Miracle-dz/UniFAR-FTUs huggingface dataset:
Ca2+ channel-forming ORAI proteins: cancer foes or cancer allies?

The ORAI family of ion channel-forming proteins in mammals includes three members, ORAI1, ORAI2 and ORAI3, encoded by homologous genes. Of these proteins the ORAI1 one received major attention as plasma membrane constituent of store-operated calcium entry (SOCE) in non-excitable cells. The functional significance of two other proteins, ORAI2 and ORAI3, is much less defined, although both of them participate to various extends in cell-specific modulation of SOCE as well as in supporting some of the store-independent calcium entry mechanisms. Calcium signaling becomes remodeled in cancer to promote cancer hallmarks - enhanced proliferation, resistance to apoptosis, motility and metastasizing. Although such remodeling commonly involves rearrangements of the whole molecular Ca2+-handling toolkit of the cell (Ca2+ pumps and transporters, Ca2+-binding and storage proteins, Ca2+ entry and release channels, Ca2+-dependent effectors), Ca2+ entry through Orai-based channels is especially important, as its dysregulation may contribute to several cancer hallmarks. The latter depend on the type of Ca2+-permeable channel formed by ORAI-proteins, spatiotemporal characteristics of Ca2+ signal that this channel contributes to, and the type Ca2+-dependent effector(s) targeted by this signal, all of which may be cancer-specific. By participating in global Ca2+ entry, ORAI-based SOCE may also contribute to cytosolic Ca2+ overload of cancer cells thereby playing pro-apoptotic, antineoplastic roles which can potentially be exploited for cancer treatment. This mini review examines various aspects of ORAI proteins in malignant transformation.
Treatment as prevention trials and ending AIDS: what do we know, when did we know it, and what do we do now?

PURPOSE OF REVIEW HIV remains a significant global public health problem. Treatment as prevention of HIV and TB illness, death and transmission was proposed in 2006 as a means to end the HIV epidemic. We review the results of the treatment as prevention trials. RECENT FINDINGS Some of the trials struggled with delivering services, however, most demonstrate that it is feasible to achieve at least the 90-90-90 target by scaling access to test-and-treat at the community level and by extension at the district or national level. Patients, if offered, will start and stay on immediate treatment even without symptoms. Community-based multidisease prevention campaigns have significant impact, especially for hard-to-reach men. Earlier treatment impacts illness and death including from HIV-associated tuberculosis. Test-and treat impacts transmission, however, some of the community cluster trials had difficulty showing an impact on incidence. Most trials showed incidence reduction in line with the level of viral suppression and suggest that achieving 95-95-95 is an important means to accelerate the end of the epidemic. SUMMARY TasP trial findings, HIV and TB program data, and PHIA study trend data will likely confirm that reaching at least 95-95-95 is both feasible and a key element in ending the epidemic.
European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2019.

