tbuckley/cabot-search huggingface dataset:
Preferential Differentiation of P19 Mouse Embryonal Carcinoma Cells Into Smooth Muscle Cells
Authors: Toru Suzuki, Hyo-Soo Kim, Masahiko Kurabayashi, Hiroshi Hamada, Hideta Fujii, Masanori Aikawa, Masafumi Watanabe, Noboru Watanabe, Yasunari Sakomura, Yoshio Yazaki, Ryozo Nagai
Journal: Circulation Research (1996)

Investigation of the molecular mechanisms that control smooth muscle cell (SMC) development and differentiation is a prerequisite in understanding the regulatory mechanisms of physiological and pathological SMC-associated vascular processes. The pluripotent murine embryonal carcinoma P19 cell, whose developmental potential resembles that of early embryonic cells, can develop into cell types derived from the neuroectoderm, mesoderm, and endoderm. In the present study, we have shown a unique strategy to enhance SMC differentiation in P19 cells. Under chemical induction of high concentrations of retinoic acid (1 micromol/L), P19 cells showed optimum differentiation into SMCs. Because the P19 cells thus induced also showed differentiation into neuronal cells, a strategy to block neuronal lineage differentiation was developed using a stable transformant antisense RNA construct against Brn-2, a neuronal lineage-specific POU-domain transcription factor; thus, by specifically inhibiting neuronal differentiation, enhanced SMC differentiation by P19 cells was attained. SMC expression was confirmed by immunohistochemical staining, RNA analysis (RNase protection assay), and protein analysis (Western blot) using SMC-specific markers (eg, SM1 and calponin) and alpha-smooth muscle actin. Our results show that the pathway of SMC differentiation may provide an in vitro system useful in the investigation of SMC regulatory mechanisms (eg, transcriptional regulation) and in the further understanding of SMC development and differentiation.
Modulating TLR responses in systemic sclerosis via heme oxygenase-1
Authors: L. van Bon, A. Scharstuhl, B. Pennings, R. J. F. Huijbens, M. H. Wenink, K. C. M. Santegoets, M. Vonk, W. van den Berg, F. Wagener, T. R. D. J. Radstake
Journal: Annals of the Rheumatic Diseases (2010)

Systemic sclerosis (SSc) is an autoimmune disease characterised by fibrosis of the skin and the internal organs. The aetiology is still unknown, but prominent features are vascular injury and chronic inflammation resulting in fibrosis. Accumulating evidence suggests a role for Toll-like receptor (TLR)-mediated activation of dendritic cells (DC). Heme oxygenase-1 (HO-1) is a known cytoprotective enzyme induced in response to stress factors like oxygen radicals or inflammation, both of which …
Novel C5-Dependent Mechanism of Neutrophil Stimulation by Bioincompatible Dialyzer Membranes
Authors: ALEXANDER R. ROSENKRANZ, GÜNTHER F. KÖRMÖCZI, FLORIAN THALHAMMER, ERNST J. MENZEL, WALTER H. HÖRL, GERT MAYER, GERHARD J. ZLABINGER
Journal: Journal of the American Society of Nephrology (1999)

