MicroRNA-301 mediates proliferation and invasion in human breast cancer

Several microRNAs have been implicated in human breast cancer but none to date have been validated or utilized consistently in clinical management. MicroRNA-301 (miR-301) overexpression has been implicated as a negative prognostic indicator in lymph node negative (LNN) invasive ductal breast cancer, but its potential functional impact has not been determined. Here we report that in breast cancer cells, miR-301 attenuation decreased cell proliferation, clonogenicity, migration, invasion, tamoxifen resistance, tumor growth, and microvessel density, establishing an important oncogenic role for this gene. Algorithm-based and experimental strategies identified FOXF2, BBC3, PTEN, and COL2A1 as candidate miR-301 targets, all of which were verified as direct targets through luciferase reporter assays. We noted that miR-301 is located in an intron of the SKA2 gene which is responsible for kinetochore assembly, and both genes were found to be coexpressed in primary breast cancer samples. In summary, our findings define miR-301 as a crucial oncogene in human breast cancer that acts through multiple pathways and mechanisms to promote nodal or distant relapses.     

Effects of cortisol on the laterality of the neural correlates of episodic memory

Alterations in the laterality of cortical activity have been shown in depressive illnesses. One possible pathophysiological mechanism for this is an effect of corticosteroids. We have previously demonstrated that endogenous cortisol concentrations correlate with the asymmetry of cortical activity related to episodic memory in healthy subjects and depressed patients. To further-examine whether this is due to a causal effect of cortisol on the laterality of episodic memory, we studied the effect of exogenous administration of cortisol in healthy subjects. Twenty-three right-handed healthy male volunteers were tested in a double-blind cross-over study. Event-related potentials (ERPs) were recorded during an episodic memory task following a four-day course of 160mg/day cortisol or placebo. Low-resolution brain electromagnetic tomography (LORETA) was used to identify brain regions involved in the neurocognitive task. Cortisol levels were measured in saliva samples. ERP and LORETA analysis following placebo demonstrated significant left parahippocampal activation associated with successful retrieval. Cortisol led to a decrease in the mean early frontal ERP voltage and an increase in the late right ERP voltage. LORETA suggested this to be due to a significant increased late activation of the right superior frontal gyrus. There was no significant effect of cortisol on episodic memory performance. This study suggests that exogenous cortisol leads to more positive-going waveforms over the right than the left hemisphere, possibly due to increased monitoring of the products of retrieval. The results support the hypothesis of causal effects of cortisol on the laterality of cortical activity occurring during an episodic memory task.     

Central glucocorticoid receptor-mediated effects of the antidepressant, citalopram, in humans: a study using EEG and cognitive testing

Our previous work in cellular and animal models has shown that antidepressants activate glucocorticoid receptor (GR) translocation, induce GR down-regulation, and decrease GR-mediated effects in the presence of GR agonists. However, whether these effects can be extrapolated to the human brain is still unclear. In this study, the effects of four days of treatment with the antidepressant, citalopram (20 mg/day), or placebo, were assessed in a double-blind, placebo-controlled, cross-over study. Central GR-mediated effects were examined by the effects of a single dose of cortisol (30 mg, orally) on two measures known to be sensitive to glucocorticoid administration: EEG alpha power and working memory function. Twenty healthy male subjects aged between 18 and 33 years participated to the study. The results suggest that GR activation by antidepressants, and the subsequent decrease in GR-mediated effects in the presence of GR agonists, indeed occurs in the human brain. Specifically, pre-treatment with citalopram decreased the well-known ability of cortisol to increase EEG alpha power and to impair working memory: cortisol-induced increase in EEG alpha power was (anteriorly) +15 to +20% (p=0.01) after placebo and +5 to +8% (p>0.5) after citalopram; and cortisol-induced increase in working memory errors was (at level 12, on average) 2.50 vs. 4.55 (p<0.05) after placebo and 4.10 vs. 3.35 (p>0.05) after citalopram. No effects were detected on alerting. These results are consistent with the notion that citalopram treatment activates GR translocation and inhibits the functional consequences of the subsequent cortisol administration. Our study further emphasizes the importance of the GR as a target for antidepressant action in humans.     

c-MET expression in colorectal adenomas and primary carcinomas with its corresponding metastases

Background

c-MET plays an important role in tumor proliferation, invasion and metastasis. In this study we examined the expression of c-MET in colorectal adenomas, primary adenocarcinomas and their corresponding lymph node, peritoneal and liver metastases. We correlated our findings with clinicopathological features.

