Elevated expression of wildtype RhoC promotes ErbB2- and Pik3ca-induced mammary tumor formation.

Copy number gains in genes coding for Rho activating exchange factors as well as losses affecting genes coding for RhoGAP proteins are common in breast cancer (BC), suggesting that elevated Rho signaling may play an important role. Extra copies and overexpression of RHOC also occur, although a role for RhoC overexpression in driving tumor formation has not been assessed in vivo. To this end, we report on the development of a Rosa26 (R26)-targeted Cre-conditional RhoC overexpression mouse (R26RhoC). This mouse was crossed to two models for ERBB2/NEU+ breast cancer: one based on expression of an oncogenic ErbB2/Neu cDNA downstream of the endogenous ErbB2 promoter (FloxNeoNeuNT), the other, a metastatic model that is based on high-level expression from MMTV regulatory elements (NIC). RhoC overexpression dramatically enhanced mammary tumor formation in FloxNeoNeuNT mice but showed a more subtle effect in the NIC line, which forms multiple mammary tumors after a very short latency. RhoC overexpression also enhanced mammary tumor formation in an activated Pik3ca model for breast cancer (Pik3caH1047R). The transforming effect of RhoC was associated with epithelial/mesenchymal transition (EMT) in ErbB2/NeuNT and Pik3caH1047R systems. Thus, our study reveals the importance of elevated wildtype Rho protein expression as a driver of breast tumor formation and highlights the significance of Copy Number Abberations that affect Rho signalling.

Ameliorative effects of pregabalin on LPS induced endothelial and cardiac toxicity.

We investigated the antioxidant, anti-inflammatory and anti-apoptotic effects of pregabalin (PREG) on lipopolysaccharide (LPS) induced sepsis related cardiotoxicity via NF-kß pathways. We used 24 female Wistar albino rats divided into three groups: control, LPS treated and LPS + PREG treated. Total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), tumor necrosis factor alpha (TNF-α), nuclear factor kappa beta (NF-kß)/p65, p-NF-kß/p65, caspase-3 (Cas-3) and cleaved Cas-3 were measured in cardiac tissues and creatine kinase MB (CKMB), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) levels were measured in blood samples. Also, Cas-3, granulocyte-colony stimulating factors (G-CSF), interleukin-6 (IL-6), serum amyloid A (SAA) and inducible nitric oxide synthase (iNOS) were measured immunohistochemically in heart and aorta tissue. In the LPS group; the levels of CKMB, AST, LDH, TOS, OSI increased and TAS decreased. TNF-α, p-NF-kß/p65 and Cas-3 protein levels also increased in the LPS group. Immunohistochemical evaluation of the heart and aorta revealed a significant increase in the levels of Cas-3, G-CSF, SAA, IL-6 and iNOS in the LPS group. PREG treatment restored all measurements to near normal. LPS induced cardiovascular toxicity was due to inflammation, oxidative stress and apoptosis. PREG ameliorated the damage by inhibition of NF-kß phosphorylation.

Parotid elastography: a potential alternative to replace labial biopsy in classification of patients with primary Sjögren's syndrome?

BACKGROUND: There has been a substantial improvement in classifying patients with primary Sjögren's syndrome (pSS), with the new 2016 ACR/EULAR classification criteria. It was aimed to investigate the potential role of parotid elastography in the classification of patients with pSS, as well as the clinical diagnosis of those who do not otherwise fulfil the criteria. METHOD: This is a cross-sectional analysis of patients with pSS followed up in tertiary out-patient rheumatology clinic. Patients' medical records were retrospectively investigated whether or not clinically diagnosed pSS patients fulfil 2016 ACR/EULAR criteria sets. Elastographic evaluation of parotid and submandibular glands bilaterally was performed when presented for follow-up. Strain ratio, shear wave velocity and Pascal values of the glands were obtained. RESULTS: Clinical data on 179 patients with Sjögren's syndrome were investigated. Ninety-six patients with pSS and 30 gender and age-matched healthy controls were included in the study. Eighty-six percent of the clinically diagnosed patients satisfied the 2016 ACR /EULAR criteria and were considered 'criteria patients', and the remaining were considered 'non-criteria patients'. Both criteria and non-criteria patients had significantly higher parotid strain ratio and submandibular velocity compared with healthy controls (p < 0.001 and p < 0.001 for parotid strain ratio and p < 0.001 and p = 0.016 for submandibular velocity, respectively). Replacing labial gland biopsy findings with parotid strain ratio in the new classification criteria resulted in similar sensitivity and lower specificity, 91.6% and 80%, respectively. CONCLUSION: Parotid shear elastography is an easy and noninvasive method and might be a useful tool for the classification of patients with pSS, especially when labial gland biopsy is not feasible. Key Points • Salivary gland elastography (SGE) is a useful tool for the classification of patients with pSS. • SGE could be performed instead of labial biopsy without changing the diagnostic power of classification criteria.

Agomelatine could prevent brain and cerebellum injury against LPS-induced neuroinflammation in rats.

