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Objectives Inorganic nitrate is one of the most effective compounds in beetroot for improving cardiovascular function due to its conversion to nitric oxide in the body. This review and meta-analysis aimed to investigate the role of beetroot inorganic nitrate supplementation on adults' cardiovascular risk factors. Methods We conducted a systematic literature review of articles published without time limitation until November 2020 in PubMed, Embase, ISI Web of Science, Scopus, Cochrane Library, and gray literature databases. We included the original randomized clinical trials (RCTs) in which the effect of beetroot inorganic nitrate supplementation on endothelial function, arterial stiffness, and blood pressure was studied. Results 43 studies were included for qualitative synthesis, out of which 27 were eligible for meta-analysis. Beetroot inorganic nitrate supplementation significantly decreased Arterial Stiffness (Pulse Wave Velocity (−0.27 m/s, p = 0.04)) and increased Endothelial function (Flow Mediated Dilation: 0.62%, p = 0.002) but did not change other parameters (p > 0.05). Conclusion Beetroot inorganic nitrate supplementation might have a beneficial effect on cardiovascular risk factors. Further high-quality investigations will be needed to provide sufficient evidence.

Introduction. Gastric bypass surgery is a gold standard therapy for severe obesity. This study aimed to evaluate anthropometric predictors for short-term excess weight loss (EWL) after Roux-en-Y gastric bypass surgery (RYGB) in a sample of severely obese patients. Materials and Methods. This cohort study was conducted on severely obese candidates for RYGB bariatric surgery in Mashhad, Iran. Indirect calorimetry, anthropometric measurements, and body composition data were collected before, one, and six months after RYGB. Results. Fifty-four participants (43, 79.6% women and 11, 20.4% men) with a mean age of 39.63 ± 9.66 years participated in this study. The mean total weight and BMI loss within six months were 32.89 ± 20.22 kg and 12.37 ± 7.34 kg/m2, respectively. The mean reduction in adipose tissue and fat-free mass was 24.49 kg and 7.46 kg, respectively. The mean resting metabolism rate (RMR) reduction at one and six months after RYGB was 260.49 kcal and 396.07 kcal, respectively. There was a significant difference in mean RMR between the baseline and one and six months after RYGB ( p < 0.001 ). There was no significant gender difference in mean weight and BMI loss percentage at six months post-RYGB ( p > 0.05 ). Baseline skeletal muscle mass (SMM), excess BMI loss (EBMIL) at first month after surgery, and baseline neck circumference (NC) could predict EWL six months after surgery. Conclusion. Reduced RMR shortly after RYGB may be due to FFM reduction. Some anthropometric and their acute changes after RYGB may predict the short-term EWL in RYGB patients.

Infantile hemangioma (IH) is the most common infantile tumor, affecting 5–10% of newborns. Propranolol, a nonselective β-adrenergic receptor (ADRB) antagonist, is currently the first-line treatment for severe IH; however, both its mechanism of action and its main cellular target remain poorly understood. Since betablockers can antagonize the effect of natural ADRB agonists, we postulated that the catecholamine produced in situ in IH may have a role in the propranolol response. By quantifying catecholamines in the IH tissues, we found a higher amount of noradrenaline (NA) in untreated proliferative IHs than in involuted IHs or propranolol-treated IHs. We further found that the first three enzymes of the catecholamine biosynthesis pathway are expressed by IH cells and that their levels are reduced in propranolol-treated tumors. To study the role of NA in the pathophysiology of IH and its response to propranolol, we performed an in vitro angiogenesis assay in which IH-derived endothelial cells, pericytes and/or telocytes were incorporated. The results showed that the total tube formation is sensitive to propranolol only when exogenous NA is added in the three-cell model. We conclude that the IH’s sensitivity to propranolol depends on crosstalk between the endothelial cells, pericytes and telocytes in the context of a high local amount of local NA.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, while no drugs have been approved for its treatment. The pieces of evidence indicate that propolis as a novel anti-inflammatory agent might be a promising candidate to treat NAFLD. We aimed to evaluate the efficacy of propolis on hepatic steatosis and fibrosis in patients with NAFLD. This randomized clinical trial was conducted on 54 patients with NAFLD. Patients were randomly assigned to receive propolis tablets at a dose of 250 mg twice daily for 4 months or placebo. The improvement in hepatic steatosis and fibrosis was evaluated using two-dimensional shear wave elastography. Improvement in the hepatic steatosis was significantly higher in the propolis group than the placebo group, even after adjustment for baseline value and changes in weight, energy intake, and physical activity (odds ratio [OR]: 5.67; 95% confidence intervals [CI]: 1.41-22.8; p = .014). A significant reduction was observed on the liver stiffness in the propolis group (-0.65 ± 0.56 kPa; p = .001), whereas it increased in the placebo group (0.27 ± 0.59 kPa; p = .037). Also, the intake of propolis significantly decreased high-sensitivity C-reactive protein (hs-CRP) levels compared with the placebo group (-0.371; 95%CI: -0.582 to -0.16 mg/L; p = .01). Changes in serum levels of fasting blood sugar, alanine aminotransferase, aspartate aminotransferase, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, cholesterol, and triglyceride did not differ significantly between the two groups (p > .05). There was no significant improvement in insulin resistance in both groups (p > .05). Propolis seems to have protective effects on hepatic steatosis and fibrosis and to reduce the serum levels of hs-CRP in patients with NAFLD.

Aims: REDOX signaling from reactive oxygen species (ROS) generated by the mitochondria (mitochondrial reactive oxygen species [mtROS]) has been implicated in cancer growth and survival. Here, we investigated the effect of 5-(4-methoxyphenyl)-3H-1,2-dithiole-3-thione (AOL), a recently characterized member of the new class of mtROS suppressors (S1QELs), on human lung adenocarcinoma proteome reprogramming, bioenergetics, and growth. Results: AOL reduced steady-state cellular ROS levels in human lung cancer cells without altering the catalytic activity of complex I. AOL treatment induced dose-dependent inhibition of lung cancer cell proliferation and triggered a reduction in tumor growth in vivo. Molecular investigations demonstrated that AOL reprogrammed the proteome of human lung cancer cells. In particular, AOL suppressed the determinants of the Warburg effect and increased the expression of the complex I subunit NDUFV1 which was also identified as AOL binding site using molecular modeling computer simulations. Comparison of the molecular changes induced by AOL and MitoTEMPO, an mtROS scavenger that is not an S1QEL, identified a core component of 217 proteins commonly altered by the two treatments, as well as drug-specific targets. Innovation: This study provides proof-of-concept data on the anticancer effect of AOL on mouse orthotopic human lung tumors. A unique dataset on proteomic reprogramming by AOL and MitoTEMPO is also provided. Lastly, our study revealed the repression of NDUFV1 by S1QEL AOL. Conclusion: Our findings demonstrate the preclinical anticancer properties of S1QEL AOL and delineate its mode of action on REDOX and cancer signaling.

Introduction Congenital fibrinogen disorders (CFDs) comprise the quantitative and qualitative fibrinogen molecule abnormalities that are caused by fibrinogen gene mutations. The objective of this cohort research was to study the molecular and clinical profiles of patients with CFDs. Materials and methods Genomic DNA Sanger sequencing of 14 Iranian patients was performed to determine CFDs-causing mutations. The disorders were diagnosed by routine and specific (fibrinogen antigen and functional assay) coagulation tests, and clinical data were obtained from medical records. Molecular dynamics (MD) simulations were performed to investigate the effect of missense mutation on the protein structure. Results Thirteen out of 14 patients had afibrinogenemia while the remaining patient had dysfibrinogenemia. Umbilical cord bleeding was the most common clinical presentation (n: 9, ~70%) which led to the diagnosis of afibrinogenemia, while menorrhagia led to the diagnosis of dysfibrinogenemia. Six homozygous mutations were identified in afibrinogenemia: three previously described variants in FGA (p.Trp52Ter, p.Ser312AlafsTer109 and p.Gly316GlufsTer105), one in FBG (p.Gly430Asp), and two novel mutations in FGB (p.Gly430Arg) and FGG (p.His366ThrfsTer40), while the FGA (p.Arg38Thr) heterozygous mutation was identified in dysfibrinogenemia. MD simulation indicated that the FGA p. Arg38Thr mutation probably interferes with polymerization of fibrin monomers. Conclusions In Iran, with its high rate of consanguinity, autosomal recessive afibrinogenemia with severe clinical presentations is relatively common due to heterogeneous molecular defects.

