Emerging Insights into the PI3K/AKT/mTOR Signaling Pathway and Non-Coding RNA-mediated Drug Resistance in Glioblastoma.

Glioblastoma multiforme [GBM] is a highly aggressive grade IV central nervous system tumor with a dismal prognosis. Factors such as late detection, treatment limitations due to its aggressive nature, and, notably, drug resistance significantly affect clinical outcomes. Despite the effectiveness of Temozolomide [TMZ], a potent chemotherapy agent, the development of drug resistance remains a major challenge. Given the poor survival rates and chemoresistance, there is an urgent need for novel treatment strategies. Non-coding RNAs, particularly microRNAs [miRNAs], offer a promising approach to GBM diagnosis and treatment. These small non-coding RNAs play crucial roles in tumor progression, either suppressing or promoting oncogenic characteristics. The phosphoinositide-3 kinase [PI3K]/AKT/ mTOR pathway, which regulates essential biological processes like proliferation and survival, is a key target of miRNAs in cancer. Studies have underscored the significance of PI3K/AKT/mTOR signaling in drug resistance development and its interplay with non-coding RNAs as mediators of tumorigenesis. This review aims to outline the involvement of PI3K/AKT/mTOR signaling in miRNA modulation and strategies to overcome chemoresistance in GBM.

Polyphenols Modulate the miRNAs Expression that Involved in Glioblastoma.

Glioblastoma multiforme (GBM), a solid tumor that develops from astrocytes, is one of the most aggressive types of brain cancer. While there have been improvements in the efficacy of treating GBM, many problems remain, especially with traditional therapy methods. Therefore, recent studies have extensively focused on developing novel therapeutic agents for combating glioblastoma. Natural polyphenols have been studied for their potential as chemopreventive and chemotherapeutic agents due to their wide range of positive qualities, including antioxidant, antiinflammatory, cytotoxic, antineoplastic, and immunomodulatory activities. These natural compounds have been suggested to act via modulated various macromolecules within cells, including microRNAs (miRNAs), which play a crucial role in the molecular milieu. In this article, we focus on how polyphenols may inhibit tumor growth by influencing the expression of key miRNAs that regulate oncogenes and tumor suppressor genes.

A placebo-controlled randomized clinical trial of amantadine hydrochloride for evaluating the functional improvement of patients following severe acute traumatic brain injury.

BACKGROUND: Considering the known derangements in the dopaminergic neurotransmitter systems following traumatic brain injury (TBI), dopamine agonists are used as a pharmacologic option. In this study, we evaluate the effects of amantadine hydrochloride on the functional improvement of severe TBI patients. METHODS: Within a triple-blinded (patients, intervention administrators, and outcome assessors) placebo-controlled randomized clinical trial, we evaluated the effects of amantadine (100 mg BD (twice a day) for 14 days, then 150 mg BD for another 7 days, and 200 mg BD for another 21 days) on outcome measurements of weekly mean Glasgow Outcome Scale (GOS) and Disability Rating Scale (DRS), through six weeks of trial for 57 patients (29 amantadine, 28 placeboes) with severe TBI admitted in our hospital. RESULTS: Although both groups had improvement in their DRS, the change from baseline was significantly better in the amantadine group (10.88±5.24 for amantadine vs. 8.04±4.07 for placebo, P=0.015). No significant difference was observed between groups for GOS (1.04±0.55 for amantadine vs. 1.12±1.05 for placebo, P=0.966). CONCLUSIONS: Based on our findings, amantadine hydrochloride might improve the speed of functional ability improvement in severe TBI patients, evaluated by DRS, and is also well tolerated by patients. Although, there were some limitations in this study, including small sample size, short time interval, not providing a wash-off period and invalidity of GOS for measuring recovery rates in short-term periods.

Neural Stem Cells Secretome Increased Neurogenesis and Behavioral Performance and the Activation of Wnt/ß-Catenin Signaling Pathway in Mouse Model of Alzheimer's Disease.