Abstract. The objective of the study was to evaluate the contribution of reactive oxygen intermediate formation for receptor modulation on neutrophils by the cellulosic dialyzer membrane cuprophan (CU). In patients dialyzed with CU, CD11b and CD66b upregulation on neutrophils (by 104.3 ± 37.9% and 85.7 ± 31.1%, respectively), and a downregulation of L-selectin (by 44.9 ± 26.9%) was seen, whereas expression of CD11 a remained unaltered. Hemodialysis with polysulfone did not bring about major changes in surface receptor expression. In vitro incubation of isolated neutrophils in the presence of serum with hollow fibers of CU or polysulfone showed similar results: Only CU resulted in upregulation of CD11b and CD66b expression (by 65.5 ± 18.7% and 60.1 ± 24%) and a decrease in CD62L expression (by 60.6 ± 18.2%). In contrast to receptor alterations, generation of reactive oxygen intermediate by CU occurred in the absence of serum. Inhibition experiments with soluble complement receptor 1, which produced only partial inhibition of receptor up-/down-regulation, indicated the existence of also other than alternate complement-dependent mechanisms for neutrophil activation. By using C5-depleted serum instead of normal human serum, up-/down-regulation of CD11b, CD62L, and CD66b by CU was dramatically reduced, whereas C3-depleted serum did not produce that effect. C5-deficient serum repleted with purified C5, as well as purified C5 alone, was able to induce receptor modulation by CU comparable to normal human serum. L-Methionine, a specific inhibitor for the oxidative activation of C5, blocked the modulatory effect of CU in assays with purified C5 as well as with serum. As a result, in addition to the alternative pathway of complement, a C5-dependent mechanism probably activated by neutrophil-derived reactive oxygen intermediate leads to receptor modulation and subsequent generation of the well known side effects of bioincompatible dialyzer membranes.
Doxorubicin Synergizes with 34.5ENVE to Enhance Antitumor Efficacy against Metastatic Ovarian Cancer
Authors: Chelsea Bolyard, Ji Young Yoo, Pin-Yi Wang, Uksha Saini, Kellie S. Rath, Timothy P. Cripe, Jianying Zhang, Karuppaiyah Selvendiran, Balveen Kaur
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Novel therapeutic regimens are needed to improve dismal outcomes associated with late-stage ovarian cancer. Oncolytic viruses are currently being tested in patients with ovarian cancer. Here, we tested the therapeutic efficacy of combining doxorubicin with 34.5ENVE, an oncolytic herpes simplex virus transcriptionally driven by a modified stem cell–specific nestin promoter, and encoding for antiangiogenic Vasculostatin-120 (VStat120) for use against progressive ovarian cancer. Experimental Design: Antitumor efficacy of 34.5ENVE was assessed in ovarian cancer cell lines, mouse ascites–derived tumor cells, and primary patient ascites–derived tumor cells by standard MTT assay. The ability of conditioned medium derived from 34.5ENVE-infected ovarian cancer cells to inhibit endothelial cell migration was measured by a Transwell chamber assay. Scope of cytotoxic interactions between 34.5ENVE and doxorubicin were evaluated using Chou–Talalay synergy analysis. Viral replication, herpes simplex virus receptor expression, and apoptosis were evaluated. Efficacy of oncolytic viral therapy in combination with doxorubicin was evaluated in vivo in the murine xenograft model of human ovarian cancer. Results: Treatment with 34.5ENVE reduced cell viability of ovarian cancer cell lines, and mouse ascites–derived and patient ascites–derived ovarian tumor cells. Conditioned media from tumor cells infected with 34.5ENVE reduced endothelial cell migration. When combined with doxorubicin, 34.5ENVE killed synergistically with a significant increase in caspase-3/7 activation, and an increase in sub-G1 population of cells. The combination of doxorubicin and 34.5ENVE significantly prolonged survival in nude mice bearing intraperitoneal ovarian cancer tumors. Conclusions: This study indicates significant antitumor efficacy of 34.5ENVE alone, and in combination with doxorubicin against disseminated peritoneal ovarian cancer. Clin Cancer Res; 20(24); 6479–94. ©2014 AACR.
β2-Adrenergic Receptor Genetic Variants and Risk of Sudden Cardiac Death
Authors: Nona Sotoodehnia, David S. Siscovick, Matteo Vatta, Bruce M. Psaty, Russell P. Tracy, Jeffrey A. Towbin, Rozenn N. Lemaitre, Thomas D. Rea, J. Peter Durda, Joel M. Chang, Thomas S. Lumley, Lewis H. Kuller, Gregory L. Burke, Susan R. Heckbert
Journal: Circulation (2006)

