The N-Terminal Phosphorylation of RB by p38 Bypasses Its Inactivation by CDKs and Prevents Proliferation in Cancer Cells.

Control of the G1/S phase transition by the Retinoblastoma (RB) tumor suppressor is critical for the proliferation of normal cells in tissues, and its inactivation is one of the most fundamental events leading to cancer. Cyclin-dependent kinase (CDK) phosphorylation inactivates RB to promote cell cycle-regulated gene expression. Here we show that, upon stress, the p38 stress-activated protein kinase (SAPK) maximizes cell survival by downregulating E2F gene expression through the targeting of RB. RB undergoes selective phosphorylation by p38 in its N terminus; these phosphorylations render RB insensitive to the inactivation by CDKs. p38 phosphorylation of RB increases its affinity toward the E2F transcription factor, represses gene expression, and delays cell-cycle progression. Remarkably, introduction of a RB phosphomimetic mutant in cancer cells reduces colony formation and decreases their proliferative and tumorigenic potential in mice.

Telemedicine for neurological diseases: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: The aim was to systematically review the effectiveness and safety of telemedicine combined with usual care (in-person visits) compared to usual care for the therapeutic management and follow-up assessment of neurological diseases. METHODS: The electronic databases MEDLINE, Embase, Web of Science and Cochrane Central Register of Controlled Trials were searched (June 2021). Randomized controlled trials (RCTs) on patients of any age with neurological diseases were considered. Two reviewers screened and abstracted data in duplicate and independently and assessed risk of bias using the Cochrane risk-of-bias tool for randomized trials (RoB 2). When possible, pooled effect estimates were calculated. RESULTS: Of a total of 3018 records initially retrieved, 25 RCTs (n = 2335) were included: 11 (n = 804) on stroke, four (n = 520) on Parkinson's disease, three (n = 110) on multiple sclerosis, two (n = 320) on epilepsy, one (n = 63) on dementia, one (n = 23) on spina bifida, one (n = 40) on migraine, one (n = 22) on cerebral palsy and one (n = 433) on brain damage. Types of telemedicine assessed were online visits (11 studies), tele-rehabilitation (seven studies), telephone calls (three), smartphone apps (two) and online computer software (two). The evidence was quite limited except for stroke. Compared to usual care alone, telemedicine plus usual care was found to improve depressive symptoms, functional status, motor function, executive function, generic quality of life, healthcare utilization and healthy lifestyle in patients in post-stroke follow-up. CONCLUSIONS: Well-designed and executed RCTs are needed to confirm our findings on stroke and to have more scientific evidence available for the other neurological diseases.

Trigeminal trophic syndrome: An unusual nasal ulceration. A case report and review of the literature.

Trigeminal trophic syndrome is a rare condition characterized by self-inflicted persistent facial ulceration. It is believed to be consequent to central or peripheral insult to trigeminal nerve, which may have taken place even years before the ulcer development. The aggression to the nerve pathway causes dysesthesias in the trigeminal dermatomes that induce a self-mutilating behavior, with repetitive pinching or scratching in order to mitigate the altered sensation. Due to associated skin anesthesia, the patient does not interrupt manipulation of the affected area despite severe skin necrosis. Ulceration typically occurs in the ala nasi and may resemble other more common cutaneous diseases, such as tumors or infections. Given that this condition is not included in our daily clinical practice, the risk is that of a diagnostic delay with devastating functional and esthetic facial consequences. We present the case of a patient with a history of meningioma resection who developed this syndrome and we have reviewed the published literature to provide an update on the etiopathogenesis, diagnosis and treatment of this rare condition.

The presence of both HLA-DRB1*04:01 and HLA-B*15:01 increases the susceptibility to cranial and extracranial giant cell arteritis.