Alzheimer's disease is a progressive and age-related neurodegenerative disorder that is manifested by neuropathological changes and clinical symptoms. Recently, cell-based therapeutic interventions have been considered as the promising and effective strategies in this field. Herein, we investigated therapeutic effects of neural stem cell secretome on Alzheimer's disease-like model by triggering of Wnt/ß-catenin signaling pathway. In this study, mice were randomly allocated into three different groups as follows: Control, AD + Vehicle, and AD + NSCs-CM groups. To induce mouse model of AD, Aß1-42 was injected into intracerebroventricular region. Following AD-like confirmation through thioflavin S staining and Passive avoidance test, about 5 µl mouse NSCs-CM was injected into the target areas 21 days after AD induction. For evaluation of endogenous proliferation rate (BrdU/Nestin+ cells), 50 µg/kbW BrdU was intraperitoneally injected for 5 consecutive days. To track NSC differentiation, percent of BrdU/NeuN+ cells were monitored via immunofluorescence staining. Histological Nissl staining was done to neurotoxicity and cell death in AD mice after NSCs-CM injection. Morris Water maze test was performed to assess learning and memory performance. Data showed that NSCs-CM could reverse the learning and memory deficits associated with Aß pathology. The reduced expression of Wnt/ß-catenin-related genes such as PI3K, Akt, MAPK, and ERK in AD mice was increased. Along with these changes, NSCs-CM suppressed overactivity of GSK3ß activity induced by Aß deposition. Besides, NSCs increased BrdU/Nestin+ and BrdU/NeuN+ cells in a paracrine manner, indicating proliferation and neural differentiation of NSCs. Moreover, neurotoxicity rate and cell loss were deceased after NSCs-CM injection. In summary, NSCs can regulate adult neurogenesis through modulating of Wnt/ß-catenin signaling pathway and enhance the behavioral performance in the AD mice. These data present the alternative and effective approach in the management of AD and other cognitive impairments.

Quercetin promotes learning and memory performance concomitantly with neural stem/progenitor cell proliferation and neurogenesis in the adult rat dentate gyrus.

The decline in neurogenesis is a very critical problem in Alzheimer disease. Different biological activities have been reported for medicinal application of quercetin. Herein, we investigated the neurogenesis potential of quercetin in a rat model of Alzheimer's disease induced by amyloid-beta injection. Rats were randomly divided into Control, Alzheimer + Saline and Alzheimer + Quercetin groups. Following the administration of Amyloid-beta, rats in the Alzheimer + Quercetin group received 40 mg/kg/day quercetin orally for one month. Our data demonstrated amyloid-ß injection could impair learning and memory processing in rats indicated by passive avoidance test evaluation. We noted that one-month quercetin treatment alleviated the detrimental effects of amyloid-ß on spatial learning and memory parameters using Morris water maze analysis. Quercetin was found to increase the number of proliferating neural stem/progenitor cells. Notably, quercetin increased the number of DCX-expressing cells, indicating the active dynamic growth of neural progenitor cells in the dentate gyrus of the hippocampus. We further observed that the quercetin improved the number of BrdU/NeuN positive cells contributed to enhanced adult neurogenesis. Based on our results, quercetin had the potential to promote the expression of BDNF, NGF, CREB, and EGR-1 genes involved in regulating neurogenesis. These data suggest that quercetin can play a valuable role in alleviating Alzheimer's disease symptoms by enhancing adult neurogenesis mechanism.

Association between knee pain and low back pain.

OBJECTIVE: To evaluate the association between knee pain and lumbar disorders. METHODS: The case-control study was conducted at Physical Medicine and Rehabilitation Department, Tabriz University of Medical Sciences, Iran, from December 2009 to March 2011, and comprised patients with primary complaint of knee pain. A separate group worked as controls. The coincidence of knee pain and lumbar disorders were assessed and compared between the two groups SPSS 15 was used for statistical analysis. RESULTS: Of the 170 patients, 90(53%) were in the case group having 20(22.2%) males and 70(77.7%) females, and 80(47%) in the control group having 18(22.5%) males and 62(77.5%) females. The overall mean age was 46.9±8.9 (range: 25-61years). Age and gender difference between two groups was not significant (p>0.05 each). Lifetime prevalence of radicular, chronic and recurrent low back pain and its point prevalence in the case group were significantly higher than the control group (p<0.05 each). Range of movement of the lower limb and lumbar region in the case group was less than the controls (p<0.05). Local subcutaneous tissue oedema of the lumbar region was more prevalent in the case group (p<0.05). There was no significant difference in vertebral column posture between the two groups (p>0.05). CONCLUSIONS: The relationship between lumbar and knee pain disorders should be considered in the assessment and management of patients with knee pain.

The effect of intravenous paracetamol on postoperative pain after lumbar discectomy.

