Miracle-dz/UniFAR-FTUs huggingface dataset:
Hepatic stellate cells: Partners in crime for liver metastases?

Hepatic stellate cells (HSCs) were recently postulated as a component of the prometastatic liver microenvironment, because they can transdifferentiate into highly proliferative and motile myofibroblasts that are implicated in the desmoplastic reaction and metastatic growth. This review focuses on bidirectional interactions between tumor cells and HSCs in the liver microenvironment and discusses mechanisms whereby tumor‐derived factors activate HSCs, and in turn, activated HSCs promote metastatic growth. Bidirectional interactions between tumors and HSCs may function as an “amplification loop” to further enhance metastatic growth in the liver. The activation of HSCs is a complex process regulated by multiple factors such as transforming growth factor‐β and platelet‐derived growth factor signaling pathways, which may present as therapeutic targets in the prevention and treatment of liver metastases. Conclusion: HSCs may present a new therapeutic target in the treatment of liver metastases. Targeting HSCs and/or myofibroblasts with transforming growth factor‐β or platelet‐derived growth factor antagonists in coordination with chemotherapy, radiotherapy, or surgery may prove to be effective at reducing liver metastases and increasing the survival benefit of patients by targeting both tumor cells and the tumor microenvironment. (HEPATOLOGY 2011;)
Discussing the predictive, prognostic, and therapeutic value of germline DNA-repair gene mutations in metastatic prostate cancer patients

ABSTRACT Recent trends in cancer therapy have begun emphasizing the use of precision medicine, especially genetic tools, in the evaluation of malignancies and decision-making. Prostate cancer is a malignancy where the benefits and utility of screening and early treatment are still heavily controversial. A recent paper in the New England Journal of Medicine found that patients with metastatic prostate cancer presented germline mutations in DNA-repair genes at a significantly higher incidence than those with localized prostate cancer. These findings indicate the need for further research in this field as genetic differences between metastatic and localized prostate cancer could have great clinical value.
Thermal unfolding and aggregation of actin

Actin is one of the most abundant proteins in nature. It is found in all eukaryotes and plays a fundamental role in many diverse and dynamic cellular processes. Also, actin is one of the most ubiquitous proteins because actin‐like proteins have recently been identified in bacteria. Actin filament (F‐actin) is a highly dynamic structure that can exist in different conformational states, and transitions between these states may be important in cytoskeletal dynamics and cell motility. These transitions can be modulated by various factors causing the stabilization or destabilization of actin filaments. In this review, we look at actin stabilization and destabilization as expressed by changes in the thermal stability of actin; specifically, we summarize and analyze the existing data on the thermal unfolding of actin as measured by differential scanning calorimetry. We also analyze in vitro data on the heat‐induced aggregation of actin, the process that normally accompanies actin thermal denaturation. In this respect, we focus on the effects of small heat shock proteins, which can prevent the aggregation of thermally denatured actin with no effect on actin thermal unfolding. As a result, we have proposed a mechanism describing the thermal denaturation and aggregation of F‐actin. This mechanism explains some of the special features of the thermal unfolding of actin filaments, including the effects of their stabilization and destabilization; it can also explain how small heat shock proteins protect the actin cytoskeleton from damage caused by the accumulation of large insoluble aggregates under heat shock conditions.
A Quantitative Review of Cognitive Functioning in Homeless Adults

Abstract Homeless people experience elevated rates of risk factors for cognitive impairment. We reviewed available peer-reviewed studies reporting data from objective measures of cognition in samples identified as homeless. Pooled sample-weighted estimates of global cognitive screening measures, full-scale intelligence quotient (IQ), and premorbid IQ were calculated, in addition to pooled sample characteristics, to understand the representativeness of available studies. A total of 24 unique studies were identified, with 2969 subjects. The pooled estimate for the frequency of cognitive impairment was 25%, and the mean full-scale IQ score was 85, 1 standard deviation below the mean of the normal population. Cognitive impairment was found to be common among homeless adults and may be a transdiagnostic problem that impedes rehabilitative efforts in this population. Comparatively little data are available about cognition in homeless women and unsheltered persons.
Obesity is an independent risk factor for clinical decompensation in patients with cirrhosis

