: M Kuroki
Journal: Annals of the Rheumatic Diseases (2002)

<b>Background:</b> A possible relation between maternal-fetal microchimerism and autoimmune diseases with some similarities to chronic graft versus host disease (cGVHD) has been reported. <b>Objective:</b> To investigate whether cells with male DNA exist in female patients with Sjögren9s syndrome (SS) as SS has clinical features similar to those of cGVHD. <b>Methods:</b> DNA was extracted from 27 samples of peripheral blood mononuclear cells (PBMC), 42 biopsy samples of labial salivary glands (LSG), and nine samples of bronchoalveolar lavage fluid (BALF) cells from 56 female patients with SS. The presence of male DNA was determined by nested polymerase chain reaction (PCR) and by fluorescence in situ hybridisation (FISH). <b>Results:</b> Among 56 female patients with SS, 42 patients had at least one male child. Among those 42 patients, none of the 22 PBMC but 10/28 (36%) LSG samples tested positive by PCR for the Y chromosome-specific sequence (p=0.0013). The Y chromosome-specific sequence was not detected in the samples of LSG in 10 patients without SS. In the BALF samples 2/9 (22%) patients with SS tested positive by PCR. Cells containing the Y chromosome were shown to exist in all the LSG specimens from three female patients with SS by FISH. <b>Conclusions:</b> Maternal-fetal microchimerism was shown for the first time to exist in the salivary glands and lungs of female patients with SS in this study. The presence of non-host cells in the inflammatory lesions but not in the peripheral blood suggests a possible role for maternal-fetal microchimerism in the pathogenesis of SS.
Temozolomide in combination with celecoxib in patients with advanced melanoma. A phase II study of the Hellenic Cooperative Oncology Group
Authors: H. Gogas, A. Polyzos, I. Stavrinidis, K. Frangia, D. Tsoutsos, P. Panagiotou, C. Markopoulos, O. Papadopoulos, D. Pectasides, M. Mantzourani, M. Middleton, G. Vaiopoulos, G. Fountzilas
Journal: Annals of Oncology (2006)
Primary Aldosteronism in Diabetic Subjects With Resistant Hypertension
Authors: Guillermo E. Umpierrez, Paul Cantey, Dawn Smiley, Andres Palacio, Diana Temponi, Karen Luster, Arlene Chapman
Journal: Diabetes Care (2007)

Despite the high prevalence of hypertension in patients with type 2 diabetes, the prevalence of primary aldosteronism in this population has not been determined.One hundred subjects with type 2 diabetes and resistant hypertension, defined as blood pressure > 140/90 mmHg despite the use of > or = 3 antihypertensive agents, were screened for primary aldosteronism. Screening was performed by measuring the plasma aldosterone (PAC)-to-plasma renin activity (PRA) ratio. Subjects with a PAC-to-PRA ratio > 30 ng x ml(-1) x h(-1) underwent confirmatory salt load testing. Diagnostic criteria included 24-h urine aldosterone > or = 12 microg during the 3rd day of the oral salt load or a PAC > or = 5 ng/dl after the 4-h intravenous saline load.Thirty-four subjects had a PAC-to-PRA ratio >30 ng x ml(-1) x h(-1). Fourteen subjects (14% [95% CI 7.2-20.8]) had a confirmed diagnosis of primary aldosteronism. Ninety-three patients were African Americans. There were no differences in age, glycemic control, and number of antihypertensive drugs between subjects with and without primary aldosteronism. Subjects with primary aldosteronism had lower serum potassium (3.7 +/- 0.4 vs. 4.0 +/- 0.4 mmol/l, P = 0.012), higher PAC (15.6 +/- 8 vs. 9.1 +/- 6 ng/dl, P = 0.0016), and higher PAC-to-PRA ratio (98 +/- 74 vs. 21 +/- 30 x ml(-1) x h(-1), P < 0.001) than patients without primary aldosteronism.Primary aldosteronism is common in diabetic patients with resistant hypertension, with a prevalence of 14%. Our results indicate that diabetic subjects with poorly controlled hypertension who are taking > or = 3 antihypertensive drugs should be screened for primary aldosteronism.
Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia
Authors: Mark R. Hutchinson, Yehuda Shavit, Peter M. Grace, Kenner C. Rice, Steven F. Maier, Linda R. Watkins
Journal: Pharmacological Reviews (2011)