STUDY DESIGN: A randomized, double-blinded controlled trial. PURPOSE: Postoperative pain relief especially using analgesic drugs with minimal side effects has considerable clinical importance. This study aimed to examine the effect of intravenous paracetamol on pain relief after lumbar discectomy as a major surgery. OVERVIEW OF LITERATURE: Patients undergoing lumbar discectomy experience a high degree of lumbar pain. Some authors emphasize the use of intravenous paracetamol to improve postoperative pain and increase patients' satisfaction following this surgery. METHODS: Fifty-two patients scheduled for lumbar discectomy were randomly allocated into two groups: a group that received intravenous paracetamol (1 g/100 mL normal saline) within the last 20 minutes of surgery as the case group (n=24) and a group that received sodium chloride 0.9% 100 mL as the control group (n=28). Postoperative pain was assessed at 1, 6, 12, 18, and 24 hours after surgery by a visual analogue scale (VAS). The dosage of the administered opioid (morphine), as well as drug-related side effects within the first 24 hours after surgery were also recorded. RESULTS: The mean VAS score was significantly lower in the paracetamol group than the controls for all of the assessed time points. Although the dose of the administered morphine was numerically lower in the paracetamol group, this difference was not statistically significant (5.53±4.49 mL vs. 7.85±4.17 mL). CONCLUSIONS: Intravenous paracetamol as a non-opioid analgesic can relieve postoperative pain in patients undergoing lumbar discectomy; however, its use alone may not represent the best regimen for reducing the needed dose of opioids after operation.

Risk factors of recurrent lumbar disk herniation.

BACKGROUND: Recurrent lumbar disc herniation (LDH) is a common cause of poor outcomes after lumbar discectomy surgery. Studies focused on risk factors of true recurrent disk herniation at the same level and side, are few. The aim of current study is to evaluate risk factors of recurrent disc herniation in Iranian population. MATERIALS AND METHODS: We retrospectively reviewed 40 patients with recurrent disc herniation and 120 patients without recurrence to evaluate possible risk factors for herniation recurrence. A clinically significant recurrent herniation was defined as a disc herniation causing leg pain with radiographic (MRI) evidence of disc material at the same side and level of the index surgery causing impingement, compression, or deviation of nerve tissue. A series of patients without recurrence was used for comparison to identify possible risk factors for recurrent LDH. RESULTS: There was significant difference between groups with and without LDH in sex (P = 0.003), smoking habit (P = 0.004), height (P = 0.04), weight (P = 0.006) and occupational characteristic (P < 0.001). By putting these differences in logistic regression analysis, it showed that gender (male), taller height, heavy works and being smoker could predict lumbar disc herniation recurrence. CONCLUSION: Considering sex, smoking and heavy works as predictors of recurrent LDH, surgeons should advice their patients to limit hard work and put away smoking especially in tall and male ones to prevent LDH recurrence.

Endovascular treatment of intracranial artery dissection: clinical and angiographic follow-up.

Background. Intracranial artery dissections are rare and many controversies exist about treatment options. The aim of this study was to evaluate the efficacy and safety of the endovascular approach in patients with an intracranial dissection presenting with different symptoms. Methods. We prospectively evaluated the clinical features and treatment outcomes of 30 patients who had angiographically confirmed nontraumatic intracranial dissections over 4 years. Patients were followed up for 17 months, and their final outcomes were assessed by the modified Rankin Score (mRS) and angiography. Results. Sixteen (53.3%) patients had a dissection of the anterior circulation, whereas 14 (46.7%) had a posterior circulation dissection. Overall, 83.3% of the patients suffered a subarachnoid hemorrhage (SAH). Grade IV Hunt and Hess score was seen in 32% of the SAH presenting cases. Parent artery occlusion (PAO) with coil embolization was used in 70% of the cases. The prevalence of overall procedural complications was 23.3%, and all were completely resolved at the end of follow-up. No evidence of in-stent occlusion/stenosis or rebleeding was observed in our cases during follow-up. Angiography results improved more frequently in the PAO with coil embolization group (100%) than in the stent-only-treated group (88.9%) (P = 0.310) and the unruptured dissection group (5/5, 100%) in comparison with the group that presented with SAH (95.8%) (P = 0.833). Conclusion. Favorable outcomes were achieved following an endovascular approach for symptomatic ruptured or unruptured dissecting aneurysms. However, the long-term efficacy and durability of these procedures remain to be determined in a larger series.

Endovascular treatment of very small and very large ruptured aneurysms of the anterior cerebral circulation: a single-center experience.

