Down regulation of C1q tumor necrosis factor-related protein 6 is associated with increased risk of breast cancer.

C1q tumor necrosis factor-related protein 6 (CTRP6), a member of the C1q tumor necrosis factor-related protein (CTRP) family, is reported to be associated with the progression of different malignancies, however, its expression levels and role in breast cancer (BC) are yet unknown. In this study, we investigated the levels of circulating CTRP6 in BC patients and evaluated its role as a potential diagnostic biomarker in BC patients. Then we investigated the effect of recombinant CTRP6 on cellular viability in MCF-7 cells along with its effects on the expression of inflammatory cytokines, interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α) in addition to the expression of vascular endothelial growth factor (VEGF) as a marker of angiogenesis. Our results showed decreased expression of circulating CTRP6 in BC patients with an inverse correlation between CTRP6 and IL-6, TNF-α and VEGF levels. Besides, Receiver operating characteristic (ROC) curve showed that the assessment of CTRP6 levels could be used to predict BC. Moreover, treatment of MCF-7 cells with recombinant CTRP6 protein reduced cellular viability and decreased IL-6, TNF-α and VEGF expression. In conclusion, these results provide new insights into the role of CTRP6 in BC pathogenesis and suggest its potential use as a novel diagnostic biomarker of BC.

Upregulation of BRCA1 and 2 protein expression is associated with dysregulation in amino acids profiles in breast cancer.

BACKGROUND: The prevalence of breast cancer (BC) is high among cancers in Egypt, ranking it the most common cause of cancer mortality in women. BRCA1 and BRCA2 tumor suppressors proteins have a specific relationship with BC. Plasma free amino acids levels (PFAAs) have been reported to exhibit altered profiles among cancer patients. Thus, the present study aims to examine the alteration of the PFAAs profiles and investigate their association with BRCA1 and 2 circulating levels in Egyptian females diagnosed with BC and in females with family history of BC to establish potential early detection strategies for BC. METHODS AND RESULTS: This study included 26 BC patients, 22 females with family history of BC (relatives) in addition to 38 healthy females as control group. Quantitative measurement of PFAAs was determined by the ion exchange separation method through high performance liquid chromatography. BRCA1 and BRCA2 concentrations were determined using ELISA. Our results showed PFAAs profiles in BC patients and in females with BC family history with significant upregulation in mean plasma levels of Alanine, Phenylalanine, Glutamate and Cysteine and downregulation of Taurine, Threonine, Serine, Glycine, Valine, Methionine and Histidine levels compared to controls. Also, a significant positive correlation was observed between plasma BRCA1 and Valine levels while a significant negative correlation was observed between BRCA2 and Lysine plasma levels. CONCLUSION: PFAAs profile can potentially be used in early screening for BC patients and for susceptible females.

MBOAT7 expression is associated with disease progression in COVID-19 patients.

BACKGROUND AND AIM: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019 caused a pandemic of acute respiratory disease, named coronavirus disease 2019 (COVID-19). COVID-19 became one of the most challenging health emergencies, hence the necessity to find different prognostic factors for disease progression, and severity. Membrane bound O-acyltransferase domain containing 7 (MBOAT7) demonstrates anti-inflammatory effects through acting as a fine-tune regulator of the amount of cellular free arachidonic acid. We aimed in this study to evaluate MBOAT7 expression in COVID-19 patients and to correlate it with disease severity and outcomes. METHODS: This case-control study included 56 patients with confirmed SARS-CoV-2 diagnosis and 28 control subjects. Patients were further classified into moderate (n = 28) and severe (n = 28) cases. MBOAT7, tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) mRNA levels were evaluated in peripheral blood mononuclear cells (PBMC) samples isolated from patients and control subjects by real time quantitative polymerase chain reaction (RT-qPCR). In addition, circulating MBOAT7 protein levels were assayed by enzyme-linked immunosorbent assay (ELISA). RESULTS: Significant lower levels of circulating MBOAT7 mRNA and protein were observed in COVID-19 patients compared to control subjects with severe COVID-19 cases showing significant lower levels compared to moderate cases. Moreover, severe cases showed a significant upregulation of TNF-α and IL-1ß mRNA. MBOAT7 mRNA and protein levels were significantly correlated with inflammatory markers (TNF-α, IL-1ß, C-reactive protein (CRP), and ferritin), liver enzymes, severity, and oxygen saturation levels. CONCLUSION: COVID-19 is associated with downregulation of MBAOT7, which correlates with disease severity.