Background Traumatic brain injury (TBI) is the most common trauma worldwide and is a leading cause of injury-related death and disability. Inflammation is initiated as a result of the TBI, which is in association with severity of illness and mortality in brain trauma patients, especially in subdural hemorrhage and epidural hemorrhage cases. A high percentage of adults admitted to the intensive care unit with TBI are diagnosed with vitamin D deficiency; this deficiency may induce impaired immune responses and increase the risk of infections. Vitamin D intervention has been shown to modulate pro- and anti-inflammatory cytokines in non-critically ill patients, but to date, there is no substantial data on the effectiveness of vitamin D for the improvement of immune function in traumatic brain injury patients. Methods/design A randomized clinical trial (RCT) will be performed on 74 Iranian adults 18–65 years old with brain trauma and will be treated daily with vitamin D supplements (100,000 IU oral drop) or a similar placebo (1000 IU) for 5 days. Discussion If this randomized clinical trial demonstrates reductions in inflammatory cytokines, it would provide evidence for a multicenter clinical trial to evaluate the efficacy of vitamin D supplementation in neurocritically ill patients. Since vitamin D supplements are inexpensive and safe, this clinical trial could have the potential to improve clinical outcomes in traumatic brain injury patients through reduction of inflammation and infection-associated morbidity and mortality rates. Trial registration Iranian Registry of Clinical Trials, IRCT20180619040151N3. Registered on 10 August 2019.

Background Overweight and obesity are major health concerns worldwide, with adverse health consequences during the life span. This study measured socioeconomic inequality in overweight and obesity among Iranian adults. Methods Data were extracted from 129,257 Iranian adults (aged 35 years and older) participated in the Prospective Epidemiologic Research Studies in IrAN (PERSIAN) in 14 provinces of Iran in 2014. Socioeconomic-related inequality in overweight and obesity was estimated using the Concentration Index (Cn). The Cn further decomposed to find factors explaining the variability within the Socioeconomic related inequality in overweight and obesity. Results Of the total number of participants, 1.98, 26.82, 40.76 and 30.43% had underweight, normal weight, overweight and obesity respectively. The age-and sex standardized prevalence of obesity was higher in females than males (39.85% vs 18.79%). People with high socioeconomic status (SES) had a 39 and 15% higher chance of being overweight and obese than low SES people, respectively. The positive value of Cn suggested a higher concentration of overweight (0.081, 95% confidence interval [CI]; 0.074–0.087) and obesity (0.027, 95% CI; 0.021–0.034) among groups with high SES. There was a wide variation in socioeconomic-related inequality in overweight and obesity rate across 14 provinces. The decomposition results suggested that SES factor itself explained 66.77 and 89.07% of the observed socioeconomic inequalities in overweight and obesity among Iranian adults respectively. Following SES, province of residence, physical activity, using hookah and smoking were the major contributors to the concentration of overweight and obesity among the rich. Conclusions Overall, we found that overweight and obesity is concentrated among high SES people in the study population. . Accordingly, it seems that intersectional actions should be taken to control and prevent overweight and obesity among higher socioeconomic groups.

Background ACEI (Angiotensin Converting Enzyme Inhibitors) inhibits tumor growth and development. Different mechanisms have been proposed for this matter, including the inhibition of enzymes that are involved in extracellular matrix degradation, matrix metalloproteinase (MMP) and etc. The present study was designed with the aim to investigate the effects of low dose ACEI on the Quality of Life (QoL) of non-hospitalized gastric cancer patients with cachexia. Materials and methods This study was a single-blinded randomized controlled clinical trial conducted in clinics affiliated with Shiraz University of Medical Sciences (SUMS). All participants were patients with gastric cancer in cancer cachexia step aged 40-80 years old who had referred to our clinics from October 2013 to April 2014. In the intervention group, patients were assigned to receive ACEI (Captopril) and the placebo group served as control and received placebo during the same time course. They were asked questions in order to fill out QLQ-C30 (Persian Version) questionnaire 3 times; baseline, 1 and 2 months after their first visit. Results The mean age of patients was 60.55 ± 12.07 (range 31-80) years and the mean BMI of the patients was 17.21 ± 2.31. In the ACEI group, physical functioning and fatigue score changes were significant 1 and 2 months after treatment. The mean of fatigue score decreased significantly in the placebo group. Overall, global health status scores significantly increased in both groups, but other items of QoL did not change significantly. Conclusion Overall, our results showed that Captopril does not have a significant positive effect on QoL of patients with cancer cachexia. .

Aims: Lung cancer is the leading cause of cancer death worldwide, and tobacco smoking is a recognized major risk factor for lung tumor development. We analyzed the effect of tobacco-specific nitrosamines (TSNAs) on human lung adenocarcinoma metabolic reprogramming, an emergent hallmark of carcinogenesis. Results: A series of in vitro and in vivo bioenergetic, proteomic, metabolomic, and tumor biology studies were performed to analyze changes in lung cancer cell metabolism and the consequences for hallmarks of cancer, including tumor growth, cancer cell invasion, and redox signaling. The findings revealed that nicotine-derived nitrosamine ketone (NNK) stimulates mitochondrial function and promotes lung tumor growth in vivo. These malignant properties were acquired from the induction of mitochondrial biogenesis induced by the upregulation and activation of the beta-2 adrenergic receptors (β2-AR)-cholinergic receptor nicotinic alpha 7 subunit (CHRNAα7)-dependent nitrosamine canonical signaling pathway. The observed NNK metabolic effects were mediated by TFAM overexpression and revealed a key role for mitochondrial reactive oxygen species and Annexin A1 in tumor growth promotion. Conversely, ectopic expression of the mitochondrial antioxidant enzyme manganese superoxide dismutase rescued the reprogramming and malignant metabolic effects of exposure to NNK and overexpression of TFAM, underlining the link between NNK and mitochondrial redox signaling in lung cancer. Innovation: Our findings describe the metabolic changes caused by NNK in a mechanistic framework for understanding how cigarette smoking causes lung cancer. Conclusion: Mitochondria play a role in the promotion of lung cancer induced by tobacco-specific nitrosamines. Antioxid. Redox Signal. 36, 525-549.

International audience; Xeroderma pigmentosum group C protein (XPC) acts as a DNA damage recognition factor for bulky adducts and as an initiator of global genome nucleotide excision repair (GG-NER). Novel insights have shown that the role of XPC is not limited to NER, but is also implicated in DNA damage response (DDR), as well as in cell fate decisions upon stress. Moreover, XPC has a proteolytic role through its interaction with p53 and casp-2S. XPC is also able to determine cellular outcomes through its interaction with downstream proteins, such as p21, ARF, and p16. XPC interactions with effector proteins may drive cells to various fates such as apoptosis, senescence, or tumorigenesis. In this review, we explore XPC's involvement in different molecular pathways in the cell and suggest that XPC can be considered not only as a genomic caretaker and gatekeeper but also as a tumor suppressor and cellular-fate decision maker. These findings envisage that resistance to cell death, induced by DNA-damaging therapeutics, in highly prevalent P53-deficent tumors might be overcome through new therapeutic approaches that aim to activate XPC in these tumors. Moreover, this review encourages care providers to consider XPC status in cancer patients before chemotherapy in order to improve the chances of successful treatment and enhance patients’ survival.