OBJECTIVES: To determine if patients with the predominant extracranial large-vessel-vasculitis (LVV) pattern of giant cell arteritis (GCA) have a distinctive HLA-B association, different from that reported in biopsy-proven cranial GCA patients. In a further step we assessed if the combination of HLA-B and HLA-DRB1 alleles confers an increased risk for GCA susceptibility, either for the cranial and extracranial LVV phenotypes. METHODS: A total of 184 patients with biopsy-proven cranial GCA, 105 with LVV-GCA and 486 healthy controls were included in our study. We compared HLA-B phenotype frequencies between the three groups. RESULTS: HLA-B*15 phenotype was significantly increased in patients with classic cranial GCA compared to controls (14.7% versus 5.8%, respectively; p<0.01; OR [95% CI] =2.81 [1.54-5.11]). It was mainly due to the HLA-B*15:01 allele (12.5% versus 4.0%, respectively; p<0.01; OR [95% CI] =3.51 [1.77-6.99]) and remained statistically significant after Bonferroni correction. Similar HLA-B*15 association was observed in patients with the LVV-GCA (11.4% versus 5.8%, p=0.04, OR [95% CI] =2.11 [1.04-4.30]). This association was also mainly due to the HLA-B*15:01 allele (10.5% versus 4.0%, respectively; p=0.0054; OR [95% CI] =2.88 [1.19-6.59]). Noteworthy, the presence of HLA-B*15:01 together with HLA-DRB1*04:01 led to an increased risk of developing both cranial and extracranial LVV-GCA. CONCLUSIONS: Susceptibility to GCA is strongly related to the HLA region, regardless of the clinical phenotype of expression of the disease.

On the mechanisms of protein interactions: predicting their affinity from unbound tertiary structures.

Motivation: The characterization of the protein-protein association mechanisms is crucial to understanding how biological processes occur. It has been previously shown that the early formation of non-specific encounters enhances the realization of the stereospecific (i.e. native) complex by reducing the dimensionality of the search process. The association rate for the formation of such complex plays a crucial role in the cell biology and depends on how the partners diffuse to be close to each other. Predicting the binding free energy of proteins provides new opportunities to modulate and control protein-protein interactions. However, existing methods require the 3D structure of the complex to predict its affinity, severely limiting their application to interactions with known structures. Results: We present a new approach that relies on the unbound protein structures and protein docking to predict protein-protein binding affinities. Through the study of the docking space (i.e. decoys), the method predicts the binding affinity of the query proteins when the actual structure of the complex itself is unknown. We tested our approach on a set of globular and soluble proteins of the newest affinity benchmark, obtaining accuracy values comparable to other state-of-art methods: a 0.4 correlation coefficient between the experimental and predicted values of ΔG and an error < 3 Kcal/mol. Availability and implementation: The binding affinity predictor is implemented and available at http://sbi.upf.edu/BADock and https://github.com/badocksbi/BADock. Contact: j.planas-iglesias@warwick.ac.uk or baldo.oliva@upf.edu. Supplementary information: Supplementary data are available at Bioinformatics online.

Subcutaneous implantable cardioverter-defibrillator in primary and secondary prevention of sudden cardiac death: A meta-analysis.

BACKGROUND: Subcutaneous implantable cardioverter-defibrillator (S-ICD) is gaining in popularity for primary and secondary prevention of sudden cardiac death. The objective was to evaluate the safety and clinical effectiveness of the S-ICD for prevention of sudden cardiac death compared to transvenous cardioverter-defibrillator (TV-ICD). METHODS: A systematic review with meta-analyses was performed. The electronic databases MEDLINE, EMBASE, SCI, and Cochrane Central Register of Controlled Trials were consulted in March 2018 with no restrictions on publication date. Predefined criteria were used to determine inclusion of studies and to assess their methodologic quality. RESULTS: Ten longitudinal-observational studies with comparison group presenting moderate methodologic flaws were included (N = 7820). The combination of results indicates that health-related quality of life is not significantly different between S-ICD and TV-ICD groups (Physical health: MD = 2.90; 95% CI = -3.88, 9.68/Mental health: MD = 0.13; 95% CI = -2.11, 2.37). Mortality occurred in 4.4% of S-ICD patients and 5.9% of TV-ICD patients died (OR = 0.79; 95% CI = 0.50, 1.24). The incidence of infections (OR = 1.79; 95% CI = 0.93, 3.43) and inappropriate shocks (OR = 1.28, 95% CI = 0.91, 1.78) is not significantly different between both groups. The S-ICD reduces complications related to electrodes/leads (OR = 0.13, 95% CI = 0.05, 0.29) and has lower electrodes/leads movement compared with TV-ICD (OR = 0.26; 95% CI 0.10, 0.67). In contrast, pneumothorax is more likely in TV-ICD than S-ICD (OR = 0.17; 95% CI = 0.03, 0.97). CONCLUSIONS: S-ICD reduces electrodes/leads movement, electrodes/leads related complications, and pneumothorax. Our study did not demonstrate a statistically significant difference in mortality, health-related quality of life, and infection rate between S-ICD and TV-ICD.

DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants.

The information about the genetic basis of human diseases lies at the heart of precision medicine and drug discovery. However, to realize its full potential to support these goals, several problems, such as fragmentation, heterogeneity, availability and different conceptualization of the data must be overcome. To provide the community with a resource free of these hurdles, we have developed DisGeNET (http://www.disgenet.org), one of the largest available collections of genes and variants involved in human diseases. DisGeNET integrates data from expert curated repositories, GWAS catalogues, animal models and the scientific literature. DisGeNET data are homogeneously annotated with controlled vocabularies and community-driven ontologies. Additionally, several original metrics are provided to assist the prioritization of genotype-phenotype relationships. The information is accessible through a web interface, a Cytoscape App, an RDF SPARQL endpoint, scripts in several programming languages and an R package. DisGeNET is a versatile platform that can be used for different research purposes including the investigation of the molecular underpinnings of specific human diseases and their comorbidities, the analysis of the properties of disease genes, the generation of hypothesis on drug therapeutic action and drug adverse effects, the validation of computationally predicted disease genes and the evaluation of text-mining methods performance.

InteractoMIX: a suite of computational tools to exploit interactomes in biological and clinical research.

Virtually all the biological processes that occur inside or outside cells are mediated by protein-protein interactions (PPIs). Hence, the charting and description of the PPI network, initially in organisms, the interactome, but more recently in specific tissues, is essential to fully understand cellular processes both in health and disease. The study of PPIs is also at the heart of renewed efforts in the medical and biotechnological arena in the quest of new therapeutic targets and drugs. Here, we present a mini review of 11 computational tools and resources tools developed by us to address different aspects of PPIs: from interactome level to their atomic 3D structural details. We provided details on each specific resource, aims and purpose and compare with equivalent tools in the literature. All the tools are presented in a centralized, one-stop, web site: InteractoMIX (http://interactomix.com).

ArchDB 2014: structural classification of loops in proteins.

The function of a protein is determined by its three-dimensional structure, which is formed by regular (i.e. ß-strands and α-helices) and non-periodic structural units such as loops. Compared to regular structural elements, non-periodic, non-repetitive conformational units enclose a much higher degree of variability--raising difficulties in the identification of regularities, and yet represent an important part of the structure of a protein. Indeed, loops often play a pivotal role in the function of a protein and different aspects of protein folding and dynamics. Therefore, the structural classification of protein loops is an important subject with clear applications in homology modelling, protein structure prediction, protein design (e.g. enzyme design and catalytic loops) and function prediction. ArchDB, the database presented here (freely available at http://sbi.imim.es/archdb), represents such a resource and has been an important asset for the scientific community throughout the years. In this article, we present a completely reworked and updated version of ArchDB. The new version of ArchDB features a novel, fast and user-friendly web-based interface, and a novel graph-based, computationally efficient, clustering algorithm. The current version of ArchDB classifies 149,134 loops in 5739 classes and 9608 subclasses.

GUILDify: a web server for phenotypic characterization of genes through biological data integration and network-based prioritization algorithms.

SUMMARY: Determining genetic factors underlying various phenotypes is hindered by the involvement of multiple genes acting cooperatively. Over the past years, disease-gene prioritization has been central to identify genes implicated in human disorders. Special attention has been paid on using physical interactions between the proteins encoded by the genes to link them with diseases. Such methods exploit the guilt-by-association principle in the protein interaction network to uncover novel disease-gene associations. These methods rely on the proximity of a gene in the network to the genes associated with a phenotype and require a set of initial associations. Here, we present GUILDify, an easy-to-use web server for the phenotypic characterization of genes. GUILDify offers a prioritization approach based on the protein-protein interaction network where the initial phenotype-gene associations are retrieved via free text search on biological databases. GUILDify web server does not restrict the prioritization to any predefined phenotype, supports multiple species and accepts user-specified genes. It also prioritizes drugs based on the ranking of their targets, unleashing opportunities for repurposing drugs for novel therapies. AVAILABILITY AND IMPLEMENTATION: Available online at http://sbi.imim.es/GUILDify.php

The impact of PKR activation: from neurodegeneration to cancer.

