Biochemical–molecular–genetic biomarkers in the tear film, aqueous humor, and blood of primary open-angle glaucoma patients

Introduction: Glaucoma is a chronic neurodegenerative disease, which is the leading cause of irreversible blindness worldwide. As a response to high intraocular pressure, the clinical and molecular glaucoma biomarkers indicate the biological state of the visual system. Classical and uncovering novel biomarkers of glaucoma development and progression, follow-up, and monitoring the response to treatment are key objectives to improve vision outcomes. While the glaucoma imaging field has successfully validated biomarkers of disease progression, there is still a considerable need for developing new biomarkers of early glaucoma, that is, at the preclinical and initial glaucoma stages. Outstanding clinical trials and animal-model study designs, innovative technology, and analytical approaches in bioinformatics are essential tools to successfully uncover novel glaucoma biomarkers with a high potential for translation into clinical practice. Methods: To better understand the clinical and biochemical-molecular-genetic glaucoma pathogenesis, we conducted an analytical, observational, and case-comparative/control study in 358 primary open-angle glaucoma (POAG) patients and 226 comparative-control individuals (CG) to collect tears, aqueous humor, and blood samples to be processed for identifying POAG biomarkers by exploring several biological pathways, such as inflammation, neurotransmitter/neurotrophin alteration, oxidative stress, gene expression, miRNAs fingerprint and its biological targets, and vascular endothelial dysfunction, Statistics were done by using the IBM SPSS 25.0 program. Differences were considered statistically significant when p ≤ 0.05. Results: Mean age of the POAG patients was 70.03 ± 9.23 years, and 70.62 ± 7.89 years in the CG. Malondialdehyde (MDA), nitric oxide (NO), interleuquin (IL)-6, endothelin-1 (ET-1), and 5 hydroxyindolacetic acid (5-HIAA), displayed significantly higher levels in the POAG patients vs. the CG (p < 0.001). Total antioxidant capacity (TAC), brain derived neurotrophic factor (BDNF), 5-hydroxy tryptamine (5-HT), solute carrier family 23-nucleobase transporters-member 2 (SLC23A2) gene, and the glutathione peroxidase 4 (GPX4) gene, showed significantly lower levelsin the POAG patients than in the CG (p < 0.001). The miRNAs that differentially expressed in tear samples of the POAG patients respect to the CG were the hsa miR-26b-5p (involved in cell proliferation and apoptosis), hsa miR-152-3p (regulator of cell proliferation, and extracellular matrix expression), hsa miR-30e-5p (regulator of autophagy and apoptosis), and hsa miR-151a-3p (regulator of myoblast proliferation). Discussion: We are incredibly enthusiastic gathering as much information as possible on POAG biomarkers to learn how the above information can be used to better steer the diagnosis and therapy of glaucoma to prevent blindness in the predictable future. In fact, we may suggest that the design and development of blended biomarkers is a more appropriate solution in ophthalmological practice for early diagnosis and to predict therapeutic response in the POAG patients

Cyclin-Dependent Kinase 4/6 Inhibitors and Dermatologic Adverse Events: Results from the EADV Task Force "Dermatology for Cancer Patients"

Treatment with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), has demonstrated significantly improved progression-free survival in patients with hormone receptor-positive, HER2-negative, advanced breast cancer, when used in combination with endocrine therapies. However, limited data exists on its cutaneous adverse events (AE). The aim of our retrospective study was to investigate the prevalence, types and management of cutaneous AE during CDK4/6i. 79 adult advanced breast cancer patients affected by 125 skin adverse events during treatment with CDK4/6i were recruited at eleven centers. The most frequent cutaneous reactions were pruritus (49/79 patients), alopecia (25/79), and ec-zematous lesions (24/79). We showed that skin reactions are usually mild in severity, and prompt management may limit the negative impact on patients, facilitating beneficial continuation of oncologic treatment

The CrowdHEALTH project and the Hollistic Health Records: Collective Wisdom Driving Public Health Policies.

Introduction: With the expansion of available Information and Communication Technology (ICT) services, a plethora of data sources provide structured and unstructured data used to detect certain health conditions or indicators of disease. Data is spread across various settings, stored and managed in different systems. Due to the lack of technology interoperability and the large amounts of health-related data, data exploitation has not reached its full potential yet. Aim: The aim of the CrowdHEALTH approach, is to introduce a new paradigm of Holistic Health Records (HHRs) that include all health determinants defining health status by using big data management mechanisms. Methods: HHRs are transformed into HHRs clusters capturing the clinical, social and human context with the aim to benefit from the collective knowledge. The presented approach integrates big data technologies, providing Data as a Service (DaaS) to healthcare professionals and policy makers towards a "health in all policies" approach. A toolkit, on top of the DaaS, providing mechanisms for causal and risk analysis, and for the compilation of predictions is developed. Results: CrowdHEALTH platform is based on three main pillars: Data & structures, Health analytics, and Policies. Conclusions: A holistic approach for capturing all health determinants in the proposed HHRs, while creating clusters of them to exploit collective knowledge with the aim of the provision of insight for different population segments according to different factors (e.g. location, occupation, medication status, emerging risks, etc) was presented. The aforementioned approach is under evaluation through different scenarios with heterogeneous data from multiple sources

CrowdHEALTH: Holistic Health Records and Big Data Analytics for Health Policy Making and Personalized Health.