Metformin modulates autophagic pathway in renal fibrosis induced by carbon tetrachloride in adult male albino rats.

BACKGROUNDS: Chronic kidney disease (CKD) is a global public health problem. All progressive chronic kidney disease (CKD) is characterized by tubulointerstitial fibrosis. Exposure to high concentrations of carbon tetrachloride (including vapor) can destroy the kidneys. Autophagy played an important role in maintaining the homeostasis of organs. Impaired autophagy was frequently associated with renal damage and fibrosis. Recent data suggests that metformin protects against a variety of kidney disorders. AIM: To investigate the protective role of metformin on carbon tetrachloride induced renal damage via autophagy pathway. MATERIALS AND METHODS: Forty adult male albino rats were divided into four equal groups (10 rats, each); Group 1: control group. Group 2: olive oil group received olive oil 1.5 mg/kg twice weekly S.C for 12 weeks. Group 3: The ccl4 group, the rats were received ccl4 1.5 mg/kg twice weekly S.C for 12 weeks. Group 4: CCL4 and Metformin group received concomitant treatment of CCL4, 1.5 mg/kg twice weekly S.C and 100 mg/kg/day Metformin orally for 12 weeks. After sacrifice, kidneys were taken from all animal groups and processed for light and electron microscopy, immunological studies and biochemical tests. Statistical analysis was done. RESULTS: Administration of ccl4 resulted in histopathological changes in the kidney tissue in the form of areas of tissue destruction, inflammatory cell infiltration, congestion and fibrosis. Ultrastructurally, irregular thickening of GBM was observed. Improvement was noticed with concomitant treatment of ccl4 with metformin. CONCLUSION: Metformin administration can modulate histological and biochemical effects in the renal tissue induced by of ccl4.

Validity of Serum Zinc/Copper Ratio as a Potential Novel Biomarker in Childhood Epilepsy.

BACKGROUND: Alterations in zinc and copper homeostasis may contribute to seizure susceptibility, development, termination, and response to antiepileptic medications. The current study examined the profile of zinc, copper, and their ratio in childhood epilepsy and its pharmacological variants (pharmacoresistant and pharmacoresponsive). METHODS: The study included 100 epileptic children (50 pharmacoresistant and 50 pharmacoresponsive) and 50 healthy, age- and gender-matched controls. History, clinical examination, and assays of serum zinc and copper were performed. Zinc/copper ratio was calculated. RESULTS: Serum zinc and the zinc/copper ratio were significantly lower in epileptic children than in controls (p < 0.001). Significantly lower zinc and zinc/copper ratio and higher copper levels were found in children treated with levetiracetam/sodium valproate/oxcarbazepine than those treated with levetiracetam alone or combined with sodium valproate (p < 0.05 for all). Epileptic children, particularly pharmacoresistant, exhibited significant negative correlations between the serum levels of zinc and copper (r = -0.279, p = 0.005, and r = -0.363 and p = 0.010, respectively). At cutoff value of zinc/copper ratio < 1.118 in diagnosing children with epilepsy, it gives a sensitivity of 64% and a specificity of 85% with the AUC = 0.8092. At cutoff value of zinc/copper ratio ≤ 0.7826 in distinguishing pharmacoresistant epilepsy, it produced 52% sensitivity, 64% specificity with AUC = 0.576 Conclusions: Low zinc and high copper levels were associated with childhood epilepsy especially those with pharmacoresistant type and treated with Oxcarbazepine. Zinc/copper ratio might be a potential biomarker in diagnosing childhood epilepsy and to some extent in predicting pharmacoresistant type.