OBJECTIVES The ESPGHAN 2012 coeliac disease (CD) diagnostic guidelines aimed to guide physicians in accurately diagnosing CD and permit omission of duodenal biopsies in selected cases. Here, an updated and expanded evidence-based guideline is presented. METHODS Literature databases and other sources of information were searched for studies that could inform on ten formulated questions on symptoms, serology, HLA genetics, and histopathology. Eligible articles were assessed using QUADAS2. GRADE provided a basis for statements and recommendations. RESULTS Various symptoms are suggested for case finding, with limited contribution to diagnostic accuracy. If CD is suspected, measurement of total serum IgA and IgA-antibodies against transglutaminase 2 (TGA-IgA) is superior to other combinations. We recommend against deamidated gliadin peptide antibodies (DGP-IgG/IgA) for initial testing. Only if total IgA is low/undetectable an IgG based test is indicated. Patients with positive results should be referred to a paediatric gastroenterologist/specialist. If TGA-IgA is ≥10 times the upper limit of normal (10xULN) and the family agrees, the no-biopsy diagnosis may be applied, provided endomysial antibodies (EMA-IgA) will test positive in a second blood sample. HLA DQ2-/DQ8 determination and symptoms are not obligatory criteria. In children with positive TGA-IgA <10xULN at least 4 biopsies from the distal duodenum and at least one from the bulb should be taken. Discordant results between TGA-IgA and histopathology may require re-evaluation of biopsies. Patients with no/mild histological changes (Marsh 0/I) but confirmed autoimmunity (TGA-IgA/EMA-IgA+) should be followed closely. CONCLUSIONS CD diagnosis can be accurately established with or without duodenal biopsies if given recommendations are followed.
Integration of Bioinformatics Resources Reveals the Therapeutic Benefits of Gemcitabine and Cell Cycle Intervention in SMAD4-Deleted Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer. The five-year survival rate of PDAC is very low (less than 8%), which is associated with the late diagnosis, high metastatic potential, and resistance to therapeutic agents. The identification of better prognostic or therapeutic biomarker may have clinical benefits for PDAC treatment. SMAD4, a central mediator of transforming growth factor beta (TGFβ) signaling pathway, is considered a tumor suppressor gene. SMAD4 inactivation is frequently found in PDAC. However, its role in prognosis and therapeutics of PDAC is still unclear. In this study, we applied bioinformatics approaches, and integrated publicly available resources, to investigate the role of SMAD4 gene deletion in PDAC. We found that SMAD4 deletion was associated with poorer disease-free, but not overall, survival in PDAC patients. Cancer hallmark enrichment and pathway analysis suggested that the upregulation of cell cycle-related genes in SMAD4-deleted PDAC. Chemotherapy response profiling of PDAC cell lines and patient-derived organoids revealed that SMAD4-deleted PDAC was sensitive to gemcitabine, the first-line treatment for PDAC, and specific cell cycle-targeting drugs. Taken together, our study provides an insight into the prognostic and therapeutic roles of SMAD4 gene deletion in PDAC, and SMAD4 gene copy numbers may be used as a therapeutic biomarker for PDAC treatment.
Measuring outcomes in complicated intra-abdominal infections.

PURPOSE OF REVIEW Complicated intra-abdominal infections (cIAIs) are associated with significant morbidity and mortality. Clinical trials should help guide and improve the management of cIAIs. However, inappropriate selection or measurement of outcomes in cIAIs clinical trials can lead to misleading results on the effectiveness of interventions. This review aims to describe how outcomes are reported in randomized controlled trials evaluating antibiotic treatment for cIAIs and discuss how outcome reporting may be improved. RECENT FINDINGS Commonly used primary outcomes are treatment success or failure, and these outcomes are endorsed by regulatory bodies. However, a consensus objective definition of either is not available and current measures are prone to bias. Variation exists in timing of outcome evaluation and analysis populations, which can lead to further bias. Use of core outcome sets can help standardize outcome reporting. SUMMARY Inconsistency in outcome selection and reporting can lead to misleading results and impedes meta-analysis of data. Further progress, engaging clinical trialists, regulatory authorities, clinicians and patients is required to achieve consensus on which outcomes should be reported and how and when to measure them.
Dynamics of cardiovascular system and adaptive potential in students with chronic bronchitis

Purpose: to determine the impact of the physical rehabilitation program on the state of the cardiovascular system and changes in the adaptive capacity of students with chronic bronchitis. Material & Methods: theoretical analysis of literature and generalization of scientific, methodological and specialized literature; pulseometry, arterial tonometry, a technique for determining the adaptive potential by R. M. Baevsky; methods of mathematical statistics. Results : a comprehensive program of physical rehabilitation was made taking into account the two stages of the period of convalescence, clinical and biological recovery, for students of the same group, additional application of varieties of walking and running on various health-normalizing regimes. After applying the program of physical rehabilitation of students of both groups, a slowdown in the recovery of all cardiovascular parameters and changes in the adaptive potential of the circulatory system was noted, however, the best results were obtained in a group of students, additionally, the versions of walking were used in various health-normalizing regimes with a combination of permutations of hand movements. Conclusion: confirmation of the effectiveness of the developed program of physical rehabilitation was a statistically significant improvement in the cardiovascular system, a slowdown in recovery processes after exercise, an increase in the number of students with a state of satisfactory adaptation.
Autologous BPTB ACL Reconstruction Results in Lower Failure Rates Than ACL Repair with and without Synthetic Augmentation at 30 Years of Follow-up: A Prospective Randomized Study.

