Glycosyltransferase ST6Gal-I promotes the epithelial to mesenchymal transition in pancreatic cancer cells [Cell Biology]

Alexandros G.Sfakianakis shared this article with you from Inoreader Glycosyltransferase ST6Gal-I promotes the epithelial to mesenchymal transition in pancreatic cancer cells [Cell Biology] Μέσω JBC Papers in Press ST6Gal-I, an enzyme upregulated in numerous malignancies, adds α2-6-linked sialic acids to select membrane receptors, thereby modulating receptor signaling and cell phenotype. In this study, we investigated ST6Gal-I's role in epithelial to mesenchymal transition (EMT) using the Suit2 pancreatic cancer cell line, which has low endogenous ST6Gal-I and limited metastatic potential, along with two metastati c Suit2-derived subclones, S2-013 and S2-LM7AA, which have upregulated ST6Gal-I. RNA-Seq results suggested that the metastatic subclones had greater activation of EMT-related gene networks than parental Suit2 cells, and forced overexpression (OE) of ST6Gal-I in the Suit2 line was sufficient to activate EMT pathways. Accordingly, we evaluated expression of EMT markers and cell invasiveness (a key phenotypic feature of EMT) in Suit2 cells with or without ST6Gal-I OE, as well as S2-013 and S2-LM7AA cells with or without ST6Gal-I knockdown (KD). Cells with high ST6Gal-I expression displayed enrichment in mesenchymal markers (N-cadherin, slug, snail, fibronectin) and cell invasiveness, relative to ST6Gal-I-low cells. Contrarily, epithelial markers (E-cadherin, occludin) were suppressed in ST6Gal-I-high cells. To gain mechanistic insight into ST6Gal-I's role in EMT, we examined the activity of EGFR, a known EMT driver. ST6Gal-I-high cells had greater α2-6 sialylation and activation of EGFR than ST6Gal-I-low cells. The EGFR inhibitor, erlotinib, neutralized ST6Gal-I-dependent differences in EGFR activation, mesenchymal marker expression and invasiveness in Suit2 and S2-LM7AA, but not S2-013, lines. Collectively, these results advance our understanding of ST6Gal-I's tumor-promoting function by highlighting a role for ST6Gal-I in EMT, which may be mediated, at least in part, by α2-6-sialylated EGFR. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Human genetic variants disrupt RGS14 nuclear shuttling and regulation of LTP in hippocampal neurons [Neurobiology]

Alexandros G.Sfakianakis shared this article with you from Inoreader Human genetic variants disrupt RGS14 nuclear shuttling and regulation of LTP in hippocampal neurons [Neurobiology] Μέσω JBC Papers in Press The human genome contains vast genetic diversity as naturally occurring coding variants, yet the impact of these variants on protein function and physiology is poorly understood. RGS14 is a multifunctional signaling protein that suppresses synaptic plasticity in dendritic spines of hippocampal neurons. RGS14 also is a nucleocytoplasmic shuttling protein, suggesting that balanced nuclear import/export and d endritic spine localization are essential for RGS14 functions. We identified genetic variants L505R (LR) and R507Q (RQ) located within the nuclear export sequence (NES) of human RGS14. Here we report that RGS14 encoding LR or RQ profoundly impacts protein functions in hippocampal neurons. RGS14 membrane localization is regulated by binding Gαi-GDP, whereas RGS14 nuclear export is regulated by Exportin 1 (XPO1). Remarkably, LR and RQ variants disrupt RGS14 binding to Gαi1-GDP and XPO1, nucleocytoplasmic equilibrium, and capacity to inhibit LTP. Variant LR accumulates irreversibly in the nucleus, preventing RGS14 binding to Gαi1, localization to dendritic spines, and inhibitory actions on LTP induction, while variant RQ exhibits a mixed phenotype. When introduced into mice by CRISPR/Cas9, RGS14-LR protein expression was detected predominantly in the nuclei of neurons within hippocampus, central amygdala, piriform cortex, and striatum, brain regions associated with learning and syna ptic plasticity. Whereas mice completely lacking RGS14 exhibit enhanced spatial learning, mice carrying variant LR exhibit normal spatial learning, suggesting that RGS14 may have distinct functions in the nucleus independent from those in dendrites and spines. These findings show that naturally occurring genetic variants can profoundly alter normal protein function, impacting physiology in unexpected ways. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

