Miracle-dz/UniFAR-FTUs huggingface dataset:
Mitochondrial pathway of apoptosis is ancestral in metazoans

The mitochondrial pathway of apoptosis is the major mechanism of physiological cell death in vertebrates. In this pathway, proapoptotic members of the Bcl-2 family cause mitochondrial outer membrane permeabilization (MOMP), allowing the release of cytochrome c, which interacts with Apaf-1 to trigger caspase activation and apoptosis. Despite conservation of Bcl-2, Apaf-1, and caspases in invertebrate phyla, the existence of the mitochondrial pathway in any invertebrate is, at best, controversial. Here we show that apoptosis in a lophotrochozoan, planaria (phylum Platyhelminthes), is associated with MOMP and that cytochrome c triggers caspase activation in cytosolic extracts from these animals. Further, planarian Bcl-2 family proteins can induce and/or regulate cell death in yeast and can replace Bcl-2 proteins in mammalian cells to regulate MOMP. These results suggest that the mitochondrial pathway of apoptosis in animals predates the emergence of the vertebrates but was lost in some lineages (e.g., nematodes). In further support of this hypothesis, we surveyed the ability of cytochrome c to trigger caspase activation in cytosolic extracts from a variety of organisms and found this effect in cytosolic extracts from invertebrate deuterostomes (phylum Echinodermata).
Glucagon and a glucagon‐GLP‐1 dual‐agonist increases cardiac performance with different metabolic effects in insulin‐resistant hearts

BACKGROUND AND PURPOSE The prevalence of heart disease continues to rise, particularly in subjects with insulin resistance (IR), and improved therapies for these patients is an important challenge. In this study we evaluated cardiac function and energy metabolism in IR JCR:LA‐cp rat hearts before and after treatment with an inotropic compound (glucagon), a glucagon‐like peptide‐1 (GLP‐1) receptor agonist (ZP131) or a glucagon‐GLP‐1 dual‐agonist (ZP2495).
"If it bleeds it leads"? Attributes of TV health news stories that drive viewer attention.

OBJECTIVE Health advocates increasing y use the news media to educate the public. However, little is known about what motivates individuals to pay attention to health news. This study investigated which characteristics of TV health news stories attract viewer interest. METHODS The authors surveyed airport patrons, the audience of a public health symposium, and municipal jurors, asking which attributes of TV heath news stories encouraged interest and which attributes discouraged interest. The authors ranked mean responses and compared them using Spearman rank correlations, RESULTS The rankings assigned by the three samples were highly correlated. Respondents reported being most attracted to health stories about personally relevant topics. Interestingly, they also reported that sensational story elements such as "showing a bloody or injured person" and "being action packed" did not substantially influence their attention. CONCLUSIONS This study suggests that viewers, regardless of their level of health knowledge, value the same attributes in TV health news stories. Emphasizing the personal relevance of health topics appears to be a viable strategy to capture viewer interest. Conversely, the tendency of broadcast news to sensationalize stories may be distracting in the case of health news.
Glipizide Pharmacokinetics: Effects of Age, Diabetes, and Multiple Dosing

Aging and disease may contribute to alterations in drug pharmacokinetics. The purpose of this study was to determine the effects of aging, the presence of NIDDM, and multiple dosing on the pharmacokinetics of glipizide, an oral hypoglycemic drug. Ten healthy young men (under age 25), ten healthy older men (over age 65) and 15 older diabetic men ingested a single 5 mg tablet of glipizide after an overnight fast. Blood samples for measurement of serum glipizide were obtained over the next 24 hours. The study was repeated in the diabetics after 2 weeks of daily therapy. The mean values for Tmax (range 2.0–2.5 hours), Cmax (385–465 μg/l), and t1/2 (4.0–4.2 hours) were not significantly different in the three populations after single doses of glipizide. Several subjects in each population had slow absorption, with peak concentrations delayed for up to 12 hours. Only one elderly diabetic subject had evidence of drug accumulation at steady state. AUC, CI, Vgs and Varea were not significantly different in the three populations or at steady state, but there was a trend for AUC to be smaller and each of the other parameters to be increased in the older diabetics. The young subjects had a significantly higher fp (0.83%) than either of the two elderly groups (0.55–0.64%), but Clint did not differ between groups. Age, diabetes, and multiple dosing appear to have little effect on the pharmacokinetics of glipizide and should have little influence on the clinical response to this drug.
Papillary neoplasms of the breast: a review.

