Miracle-dz/UniFAR-FTUs huggingface dataset:
Tumor Necrosis Factor (TNF)-induced Germinal Center Kinase-related (GCKR) and Stress-activated Protein Kinase (SAPK) Activation Depends upon the E2/E3 Complex Ubc13-Uev1A/TNF Receptor-associated Factor 2 (TRAF2)*

Tumor necrosis factor (TNF)-induced activation of apoptosis signal-regulating kinase 1 (ASK1) and germinal center kinases (GCKs) and the subsequent activation of stress-activated protein kinases (SAPKs and c-Jun NH2-terminal kinases) requires TNF receptor-associated factor 2 (TRAF2). Although the TRAF2 TRAF domain binds ASK1, GCK, and the highly related kinase GCKR, the RING finger domain is needed for their activation. Here, we report that TNF activates GCKR and the SAPK pathway in a manner that depends upon TRAF2 and Ubc13, a member along with Uev1A of a dimeric ubiquitin-conjugating enzyme complex. Interference with Ubc13 function or expression inhibits both TNF- and TRAF2-mediated GCKR and SAPK activation, but has a minimal effect on ASK1 activation. TNF signaling leads to TRAF2 polyubiquitination and oligomerization and to the oligomerization, ubiquitination, and activation of GCKR, all of which are sensitive to the disruption of Ubc13 function. These results indicate that the assembly of a TRAF2 lysine 63-linked polyubiquitin chain by Ubc13/Uev1A is required for TNF-mediated GCKR and SAPK activation, but may not be required for ASK1 activation.
Spinal Muscular Atrophy: From Defective Chaperoning of snRNP Assembly to Neuromuscular Dysfunction

Spinal Muscular Atrophy (SMA) is a neuromuscular disorder that results from decreased levels of the survival motor neuron (SMN) protein. SMN is part of a multiprotein complex that also includes Gemins 2–8 and Unrip. The SMN-Gemins complex cooperates with the protein arginine methyltransferase 5 (PRMT5) complex, whose constituents include WD45, PRMT5 and pICln. Both complexes function as molecular chaperones, interacting with and assisting in the assembly of an Sm protein core onto small nuclear RNAs (snRNAs) to generate small nuclear ribonucleoproteins (snRNPs), which are the operating components of the spliceosome. Molecular and structural studies have refined our knowledge of the key events taking place within the crowded environment of cells and the numerous precautions undertaken to ensure the faithful assembly of snRNPs. Nonetheless, it remains unclear whether a loss of chaperoning in snRNP assembly, considered as a “housekeeping” activity, is responsible for the selective neuromuscular phenotype in SMA. This review thus shines light on in vivo studies that point toward disturbances in snRNP assembly and the consequential transcriptome abnormalities as the primary drivers of the progressive neuromuscular degeneration underpinning the disease. Disruption of U1 snRNP or snRNP assembly factors other than SMN induces phenotypes that mirror aspects of SMN deficiency, and splicing defects, described in numerous SMA models, can lead to a DNA damage and stress response that compromises the survival of the motor system. Restoring the correct chaperoning of snRNP assembly is therefore predicted to enhance the benefit of SMA therapeutic modalities based on augmenting SMN expression.
Direct validation of NGcGM3 ganglioside as a new target for cancer immunotherapy

Objective: The target concept means not only an aberrant expression of a particular molecule in tumour tissues but also evidence of a clear therapeutic advantage, as a consequence of immune-intervention, in an antigen-positive relevant tumour model. Since we reported the presence of NGcGM3 ganglioside in human breast tumours years ago and though Phase I clinical trials of a ganglioside containing vaccine have been conducted, a definitive direct validation of this peculiar molecule as target for cancer immunotherapy has remained unperformed. Methods: Two animal models were used: leghorn chickens and C57BL/6 mice. The murine 3LL-D122 cell line, the derived subcutaneous tumours and metastatic lung lesions were processed for gangliosides identification. Active immunotherapy experiments in the 3LL-D122 spontaneous lung metastasis model were performed with NGcGM3/VSSP vaccine prepared by conjugation of NGcGM3 with the outer membrane proteins of Neisseria meningitides. Results: The 3LL-D122 Lewis lung carcinoma results were consistent with an increased expression of NGcGM3 from primary tumours to metastatic lesions, as observed in human breast cancer samples. Both vaccines, prepared with synthetic or natural-source-derived ganglioside, showed similar anti-tumour and immunogenicity profiles. Finally, a clear involvement of NK1.1+ cells and CD8+ T cells in the anti-metastatic effect elicited by the vaccine was manifested. Conclusions: While ‘proof of concept’ Phase II and III clinical trials with the NGcGM3/VSSP vaccine in cancer patients are currently ongoing these results reasonably sustain the validation of this peculiar ganglioside as a novel target for cancer immunotherapy.
Cytology of metastatic appendiceal goblet cell carcinoid in pleural effusion fluid: A case report