Sepsis, systemic hyper-inflammatory immune response, causes the increase of morbidity and mortality rates due to multi-organ diseases such as neurotoxicity. Lipopolysaccharide (LPS) induces inflammation, oxidative stress and apoptosis to cause brain damage. We aimed to evaluate the antioxidant, anti-inflammatory and antiapoptotic effects of Agomelatine (AGM) on LPS induced brain damage via NF-kB signaling. Twenty-four animals were divided into three groups as control, LPS (5 mg/kg) and LPS + AGM (20 mg/kg). Six hours after the all administrations, rats were sacrificed, brain tissues were collected for biochemical, histopathological and immunohistochemical analysis. In LPS group; total oxidant status (TOS), OSI index, Caspase-8 (Cas-8), NF-kß levels increased and Total antioxidant status (TAS) levels decreased biochemically and Cas-8, haptoglobin and IL-10 expressions increased and sirtuin-1 (SIRT-1) levels decreased immunohistochemically. AGM treatment reversed these parameters except haptoglobin levels in hippocampus and SIRT-1 levels in cerebellum. Besides, AGM treatment blocked the phosphorylation of NF-kB biochemically and ameliorated increased the levels of hyperemia, edema and degenerative changes histopathologically. In conclusion, AGM enhanced SIRT-1 levels to negatively regulate the transcription and activation of p-NF-kB/p65 which caused to ameliorate inflammation, oxidative stress and apoptosis.

Utility of DN4 questionnaire in assessment of neuropathic pain and its clinical correlations in Turkish patients with diabetes mellitus.

AIM: We aimed to assess the utility of DN4 questionnaire (Douleur Neuropathique en 4 questions) to define the frequency and severity of neuropathic pain (NP) and also its clinical correlation to daily clinical practice. METHODS: We included 1357 patients with diabetes (56.5% women, 90.4% type 2 diabetes) who were followed up in our diabetes outpatient clinic. Presence of NP was evaluated by performing simultaneous DN4 questionnaires and physical examination. Those who had a DN4 score ≥4 were considered to have NP. RESULTS: The mean age was 58.2±12.1 years, mean duration was 12.5±7.5; (min-max: 1-45) years, mean HbA1c level was 7.8±1.6% (min-max: 5-16.2%), (61.7±6.0mmol/mol; min-max: 31.1-153.6mmol/mol). Three hundred thirteen patients (23%) were diagnosed with NP using the DN4 tool. Male gender (p=0.01), receiving antihypertensive treatment (p=0.01), presence of retinopathy (p<0.001), cardiovascular disease (CVD) (p=0.01) and previously diagnosed neuropathy (p<0.001) were significantly associated with higher NP scores. Those who had increased DN4 scores were more likely to be on oral hypoglycemic agents (OHA)+insulin combinations (p<0.001), had longer diabetes duration (p<0.001) and higher HbA1c levels (p=0.001). Logistic regression model revealed that diabetes duration (OR: 1.02, 95% CI: 1.00-1.04, p=0.007), elevated HbA1c levels (1.11, 1.02-1.21, 0.015), presence of retinopathy (1.41, 1.20-1.64, <0.001), management with at least one OHA (1.47; 1.12-1.92; 0.004) or any insulin regimen (1.62; 1.16-2.27; 0.005) (compared with diet only-regimens) were significantly associated with NP. CONCLUSION: Utilization of DN4 questionnaire in daily clinical practice is an effective tool in the identification of pain related with peripheral diabetic polyneuropathy.

Comparison of the effects of 0.5% timolol maleate, 2% carteolol hydrochloride, and 0.3% metipranolol on intraocular pressure and perimetry findings and evaluation of their ocular and systemic effects.

PURPOSE: To compare the effects of 0.5% timolol maleate, 2% carteolol, and 0.3% metipranolol on intraocular pressure (IOP) in 45 patients with primary open-angle glaucoma (POAG) and ocular hypertension. A secondary goal of this study was to evaluate the ocular and systemic side effects of these medications. METHODS: Measurements of IOP were taken at baseline (pretreatment) and 2, 6, and 12 hours after instillation on treatment days 15, 30, 60, and 90. Mean sensitivity (MS) and mean defect (MD) values of perimetry before and after treatment and the effects of the three beta blockers on serum lipid profiles were determined. Ocular and systemic side effects were recorded. RESULTS: The most prominent IOP lowering effect was noted with metipranolol at 2 and 6 hours on day 15, and with timolol maleate at 12 hours on day 15 and at all hours of the subsequent days on which measurements were taken. Timolol maleate produced a significant decrease in IOP at 12 hours on day 15 compared with carteolol. There was not a statistically significant difference between the MS and MD values on perimetry before and after treatment for any treatment. There was a statistically significant decrease in levels of total cholesterol and high-density lipoprotein (HDL) cholesterol and a significant increase in triglyceride levels; these changes were observed for all treatments. CONCLUSION: The effects of the three medications were not statistically different from each other in terms of IOP reduction and visual field changes. Careful monitoring of blood lipid levels is necessary with long-term treatment with beta blockers, because these agents reduced serum levels of HDL and total cholesterol while increasing triglycerides. Such changes in lipid levels could lead to increased incidence of complications, particularly in patients with atherosclerosis or coronary heart disease.

Hormonal evidence for the dissemination through the cerebrospinal fluid, of secreting cells from invasive pituitary adenomas.

In 13 patients with invasive pituitary adenomas submitted to pituitary surgery (5 HGH-secreting adenomas, 6 prolactin-secreting adenomas, 2 non-secreting adenomas), the concentrations of HGH and prolactin (PRL) constantly decreased after operation both in the cerebrospinal fluid (CSF) and serum, and the CSF/serum ratio remained under one, with few exceptions. These last cases (2 with acromegaly, 2 with invasive prolactinomas), showed an increase of HGH or PRL concentrations in CSF when serum levels decreased; the CSF/serum ratio rose above one within 2 weeks post surgery in 2 patients, and within 2 years post surgery in another two. The circulation of CSF was not obstructed. This indicated the appearance of a new, extrapituitary source for secreting HGH or PRL directly into the CSF, a source which most probably developed through the dissemination, via CSF, of secreting cells from malignant pituitary adenomas.