Lack of Association between CD33 rs3865444 and Amyotrophic Lateral Sclerosis: A Case-Control Study.

BACKGROUND: Microglial activation is considered to assume a role in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). To date, the relationship between ALS and the rs3865444 polymorphism of the cluster of differentiation 33 (CD33) has not been explored. The current report aimed to investigate the potential connection between CD33 rs3865444 and ALS. METHODS: Patients diagnosed with sporadic ALS according to the revised El Escorial criteria, as well as age and sex matched community controls, were enrolled. Two evenly numbered, age and sex matched groups of 155 participants each were genotyped. RESULTS: No association was found between rs3865444 and ALS [log-additive odds ratio (OR) = 0.83 (0.57, 1.22), over-dominant OR = 0.86 (0.55, 1.36), recessive OR = 0.73 (0.25, 2.17), dominant OR = 0.82 (0.52, 1.29), co-dominant OR1 = 0.68 (0.23, 2.05) and co-dominant OR2 = 0.84 (0.53, 1.33)]. Moreover, no relationship was established between rs3865444 and the age of ALS onset based on both unadjusted and sex adjusted Cox-proportional hazards models. Finally, no association between rs3865444 and ALS was found in subgroup analyses based on the site of ALS onset (bulbar or spinal) and sex. CONCLUSIONS: The current analysis is the first to report that rs3865444 is not linked to ALS. Larger multi-racial studies are required to confirm these findings.

Baseline neurofilament levels in cerebrospinal fluid do not correlate with long-term prognosis in multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS) is the most common autoimmune disease of the central nervous system. Up to this day, no single accurate prognostic biomarker has been established in this disease. Neurofilaments are neuronal scaffold proteins released upon axonal damage and have gained attention as potential biomarkers in MS. METHODS: Neurofilament light-chain (NfL) levels were measured in the cerebrospinal fluid (CSF) of 83 MS patients at their first hospital admission. The patients were longitudinally followed up and EDSS assessments (MS disability) were performed. MSSS scores (MS severity) were also calculated. For disability, patients were allocated to a benign (EDSS≤3) and non-benign course (EDSS>3), and for severity, to benign, moderate, and severe disease courses (benign: 0-1.999, moderate: 2-6.999, severe: 7-10). RESULTS: NfL levels ranged between 185.8 and 24,440.0 ng/dl (median=995.8 ng/dl, mean=2032.9 ng/dl ±3107.8). The mean follow-up was 12.3 years (±6.7), ranging between 2 and 41 years (median=11 years). No significant association was found between NfL levels and age of onset (p = 0.858), disability (OR benign vs. non-benign: 0.916, p = 0.725), or severity (OR moderate vs. benign: 1.077, p = 0.791, OR severe vs. benign: 1.163, p = 0.642). A significant association was found between older age of onset and disability (OR benign vs. non-benign: 1.073, p = 0.005), and severity (OR moderate vs. benign: 1.063, p = 0.039, OR severe vs. benign: 1.122, p = 0.001). CONCLUSIONS: CSF NfL do not seem to be the ideal prognostic marker in MS. More research in this direction, with large follow-up periods, is needed to confirm our findings.

Deciphering the Role of the rs2651899, rs10166942, and rs11172113 Polymorphisms in Migraine: A Meta-Analysis.