Knowledge and Perceived Effectiveness of Infection Prevention and Control Measures Among Health Care Workers During the COVID-19 Pandemic: A National Survey.

BACKGROUND: Being the first line of defense against COVID-19 infection, health care workers (HCWs) are at an increased risk of getting infected. Infection prevention and control (IPC) measures were deemed to be instrumental in protecting them and their patients against infection. PURPOSE: To assess HCWs' knowledge of IPC measures and their perceived effectiveness in protecting against COVID-19. METHODS: A national web-based survey was conducted in different health care sectors in Qatar. RESULTS: A total of 1757 HCWs completed the survey. HCWs believed in applying stricter IPC precautions while dealing with confirmed COVID-19 cases than with suspected cases. Males and physicians were more likely to have high perceived effectiveness of IPC measures than females, nurses, and pharmacists. Higher proportions of HCWs believed in the effectiveness of hand hygiene than most types of personal protective equipment. CONCLUSION: Further research is recommended to assess the impact of HCWs' knowledge and perceived effectiveness of IPC measures on their compliance.

Comparative Evaluation of Twin Block Appliance and Fixed Orthodontic Appliance in Early Class II Malocclusion Treatment: A Randomized Controlled Trial.

AIMS: To compare skeletal, dentoalveolar, and soft tissue changes between Twin block and early fixed orthodontic appliance for class II division 1 malocclusion treatment through a randomized controlled trial. MATERIALS AND METHODS: Sample and randomization: This study was a randomized controlled trial with a 1:1 allocation ratio in which 40 patients were divided equally into two groups: control and experimental; each group had an equal number of boys and girls. Randomization was achieved using random blocks of 20 patients with allocation concealed in sequentially numbered, opaque, and sealed envelopes. Blinding was only applicable for data analysis of radiographic measurements. Intervention: Twin block appliance was used in the experimental group for 1 year. However, control group was treated with fixed appliance. Inclusion criteria: Skeletal class II division 1 malocclusion with mandibular retrognathism; cephalometric angular measurements: SNA ≥ 82, SNB ≤ 78, ANB ≥ 4; overjet ≥6 mm; and patient in circumpubertal stage cervical vertebral maturation (CVM2 and CVM3). Parameters for evaluation: Cephalometric skeletal, dental, and soft tissue angular and linear measurements were used for evaluation. RESULTS: SNB increased remarkably by 4° in the Twin block group, but only by 0.68 in the control group. There was a significant decrease in vertical dimensions (SN-GoGn) in the Twin block group compared to control group (p = 0.002). Significant enhancement in the facial profile of the patients was observed. CONCLUSIONS: The Twin block appliance induced significant skeletal and dental changes. These changes were more obvious relative to the slight changes induced by natural growth. CLINICAL SIGNIFICANCE: Early treatment of Class II due to mandibular retrusion with Twin block functional appliance is recommended due to its favourable skeletal effect. Early treatment with fixed appliance affects mainly the dentoalveolar component. Long term follow-up is needed for further insights.

National clinical guidelines: The diagnosis and management of asthma in adults.