CONTEXT Interpretation of papillary lesions of the breast remains a challenging task because of the wide morphologic spectrum encountered in the benign, atypical, and malignant subtypes. Data on clinical significance and outcome of papillary lesions, with superimposed atypia or areas similar to ductal carcinoma in situ partially replacing the benign elements, are sparse. Furthermore, complete excision of even a fully developed papillary carcinoma confined to a dilated or cystic duct is associated with an excellent prognosis, whereas a complex papilloma extending into multiple branches of a duct may ultimately recur as a carcinoma because of incomplete excision of microscopic foci. This makes an outcome-based classification difficult. OBJECTIVE An arbitrary yet practical approach to classification is outlined, with discussion of methods to circumvent the various diagnostic difficulties. The limitations in precise diagnosis of papillary lesions in aspirates are addressed, and the implications of finding papillary lesions in core biopsies are discussed. Although the focus is on intraductal lesions, associated invasive carcinomas and invasive micropapillary carcinoma are also presented. DATA SOURCES The literature on papillary lesions and invasive micropapillary carcinoma is reviewed. CONCLUSIONS It would be prudent to completely excise any papillary lesion that has not been entirely removed by the initial core biopsy. The optimal management of localized papillary lesions is complete excision with a small rim of uninvolved breast tissue without any prior needle instrumentation if and when the papillary nature can be determined by imaging. Thus managed, most of these lesions behave indolently, and outcome is usually excellent.
Bank Solvency and Funding Cost: New Data and New Results

This paper presents new evidence on the empirical relationship between bank solvency and funding costs. Building on a newly constructed database drawing on supervisory data, we use a simultaneous equation approach in a panel set-up to estimate the contemporaneous interaction between bank solvency and bank funding costs. Our results show that this interaction can be more material than suggested by the empirical literature; it usually focuses on the unidirectional effects of solvency on funding costs which results in severe endogeneity and simultaneity biases. A 100 bps increase in regulatory capital ratios is associated with a decrease of our proxy for bank funding costs, CDS spreads, of about 110 bps. A 100 bps increase in this proxy of bank funding costs reduces regulatory capital buffers by 32 bps. We also find evidence of non-linear effects between solvency and funding costs. Understanding the impact of solvency on funding costs is particularly relevant for macroprudential stress testing (incl. second round effects, such as the interaction between solvency and funding costs) and for impact assessments of macroprudential policy measures. Our analysis suggests that stress test models that do not take into account the interaction between solvency and funding costs are likely to underestimate the impact of stress on financial stability.
Do Takeover Defense Indices Measure Takeover Deterrence?

Many researchers use the G-index or E-index to measure firms’ takeover defenses. Others argue that these indices are not related to firms’ takeover likelihoods. We find that, unlike their raw values, the instrumented versions of these indices are significantly and negatively related to acquisition likelihood. The difference between the raw and instrumented results indicates that the G-index and E-index include an endogenous component and highlights the importance of accounting for endogeneity in tests that use takeover indices to measure takeover deterrence. We provide data on new instruments that researchers can use to address these issues.Received April 13, 2016; editorial decision October 14, 2016 by Editor David Dennis.
Expression of FGFR3 Protein and Gene Amplification in Urinary Bladder Lesions in Relation to Schistosomiasis