The genetic basis of migraine is rather complex. The rs2651899 in the PR/SET domain 16 (PRDM16) gene, the rs10166942 near the transient receptor potential cation channel subfamily M member 8 (TRPM8) gene, and the rs11172113 in the LDL receptor-related protein 1 (LRP1) gene, have been associated with migraine in a genome-wide association study (GWAS). However, data from subsequent studies examining the role of these variants and their relationship with migraine remain inconclusive. The aim of the present study was to meta-analyze the published data assessing the role of these polymorphisms in migraine, migraine with aura (MA), and migraine without aura (MO). We performed a search in the PubMed, Scopus, Web of Science, and Public Health Genomics and Precision Health Knowledge Base (v7.7) databases. In total, eight, six, and six studies were included in the quantitative analysis, for the rs2651899, rs10166942, and rs11172113, respectively. Cochran's Q and I2 tests were used to calculate the heterogeneity. The random effects (RE) model was applied when high heterogeneity was observed; otherwise, the fixed effects (FE) model was applied. The odds ratios (ORs) and the respective 95% confidence intervals (CIs) were calculated to estimate the effect of each variant on migraine. Funnel plots were created to graphically assess publication bias. A significant association was revealed for the CC genotype of the rs2651899, with the overall migraine group (RE model OR: 1.32; 95% CI: 1.02−1.73; p-value = 0.04) and the MA subgroup (FE model OR: 1.40; 95% CI: 1.12−1.74; p-value = 0.003). The rs10166942 CT genotype was associated with increased migraine risk (FE model OR: 1.36; 95% CI: 1.18−1.57; p-value < 0.0001) and increased MO risk (FE model OR: 1.41; 95% CI: 1.17−1.69; p-value = 0.0003). No association was detected for the rs11172113. The rs2651899 and the rs10166942 have an effect on migraine. Larger studies are needed to dissect the role of these variants in migraine.

Testosterone and dihydrotestosterone modulate the redox homeostasis of endothelium.

The predominance of cardiovascular diseases among men compared to premenopausal women has been attributed to testosterone, which is implicated in vascular remodeling. Molecular mechanisms underlying its role have not been clarified but oxidative stress-induced inflammation may be important. We therefore investigated in vitro the effects of testosterone and dihydrotestosterone, (a nonaromatized androgen), on redox homeostasis in absence (basal conditions) and after corticotropin-releasing hormone-induced pro-oxidant action in macroendothelial cells. More specifically, we explored their role on well-established antioxidant enzymes activity, namely endothelial nitric oxide synthase, superoxide dismutase, catalase, and glutathione. We observed that both androgens significantly increased the intracellular reactive oxygen species levels, endothelial nitric oxide synthase activity, nitric oxide concentration as well as superoxide dismutase activity and decreased catalase activity. These effects of Testosterone and DHT were reversed in the presence of the androgen receptor antagonist, flutamide. Moreover, testosterone and dihydrotestosterone similarly enhanced the stimulatory effect of corticotropin-releasing hormone on intracellular reactive oxygen species levels and superoxide dismutase activity but did not influence the inhibitory effect on endothelial nitric oxide synthase activity, nitric oxide release and catalase activity. Finally, androgens did not have a detectable effect on glutathione levels or the glutathione/glutathione plus glutathione disulfide ratio. Our results reveal that testosterone and DHT rise the intracellular redox threshold of the endothelial cell and increases NO synthesis. These findings suggest that the action of testosterone is affected by the redox status of the endothelium and help to explain its controversial effects on the cardiovascular system.

Myelin-associated oligodendrocyte basic protein rs616147 polymorphism as a risk factor for Parkinson's disease.

BACKGROUND: The rs616147 polymorphism of the myelin-associated oligodendrocyte basic protein (MOBP) gene locus has been associated with amyotrophic lateral sclerosis (ALS). ALS and Parkinson's disease (PD) are two common neurodegenerative disorders that share features regarding their etiology, pathophysiology, and genetic backgrounds. While the MOBP rs616147 polymorphism has been associated with ALS, little is known about its role in PD. OBJECTIVE: To assess the role of MOBP rs616147 on PD risk. METHODS: This case-control comparison study consists of 358 PD-affected cases and 358 controls from the Neurology Clinic of the University Hospital of Larissa, University of Thessaly, Faculty of Medicine, in Greece. The diagnosis of PD was made by a specialist neurologist according to the UK Parkinson's Disease Society Brain Bank's clinical criteria. All the participants were genotyped for the MOBP rs616147. Furthermore, in order to validate our results, we genotyped 327 patients with Alzheimer's disease (AD) for MOBP rs616147 and compared them with the control group. RESULTS: According to the univariate analysis, there was a significant association between rs616147 and PD in the dominant (OR [95% C.I.] = 0.70 [0.52-0.94], p = .018), the overdominant (OR [95% C.I.] = 0.68 [0.50-0.92], p = .011), and in the codominant (G/A VS G/G; OR [95% C.I.] = 0.66 [0.48-0.91], p = .035) modes of inheritance. In contrast, there was no association between the MOBP rs616147 polymorphism and AD. CONCLUSIONS: We provide preliminary results associating MOBP rs616147 genetic variant with PD.