Goblet cell appendiceal carcinoid (GCAC) is a rare neoplasm. We described the case of a 72‐year‐old man who presented with symptoms related to ascites. A computed tomography (CT) scan showed a mass involving the base of the appendix, ascites and concomitant pleural effusion. Thoracentesis of the pleural fluid showed metastatic GCAC. The appendiceal mass was biopsied and diagnosed as a GCAC. We describe the cytologic features of the metastatic GCAC to pleural fluid. To our knowledge this is the first such described case. Diagn. Cytopathol. 2008. © 2008 Wiley‐Liss, Inc.
Multiplane transoesophageal echocardiography and morphology of regurgitant mitral valves in surgical repair.

BACKGROUND An essential step in the surgical management of patients with mitral regurgitation, is a thorough understanding of the pathophysiological mechanism. This information can be obtained by multiplane transoesophageal echocardiography which displays all the components of the incompetent valve. METHODS AND RESULTS Forty-nine patients were scanned intra-operatively by multiplane transoesophageal echocardiography, and findings compared with those at visual inspection during surgery. The pre-operative diagnosis was prolapse of the anterior mitral leaflet in nine patients (sensitivity 100%, specificity 95%), prolapse of the posterior leaflet in 17 patients (sensitivity 100%, specificity 94%) and prolapse of both leaflets in eight patients (sensitivity 87%, specificity 100%). In 11 patients annular dilatation with no abnormalities in mitral leaflet closure or motion was diagnosed (sensitivity 73%, specificity 100%). Two patients had a false-positive diagnosis of prolapse of the anterior leaflet, two others on the posterior leaflet. A prolapse of both leaflets was overlooked in one patient. Multiplane transoesophageal echocardiography scanned the mitral valve, disclosing the extent of pathology along the closure line of leaflets in 88% of patients with mitral valve prolapse. The antero-posterior diameter of the mitral annulus was measured: a diameter over 35 mm indicated annular dilatation. Using this criterion, sensitivity was 89% and specificity 100%. CONCLUSIONS Multiplane transoesophageal echocardiography enabled components of the mitral valve to be examined systematically, and provided important information on the pathophysiological mechanism of mitral regurgitation before surgical repair. The method also allowed the surgical outcome to be assessed, offering the possibility of optimal repair.
Analysis of 177Lu-DOTA-Octreotate Therapy–Induced DNA Damage in Peripheral Blood Lymphocytes of Patients with Neuroendocrine Tumors

Ionizing radiation–induced DNA double-strand breaks (DSBs) can lead to cell death, genome instability, and carcinogenesis. Immunofluorescence detection of phosphorylated histone variant H2AX (γ‐H2AX) is a reliable and sensitive technique to monitor external-beam ionizing radiation–induced DSBs in peripheral blood lymphocytes (PBLs). Here, we investigated whether γ-H2AX could be used as an in vivo marker to assess normal-tissue toxicity after extended internal irradiation with 177Lu-DOTA-octreotate (LuTate) peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors. Methods: We analyzed the kinetics of γ-H2AX foci in PBLs of 11 patients undergoing PRRT. The number of γ-H2AX foci was determined before and up to 72 h after treatment. These values were compared with the estimated absorbed dose to blood, spleen, bone marrow, and tumor and with subsequent PBL reduction. Results: The decrease in 177Lu activity in blood with time followed a biexponential kinetic pattern, with approximately 90% of circulating activity in blood cleared within 2 h. Absorbed dose to blood, but not to spleen or bone marrow, correlated with the administered 177Lu activity. PRRT increased γ-H2AX foci in lymphocytes in all patients, relative to pretherapy values. The response varied significantly between patients, but the average number of foci indicated a general trend toward an increase at 0.5–4 h with a subsequent decrease by 24–72 h after treatment. The peak number of foci correlated with the absorbed dose to tumor and bone marrow and the extent of PBL reduction. Conclusion: γ-H2AX can be exploited in the LuTate PRRT as a biomarker of PBL cytotoxicity. Long-term follow-up studies investigating whether elevated residual γ-H2AX values are associated with acute myelotoxicity and secondary blood malignancy may be worthwhile.
Effect of Continuous Positive Airway Pressure on C-reactive Protein Levels in Sleep Apnea