BACKGROUND: Bladder cancer represents the fifth most common malignancy worldwide and a major cause of cancer-related morbidity and death. Incidence and mortality rates have remained relatively constant over the past four decades. Urothelial bladder cancers have identified multiple risk factors. AIM: We aimed at evaluating the expression of the FGFR3 protein and gene amplification in the urothelial cells of neoplastic and non-neoplastic urothelial lesions of the urinary bladder, and correlation with tumour grade, stage and associated bilharziasis. MATERIAL AND METHODS: One hundred and five different urinary bladder lesions were studied, including 15 cystitis cases (9 bilharzial and 6 non-bilharzial cystitides), 75 urothelial carcinoma cases (18 bilharzial associated and 57 non-bilharzial associated) and 15 squamous cell carcinoma associated with bilharziasis, beside 5 control cases. Data concerning age, sex, tumour grade, stage, and associated bilharziasis were obtained. Each case was studied for FGFR3 expression, and FISH technique was applied on forty malignant cases that show high protein expression. RESULTS: The highest incidence of cystitis was in the fourth decade while of bladder cancer was in the seventh decade. Tumour grade was correlated significantly with tumour stage. FGFR3 correlates significantly with tumour grade, stage and with a bilharzial infestation. FGFR3 gene amplification was reported mainly in low grade and NNMBIC tumours. CONCLUSIONS: FGFR3 overexpression in malignant cases was significantly higher than in chronic cystitis. FGFR3 gene amplification was reported mainly in low grade and NNMBIC tumours. FGFR3 may be further studied as a subject for target therapy of bladder cancer.
Beyond geopolitics: exploring the impact of the EU and Russia in the “contested neighborhood”

While the geopolitical rivalry between the European Union (EU) and Russia over their common neighborhood has increasingly attracted academic and public attention, relatively little is known of its actual influence on domestic institutions and policies. This special issue aims to address this deficit by investigating the joint impact of the EU and Russia on the domestic dynamics of sectoral reform in neighboring countries (NCs) – a key declared goal of the European Neighborhood Policy (ENP) and the Eastern Partnership (EaP) – in the areas of trade, natural resources, and migration and mobility. It examines the nature of the instruments deployed by the EU and Russia to change domestic reform processes and their impact on domestic actors in the post-Soviet space. This introductory article outlines the key research questions to which answers have been sought by experts in their respective fields and summarizes their key empirical findings in the context of broader conceptual debates. Overall, the contributions to this special issue find a strong disconnect between participation in the EU’s or Russia’s macro-frameworks for regional integration and domestic sectoral reforms. We show that despite the increasing external competition over the post-Soviet space, domestic actors remain the key agents to account for the pattern of change in the contested neighborhood.
Characterization and pathological significance of monoclonal DNA-binding antibodies from mice with experimental malaria infection

Malaria infection is accompanied by the production of a number of autoantibodies, including some that react with DNA. Epidemiological evidence implicates these in the nephritides that arise in human quartan malaria and in experimental malaria infections in mice. Through parallels with the involvement of DNA-reactive antibodies in the autoimmune syndrome systemic lupus erythematosus, a role for DNA-reactive antibodies in forming phlogistic immune deposits in the kidneys is implied. To more fully understand the relationship between antibodies of this specificity made in malaria and systemic lupus erythematosus, we prepared monoclonal DNA-reactive antibodies from BALB/c mice infected with Plasmodium berghei (clone RC) and compared their properties with those of other antibodies previously isolated from lupous MRL/Mp lpr/lpr and (NZB x NZW)F1 mice. Antibodies from malarial mice were all immunoglobulin M class and bound to single-stranded but not double-stranded DNA in an enzyme-linked immunosorbent assay. They also reacted with synthetic polyribonucleotides in the enzyme-linked immunosorbent assay and with parasitized erythrocytes and parasite pigment in kidney sections. None of the antibodies from lupous mice had identical specificities. The potential involvement of the DNA-reactive antibodies in malarial nephritis was demonstrated, by use of immunocytochemical methods, on the basis of their binding to existing immune deposits in kidney sections from malarial mice, a similar property having been previously demonstrated for antibodies from lupous mice. Furthermore, antibodies from malarial mice expressed public idiotypes, notably Id.V-88, which is a member of the Id.16/6 family, commonly found on DNA-reactive antibodies in lupus and other infectious and connective tissue diseases. This study indicates that DNA-reactive antibodies in malaria have immunochemical properties similar but not identical to those of such antibodies in systemic lupus erythematosus and that they have the potential to participate in the formation of immune deposits in nephritic malarial kidneys.
Analysis of islet beta cell functions and their correlations with liver dysfunction in patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD)