Accuracy of the sleep clinical record for the diagnosis of pediatric moderate-to-severe obstructive sleep apnea syndrome.

PURPOSE: The sleep clinical record (SCR) has been used to diagnose obstructive sleep apnea syndrome (OSAS) in children when access to polysomnography (PSG) is limited. Our aim was to determine the best SCR score that could facilitate diagnosis of moderate-to-severe OSAS in children with snoring. METHODS: Healthy children with history of snoring, who were referred for PSG, were prospectively recruited. The SCR score was calculated. Receiver operating characteristic curves (ROCs) were plotted to determine the area under curve (AUC), and the optimum SCR cutoff value was determined using the Youden index (J). RESULTS: Two hundred and seventy-three children were recruited (mean age 6.3 ± 2.5 years; median obstructive apnea-hypopnea index 1.5 episodes/h; range 0-61.1). The mean SCR score was 6.9 ± 3.6. Forty-six children had moderate-to-severe OSAS. Subjects with moderate-to-severe OSAS had a significantly higher mean SCR score (10.2 ± 2.9) than those with mild OSAS (6.2 ± 3.3; P < 0.001). Based on the plotted ROC, the AUC was 0.811 (95% confidence interval: 0.747-0.876; P < 0.001). Calculation of J, based on its ROC coordinates, indicated that the optimum cutoff SCR score to predict moderate-to-severe OSAS was 8.25, corresponding to a sensitivity of 83% and a specificity of 70%. CONCLUSION: Among children with history of snoring, an SCR score above 8.25 can identify those with moderate-to-severe OSAS.

MOBP rs616147 Polymorphism and Risk of Amyotrophic Lateral Sclerosis in a Greek Population: A Case-Control Study.

Background and Objectives: To date, only one study has investigated the association between the rs616147 polymorphism of the Myelin-associated Oligodendrocyte Basic Protein (MOBP) locus and Amyotrophic Lateral Sclerosis (ALS). Materials and Methods: A case-control study was performed. Patients with definite sporadic ALS were prospectively and consecutively recruited from the inpatient and outpatient clinics of the Neurology Department of the General University Hospital of Larissa, Central Greece. Community based, age and sex matched healthy individuals with a free personal and family history constituted the control group. Results: A total of 155 patients with definite sporadic ALS and an equal number of healthy controls were genotyped. The power of our sample size was slightly above 80% and MOBP rs616147 was determined to be in Hardy-Weinberg Equilibrium among healthy participants (p = 1.00). According to the univariate analysis, there was no significant relationship between rs616147 and ALS [log-additive OR = 0.85 (0.61, 1.19), over-dominant OR = 0.73 (0.46, 1.15), recessive OR = 1.02 (0.50, 2.09), dominant OR = 0.74 (0.47, 1.16), co-dominant OR1 = 0.71 (0.44, 1.14) and co-dominant OR2 = 0.88 (0.42, 1.84). Additionally, the effect of rs616147 on the age of ALS onset was determined insignificant using both unadjusted and adjusted (sex, site of onset) cox-proportional models. Finally, rs616147 was not related to the site of ALS onset. Conclusions: Our study is the first to report the absence of an association between MOBP rs616147 and ALS among individuals of Greek ancestry. Additional, larger nationwide and multi-ethnic studies are warranted to shed light on the connection between rs616147 and ALS.

