IRE1α deficiency promotes tumor cell death and eIF2α degradation through PERK dipendent autophagy

Sensors of endoplasmic reticulum (ER) stress function in a co-ordinated manner. In the present study we investigated the relationship between IRE1α and PERK pathways and survival of ER stressed U937 cells and BC3 cells. To this end, we investigated the effects of a subcytotoxic concentration of Tunicamycin in IRE1α-proficient and in IRE1α-deficient cells, by pharmacological inhibition with 4μ8 C or down-regulation by specific siRNA. We show that either type of IRE1α deficiency affects eIF2α expression and causes cell death increase. GSK2606414, a PERK inhibitor, and PERK specific siRNA prevent eIF2α down-regulation and restore cell survival. Degradation of this protein is due to autophagy, as it is prevented by bafilomycin and not by proteasome inhibition. Furthermore, activation of the autophagy flux is PERK dependent. Also the Cathepsin B inhibitor CA074 prevents eIF2α from degradation and reduces cell death. Altogether, these results show that IRE1α deficiency in ER stressed cells leads to an unexpected decrease of eIF2α, an important molecule for protein translation, through PERK dependent autophagy. Thus, IRE1/XBP1 inhibitors may represent a feasible strategy for tumor therapy, while PERK inhibitors may vanish the goal

Thyroid autoantibodies and breast cancer

Dear Editor We read with interest the recent article by Shi and colleagues (2014) reporting a meta-analysis on the relationship between thyroid hormones, thyroid autoantibodies and breast cancer (BC). In the paper, the authors analyzed eight different studies, including 4,189 participants, and concluded that serum levels of free-triiodothyronine, thyroperoxidase and thyroglobulin autoantibodies are higher in patients affected by BC, compared with the control group. These findings are in agreement with the meta-analysis reported by Hardefeldt and colleagues, showing an increased risk of BC in patients with autoimmune thyroid disease, and with a recent article by our group in which the prevalence of BC in 3,921 female patients affected by both benign and malignant thyroid diseases was evaluated (Hardefeldt et al., 2012; Prinzi et al., 2014). In the latter, we showed that the prevalence of BC in patients affected by thyroid disease, as a whole, was significantly higher, compared to the general population (OR 3.3). Moreover, the age-matched analysis showed that the risk of BC was higher in younger patients (0–44 yr, OR 15.2), to decline with the increasing age. In the same study, when patients were dichotomized based on the presence or the absence of thyroglobulin and/or thyroperoxidase autoantibodies, both groups showed a higher risk of BC, compared to the general female population. When the two groups were compared to each other, however, the risk of BC was significantly lower in autoantibody positive patients. Thus, as clearly stated in our article, among patients affected by thyroid diseases, the presence of thyroid autoantibodies may have a protective role against BC (Prinzi et al., 2014). As a consequence, the sentence reported by Shi and colleagues in the Discussion section of their article stating that their findings are in disagreement with our data is not correct and should be, if at all possible, amended

Cardiovascular risk in chronic autoimmune thyroiditis and subclinical hypothyroidism patients. A cluster analysis