Sympathetic activation influences the risk of ventricular arrhythmias and sudden cardiac death (SCD), mediated in part by the beta2-adrenergic receptor (B2AR). We investigated whether variation in the B2AR gene is associated with SCD risk.In this study, 4441 white and 808 black Cardiovascular Health Study (CHS) participants were followed up prospectively for SCD and genotyped for B2AR Gly16Arg and Gln27Glu polymorphisms. The study was replicated in 155 case and 144 control white subjects in a population-based case-control study of SCD, the Cardiac Arrest Blood Study (CABS). In CHS, Gly16 and Gln27 allele frequencies were 62.4% and 57.1% among white and 50.1% and 81.4% among black participants. Over a median follow-up of 11.1 years, 156 and 39 SCD events occurred in white and black participants, respectively. The Gln27Glu variant was associated with SCD risk (P=0.008 for general model). SCD risk was higher in Gln27 homozygous participants than in Glu27 carriers (ethnicity-adjusted hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.17 to 2.09; P=0.003). The increased risk did not differ significantly between white (HR, 1.62; 95% CI, 1.18 to 2.23) and black (HR, 1.23; 95% CI, 0.61 to 2.48) participants, although the confidence interval was wide in blacks. In the CABS replication study, Gln27 homozygous participants similarly had higher SCD risk than Glu27 carriers (odds ratio, 1.64; 95% CI, 1.02 to 2.63; P=0.040). Gly16Arg was not associated with SCD risk in either study.Gln27 homozygous individuals have an increased risk of SCD in 2 study populations. Our findings suggest that B2AR plays a role in SCD in humans. Study of genetic variation within the B2AR gene may help identify those at increased SCD risk.
Chronic hypoxia increases rat diaphragm muscle endurance and sodium-potassium ATPase pump content
Authors: C. McMorrow, A. Fredsted, J. Carberry, R.A. O’Connell, A. Bradford, J.F.X. Jones, K.D. O’Halloran
Journal: European Respiratory Journal (2010)

The effects of chronic hypoxia (CH) on respiratory muscle are poorly understood. The aim of the present study was to examine the effects of CH on respiratory muscle structure and function, and to determine whether nitric oxide is implicated in respiratory muscle adaptation to CH. Male Wistar rats were exposed to CH for 1–6 weeks. Sternohyoid and diaphragm muscle contractile properties, muscle fibre type and size, the density of fibres expressing sarco/endoplasmic reticulum calcium-ATPase (SERCA) 2 and sodium–potassium ATPase (Na + ,K + -ATPase) pump content were determined. Muscle succinate dehydrogenase (SDH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) dehydrogenase activities were also assessed. Acute and chronic blockade of nitric oxide synthase (NOS) was employed to determine whether or not NO is critically involved in functional remodelling in CH muscles. CH improved diaphragm, but not sternohyoid, fatigue tolerance in a time-dependent fashion. This adaptation was not attributable to increased SDH or NADPH dehydrogenase activities. The areal density of muscle fibres and relative area of fibres expressing SERCA2 were unchanged. Na + ,K + -ATPase pump content was significantly increased in CH diaphragm. Chronic NOS inhibition decreased diaphragm Na + ,K + -ATPase pump content and prevented CH-induced increase in muscle endurance. This study provides novel insight into the mechanisms involved in CH-induced muscle plasticity. The results may be of relevance to respiratory disorders characterised by CH, such as chronic obstructive pulmonary disease.
C4BP runs damage control
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

The complement inhibitor C4b-binding protein (C4BP) prevents necrotic cells from spilling their pro-inflammatory guts, according to a study on page 1937. Trouw and colleagues now show that C4BP and its binding partner, anticoagulant protein S (PS), cooperate to grab onto necrotic cells and to inhibit the release of cellular DNA.






Figure 

The complement inhibitory protein C4b-binding protein (brown) binds to necrotic cells and limits the release of cellular DNA.




C4BP short-circuits the complement cascade by binding to the activated complement components C3b and C4b and presenting them to the proteolytic complement inhibitor Factor I for degradation. This inhibitory capacity of C4BP can be coopted by bacterial pathogens, which coat themselves with this protein to avoid complement-mediated destruction by phagocytic cells.

This group recently identified a role for the C4BP–PS complex: it binds to apoptotic cells through the phosphatidylserine-binding domain of PS. This association could prevent the deposition and activation of complement on the surface of the apoptotic cells, allowing the dying cells to be removed without provoking an inflammatory response.

