tbuckley/cabot-search huggingface dataset:
FGF21 and the late adaptive response to starvation in humans
Authors: Pouneh K. Fazeli, Mingyue Lun, Soo M. Kim, Miriam A. Bredella, Spenser Wright, Yang Zhang, Hang Lee, Ciprian Catana, Anne Klibanski, Parth Patwari, Matthew L. Steinhauser
Journal: Journal of Clinical Investigation (2015)

In mice, FGF21 is rapidly induced by fasting, mediates critical aspects of the adaptive starvation response, and displays a number of positive metabolic properties when administered pharmacologically. In humans, however, fasting does not consistently increase FGF21, suggesting a possible evolutionary divergence in FGF21 function. Moreover, many key aspects of FGF21 function in mice have been identified in the context of transgenic overexpression or administration of supraphysiologic doses, rather than in a physiologic setting. Here, we explored the dynamics and function of FGF21 in human volunteers during a 10-day fast. Unlike mice, which show an increase in circulating FGF21 after only 6 hours, human subjects did not have a notable surge in FGF21 until 7 to 10 days of fasting. Moreover, we determined that FGF21 induction was associated with decreased thermogenesis and adiponectin, an observation that directly contrasts with previous reports based on supraphysiologic dosing. Additionally, FGF21 levels increased after ketone induction, demonstrating that endogenous FGF21 does not drive starvation-mediated ketogenesis in humans. Instead, a longitudinal analysis of biologically relevant variables identified serum transaminases — markers of tissue breakdown — as predictors of FGF21. These data establish FGF21 as a fasting-induced hormone in humans and indicate that FGF21 contributes to the late stages of adaptive starvation, when it may regulate the utilization of fuel derived from tissue breakdown.
Painful knee but not hand osteoarthritis is an independent predictor of mortality over 23 years follow-up of a population-based cohort of middle-aged women
Authors: S Kluzek, M T Sanchez-Santos, K M Leyland, A Judge, T D Spector, D Hart, C Cooper, J Newton, N K Arden
Journal: Annals of the Rheumatic Diseases (2015)

To assess whether joint pain or radiographic osteoarthritis (ROA) of the knee and hand is associated with all-cause and disease-specific mortality in middle-aged women. <h3>Methods</h3> Four subgroups from the prospective community-based Chingford Cohort Study were identified based on presence/absence of pain and ROA at baseline: (Pain−/ROA−; Pain+/ROA−; Pain−/ROA+; Pain+/ROA+). Pain was defined as side-specific pain in the preceding month, while side-specific ROA was defined as Kellgren–Lawrence grade ≥2. All-cause, cardiovascular disease (CVD) and cancer-related mortality over the 23-year follow-up was based on information collected by the Office for National Statistics. Associations between subgroups and all-cause/cause-specific mortality were assessed using Cox regression, adjusting for age, body mass index, typical cardiovascular risk factors, occupation, past physical activity, existing CVD disease, glucose levels and medication use. <h3>Results</h3> 821 and 808 women were included for knee and hand analyses, respectively. Compared with the knee Pain−/ROA− group, the Pain+/ROA− group had an increased risk of CVD-specific mortality (HR 2.93 (95% CI 1.47 to 5.85)), while the knee Pain+/ROA+ group had an increased HR of 1.97 (95% CI 1.23 to 3.17) for all-cause and 3.57 (95% CI 1.53 to 8.34) for CVD-specific mortality. We found no association between hand OA and mortality. <h3>Conclusion</h3> We found a significantly increased risk of all-cause and CVD-specific mortality in women experiencing knee pain with or without ROA but not ROA alone. No relationship was found between hand OA and mortality risk. This suggests that knee pain, more than structural changes of OA is the main driver of excess mortality in patients with OA.
Dementia in Elderly Persons in a General Hospital
Authors: C G Lyketsos, J M Sheppard, P V Rabins
Journal: American Journal of Psychiatry (2000)