From pathogen to a commensal: modification of the Microbacterium nematophilum-Caenorhabditis elegans interaction during chronic infection by the absence of host insulin signalling [RESEARCH ARTICLE]

Alexandros G.Sfakianakis shared this article with you from Inoreader From pathogen to a commensal: modification of the Microbacterium nematophilum-Caenorhabditis elegans interaction during chronic infection by the absence of host insulin signalling [RESEARCH ARTICLE] Μέσω Biology Open current issue Maria Gravato-Nobre, Jonathan Hodgkin, and Petros Ligoxygakis The nematode worm Caenorhabditis elegans depends on microbes in decaying vegetation as its food source. To survive in an environment rich in opportunistic pathogens, C. elegans has evolved an epithelial defence system where surface-exposed tissues such as epidermis, pharynx, intestine, vulva and hindgut have the capacity of eliciting appropriate immune defences to acute gut infection. However, it is unclear how the worm responds to chronic intestinal infections. To this end, we have surveyed C. elegans mutants that are involved in inflammation, immunity and longevity to find their phenotypes during chronic infection. Worms that grew in a monoculture of the natural pathogen Microbacterium nematophilum (CBX102 strain) had a reduced lifespan and vigour. This was independent of intestinal colonisation as both CBX102 and the derived avirulent strain UV336 were early persistent colonisers. In contrast, the long-lived daf-2 mutant was resi stant to chronic infection, showing reduced colonisation and higher vigour. In fact, UV336 interaction with daf-2 resulted in a host lifespan extension beyond OP50, the Escherichia coli strain used for laboratory C. elegans culture. Longevity and vigour of daf-2 mutants growing on CBX102 was dependent on the FOXO orthologue DAF-16. Our results indicate that the interaction between host genotype and strain-specific bacteria determines longevity and health for C. elegans. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

De-Ritis Ratio Is Associated with Mortality after Cardiac Arrest

Alexandros G.Sfakianakis shared this article with you from Inoreader De-Ritis Ratio Is Associated with Mortality after Cardiac Arrest Μέσω Hindawi Publishing Corporation Introduction. The aim of our study was to explore the associations of the aspartate transaminase/alanine transaminase (De-Ritis) ratio with outcomes after cardiac arrest (CA). Methods. This retrospective study included 374 consecutive adult cardiac arrest patients. Information on the study population was obtained from the Dryad Digital Repository. Patients were divided into tertiles based on their De-Ritis ratio. The logistic regression hazard analysis was used to assess the independent relationship between the De-Ritis ratio and mortality. The Kaplan-Meier method and log-rank test were used to estimate the survival of different groups. Receiver operating characteristic (ROC) curve analysis was utilized to compare the prognostic ability of biomarkers. A model combining the De-Ritis ratio was established, and its performance was evaluated using the Akaike information criterion (AIC). Results. Of the 374 patients who were included in the study, 194 patients (51.9%) died in the intensive care unit (ICU), 213 patients (57.0%) died during hospitalization, and 226 patients (60.4%) had an unfavorable neurologic outcome. Logistic regression analysis including potentially confounding factors showed that the De-Ritis ratio was independently associated with mortality, yielding a more than onefold risk of ICU mortality (OR 1.455; 95% CI 1.088-1.946; ) and hospital mortality (OR 1.378; 95% CI 1.031-1.842; ). Discriminatory performance assessed by ROC curves showed an area under the curve of 0.611 (95% CI 0.553-0.668) for ICU mortality and 0.625 (0.567-0.682) for hospital mortality. Further, the likelihood ratio test (LRT) analysis showed that the model combining the De-Ritis ratio had a smaller AIC and higher likelihood ratio score than the model without the De-Ritis ratio. The Kaplan-Meier curves sho wed that the CA patients in the De-Ritis ratio tertile 3 group clearly had a significantly higher incidence of ICU mortality ().Conclusion. An elevated De-Ritis ratio on admission was significantly associated with ICU mortality and hospital mortality after CA. Assessment of the De-Ritis ratio might help identify groups at high risk for mortality. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Cervical Cancer Screening Guidelines in the Postvaccination Era: Review of the Literature