Trouw et al. now show that C4BP-PS complexes bind to necrotic cells in the same manner. This binding limited complement deposition and decreased the capacity of necrotic cells to induce inflammatory cytokine production by macrophages. Once bound to necrotic cells via PS, C4BP could bind and trap cellular DNA as it leaked out of the dying cells. The authors suggest that this function of C4BP may be critical for host protection from autoimmunity, as free DNA can trigger inflammation and elicit the production of anti-DNA antibodies.
Concussive head injury in children and adolescents related to sports and other leisure physical activities
Authors: G J Browne, L T Lam
Journal: British Journal of Sports Medicine (2006)

Objective: To compare the characteristics of children and adolescents with concussive head injury (CHI) sustained during organised sports or other leisure physical activity. Methods: This was a case series study reviewing the medical records retrospectively over a four year period of children 6–16 years presenting to the emergency department with a CHI after participating in sport and/or recreation activity. Results: There were 592 cases of sport and recreation related concussion over the study period (2000–2003). Most of the patients (n = 424, 71.6%) were male, with half (n = 304, 51.4%) being older than 10 years of age. A total of 152 (25.7%) cases of CHI were related to playing sports. Most cases (71.2%) were mild concussion. The cause of injury was a fall (n = 322, 54.4%) or a collision. Nearly a quarter of the children (n = 143, 24.2%) were admitted to hospital, with imaging performed in 134 (22.7%). Most children were treated appropriately and no adverse events were reported. Conclusions: A severe CHI in a child is six times more likely to have resulted from organised sport than from other leisure physical activities. Outcomes for CHI in children is excellent, although their management places a considerable burden on emergency services. The need for activity restriction and the benefits of this in reducing long term cognitive effects of CHI are uncertain.
Joint Appraisal of the Radical Prostatectomy Specimen by the Urologist and the Uropathologist: Together, We Can Do It Better
Authors: Rodolfo Montironi, Liang Cheng, Antonio Lopez-Beltran, Roberta Mazzucchelli, Marina Scarpelli, Ziya Kirkali, Francesco Montorsi
Journal: European Urology (2009)
The effect of diastolic vibration on the relaxation of rat papillary muscle
Authors: P Janssen
Journal: Cardiovascular Research (1996)

Objective: It has been demonstrated that the application of an external mechanical vibration during the ventricular relaxation phase of the heart (diastolic vibration) decreases the time needed for myocardial relaxation. The objective of this study is to see whether this vibration-induced decrease in relaxation time is an intrinsic property of the contractile proteins. We hypothesize that this decrease in duration of the late systolic phase by diastolic vibration is likely to be due to a forced detachment of crossbridges from the actin filament. This would then result in a decrease in the relaxation time of myocardial tissue. Methods: A controlled vibration of variable amplitude and frequency was applied to isolated twitching rat papillary muscles. Vibration was initiated from directly after peak tension development and ended when tension had returned to baseline. Effects of applied vibration were expressed as changes in the time interval from 90% rising- to 50% falling-force level, which was termed the 'late systolic phase'. Results: The data showed that in general diastolic vibration decreased the duration of this late systolic phase. A vibration of 1.0% of Lmax at 50 Hz in the late systolic phase shortened this period by 27 ms (20–30%) on average. At increasing amplitude of vibration the increase in the rate of relaxation was even more pronounced. Shortening of this duration was slightly less at frequencies of vibration below 40 Hz than at higher frequencies of vibration. Changes in the resting muscle length did not result in significant changes in shortening of the studied relaxation period. Conclusion: The results show that relaxation is accelerated during application of an external vibration during the period of tension fall of an isolated cardiac muscle preparation. Therefore, we can conclude that the acceleration of relaxation due to vibration is primarily due to properties of the myocytes themselves rather than to the complex geometric structure of the heart. Tension in the relaxation phase was reduced during diastolic vibration, which suggests that the number of crossbridges bound to the actin filament was reduced by the length perturbation.
Treatment of primary Sjögren syndrome with rituximab: extended follow-up, safety and efficacy of retreatment: Figure 1
Authors: J M Meijer, J Pijpe, A Vissink, C G M Kallenberg, H Bootsma
Journal: Annals of the Rheumatic Diseases (2009)