INTRODUCTION: Endovascular treatment of aneurysms has been introduced as a less invasive method for decreasing the rate of aneurysm rerupture and subsequent subarachnoid hemorrhage. The outcome and complication rate for endovascular treatment of very small (≤3 mm) and very large (15-25 mm) intracranial aneurysms has been controversial. Here we report our experience with endovascular coiling of very small and very large ruptured aneurysms of the anterior cerebral circulation. METHODS: Patients were included in the study if the maximum dimension of the intracranial ruptured aneurysm was reported to be ≤3 mm or 15-25 mm and if the aneurysm was within the anterior cerebral circulation. The largest dimension was calculated using CT angiography and was confirmed by digital subtraction angiography. Endovascular coiling was performed using Guglielmi detachable coils. All patients underwent follow-up contrast MR angiography every 6 months. RESULTS: A total of 40 cases (18 females and 22 males) were included in this single-center study. Twenty-one very small and 19 very large ruptured aneurysms were analyzed. Preprocedural Hunt and Hess grades were determined. Endovascular coiling was performed successfully in most cases (97.5%), with unsuccessful coiling in 1 patient with a very small ruptured aneurysm. In the very small aneurysm group, the most common location was the anterior communicating artery and, in the large aneurysm group, the most common location was the middle cerebral artery (MCA) bifurcation. The mean follow-up time was 15.08 months (range: 6-30 months). The 6th month modified Rankin scale (mRS) values for very small aneurysm cases were 0 (no symptoms at all) in 16 cases (76.2%) and 1 (no significant disability despite symptoms) in 5 cases (23.80%). For the very large aneurysm cases, the mRS values were 1 in 2 cases (10.5%), 2 in 7 cases (36.8%), 3 in 6 cases (31.6%), 4 in 3 cases (15.8%) and 6 in 1 case (died due to vasospasm 72 h later; 5.2%). The immediate complications that were observed were MCA branch occlusion in 1 very small aneurysm patient and early vasospasms in 3 very large aneurysm patients. The late complication that was observed was recanalization in 1 very small aneurysm case (1/21, 4.76%) and in 5 very large aneurysm cases (5/18, 27.77%). CONCLUSION: Endovascular treatment of very small aneurysms is an effective method of treatment with acceptable immediate and long-term outcomes. Immediate and long-term complications were more prevalent in very large ruptured aneurysms.

Extramedullary plasmacytoma presenting as a solitary mass in the intracranial posterior fossa.

A patient with a 3-month history of headache refractory to pain medication was admitted. The CT scan and MRI showed evidence of a posterior fossa mass. This was pathologically confirmed as an extra medullary plasmacytoma (EMP). He had a pathologic fracture of the left humerus 7 years ago while the radiologist was unaware at the time of diagnosis. A solitary bone plasmacytoma (SBP) was the cause of the pathologic fracture. This report includes the first description of MRI findings in a patient with a rare-incidence intracranial solitary extra medullary plasmacytoma (SEP) in Iran. There is a striking similarity between the features of intracranial SEP and meningiomas. Intracranial SEP, although rare, should be included in the differential diagnosis of brain tumors in areas where meningiomas commonly arise. The MRI findings and differential diagnosis of plasmacytoma are reviewed. Before this case report, only few cases have been reported in the literature. Nonetheless, this is the first report of posterior fossa EMP from Iran.

Effect of E. laciniata (L) ointment on mild and moderate carpal tunnel syndrome: a double-blind, randomized clinical trial.

This paper concerns the effects of methanol extract of Eremostachys laciniata on mild and moderate Carpal Tunnel Syndrome (CTS). Forty patients, including sixty hands affected by CTS, were randomly categorized in two different groups. Group A and Group B were treated with E. laciniata extract and placebo as the ointment, respectively. Tests, including the palmar prehension (pound), grip power (kg), visual analog scale (VAS) and electrodiagnostic study, were performed on all patients before and after the trial. During the trial, all patients receive Sodium Diclofenac (25 mg twice a day) orally. In addition, they utilized a night wrist splint. After four weeks of treatment, the state of mean palmer prehension in both groups improved yet, the statistics show that group A prevailed by (p = 0.01). Grip power increased in both groups as well, but this increase was not significant within-groups (p = 0.18 and p = 0.54 in group A and B, respectively) or between-groups (p = 0.053). Although the VSA decreased in both groups, group A prevailed again by (p < 0.001). After four weeks, no significant electrodiagnostic change was detected between the two groups. According to this study, the methanol extract of E. laciniata can be effective in treatment of mild and moderate CTS in combination with the wrist night splint, especially in alleviating the severity of the syndrome and increasing the palmer prehension power.

Bowel perforation by ventriculoperitoneal shunt catheter mimicking gastroenteritis.

Colon perforation is a rare and serious complication of ventriculoperitoneal shunt. The authors report a 7-month-old male infant with vomiting and watery diarrhea after colon perforation by a ventriculoperitoneal shunt. A minimal laparotomy incision was performed accurately where preoperative colonoscopy had detected the penetration site of shunting tube in the left colon.