BACKGROUND The aim of this study was to compare the 30-year follow-up results after treatment of anterior cruciate ligament (ACL) ruptures with 3 different surgical procedures. METHODS A total of 150 patients with acute rupture of the ACL who were managed between 1986 and 1988 were randomized into 1 of 3 open repair methods: acute primary repair (n = 49), acute repair with a synthetic ligament augmentation device (LAD) (n = 50), or reconstruction with an autologous bone-patellar tendon-bone (BPTB) graft with retention of the ACL remnants (n = 51). The 30-year follow-up included evaluation of clinical findings, the Tegner and Lysholm questionnaires, radiographic examination, and registration of revisions and knee arthroplasties. RESULTS A total of 113 patients (75%) were available for the follow-up evaluation; 39 patients were in the primary repair group, 39 in the LAD group, and 35 in the BPTB group. Through telephone calls and investigation of patient medical records, 40 of these patients were excluded from further analyses because of revision surgery, knee arthroplasty in the involved or contralateral knee, or ACL reconstruction in the contralateral knee. One patient in the BPTB group had undergone revision ACL reconstruction compared with 12 in the primary repair group (p = 0.002) and 9 in the LAD group (p = 0.015). Seven patients had undergone knee arthroplasty in the involved knee, with no significant difference among the groups. In the remaining patients, no significant differences were found among the 3 groups with regard to range of motion, laxity, or Tegner and Lysholm scores. Radiographic evidence of osteoarthritis, defined as an Ahlbäck grade of 2 through 5, was found in 42% of the operatively treated knees, with no significant differences among the groups. CONCLUSIONS In the present 30-year follow-up results of a randomized controlled study, the BPTB graft augmented with the remnants of the ruptured ligament provided superior results with regard to the number of revisions compared with both the primary repair and LAD groups. No significant differences were found with respect to range of motion, laxity, activity, function, radiographic evidence of osteoarthritis, and knee arthroplasties. LEVEL OF EVIDENCE Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
Application of 1H-NMR Metabolomics for the Discovery of Blood Plasma Biomarkers of a Mediterranean Diet

The Mediterranean diet (MD) is a dietary pattern well-known for its benefits in disease prevention. Monitoring adherence to the MD could be improved by discovery of novel dietary biomarkers. The MEDiterranean Diet in Northern Ireland (MEDDINI) intervention study monitored the adherence of participants to the MD for up to 12 months. This investigation aimed to profile plasma metabolites, correlating each against the MD score of participants (n = 58). Based on an established 14-point scale MD score, subjects were classified into two groups (“low” and “high”). 1H-Nuclear Magnetic Resonance (1H-NMR) metabolomic analysis found that citric acid was the most significant metabolite (p = 5.99 × 10−4*; q = 0.03), differing between ‘low’ and ‘high’. Furthermore, five additional metabolites significantly differed (p < 0.05; q < 0.35) between the two groups. Discriminatory metabolites included: citric acid, pyruvic acid, betaine, mannose, acetic acid and myo-inositol. Additionally, the top five most influential metabolites in multivariate models were also citric acid, pyruvic acid, betaine, mannose and myo-inositol. Metabolites significantly correlated with the consumption of certain food types. For example, citric acid positively correlated fruit, fruit juice and vegetable constituents of the diet, and negatively correlated with sweet foods alone or when combined with carbonated drinks. Citric acid was the best performing biomarker and this was enhanced by paired ratio with pyruvic acid. The present study demonstrates the utility of metabolomic profiling for effectively assessing adherence to MD and the discovery of novel dietary biomarkers.
Modeling spatial variation in density of golden eagle nest sites in the western United States

