Impact of Age and Body Site on Adult Female Skin Surface pH

Background: pH is known as an important parameter in epidermal barrier function and homeostasis. Aim: The impact of age and body site on skin surface pH (pH(SS)) of women was evaluated in vivo. Methods: Time domain dual lifetime referencing with luminescent sensor foils was used for pH(SS) measurements. pH(SS) was measured on the forehead, the temple, and the volar forearm of adult females (n = 97, 52.87 +/- 18.58 years, 20-97 years). Every single measurement contained 2,500 pH values due to the luminescence imaging technique used. Results: pH(SS) slightly increases with age on all three investigated body sites. There are no significant differences in pH(SS) between the three investigated body sites. Conclusion: Adult pH(SS) on the forehead, the temple and the volar forearm increases slightly with age. This knowledge is crucial for adapting medical skin care products. Copyright (C) 2012 S. Karger AG, Base

Autofluorescent Imaging in Patients With Peritoneal Carcinomatosis

Background and objectives. Autofluorescence imaging (AFI) is mainly used to detect (pre)cancerous colorectal and pulmonal lesions. This is the first report establishing the feasibility of AFI in patients with peritoneal carcinomatosis (PC). Methods. This is a prospective analysis of 10 patients undergoing conventional white-light laparoscopy (WL) and AFI for PC of different gastrointestinal tumors and 1 ovarian cancer. Before taking biopsies, suspicious peritoneal lesions were first detected by WL and then investigated by AFI. The intraoperative findings were photographed and then correlated with histological results. Results. Conventional WL and AFI evaluation was successful in all patients. A total of 38 biopsies were taken. The neoplasm detection rate under WL was 66% and increased to 86% when using AFI. The positive tumor detection rate was slightly higher in low AF lesions (83 vs 88%) and higher in tumor nodules (94%) than in flat peritoneal lesions (75%). For tumor nodules, the sensitivity was 94%, and the specificity was 100%. For flat lesions, the sensitivity was 75% and specificity 50%. Conclusions. We demonstrate the feasibility and effectiveness of AFI in patients with PC

pH sensing in skin tumors: Methods to study the involvement of GPCRs, acid‐sensing ion channels and transient receptor potential vanilloid channels

Solid tumors exhibit an inversed pH gradient with increased intracellular pH (pH(i)) and decreased extracellular pH (pH(e)). This inside-out pH gradient is generated via sodium/hydrogen antiporter 1, vacuolar-type H + ATPases, monocarboxylate transporters, (bi)carbonate (co)transporters and carboanhydrases. Our knowledge on how pH(e)-signals are sensed and what the respective receptors induce inside cells is scarce. Some pH-sensitive receptors (GPR4, GPR65/TDAG8, GPR68/OGR1, GPR132/G2A, possibly GPR31 and GPR151) and ion channels (acid-sensing ion channels ASICs, transient receptor potential vanilloid receptors TRPVs) transduce signals inside cells. As little is known on the expression and function of these pH sensors, we used immunostainings to study tissue samples from common and rare skin cancers. Our current and future work is directed towards investigating the impact of all the pH-sensing receptors in different skin tumors using cell culture techniques with selective knockdown/knockout (siRNA/CRISPR-Cas9). To study cell migration and proliferation, novel impedance-based wound healing assays have been developed and are used. The field of pH sensing in tumors and wounds holds great promise for the development of pH-targeting therapies, either against pH regulators or sensors to inhibit cell proliferation and migration

OSCC in Never-Smokers and Never-Drinkers Is Associated with Increased Expression of Tumor-Infiltrating Lymphocytes and Better Survival