Background Enteral feeding intolerance, energy-protein malnutrition, and muscle wasting are common conditions in the critical care setting. The primary aim of this study was to investigate the effect of synbiotic supplementation on enteral feed volume, energy and protein homeostasis, and muscle mass maintenance in critically ill adult patients. Methods A consecutive of 42 patients admitted to the Edalatian Medical ICU, requiring enteral nutrition (EN), were prospectively randomized to receive the synbiotic capsule (containing a combination of Lactobacillus, Bifidobacterium, Streptococcus, and fructooligosaccharides) or placebo (21 patients in each group) for a maximum of 14 days. Enteral intolerance and energy homeostasis were evaluated on a daily basis. Nitrogen balance and 24-h urine creatinine excretion were recorded on days 1 and 14. Mid-arm circumference was recorded every 3 days. Results Mean EN volume, energy, and protein intake per day were 962.5 ± 533.82 ml, 770 ± 427.05 kcal, and 38.5 ± 21.35 g (fourth day) vs. 590 ± 321.1 ml, 472 ± 256.81 kcal, and 23.6 ± 12.84 g (first day) in the synbiotic group (p p = 0.003). On day 14, NB was − 14.18 ± 13.05 in the synbiotic and − 9.59 ± 7.71 in the placebo group (p = 0.41). Mid-arm circumference (MAC), 24-h urine creatinine, and creatinine-height index were almost steady in the synbiotic group, while they decreased in the placebo group. Conclusion Overall, it can be concluded that enteral nutrition supplemented with synbiotics has no statistically significant effect on energy and protein homeostasis and muscle mass maintenance of critically ill patients on day 14, but it can increase enteral feed volume and energy and protein intake during the first 4 days of ICU admission. Trial registration The trial protocol has been approved in Iranian Registry of Clinical Trials on March 17, 2019. The registration reference is IRCT20190227042857N1.

Background and aims The aim of the present study was to investigate the effects of gut microbiota modulation through synbiotic supplementation on lipid and glucose homeostasis in tube-fed critically-ill adult patients. Methods This study is placebo-controlled, parallel, single-center, double-blind clinical trial. 42 patients were randomly distributed in placebo and synbiotic groups to receive intervention for a maximum of 14 days. Serum levels of fasting glucose, total cholesterol, and triglycerides, insulin, and free fatty acids were obtained from blood sampling at baseline and the end of the study. Also, insulin resistance was determined by homeostasis model assessment of insulin resistance (HOMA-IR). Result Fasting glucose level (Day0 = 87.84 ± 15.51, Day14 = 83.76 ± 8.71 mg/dl, P = 0.51), fasting insulin level (Day0 = 9.46 ± 7.31, Day14 = 7.97 ± 5.19 mIU/L, P = 1.00), and HOMA index (Day0 = 1.89 ± 1.48, Day14 = 1.72 ± 1.17, P = 0.75) during the study were decreasing in both groups, but the decreases were not significant. Serum levels of total cholesterol, triglyceride, and free fatty acidsat the beginning of the study were 114.18 ± 43.43 mg/dl, 146.59 ± 53.99 mg/dl, 0.83 ± 0.57 mmol/L, and at the end of the study were 129.10 ± 39.05 mg/dl, 127.40 ± 91.88 mg/dl, 0.88 ± 0.77 mmol/L, respectively. None of these changes were significant either (P = 0.99, P = 0.38, P = 0.90, respectively). Conclusions According to our findings, synbiotics supplementation in critically ill patients has no significant effect on lipid and glucose profile.

Background: Distinction between alopecia areata (AA) and androgenic alopecia (AGA) can be made according to clinical presentation and biopsy findings. However, it is sometimes difficult to differentiate them, especially when the diffuse pattern of both AA and AGA is in the differential diagnosis of hair loss in androgen-dependent areas.Objectives: To evaluate the characteristics of inflammatory cell infiltration using CD3, CD4, CD8, and CD20 antigens, in AA and AGA to find some consistent histological clues for distinguishing these two entities.Methods: A retrospective analysis of patients with diagnosed AA (30 cases) and AGA (30 cases) was performed based on the clinical and histopathological criteria. We studied immunohistochemical findings for CD3, CD4, CD8, and CD20 in all selected cases.Results: Immunohistochemical stains for CD4 and CD20 were not helpful in differentiating AA from AGA, but the inflammation density for AA was significantly (P-value = .025, .001) higher than AGA in CD3 (specificity= 86.7% and sensitivity= 96.7%) and CD8 (specificity= 50% and sensitivity=86.6%). Our findings revealed that intrafollicular CD3 (P-value = .017) and CD8 (P-value = ˂.001) infiltrations were significantly higher in AA samples in comparison with AGA.Conclusion: Characterization of CD3 and CD8 in IHC samples is helpful, especially when the density of CD3 and CD8 T cells are significant in more than 50% of the infiltrated cells and are located intrafolliculary. Moreover, the most specific and sensitive test for differentiating of AA from AGA is CD3.

IntroductionCoronary artery disease (CAD), classified into the atherosclerosis category, is a prevalent cardiovascular disease worldwide that is associated with serious comorbidities and death. The purpose of this study was to evaluate the effect of beetroot/beetroot plus vitamin C on cardiovascular health status and function in patients with CAD.Method and analysisA randomised, placebo-controlled, double-blind clinical trial to recruit 90 patients with CAD at the cardiac outpatient clinic and Imam Reza Hospital, Mashhad, Iran. Participants will be divided into three groups: (1) Those who receive 500 mg three times a day of beetroot capsules, (2) Those who receive 500 mg three times a day of beetroot plus vitamin C capsules, and (3) Those who receive placebo capsules three times a day for 4 weeks. Pulse wave velocity, Augmentation Index, heart rate, volume of oxygen (VO2) max/VO2 peak, peak heart rate, blood pressure, interleukin 6 (IL-6), high sensitivity C reactive protein, intercellular adhesion molecule, vascular cell adhesion molecule, lipid profile and anthropometry will be measured at the beginning and end of the intervention.Ethics and disseminationThis study was approved by the Ethics Committee of Mashhad University of Medical Sciences (IR.MUMS.MEDICAL.REC.1399.717). All participants will be asked to complete the consent form at the beginning of the study. The results will be actively disseminated through peer-reviewed journals and conference presentations.Trial registration numberIranian Registry of Clinical Trials, IRCT20210217050393N1 (registered 16 May 2021).

Objective: Breast cancer is the most common cancer and leading cause of mortality in women worldwide. Diagnosis of axillary lymph node involvement, frequently by axillary ultrasonography (AUS), is an important step in patients with primary breast cancer, while the gold standard pathological examination is only applicable during surgery. Thus, we aimed to evaluate the predictive value of AUS in detection of lymph node involvement. Methods: A total of 56 patients with primary breast cancer, who were candidate of mastectomy were included in this study. A single radiologist performed pre-operative axillary sonography for all the patients and reported the results in a checklist. The results were then compared with intra-operative pathological results of lymph node dissection to evaluate the sensitivity, specificity, positive and negative predictive values of AUS in detection of the disease. Result: The results showed that pre-operative AUS had a sensitivity of 63.3%, specificity of 84.6%, positive predictive value of 82.6%, and negative predictive value of 66.6%. Correlation between axillary lymph node characteristics revealed that the absence of fatty hilum, cortical thickness, and loss of ovality of the lymph nodes were the most specific factors in detection of lymph nodes’ involvement. Conclusion: AUS has a low sensitivity and cannot determine the presence of micro-metastases and suspicious lymph nodes accurately in early stages of the disease, and it seems that defining new parameters may help for increasing the sensitivity and specificity of the axillary lymph node sonography. Apparently, pathological examination remains the gold standard diagnostic method.