This study investigated the prevalence of dementia in a general hospital, reasons for which patients with dementia were admitted, and the relationship between dementia and length of stay, cost, and in-hospital mortality rate.The study focused on data from the hospital database on 21,251 patients aged 60 and older who were discharged in 1996 and 1997. Patients were grouped as with or without a discharge diagnosis of dementia by ICD-9-CM criteria. The groups were compared on sociodemographic characteristics, principal discharge diagnoses, lengths of stay, costs, and in-hospital mortality rates.The prevalence of dementia among discharged patients was 3.9% (N=823); it was dependent on age (age 60-64, prevalence=2.6%; age 85 and older, prevalence=8.9%). The primary discharge diagnoses of the groups were different. The mean length of stay was 10.4 days for patients with dementia and 6.5 days for patients without dementia. Per capita hospital costs were $4,000 higher for patients with dementia. Differences in lengths of stay and per capita costs were statistically significant after adjusting for age, race, and sex. Lengths of stay and hospital costs for patients with dementia were significantly higher for eight primary discharge diagnoses after adjusting for age, race, and sex.Dementia is present in a significant proportion of patients admitted to general inpatient units. Patients with dementia are admitted for different reasons than patients without dementia and appear to have longer stays, which are associated with higher costs. Efforts to identify dementia early during hospitalization could improve patient care and reduce costs.
The BTB-Kelch Protein KLEIP Controls Endothelial Migration and Sprouting Angiogenesis
Authors: Tanju G. Nacak, Abdullah Alajati, Kerstin Leptien, Christine Fulda, Holger Weber, Toru Miki, Frauke S. Czepluch, Johannes Waltenberger, Thomas Wieland, Hellmut G. Augustin, Jens Kroll
Journal: Circulation Research (2007)

Sprouting and invasive migration of endothelial cells are important steps of the angiogenic cascade. Vascular endothelial growth factor (VEGF) induces angiogenesis by activating intracellular signal transduction cascades, which regulate endothelial cell morphology and function. BTB-kelch proteins are intracellular proteins that control cellular architecture and cellular functions. The BTB-kelch protein KLEIP has been characterized as an actin-binding protein that interacts with the nucleotide exchange factor ECT2. We report that KLEIP is preferentially expressed in endothelial cells, suggesting that it may play a critical role in controlling the functions of migrating, proliferating, and invading endothelial cells during angiogenesis. KLEIP mRNA level in endothelial cells is strongly regulated by hypoxia which is controlled by hypoxia-inducible factor-1alpha. Functional analysis of KLEIP in endothelial cells revealed that it acts as an essential downstream regulator of VEGF- and basic fibroblast growth factor-induced migration and in-gel sprouting angiogenesis. Yet, it is not involved in controlling VEGF- or basic fibroblast growth factor-mediated proliferative responses. The depletion of KLEIP in endothelial cells blunted the VEGF-induced activation of the monomeric GTPase RhoA but did not alter the VEGF-stimulated activation of extracellular signal-regulated kinase 1/2. Moreover, VEGF induced a physical association of KLEIP with the guanine nucleotide-exchange factor ECT2, the depletion of which also blunted VEGF-induced sprouting. We conclude that the BTB-kelch protein KLEIP is a novel regulator of endothelial function during angiogenesis that controls the VEGF-induced activation of Rho GTPases.
Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients
Authors: Lisa M. Rice, Cristina M. Padilla, Sarah R. McLaughlin, Allison Mathes, Jessica Ziemek, Salma Goummih, Sashidhar Nakerakanti, Michael York, Giuseppina Farina, Michael L. Whitfield, Robert F. Spiera, Romy B. Christmann, Jessica K. Gordon, Janice Weinberg, Robert W. Simms, Robert Lafyatis
Journal: Journal of Clinical Investigation (2015)