Objective Evaluate the effects of continuous positive airway pressure (CPAP) on C-reactive protein (CRP) levels, reported either as a primary or secondary end point among patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) based on a meta-analysis of published studies. Data Sources English-language searches of PubMed, Ovid, and the Cochrane databases were completed. Reference sections of identified studies were also examined for additional relevant articles to review. Review Methods Studies of adult patients with OSAHS who reported pre- and post-CPAP treatment CRP were reviewed and analyzed. Two independent reviewers extracted data from 10 peer-reviewed studies, which were combined using a random effects meta-analysis model. Results The CPAP treatment was found to lead to a significant reduction in CRP levels (17.8%, P = .002). This corresponds to an effect size of −0.485 (−0.731, −0.240). Sensitivity analysis was done to determine the impact of study design. Both case-control studies and case-series studies yielded a significant effect. Sensitivity analysis also yielded a significant effect for studies with average body mass index <30, studies where CPAP was employed over automatic positive airway pressure, and studies treating patients ≤3 months. Analysis of publication bias, however, revealed a likelihood of “missing” studies. Conclusion Although there is a significant lack of high-quality studies addressing this question, this analysis suggests that treatment with CPAP leads to a statistically significant reduction in CRP levels. However, the mean pre- and posttreatment CRP levels observed are considered “high risk” for cardiovascular morbidity. The clinical significance of this finding as it relates to cardiovascular risk reduction and the relationship between CRP and OSAHS requires further study.
Different Sensitivity to Apoptosis in Cells of Monocytic or Lymphocytic Origin Chronically Infected with Human Immunodeficiency Virus Type-1

Apoptotic death of CD4+ T lymphocytes is a major cause of the immunodeficiency caused by human immunodeficiency virus (HIV), but it is still unclear how this process precisely occurs. To characterize a potentially useful cellular model, we have analyzed the tendency of chronically HIV-infected CD4+ human cell lines of different origin to undergo apoptosis. We studied ACH-2 and U1 lines, derived from the CD4+ T-cell A301 and the promonocytic U937 cell lines, respectively, and induced apoptosis via several stimuli that trigger different pathways. Their capacity to regulate plasma membrane CD95 expression and to produce soluble CD95 was also analyzed. Using staurosporine, TNF-α plus cycloheximide, and 7-radiations, we observed that ACH-2 were more sensitive to programmed cell death than A301, while U1 were less sensitive than U937. Both infected cell types had a lower sensitivity to CD95-induced apoptosis; the analysis of changes in mitochondrial membrane potential corroborated these observations. Plasma membrane CD95 was similarly regulated in all cell types, which, however, presented a different capacity to produce soluble CD95 molecules. Our in vitro results may offer a new perspective for developing further studies on the pathogenesis of HIV infection. A chronically infected cell line of lymphocytic origin is more susceptible to apoptosis than its parental cell type, while infected monocytic cells are less sensitive than their uninfected counterpart. Thus, it is possible to hypothesize that one of the reasons by which circulating monocytes survive and represent a viral reservoir is the capacity of HIV to decrease the sensitivity to apoptosis of this cell type. However, further studies on ex-vivo collected fresh cells, as well as on other cell lines, are urgently needed to confirm such hypothesis.
T4b gastric carcinoma: 12 years of experience at an University Hospital.