BACKGROUND: Qatar has culturally diverse health professionals; and therefore, the care provided may vary according to their background, resulting in variations in care. To bridge this gap, the Ministry of Public Health (MOPH) has established the National Clinical Guidelines (NCG) Program, which aims to reduce variation in care delivery, improve value-add from the healthcare system, adopt international best practices to local context, and enable insurers and providers to access the most currently reviewed evidence-based practice in diagnosis and management of diseases. The NCG for "Diagnosis and Management of Asthma in Adults" was developed in collaboration between Strategic Planning and Performance Department and Subject Matter Experts (SMEs) who are practicing healthcare professionals representing different healthcare organizations in Qatar. The NCG aims to standardize the management and treatment received by adult patients with asthma across the healthcare system and adapt the best practice recommendations in the management of asthma to the culture, customs, practice, and formulary of Qatar. METHODS: This NCG has been developed through a rigorous process that aligns with international best practices and localized to the context of Qatar, involving:• Extensive literature search for reputed published evidence specific to NCGs.• Critical appraisal of the literature.• Development of a baseline draft guideline.• Review of the baseline draft by SMEs and patients.• Review of the guidelines by the National Clinical Guidelines and Pathways Committee (NCGPC) from stakeholder organizations across Qatar. RESULTS: The first edition of the NCG was published on the MOPH website on December 14, 2016; and it was updated and republished on August 22, 2019. A Patient Information Leaflet (PIL) was prepared from the NCG using simple language for use by the patients. The NCG is currently under an updation process based on new evidence since August 22, 2019. A live demo was developed on how to access the NCG and its relevant pathways from the MOPH website and navigate each section of the guidelines. CONCLUSION: These NCGs will improve the quality of care for patients with asthma and advocate for the best clinical practice strategies on the management of asthma in adults.

Novel therapeutic regimens for urethane-induced early lung cancer in rats: Combined cisplatin nanoparticles with vitamin-D3.

Lung cancer remains incurable; therefore, novel therapeutical approaches are of great demand. This study was designed to investigate the effectiveness of cisplatin nanoparticles combined with vitamin-D3 on urethane-induced early lung cancer in rats and to clarify the underlying signaling mechanisms. Early lung cancer was induced in male Wistar rats by urethane. Rats were divided into six groups: I-control, II-cancer untreated, III-cancer + free cisplatin, IV-cancer + cisplatin nanoparticles, V-cancer + free cisplatin + vitamin-D3 , VI-cancer + cisplatin nanoparticles + vitamin-D3 . Inflammation, proliferation, and apoptosis were evaluated together with the levels of tumor marker CK-19 along with histological assessment. Treatment of lung cancer with either free or nanoparticles of cisplatin alone demonstrated significant suppression in the expression of inflammatory, anti-apoptotic and tumor markers compared to rats with lung cancer. Moreover, vitamin-D3 supplementation with either cisplatin forms lead to a further decrease of all markers, markedly with cisplatin nanoparticles. The present study shows the synergistic effect of cisplatin-nanoparticles combined with vitamin-D3 as a new therapy regimen against lung cancer. Further studies with larger sample sizes and longer duration are needed to confirm these results.

Lisofylline mitigates cardiac inflammation in a mouse model of obesity through improving insulin secretion and activating cardiac AMPK signaling pathway.

Obesity has emerged as a leading cause of death in the last few decades, mainly due to associated cardiovascular diseases. Obesity, inflammation, and insulin resistance are strongly interlinked. Lisofylline (LSF), an anti-inflammatory agent, demonstrated protection against type 1 diabetes, as well as reduced obesity-induced insulin resistance and adipose tissue inflammation. However, its role in mitigating cardiac inflammation associated with obesity is not well studied. Mice were divided into 4 groups; the first group was fed regular chow diet, the second was fed regular chow diet and treated with LSF, the third was fed high fat diet (HFD), and the fourth was fed HFD and treated with LSF. Cardiac inflammation was interrogated via expression levels of TNF α, interleukins 6 and 10, phosphorylated STAT4 and lipoxygenases 12 and 12/15. Apoptosis and expression of the survival gene, AMPK, were also evaluated. We observed that LSF alleviated obesity-induced cardiac injury indirectly by improving both pancreatic ß-cell function and insulin sensitivity, as well as, directly via upregulation of cardiac AMPK expression and downregulation of cardiac inflammation and apoptosis. LSF may represent an effective therapy targeting obesity-induced metabolic and cardiovascular complications.

Olmesartan niosomes ameliorates the Indomethacin-induced gastric ulcer in rats: Insights on MAPK and Nrf2/HO-1 signaling pathway.