Erythropoietin levels in children with obstructive sleep apnea.

OBJECTIVE: High serum erythropoietin (EPO) levels have been reported in adult patients with obstructive sleep apnea (OSA), however there is a lack of related literature in children with OSA. The main objective of this study was to explore the potential use of EPO as a pediatric OSA biomarker by exploring the relationship between serum EPO levels and the presence of pediatric OSA. METHODS AND MATERIALS: A prospective study was conducted on children (4-12 years old) referred for overnight PSG. Thirty (30) consecutive children with mild. 30 consecutives with moderate, and 30 consecutives with severe OSA (OSA group), as well as 30 consecutive children with AHI≤1 (non-OSA group) were recruited. Morning blood specimens after PSG studies were obtained in order to compare EPO levels. RESULTS: Finally, 115 children included for analysis. Non-OSA group consisted of 29 children (mean age: 6.93 ± 2.10) and OSA-group of 86 children (mean age: 6.78 ± 2.53). Mean EPO values for the non-OSA and OSA groups were 5.46 ± 2.29 mIU/ml and 8.33 ± 4.10 mIU/ml respectively. OSA-group had significant higher EPO levels than non-OSA (P: 0.01) while EPO levels were significantly correlated with AHI (p < 0.001). CONCLUSION: Our study showed that serum EPO levels of children with OSA are significantly higher than those without OSA and correlate significantly with AHI. These results suggest that EPO may be considered as a biomarker candidate for pediatric OSA. Since this may be the first study on the topic further research is needed.

Novel HIF-2α interaction with Reptin52 impairs HIF-2 transcriptional activity and EPO secretion.

Hypoxia-inducible factor 2 (HIF-2), is essential for cellular response to hypoxia and holds an important role in erythropoiesis, angiogenesis, tissue invasion and metastasis, thus, constituting an important therapeutic target. Maximal HIF-2 transcriptional activation requires HIF-2α phosphorylation by ERK1/2 that impairs its CRM1-mediated nuclear export. Herein, we reveal a novel interaction of HIF-2α with Reptin52, a multifunctional protein involved in cellular functions orchestrated both in the nucleus and the cytoplasm. HIF-2α and Reptin52 interact both in nuclear and cytoplasmic fractions, however, ERK1/2 pathway inactivation seems to favour their association in the cytoplasm. Notably, we demonstrate that Reptin52 reduces HIF-2 transcriptional activity, which results in decreased EPO secretion under hypoxia, by impairing HIF-2α stability via a non-canonical PHD-VHL-proteasome independent mechanism. This interaction represents a novel HIF-2 fine tuning mechanism that allows for distinct HIF1/2 isoforms regulation.

CD33 rs3865444 as a risk factor for Parkinson's disease.

BACKGROUND: Alzheimer's (AD) and Parkinson's diseases (PD) share a few elements of their clinical, pathological and genetic backgrounds. The CD33 rs3865444 has emerged as a strong genetic locus associated with AD through genome-wide association study (GWAS). However, little is known for its role in PD. OBJECTIVE: To assess the role of CD33 rs3865444 on PD risk. METHODS: We genotyped 358 patients with PD and 358 healthy controls for theCD33 rs3865444. Odds ratios (ORs) with the respective 95% confidence intervals (CIs)], were calculated with the SNPStats software, assuming five genetic models (co-dominant, dominant, recessive, over-dominant and log-additive), with the G allele as the reference allele. RESULTS: The CD33 rs3865444 was associated with decreased PD risk in the dominant [GG vs GT + TT; OR (95% CI) = 0.61 (0.45-0.82), p = 0.001], the over-dominant [GG + TT vs GT; OR (95% CI) = 0.65 (0.48-0.89), p = 0.0061], log-additive [OR (95% CI) = 0.67 (0.52-0.86), p = 0.0014], and co-dominant [with overall p = 0.0043, and OR (95% CI) = 0.62 (0.45-0.84) for the TG genotype compared to the GG], modes of inheritance. CONCLUSIONS: The CD33 rs3865444 is associated with decreased PD risk, and larger studies investigating the role of CD33 rs3865444 on PD are needed.