Abstract Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) primarily manifests in neonates or infants with hepatomegaly, liver dysfunction, and hypoglycemia. This study investigated the functions of islet beta cells and their correlations with liver dysfunction in NICCD patients. We retrospectively analyzed clinical data on liver function and islet beta cell functions for 36 patients diagnosed with NICCD and 50 subjects as the control group. The NICCD group had significantly higher total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), aspartate amino transferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP) and alpha-fetoprotein (AFP) levels and albumin/globulin ratio (A/G) (P < .05), and lower ALB and GLB levels than the control group (P < .05). The differences in fasting blood glucose (FBG), fasting insulin, C-peptide (C-P), the homeostasis model of assessment for the insulin resistance index (HOMA-IR), fasting beta cell function (FBCI), and the HOMA beta cell function index (HBCI) between the NICCD and control groups were not significant (P > .05). A linear correlation was found between FBG and fasting insulin (P < .001) and between FBG and C-P in the NICCD patients (P = .001). Fasting insulin (P = .023), HOMA-IR (P = .023), FBCI (P = .049), and HBCI (P = .048) were positively correlated with increases in the ALT level. There was no difference in islet beta cell functions between the NICCD and control groups. The liver dysfunction may be correlated with islet beta cell functions in NICCD patients.
Cytochrome P450 regulation by hepatocyte nuclear factor 4 in human hepatocytes: A study using adenovirus‐mediated antisense targeting

Hepatocyte nuclear factor 4 (HNF4) is a member of the nuclear receptor super‐family that has shown activating effects on particular cytochrome P450 (CYP) promoters from several species. However, its role in the regulation of human CYPs in the liver is still poorly understood, as no comprehensive studies in human‐relevant models have been performed. In the present study, we have investigated whether HNF4 plays a general role in the expression of 7 major CYP genes in primary cultured human hepatocytes. To this end, we developed an adenoviral vector for efficient expression of HNF4 antisense RNA. Transduction of human hepatocytes with the recombinant adenovirus resulted in a time‐dependent increase in the antisense transcript, followed by a concomitant decrease in apolipoprotein C III mRNA (a target gene of HNF4). Specificity was confirmed by showing that increasing levels of HNF4 antisense RNA resulted in the reduction of HNF4 protein, whereas retinoic X receptorα‐(RXRα), the closest homologous member of the nuclear receptor super‐family, was unaffected. Analysis of CYP gene expression in human hepatocytes transfected with HNF4 antisense RNA revealed singular behaviors: (1) CYP3A4, CYP3A5, and CYP2A6 showed an important, dose‐dependent down‐regulation on blockage of HNF4 translation; (2) a moderate inhibition of CYP2B6, CYP2C9, and CYP2D6 expression was observed (40%‐45% reduction); (3) the levels of CYP2E1 were not affected even in the absence of this transcription factor. In conclusion, using an original strategy (efficient antisense RNA expression vector), our study shows that HNF4 is a general regulator supporting the expression of major drug‐metabolizing CYPs in human hepatocytes.
Pro-apoptotic tumor necrosis factor-alpha transduction pathway in normal prostate, benign prostatic hyperplasia and prostatic carcinoma.

PURPOSE Tumor necrosis factor-alpha (TNF-alpha) exerts apoptosis throughout an intracellular transduction pathway that involves the protein kinases TRAF-2 (integration point of apoptotic and survival signals), signal regulating kinase (ASK-1) (pro-apoptotic protein), mitogen activated protein kinase-kinase 4 (MEK-4) (p38 activator and metastasis suppressor gene), Jun N-terminal kinase (JNK) (stress mitogen activated protein kinase) and the transcription factor activator protein-1 (AP-1). MATERIALS AND METHODS Biopsies from 20 normal, 35 hyperplastic and 27 carcinomatous human prostates were obtained for immunohistochemical and Western blot studies of the mentioned TNF-alpha/AP-1 transduction pathway members. RESULTS In normal prostates immunoreactions to TRAF-2, ASK-1, MEK-4 and JNK were positive, while no immunoreaction to AP-1 was detected. Although in benign prostatic hyperplasia the percent of immunostained specimens and intensity of immunoreactions to TRAF-2, ASK-1, MEK-4 and JNK decreased, the immunoreaction to AP-1 was positive in 27.3%. In most carcinomatous specimens the immune reaction was negative for all proteins of the TRAF-2/AP-1 pathway. CONCLUSIONS The TNF-alpha/AP-1 pathway might be a response to the excessive proliferative stimulus, although this response seems to be insufficient to counteract extracellular signals of cell proliferation. In prostate cancer this pathway is probably inactivated by other factors, such as p21 (at the ASK-1 level) or bcl-2 (at the JNK level).
Spatial language and converseness