Alexandros G.Sfakianakis shared this article with you from Inoreader Cervical Cancer Screening Guidelines in the Postvaccination Era: Review of the Literature Μέσω Hindawi Publishing Corporation Cervical cancer is relatively rare in high-income countries, where organized screening programs are in place, as well as opportunistic ones. As the human papillomavirus (HPV) vaccination rates increase, the prevalence of cervical precancers and cancers is going to decrease rapidly very soon, even if, in the most optimistic scenario, it is unlikely that optimal vaccination coverage will be achieved. Then, the optimal screening paradigm for cervical cancer prevention in the postvaccination era is still debated. Screening guidelines are being developed with the aim of reducing the number of tests a woman needs during her lifetime, in order to receive the maximum benefit from screening, while decreasing potential harms that may result with the use of a screening strategy (overdiagnosis, overtreatment, anxiety, and c osts). With this purpose in mind, new management guidelines for cervical cancer screening abnormalities are recommendations based on risks, not on results. This review aims to summarize the process that led to the introduction of the HPV DNA test in screening programs and the different screening strategies. Moreover, it aims to introduce the new risk-based guidelines for the future, where full HPV genotyping can resize the risk on the basis of specific high-risk genotypes. In the same way, the data regarding HPV vaccination could be introduced as soon as women vaccinated with the nonavalent vaccine reach the screening age, with the recommendation of a prolonged screening interval. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Skin Diseases among the Old Age Residents in a Nursing Home: A Neglected Problem

Alexandros G.Sfakianakis shared this article with you from Inoreader Skin Diseases among the Old Age Residents in a Nursing Home: A Neglected Problem Μέσω Hindawi Publishing Corporation Background. Geriatric health care has become a worldwide concern, but a few statistical studies were carried out about skin diseases in this age group in the nursing home of Iran. Aims. In this study, we set out to determine the frequency as well as the age and gender distribution of dermatological diseases in nursing home old age residents. Methods. In a cross-sectional study, all patients over 60 years who were living in a charity nursing home complex of Rasht in 2017 participated in this study. Baseline information on sociodemographic variables, past medical history, and medication were gathered by medical staff during a face-to-face interview. Full-body skin examination was done by dermatologists. Biopsy, and pathological and laboratory methods were used to confirm the diagnosis of suspected lesions or di sease. Results. In this study, 259 people underwent the study. 52.9% were male, and their mean age was 73.5 years (SD = 9.1 years). Hypertension (20.9%); diabetes mellitus (9.7%), and hypothyroidism (2.3%) were the most common underlying diseases. Most of them (85.7%) had age-related skin changes. The benign neoplasm was the most common skin disease among patients (68.3%), followed by infectious diseases (46.3%) and erythemo-squamous (31.6%). None of them had precancerous lesions or skin cancers. There were not any differences between skin disorders and gender or age groups in this study. Conclusion. Our study suggests that skin manifestations and diseases are common among nursing home old age residents in this area. Therefore, this should constitute one of the top priorities of aged care physicians and nurses. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Effects of Yinzhihuang Granules on Serum Liver Enzymes in Jaundice Patients: A Real-World Study Based on HIS Data