ADORA2A rs5760423 and CYP1A2 rs762551 Polymorphisms as Risk Factors for Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) is the second commonest neurodegenerative disease. The genetic basis of PD is indisputable. Both ADORA2A rs5760423 and CYP1A2 rs762551 have been linked to PD, to some extent, but the exact role of those polymorphisms in PD remains controversial. OBJECTIVE: We assessed the role of ADORA2A rs5760423 and CYP1A2 rs762551 on PD risk. METHODS: We genotyped 358 patients with PD and 358 healthy controls for ADORA2A rs5760423 and CYP1A2 rs762551. We also merged and meta-analyzed our data with data from previous studies, regarding these two polymorphisms and PD. RESULTS: No significant association with PD was revealed (p > 0.05), for either ADORA2A rs5760423 or CYP1A2 rs762551, in any of the examined genetic model of inheritance. In addition, results from meta-analyses yield negative results. CONCLUSIONS: Based on our analyses, it appears rather unlikely that ADORA2A rs5760423 or CYP1A2 rs762551 is among the major risk factors for PD, at least in Greek patients with PD.

CYP1A2 rs762551 polymorphism and risk for amyotrophic lateral sclerosis.

BACKGROUND: Genetic variability is considered to confer susceptibility to amyotrophic lateral sclerosis (ALS). Oxidative stress is a significant contributor to ALS-related neurodegeneration, and it is regulated by cytochromes P450 (CYPs), such as CYP1A2; these are responsible for the oxidative metabolism of both exogenous and endogenous substrates in the brain, subsequently impacting ALS. The function of CYP1A2 is largely affected by genetic variability; however, the impact of CYP1A2 polymorphisms in ALS remains underinvestigated. OBJECTIVE: This study aims to examine the possible association of ALS with the CYP1A2 rs762551 polymorphism, which codes for the high inducibility form of the enzyme. METHODS: One hundred and fifty-five patients with sporadic ALS and 155 healthy controls were genotyped for the CYP1A2 rs762551. Statistical testing for the association of CYP1A2 rs762551 with risk for ALS was performed using SNPstats. RESULTS: The CYP1A2 rs762551 C allele was associated with a decreased risk of ALS development. In the subgroup analysis according to the ALS site of onset, an association between CYP1A2 rs762551 and limb and bulbar onset of ALS was shown. Cox proportional-hazard regression analyses revealed a significant effect of the CYP1A2 rs762551 on the age of onset of ALS. CONCLUSIONS: Based on our results, a primarily potential link between the CYP1A2 rs762551 polymorphism and ALS risk could exist.

Calcitriol Suppresses HIF-1 and HIF-2 Transcriptional Activity by Reducing HIF-1/2α Protein Levels via a VDR-Independent Mechanism.

Hypoxia-inducible transcription factors 1 and 2 (HIFs) are major mediators of cancer development and progression and validated targets for cancer therapy. Although calcitriol, the biologically active metabolite of vitamin D, was attributed with anticancer properties, there is little information on the effect of calcitriol on HIFs and the mechanism underling this activity. Here, we demonstrate the negative effect of calcitriol on HIF-1/2α protein levels and HIF-1/2 transcriptional activity and elucidate the molecular mechanism of calcitriol action. We also reveal that the suppression of vitamin D receptor (VDR) expression by siRNA does not abrogate the negative regulation of HIF-1α and HIF-2α protein levels and HIF-1/2 transcriptional activity by calcitriol, thus testifying that the mechanism of these actions is VDR independent. At the same time, calcitriol significantly reduces the phosphorylation of Akt protein kinase and its downstream targets and suppresses HIF-1/2α protein synthesis by inhibiting HIF1A and EPAS1 (Endothelial PAS domain-containing protein 1) mRNA translation, without affecting their mRNA levels. On the basis of the acquired data, it can be proposed that calcitriol reduces HIF-1α and HIF-2α protein levels and inhibits HIF-1 and HIF-2 transcriptional activity by a VDR-independent, nongenomic mechanism that involves inhibition of PI3K/Akt signaling pathway and suppression of HIF1A and EPAS1 mRNA translation.