An inverse association between cancer and neurodegeneration is plausible because these biological processes share several genes and signaling pathways. Whereas uncontrolled cell proliferation and decreased apoptotic cell death governs cancer, excessive apoptosis contributes to neurodegeneration. Protein kinase R (PKR), an interferon-inducible double-stranded RNA protein kinase, is involved in both diseases. PKR activation blocks global protein synthesis through eIF2α phosphorylation, leading to cell death in response to a variety of cellular stresses. However, PKR also has the dual role of activating the nuclear factor κ-B pathway, promoting cell proliferation. Whereas PKR is recognized for its negative effects on neurodegenerative diseases, in part, inducing high level of apoptosis, the role of PKR activation in cancer remains controversial. In general, PKR is considered to have a tumor suppressor function, and some clinical data show a correlation between suppressed or inactivated PKR and a poor prognosis for several cancers. However, other studies show high PKR expression and activation levels in various cancers, suggesting that PKR might contribute to neoplastic progression. Understanding the cellular factors and signals involved in the regulation of PKR in these age-related diseases is relevant and may have important clinical implications. The present review highlights the current knowledge on the role of PKR in neurodegeneration and cancer, with special emphasis on its regulation and clinical implications.

Protein kinase CK2-dependent phosphorylation of the human Regulators of Calcineurin reveals a novel mechanism regulating the calcineurin-NFATc signaling pathway.

Cyclosporine A and FK506 produce immunosuppression by blocking calcineurin phosphatase activity and consequently activation of cytosolic Nuclear Factor of Activated T-cell (NFATc) transcription factor. Due to the chronic toxicity associated with their administration, the development of more specific immunosuppressants is currently an important unmet medical need. In this context, an immunosuppressant peptide derived from the CIC motif of the human Regulators of Calcineurin (RCAN) proteins has been shown to inhibit NFATc signaling without affecting general phosphatase activity of calcineurin. Here we show that protein kinase CK2 phosphorylates a conserved serine residue within the CIC motif of vertebrate RCANs, which increases its affinity for calcineurin and consequently its inhibition of NFATc-dependent gene expression in activated T-cells. Molecular modeling studies have led us to identify a positively charged interaction site on the surface of calcineurin where the phosphorylated serine residue of the CIC motif would normally locate. Finally, we have also identified RCAN3 as a new phosphoprotein with multiple phosphorylation sites. Therefore, our findings reveal for the first time a novel molecular mechanism underlying the regulation of calcineurin-NFATc signaling by means of phosphorylation of the CIC motif of RCAN proteins. The knowledge of how RCAN proteins modulate the calcineurin-NFATc pathway paves the way for the development of potent novel selective immunosuppressant drugs.

iLoops: a protein-protein interaction prediction server based on structural features.

SUMMARY: Protein-protein interactions play a critical role in many biological processes. Despite that, the number of servers that provide an easy and comprehensive method to predict them is still limited. Here, we present iLoops, a web server that predicts whether a pair of proteins can interact using local structural features. The inputs of the server are as follows: (i) the sequences of the query proteins and (ii) the pairs to be tested. Structural features are assigned to the query proteins by sequence similarity. Pairs of structural features (formed by loops or domains) are classified according to their likelihood to favor or disfavor a protein-protein interaction, depending on their observation in known interacting and non-interacting pairs. The server evaluates the putative interaction using a random forest classifier. AVAILABILITY: iLoops is available at http://sbi.imim.es/iLoops.php CONTACT: baldo.oliva@upf.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BIPS: BIANA Interolog Prediction Server. A tool for protein-protein interaction inference.