Alexandros G.Sfakianakis shared this article with you from Inoreader Effects of Yinzhihuang Granules on Serum Liver Enzymes in Jaundice Patients: A Real-World Study Based on HIS Data Μέσω Hindawi Publishing Corporation Objective. Our aim was to analyze the influence of Yinzhihuang granules on serum liver enzymes in jaundice patients and to provide real-world evidence for the efficacy evaluation of Yinzhihuang granules in treating jaundice. Methods. We constructed a data warehouse which integrates real-world electronic medical records from the hospital information system of multiple 3A hospitals in China and used a descriptive statistical method to analyze the changes in the serum liver enzymes of the jaundice patients treated with Yinzhihuang granules and then used Wilcoxon signed-rank to test the changes in the indicators caused by the treatment. Results. After being treated with Yinzhihuang granules, the jaundice patients had a decrease in the average serum levels of total bilirubin, indirect bilirubin, aspartate amino transferase, glutamyl transpeptidase, and alkaline phosphatase, and the differences were statistically significant () but had no significant changes in the average serum levels of direct bilirubin and alanine aminotransferase ().Conclusion. The data analysis on the real-world electronic medical records demonstrate that Yinzhihuang granules help to reduce jaundice patients' serum levels of total bilirubin, indirect bilirubin, aspartate aminotransferase, glutamyl transpeptidase, and alkaline phosphatase, but there is no evidence that Yinzhihuang granules help to reduce the jaundice patients' serum levels of direct bilirubin and alanine aminotransferase. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Palbociclib Plus Exemestane with GnRH Agonist versus Capecitabine in Premenopausal Women with Hormone Receptor-Positive Metastatic Breast Cancer: A Prospective, Open-Label, Randomized Phase ll Trial (KCSG-BR 15-10)

Alexandros G.Sfakianakis shared this article with you from Inoreader Cancers, Vol. 12, Pages 3265: Patient-Reported Outcomes of Palbociclib Plus Exemestane with GnRH Agonist versus Capecitabine in Premenopausal Women with Hormone Receptor-Positive Metastatic Breast Cancer: A Prospective, Open-Label, Randomized Phase ll Trial (KCSG-BR 15-10) Μέσω Cancers Cancers, Vol. 12, Pages 3265: Patient-Reported Outcomes of Palbociclib Plus Exemestane with GnRH Agonist versus Capecitabine in Premenopausal Women with Hormone Receptor-Positive Metastatic Breast Cancer: A Prospective, Open-Label, Randomized Phase ll Trial (KCSG-BR 15-10) Cancers doi: 10.3390/cancers12113265 Authors: Soohyeon Lee Seock-Ah Im Gun Min Kim Kyung Hae Jung Seok Yun Kang In Hae Park Jee Hyun Kim Kyoung Eun Lee Hee Kyung Ahn Moon Hee Lee Hee-Jun Kim Han Jo Kim Jong In Lee Su-Jin Koh Yeon Hee Park In the era of CDK4/6 inhibitors in hormone receptor (HR)-positive, HER2-negative metastatic breast cancer, few trials have been specifically studied to compare quality of life between palbociclib plus endocrine therapy (ET) and cytotoxic chemotherapy exclusively in premenopausal women. We aimed to evaluate differences of patient report outcomes (PROs) between palbociclib plus ET and capecitabine. PROs were assessed using EORTC QLQ-C30 at baseline, every 6 weeks, and the end of treatment. All EORTC QLQ-30 scores were maintained from baseline to the end of treatment. Patients treated palbociclib plus ET arm experienced delay in time-to-deterioration of physical functioning (HR = 0.58, 95% CI, 0.36 to 0.84, p = 0.0058), nausea and vomiting (HR = 0.48; 95% CI, 0.32 to 0.73, p = 0.0005), and diarrhea (HR = 0.42; 95% CI, 0.27 to 0.65, p = 0.001). There was a numeric trend for worsening of insomnia (HR = 1.43; 95% CI, 0.96 to 2.16, p = 0.079) and favoring of appetite loss (HR = 0.69, 95 % CI, 0.44 to 1.07, p = 0.09) in the palbociclib plus ET arm. Premenopausal patients with palbociclib plus ET maintained QoL without compromising treatment efficacy. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Effectiveness of Perindopril/Indapamide Single-Pill Combination in Uncontrolled Patients with Hypertension: A Pooled Analysis of the FORTISSIMO, FORSAGE, ACES and PICASSO Observational Studies