Vastly stimulated by the discovery of opioid receptors in the early 1970s, preclinical and clinical research was directed at the study of stereoselective neuronal actions of opioids, especially those played in their crucial analgesic role. However, during the past decade, a new appreciation of the non-neuronal actions of opioids has emerged from preclinical research, with specific appreciation for the nonclassic and nonstereoselective sites of action. Opioid activity at Toll-like receptors, newly recognized innate immune pattern recognition receptors, adds substantially to this unfolding story. It is now apparent from molecular and rodent data that these newly identified signaling events significantly modify the pharmacodynamics of opioids by eliciting proinflammatory reactivity from glia, the immunocompetent cells of the central nervous system. These central immune signaling events, including the release of cytokines and chemokines and the associated disruption of glutamate homeostasis, cause elevated neuronal excitability, which subsequently decreases opioid analgesic efficacy and leads to heightened pain states. This review will examine the current preclinical literature of opioid-induced central immune signaling mediated by classic and nonclassic opioid receptors. A unification of the preclinical pharmacology, neuroscience, and immunology of opioids now provides new insights into common mechanisms of chronic pain, naive tolerance, analgesic tolerance, opioid-induced hyperalgesia, and allodynia. Novel pharmacological targets for future drug development are discussed in the hope that disease-modifying chronic pain treatments arising from the appreciation of opioid-induced central immune signaling may become practical.
A phase I pharmacokinetic and pharmacodynamic study of the DNA methyltransferase 1 inhibitor MG98 administered twice weekly
Authors: D.J. Stewart, R.C. Donehower, E.A. Eisenhauer, N. Wainman, A.K. Shah, C. Bonfils, A.R. MacLeod, J.M. Besterman, G.K. Reid
Journal: Annals of Oncology (2003)
T Cell Dynamics in HIV-1 Infection
Authors: Daniel C. Douek, Louis J. Picker, Richard A. Koup
Journal: Annual Review of Immunology (2003)

In the absence of antiretroviral treatment, HIV-1 establishes a chronic, progressive infection of the human immune system that invariably, over the course of years, leads to its destruction and fatal immunodeficiency. Paradoxically, while viral replication is extensive throughout the course of infection, deterioration of conventional measures of immunity is slow, including the characteristic loss of CD4(+) T cells that is thought to play a key role in the development of immunodeficiency. This conundrum suggests that CD4(+) T cell-directed viral cytopathicity alone cannot explain the course of disease. Indeed, recent advances now indicate that HIV-1 pathogenesis is likely to result from a complex interplay between the virus and the immune system, particularly the mechanisms responsible for T cell homeostasis and regeneration. We review these data and present a model of HIV-1 pathogenesis in which the protracted loss of CD4(+) T cells results from early viral destruction of selected memory T cell populations, followed by a combination of profound increases in overall memory T cell turnover, damage to the thymus and other lymphoid tissues, and physiological limitations in peripheral CD4(+) T cell renewal.
The Prognostic Significance of Various 13q14 Deletions in Chronic Lymphocytic Leukemia
Authors: Peter Ouillette, Roxane Collins, Sajid Shakhan, Jinghui Li, Cheng Li, Kerby Shedden, Sami N. Malek
Journal: Clinical Cancer Research (2011)

To further our understanding of the biology and prognostic significance of various chromosomal 13q14 deletions in chronic lymphocytic leukemia (CLL).We analyzed data from SNP 6.0 arrays to define the anatomy of various 13q14 deletions in a cohort of 255 CLL patients and have correlated two subsets of 13q14 deletions (type I exclusive of RB1 and type II inclusive of RB1) with patient survival. Furthermore, we measured the expression of the 13q14-resident microRNAs by quantitative PCR (Q-PCR) in 242 CLL patients and subsequently assessed their prognostic significance. We sequenced all coding exons of RB1 in patients with monoallelic RB1 deletion and have sequenced the 13q14-resident miR locus in all patients.Large 13q14 (type II) deletions were detected in approximately 20% of all CLL patients and were associated with shortened survival. A strong association between 13q14 type II deletions and elevated genomic complexity, as measured through CLL-FISH or SNP 6.0 array profiling, was identified, suggesting that these lesions may contribute to CLL disease evolution through genomic destabilization. Sequence and copy number analysis of the RB1 gene identified a small CLL subset that is RB1 null. Finally, neither the expression levels of the 13q14-resident microRNAs nor the degree of 13q14 deletion, as measured through SNP 6.0 array-based copy number analysis, had significant prognostic importance.Our data suggest that the clinical course of CLL is accelerated in patients with large (type II) 13q14 deletions that span the RB1 gene, therefore justifying routine identification of 13q14 subtypes in CLL management.
The Dicey Role of Dicer: Implications for RNAi Therapy
Authors: William M. Merritt, Menashe Bar-Eli, Anil K. Sood
Journal: Cancer Research (2010)