Today's rich digital information environment is characterized by the multitude of data sources providing information that has not yet reached its full potential in eHealth. The aim of the presented approach, namely CrowdHEALTH, is to introduce a new paradigm of Holistic Health Records (HHRs) that include all health determinants. HHRs are transformed into HHRs clusters capturing the clinical, social and human context of population segments and as a result collective knowledge for different factors. The proposed approach also seamlessly integrates big data technologies across the complete data path, providing of Data as a Service (DaaS) to the health ecosystem stakeholders, as well as to policy makers towards a "health in all policies" approach. Cross-domain co-creation of policies is feasible through a rich toolkit, being provided on top of the DaaS, incorporating mechanisms for causal and risk analysis, and for the compilation of predictions

Extreme genetic fragility of the HIV-1 capsid

Genetic robustness, or fragility, is defined as the ability, or lack thereof, of a biological entity to maintain function in the face of mutations. Viruses that replicate via RNA intermediates exhibit high mutation rates, and robustness should be particularly advantageous to them. The capsid (CA) domain of the HIV-1 Gag protein is under strong pressure to conserve functional roles in viral assembly, maturation, uncoating, and nuclear import. However, CA is also under strong immunological pressure to diversify. Therefore, it would be particularly advantageous for CA to evolve genetic robustness. To measure the genetic robustness of HIV-1 CA, we generated a library of single amino acid substitution mutants, encompassing almost half the residues in CA. Strikingly, we found HIV-1 CA to be the most genetically fragile protein that has been analyzed using such an approach, with 70% of mutations yielding replication-defective viruses. Although CA participates in several steps in HIV-1 replication, analysis of conditionally (temperature sensitive) and constitutively non-viable mutants revealed that the biological basis for its genetic fragility was primarily the need to coordinate the accurate and efficient assembly of mature virions. All mutations that exist in naturally occurring HIV-1 subtype B populations at a frequency >3%, and were also present in the mutant library, had fitness levels that were >40% of WT. However, a substantial fraction of mutations with high fitness did not occur in natural populations, suggesting another form of selection pressure limiting variation in vivo. Additionally, known protective CTL epitopes occurred preferentially in domains of the HIV-1 CA that were even more genetically fragile than HIV-1 CA as a whole. The extreme genetic fragility of HIV-1 CA may be one reason why cell-mediated immune responses to Gag correlate with better prognosis in HIV-1 infection, and suggests that CA is a good target for therapy and vaccination strategies

Measurement of the t t-bar production cross section in the dilepton channel in pp collisions at sqrt(s) = 7 TeV

The t t-bar production cross section (sigma[t t-bar]) is measured in proton-proton collisions at sqrt(s) = 7 TeV in data collected by the CMS experiment, corresponding to an integrated luminosity of 2.3 inverse femtobarns. The measurement is performed in events with two leptons (electrons or muons) in the final state, at least two jets identified as jets originating from b quarks, and the presence of an imbalance in transverse momentum. The measured value of sigma[t t-bar] for a top-quark mass of 172.5 GeV is 161.9 +/- 2.5 (stat.) +5.1/-5.0 (syst.) +/- 3.6(lumi.) pb, consistent with the prediction of the standard model.Comment: Replaced with published version. Included journal reference and DO

Combined search for the quarks of a sequential fourth generation

Results are presented from a search for a fourth generation of quarks produced singly or in pairs in a data set corresponding to an integrated luminosity of 5 inverse femtobarns recorded by the CMS experiment at the LHC in 2011. A novel strategy has been developed for a combined search for quarks of the up and down type in decay channels with at least one isolated muon or electron. Limits on the mass of the fourth-generation quarks and the relevant Cabibbo-Kobayashi-Maskawa matrix elements are derived in the context of a simple extension of the standard model with a sequential fourth generation of fermions. The existence of mass-degenerate fourth-generation quarks with masses below 685 GeV is excluded at 95% confidence level for minimal off-diagonal mixing between the third- and the fourth-generation quarks. With a mass difference of 25 GeV between the quark masses, the obtained limit on the masses of the fourth-generation quarks shifts by about +/- 20 GeV. These results significantly reduce the allowed parameter space for a fourth generation of fermions.Comment: Replaced with published version. Added journal reference and DO

Search for new physics with same-sign isolated dilepton events with jets and missing transverse energy

A search for new physics is performed in events with two same-sign isolated leptons, hadronic jets, and missing transverse energy in the final state. The analysis is based on a data sample corresponding to an integrated luminosity of 4.98 inverse femtobarns produced in pp collisions at a center-of-mass energy of 7 TeV collected by the CMS experiment at the LHC. This constitutes a factor of 140 increase in integrated luminosity over previously published results. The observed yields agree with the standard model predictions and thus no evidence for new physics is found. The observations are used to set upper limits on possible new physics contributions and to constrain supersymmetric models. To facilitate the interpretation of the data in a broader range of new physics scenarios, information on the event selection, detector response, and efficiencies is provided.Comment: Published in Physical Review Letter

Azimuthal anisotropy of charged particles at high transverse momenta in PbPb collisions at sqrt(s[NN]) = 2.76 TeV

The azimuthal anisotropy of charged particles in PbPb collisions at nucleon-nucleon center-of-mass energy of 2.76 TeV is measured with the CMS detector at the LHC over an extended transverse momentum (pt) range up to approximately 60 GeV. The data cover both the low-pt region associated with hydrodynamic flow phenomena and the high-pt region where the anisotropies may reflect the path-length dependence of parton energy loss in the created medium. The anisotropy parameter (v2) of the particles is extracted by correlating charged tracks with respect to the event-plane reconstructed by using the energy deposited in forward-angle calorimeters. For the six bins of collision centrality studied, spanning the range of 0-60% most-central events, the observed v2 values are found to first increase with pt, reaching a maximum around pt = 3 GeV, and then to gradually decrease to almost zero, with the decline persisting up to at least pt = 40 GeV over the full centrality range measured.Comment: Replaced with published version. Added journal reference and DO