Alexandros G.Sfakianakis shared this article with you from Inoreader Effectiveness of Perindopril/Indapamide Single-Pill Combination in Uncontrolled Patients with Hypertension: A Pooled Analysis of the FORTISSIMO, FORSAGE, ACES and PICASSO Observational Studies Μέσω Advances in Therapy Abstract Introduction Our objective was to determine the effectiveness of a perindopril/indapamide (Per/Ind) single-pill combination (SPC) in a broad range of patient profiles, including subgroups with varying hypertension severity, age and cardiovascular risk profiles. Methods Patient data from four large prospective observational studies (FORTISSIMO, FORSAGE, PICASSO, ACES) were pooled. In each study, patients already treated for hypertension were switched to Per/Ind 10/2.5 mg SPC and systolic and diastolic blood pressure (SBP/DBP) measured at the 1-month (M1) and 3-month (M3) visits. Study endpoints included change in SBP and DBP from baseline to M1 and M3 and the percentage of patients achieving BP control (SBP/DBP < 140/90 mmHg for patients without diabetes or < 140/85 mmHg for patients with diabetes). Results A total of 16,763 patients were enrolled and received Per/Ind (94% received the full dose of 10/2.5). Mean patient age was 61.4 years (36% were ≥ 65 years old), 57% were women, and 16% had isolated systolic hypertension (ISH). Mean baseline office SBP/DBP was 162/94 mmHg, and mean duration of hypertension was 11 years. Cardiovascular risk factors and comorbid conditions were common in this population. Significant mean reductions in SBP (− 23 mmHg) and DBP (− 11 mmHg) were observed at M1 compared with baseline (P < 0.001), which were maintained at M3 (− 30 mmHg and − 14 mmHg, respectively). At M3, BP control was achieved by 70% of patients (78% for ISH). In patients with SBP ≥ 180 mmHg at baseline (grade III hypertension), the mean SBP/DBP decrease was − 51/− 20 mmHg and 53% achieved BP control. Per/Ind was well tolerated with an overall rate of adv erse events of 1.3%, most frequently cough and dizziness at rates of 0.3% and 0.2%, respectively. Conclusion In this hypertensive population including difficult-to-control patient subgroups, switching to Per/Ind 10/2.5 mg SPC led to rapid and important reductions in BP. BP control was achieved in 70% of patients overall in an everyday practice context. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Cinacalcet as a First-Line Treatment in Neonatal Severe Hyperparathyroidism Secondary to Calcium Sensing Receptor (CaSR) Mutation