Background Subclinical hypothyroidism (SCH) and chronic autoimmune thyroiditis (CAT) are linked to an increased risk of atherosclerosis and coronary heart disease (CHD). The aim of this study was to look for positive markers of CHD and correlations with thyroid blood tests in patients with SCH or CAT, but no symptoms of CHD, so as to identify CHD risk conditions that otherwise would likely be missed. Methods We measured a series of thyroid, clinical-metabolic and cardiovascular parameters in 30 consecutive endocrinology patients enrolled in our ambulatory endocrinological referral center of “Sapienza” University of Rome. (19 with CAT, 11 with SCH) from January 2015 to March 2015. 13 asymptomatic subjects were enrolled as controls. In each patient, we measured a series of 34 thyroid, clinical-metabolic and cardiovascular parameters. Results in the statistical analysis of collected data, the oblique principal components clustering procedure (OPC) revealed the presence of an interesting mixed cluster, composed of a thyroid parameter (TPO-Ab), a metabolic parameter (homocysteine level) and a cardiovascular parameter (MAPSE), in which we assessed the relationships between the single components. Our preliminary results indicate that in both groups of patients elevated TPO-Ab, when accompanied by reduced MAPSE and increased IMT and homocysteine values, may be taken to indicate the presence of clinically unrecognized CHD. Conclusions Confirmation of these results in larger series of patients could justify hormone therapy for prevention of CHD in these thyroid patients versus placebo treatmentBackground Subclinical hypothyroidism (SCH) and chronic autoimmune thyroiditis (CAT) are linked to an increased risk of atherosclerosis and coronary heart disease (CHD). The aim of this study was to look for positive markers of CHD and correlations with thyroid blood tests in patients with SCH or CAT, but no symptoms of CHD, so as to identify CHD risk conditions that otherwise would likely be missed. Methods We measured a series of thyroid, clinical-metabolic and cardiovascular parameters in 30 consecutive endocrinology patients enrolled in our ambulatory endocrinological referral center of “Sapienza” University of Rome. (19 with CAT, 11 with SCH) from January 2015 to March 2015. 13 asymptomatic subjects were enrolled as controls. In each patient, we measured a series of 34 thyroid, clinical-metabolic and cardiovascular parameters. Results in the statistical analysis of collected data, the oblique principal components clustering procedure (OPC) revealed the presence of an interesting mixed cluster, composed of a thyroid parameter (TPO-Ab), a metabolic parameter (homocysteine level) and a cardiovascular parameter (MAPSE), in which we assessed the relationships between the single components. Our preliminary results indicate that in both groups of patients elevated TPO-Ab, when accompanied by reduced MAPSE and increased IMT and homocysteine values, may be taken to indicate the presence of clinically unrecognized CHD. Conclusions Confirmation of these results in larger series of patients could justify hormone therapy for prevention of CHD in these thyroid patients versus placebo treatmen

Central neck dissection in papillary thyroid carcinoma: results of a retrospective study.

Aims of the study: The aim of this retrospective study was to appraise the impact of central neck dissection (CND) when treating papillary thyroid carcinoma (PTC) and identifying predictors of tumour recurrence by analysing the results and complications related to this surgical procedure. Materials and methods: The study examined the histories of 347 patients with PTC, divided into two groups: group A including 284 patients who underwent total thyroidectomy (TT) only; group B including 63 patients who underwent TT and CND and possible lateral neck dissection (LND). Results: The patients in the B group were younger than those in the A group (an average of 44.5 vs. 48.6; p ¼ 0.03) and their tumours were larger (1.91 cm vs 1.27 cm, p ¼ 0.001). Multifocality, extra-capsular extensions of the neoplastic mass and high cell histological variant were more prevalent in the B group. The incidence of permanent hyperparathyroidism was higher in group B than in group A (25.4% vs 9.5%, p ¼ 0.0006). Recurrence of disease and the numbers requiring reoperation were also higher in group B: (24.1% in group B vs 6.6 in group A, p < 0.0001). Patients classified as clinically N0 at their first operation and who were most probably clinically N1, totalled 6.6%. Conclusions: Our data show that only extra-capsular extension may be considered a predictor of recurrence. The findings of our study support the idea of carrying out “therapeutic” CND only in cases of preoperative or macroscopic intraoperative clinical evidence of lymph-node involvement.Aims of the study: The aim of this retrospective study was to appraise the impact of central neck dissection (CND) when treating papillary thyroid carcinoma (PTC) and identifying predictors of tumour recurrence by analysing the results and complications related to this surgical procedure. Materials and methods: The study examined the histories of 347 patients with PTC, divided into two groups: group A including 284 patients who underwent total thyroidectomy (TT) only; group B including 63 patients who underwent TT and CND and possible lateral neck dissection (LND). Results: The patients in the B group were younger than those in the A group (an average of 44.5 vs. 48.6; p ¼ 0.03) and their tumours were larger (1.91 cm vs 1.27 cm, p ¼ 0.001). Multifocality, extra-capsular extensions of the neoplastic mass and high cell histological variant were more prevalent in the B group. The incidence of permanent hyperparathyroidism was higher in group B than in group A (25.4% vs 9.5%, p ¼ 0.0006). Recurrence of disease and the numbers requiring reoperation were also higher in group B: (24.1% in group B vs 6.6 in group A, p < 0.0001). Patients classified as clinically N0 at their first operation and who were most probably clinically N1, totalled 6.6%. Conclusions: Our data show that only extra-capsular extension may be considered a predictor of recurrence. The findings of our study support the idea of carrying out “therapeutic” CND only in cases of preoperative or macroscopic intraoperative clinical evidence of lymph-node involvement