In order to contribute to conservation planning efforts for golden eagles (Aquila chrysaetos) in the western U.S., we developed nest site models using >6,500 nest site locations throughout a >3,483,000 km2 area of the western U.S. We developed models for twelve discrete modeling regions, and estimated relative density of nest sites for each region. Cross-validation showed that, in general, models accurately estimated relative nest site densities within regions and sub-regions. Areas estimated to have the highest densities of breeding golden eagles had from 132–2,660 times greater densities compared to the lowest density areas. Observed nest site densities were very similar to those reported from published studies. Large extents of each modeling region consisted of low predicted nest site density, while a small percentage of each modeling region contained disproportionately high nest site density. For example, we estimated that areas with relative nest density values <0.3 represented from 62.8–97.8% (x¯ = 82.5%) of each modeling area, and those areas contained from 14.7–30.0% (x¯ = 22.1%) of the nest sites. In contrast, areas with relative nest density values >0.5 represented from 1.0–12.8% (x¯ = 6.3%) of modeling areas, and those areas contained from 47.7–66.9% (x¯ = 57.3%) of the nest sites. Our findings have direct application to: 1) large-scale conservation planning efforts, 2) risk analyses for land-use proposals such as recreational trails or wind power development, and 3) identifying mitigation areas to offset the impacts of human disturbance.
ROCP: A Rapid Ontology Construction Platform from Unstructured Data

The domain ontology, which plays a significant role in knowledge-based systems, still needs the manual work of domain experts to be constructed currently. The main motivation of this paper is to provide a semi-automatic platform which can construct fairly comprehensive domain ontology from unstructured data. Meanwhile, a brief QA System is proposed to simplify the interaction with the domain experts. A novel algorithm MPVW, which extends from the classical algorithm TF-IDF, is proposed to extract the terminologies from domain documents. MPVW balanced more parameters and factors to evaluate the feature of terminologies. The 3-layers taxonomy and terminology hyponymy height provide sufficient guide and prompt for domain experts to construct ontology from terminologies. According to our approach we have developed ROCP, a rapid ontology construction platform which has been applied in the space debris mitigation domain. The experimental data indicates that ROCP has sufficient accuracy to extract terminologies. Meanwhile, it is effective to relieve the labor of domain experts to construct domain ontology.
In Vivo Microdialysis of Endogenous and 13C-labeled TCA Metabolites in Rat Brain: Reversible and Persistent Effects of Mitochondrial Inhibition and Transient Cerebral Ischemia

Cerebral micro-dialysis allows continuous sampling of extracellular metabolites, including glucose, lactate and pyruvate. Transient ischemic events cause a rapid drop in glucose and a rise in lactate levels. Following such events, the lactate/pyruvate (L/P) ratio may remain elevated for a prolonged period of time. In neurointensive care clinics, this ratio is considered a metabolic marker of ischemia and/or mitochondrial dysfunction. Here we propose a novel, sensitive microdialysis liquid chromatography-mass spectrometry (LC-MS) approach to monitor mitochondrial dysfunction in living brain using perfusion with 13C-labeled succinate and analysis of 13C-labeled tricarboxylic acid cycle (TCA) intermediates. This approach was evaluated in rat brain using malonate-perfusion (10–50 mM) and endothelin-1 (ET-1)-induced transient cerebral ischemia. In the malonate model, the expected changes upon inhibition of succinate dehydrogenase (SDH) were observed, i.e., an increase in endogenous succinate and decreases in fumaric acid and malic acid. The inhibition was further elaborated by incorporation of 13C into specific TCA intermediates from 13C-labeled succinate. In the ET-1 model, increases in non-labeled TCA metabolites (reflecting release of intracellular compounds) and decreases in 13C-labeled TCA metabolites (reflecting inhibition of de novo synthesis) were observed. The analysis of 13C incorporation provides further layers of information to identify metabolic disturbances in experimental models and neuro-intensive care patients.
A Review of Sclerosing Foam Stability in the Treatment of Varicose Veins.