Background Although life-threatening hemorrhage is a usual manifestation of acute promyelocytic leukemia (APL), thrombotic events seem to be more common in APL compared to other subtypes of acute leukemia. The treatment and prophylaxis of thrombosis are controversial due to the high risk of bleeding caused by disseminated intravascular coagulation (DIC) and thrombocytopenia. To the best of our knowledge we report the first case of APL in a patient with prosthetic heart valves successfully treated with a combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). We hope this case report helps clinicians to manage different spectra of coagulopathy in APL successfully. Case presentation A 38-year-old Asian man presented with diagnosis of APL confirmed by bone marrow biopsy. He was on warfarin due to prosthetic mitral and aortic valves. He was at risk of both hemorrhagic events due to DIC and life-threatening valve thrombosis. Our management regimen included unfractionated heparin adjusted according to the platelet count to prevent both valve thrombosis and bleeding events. The patient tolerated treatment well without any hemorrhagic or thrombotic events, and complete molecular remission was achieved by ATRA and ATO without the need for chemotherapeutic agents. Conclusion Although this case is exceptional, a precise evaluation may be needed to select the appropriate dose and type of anticoagulant to treat a patient with APL.

Objective:Many arthritic patients have the belief that dietary habits can worsen or ameliorate their symptoms. Whether diet quality can modify the risk of rheumatoid arthritis (RA) is an issue of continued scientific debate and interest. Therefore, we aimed to examine the association between both overall diet quality and the overall diet inflammatory potential on the risk of RA.Design:Overall diet quality and the overall inflammatory potential of the diet were evaluated with the use of Dietary Inflammatory Index (DII) and the Healthy Eating Index (HEI)-2015, respectively. Both DII and HEI-2015 scores were calculated based on a validated semi-quantitative FFQ. Multivariable-adjusted odds of RA were calculated across tertiles of HEI, and energy-adjusted DII (E-DII) scores using binary logistic regression.Setting:Mashhad, Iran.Participants:Fifty newly diagnosed RA cases and 100 well-matched healthy people controls.Results:Individuals in the highest tertile of DII scores, indicating the most pro-inflammatory diet, were about three times more likely to have RA than those in the lowest tertile (OR: 2·99; 95 % CI 1·08, 8·24; P-trend: 0·037), whereas individuals in the highest tertile of HEI scores, indicating more top dietary quality, had a significantly lower odds of RA than those in the lowest tertile (OR: 0·33; 95 % CI 0·12, 0·87; P-trend: 0·024).Conclusions:Our findings show that E-DII and HEI-2015 are positively and negatively associated, respectively, with the odds of RA in a convenience sample of Iranians. These results highlight the importance of overall diet quality in modulating the risk of RA.

Propranolol, a nonselective β-adrenergic receptor (ADRB) antagonist, is the first-line therapy for severe infantile hemangiomas (IH). Since the incidental discovery of propranolol efficacy in IH, preclinical and clinical investigations have shown evidence of adjuvant propranolol response in some malignant tumors. However, the mechanism for propranolol antitumor effect is still largely unknown, owing to the absence of a tumor model responsive to propranolol at nontoxic concentrations. Immunodeficient mice engrafted with different human tumor cell lines were treated with anti-VEGF bevacizumab to create a model sensitive to propranolol. Proteomics analysis was used to reveal propranolol-mediated protein alteration correlating with tumor growth inhibition, and Aquaporin-1 (AQP1), a water channel modulated in tumor cell migration and invasion, was identified. IH tissues and cells were then functionally investigated. Our functional protein association networks analysis and knockdown of ADRB2 and AQP1 indicated that propranolol treatment and AQP1 down-regulation trigger the same pathway, suggesting that AQP1 is a major driver of beta-blocker antitumor response. Examining AQP1 in human hemangioma samples, we found it exclusively in a perivascular layer, so far unrecognized in IH, made of telocytes (TCs). Functional in vitro studies showed that AQP1-positive TCs play a critical role in IH response to propranolol and that modulation of AQP1 in IH-TC by propranolol or shAQP1 decreases capillary-like tube formation in a Matrigel-based angiogenesis assay. We conclude that IH sensitivity to propranolol may rely, at least in part, on a cross talk between lesional vascular cells and stromal TCs.

BackgroundNeoadjuvant chemotherapy (NACT) is the prime approach to the management of locally advanced breast cancer (LABC). Influenced by different factors such as pathologic tumor characteristics, hormone receptor status, HER2 and proliferation marker expressions, response to therapy cannot be easily predicted. Pathologic complete response (pCR) has been considered as an endpoint to NACT; however, pCR rates have been unsatisfactory in such patients. In this randomized trial, we studied the efficacy of carboplatin/gemcitabine as second-line NACT while evaluating the impact of different factors affecting response.MethodsIn this randomized controlled trial, 52 clinically non-responsive (confirmed by palpation and/or ultrasonography) LABC patients to 4 cycles of doxorubicin/cyclophosphamide followed by 4 cycles of paclitaxel ± trastuzumab were randomly allocated to two groups. “Control” group underwent breast surgery and were further evaluated for pCR (ypT0/is ypN0). “Intervention” group received 2 cycles of carboplatin/gemcitabine and patients were further evaluated for pCR following surgery.ResultsIn a total of 52 patients, pCR rate was 30.7%. pCR and response rate in lymph nodes were higher in carboplatin/gemcitabine recipients (32% vs 29.7 and 44% vs 40.7% respectively), however differences were insignificant. In both the “intervention” group and total study population, most pCR cases were of the hormone receptor (HR)+/HER2+ subtype (87.5% and 75% respectively). HER2 positivity, ki67 expression, lower extent of ER positivity, higher tumor grade and tumor-infiltrating lymphocyte (TIL) lead to higher pCR rates. Adverse events following addition of carboplatin/gemcitabine were mostly hematologic and none required hospitalization. Anemia was the most common grade 3 adverse event observed. No grade 4 toxicity was evident.ConclusionAlthough the proposed carboplatin/gemcitabine combination could not improve pCR rates as expected, probability of immune activation following use of carboplatin in achieving response to NACT may be considered. Accounting for the highest number of pCR cases in the “intervention” group, the HR+/HER2+ subtype with high TILs may be considered as most responsive to the proposed regimen in this study. It is noteworthy that the proposed combination imposed minimal toxicity.Trial registrationThis trial was prospectively registered in IRCT.ir (IRCT2017100136491N1). Date of registration: 19 November 2017.

International audience; Metabolic reprogramming is a common hallmark of cancer, but a large variability in tumor bioenergetics exists between patients. Using high-resolution respirometry on fresh biopsies of human lung adenocarcinoma, we identified 2 subgroups reflected in the histologically normal, paired, cancer-adjacent tissue: high (OX+) mitochondrial respiration and low (OX-) mitochondrial respiration. The OX+ tumors poorly incorporated [F-18]fluorodeoxy-glucose and showed increased expression of the mitochondrial trifunctional fatty acid oxidation enzyme (MTP; HADHA) compared with the paired adjacent tissue. Genetic inhibition of MTP altered OX+ tumor growth in vivo. Trimetazidine, an approved drug inhibitor of MTP used in cardiology, also reduced tumor growth and induced disruption of the physical interaction between the MTP and respiratory chain complex I, leading to a cellular redox and energy crisis. MTP expression in tumors was assessed using histology scoring methods and varied in negative correlation with [F-18]fluorodeoxy-glucose incorporation. These findings provide proof-of-concept data for preclinical, precision, bioenergetic medicine in oxidative lung carcinomas.