The role of sleeve gastrectomy in reducing cardiovascular risk

BACKGROUND: Obesity is an independent cardiovascular risk factor and a catalyst of other cardiovascular risk factors, such as hypertension, dyslipidemia, type 2 diabetes mellitus (DM2) and metabolic syndrome. METHODS: We analyzed cardiovascular risk in obese patients before and after sleeve gastrectomy (SG). To this end, we studied changes in body mass index (BMI), blood chemistry parameters that characterize the risk of atherosclerosis and instrumental parameters (objective markers of this risk), namely intima-media thickness (IMT) and flow-mediated dilation (FMD), the latter reflecting endothelial function. We also considered purely cardiac parameters-mitral annular plane systolic excursion (MAPSE) and tricuspid annular plane systolic excursion (TAPSE)-which describe cardiac risk more specifically than the ejection fraction. Alteration of one or more of these parameters determines an increase in cardiovascular morbidity and mortality. RESULTS: The results showed that weight loss, in patients undergoing SG, is accompanied by a reduced BMI and a marked improvement in blood chemistry, confirming what has already been shown in many other studies, but the most interesting finding was the effect of SG on the instrumental markers of atherosclerosis. In particular, carotid IMT was significantly reduced (p < 0.001) and FMD significantly improved. MAPSE and TAPSE also improved significantly at both follow-up assessments (p < 0.001). CONCLUSIONS: This study suggests that SG should be considered from a broader perspective, i.e. as a weight loss treatment that also improves obesity-related morbidity and mortality, benefitting both the patient and, in an economic sense, the society as a whole.BACKGROUND: Obesity is an independent cardiovascular risk factor and a catalyst of other cardiovascular risk factors, such as hypertension, dyslipidemia, type 2 diabetes mellitus (DM2) and metabolic syndrome. METHODS: We analyzed cardiovascular risk in obese patients before and after sleeve gastrectomy (SG). To this end, we studied changes in body mass index (BMI), blood chemistry parameters that characterize the risk of atherosclerosis and instrumental parameters (objective markers of this risk), namely intima-media thickness (IMT) and flow-mediated dilation (FMD), the latter reflecting endothelial function. We also considered purely cardiac parameters-mitral annular plane systolic excursion (MAPSE) and tricuspid annular plane systolic excursion (TAPSE)-which describe cardiac risk more specifically than the ejection fraction. Alteration of one or more of these parameters determines an increase in cardiovascular morbidity and mortality. RESULTS: The results showed that weight loss, in patients undergoing SG, is accompanied by a reduced BMI and a marked improvement in blood chemistry, confirming what has already been shown in many other studies, but the most interesting finding was the effect of SG on the instrumental markers of atherosclerosis. In particular, carotid IMT was significantly reduced (p < 0.001) and FMD significantly improved. MAPSE and TAPSE also improved significantly at both follow-up assessments (p < 0.001). CONCLUSIONS: This study suggests that SG should be considered from a broader perspective, i.e. as a weight loss treatment that also improves obesity-related morbidity and mortality, benefitting both the patient and, in an economic sense, the society as a whole