Methods

Twenty three cases of colorectal adenoma and 102 cases of primary colorectal carcinoma and their corresponding metastases (44 lymph nodes, 21 peritoneal deposits and 16 liver metastases) were studied to evaluate c-MET expression by immunohistochemistry. For comparison, 12 sections of adjacent healthy colorectal mucosa were examined.

Results

Statistically significant differences were present among normal tissues, colorectal adenomas and primary colorectal carcinomas (P=0.011). Normal tissues showed a negative or weak reaction in 66.67% and 33.33% of cases respectively. Expression of c-MET was positive in 47.8% of adenomas. A significant positive association was identified between c-MET high expression and degree of dysplasia (P=0.024). c-MET was highly expressed in 66.7% of primary colorectal carcinoma. Significant positive correlations were detected between c-MET expression and TNM stage (P=0.036), lymph node metastasis (LNM), peritoneal deposits and liver metastasis (P=0.038, P=0.094 and P=0.045, respectively). c-MET expression in metastatic tissues was significantly higher than that of the primary tumor.

Conclusions

c-MET expression is gradually up-regulated in the development and progression of colorectal cancer (CRC) from normal epithelium to adenoma to colorectal carcinoma to metastases.     

Combretastatin A4-camptothecin micelles as combination therapy for effective anticancer activity

Cancer is a major worldwide health problem, for which chemotherapy is a common treatment option. However drug toxicity and the development of resistance to chemotherapy are two main challenges associated with the traditional anticancer drugs. Combined pharmacological therapy based on different mechanisms might be an effective strategy in cancer treatment, and could exhibit a synergistic therapeutic efficacy. Herein, we aim to combine combretastatin A4 (CA4) and camptothecin (Cpt) chemically into a codrug through two hydrophilic linkers utilizing click chemistry to improve their water solubility and anticancer activity. The synthesized amphiphilic structure could self-assemble into a micelle structure as confirmed by atomic force microscopy (AFM) and dynamic light scattering (DLS), which showed a high stability and improved water solubility at pH 7.4, with a low critical micelle concentration (CMC) value of 0.9 mM. Moreover, in vitro hydrolysis was observed upon incubation of the hybrid compound with an esterase enzyme, which suggested a complete disassembly into the starting active drugs. Finally, cytotoxicity studies on HeLa cancer cells showed that the codrug demonstrated an enhanced (five fold) cytotoxicity as compared with the free drugs. In addition the combination index (CI) was <1, which suggests a synergistic activity for the codrug. Moreover, the tested concentrations of the codrug were not significantly cytotoxic to a noncancerous fibroblast cell line. The imaging of HeLa cells treated with FITC-loaded micelles showed a rapid internalization. In conclusion, the codrug of CA4 and Cpt might be a potential novel anticancer drug as it demonstrated a synergistic cytotoxic activity that might spare noncancerous cells.

Novel CA4-TEG-triazole-TEG-Cpt (codrug 9) was synthesized and self-assembled into a micelle structure that showed a great synergistic anticancer activity on HeLa cancer cells without affecting the viability of 3T3 normal cells.     

The association between micronutrient status and sleep quality in patients with depression: a case-control study

Sleep and Breathing - Few previous studies estimated the association between micronutrient status and sleep quality; no previous work was done in patients with depression compared with healthy...     

Association between polymorphisms in apoptotic genes and susceptibility for developing breast cancer in Syrian women

Apoptosis is a major protective mechanism against cancer. The tumor suppressor protein p53 is the central protein in the apoptotic pathway and was shown to harbor mutations in a considerable fraction of breast cancer tumors. The NQO1 was shown to act as a p53 stabilizer and was suggested to play an important role in the protection against carcinogenic catechol estrogens. Functional polymorphisms in TP53 and NQO1 were investigated in relation to breast cancer susceptibility in several studies, primarily involving Asian and Caucasian populations. The aim of the present study was to investigate TP53 and NQO1 polymorphisms and their combined effects with respect to breast cancer susceptibility in a Syrian study cohort. The study cohort consisted of 122 cases and 139 controls. The tetra-primer ARMS-PCR method was used to genotype three TP53 polymorphisms; namely, exon 4 G>C Arg72Pro, IVS3 16 bp Del/Ins, and MspI IVS6+62A>G, and NQO1 C609T (Pro187Ser) polymorphism. Association was tested under six genetic models. We found a significant association for the heterozygous Arg/Pro genotype when combined with heterozygosity for IVS3 16 bp Del/Ins and MspI IVS6+62A>G (OR = 2.05 (1.22–3.47), P = 0.006). No significant association was found for NQO1 C609T or its combinations with TP53 polymorphisms. Our results support an association for TP53 polymorphisms with breast cancer susceptibility in the Syrian population.     