Obesity is associated with an aggressive course in chronic viral hepatitis; however, its impact in the development of clinical decompensation (CD) in patients with established cirrhosis is uncertain. We evaluated the role of obesity, in relationship to other recognized predictors, in the development of CD in patients with compensated cirrhosis. The study population, a subset of patients included in a randomized trial of beta‐blockers in the prevention of varices in whom data on body mass index (BMI) was available, consisted of 161 patients with compensated cirrhosis. Laboratory tests and portal pressure (assessed by the hepatic venous pressure gradient or HVPG) were assessed on inclusion. Patients were followed until CD (ascites, hepatic encephalopathy, or variceal hemorrhage), or until September 2002. Altogether, 29% had a normal BMI, 40% were overweight, and 30% were obese. In a median follow‐up of 59 months, CD occurred in 48/161 (30%) patients with an increasingly higher rate according to BMI group (15% in those with normal BMI; 31% in overweight; 43% in obese patients, P = 0.011). The actuarial probability of developing CD was significantly higher in the abnormal BMI groups (P = 0.022). In a multivariate model that included parameters previously identified as being predictive of CD (HVPG, albumin, Mayo endstage liver disease score), etiology, and treatment group, BMI (hazard ration 1.06; 95% confidence interval 1.01‐1.12), P = 0.02] was an independent predictor of decompensation, together with HVPG and albumin. Conclusion: Obesity has a deleterious effect on the natural history of compensated cirrhosis of all etiologies, independent of portal pressure and liver function. Weight reduction may be a valuable therapeutic measure in this patient population. (HEPATOLOGY 2011;)
Prognosis and Psychosocial Outcomes of Attempted Suicide by Early Adolescence: A 6-Year Follow-Up of School Students Into Early Adulthood

Abstract Adulthood psychiatric and psychosocial outcomes of early adolescence suicidal acts were studied. A representative sample of school adolescents (T1, mean age, 13.7 years; n = 2464; 50.8% female; 88.3% participation) was followed up a year later with the same questionnaire (T2). High scorers of depression were matched with low or moderate scorers and interviewed using the Kiddie–Schedule for Affective Disorders and Schizophrenia–Present and Lifetime version (mean age, 14.9 years; n = 345; 94% participation). They were reassessed after 5 years (T3, mean age, 20.0 years; n = 242; 73% participation). Those who attempted suicide before the age of 14 years and repeated suicidal acts between ages 14 and 15 years had worser prognostic profiles than incident cases between ages 14 and 15 years. Male attempters had better psychiatric prognosis than female attempters. Attempters were more likely to have contacted child protection services but not mental health services. Clinicians need to be aware of long-term pervasive outcomes of adolescent suicidality.
The Drosophila homeodomain transcription factor, Vnd, associates with a variety of co‐factors, is extensively phosphorylated and forms multiple complexes in embryos

Vnd is a dual transcriptional regulator that is essential for Drosophila dorsal–ventral patterning. Yet, our understanding of the biochemical basis for its regulatory activity is limited. Consistent with Vnd’s ability to repress target expression in embryos, endogenously expressed Vnd physically associates with the co‐repressor, Groucho, in Drosophila Kc167 cells. Vnd exists as a single complex in Kc167 cells, in contrast with embryonic Vnd, which forms multiple high‐molecular‐weight complexes. Unlike its vertebrate homolog, Nkx2.2, full‐length Vnd can bind its target in electrophoretic mobility shift assay, suggesting that co‐factor availability may influence Vnd’s weak regulatory activity in transient transfections. We identify the high mobility group 1‐type protein, D1, and the novel helix–loop–helix protein, Olig, as novel Vnd‐interacting proteins using co‐immunoprecipitation assays. Furthermore, we demonstrate that both D1 and Olig are co‐expressed with Vnd during Drosophila embryogenesis, consistent with a biological basis for this interaction. We also suggest that the phosphorylation state of Vnd influences its ability to interact with co‐factors, because Vnd is extensively phosphorylated in embryos and can be phosphorylated by activated mitogen‐activated protein kinase in vitro. These results highlight the complexities of Vnd‐mediated regulation.
Avaliação da cavidade nasal e nasofaringe através da rinometria acústica antes e após adenoidectomia