Background: Arterial stiffness (AS) indicates the initial stage of cardiovascular disease (CVD), which associated with modifiable and lifestyle risk factors. We aimed to examine the association of AS with anthropometric indices, lipid profiles, and physical activity. Methods: 658 healthy middle-aged adults selected and anthropometric indices (body mass index (BMI), waist circumferences (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), neck circumferences (NC), a body shape index (ABSI), body roundness index (BRI), body-fat mass (BFM), visceral-fat, fat-free mass(FFM), lipid profiles, and PA were measured. Arterial Stiffness measured by carotid-femoral pulse wave velocity (cf-PWV) and central augmentation index (cAIx). Results: Our results show, cf-PWV positively associated with TGs (β = 0.10, p = 0.01) and in anthropometric indices corelated with, WC (β = 0.11, p = 0.02), WHR (β = 0.09, p = 0.03), WHtR (β = 0.1, p = 0.02), and BRI (β = 0.09, p = 0.04). cAIx was independently positive association with cholesterol (β = 0.08, p = 0.03), WC (β = 0.1, p = 0.03), WHR (β = 0.09, p = 0.02), ABSI (β = 0.09, p = 0.01), BRI (β = 0.08, p = 0.05), visceral-fat area (β = 0.09, p = 0.03) and BFM (β = 0.08, p = 0.04) and negatively associated with PA (β = -0.08, p = 0.03). Conclusions: WC, WHR, and BRI were associated with both cf-PWV and cAIx. TGs and WHtR associated with cf-PWV, while cAIx was associated with ABSI, so improving these indices may be helpful to prevent CVD.

Purpose The objective of this systematic review was to evaluate the effect of pre-, pro-, and synbiotics on feeding tolerance of enterally fed critically ill adult patients. Methods MEDLINE, Science Direct, Web of Knowledge, and the Cochrane Central Register of Controlled Trials were searched up to November 2019. English language randomized controlled trials reporting the effect of pre, pro or synbiotics on the feeding tolerance of enterally fed critically ill adult patients were included. Results Overall, 15 papers were selected for review. Among six studies reporting the energy intake, only two studies showed significantly higher energy intake in the prebiotic-receiving groups. Among four RCTs reporting frequency or time to achieve the target calorie, only one found a significant effect of probiotics to reduce the time to achieve a target dose of calorie. About the prevalence or duration of diarrhea, 7 out of 12 RCTs reported a beneficial effect. All but one study found no beneficial effects for gut microbiota manipulation on clinical endpoints including length of stay (LOS) in hospital and intensive care unit (ICU). Conclusion It should be noticed that the heterogeneity in study designs, product format, and ICU patient populations makes it difficult to draw any general conclusion. Overall, it seems that pre, pro, or synbiotics have no significant beneficial effect on feeding tolerance and clinical endpoints in critically ill adults, but they may reduce the prevalence or duration of diarrhea.

Targeting oncogenic signaling pathways by small molecules has emerged as a potential treatment strategy for cancer. reactivation of p53 and induction of tumor cell apoptosis (RITA) is a promising anticancer small molecule that reactivates p53 and induces exclusive apoptosis in tumor cells. Less well appreciated was the possible effect of small molecule RITA on p53-null leukemia cells. In this study, we demonstrated that RITA has potent antileukemic properties against p53-null chronic myeloid leukemia (CML)-derived K562 cells. RITA triggered apoptosis through caspase-9 and caspase-3 activation and poly (ADP-ribose) polymerase cleavage. RITA decreased STAT5 tyrosine phosphorylation, although it did not inhibit phosphorylation of the direct BCR-ABL substrate CrkL. Real-time PCR analysis showed that RITA downregulates antiapoptotic STAT5 target genes Bcl-xL and MCL-1. The downregulation of nuclear factor-κB (NF-κB), as evidenced by inhibition of IκB-α phosphorylation and its degradation, was associated with inhibition of Akt phosphorylation in RITA-treated cells. Furthermore, consistent with the decrease of mRNA levels, protein levels of the nuclear factor-κB-regulated antiapoptotic (cIAP1, XIAP, and Bcl-2) and proliferative (c-Myc) genes were downregulated by RITA in K562 cells. In conclusion, the ability of RITA to inhibit prosurvival signaling pathways in CML cells suggests a potential application of RITA in CML therapeutic protocols.

Background An extreme and persistent dysbiosis occurs among critically ill patients, regardless of the heterogeneity of disease. Dysbiosis in critically ill patients may make them prone to hospital-acquired infections, sepsis, multi-organ failure (MOF), energy homeostasis disturbance, muscle wasting, and cachexia. Modulation of gut microbiota through synbiotics can be considered as a potential treatment for muscle wasting and macronutrient homeostasis disturbances. Methods This is a prospective, single-center, double-blind, parallel randomized controlled trial with the aim to evaluate the effects of synbiotic supplementation on energy and macronutrient homeostasis and muscle wasting in critically ill patients. A total of 40 hemodynamically stable, adult, critically ill patients who receive enteral nutrition via a nasogasteric tube (NGT) in the 24–48 h after admission to critical care will be included in this study. Eligible patients will be randomly assigned to receive Lactocare (ZistTakhmir) capsules 500 mg every 12 h or a placebo capsule, which contains only the sterile maize starch and is similar to synbiotic capsules for 14 days. The synbiotic and placebo capsules will be given through the nasogastric tube, separately from gavage, after feeding. Discussion Gut microbiota modulation through synbiotics is proposed to improve clinical prognosis and reduce infectious complications, ventilator dependency, and length of ICU stay by improving energy and macronutrient homeostasis and reducing muscle protein catabolism. Trial registration Iranian Registry of Clinical Trials, IRCT20190227042857N1. Registered on 17 March 2019.

International audience

Skin cancers are the most common cancers worldwide. The incidence of common skin cancers, including basal cell carcinomas (BCCs), squamous cell carcinomas (SCCs) and melanomas, continues to rise by 5 to 7% per year, mainly due to ultraviolet (UV) exposure and partly because of aging. This suggests an urgent necessity to improve the level of prevention and protection for skin cancers as well as developing new prognostic and diagnostic markers of skin cancers. Moreover, despite innovative therapies especially in the fields of melanoma and carcinomas, new therapeutic options are needed to bypass resistance to targeted therapies or treatment's side effects. Since reprogramming of cellular metabolism is now considered as a hallmark of cancer, some of the recent findings on the role of energy metabolism in skin cancer initiation and progression as well as its effect on the response to targeted therapies are discussed in this review. This article is part of a Special Issue entitled Mitochondria in cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.

Chemotherapies alter cellular redox balance and reactive oxygen species (ROS) content. Recent studies have reported that chemoresistant cells have an increased oxidative state in hematologic malignancies. In this study, we demonstrated that chemoresistant acute myeloid leukemia (AML) cells had a lower level of mitochondrial and cytosolic ROS in response to cytarabine (AraC) and overexpressed myeloperoxidase (MPO), a heme protein that converts hydrogen peroxide to hypochlorous acid (HOCl), compared with sensitive AML cells. High MPO-expressing AML cells were less sensitive to AraC in vitro and in vivo. They also produced higher levels of HOCl and exhibited an increased rate of mitochondrial oxygen consumption when compared with low MPO-expressing AML cells. Targeting MPO expression or enzyme activity sensitized AML cells to AraC treatment by triggering oxidative damage and sustaining oxidative stress, particularly in high MPO-expressing AML cells. This sensitization stemmed from mitochondrial superoxide accumulation, which impaired oxidative phosphorylation and cellular energetic balance, driving apoptotic death and selective eradication of chemoresistant AML cells in vitro and in vivo. Altogether, this study uncovers a noncanonical function of MPO enzyme in maintaining redox balance and mitochondrial energetic metabolism, therefore affecting downstream pathways involved in AML chemoresistance. Significance: These findings demonstrate the role of myeloperoxidase in the regulation of ROS levels and sensitivity of AML cells to cytarabine, an essential chemotherapeutic backbone in the therapy of AML.