Typical spatial language sentences consist of describing the location of an object (the located object) in relation to another object (the reference object) as in “The book is above the vase”. While it has been suggested that the properties of the located object (the book) are not translated into language because they are irrelevant when exchanging location information, it has been shown that the orientation of the located object affects the production and comprehension of spatial descriptions. In line with the claim that spatial language apprehension involves inferences about relations that hold between objects it has been suggested that during spatial language apprehension people use the orientation of the located object to evaluate whether the logical property of converseness (e.g., if “the book is above the vase” is true, then also “the vase is below the book” must be true) holds across the objects’ spatial relation. In three experiments using sentence acceptability rating tasks we tested this hypothesis and demonstrated that when converseness is violated people's acceptability ratings of a scene's description are reduced indicating that people do take into account geometric properties of the located object and use it to infer logical spatial relations.
Rare bleeding disorders

Summary. During the haemostatic response, the formation of a primary platelet plug limits bleeding and provides a surface for clotting factors to assemble and become activated. The initial platelet plug is stabilized by fibrin monomers, covalently cross‐linked by FXIII, forming a platelets‐fibrin thrombus. Defects in platelets as well as inherited deficiencies of coagulation factors including fibrinogen, FII, FV, FV + FVIII, FVII, FX, FXI and FXIII deficiencies, generally lead to lifelong bleeding disorders, whose severity of bleeding symptoms is heterogeneous in platelets abnormalities but generally inversely proportional to the degree of the factor deficiency in rare bleeding disorders (RBDs). The prevalence of platelet defects among the general population has not been established, whereas for RBDs it ranges from approximately 1 in 2 million to 1 in 500 000, being higher in countries where consanguineous marriages are diffused. As a consequence of the rarity of these deficiencies, the type and severity of bleeding symptoms, the underlying molecular defects, and the actual management of bleeding episodes are not well established. In this review the main features, diagnosis, available treatment options and treatment complications of the platelet disorders, caused by abnormalities in platelet receptors for adhesive proteins, platelet receptors for soluble agonists, platelet granules, signal transduction pathways, or procoagulant phospholipids will be discussed by Dr Cattaneo, whereas fibrinogen deficiency and FXIII deficiency will be described by Dr Inbal and Dr de Moerloose, respectively. Finally, the update of the Rare Bleeding Disorders Database will be presented by Dr Spreafico.
Prognostic significance of EZH2 expression in patients with digestive cancers: a meta-analysis.

BACKGROUND Enhancer of zeste 2 (EZH2), a key component of polycomb repressive complex 2 (PRC2), was of great importance in human cancer pathogenesis. Various studies examined the relationship between EZH2 overexpression with the clinical outcome in patients with digestive cancers, but yielded inconsistent results. METHODS Electronic databases updated to January 2015 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between EZH2 overexpression and survival of patients with digestive cancers. Survival data were aggregated and quantitatively analyzed. RESULTS We performed a meta-analysis of 10 studies (n = 1,461 patients) that evaluated the correlation between EZH2 overexpression and survival in patients with digestive cancers. Combined hazard ratios suggested that EZH2 overexpression was associated with poor prognosis of overall survival (HR = 1.54, 95% CI: 1.27-1.81) in patients with esophageal cancer. In the stratified analysis, no significantly risks were found among gastric cancer (HR = 0.66, 95% CI: 0.16-1.15) and colorectal cancer (HR = 0.91, 0.63-1.19), indicating EZH2 was not an indicator of poor prognosis in gastric cancer or colorectal cancer. CONCLUSIONS EZH2 overexpression indicates a poor prognosis for patients with esophageal cancer, but not among gastric cancer or colorectal cancer.