INTRODUCTION: The authors evaluate the minimum cross-sectional area (MCA) and nasal volume (NV) of the nasal cavity and nasopharynx before and after adenoidectomy. STUDY DESIGN: Clinical prospective. AIM: Evaluate changes of nasal cavity and nasopharynx before and after adenoidectomy using objective technique for assessment the nasal patency, acoustic rhinometry. MATERIAL AND METHOD: Twenty-three children (52 nasal cavities) with surgical indication for adenoidectomy were evaluated with acoustic rhinometry before and 15 days after surgery. RESULTS: The MCA of nasal cavity changed, before decongestion, from 0,73 cm2 preoperatively into 0,79 cm2 postoperatively and after decongestion, from 0,87 cm2 preoperatively into 0,93 cm2 postoperatively. The volume of nasal cavity changed, before decongestion, from 6,18 cm3 preoperatively into 6,47 cm3 postoperatively and after decongestion, from 8,31 cm3 preoperatively into 8,65 cm3 postoperatively. The MCA of nasopharynx changed, before decongestion, from 2,43 cm2 preoperatively into 2,69 cm2 postoperatively and after decongestion, from 2,76 cm2 preoperatively into 3,79 cm2 postoperatively. The volume of nasopharynx changed, before decongestion, from 5,57 cm3 preoperatively into 6,14 cm3 postoperatively and after decongestion, from 6,51 cm3 preoperatively into 8,78 cm3 postoperatively. CONCLUSION: The increase of MCA and volume of the nasopharynx agree with the improvement of the symptoms that patients or parents reported after adenoidectomy.
RecQ4 promotes the conversion of the pre-initiation complex at a site-specific origin for DNA unwinding in Xenopus egg extracts

Eukaryotic DNA replication is initiated through stepwise assembly of evolutionarily conserved replication proteins onto replication origins, but how the origin DNA is unwound during the assembly process remains elusive. Here, we established a site-specific origin on a plasmid DNA, using in vitro replication systems derived from Xenopus egg extracts. We found that the pre-replicative complex (pre-RC) was preferentially assembled in the vicinity of GAL4 DNA-binding sites of the plasmid, depending on the binding of Cdc6 fused with a GAL4 DNA-binding domain in Cdc6-depleted extracts. Subsequent addition of nucleoplasmic S-phase extracts to the GAL4-dependent pre-RC promoted initiation of DNA replication from the origin, and components of the pre-initiation complex (pre-IC) and the replisome were recruited to the origin concomitant with origin unwinding. In this replication system, RecQ4 is dispensable for both recruitment of Cdc45 onto the origin and stable binding of Cdc45 and GINS to the pre-RC assembled plasmid. However, both origin binding of DNA polymerase α and unwinding of DNA were diminished upon depletion of RecQ4 from the extracts. These results suggest that RecQ4 plays an important role in the conversion of pre-ICs into active replisomes requiring the unwinding of origin DNA in vertebrates.
Ligand binding promotes prion protein aggregation – role of the octapeptide repeats

Aggregation of the normal cellular prion protein, PrP, is important in the pathogenesis of prion disease. PrP binds glycosaminoglycan (GAG) and divalent cations, such as Cu2+ and Zn2+. Here, we report our findings that GAG and Cu2+ promote the aggregation of recombinant human PrP (rPrP). The normal cellular prion protein has five octapeptide repeats. In the presence of either GAG or Cu2+, mutant rPrPs with eight or ten octapeptide repeats are more aggregation prone, exhibit faster kinetics and form larger aggregates than wild‐type PrP. When the GAG‐binding motif, KKRPK, is deleted the effect of GAG but not that of Cu2+ is abolished. By contrast, when the Cu2+‐binding motif, the octapeptide‐repeat region, is deleted, neither GAG nor Cu2+ is able to promote aggregation. Therefore, the octapeptide‐repeat region is critical in the aggregation of rPrP, irrespective of the promoting ligand. Furthermore, aggregation of rPrP in the presence of GAG is blocked with anti‐PrP mAbs, whereas none of the tested anti‐PrP mAbs block Cu2+‐promoted aggregation. However, a mAb that is specific for an epitope at the N‐terminus enhances aggregation in the presence of either GAG or Cu2+. Therefore, although binding of either GAG or Cu2+ promotes the aggregation of rPrP, their aggregation processes are different, suggesting multiple pathways of rPrP aggregation.
Decreased Regional Homogeneity in Patients With Acute Mild Traumatic Brain Injury: A Resting-State fMRI Study