BACKGROUND Gastric neoplasia is a heterogeneous and multifactorial disease and its incidence and mortality vary widely based on geographic location. Approximately 60% of the diagnoses of patients from occidental countries were made on the stages III and IV. The best treatment still is to realize a surgical procedure. AIM Identify the epidemiological aspects of the patients diagnosed with T4b gastric adenocarcinoma. METHODS The study was observational, transversal and retrospective; it was also based on secondary sources from patients diagnosed with T4b gastric adenocarcinoma, through pathologic stages. A total of 815 charts were analyzed and 27 patients studied. The variables were: demographic aspects, main symptoms, risk factors, access to health system, surgical aspects, morbidity, mortality and survival. RESULTS Were included 22 men (81,5%) and five woman (18,5%), in the age group between 38 and 87 years old - median age of 58. The time, in months, to access the health system varied from one to 120, average of 12,5 months. The most prevalent signs and symptoms were: weight loss 23 (85,2%), epigastric pain 22 (81,5%), vomit 16 (59,3%) and gastric fullness 12 (44,4%). The frequency of the affected adjacent body structures was: pancreas 8 (29,6%), liver 7 (25,9%), transverse colon 6 (22,2%), small intestine 6 (22,2%), mesocolon 3 (11,1%), spleen 1 (3,7%) and gallbladder 1 (3,7%). Postoperative morbidity occurred in 51, 85% of the patients. There were a significative association between surgical mortality and the occurrence of fistula/ dehiscence, septic shock and bleeding. The survival rate after six months was 63,27%. CONCLUSION The mean time between onset of symptoms and access to specialized health services was high. More than half of the patients had postoperative morbidities. Patients who had fistula / dehiscence, bleeding and septic shock were significantly associated with surgical mortality. The survival rate after six months was 63.27%.
Long-Range Correlation Underlying Childhood Language and Generative Models

Long-range correlation, a property of time series exhibiting relevant statistical dependence between two distant subsequences, is mainly studied in the statistical physics domain and has been reported to exist in natural language. By using a state-of-the-art method for such analysis, long-range correlation is first shown to occur in long CHILDES data sets. To understand why, generative stochastic models of language, originally proposed in the cognitive scientific domain, are investigated. Among representative models, the Simon model is found to exhibit surprisingly good long-range correlation, but not the Pitman-Yor model. Because the Simon model is known not to correctly reflect the vocabulary growth of natural languages, a simple new model is devised as a conjunct of the Simon and Pitman-Yor models, such that long-range correlation holds with a correct vocabulary growth rate. The investigation overall suggests that uniform sampling is one cause of long-range correlation and could thus have some relation with actual linguistic processes.
Persistence of transplanted oral mucosal epithelial cells in human cornea.

PURPOSE To determine the expression of differentiation and progenitor cell markers in corneal tissues that previously underwent autologous cultivated oral mucosal epithelial transplantation (COMET). METHODS Four eyes from three alkaline-injured patients and one thermally injured patient underwent COMET to promote re-epithelialization or corneal reconstruction. Between 10 and 22 months (mean, 14.2 +/- 5.5 months [SD]) after COMET, the corneal tissues were obtained after penetrating keratoplasty (n = 1) or autologous limbal transplantation (n = 3). Immunoconfocal microscopy for keratin (K)3, -12, -4, -13, and -8; connexin (Cx)43; MUC5AC; laminin-5; pan-p63; ABCG2; and p75 was performed in those specimens as well as in the oral mucosa and cultivated oral mucosal epithelial cells (OMECs). RESULTS All four specimens were unanimously positive for K3, -4, and -13 but negative for K8 and MUC5AC, suggesting that the keratinocytes were oral mucosa-derived. However, peripheral K12 staining was positive only in patient 2, suggesting a mixed oral and corneal epithelium in that case. Cx43 staining in the basal epithelium was negative in patients 1, 2, and 3, but was positive in patient 4. Small, compact keratinocytes in the basal epithelium preferentially expressed pan-p63, ABCG2, and p75. Although the staining of pan-p63 and ABCG2 tended to be more than one layer, signal for p75 was consistently localized only to the basal layer. CONCLUSIONS The study demonstrated the persistence of transplanted OMECs in human corneas. In addition, small, compact cells in the basal epithelium preferentially expressed the keratinocyte stem/progenitor cell markers, which may be indicative of the engraftment of the progenitor cells after transplantation.
Does obesity affect the biomechanics of the foot? A preliminary computational and experimental study