Purpose The purpose of this study was to compare the efficacy and safety of a proposed bevacizumab biosimilar to those of the reference product in patients with metastatic colorectal cancer (mCRC). Methods This Phase III, multicenter, randomized, double-blind (patient- and assessor-blind), active-controlled, 2-armed, parallel-group, noninferiority trial was conducted in patients with histologically verified colorectal cancer with evidence of at least 1 metastasis. Patients with mCRC were randomized 2:1 to receive 5 mg/kg IV of either study drug plus FOLFIRI-3 (with repeated irinotecan 100 mg/m2 60-min infusion on day 3) or the reference drug plus FOLFIRI-3 every 2 weeks for 1 year. Progression-free survival (PFS) was the primary end point, and overall survival, objective response rate, and time to treatment failure as well as safety and immunogenicity were secondary end points. The population assessable for PFS was per protocol, and the intention-to-treat population was used for sensitivity analysis. Safety was assessed based on reports of adverse events, laboratory test results, and vital sign measurements. Findings A total of 126 patients were enrolled; PFS values in the biosimilar and reference arms were 232 days (7.7 months) and 210 days (7 months), respectively (P = 0.47). The hazard ratio of the biosimilar arm versus the reference arm was 0.79 in the per-protocol population (90% CI, 0.46–1.35; P = 0.47). The upper limit for the 2-sided 90% CI was lower than the margin of 1.44, indicating that the biosimilar drug was noninferior to the reference drug. The hazard ratio for overall survival in the intent-to-treat population was 0.99 (95% CI, 0.55–1.80; P = 0.99). The difference between other efficacy end points among the groups was not statistically significant. No significant difference was observed in the comparison of the two arms for safety. The antidrug antibody was positive in 1 patient in each arm. Implications The proposed biosimilar BE1040V was noninferior to the reference product in terms of efficacy in the treatment of mCRC, and tolerability was comparable between the 2 drugs. ClinicalTrials.gov identifier: NCT03288987.

International audience; No abstract available

The continuous exposure of the human body’s cells to radiation and genotoxic stresses leads to the accumulation of DNA lesions. Fortunately, our body has several effective repair mechanisms, among which is nucleotide excision repair (NER), to counteract these lesions. NER includes both global genome repair (GG-NER) and transcription-coupled repair (TC-NER). Deficiencies in the NER pathway underlie the development of several DNA repair diseases, such as xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). Deficiencies in GG-NER and TC-NER render individuals to become prone to cancer and neurological disorders, respectively. Therefore, NER regulation is of interest in fine-tuning these risks. Distinct signaling cascades including the NFE2L2 (NRF2), AHR, PI3K/AKT1, MAPK, and CSNK2A1 pathways can modulate NER function. In addition, several chemical and biological compounds have proven success in regulating NER’s activity. These modulators, particularly the positive ones, could therefore provide potential treatments for genetic DNA repair-based diseases. Negative modulators, nonetheless, can help sensitize cells to killing by genotoxic chemicals. In this review, we will summarize and discuss the major upstream signaling pathways and molecules that could modulate the NER’s activity.

Nonalcoholic fatty liver disease (NAFLD) is common among severely obese patients. Two-dimensional shear wave elastography (2D-SWE) has been validated as a noninvasive diagnostic tool for liver stiffness measurement. However, the technical feasibility and accuracy of this method in severely obese patients are still under debate. We aimed to assess the diagnostic accuracy of 2D-SWE in bariatric surgery candidates in comparison with the gold standard liver biopsy. Ninety severely obese candidates for bariatric surgery were included. Liver stiffness was measured using 2D-SWE 14 days before liver biopsy. Liver biopsy was taken on the day of surgery. The area under the receiver operating curve (AUROC) was calculated for the staging of liver fibrosis. 2D-SWE was performed in 97.3% of patients successfully. Histologic stages of fibrosis (F0-F4) were detected in 34.2%, 36%, 6.3%, 3.6%, and 0.9% of patients, respectively. The AUROC for 2D-SWE was 0.77 for F1, 0.72 for F2, 0.77 for F3, and 0.70 for F4. In univariate analysis, 2D-SWE values were correlated with BMI, waist circumference, NAFLD activity score (NAS), and steatosis, whereas these components did not affect liver stiffness in multivariate analysis. Two-dimensional shear wave elastography of the liver can be feasible and has good accuracy in severely obese candidates for bariatric surgery. Therefore, 2D-SWE may be a good option for assessing liver fibrosis, especially in the early stages of fibrosis to lessen complications of surgery in this population. However, this method should be applied on a larger scale for late stage of fibrosis.

Congenital factor VII (FVII) deficiency is a rare bleeding disorder with an estimated prevalence of 1 per 500 000 in the general population. On-demand replacement therapy is the main therapeutic choice in patients with congenital FVII deficiency. Inhibitor formation against exogenous FVII is very rare and can cause challenges in the management of the disorder. The present study was conducted to assess the prevalence of FVII inhibitor in 50 patients with congenital FVII deficiency under on-demand or prophylaxis treatment by recombinant activated FVII. All patients with confirmed congenital FVII deficiency were assessed for inhibitor development in regular intervals. Inhibitor titer was determined by a modified Nijmegen-Bethesda assay. The study results were analyzed by SPSS software. Among all cases, two patients (4%) developed an FVII inhibitor. Case 1 was a 14-year-old boy with severe FVII deficiency (FVII activity1%) with regular prophylaxis. The patient was a high-responder with high-titer FVII inhibitor (170 Bethesda Unit). This patient, who had a history of intracranial hemorrhage, had undergone brain surgery three times. The second patient was a 70-years old man with on-demand therapy that also developed a high-titer inhibitor (10 Bethesda Unit). This patient had experienced easy bruising and endured a few surgeries for his brain tumor and, finally, succumbed to the disease. Although the inhibitor formation is a rare phenomenon, it may result in a significant challenge to manage the affected patients.

Imatinib mesylate (IM) is a frontline treatment in the early chronic phase of chronic myeloid leukemia (CML). However, intrinsic and acquired resistance against this drug has been defined and this issue has become a problem and a challenge in CML treatment. According to new findings, the inhibition of Janus kinase 2 (Jak2) in Bcr-Abl+ cells can promote apoptosis in IM-resistant cells. microRNAs (miRNAs) regulate the gene expression by targeting the messenger RNA (mRNA) for degradation. Recently, a growing body of evidence has implicated that dysregulation of miRNAs is associated with cancer initiation and development. In this report, we proposed that miRNA-101 targets Jak2 mRNA and regulates its expression and induces K562 leukemia cell apoptosis. Here, we transduced the K562 cell line with a miR-101-overexpressing vector and evaluated the Jak2 mRNA level. Our results showed that miR-101 overexpression in Bcr-Abl+ cells reduced the Jak2 mRNA level. Moreover, imatinib treatment and miR-101 upregulation led to miR-23a overexpression, which has putative binding site(s) on 3'-untranslated regions (3'-UTRs) of STAT5, CCND1, and Bcl-2 genes. Our results also indicated that miR-101 overexpression inhibited cell proliferation indicated by the MTT assay and promoted apoptosis detected via flow cytometry. Importantly, mRNA expression of NF-kappa B-regulated anti-apoptotic (Bcl-2, Bcl-xl, MCL-1, XIAP, and survivin) and proliferative (c-Myc and CCND1) genes was decreased. These findings suggest that miR-101 acts as a tumor suppressor by downregulating Jak2 expression and sensitizing K562 cells to imatinib. Therefore, restoration of miR-101 may be a therapeutic approach for CML treatment.