Protein-protein interactions (PPIs) play a crucial role in biology, and high-throughput experiments have greatly increased the coverage of known interactions. Still, identification of complete inter- and intraspecies interactomes is far from being complete. Experimental data can be complemented by the prediction of PPIs within an organism or between two organisms based on the known interactions of the orthologous genes of other organisms (interologs). Here, we present the BIANA (Biologic Interactions and Network Analysis) Interolog Prediction Server (BIPS), which offers a web-based interface to facilitate PPI predictions based on interolog information. BIPS benefits from the capabilities of the framework BIANA to integrate the several PPI-related databases. Additional metadata can be used to improve the reliability of the predicted interactions. Sensitivity and specificity of the server have been calculated using known PPIs from different interactomes using a leave-one-out approach. The specificity is between 72 and 98%, whereas sensitivity varies between 1 and 59%, depending on the sequence identity cut-off used to calculate similarities between sequences. BIPS is freely accessible at http://sbi.imim.es/BIPS.php.

Influence of the flow split ratio on the position of the main atrial vortex: Implications for stasis on the left atrial appendage.

BACKGROUND: Despite the recent advances in computational fluid dynamics (CFD) techniques applied to blood flow within the left atrium (LA), the relationship between atrial geometry, flow patterns, and blood stasis within the left atrial appendage (LAA) remains unclear. A better understanding of this relationship would have important clinical implications, as thrombi originating in the LAA are a common cause of stroke in patients with atrial fibrillation (AF). AIM: To identify the most representative atrial flow patterns on a patient-specific basis and study their influence on LAA blood stasis by varying the flow split ratio and some common atrial modeling assumptions. METHODS: Three recent techniques were applied to nine patient-specific computational fluid dynamics (CFD) models of patients with AF: a kinematic atrial model to isolate the influence of wall motion because of AF, projection on a universal LAA coordinate system, and quantification of stagnant blood volume (SBV). RESULTS: We identified three different atrial flow patterns based on the position of the center of the main circulatory flow. The results also illustrate how atrial flow patterns are highly affected by the flow split ratio, increasing the SBV within the LAA. As the flow split ratio is determined by the patient's lying position, the results suggest that the most frequent position adopted while sleeping may have implications for the medium- and long-term risks of stroke.

Vascular anatomy of the breast and its implications in the breast-sharing reconstruction technique.

The most frequently described breast-sharing procedure consists in a pedicled technique where the transferred lower breast pole is based on the lower perforators of the internal mammary (IM) artery. The current article investigates the vascular supply of the breast and its surgical implications in breast-sharing reconstruction. Contrast-enhanced magnetic resonance images of 55 patients (110 breasts) were retrospectively examined. A total of 473 branches of the IM, lateral thoracic (LT) and anterior intercostal (AI) arteries with a diameter greater than 0.5 mm were traced throughout their course in the breast. Distinct connections between the vessels were equally recorded. Although any vessel could vascularise any quadrant in the individual patient, blood supply to the lower quadrants came fundamentally from the AI arteries (76.2% of all the perforators). Lower IM branches (4th-5th) were seen to reach both lower quadrants in only 6.4% of the breasts, whereas LT branches did in 15.5%. In 86.4% of the breasts, at least a distinct AI perforator was seen to perfuse both lower quadrants. Well-defined connections between the IM and the LT arteries were observed in 41.8% of the breasts, always at or above the nipple-areola level. Other connections were far less common. Our study strongly indicates that the breast-sharing technique based on 4th-5th contralateral branches of the IM or LT arteries is unreliable in most patients. Given the unpredictable vascularization pattern in the lower breast pole, a preoperative imaging study is mandatory when the use of the contralateral breast is considered. Due to its accuracy, availability, and anatomical reliability, contrast-enhanced magnetic resonance is the best technique in the preoperative evaluation of the breast-sharing reconstruction.

Preoperative EUS vs. PET-CT Evaluation of Response to Neoadjuvant Therapy for Esophagogastric Cancer and Its Correlation with Survival.