FGF-2 and HGF reverse abiraterone's effect οn intracellular levels of DHT in androgen-dependent and androgen independent prostate cancer cell lines.

PURPOSE: Growth factors such as fibroblast growth factor 2 (FGF-2) and hepatocyte growth factor (HGF) appear at high levels in prostate cancer (PC). Abiraterone is an androgen biosynthesis inhibitor which is currently in use as a standard treatment in clinics to impair tumor growth. Development of resistance to anticancer therapies is unfortunately a very common feature of cancer cells that threatens the patient lives. This study aimed to investigate whether FGF-2 and HGF act as a possible resistant mechanism to the abiraterone activity on the androgen synthesis pathway in PC. METHODS: The intracellular levels of 17-OH progesterone and dihydrotestosterone (DHT) were determined by enzyme immunoassays in cell lysates of LNCaP and PC3 PC cells upon co-treatment of cells with abiraterone and FGF-2 or HGF. RESULTS: Abiraterone treatment resulted in significant reduction in the intracellular levels of 17-OH progesterone and DHT in both LnCap and PC3 cells. FGF-2 and HGF were found to decrease the intracellular levels of 17-OH progesterone in both cell lines, whereas HGF alone was found to increase the intracellular levels of DHT only in PC3 cells. However, the simultaneous exposure of cells to abiraterone and FGF-2 or HGF was found to result in an increase in the intracellular levels of DHT, while it did not result in changes in the intracellular levels of 17-OH progesterone. CONCLUSION: These findings suggest that FGF-2 and HGF may act as an escape mechanism, aiding the development of resistance to abiraterone by restoring intra-tumoral androgen synthesis that may contribute to disease progression.

High-Tidal-Volume Mechanical Ventilation and Lung Inflammation in Intensive Care Patients With Normal Lungs.

BACKGROUND: This study was conducted to investigate whether high-tidal-volume mechanical ventilation is associated with increased lung inflammation compared with low-tidal-volume mechanical ventilation in critically ill patients with no evidence of lung injury. METHODS: In this prospective, single-blind, randomized (1:1), parallel-group study, 18 critically ill patients with normal lungs were randomly assigned to receive mechanical ventilation with a tidal volume of either 6 mL/kg (low tidal volume) or 12 mL/kg (high tidal volume) during the first 4 days in the intensive care unit. RESULTS: At baseline and at 24, 48, and 96 hours, exhaled breath condensate was collected to measure interleukin 1ß, interleukin 10, tumor necrosis factor α, and total nitric oxide metabolites. Interleukin 1ß levels in exhaled breath condensate were significantly increased at 24 hours compared with baseline in the high-tidal-volume group but not in the low-tidal-volume group. The interleukin 1ß increase in the high-tidal-volume group was transient. Exhaled breath condensate levels of interleukin 1ß, interleukin 10, tumor necrosis factor α, and total nitric oxide metabolites did not differ significantly between the high-tidal-volume and low-tidal-volume groups at any time point. CONCLUSION: Short-term mechanical ventilation with a tidal volume of 12 mL/kg may trigger inflammatory responses in the lungs of intensive care unit patients without preexisting lung injury.

17-ß estradiol attenuates the pro-oxidant activity of corticotropin-releasing hormone in macroendothelial cells.