Abstract Mild traumatic brain injury (mTBI) is characterized by structural disconnection and large-scale neural network dysfunction in the resting state. However, little is known concerning the intrinsic changes in local spontaneous brain activity in patients with mTBI. The aim of the current study was to assess regional synchronization in acute mTBI patients. Fifteen acute mTBI patients and 15 sex-, age-, and education-matched healthy controls (HCs) were studied. We used the regional homogeneity (ReHo) method to map local connectivity across the whole brain and performed a two-sample t-test between the two groups. Compared with HCs, patients with acute mTBI showed significantly decreased ReHo in the left insula, left precentral/postcentral gyrus, and left supramarginal gyrus (p < 0.05, AlphaSim corrected). The ReHo index of the left insula showed a positive correlation with the Mini-Mental State Examination (MMSE) scores across all acute mTBI patients (p < 0.05, uncorrected). The ReHo method may provide an objective biomarker for evaluating the functional abnormity of mTBI in the acute setting.
Screening for Body Dysmorphic Disorder in Dermatological Outpatients

Background: Although body dysmorphic disorder (BDD) is frequently found in dermatological settings, it often remains unrecognised. The aims of the current study were to validate the Dysmorphic Concern Questionnaire (DCQ) as a screening instrument; and to estimate the frequency of dysmorphic concerns in a dermatological sample of female outpatients. Patients and Methods: Item characteristics and factor structure of the DCQ were analysed on the basis of data from an unselected sample of 156 dermatological outpatients. In addition, to investigate discriminative validity of the DCQ, 65 patients, including 22 patients with BDD, 21 patients with disfiguring dermatological conditions and 21 patients with non-disfiguring, mild dermatological conditions participated in the study. Diagnoses were based on the Body Dysmorphic Disorder Diagnostic Module. Additionally, the Yale-Brown Obsessive Compulsive Scale modified for BDD was applied, and the patients completed a depression questionnaire. Results: The factor structure and internal consistency of the DCQ were satisfactory. Significant correlations with depressive mood and obsessive-compulsive symptoms confirm its convergent validity. The DCQ revealed significant differences between BDD patients, patients with disfiguring disorders, and patients with non-disfiguring disorders, thus demonstrating a high discriminative validity. A cut-off value of ≧14 provided the best balance of sensitivity and specificity and resulted in correct classification of 84.6% of the patients. Of the unselected outpatients sample 9% achieved positive test results that indicate clinically significant dysmorphic concerns. Conclusion: The results confirm the validity of the DCQ as a sensitive and specific screening instrument that can be recommended as a routine assessment instrument in clinical practice.
Murine serum nucleases – contrasting effects of plasmin and heparin on the activities of DNase1 and DNase1‐like 3 (DNase1l3)

DNase1 is regarded as the major serum nuclease; however, a systematic investigation into the presence of additional serum nuclease activities is lacking. We have demonstrated directly that serum contains DNase1‐like 3 (DNase1l3) in addition to DNase1 by an improved denaturing SDS‐PAGE zymography method and anti‐murine DNase1l3 immunoblotting. Using DNA degradation assays, we compared the activities of recombinant murine DNase1 and DNase1l3 (rmDNase1, rmDNase1l3) with the serum of wild‐type and DNase1 knockout mice. Serum and rmDNase1 degrade chromatin effectively only in cooperation with serine proteases, such as plasmin or thrombin, which remove DNA‐bound proteins. This can be mimicked by the addition of heparin, which displaces histones from chromatin. In contrast, serum and rmDNase1l3 degrade chromatin without proteolytic help and are directly inhibited by heparin and proteolysis by plasmin. In previous studies, serum DNase1l3 escaped detection because of its sensitivity to proteolysis by plasmin after activation of the plasminogen system in the DNA degradation assays. In contrast, DNase1 is resistant to plasmin, probably as a result of its di‐N‐glycosylation, which is lacking in DNase1l3. Our data demonstrate that secreted rmDNase1 and murine parotid DNase1 are mixtures of three different di‐N‐glycosylated molecules containing two high‐mannose, two complex N‐glycans or one high‐mannose and one complex N‐glycan moiety. In summary, serum contains two nucleases, DNase1 and DNase1l3, which may substitute or cooperate with each other during DNA degradation, providing effective clearance after exposure or release from dying cells.
Biomarkers of liver fibrosis: What lies beneath the receiver operating characteristic curve?

