ROCK ‘n TOR: An Outlook on Keratinocyte Stem Cell Expansion in Regenerative Medicine via Protein Kinase Inhibition

Keratinocyte stem cells play a fundamental role in homeostasis and repair of stratified epithelial tissues. Transplantation of cultured keratinocytes autografts provides a landmark example of successful cellular therapies by restoring durable integrity in stratified epithelia lost to devastating tissue conditions. Despite the overall success of such procedures, failures still occur in case of paucity of cultured stem cells in therapeutic grafts. Strategies aiming at a further amplification of stem cells during keratinocyte ex vivo expansion may thus extend the applicability of these treatments to subjects in which endogenous stem cells pools are depauperated by aging, trauma, or disease. Pharmacological targeting of stem cell signaling pathways is recently emerging as a powerful strategy for improving stem cell maintenance and/or amplification. Recent experimental data indicate that pharmacological inhibition of two prominent keratinocyte signaling pathways governed by apical mTOR and ROCK protein kinases favor stem cell maintenance and/or amplification ex vivo and may improve the effectiveness of stem cell-based therapeutic procedures. In this review, we highlight the pathophysiological roles of mTOR and ROCK in keratinocyte biology and evaluate existing pre-clinical data on the effects of their inhibition in epithelial stem cell expansion for transplantation purposes

Cyclooxygenase Inhibition Safety and Efficacy in Inflammation-Based Psychiatric Disorders

According to the World Health Organization, the major psychiatric and neurodevelopmental disorders include major depression, bipolar disorder, schizophrenia, and autism spectrum disorder. The potential role of inflammation in the onset and progression of these disorders is increasingly being studied. The use of non-steroidal anti-inflammatory drugs (NSAIDs), well-known cyclooxygenase (COX) inhibitors, combined with first-choice specific drugs have been long investigated. The adjunctive administration of COX inhibitors to classic clinical treatments seems to improve the prognosis of people who suffer from psychiatric disorders. In this review, a broad overview of the use of COX inhibitors in the treatment of inflammation-based psychiatric disorders is provided. For this purpose, a critical analysis of the use of COX inhibitors in the last ten years of clinical trials of the major psychiatric disorders was carried out

Cervicoscopy and Microcolposcopy in the Evaluation of Squamo Columnar Junction and Cervical Canal in LSIL Patients with Inadequate or Negative Colposcopy

OBJECTIVE: The present study evaluated indications’ validity of cervicoscopic and microcolposcopic examination in LSIL patients with unsatisfactory or negative colposcopy. MATHERIAL AND METHODS: In the cervico-vaginal pathology unit of the “San Giovanni Calibita Fatebenefratelli” University of Rome “Tor Vergata”, 119 patients with a positive cervical cytology (LSIL), were submitted to the exam for the following two indications: 1) unsatisfactory colposcopy 37 (31.1%); 2) negative colposcopy 82 (68.9%). RESULTS: Cervicoscopy allowed the SCJ visualization in 115 (9.6%) patients. In 4 patients 3.4%, the SCJ visualization was not possible due to cervical stenosis. Cervicoscopy without staining, revealed endocervical squamous columnar junction in 33 (28.7%) patients. The blue dye in panoramic view detected endocervical SCJ in 41 (35.7%), out of 115 patients (>5 mm in 34 (29.6%) patients and >10 mm in 7 (6.1%)). CONCLUSIONS: Cervicoscopic examination revealed 7.8% of CIN2-3 in LSIL patients with inadequate or negative colposcopy. In patients with negative colposcopy the percentage of undiagnosed lesions inside the cervical canal was very low. The blue dye added sensitivity to the exam

Improving cuff-less continuous blood pressure estimation with linear regression analysis

In this work, the authors investigate the cuff-less estimation of continuous BP through pulse transit time (PTT) and heart rate (HR) using regression techniques, which is intended as a first step towards continuous BP estimation with a low error, according to AAMI guidelines. Hypertension (the 'silent killer') is one of the main risk factors for cardiovascular diseases (CVDs), which are the main cause of death worldwide. Its continuous monitoring can offer a valid tool for patient care, as blood pressure (BP) is a significant indicator of health and, using it together with other parameters, such as heart and breath rates, could strongly improve prevention of CVDs. The novelties introduced in this work are represented by the implementation of pre-processing and by the innovative method for features research and features processing to continuously monitor blood pressure in a non-invasive way. Currently, invasive methods are the only reliable methods for continuous monitoring, while non-invasive techniques measure the values every few minutes. The proposed approach can be considered the first step for the integration of these types of algorithms on wearable devices, in particular on those developed for the SINTEC project

Synthesis of Atropisomeric Hydrazides by One-Pot Sequential Enantio- and Diastereoselective Catalysis

The first catalytic enantioselective and diastereoselective synthesis of atropisomeric hydrazides was achieved using a sequential catalysis protocol. This strategy is based on a one-pot sequence of two organocatalytic cycles featuring the enamine amination of branched aldehydes followed by nitrogen alkylation under phase-transfer conditions. The resulting axially chiral hydrazides were obtained directly from commercially available reagents in high yields and with good stereocontrol. The permutation of organocatalysts allowed easy access to all stereoisomers, enabling a stereodivergent approach to enantioenriched atropisomeric hydrazides