The aim of this study was to investigate the clinical, histopathologic, and immunologic differences of oral squamous cell carcinoma of never-smokers/never drinkers and smokers/drinkers. Immunohistochemical staining for CD4, CD8, FoxP3, CD1a, and p16 was performed in 131 oral squamous cell carcinomas from smokers/drinkers and never-smokers/never-drinkers. Associations of smoking/drinking status with clinicopathologic data, immunohistochemical antibody expression, and survival were examined. Oral squamous cell carcinoma in never-smokers/never-drinkers was associated with the female gender (p < 0.001). Never-smokers/never-drinkers were older at diagnosis than smokers/drinkers (p < 0.001). Never-smokers/never-drinkers had more tumors in the maxilla, mandible, and tongue (p < 0.001). Pre-existing oral potentially malignant disorders appeared to be more common in never-smokers/never-drinkers (p < 0.001). Perineural invasion was more common in smokers/drinkers (p = 0.039). Never-smoking/never-drinking was associated with better overall survival (p = 0.004) and disease-specific survival (p = 0.029). High CD4+ T cell infiltration was associated with never-smoking/never-drinking (p = 0.008). Never-smokers/never-drinkers also showed increased CD8+ T cell infiltration (p = 0.001) and increased FoxP3+ Treg infiltration (p = 0.023). Furthermore, the total group of tumor-infiltrating lymphocytes was associated with never smoking/never drinking (p = 0.005). To conclude oral squamous cell carcinoma of the never-smokers/never-drinkers appears to be a distinct type of tumor, as it appears to have unique clinical and pathologic features and a more immunogenic microenvironment

Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms

YesRecent clinical trials of the hypoglycaemic sodium-glucose co-transporter-2 (SGLT2) inhibitors, which inhibit renal glucose reabsorption, have reported beneficial cardiovascular outcomes. Whether SGLT2 inhibitors directly affect cardiovascular tissues, however, remains unclear. We have previously reported that the SGLT2 inhibitor canagliflozin activates AMP-activated protein kinase (AMPK) in immortalised cell lines and murine hepatocytes. As AMPK has anti-inflammatory actions in vascular cells, we examined whether SGLT2 inhibitors attenuated inflammatory signalling in cultured human endothelial cells. Incubation with clinically-relevant concentrations of canagliflozin, but not empagliflozin or dapagliflozin activated AMPK and inhibited IL-1β-stimulated adhesion of pro-monocytic U937 cells and secretion of IL-6 and monocyte chemoattractant protein-1 (MCP-1). Inhibition of MCP-1 secretion was attenuated by expression of dominant-negative AMPK and was mimicked by the direct AMPK activator, A769662. Stimulation of cells with either canagliflozin or A769662 had no effect on IL-1β-stimulated cell surface levels of adhesion molecules or nuclear factor-κB signalling. Despite these identical effects of canagliflozin and A769662, IL-1β-stimulated IL-6/MCP-1 mRNA was inhibited by canagliflozin, but not A769662, whereas IL-1β-stimulated c-jun N-terminal kinase phosphorylation was inhibited by A769662, but not canagliflozin. These data indicate that clinically-relevant canagliflozin concentrations directly inhibit endothelial pro-inflammatory chemokine/cytokine secretion by AMPK-dependent and -independent mechanisms without affecting early IL-1β signalling.Project Grant (PG/13/82/30483 to IPS and TMP) and PhD studentships (FS/16/55/32731 and FS/14/61/31284 to DB and AS) from the British Heart Foundation and an equipment grant (BDA11/0004309 to IPS and TMP) from Diabetes UK. OJK was supported by a Scholarship from the Iraqi Ministry of Higher Education and Scientific Research. TAA was supported by a Libyan Ministry of Education PhD Studentship

Effects of Hydrogen Peroxide on Wound Healing in Mice in Relation to Oxidative Damage

10.1371/journal.pone.0049215PLoS ONE711

Reversible molecular pathology of skeletal muscle in spinal muscular atrophy

Low levels of full-length survival motor neuron (SMN) protein cause the motor neuron disease, spinal muscular atrophy (SMA). Although motor neurons undoubtedly contribute directly to SMA pathogenesis, the role of muscle is less clear. We demonstrate significant disruption to the molecular composition of skeletal muscle in pre-symptomatic severe SMA mice, in the absence of any detectable degenerative changes in lower motor neurons and with a molecular profile distinct from that of denervated muscle. Functional cluster analysis of proteomic data and phospho-histone H2AX labelling of DNA damage revealed increased activity of cell death pathways in SMA muscle. Robust upregulation of voltage-dependent anion-selective channel protein 2 (Vdac2) and downregulation of parvalbumin in severe SMA mice was confirmed in a milder SMA mouse model and in human patient muscle biopsies. Molecular pathology of skeletal muscle was ameliorated in mice treated with the FDA-approved histone deacetylase inhibitor, suberoylanilide hydroxamic acid. We conclude that intrinsic pathology of skeletal muscle is an important and reversible event in SMA and also suggest that muscle proteins have the potential to act as novel biomarkers in SMA