Noninvasive biomarkers of liver fibrosis represent an intense area of research with the goals of improving patient care, disease stratification, and aiding the development of future antifibrotic therapies. Despite the rapid progress in recent years, there remain questions about how diagnostic studies are designed, statistical methods to account for spectrum bias, clinically relevant thresholds of fibrosis that should be delineated, how diagnostics can be improved, and strengthening the reference test to judge emerging biomarkers. This review discusses the current methods to address these issues and where further progress is needed. (HEPATOLOGY 2011;)
Mitogen‐activated protein kinase phosphatase‐1 modulated JNK activation is critical for apoptosis induced by inhibitor of epidermal growth factor receptor‐tyrosine kinase

Alterations resulting in enhanced epidermal growth factor receptor (EGFR) expression or function have been documented in a variety of tumors. Therefore, EGFR‐tyrosine kinase is a promising therapeutic target. Although in vitro and in vivo studies have shown the anti‐tumor activity of EGFR‐tyrosine kinase inhibitors against various tumor types, little is known about the mechanism by which such inhibitors effect their anti‐tumor action. AG1478 is known to selectively inhibit EGFR‐tyrosine kinase. In this study, we showed that AG1478 caused apoptosis and apoptosis‐related reactions such as the activation of caspase 3 in human non‐small cell lung cancer cell line PC‐9. To investigate the signaling route by which AG1478 induced apoptosis, we examined the activation of c‐Jun N‐terminal kinase (JNK) and mitogen‐activated protein kinase p38 in AG1478‐treated PC‐9 cells. JNK, but not p38, was significantly activated by AG1478 as determined by both immunoblot analysis for levels of phosphorylated JNK and an in vitro activity assay. Various types of stimuli activated JNK through phosphorylation by the dual‐specificity JNK kinases, but the dual‐specificity JNK kinases MKK4 and MKK7 were not activated by AG1478 treatment. However, JNK phosphatase, i.e. mitogen‐activated protein kinase phosphatase‐1 (MKP‐1), was constitutively expressed in the PC‐9 cells, and its expression level was reduced by AG1478. The inhibition of JNK activation by ectopic expression of MKP‐1 or a dominant‐negative form of JNK strongly suppressed AG1478‐induced apoptosis. These results reveal that JNK, which is activated through the decrease in the MKP‐1 level, is critical for EGFR‐tyrosine kinase inhibitor‐induced apoptosis.
Novel feedback inhibition of surface antigen synthesis by mammalian target of rapamycin (mTOR) signal and its implication for hepatitis B virus tumorigenesis and therapy

Ground glass hepatocytes (GGHs) harboring hepatitis B virus (HBV) pre‐S mutants have been recognized as precursor lesions of hepatocellular carcinoma (HCC). Previously, we observed the activation of mammalian target of rapamycin (mTOR) in GGHs and HCCs, together with a decreased expression of HBV surface antigen (HBsAg) in HCC tissues. It is, therefore, hypothesized that the activation of mTOR during HBV tumorigenesis may potentially down‐regulate HBsAg expression. In this study, we verified an inverse relationship between the expression of HBsAg and phosphorylated mTOR (p‐mTOR) in 13 of 20 paired nontumorous liver and HCC tissues. In vitro, wild‐type or mutant pre‐S proteins could activate mTOR in the HuH‐7 cell line. Interestingly, the up‐regulated mTOR, in turn, suppressed HBsAg synthesis at the transcriptional level via the transcription factor, Yin Yang 1 (YY1), which bound to nucleotide 2812‐2816 of the pre‐S1 promoter. This inhibitory effect by the mTOR signal could be abolished by the knockdown of histone deacetylase 1 (HDAC1). Furthermore, YY1 was physically associated with HDAC1 in a manner dependent on mTOR activation. Collectively, pre‐S protein‐induced mTOR activation may recruit the YY1‐HDAC1 complex to feedback suppress transcription from the pre‐S1 promoter. Conclusion: The activation of mTOR signal in GGHs may feedback suppress HBsAg synthesis during HBV tumorigenesis and explain the observed decrease or absence of HBsAg in HCC tissues. Therapy using mTOR inhibitors for HCCs may potentially activate HBV replication in patients with chronic HBV infection. (HEPATOLOGY 2011 )