BACKGROUND: The objective of our study was to investigate whether Endoscopic Ultrasonography (EUS) and Positron Emission Tomography-Computed Tomography (PET-CT) restaging can predict survival in upper gastrointestinal tract adenocarcinomas and to assess their accuracy when compared to pathology. METHODS: We conducted a retrospective study on all patients who underwent EUS for staging of gastric or esophago-gastric junction adenocarcinoma between 2010 and 2021. EUS and PET-CT were performed, and preoperative TNM restaging was conducted using both procedures within 21 days prior to surgery. Disease-free survival (DFS) and overall survival (OS) were evaluated. RESULTS: A total of 185 patients (74.7% male) were included in the study. The accuracy of EUS for distinguishing between T1-T2 and T3-T4 tumors after neoadjuvant therapy was 66.7% (95% CI: 50.3-77.8%), and for N staging, the accuracy was 70.8% (95% CI: 51.8-81.8%). Regarding PET-CT, the accuracy for N positivity was 60.4% (95% CI: 46.3-73%). Kaplan-Meier analysis revealed a significant correlation between positive lymph nodes on restaging EUS and PET-CT with DFS. Multivariate COX regression analysis identified N restaging with EUS and PET-CT, as well as the Charlson comorbidity index, as correlated factors with DFS. Positive lymph nodes on EUS and PET-CT were predictors of OS. In multivariate Cox regression analysis, the independent risk factors for OS were found to be the Charlson comorbidity index, T response by EUS, and male sex. CONCLUSION: Both EUS and PET-CT are valuable tools for determining the preoperative stage of esophago-gastric cancer. Both techniques can predict survival, with preoperative N staging and response to neoadjuvant therapy assessed by EUS being the main predictors.

Prediction and comparison of Salmonella-human and Salmonella-Arabidopsis interactomes.

Salmonellosis caused by Salmonella bacteria is a food-borne disease and a worldwide health threat causing millions of infections and thousands of deaths every year. This pathogen infects an unusually broad range of host organisms including human and plants. A better understanding of the mechanisms of communication between Salmonella and its hosts requires identifying the interactions between Salmonella and host proteins. Protein-protein interactions (PPIs) are the fundamental building blocks of communication. Here, we utilize the prediction platform BIANA to obtain the putative Salmonella-human and Salmonella-Arabidopsis interactomes based on sequence and domain similarity to known PPIs. A gold standard list of Salmonella-host PPIs served to validate the quality of the human model. 24,726 and 10,926 PPIs comprising interactions between 38 and 33 Salmonella effectors and virulence factors with 9,740 human and 4,676 Arabidopsis proteins, respectively, were predicted. Putative hub proteins could be identified, and parallels between the two interactomes were discovered. This approach can provide insight into possible biological functions of so far uncharacterized proteins. The predicted interactions are available via a web interface which allows filtering of the database according to parameters provided by the user to narrow down the list of suspected interactions. The interactions are available via a web interface at http://sbi.imim.es/web/SHIPREC.php.

Spontaneous resolution of ureterovaginal fistula.

OBJECTIVE: We report one case of a spontaneous resolution of a uretero-vaginal fistula, and we review the current diagnostic and therapeutic features of this condition in the literature. METHODS: We present the case of a 41-year-old woman who, during the late postoperative period of a radical hysterectomy, presented episodes of daily and nocturnal incontinence with episodic flank pain compatible with uretero-vaginal fistula. RESULTS: One month after diagnosis the patient does not report incontinence during day or night, and the lumbar pain has disappeared. An intravenous urography shows that there has been a spontaneous resolution of the uretero-vaginal fistula. CONCLUSIONS: Spontaneous resolution of a uretero-vaginal fistula is rare. Most fistulas require endourological or surgical treatment.

Evaluation of the Efficiency of European Health Systems Using Fuzzy Data Envelopment Analysis.

Many studies that assess efficiency in health systems are based on output mean values. That approach ignores the representativeness of the average statistic, which can become a serious problem in estimation. To solve this question, this research contributes in three different ways: the first aim is to evaluate the technical efficiency in the management of European health systems considering a set of DEA (Data Envelopment Analysis) and FDEA (Fuzzy Data Envelopment Analysis) models. A second goal is to assess the bias in the estimation of efficiency when applying the conventional DEA. The third objective is the evaluation of the statistical relationship between the bias in the efficiency estimation and the macroeconomic variables (income inequality and economic freedom). The main results show positive correlations between DEA and FDEA scores. Notwithstanding traditional DEA models overestimate efficiency scores. Furthermore, the size of the bias is positively related to income inequality and negative with economic freedom in the countries evaluated.