We previously reported that B cell depletion therapy with rituximab (4 weekly infusions of 375 mg/m2, premedication: 25 mg prednisolone intravenously) in eight patients with early primary Sjogren syndrome (pSS) and seven patients with mucosa-associated lymphatic tissue (MALT)/pSS was effective in reducing subjective and objective symptoms after 12 weeks of follow-up.1 Three patients with early pSS developed serum sickness-like disease, of whom one patient declined to further participate. The MALT component of six of the seven patients with MALT/pSS was initially effectively treated with rituximab, one of these six patients was successfully retreated 9 months after the first treatment and all six patients are …
Physical activity levels during phase IV cardiac rehabilitation in a group of male myocardial infarction patients * Commentary
Authors: K Woolf-May, S Bird
Journal: British Journal of Sports Medicine (2005)

Objective: To determine physical activity levels during phase IV cardiac rehabilitation in 31 male myocardial infarction patients (median age 62, range 53–77 years). Methods: Patients recorded daily physical activity over 16 weeks in a diary. Diaries were analysed for total general physical activity (TGPA), leisure time physical activity (LTPA), and “active for life” exercise classes (AFL). Pre- and post-observation period (OP) subjects underwent a 10 m shuttle walking test (SWT) to determine changes in aerobic fitness. Rate of perceived exertion (RPE) determined exercise intensity. Estimated gross energy expenditure (EEE) was determined by a regression equation between RPE and Vo 2 (l min −1 ) during SWT. A total of 97% of subjects were on lipid lowering medication. Results: There were no correlations between Vo 2 (l min −1 ) and body mass, therefore kcal min −1 indicated activity intensity. There were no significant changes in physical activity patterns or in aerobic fitness. Estimated total LTPA (median 1376, range 128–3380 kcal week −1 ) was less than that recommended to improve aerobic fitness and/or slow progression of coronary artery disease. Sixteen subjects attended a median of 29 (range 1–46) AFL during LTPA; one way ANOVA showed these subjects worked at greater EEE (AFL, n = 16, 6.6 (standard deviation 1.4) v no-AFL, n = 15, 5.1 (1.8) EEE kcal min −1 , p = 0.017). Conclusion: Physical activity was stable, but patients’ EEE appeared insufficient to improve aerobic fitness or slow progression of coronary artery disease. It was suggested that the promotion of LTPA and the availability of AFL classes should be reconsidered.
Blood Pressure and Body Mass Index in Long-Term Survivors of Testicular Cancer
Authors: H. Sagstuen, N. Aass, S.D. Fosså, O. Dahl, O. Klepp, E.A. Wist, T. Wilsgaard, R.M. Bremnes
Journal: Journal of Clinical Oncology (2005)

Purpose To evaluate blood pressure and body mass index (BMI) in long-term survivors of testicular cancer (TC) treated with different modalities. Patients and Methods One thousand eight hundred fourteen patients treated for unilateral TC in Norway (1980 to 1994) were invited to participate in a follow-up study (1998 to 2002), including measurements of systolic blood pressure (SBP), diastolic blood pressure (DBP), and BMI. Of these patients, 1,289 patients (71%) participated in the study. The patients were categorized into four treatment groups: surgery (n = 242), radiotherapy (n = 547), and two chemotherapy groups, cumulative cisplatin dose ≤ 850 mg (n = 402) and cumulative cisplatin dose more than 850 mg (n = 98). A control group consisted of healthy males from the Tromsø Population Study (n = 2,847). Results At diagnosis, age-adjusted regression analyses showed no differences between the treatment groups for any variables. After a median follow-up time of 11.2 years, age-adjusted SBP and DBP were significantly higher for both chemotherapy groups compared with the surgery group. Chemotherapy-treated patients had increased odds for hypertension at follow-up compared with the surgery group, and the odds were highest for the cisplatin more than 850 mg group (odds ratio = 2.4; 95% CI, 1.4 to 4.0). The cisplatin more than 850 mg group had a significantly higher 10-year BMI increase and a higher prevalence of obesity at follow-up than the surgery group. Compared with healthy controls, chemotherapy-treated patients had, at follow-up, increased SBP, increased DBP, excessive BMI increase, and a higher prevalence of hypertension. Conclusion Five to 20 years after therapy, cured TC patients treated with cisplatin-based chemotherapy had significantly higher levels of blood pressure, a higher prevalence of hypertension, and an excessive weight gain compared with patients treated with other modalities and compared with healthy controls.