Self-organizing & stochastic behaviors during the regeneration of hair stem cells

Stem cells cycle through active and quiescent states. Large populations of stem cells in an organ may cycle randomly or in a coordinated manner. Although stem cell cycling within single hair follicles has been studied, less is known about regenerative behavior in a hair follicle population. By combining predictive mathematical modeling with in vivo studies in mice and rabbits, we show that a follicle progresses through cycling stages by continuous integration of inputs from intrinsic follicular and extrinsic environmental signals based on universal patterning principles. Signaling from the WNT/bone morphogenetic protein activator/inhibitor pair is coopted to mediate interactions among follicles in the population. This regenerative strategy is robust and versatile because relative activator/inhibitor strengths can be modulated easily, adapting the organism to different physiological and evolutionary needs

Molecular and Functional Characterization of Three Different Postzygotic Mutations in PIK3CA-Related Overgrowth Spectrum (PROS) Patients: Effects on PI3K/AKT/mTOR Signaling and Sensitivity to PIK3 Inhibitors

BACKGROUND PIK3CA-related overgrowth spectrum (PROS) include a group of disorders that affect only the terminal portion of a limb, such as type I macrodactyly, and conditions like fibroadipose overgrowth (FAO), megalencephaly-capillary malformation (MCAP) syndrome, congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies (CLOVES) syndrome and Hemihyperplasia Multiple Lipomatosis (HHML). Heterozygous postzygotic PIK3CA mutations are frequently identified in these syndromes, while timing and tissue specificity of the mutational event are likely responsible for the extreme phenotypic variability observed. METHODS: We carried out a combination of Sanger sequencing and targeted deep sequencing of genes involved in the PI3K/AKT/mTOR pathway in three patients (1 MCAP and 2 FAO) to identify causative mutations, and performed immunoblot analyses to assay the phosphorylation status of AKT and P70S6K in affected dermal fibroblasts. In addition, we evaluated their ability to grow in the absence of serum and their response to the PI3K inhibitors wortmannin and LY294002 in vitro. RESULTS AND CONCLUSION: Our data indicate that patients' cells showed constitutive activation of the PI3K/Akt pathway. Of note, PI3K pharmacological blockade resulted in a significant reduction of the proliferation rate in culture, suggesting that inhibition of PI3K might prove beneficial in future therapies for PROS patients

Imaging in situ breast carcinoma (with or without an invasive component) with technetium-99m pentavalent dimercaptosuccinic acid and technetium-99m 2-methoxy isobutyl isonitrile scintimammography

INTRODUCTION: The aim of the study was to retrospectively define specific features of the technetium-99m pentavalent dimercaptosuccinic acid ((99m)Tc-(V)DMSA) and technetium-99m 2-methoxy isobutyl isonitrile ((99m)Tc-Sestamibi [(99m)Tc-MIBI]) distribution in ductal breast carcinoma in situ and lobular breast carcinoma in situ (DCIS/LCIS), in relation to mammographic, histological and immunohistochemical parameters. MATERIALS AND METHODS: One hundred and two patients with suspicious palpation or mammographic findings were submitted preoperatively to scintimammography (a total of 72 patients with (99m)Tc-(V)DMSA and a total of 75 patients with (99m)Tc-Sestamibi, 45 patients receiving both radiotracers). Images were acquired at 10 min and 60 min, and were evaluated for a pattern of diffuse radiotracer accumulation. The tumor-to-background ratios were correlated (T-pair test) with mammographic, histological and immunohistochemical characteristics. RESULTS: Histology confirmed malignancy in 46/102 patients: 20/46 patients had DCIS/LCIS, with or without coexistent invasive lesions, and 26/46 patients had isolated invasive carcinomas. Diffuse (99m)Tc-(V)DMSA accumulation was noticed in 18/19 cases and (99m)Tc-Sestamibi in 6/13 DCIS/LCIS cases. Epithelial hyperplasia demonstrated a similar accumulation pattern. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value for each tracer were calculated. Solely for (99m)Tc-(V)DMSA, the tumor-to-background ratio was significantly higher at 60 min than at 10 min and the diffuse uptake was significantly associated with suspicious microcalcifications, with the cell proliferation index ≥ 40% and with c-erbB-2 ≥ 10%. CONCLUSION: (99m)Tc-(V)DMSA showed high sensitivity and (99m)Tc-Sestamibi showed high specificity in detecting in situ breast carcinoma ((99m)Tc-(V)DMSA especially in cases with increased cell proliferation), and these radiotracers could provide clinicians with preoperative information not always obtainable by mammography

Foregut caustic injuries: Results of the world society of emergency surgery consensus conference