TGF-β has potent profibrotic activity in vitro and has long been implicated in systemic sclerosis (SSc), as expression of TGF-β-regulated genes is increased in the skin and lungs of patients with SSc. Therefore, inhibition of TGF-β may benefit these patients.Patients with early, diffuse cutaneous SSc were enrolled in an open-label trial of fresolimumab, a high-affinity neutralizing antibody that targets all 3 TGF-β isoforms. Seven patients received two 1 mg/kg doses of fresolimumab, and eight patients received one 5 mg/kg dose of fresolimumab. Serial mid-forearm skin biopsies, performed before and after treatment, were analyzed for expression of the TGF-β-regulated biomarker genes thrombospondin-1 (THBS1) and cartilage oligomeric protein (COMP) and stained for myofibroblasts. Clinical skin disease was assessed using the modified Rodnan skin score (MRSS).In patient skin, THBS1 expression rapidly declined after fresolimumab treatment in both groups (P = 0.0313 at 7 weeks and P = 0.0156 at 3 weeks), and skin expression of COMP exhibited a strong downward trend in both groups. Clinical skin disease dramatically and rapidly decreased (P < 0.001 at all time points). Expression levels of other TGF-β-regulated genes, including SERPINE1 and CTGF, declined (P = 0.049 and P = 0.012, respectively), and a 2-gene, longitudinal pharmacodynamic biomarker of SSc skin disease decreased after fresolimumab treatment (P = 0.0067). Dermal myofibroblast infiltration also declined in patient skin after fresolimumab (P < 0.05). Baseline levels of THBS1 were predictive of reduced THBS1 expression and improved MRSS after fresolimumab treatment.The rapid inhibition of TGF-β-regulated gene expression in response to fresolimumab strongly implicates TGF-β in the pathogenesis of fibrosis in SSc. Parallel improvement in the MRSS indicates that fresolimumab rapidly reverses markers of skin fibrosis.Clinicaltrials.gov NCT01284322.
215 CYCLOOXYGENASE-2, TUMOR NECROSIS FACTOR-a, VASCULAR ENDOTHELIAL GROWTH FACTOR-A AND IL-6 GENES SNPS AND IL-6 SERUM LEVELS IN LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA
Authors: L. Giannitrapani, A. Giacalone, M. Soresi, M.E. Campagna, E. La Spada, M. Cervello, G. Montalto
Journal: Journal of Hepatology (2011)
FIFA Women's World Cup 2011: Pre-Competition Medical Assessment of female referees and assistant referees
Authors: Dagmar I Keller, Mario Bizzini, Nina Feddermann, Astrid Junge, Jiri Dvorak
Journal: British Journal of Sports Medicine (2012)

Background Precompetition screening was implemented for male referees during the 2010 Fédération Internationale de Football Association (FIFA) Word Cup. In contrast, female football referees have been neglected in this respect although they experience similar physical work loads compared to male referees. Methods The standardised football-specific Pre-Competition Medical Assessment (PCMA) was performed in 51 referees and assistant referees selected for the 2011 FIFA Women's World Cup. Results Family history for sudden cardiac death (SCD) was positive in four referees (7.8%), but cardiac examinations did not reveal any pathological findings. Training-unrelated ECG changes were identified in three referees (5.9%), all without correlates in echocardiography or clinical examination. Most common echocardiography findings (66.6%, n=34) were asymptomatic tricuspid and mitral regurgitations. Conclusions During the present screening, no elite female referee was identified being at risk for SCD, and no referee had to be excluded from participating in the 2011 FIFA Women's World Cup.
Hyperplasia and Carcinomas in Pten-Deficient Mice and Reduced PTEN Protein in Human Bladder Cancer Patients
Authors: Hiroshi Tsuruta, Hiroyuki Kishimoto, Takehiko Sasaki, Yasuo Horie, Miyuki Natsui, Yoshiko Shibata, Koichi Hamada, Nobuyuki Yajima, Koichi Kawahara, Masato Sasaki, Norihiko Tsuchiya, Katsuhiko Enomoto, Tak Wah Mak, Toru Nakano, Tomonori Habuchi, Akira Suzuki
Journal: Cancer Research (2006)

Abstract PTEN is a tumor suppressor gene mutated in many human cancers. We used the Cre-loxP system to generate an urothelium-specific null mutation of Pten in mice [FabpCrePtenflox/flox (FPtenflox/flox) mice]. Histologic examination revealed that all FPtenflox/flox mice exhibited urothelial hyperplasia in which component cells showed enlarged nuclei and increased cell size. With time, 10% of FPtenflox/flox mice spontaneously developed pedicellate papillary transitional cell carcinomas (TCC). This type of tumor also arose in FPtenflox/flox mice treated with the chemical carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine. FPtenflox/flox urothelial cells were hyperproliferative and showed increased activation of the survival signaling molecules Akt and extracellular signal-regulated kinase. In humans, 53% of primary bladder cancer patients exhibited decreased or absent expression of PTEN protein in either the cytoplasm or nucleus of tumor cells. In early bladder cancers, PTEN expression was repressed in 42% of superficial papillary TCC but in only 8% of cases of carcinoma in situ (CIS). In advanced bladder cancers, PTEN protein was significantly reduced (particularly in the nucleus) in 94% of cases, and this decrease in PTEN correlated with disease stage and grade. Thus, PTEN deficiency may contribute to bladder cancer both by initiating superficial papillary TCC and by promoting the progression of CIS to advanced invasive and metastatic forms. (Cancer Res 2006; 66(17): 8389-95)
Shock-Induced Depolarization of Refractory Myocardium Prevents Wave-Front Propagation in Defibrillation
Authors: Kevin F. Kwaku, Stephen M. Dillon
Journal: Circulation Research (1996)