BACKGROUND Varicose veins are common clinical entities. Foam sclerotherapy is a minimally invasive and simple procedure; however, the side effects, efficacy, and stability of sclerosing foam are not ideal. OBJECTIVE To summarize the current studies on sclerosing foam stability and promote foam sclerotherapy development. MATERIALS AND METHODS We reviewed the literature before June 2018 and included only representatives studies on sclerosing foam stability. We summarized the foam half-life time (FHT) of polidocanol (POL) under 17 preparation conditions and the FHT of sodium tetradecyl sulfate under 21 preparation conditions. The preparation conditions included various combinations of temperature, liquid-gas ratio, preparation method, etc. RESULTS: The FHT of POL varied between 40 and 4,000 seconds under different conditions. The FHT of sodium tetradecyl sulfate varied from 25.7 to 390 seconds. The higher the drug concentration, the lower the temperature required to increase foam stability. The addition of surfactant greatly increased foam stability. For different gas compositions, the FHT sequence was as follows: CO2 < CO2 + O2 < O2 < air. CONCLUSION Foam stability can be improved by changing the preparation conditions; therefore, the role of surfactants and predictive methods for FHT are worth investigating further.
Breast cancer prevention in premenopausal women: role of the Mediterranean diet and its components

Abstract Breast cancer (BC) is a growing public health concern in most developed and developing countries. Since an increasing number of patients with BC are diagnosed before the menopause and premenopausal women show a more aggressive phenotype, there is consistent interest in promoting prevention strategies in order to reduce the incidence of BC in the premenopause. The Mediterranean diet (MD) has been reported to have beneficial effect in terms of cancer prevention. This healthy dietary pattern consists primarily of foods having important antioxidant properties along with a favourable fatty acid profile, all associated with a reduced risk of cancer. Due to the large variability in study subject characteristics, the protective role of the MD on BC still remains controversial and studies that have investigated the association between adherence to the MD and risk of BC in premenopausal women are fewer than those in postmenopausal women. In addition, the possibility that the beneficial effects of the MD are due to a single component or might more probably derive from the synergic effects of all components of the MD remains a scantly explored field. Considering the increased risk of recurrence and mortality rate of BC in premenopausal women as compared with postmenopausal women, the aim of the present report is to provide a general overview of the current evidence on the relationship between BC and the MD specifically in premenopausal women, and to emphasise the potential role of the MD as an effective measure to reduce the risk of developing BC in premenopausal women.
Role of Memory B Cells in Hemagglutinin-Specific Antibody Production Following Human Influenza A Virus Infection

When influenza A virus infects an immune individual, preexisting memory B cell (MBC) activation and rapid anamnestic antibody production plays a key role in viral clearance. The most effective neutralizing antibodies target the antigenically variable head of the viral hemagglutinin (HA); antibodies against the conserved HA stalk provide broader but less potent protection. In this review, we provide a comprehensive picture of an adult’s HA-specific antibody response to influenza virus infection. The process is followed from preexisting HA-specific MBC activation and rapid production of anti-HA antibodies, through to germinal center seeding and adaptation of the response to novel features of the HA. A major focus of the review is the role of competition between preexisting MBCs in determining the character of the HA-reactive antibody response. HA novelty modifies this competition and can shift the response from the immunodominant head to the stalk. We suggest that antibodies resulting from preexisting MBC activation are important regulators of anti-HA antibody production and play a role in positive selection of germinal center B cells reactive to novel HA epitopes. Our review also considers the role of MBCs in the effects of early-life imprinting on HA head- and stalk-specific antibody responses to influenza infection. An understanding of the processes described in this review will guide development of vaccination strategies that provide broadly effective protection.