AIMS: Gastric ulcer is a continuous worldwide threat that inquires protective agents. Olmesartan (OLM) has potent anti-oxidant and anti-inflammatory characters, yet having limited bioavailability. We targeted the gastro-protective potential and probable mechanism of OLM and its niosomal form against indomethacin (IND) induced-gastric ulcer in rats. MAIN METHODS: we prepared OLM niosomes (OLM-NIO) with different surfactant: cholesterol molar ratios. We evaluated particle size, zeta-potential, polydispersity, and entrapment efficiency. In-vitro release study, Fourier transform infrared spectroscopy, differential scanning calorimetry, and transmission electron microscopy were performed for selected niosomes. In-vivo, we used oral Omeprazole (30 mg/kg), OLM or OLM-NIO (10 mg/kg) for 3 days before IND (25 mg/kg) ingestion. We assessed gastric lesions, oxidative and inflammatory markers. KEY FINDINGS: OLM-NIO prepared with span 60:cholesterol ratio (1:1) showed high entrapment efficiency 93 ± 2%, small particle size 159.3 ± 6.8 nm, low polydispersity 0.229 ± 0.009, and high zeta-potential -35.3 ± 1.2 mV, with sustained release mechanism by release data. In-vivo macroscopical and histological results showed gastro-protective effects of OLM pretreatment, which improved oxidative stress parameters and enhanced the gastric mucosal cyclooxygenase-1 (COX-1) and prostaglandin E2 (PGE2) contents. OLM pretreatment suppressed interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) contents and translocation of p38 mitogen-activated protein kinase (p38-MAPK). Besides, OLM substantially promoted the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) protective pathway. OLM-NIO furtherly improved all previous outcomes. SIGNIFICANCE: We explored OLM anti-ulcerative effects, implicating oxidative stress and inflammation improvement, mediated by the Nrf2/HO-1 signaling pathway and p38-MAPK translocation. Meanwhile, the more bioavailable OLM-NIO achieved better gastro-protective effects compared to conventional OLM form.

CXC Chemokine Receptor Type 5 Gene Polymorphisms in a Cohort of Egyptian Patients with Diffuse Large B-Cell Lymphoma.

BACKGROUND: The chemokine receptor CXCR5 is selectively expressed on B cells; it is involved in lymphocyte homing and the development of normal lymphoid tissue. Its principle ligand is CXCL13 or B lymphocyte chemoattractant. Three polymorphisms in the CXCR5 gene, rs148351692 C/G, rs6421571 C/T, and rs78440425 G/A, have been identified. OBJECTIVE: To assess the genetic polymorphisms of CXCR5 and evaluate their possible contribution to the susceptibility and response to therapy of diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: Fifty DLBCL (not otherwise specified) patients and 50 control subjects were included in this study. CXCR5 genotypes were determined by PCR-RFLP. RESULTS: Our study revealed that the CXCR5 rs148351692 C/G and rs6421571 C/T gene polymorphisms are associated with an increased risk of developing DLBCL (OR 28.57 [95% CI 8.96-96.56] and 3.45 [1.67-11.83] respectively), while CXCR5 rs78440425 G/A showed no association with the risk of lymphoma. Moreover, the double and triple combined gene polymorphisms are associated with an increased risk of developing DLBCL of approximately 120-fold and 105-fold, respectively. CXCR5 gene polymorphisms had no significant impact on disease outcome or response to therapy. CONCLUSIONS: CXCR5 gene polymorphisms could be considered a potential risk factor for the development of DLBCL.

Evaluation of circulating microRNAs-211 and 25 as diagnostic biomarkers of colorectal cancer.