Corticotropin-releasing hormone, which is the predominant regulator of neuroendocrine responses to stress, attenuates inflammation through stimulation of glucocorticoid release. Enhanced corticotropin-releasing hormone expression has been detected in inflammatory cells of the vascular endothelium, where it acts as a local regulator of endothelial redox homeostasis. Estrogens have beneficial effects on endothelial integrity and function, though the mechanism underlying their antioxidative effect remains as yet largely unknown. We therefore investigated the effect of 17ß-estradiol on pro-oxidant action of corticotropin-releasing hormone in vitro in macroendothelial cells, and, more specifically, the role of 17ß-estradiol on corticotropin-releasing hormone-induced activities/release of the antioxidant enzymes namely, endothelial nitric oxide synthase, superoxide dismutase, catalase, and glutathione. We observed that 17ß-estradiol abolished the stimulatory effect of corticotropin-releasing hormone on intracellular reactive oxygen species levels and counteracted its inhibitory effect on endothelial nitric oxide synthase activity and nitric oxide release. In addition, 17ß-estradiol significantly induced superoxide dismutase and catalase activity, an effect that was not significantly influenced by corticotropin-releasing hormone. Finally, 17ß-estradiol significantly increased glutathione levels and the glutathione/glutathione + glutathione disulfide ratio, an action that was partially blocked by corticotropin-releasing hormone. Our results reveal that 17ß-estradiol counterbalances corticotropin-releasing hormone-mediated pro-inflammatory action and thereby maintains the physiological threshold of the endothelial cell redox environment. These observations may be of importance, considering the protective role of estrogen in the development of atherosclerosis.

Clinical value of significance of Hypoxia Inducible Factor-1α, Glucose Transporter-1 and Carbonic Anhydrase IX in rectal cancer after preoperative chemoradiotherapy.

PURPOSE: The standard treatment of rectal cancer is surgery along with preoperative radiotherapy, administered alone or in combination with chemotherapy. Preoperative chemoradiotherapy (preCRT) is widely used as it allows better local control and the use of sphincter-saving surgery. Pathological response after preCRT has been shown to be a significant prognostic factor of rectal cancer recurrence and survival. In this review we will assess the value of Hypoxia Induced Factor 1α (HIF-1α), Carbonic Anhydrase IX (CA-9) and Glucose Transporter 1 (GLUT-1) genes as predictive markers of the course of local advanced rectal cancer in patients who underwent pre-CRT. METHODS: We searched studies, from Pubmed and in English language, obtained the information by using "HIF-1 alpha", "Carbonic Anhydrase IX (CA-9)", "Glucose Transporter 1 (GLUT-1)" and "rectal cancer" as key words. RESULTS: 27 relevant articles were retrieved in initial stage. After full-text review, 13 articles were selected for the final analysis. CONCLUSIONS: HIF-1α, GLUT-1 and CA-IX may be connected with tumor response to preCRT, however, there is still skepticism towards their clinical use as predictors of outcome. Therefore, there is a need to conduct larger and more extensive cohort studies in order to find whether these predictors can be used in practice.

ERK1/2 phosphorylates HIF-2α and regulates its activity by controlling its CRM1-dependent nuclear shuttling.

Hypoxia-inducible factor 2 (HIF-2) is a principal component of the cellular response to oxygen deprivation (hypoxia). Its inducible subunit, HIF-2α (also known as EPAS1), is controlled by oxygen-dependent as well as oxygen-independent mechanisms, such as phosphorylation. We show here that HIF-2α is phosphorylated under hypoxia (1% O2) by extracellular signal-regulated protein kinases 1 and 2 (ERK1/2; also known as MAPK3 and MAPK1, respectively) at serine residue 672, as identified by in vitro phosphorylation assays. Mutation of this site to an alanine residue or inhibition of the ERK1/2 pathway decreases HIF-2 transcriptional activity and causes HIF-2α to mislocalize to the cytoplasm without changing its protein expression levels. Localization, reporter gene and immunoprecipitation experiments further show that HIF-2α associates with the exportin chromosomal maintenance 1 (CRM1, also known as XPO1) in a phosphorylation-sensitive manner and identify two critical leucine residues as part of an atypical CRM1-dependent nuclear export signal (NES) neighboring serine 672. Inhibition of CRM1 or mutation of these residues restores nuclear accumulation and activity of HIF-2α lacking the ERK1/2-mediated modification. In summary, we reveal a novel regulatory mechanism of HIF-2, involving ERK1/2-dependent phosphorylation of HIF-2α, which controls its nucleocytoplasmic shuttling and the HIF-2 transcriptional activity.This article has an associated First Person interview with the first author of the paper.