The elimination of most, if not all, propagating wave fronts of electrical activation by a shock constitutes a minimum prerequisite for successful defibrillation. However, the factors responsible for the prevention of postshock propagating activity are unknown. We investigated the determinants of this effect of defibrillation shocks in 23 Langendorff-perfused rabbit hearts by optically mapping cardiac cellular electrical activity by means of laser scanning. The optical action potentials obtained by this method were continuously recorded from 100 ventricular epicardial sites before, during, and after shock delivery during fibrillation. Analysis of activation maps showed that postshock propagating activity arose from areas depolarized by the shock. In 273 shock episodes, 898 sites at the border of shock-depolarized areas (BSDAs) from which wave-front propagation could have arisen were identified. The incidence of postshock propagation from BSDA sites was inversely related to refractoriness, as indexed by coupling interval (CI) or the optical takeoff potential (V¯ m ). Specifically, there was a near-zero probability of postshock propagation if the shock caused depolarization at CIs &lt;50% of the fibrillation cycle length or from myocardium still depolarized to ≥60% of the amplitude of a paced action potential (APA). Furthermore, incidences of wave-front propagation following shocks were consistently lower than the propagation incidences of naturally occurring unshocked fibrillation wave fronts, at comparable CIs and V¯ m s. We conclude that the incidence of postshock wave-front propagation decreases with increasing refractoriness at the BSDA and that shock-induced depolarization of effectively refractory myocardium (ie, depolarized to ≥60% APA) is required to guarantee the cessation of continued wave-front propagation in defibrillation.
Properties of a purified pore-forming protein (perforin 1) isolated from H-2-restricted cytotoxic T cell granules.
Authors: J D Young, E R Podack, Z A Cohn
Journal: The Journal of Experimental Medicine (1986)

Histocompatibility-restricted cytotoxic T lymphocytes produce circular lesions on target cell membranes. The pore-forming protein (PFP or perforin 1) that forms these membrane lesions has been purified from lymphocytes. At 37 degrees C, in the presence of Ca2+, this protein polymerizes into a supramolecular tubular complex of Mr greater than 10(6) that partially resists dissociation by SDS and reducing agents. It incorporates spontaneously into planar lipid bilayers during polymerization to form nonselective ion channels, showing heterogeneous size distribution, the smallest conductance per unit being identified as 400 pS in 0.1 M NaCl. PFP/P1 that had been assembled in lipid vesicles before incorporation into planar bilayer show much larger single channel conductance, ranging from 1 to 6 nS in 0.1 M NaCl, suggesting that PFP/P1 may assume multiple functional sizes in proportion to its state of polymerization. The reconstituted channels are relatively voltage-insensitive, with most channels persisting in the open state for seconds to minutes. Nucleated cells are rapidly depolarized by this protein. The purified protein lyses a variety of tumor cells. Polymerization and functional channel activity are absolutely Ca2+-dependent. The activity of this protein may play a direct role in T lymphocyte-mediated cytolysis.
The structure of human CD23 and its interactions with IgE and CD21
Authors: Richard G. Hibbert, Peter Teriete, Gabrielle J. Grundy, Rebecca L. Beavil, Rajko Reljić, V. Michael Holers, Jonathan P. Hannan, Brian J. Sutton, Hannah J. Gould, James M. McDonnell
Journal: The Journal of Experimental Medicine (2005)