Colorectal cancer is one of the most prevalent and deadly cancers worldwide. MicroRNAs are short single stranded non-coding RNAs that play important roles in carcinogenesis, tumor growth and tumor survival. Circulating microRNAs are increasingly becoming efficient and important biomarkers for several types of cancers. Herein, we aim to evaluate the diagnostic potentials of plasma microRNA-211 and microRNA-25 in colorectal cancer patients. Forty-four patients diagnosed with colorectal cancer and 40 healthy controls were recruited for the present study. Expressions of circulating microRNAs -211 and 25 were assessed by quantitative real-time polymerase chain reaction (RT-qPCR). Expression of transforming growth factor-beta, a key factor in tumorigenesis and a key inducer of epithelial to mesenchymal transition was assessed by enzyme-linked immunosorbent assay (ELISA) in patients' tissue and plasma. Our results demonstrated upregulated expressions of plasma microRNAs-211 and 25 correlated with the high transforming growth factor-beta (TGF-ß1) expression in patients. In addition, plasma levels were positively correlated with lymph node metastasis. Moreover, receiver operating characteristic analysis demonstrated the reliability of microRNAs-211 and 25 for discriminating colorectal cancer patients from healthy individuals. MicroRNA-211 and microRNA-25 might have a tumorigenic role in colorectal cancer and their plasma levels could be potential biomarkers in its diagnosis.

Compliance and barriers to the use of infection prevention and control measures among health care workers during COVID-19 pandemic in Qatar: A national survey.

AIM: To assess health care workers' compliance with infection prevention and control measures in different health care sectors in Qatar during COVID-19 pandemic. BACKGROUND: Being the first line of defence against COVID-19 infection, health care workers are particularly at increased risk of getting infected. Compliance with infection prevention and control measures is essential for their safety and the safety of patients. METHODS: A web-based national survey was conducted between November 2020 and January 2021 targeting all health care workers in governmental, semi-governmental and private health care sectors. RESULTS: Of 1,757 health care workers, 49.9% were between 30 and 39 years of age; the majority (47.5%) were nurses. Participants reported a significant increase in the median self-rated compliance scores during the pandemic compared with before it (p < .001). During the pandemic, 49.7% of health care workers were fully compliant with personal protective equipment (PPE) use; 83.1% were fully compliant with hand hygiene. Overall, 44.1% were fully compliant with infection prevention and control measures (PPE and hand hygiene). Nationality, health sector, profession and frequency of interactions with suspected or confirmed COVID-19 cases were significantly associated with compliance with overall infection prevention and control measures. The most reported barriers were work overload and shortages of PPE and handwashing agents. CONCLUSIONS: Compliance of health care workers with infection prevention and control measures needs further improvement. IMPLICATIONS FOR NURSING MANAGEMENT: Frequent quality checks, provision of adequate supplies and behaviour change interventions are recommended strategies for hospital and nursing administrators to improve health care workers' compliance.

Inhibition of endoplasmic reticulum stress ameliorates cardiovascular injury in a rat model of metabolic syndrome.

Metabolic (Met) syndrome is characterized by hypertension, insulin resistance and dyslipidaemia with high risk of cardiovascular disease. Endoplasmic reticulum (ER) stress is a key contributor in the pathogenesis of Met syndrome. The current study investigates the effect of Tauroursodeoxycholate (TUDCA), an ER stress inhibitor, on Met syndrome-induced cardiovascular complications and the possible underlying signalling mechanisms. Met syndrome was induced in rats, which were then treated with TUDCA. Body weight, blood pressure, glucose tolerance and insulin tolerance tests were performed. ER stress, survival and oxidative stress markers were measured in heart and aorta tissue. The results showed that TUDCA improved metabolic parameters in rats with Met syndrome. Treatment mitigated the Met syndrome-induced cardiovascular complications through upregulating survival markers and downregulating ER and oxidative stress markers. These results highlight the protective effect of ER stress inhibition as a potential target in the management of cardiovascular complications associated with Met syndrome.

The impact of cytokine gene polymorphisms on the outcome of HLA matched sibling hematopoietic stem cell transplantation.

Graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic stem cell transplantation (HSCT); cytokines are recognized as important mediators in its pathogenesis. In this study we investigated the role of cytokine gene polymorphisms on HSCT outcome. A total of 106 patient and 98 donors were genotyped by polymerase chain reaction sequence specific primers (PCR-SSP) based assay for tumor necrosis factor-α-308 (TNFα -308), interleukin (IL)-6-174, IL-10-1082, -819, -592, Interferon-γ+874 (IFN-γ+874), and transforming growth factor-ß1 (TGF-ß1) codon10 and 25 polymorphisms. Except one in each category, all patients and donors were TNFα -308 high producers and the majority were IL-6-174 high producers (93.3% and 90.8% respectively); a pattern that would alleviate any potential biological impact. Patient's IFN-γ+874 showed significant association with the development of chronic GVHD. Patients with IFN-γ +874 high producer showed an 8 folds likelihood to develop chronic GVHD as compared to those with IFN-γ+874 low producer predicted phenotype (95% CI: 1.59-40.2, p = 0.01). Patient's TGFß1-codon 10 and 25 high/intermediate producers showed a lower incidence of acute GVHD though it did not achieve statistical significance (p = 0.065) on account of the low frequency of this genotype in our patients and donors (11.4 and 8.2% respectively). Other factors contributing to risk of GVHD included older age for both acute and chronic (p = 0.01 and 0.02 respectively) with age 24 as the best discriminating cutoff; CD34+ cell dose for chronic GVHD (p = 0.045) with a dose of 8 × 106/kg as the best discriminating cutoff; and conditioning regimen with Flu/Bu associated with the lowest incidence of acute GVHD (p = 0.003) and no impact on chronic GVHD. In conclusion the current study further indicates a potential role of some cytokine gene polymorphisms in the development of GVHD. The relative distribution of high and low producer genotypes in different ethnic groups contributes to their biological impact in different populations.

Essential Role of Smooth Muscle STIM1 in Hypertension and Cardiovascular Dysfunction.

OBJECTIVES: Chronic hypertension is the most critical risk factor for cardiovascular disease, heart failure, and stroke. APPROACH AND RESULTS: Here we show that wild-type mice infused with angiotensin II develop hypertension, cardiac hypertrophy, perivascular fibrosis, and endothelial dysfunction with enhanced stromal interaction molecule 1 (STIM1) expression in heart and vessels. All these pathologies were significantly blunted in mice lacking STIM1 specifically in smooth muscle (Stim1(SMC-/-)). Mechanistically, STIM1 upregulation during angiotensin II-induced hypertension was associated with enhanced endoplasmic reticulum stress, and smooth muscle STIM1 was required for endoplasmic reticulum stress-induced vascular dysfunction through transforming growth factor-ß and nicotinamide adenine dinucleotide phosphate oxidase-dependent pathways. Accordingly, knockout mice for the endoplasmic reticulum stress proapoptotic transcriptional factor, CCAAT-enhancer-binding protein homologous protein (CHOP(-/-)), were resistant to hypertension-induced cardiovascular pathologies. Wild-type mice infused with angiotensin II, but not Stim1(SMC-/-) or CHOP(-/-) mice showed elevated vascular nicotinamide adenine dinucleotide phosphate oxidase activity and reduced phosphorylated endothelial nitric oxide synthase, cGMP, and nitrite levels. CONCLUSIONS: Thus, smooth muscle STIM1 plays a crucial role in the development of hypertension and associated cardiovascular pathologies and represents a promising target for cardiovascular therapy.

Increased Expression of Neprilysin Is Associated with Inflammation in Preeclampsia.