Adhesion Prevention to Polypropylene Meshes Using Combined Icodextrin Four Percent and Dimetindene Maleate.

BACKGROUND: The use of surgical meshes in ventral hernia repair has significantly reduced hernia recurrence rates. However, when placed intraperitoneally prosthetic materials can trigger the development of peritoneal adhesions. The present experimental study evaluated the combined icodextrin 4% and dimetindene maleate treatment in preventing peritoneal adhesion formation to polypropylene and titanium-coated polypropylene meshes. MATERIALS AND METHODS: Sixty female white rabbits were divided into four groups. A 2 × 2 cm piece of mesh was fixed to intact peritoneum in all animals through a midline laparotomy. A lightweight polypropylene mesh was implanted in groups 1 and 2 and a titanium-coated polypropylene mesh in groups 3 and 4. Groups 2 and 4 were treated, intraoperatively, with intravenous dimetindene maleate (0.1 mg/kg) and intraperitoneal solution of icodextrin 4% (20 mL/kg) and for the next 6 d with dimetindene maleate intramuscularly. The observation period lasted 15 d. Adhesion scores, percentage of mesh affected surface, tissue hydroxyproline levels, and tissue histopathology were examined. RESULTS: All animals in group 1 and 57% of animals in group 3 presented postoperative adhesions. The combination of antiadhesives significantly reduced the extent and severity of adhesions as well as the hydroxyproline levels in groups 2 and 4 compared with groups 1 and 3. On microscopic evaluation, animals in group 1 exhibited higher inflammation scores compared with group 2, whereas animals in groups 2 and 4 had better mesotheliazation compared with groups 1 and 3. CONCLUSIONS: The combined administration of icodextrin 4% and dimetindene maleate reduces the extent and severity of adhesions and may be successfully used to prevent adhesion formation after mesh intraperitoneal placement.

The Role of Tissue Oxygen Tension in Dengue Virus Replication.

Low oxygen tension exerts a profound effect on the replication of several DNA and RNA viruses. In vitro propagation of Dengue virus (DENV) has been conventionally studied under atmospheric oxygen levels despite that in vivo, the tissue microenvironment is hypoxic. Here, we compared the efficiency of DENV replication in liver cells, monocytes, and epithelial cells under hypoxic and normoxic conditions, investigated the ability of DENV to induce a hypoxia response and metabolic reprogramming and determined the underlying molecular mechanism. In DENV-infected cells, hypoxia had no effect on virus entry and RNA translation, but enhanced RNA replication. Overexpression and silencing approaches as well as chemical inhibition and energy substrate exchanging experiments showed that hypoxia-mediated enhancement of DENV replication depends on the activation of the key metabolic regulators hypoxia-inducible factors 1α/2α (HIF-1α/2α) and the serine/threonine kinase AKT. Enhanced RNA replication correlates directly with an increase in anaerobic glycolysis producing elevated ATP levels. Additionally, DENV activates HIF and anaerobic glycolysis markers. Finally, reactive oxygen species were shown to contribute, at least in part through HIF, both to the hypoxia-mediated increase of DENV replication and to virus-induced hypoxic reprogramming. These suggest that DENV manipulates hypoxia response and oxygen-dependent metabolic reprogramming for efficient viral replication.