Alexandros G.Sfakianakis shared this article with you from Inoreader Cinacalcet as a First-Line Treatment in Neonatal Severe Hyperparathyroidism Secondary to <b><i>Calcium Sensing Receptor (CaSR)</i></b> Mutation Μέσω HRP : Last 20 articles Introduction: Neonatal severe hyperparathyroidism (NSHPT) is a rare cause of neonatal hypercalcemia caused by a loss of function mutation in the calcium-sensing receptor (CaSR). Hypercalcemia in NSHPT can be life-threatening. Maintenance of serum calcium within a safe range is the primary goal of treatment through hydration, forced diuresis, and bisphosphonate treatment, nevertheless most cases require parathyroidectomy. We report a case with NSHPT diagnosed on the first day of life (DoL) and successfully treated with cinacalcet as the first-line treatment from the 2nd DoL up to the age of 18 months. Case Report: A full-term baby evaluated for weight loss at postnatal 14th hour and found to have hypercalcemia (14.4 mg/dL, reference range [RR]: 8.0–11.3). Despite hydration and diuresis, hypercalcemia persisted. Further evaluation revealed a parathyroid hormone (PTH) level of 1,493 pg/mL (RR: 15–65) and urine Ca/Cr of 0.09 mg/mg (RR: 0.03– 0.81). Cinacalcet treatment was initiated on the 2nd DoL with the diagnosis of NSHPT due to hypocalciuric hypercalcemia and elevated PTH level. Ca levels decreased to normal levels on the 7th DoL. She was discharged from hospital at postnatal day 15 on cinacalcet treatment and still continued at 18 months of age. Sequencing of CaSR revealed a novel homozygous c.1836G#x3e;A (p.G613E) mutation in the patient, for which the parents and sister were heterozygous. Conclusion: This case represents the youngest age at cinacalcet initiation and the longest duration without parathyroidectomy in a homozygous NSHPT and demonstrates that cinacalcet is an effective first-line treatment in patients who are responsive to this treatment modality and allows avoiding/delay in surgical intervention in NSHPT. Horm Res Paediatr View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Assessment of D-Shaped Annulus of Mitral Valve in Patients with Severe MR Using Semi-Automated 4-Dimensional Analysis: Implications for Transcatheter Interventions

Alexandros G.Sfakianakis shared this article with you from Inoreader JCDD, Vol. 7, Pages 48: Assessment of D-Shaped Annulus of Mitral Valve in Patients with Severe MR Using Semi-Automated 4-Dimensional Analysis: Implications for Transcatheter Interventions Μέσω Journal of Cardiovascular Development and Disease JCDD, Vol. 7, Pages 48: Assessment of D-Shaped Annulus of Mitral Valve in Patients with Severe MR Using Semi-Automated 4-Dimensional Analysis: Implications for Transcatheter Interventions Journal of Cardiovascular Development and Disease doi: 10.3390/jcdd7040048 Authors: N. Mai Vo Suzanne E. van Wijngaarden Nina Ajmone Marsan Jeroen J. Bax Victoria Delgado The development of transcatheter mitral valve replacement therapies requires accurate post-processing analysis tools to provide D-shaped mitral annulus dimensions from 3-dimensional (3D) data. The agreement between two semi-automated, software packages to process 3D transesophageal echocardiography (TEE) data for the measurement of the mitral valve annulus dimensions was evaluated. 3DTEE data of patients with moderate–severe mitral regurgitation (MR) were postprocessed with semi-automated, vendor-independent (VI) software and vendor-specific (VS) software. Both post-processing software provided key measurements for the selection of transcatheter valve prosthesis size: annulus area, annulus circumference and the septal-to-lateral distance of the annulus. The intertrigonal distance was provided only by the VS software. The inter- and intra-observer agreements were assessed with Bland–Altman analysis. Of 105 patients (63.8 ± 11 years, 66% male) with MR , 28 had secondary MR, 45 fibroelastic deficiency, and 32 Barlow’s disease. Using VS software, the dimensions for the overall population were 16.1 ± 4.6 cm2 for annulus area, for circumference 14.4 ± 1.9 cm, intertrigonal distance 3.4 ± 0.5 cm and septal-to-lateral distance 3.8 ± 0.6 cm. Similar dimensions were obtained using VI software: 15.7 ± 4.6 cm2 for annulus area, 14.5 ± 2.0 cm for circumference, and 4.1 ± 0.6 cm for septal-to-lateral distance. The inter- and intra-observer agreement for both software programs was excellent. In conclusion, current post-processing software programs for 3DTEE data of the mitral valve annulus provide good reproducibility of key measurements to select the transcatheter prosthesis size. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.