Differential ttbar cross-section measurements using boosted top quarks in the all-hadronic final state with 139 fb-1 of ATLAS data

Measurements of single-, double-, and triple-differential cross-sections are presented for boosted top-quark pair-production in 13 TeV proton–proton collisions recorded by the ATLAS detector at the LHC. The top quarks are observed through their hadronic decay and reconstructed as large-radius jets with the leading jet having transverse momentum (pT) greater than 500 GeV. The observed data are unfolded to remove detector effects. The particle-level cross-section, multiplied by the t¯t ! WWb¯b branching fraction and measured in a fiducial phase space defined by requiring the leading and second-leading jets to have pT > 500 GeV and pT > 350 GeV, respectively, is 331 ± 3(stat.) ± 39(syst.) fb. This is approximately 20% lower than the prediction of 398+48−49 fb by Powheg+Pythia 8 with next-to-leading-order (NLO) accuracy but consistent within the theoretical uncertainties. Results are also presented at the parton level, where the effects of top-quark decay, parton showering, and hadronization are removed such that they can be compared with fixed-order next-to-next-to-leading-order (NNLO) calculations. The partonlevel cross-section, measured in a fiducial phase space similar to that at particle level, is 1.94 ± 0.02(stat.) ± 0.25(syst.) pb. This agrees with the NNLO prediction of 1.96+0.02−0.17 pb. Reasonable agreement with the differential cross-sections is found for most NLO models, while the NNLO calculations are generally in better agreement with the data. The differential cross-sections are interpreted using a Standard Model effective field-theory formalism and limits are set on Wilson coefficients of several four-fermion operators

Measurement of the polarisation of single top quarks and antiquarks produced in the t-channel at sqrt(s) = 13 TeV and bounds on the tWb dipole operator from the ATLAS experiment

A simultaneous measurement of the three components of the top-quark and top-antiquark polarisation vectors in t-channel single-top-quark production is presented. This analysis is based on data from proton-proton collisions at a centre-of-mass energy of 13 TeV corresponding to an integrated luminosity of 139 fb(-1), collected with the ATLAS detector at the LHC. Selected events contain exactly one isolated electron or muon, large missing transverse momentum and exactly two jets, one being b-tagged. Stringent selection requirements are applied to discriminate t-channel single-top-quark events from the background contributions. The top-quark and top-antiquark polarisation vectors are measured from the distributions of the direction cosines of the charged-lepton momentum in the top-quark rest frame. The three components of the polarisation vector for the selected top-quark event sample are P-x' = 0.01 +/- 0.18, P-y' = -0.029 +/- 0.027, P-z' = 0.91 +/- 0.10 and for the top-antiquark event sample they are P-x' = -0.02 +/- 0.20, P-y' = -0.007 +/- 0.051, P-z' = -0.79 +/- 0.16. Normalised differential cross-sections corrected to a fiducial region at the stable-particle level are presented as a function of the charged-lepton angles for top-quark and top-antiquark events inclusively and separately. These measurements are in agreement with Standard Model predictions. The angular differential cross-sections are used to derive bounds on the complex Wilson coefficient of the dimension-six O-tW operator in the framework of an effective field theory. The obtained bounds are C-tW is an element of[-0.9, 1.4] and C-itW is an element of [-0.8, 0.2], both at 95% confidence level

On the Nature of the Rotational Energy Barrier of Atropisomeric Hydrazides

N-N atropisomers represent a useful class of compounds that has recently received important attention from many research groups. This article presents an in-depth analysis of the energy barrier needed for the racemization process of atropoisomeric hydrazides, combining an experimental and computational approach. The focus is on examining how electronic and steric factors impact the racemization process. The results obtained indicate that the barrier observed during the racemization process mainly arises from an increase in the p-orbital character of the nitrogen atoms

TLR3 expression induces apoptosis in human non‐small‐cell lung cancer

The prognostic value of Toll\u2010like receptor 3 (TLR3) is debated in cancer, differing between tumor types, methods, and cell types. We recently showed for the first time that TLR3 expression on early stage non\u2010small\u2010cell lung cancer (NSCLC) results associated with a good prognosis. Here, we provide experimental evidences explaining the molecular reason behind TLR3\u2019s favorable prognostic role. We demonstrated that TLR3 activation in vitro induces apoptosis in lung cancer cell lines and, accordingly, that TLR3 expression is associated with caspase\u20103 activation in adenocarcinoma NSCLC specimens, both evaluated by immunohistochemistry. Moreover, we showed that TLR3 expression on cancer cells contributes to activate the CD103+ lung dendritic cell subset, that is specifically associated with processing of antigens derived from apoptotic cells and their presentation to CD8+ T lymphocytes. These findings point to the relevant role of TLR3 expression on lung cancer cells and support the use of TLR3 agonists in NSCLC patients to re\u2010activate local innate immune response