HIF-1α is constitutively expressed in mouse and human epidermis. It plays a crucial role in skin physiology, including the response of keratinocytes to UVR. However, little information is available about its role in photocarcinogenesis. Using a multistage model of UVB radiation-induced skin cancer, we show that the knockout of Hif-1α in the epidermis prevents tumorigenesis but at the same time triggers the formation of hyperkeratotic plaques. Our results indicate that the absence of oncogenic transformation in Hif-1α–ablated mice is related to increased DNA repair in keratinocytes, whereas the formation of hyperkeratotic plaques is caused by an increase in the levels of reactive oxygen species. Indeed, impairing the DNA repair machinery by ablating xeroderma pigmentosum C restored the UVB-induced neoplastic transformation of Hif-1α–ablated keratinocytes, whereas the development of hyperkeratotic plaques was blocked by chronic antioxidant treatment. We conclude that HIF-1α plays a procarcinogenic role in UVB-induced tumorigenesis.

Skin pigmentation abnormalities are manifested in several disorders associated with deficient DNA repair mechanisms such as nucleotide excision repair (NER) and double-strand break (DSB) diseases, a topic that has not received much attention up to now. Hereditary disorders associated with defective DNA repair are valuable models for understanding mechanisms that lead to hypo- and hyperpigmentation. Owing to the UV-associated nature of abnormal pigmentary manifestations, the outcome of the activated DNA damage response (DDR) network could be the effector signal for alterations in pigmentation, ultimately manifesting as pigmentary abnormalities in repair-deficient disorders. In this review, the role of the DDR network in the manifestation of pigmentary abnormalities in NER and DSB disorders is discussed with a special emphasis on NER disorders.

Xeroderma pigmentosum type C (XP-C) is characterized mostly by a predisposition to skin cancers and accelerated photoaging, but little is known about premature skin aging in this disease. By comparing young and old mice, we found that the level of progerin and p16 INK4a expression, β-galactosidase activity, and reactive oxygen species, which increase with age, were higher in young Xpc -/- mice than in young Xpc +/+ ones. The expression level of mitochondrial complexes and mitochondrial functions in the skin of young Xpc -/- was as low as in control aged Xpc +/+ animals. Furthermore, the metabolic profile in young Xpc -/- mice resembled that found in aged Xpc +/+ mice. Furthermore, premature skin aging features in young Xpc -/- mice were mostly rescued by inhibition of nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1) activity by using a NOX1 peptide inhibitor, suggesting that the continuous oxidative stress due to overactivation of NOX1 has a causative role in the underlying pathophysiology.

Nucleotide excision repair (NER) is an important DNA repair pathway involved in the removal of a wide array of DNA lesions. The absence or dysfunction of NER results in the following distinct disorders: xeroderma pigmentosum (XP), Cockayne syndrome (CS), cerebro-oculo-facio-skeletal (COFS) syndrome, UV-sensitive syndrome (UVSS), trichothiodystrophy (TTD), or combined syndromes including XP/CS, XP/TTD, CS/TTD, and COFS/TTD. In addition to their well-characterized role in the NER signaling pathway, NER factors also seem to be important in biological processes that are not directly associated with DNA damage responses, including mitochondrial function and redox homeostasis. The potential causative role of these factors in the large clinical spectrum seen in NER diseases is discussed in this review.

Skin protects the body from dehydration, pathogens, and external mutagens. NADPH oxidases are central components for regulating the cellular redox balance. There is increasing evidence indicating that reactive oxygen species (ROS) generated by members of this enzyme family play important roles in the physiology and pathophysiology of the skin. Recent Advances: NADPH oxidases are active producers of ROS such as superoxide and hydrogen peroxide. Different isoforms are found in virtually all tissues. They play pivotal roles in normal cell homeostasis and in the cellular responses to various stressors. In particular, these enzymes are integral parts of redox-sensitive prosurvival and proapoptotic signaling pathways, in which they act both as effectors and as modulators. However, continuous (re)activation of NADPH oxidases can disturb the redox balance of cells, in the worst-case scenario in a permanent manner. Abnormal NADPH oxidase activity has been associated with a wide spectrum of diseases, as well as with aging and carcinogenesis.Sunlight with its beneficial and deleterious effects induces the activation of NADPH oxidases in the skin. Evidence for the important roles of this enzyme family in skin cancer and skin aging, as well as in many chronic skin diseases, is now emerging.Understanding the precise roles of NADPH oxidases in normal skin homeostasis, in the cellular responses to solar radiation, and during carcinogenesis will pave the way for their validation as therapeutic targets not only for the prevention and treatment of skin cancers but also for many other skin-related disorders. Antioxid. Redox Signal. 28, 1238-1261.

International audience; The complementation group F of Xeroderma pigmentosum (XP-F) is rare in the Caucasian population, and usually devoid of neurological symptoms. We report two cases, both Caucasian, who exhibited progressive cerebellar ataxia, chorea, a mild subcortical frontal cognitive impairment, and in one case severe polyneuropathy. Brain MRI demonstrated cerebellar (2/2) and cortical (1/2) atrophy. Both patients had only mild sunburn sensitivity and no skin cancer. Mini-exome sequencing approach revealed in ERCC4, two heterozygous mutations, one of which was never described (c.580-584+1delCCAAGG, exon 3), in the first case, and an already reported homozygous mutation, in the second case. These cases emphasize that XP-F is a rare cause of recessive cerebellar ataxia and can in some cases clinically mimic Huntington's disease due to chorea and executive impairment. The association of ataxia, chorea, and sun hypersensitivity are major guidance for the diagnosis, which should not be missed, in order to prevent skin neoplastic complications.

In order to evaluate biological potential of a novel synthesized complex [Nd(dmp)2Cl3.OH2] where dmp is 29-dimethyl 110-phenanthroline, the DNA-binding, cleavage, BSA binding, and antimicrobial activity properties of the complex are investigated by multispectroscopic techniques study in physiological buffer (pH 7.2).The intrinsic binding constant (Kb) for interaction of Nd(III) complex and FS–DNA is calculated by UV–Vis (Kb = 2.7 ± 0.07 × 105) and fluorescence spectroscopy (Kb = 1.13 ± 0.03 × 105). The Stern–Volmer constant (KSV), thermodynamic parameters including free energy change (ΔG°), enthalpy change (∆H°), and entropy change (∆S°), are calculated by fluorescent data and Vant’ Hoff equation. The experimental results show that the complex can bind to FS–DNA and the major binding mode is groove binding. Meanwhile, the interaction of Nd(III) complex with protein, bovine serum albumin (BSA), has also been studied by using absorption and emission spectroscopic tools. The experimental results show that the complex exhibits good binding propensity to BSA. The positive ΔH° and ∆S° values indicate that the hydrophobic interaction is main force in the binding of the Nd(III) complex to BSA, and the complex can quench the intrinsic fluorescence of BSA remarkably through a static quenching process. Also, DNA cleavage was investigated by agarose gel electrophoresis that according to the results cleavage of DNA increased with increasing of concentration of the complex. Antimicrobial screening test gives good results in the presence of Nd(III) complex system.