The dynamic properties of RNA interference (RNAi) in cancer biology have led investigators to pursue with significant interest its role in tumorigenesis and cancer therapy. We recently reported that decreased expression of key RNAi enzymes, Dicer and Drosha, in epithelial ovarian cancers was associated with poor clinical outcome in patients. Dicer expression was also functionally relevant in that targeted silencing was limited with RNAi fragments that require Dicer function compared with those that do not. Together, this and other studies suggest that RNAi machinery expression may affect key pathways in tumorigenesis and cancer biology. Understanding alterations in the functional RNAi machinery is of fundamental importance as we strive to develop novel therapies using RNAi strategies.
Losartan Metabolite EXP3179 Activates Akt and Endothelial Nitric Oxide Synthase via Vascular Endothelial Growth Factor Receptor-2 in Endothelial Cells
Authors: Tetsu Watanabe, Jun Suzuki, Hideyuki Yamawaki, Virendra K. Sharma, Shey-Shing Sheu, Bradford C. Berk
Journal: Circulation (2005)

Recent studies suggest that angiotensin type 1 receptor (AT1R) blockers have vascular protective effects beyond blood pressure lowering. Because of the importance of endothelial nitric oxide synthase (eNOS) in vascular and platelet function, we hypothesized that losartan and its metabolites would stimulate eNOS and its upstream activators Akt and phosphatidylinositol 3-kinase (PI3K).Losartan is metabolized into EXP3174 (AT1R-blocking metabolite) and EXP3179 (no AT1R-blocking properties). Treatment of endothelial cells (ECs) with losartan and both metabolites stimulated phosphorylation of Akt and eNOS in the absence of angiotensin II. However, the magnitude for EXP3179 was much greater than EXP3174, and the EC50 was significantly lower (-logEC50, 8.2+/-0.1 versus 5.4+/-0.2 mol/L), suggesting an AT1R-independent effect. Inhibiting PI3K or vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine phosphorylation abrogated EXP3179-induced eNOS phosphorylation. In endothelium of intact rat aorta, EXP3179 also stimulated Akt and eNOS phosphorylation. VEGFR2 activation was shown to be calcium and Src family kinase dependent by use of specific drug inhibitors and dominant negative kinase transfection. EXP3179 significantly inhibited tumor necrosis factor alpha-induced apoptosis by approximately 60% (from 30.1+/-5.8% to 12.2+/-2.0% TUNEL-positive cells), which was abolished by pretreatment with the PI3K inhibitor LY294002. Cleaved caspase-3 was suppressed by 48% with EXP3179.The losartan metabolite EXP3179 stimulates eNOS phosphorylation and suppresses tumor necrosis factor alpha-induced EC apoptosis by activating the VEGFR2/PI3K/Akt pathway.
The Elusive Pathophysiology of Neurally Mediated Syncope
Authors: Rogelio Mosqueda-Garcia, Raffaello Furlan, Jens Tank MD, Roxana Fernandez-Violante
Journal: Circulation (2000)

yncope is defined as a sudden transient loss of conscious- ness and postural tone due to cerebral hypoperfusion.Although no permanent medical sequelae should result from syncope itself, isolated or recurrent events are often dramatic and disrupt the lifestyle of affected individuals.Syncope is a common clinical problem that affects up to 3.5% of the general population. 1 Strikingly, in close to 40% of cases, the exact cause of syncope remains elusive, and Ϸ30% of affected patients will experience recurrent episodes. 1eurally mediated syncope (NMS) is a common type of syncope (Figure 1); clinical descriptions of it have been present in the medical literature for Ͼ100 years.Despite its prevalence, significant gaps in our understanding of its pathophysiology and treatment remain.The purpose of this review is to critically evaluate proposed theories that attempt to explain the pathophysiological mechanisms of NMS.
Working in a Flawed Mental Health Care System: An Ethical Challenge
Authors: S A Green, S Bloch
Journal: American Journal of Psychiatry (2001)

Psychiatrists are under immense ethical pressure when practicing in circumstances that reasonable, informed colleagues would regard as not "good enough" in that they do not adequately meet the needs of patients and patients' families. This article is an examination of the ethical quandaries that ensue and options for response.The authors explore the ways in which mental health systems may become flawed and compare philosophical arguments that deal with the predicament of working in such systems.The principle of fidelity to the patient is compromised in flawed systems, thus threatening professional integrity. Arguments for efficiency or the greater good in the provision of mental health care fail as remedies since they both lead to harms for particular clinical groups, as well as downgrading of a psychiatrist's integrity.Psychiatrists should submit to the principle of fidelity in working with patients. Since flawed systems undermine fidelity, threatening the patient's interests, psychiatrists are morally responsible for working to improve such systems.