Introduction: Lesions of the upper digestive tract due to ingestion of caustic agents still represent a major medical and surgical emergency worldwide. The work-up of these patients is poorly defined and no clear therapeutic guidelines are available. Purpose of the study: The aim of this study was to provide an evidence-based international consensus on primary and secondary prevention, diagnosis, staging, and treatment of this life-threatening and potentially disabling condition. Methods: An extensive literature search was performed by an international panel of experts under the auspices of the World Society of Emergency Surgery (WSES). The level of evidence of the screened publications was graded using the Oxford 2011 criteria. The level of evidence of the literature and the main topics regarding foregut caustic injuries were discussed during a dedicated meeting in Milan, Italy (April 2015), and during the 3rd Annual Congress of the World Society of Emergency Surgery in Jerusalem, Israel (July 2015). Results: One-hundred-forty-seven full papers which addressed the relevant clinical questions of the research were admitted to the consensus conference. There was an unanimous consensus on the fact that the current literature on foregut caustic injuries lacks homogeneous classification systems and prospective methodology. Moreover, the non-standardized definition of technical and clinical success precludes any accurate comparison of therapeutic modalities. Key recommendations and algorithms based on expert opinions, retrospective studies and literature reviews were proposed and approved during the final consensus conference. The clinical practice guidelines resulting from the consensus conference were approved by the WSES council. Conclusions: The recommendations emerging from this consensus conference, although based on a low level of evidence, have important clinical implications. A world registry of foregut caustic injuries could be useful to collect a homogeneous data-base for prospective clinical studies that may help improving the current clinical practice guidelines

Fungal Origins of the Bicyclo[2.2.2]diazaoctane Ring System of Prenylated Indole Alkaloids

Over eight different families of natural products, consisting of nearly seventy secondary metabolites, which contain the bicyclo[2.2.2]diazaoctane ring system, have been isolated from various Aspergillus, Penicillium, and Malbranchea species. Since 1968, these secondary metabolites have been the focus of numerous biogenetic, synthetic, taxonomic, and biological studies, and, as such, have made a lasting impact across multiple scientific disciplines. This review covers the isolation, biosynthesis, and biological activity of these unique secondary metabolites containing the bridging bicyclo[2.2.2]diazaoctane ring system. Furthermore, the diverse fungal origin of these natural products is closely examined and, in many cases, updated to reflect the currently accepted fungal taxonomy

Variation of PEAR1 DNA methylation influences platelet and leukocyte function.

Background Platelet-endothelial aggregation receptor 1 (PEAR-1) is a transmembrane receptor involved in platelet activation and megakaryopoiesis whose expression is driven by DNA methylation. PEAR1 variants were associated with differential platelet response to activation and cardiovascular outcomes. We aimed at investigating the link between PEAR1 methylation and platelet and leukocyte function markers in a family-based population. Results We measured PEAR1 methylation in 605 Moli-family participants with available blood counts, plasma P-selectin and C-reactive protein, whole blood platelet P-selectin, and platelet-leukocyte mixed conjugate measurements. We performed principal component analysis (PCA) to identify groups of highly correlated CpG sites. We used linear mixed regression models (using age, gender, BMI, smoking, alcohol drinking, being a proband for family recruitment, being a member of myocardial infarction (MI) family as fixed effects, and family as a random effect) to evaluate associations between PEAR1 methylation and phenotypes. PEAR1 methylation Factor2, characterized by the previously identified megakaryocyte-specific CpG sites, was inversely associated with platelet-monocyte conjugates, P-selectin, and WBC counts, while positively associated with the platelet distribution width (PDW) and with leukocyte CD11b and L-selectin. Moreover, PEAR1 Factor2 methylation was negatively associated with INFLAscore, a low-grade inflammation score. The latter was partially mediated by the PEAR1 methylation effect on platelet variables. PEAR1 methylation association with WBC measurements and INFLAscore was confirmed in the independent cohort FLEMENGHO. Conclusions We report a significant link between epigenetic signatures in a platelet functional gene and inflammation-dependent platelet function variability measured in two independent cohorts

The role of presumed probability density functions in the simulation of nonpremixed turbulent combustion

Flamelet-Progress-Variable (FPV) combustion models allow the evaluation of all thermochemical quantities in a reacting flow by computing only the mixture fraction Z and a progress variable C. When using such a method to predict turbulent combustion in conjunction with a turbulence model, a probability density function (PDF) is required to evaluate statistical averages (e. g., Favre averages) of chemical quantities. The choice of the PDF is a compromise between computational costs and accuracy level. The aim of this paper is to investigate the influence of the PDF choice and its modeling aspects to predict turbulent combustion. Three different models are considered: the standard one, based on the choice of a β-distribution for Z and a Dirac-distribution for C; a model employing a β-distribution for both Z and C; and the third model obtained using a β-distribution for Z and the statistically most likely distribution (SMLD) for C. The standard model, although widely used, does not take into account the interaction between turbulence and chemical kinetics as well as the dependence of the progress variable not only on its mean but also on its variance. The SMLD approach establishes a systematic framework to incorporate informations from an arbitrary number of moments, thus providing an improvement over conventionally employed presumed PDF closure models. The rational behind the choice of the three PDFs is described in some details and the prediction capability of the corresponding models is tested vs. well-known test cases, namely, the Sandia flames, and H2-air supersonic combustion