Electrophysiologic severity of carpal tunnel syndrome in diabetic patients of the Saudi population

Objectives:To study the frequency of multiple vascular risk factors and electrophysiological severity of carpal tunnel syndrome (CTS) in Saudi diabetic patients.Methods:This retrospective cross-sectional study was conducted in Neurology Department, King Fahd Hospital of University, Al-Khobar, Kingdom of Saudi Arabia from April 2017 to March 2018 and included 200 patients with CTS. Body parameters, such as blood pressure (BP), weight, height, and body mass index (BMI), along with laboratory and median nerve electrophysiological parameters, of diabetic and non-diabetic patients were compared, and a p-value<0.05 was considered significant.Results:Frequency of hypertension (HTN) and obesity was significantly higher in diabetic patients (p<0.05). Mean median nerve sensory amplitude (MNSA) was lower in diabetic patients (p<0.05).Non-recordable nerves, as well as bilateral and extremely severe CTS (p<0.05), were more frequently seen in diabetic patients. Age, BMI, systolic BP, low serum high density lipoprotein (HDL), high triglycerides, high fasting blood sugar, and high glycated hemoglobin (Hba1c) levels, known to affect the electrophysiological severity of CTS, had a statistically significant association with diabetes.Conclusion:Diabetes mellitus (DM) and obesity are the most commonly identified risk factors of CTS. Dyslipidemia, HTN and obesity are more frequently seen in diabetic patients with CTS. These concurrent risk factors are confounding the electrophysiological severity of CTS in these patients. Further larger-scale studies with the control of confounding factors are recommended.

Carpal tunnel syndrome (CTS) is known to have a frequent nerve entrapment syndrome and encompasses 45% of non-traumatic nerve lesions.1,2 Carpal tunnel syndrome can result in various problems, including pain and paresthesia in the median nerve distribution, swelling, and in severe cases weakness of the thumb and lateral 3 fingers.3 It affects the daily life activities, such as holding and gripping things by hand, brushing teeth, and driving.4 Carpal tunnel syndrome can be associated with any risk factor that causes pressure on the median nerve inthe wrist, including coexisting comorbidities and working conditions of the individuals.5 Some common conditions that can lead to CTS includes obesity, DM, oral contraceptives, smoking, corticosteroid use, pregnancy, hypothyroidism, rheumatoid arthritis, osteoarthritis, and wrist fracture.6The prevalence of CTS in diabetic patients is 14% without diabetic neuropathy and 30% with diabetic neuropathy.7 Literature has shown a high incidence of CTS in pre-diabetic states.8 Some researchers have also found a relationship between duration of diabetes, Hba1c, and micro vascular complications.9 Although type 2 diabetes is more frequently diagnosed among CTS patients, some studies had reported that the association between diabetes and CTS represents a confusion bias, most likely due to the strong relationship between obesity and type 2 diabetes.10 It has been shown that age, BMI, and other vascular risk factors, including metabolic syndrome, could affect the electrophysiological severity of CTS. Elevated low density lipoprotein (LDL) cholesterol and hyperglycemia were reported as independent risk factors for CTS in some studies.8,11,12 Similarly, obesity, elevated triglycerides, elevated LDL cholesterol and hypertension were shown to be strongly associated with CTS.13 In the study conducted by Balci et al,14 75% of the CTS patients were found to have metabolic syndrome, and the electrophysiological parameters (median nerve sensory onset latency, sensory conduction velocity, sensory amplitude, distal motor latency, motor conduction velocity, and motor amplitude) were worse in patients with metabolic syndrome. Gül et al,15 similarly showed that severity of CTS was even more severe in patients with metabolic syndrome than in those with diabetes.The aim of the present study was to study the frequency of multiple vascular risk factors, such as HTN, dyslipidemia and obesity in CTS patients, and to compare the electrophysiological severity of CTS in Saudi diabetic and non diabetic patients. This population is facing a high burden of multiple vascular risk factors, which are also affecting the severity of CTS.