Obesity is becoming a widely prevalent issue worldwide. The excessive loading placed on the foot due to obesity can cause damage to the soft tissue and musculoskeletal structure which leads to foot discomfort and the development of foot pathologies. Experimental and computational methods of analysis were combined in this study to analyse the effects of obesity on the foot. It has been shown previously that foot pathology often starts subcutaneously and spreads towards the foot plantar. Hence the effect of obesity on the biomechanical behaviour of the foot was studied through an internal study of the bone structure using the modelling technique of finite element analysis. A 3-D anatomically correct model of a foot was created using density segmentation techniques reconstructed from Magnetic Resonance (MR) images. A non-linear finite element analysis of the reconstructed foot during balanced standing was conducted. The biomechanical differences were further classified through an external study of the foot using a gait measuring system. The finite element model of the obese foot suggests greater peak contact pressure. Experimental results suggest reduced joint angles and adjustments in the gait pattern. Preliminary results show that some differences in the biomechanical behaviour of the obese and non-obese feet are present where obese subjects compensate for the greater loading through changes in their gait.
The perception of friendship in adults with Down syndrome.

BACKGROUND Measuring the perception of friendship in adults with Down syndrome (DS) has long been a research challenge. While there have been studies investigating the number of friends children with DS have in, the study of how adults with DS view the concept of friendship has been relatively unexplored. The aim of this study was to evaluate the perception of friendship in adults with DS using a visually based scale. METHODS Sixty-six individuals participated in this study: 22 adults with DS, 22 typical mental age (MA) matched children and 22 typical adults matched for chronological age (CA). We administered a visually based Friendship scale made up of photographs depicting social interactions between individuals or groups. The scale was composed of two parts. In Part 1 participants were shown two photographs and asked to select the photograph that best depicted friends. In Part 2 participants were asked to view one photograph and asked, 'Is it okay for friends to do this? ' RESULTS Adults with DS scored lower on the Friendship scale in comparison with the CA and MA matched groups. Adults with DS made more errors in identifying 'friends' from 'non-friends' but were equally able to distinguish friendly behaviours and actions from non-friendly behaviours as their CA and MA matched peers. Individuals with DS were more likely to incorrectly identify photographs depicting a teacher, or a mother with a child as friends. Actions or behaviours that depicted subtle negative emotions were also incorrectly identified. CONCLUSIONS These results are an important first step in understanding the perception of friendship and social behaviours related to friendship in adults with DS.
Cell‐free RNA content in urine as a possible molecular diagnostic tool for clear cell renal cell carcinoma

There is limited research on cell‐free RNA (cf‐RNA) in the urine of cancer patients. The present study was performed to detect the cf‐RNA in the urine of patients with clear cell renal cell carcinoma (ccRCC). Ninety‐five urine samples from ccRCC patients and 50 urine samples from control subjects were analyzed. The cf‐RNA integrity index was calculated by using quantitative real‐time RT‐PCR assays of the small‐sized fragment (106 bp) and the big‐sized fragment (416 bp) in GAPDH mRNA. The initial analysis showed that cf‐RNA was stable and detectable in the urine. The mean cf‐RNA integrity index was significantly lower in the urine of ccRCC patients (mean: 0.07, 95%CI: 0.05–0.10) when compared with the urine from control subjects (mean: 0.25, 95%CI: 0.16–0.33) (p < 0.001). The value of the area under the receiver‐operating characteristic curve by using the cf‐RNA integrity index for the diagnosis of ccRCC was 0.858 with a sensitivity of 68.0% and a specificity of 92.6%. Moreover, the small‐sized VEGF mRNA fragment (98 bp) was detected in 31 of 50 urine samples of patients with ccRCC and in only 2 of 50 urine samples of control subjects (p < 0.001) while the detection of the big‐sized (420 bp) VEGF mRNA fragment was an infrequent event. Our findings suggest that the small‐sized cf‐RNA in urine was more abundant in cancer patients. The tumor‐related gene VEGF mRNA fragment was detectable in the urine of cancer patients. Our finding may provide a new molecular assay for the diagnosis of renal cell carcinoma.
Media and Young Minds

Infants, toddlers, and preschoolers are now growing up in environments saturated with a variety of traditional and new technologies, which they are adopting at increasing rates. Although there has been much hope for the educational potential of interactive media for young children, accompanied by fears about their overuse during this crucial period of rapid brain development, research in this area still remains limited. This policy statement reviews the existing literature on television, videos, and mobile/interactive technologies; their potential for educational benefit; and related health concerns for young children (0 to 5 years of age). The statement also highlights areas in which pediatric providers can offer specific guidance to families in managing their young children’s media use, not only in terms of content or time limits, but also emphasizing the importance of parent–child shared media use and allowing the child time to take part in other developmentally healthy activities.