Preeclampsia (PE) is associated with a finely tuned equilibrium between trophoblast cell invasion and fetal-maternal immunological tolerance. An imbalance between proinflammatory (IL-6) and anti-inflammatory (IL-10) cytokines is a hallmark of PE. Neprilysin (NEP), a membrane-bound metalloprotease, is vulnerable to the inflammatory environment and plays a significant role in modulating vascular tone. The aim of this study was to determine the correlation between NEP (mRNA and protein) levels and the inflammatory status in PE patients compared to healthy pregnant women and to identify the role of NEP in evaluating the severity of preeclampsia. The study group comprised 52 pregnant women with PE while the control group comprised 47 normotensive pregnant women. After a caesarean section, placental tissue samples from patients and controls were collected to measure the expression levels of IL-6, TGF-ß, IL-10, and NEP mRNA. In addition, an enzyme-linked immunosorbent assay was used to assess the quantity of NEP protein in blood samples. Our results revealed a significant positive correlation between NEP (mRNA and protein) and proinflammatory markers IL-6 and TGF-ß levels in patients compared to controls and a significant inverse correlation between NEP and anti-inflammatory cytokine IL-10. Moreover, this is the first study to find a strong positive correlation between NEP level and PE severity. In conclusion, in PE patients, there is a substantial relationship between NEP, the degree of inflammation, and PE severity. NEP could act as a potential biomarker for diagnosis and prognosis of PE.

Pharmacogenetic study of phosphatase and tensin homolog polymorphism (rs701848) in childhood epilepsy: relation to circulating Wnt signaling.

OBJECTIVE: The present study aimed at evaluating the potential contribution of Phosphatase and Tensin Homolog (PTEN) and its gene polymorphism (PTEN rs701848 T/C) in relation to Wingless/integrase-1 (Wnt) signaling in childhood epilepsy and the impact of antiepileptic medications on their serum levels. METHODS: This study included 100 children with epilepsy (50 pharmacoresistant and 50 pharmacoresponsive) and 50 matched controls. All subjects had their genotypes for the PTEN rs701848T/C polymorphism assessed using TaqManTM assays and real-time PCR. By using the sandwich ELISA technique, the blood concentrations of PTEN and Wnt3a were measured. RESULTS: Serum Wnt3a levels in epileptic patients were significantly higher than in the control group, p < 0.001. Children with epilepsy who received oxcarbazepine had considerably lower serum Wnt3a levels than those who didn't, p < 0.001.With an AUC of 0.71, the cutoff value for diagnosing epilepsy as serum Wnt3a > 6.2 ng/mL has a sensitivity of 55% and a specificity of 80%. When compared to controls, epileptic children had considerably more (TT) genotype and less (TC and CC) genotypes, p < 0.05 for all. Epileptic children had significantly higher (T) allele frequency than controls, p = 0.006 with OR (95%CI) = 1.962(1.206-3.192). Pharmacoresistant epileptic children had significantly higher (TT) genotype compared to pharmacoresponsive type (p = 0.020). CONCLUSION: We originally found a strong association between PTEN rs701848 T/C and childhood epilepsy, in particular pharmacoresistant type. Serum Wnt3a levels increased in epilepsy, but were not significantly different between different alleles of PTEN. In pharmaco-responsive children Wnt3a levels differed significantly between the different PTEN genotypes. Antiepileptics may affect Wnt3a levels.

Evaluation of novel synthesized thiazole derivatives as potential aromatase inhibitors against breast cancer.

Background: 4-Methylacetophenone is used in the preparation of starting materials, 4-methylphenacyle bromide (2) and 4-methylacetophenone thiosemicarbazole (3). Results: Several novel 2,4-disubstituted-1,3-thiazole analogues were obtained via the treatment of starting materials with 4-methylphenacyl bromide, acetyl chloride, aromatic aldehydes and bromination providing thiazole derivatives 5-8 respectively. Conclusion: Compounds 5-8 were investigated for their cytotoxic activity on MCF-7 and normal breast cells. Active compounds were found and in contrast to staurosporine, compound 8 displayed the most potent cytotoxic action that showed a strong inhibitory effect (aromatase) and (protein tyrosine kinase) enzymes, proving that the novel thiazole derivatives promoted the effective anticancer drug candidates.