SummaryObjective Sex steroid hormones play an important regulatory role in fat metabolism and obesity. We hypothesized involvement of interactions between ovarian hormones with acylation stimulating protein (ASP). Design, patients and measurements In 392 women with wide age (18–69 years) and body size (BMI: 17 to 90 kg/m2) ranges, fasting plasma levels of ASP, ovarian hormones, glucose, adiponectin and lipids/apolipoproteins were assessed, along with determination of metabolic syndrome (MS) features. Gene expression of C3 (ASP precursor) and related receptors C5L2, C3aR and C5aR in subcutaneous and omental adipose tissues was measured in a subset. Results Acylation stimulating protein correlated negatively with concentrations of estradiol (P

Purpose Bioactive glass air abrasion is a conservative technique for removal of initial decalcified enamel superficial layer and caries vs alumina air abrasion. This study evaluated shear bond strength of composite resin to sound and decalcified deciduous enamel using etch-and-rinse and self-etch adhesives after alumina and bioactive glass air abrasion. Materials and methods Ninety-six flat enamel surfaces, mounted in acrylic resin, were prepared from 48 deciduous molars. Half of the specimens were decalcified with a demineralizing solution. Both intact and decalcified specimens were assigned to two groups for alumina and bioactive glass air abrasion. In each group, the specimens were subdivided into two groups for application of Clearfil SE Bond or Optibond FL adhesives (n = 12). After composite resin bonding, the specimens underwent shear bond test. Data were analyzed using three-way analysis of variance (ANOVA), linear regression model and independentsample t-test (á = 0.05). Results No significant differences were noted in bond strength of composite resin after alumina or bioactive glass air abrasion (p = 0.272). Optibond FL adhesive and enamel decalcification produced higher bond strength (p = 0.000, p = 0.001 respectively). Conclusion In this study, bioactive glass air abrasion produced bond strength comparable to the conventional method. This technique might be an alternative method for preparation of normal and/or decalcified enamel of deciduous teeth for resin bonding. How to cite this article Eshghi A, Khoroushi M, Rezvani A. Resin Bonding using Etch-and-Rinse and Self-etch Adhesives to Decalcified Deciduous Enamel after Bioactive Glass Air Abrasion. J Contemp Dent Pract 2014;15(5):595-602.

Objective While a Mediterranean dietary pattern (MedDiet) has been associated with favorable changes in several features of metabolic syndrome (MetS), its impact on plasma adipokine concentrations remains largely unknown. The objective of this study was to determine the impact of the MedDiet consumed under controlled feeding conditions, without (− WL) and with weight loss (+ WL), on plasma adipokine concentrations in adult men with MetS (NCEP-ATP III). Materials/Methods The diet of 26 men with MetS (age 24 to 62 yrs) was first standardized to a North American control diet for 5 weeks. Participants then consumed a pre-determined MedDiet for 5 weeks. Both diets were consumed under weight-maintaining isoenergetic feeding conditions. Participants then underwent a 20-week free-living caloric restriction period, after which they consumed the MedDiet again in weight stabilizing, isoenergetic feeding conditions. Results Body weight was reduced by 10.2% ± 2.9% and waist circumference by 8.6 ± 3.3 cm after the weight loss period and stabilization on MedDiet (P

The ubiquitin-proteasome pathway is involved in the pathogenesis of several neurogenetic diseases. We describe a Mauritanian patient harboring a homozygous deletion restricted to two contiguous genes HERC2 and OCA2 and presenting with severe developmental abnormalities. The deletion causes the complete loss of HERC2 protein function, an E3-ubiquitin ligase. HERC2 is known to target XPA and BRCA1 for degradation and a mechanism whereby it is involved in DNA repair and cell cycle regulation. We showed that loss of HERC2 function leads to the accumulation of XPA and BRCA1 in the patient's fibroblasts and generates decreased sensitivity to apoptosis and increased level of DNA repair. Our data describe for the first time the phenotypic consequences, both at the clinical and cellular levels, of a complete loss of HERC2 function in a patient. They strongly suggest that profound ubiquitin ligase - associated dysfunction is responsible for the severe phenotype in this patient, and that dysfunction of this pathway may be involved in other patients with similar neurodevelopmental diseases.

Cancer cells utilize complex mechanisms to remodel their bioenergetic properties. We exploited the intrinsic genomic stability of xeroderma pigmentosum C (XPC) to understand the inter-relationships between genomic instability, reactive oxygen species (ROS) generation, and metabolic alterations during neoplastic transformation. We showed that knockdown of XPC (XPC KD ) in normal human keratinocytes results in metabolism remodeling through NADPH oxidase-1 (NOX-1) activation, which in turn leads to increased ROS levels. While enforcing antioxidant defenses by overexpressing catalase, CuZnSOD, or MnSOD could not block the metabolism remodeling, impaired NOX-1 activation abrogates both alteration in ROS levels and modifications of energy metabolism. As NOX-1 activation is observed in human squamous cell carcinomas (SCCs), the blockade of NOX-1 could be a target for the prevention and the treatment of skin cancers. This article is part of a Special Issue entitled: Bioenergetics of Cancer.

DNA-damaging agents can induce premature senescence in cancer cells, which contributes to the static effects of cancer. However, senescent cancer cells may re-enter the cell cycle and lead to tumor relapse. Understanding the mechanisms that control the viability of senescent cells may be helpful in eliminating these cells before they can regrow. Treating human squamous cell carcinoma (SCC) cells with the anti-cancer compounds, resveratrol and doxorubicin, triggered p53-independent premature senescence by invoking oxidative stress-mediated DNA damage. This process involved the mTOR-dependent phosphorylation of SIRT1 at serine 47, resulting in the inhibition of the deacetylase activity of SIRT1. SIRT1 phosphorylation caused concomitant increases in p65/RelA NF-κB acetylation and the expression of an anti-apoptotic Bfl-1/A1. SIRT1 physically interacts with the mTOR-Raptor complex, and a single amino acid substitution in the TOS (TOR signaling) motif in the SIRT1 prevented Ser-47 phosphorylation and Bfl-1/A1 induction. The pharmacologic and genetic inhibition of mTOR, unphosphorylatable S47A, or F474A TOS mutants restored SIRT1 deacetylase activity, blocked Bfl-1/A1 induction, and sensitized prematurely senescent SCC cells for apoptosis. We further show that the treatment of UVB-induced SCCs with doxorubicin transiently stabilized tumor growth but was followed by tumor regrowth upon drug removal in p53(+/-)/SKH-1 mice. The subsequent treatment of stabilized SCCs with rapamycin decreased tumor size and induced caspase-3 activation. These results demonstrate that the inhibition of SIRT1 by mTOR fosters survival of DNA damage-induced prematurely senescent SCC cells via Bfl-1/A1 in the absence of functional p53.

The DNA binding behavior of [Cu(phen)(phen-dione)Cl]Cl (1) and [Cu(bpy)(phen-dione)Cl]Cl (2) was studied with a series of techniques including UV-vis absorption, circular dichroism spectroscopy, and viscometric methods. Cytotoxicity effect and DNA unwinding properties were also investigated. The results indicate that the Cu(II) complexes interact with calf-thymus DNA by both partially intercalative and hydrogen binding. These findings have been further substantiated by the determination of intrinsic binding constants spectrophotometrically, 12.5 × 10(5) and 5 × 10(5) for 1 and 2, respectively. Our findings suggest that the type of ligands and structure of complexes have marked effect on the binding affinity of complexes involving CT-DNA. Circular dichroism results show that complex 1 causes considerable increase in base stacking of DNA, whereas 2 decreases the base stacking, which is related to more extended aromatic area of 1,10-phenanthroline in 1 rather than bipyridine in 2. Slow decrease in DNA viscosity indicates partially intercalative binding in addition to hydrogen binding on the surface of DNA. The second binding mode was also confirmed by additional tests: interaction in denaturation condition and acidic pH. Also, these new complexes induced cleavage in pUC18 plasmid DNA as indicated in gel electrophoresis and showed excellent antitumor activity against K562 (human chronic myeloid leukemia) cells.