The low-affinity immunoglobulin E (IgE) receptor, CD23 (FcεRII), binds both IgE and CD21 and, through these interactions, regulates the synthesis of IgE, the antibody isotype that mediates the allergic response. We have determined the three-dimensional structure of the C-type lectin domain of CD23 in solution by nuclear magnetic resonance spectroscopy. An analysis of concentration-dependent chemical shift perturbations have allowed us to identify the residues engaged in self-association to the trimeric state, whereas ligand-induced changes have defined the binding sites for IgE and CD21. The results further reveal that CD23 can bind both ligands simultaneously. Despite the C-type lectin domain structure, none of the interactions require calcium. We also find that IgE and CD23 can interact to form high molecular mass multimeric complexes. The interactions that we have described provide a solution to the paradox that CD23 is involved in both up- and down-regulation of IgE and provide a structural basis for the development of inhibitors of allergic disease.
Effects of Montelukast on Surrogate Inflammatory Markers in Corticosteroid-treated Patients with Asthma
Authors: Graeme P. Currie, Daniel K. C. Lee, Kay Haggart, Caroline E. Bates, Brian J. Lipworth
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

We evaluated whether montelukast conferred additive effects in patients with asthma receiving fluticasone/salmeterol (FP/SM) combination and FP alone. Twenty-two patients with mild to moderate asthma completed a double-blind, placebo-controlled study. After a 2-week run-in using FP 250 μg/SM 50 μg 1 puff twice daily, patients entered a randomized crossover period to receive additional montelukast 10 mg daily or placebo for 3 weeks each. For the first 2 weeks, they received FP/SM 1 puff BID, and then they received FP 250 μg 1 puff BID for the 3rd week. The primary outcome was adenosine monophosphate challenge threshold and recovery time; secondary outcomes included surrogate inflammatory markers and lung function. Compared with FP/SM run-in, adding montelukast to FP/SM was better (p < 0.05) than placebo for inflammatory markers but not for lung function. For adenosine monophosphate threshold, recovery, exhaled nitric oxide, and blood eosinophils, there were 1.4 (95% confidence interval, 1.1–1.8) geometric mean fold, 10 minutes (3–17 minutes), 2.1 parts per billion (0.2–3.9 parts per billion), and 88 (34–172) × 106/L differences, respectively. The combination of FP plus montelukast was superior to FP/SM for inflammatory markers but was inferior for lung function. Thus, in patients taking FP/SM or FP, montelukast conferred complimentary effects on surrogate inflammatory markers, which were dissociated from lung function. Further studies are required to evaluate whether these effects of montelukast translate into clinical benefits.
Detection of the multidrug resistance marker P-glycoprotein by immunohistochemistry in malignant lung tumours.
Authors: T. W. Beer, D. C. Rowlands, J. Crocker
Journal: Thorax (1996)

The multidrug resistance marker P-glycoprotein (P-gp) was studied immunohistochemically in 78 primary malignant lung tumours. P-gp is a 170 kD transmembrane ATP dependent drug efflux pump which has been shown to be important in the resistance of some tumours to chemotherapy. Certain normal tissues express P-gp and tumours derived from these tissues are often insensitive to cytotoxic agents, showing raised P-gp levels innately or following chemotherapy or radiotherapy.Samples from 78 patients undergoing surgery for primary malignant lung tumours were snap frozen and stained immunohistochemically using the monoclonal antibody C219 which reacts with a P-gp epitope. None of the study group had received chemotherapy or radiotherapy before surgery was performed.Twenty seven of the 78 lung tumours (34.6%) showed immunohistochemically detectable levels of P-gp which varied with tumour type; 17 of 54 squamous cell carcinomas (31.5%), seven of 15 adenocarcinomas (46.7%), and neither of two small cell carcinomas showing positive staining. In six of seven cases normal respiratory epithelium present showed the presence of P-gp.P-gp is immunohistochemically detectable in frozen tissue from a proportion of malignant lung tumours before exposure to radiotherapy or drugs associated with multidrug resistance. It may have a role in tumour resistance to cytotoxic drugs, but further clinical studies will be required to evaluate any correlation between P-gp levels and response to treatment.
Improved Survival in Stage III Non-Small-Cell Lung Cancer: Seven-Year Follow-up of Cancer and Leukemia Group B (CALGB) 8433 Trial
Authors: R. O. Dillman, J. Herndon, S. L. Seagren, W. L. Eaton, M. R. Green
Journal: JNCI Journal of the National Cancer Institute (1996)

Background:For many years, high-dose radiation therapy was the standard treatment for patients with locally or regionally advanced non-small-cell lung cancer (NSCLC), despite a 5-year survival rate of only 3%–10% following such therapy. From May 1984 through May 1987, the Cancer and Leukemia Group B (CALGB) conducted a randomized trial that showed that induction chemotherapy before radiation therapy improved survival during the first 3 years of follow-up.