Prevalence of Medication Associated with QTc Prolongation Used Among Critically Ill Patients.

Background: Acquired prolonged corrected QT (QTc) interval can lead to life-threatening Torsade de Pointes (TdP) arrhythmia. Multiple risk factors including medications, comorbidities, and electrolyte imbalances contribute significantly to acquired manifestations of the QTc prolongation. Critically ill patients are particularly more vulnerable to TdP due to complex medical conditions, aging, and polypharmacy. Objective: This study aimed to assess the prevalence of TdP-associated medication prescribing, identify risk factors for QTc prolongation and TdP, and determine primary predictors of high TdP medication usage in critically ill patients in Jordan. Methods: We conducted a retrospective cross-sectional analysis of electronic medical records for patients from King Abdullah University Hospital who were admitted to Intensive Care Unit (ICU) between (July 2012-July 2022). We collected data on patients' demographics, clinical characteristics, comorbidities, laboratory results, and prescribed medications. Medications were categorized into three TdP risk levels according to CredibleMeds® assessment tool. Data were analyzed using descriptive statistics and a binary logistic regression model. Results: Of the 13,300 patients (58.2% male, median age 62 years). Prescribing prevalence for medications with known TdP risk was 19%, possible risk (24.7%), conditional risk (21.6%), and confirmed conditional risk (8.3%). Common comorbidities included hypertension (40.9%), diabetes (33.3%), and cancer (15.4%). Drugs with known TdP risk included citalopram, amiodarone, clarithromycin, and ciprofloxacin. A binary regression model revealed that as age increased, the odds of TdP associated medication prescribing decreased (OR = 0.989, p < 0.001), while patients on more than five medications had higher odds (OR = 4.281, p < 0.001). Conclusion: The study identified a notable prevalence of prescribing for medications with QTc prolongation/TdP risk in critically ill patients. Healthcare providers in the ICU should exercise caution to minimize the inadvertent prescription of TdP associated medications especially among older patients and those with polypharmacy.

Adherence and utilization of short-term antibiotics: Randomized controlled study.

Enhancing adherence to medication has the potential to improve clinical outcomes and decrease healthcare cost. The role of clinical pharmacist-led education on adherence to short-term antibiotic has never been investigated in Jordan. This study aimed to evaluate the impact of an educational intervention on antibiotic short-term adherence and to assess the antibiotic utilization pattern. A prospective, single blinded, randomized controlled study was conducted in a tertiary referral hospital in Jordan. Adult patients diagnosed with acute infection and prescribed a short-term antibiotic course (< 30 day) were included in the study. Recruited patients were randomly allocated into control and intervention groups. Pharmaceutical education about the correct use of antibiotic/s was provided to the intervention group. The results showed that penicillins were the most prescribed antibiotics (38.7%) followed by fluoroquinolones (23.9%) and cephalosporines (20.9%). Patients in the intervention group were more likely to be adherent to the prescribed antibiotics compared to control group (OR = 1.445, 95CI% = 1.029-2.030, p = 0.033). Employed patients, less frequent administration of antibiotic, and searching information related to the prescribed antibiotics were factors associated with better adherence to short-term antibiotic (p<0.05). The most common reasons for non-adherence were feeling better and forgetfulness to take medication. These findings highlighted that pharmacist-led educational intervention significantly enhance adherence to prescribed short-term antibiotics which is a major drive to control antibiotic resistance. Initiatives should be adopted to include patient education as a regular element in the medication dispensing process. Clinical trial registration: The trial is registered at ClinicalTrials.gov (identifier: NCT05293977).

Students' experiences and attitudes toward a newly developed simulation-based pharmaceutical care clinical rotation: A pre-post study design.

Purpose: This study aims to evaluate Doctor of Pharmacy (PharmD) students' experience with the newly developed simulation-based pharmaceutical care (PC) rotation by evaluating their knowledge and attitudes towards PC before and after the rotation. Methods: A self-administered questionnaire was distributed to sixth year PharmD students enrolled in the clinical training rotation "Comprehensive Pharmaceutical Care" during the 2020/2021 academic semesters at Jordan University of Science and Technology's (JUST) Faculty of Pharmacy. Questionnaires were distributed before and after completing four experiential training weeks and consisted of three sections. The first section collected students' demographic details while the second and third sections evaluated students' knowledge about, and attitudes toward PC, respectively. Descriptive statistics were used to describe and compare changes in students' knowledge and attitudes pre-and post-rotation. Results: A total of 106 valid questionnaires were completed with a response rate of 99.07%. The rates of correct answers increased after the rotation with median total knowledge score increasing from 8 to 10 (out of 13, P value < 0.001). Significant improvements in students' understanding of aspects relating to the concept and process of PC, and the role of clinical pharmacist in PC provision, were shown post the simulation-based clinical rotation. Similarly, their attitudes toward performing PC were either improved or emphasized. In contrast results also revealed that specific aspects of the rotation require further refinement, such as the comprehensiveness of the PC process and responsibilities in providing PC. Conclusions: PharmD students' understanding and attitudes toward PC were either improved or emphasized after the simulation-based PC rotation. This study highlights the value of simulation as a unique instructional technique that can assist educators to develop PC competencies for pharmacy students.

Rapid high performance liquid chromatography method for erlotinib quantification in vitro: Application to study the effect of resveratrol on metabolism and cellular uptake of erlotinib.

BACKGROUND: Erlotinib is a selective epidermal growth factor receptor inhibitor that is used for the treatment of non-small cell lung cancer and pancreatic cancer. Its metabolism is mainly mediated by cytochrome P450 3A (CYP 3A). Resveratrol, a natural compound found in many plants and supplements, is known to inhibit CYP3A enzyme, therefore, it may act as an inhibitor for the metabolism of erlotinib. OBJECTIVE: Development of a rapid high performance liquid chromatography with photodiode array detection (HPLC-PDA) method for the quantification of erlotinib in liver microsomes and cancer cells and its application to study resveratrol effect on metabolism and cellular uptake of erlotinib. METHODS: HPLC-PDA was used to develop an efficient bioanalytical method with a 2.5-min runtime preceded by a simple protein precipitation step. The method was validated according to the European Medicines Agency guidelines. Erlotinib metabolic stability and resveratrol effect on erlotinib metabolite formation were evaluated in rat liver microsomes. Furthermore, the method was used to measure the intracellular concentrations of erlotinib in cancer colorectal cells and investigating resveratrol effect on the cellular uptake of erlotinib. RESULTS: A rapid HPLC-PDA method was developed and validated for the first time to address potential drug interaction of erlotinib with resveratrol. Resveratrol was a strong inhibitor of erlotinib metabolism in vitro with IC50 = 4.03 µM. Resveratrol, however, had no effect on erlotinib cellular uptake after 1 h incubation in human colorectal cancer cells. CONCLUSION: The study suggests that resveratrol may produce a potential herb-drug interaction with erlotinib at the metabolism level and should be investigated in patients in the clinic.

Involvement and possible role of transglutaminases 1 and 2 in mediating fibrotic signalling, collagen cross-linking and cell proliferation in neonatal rat ventricular fibroblasts.

Transglutaminase (TG) isoforms control diverse normal and pathophysiologic processes through their capacity to cross-link extracellular matrix (ECM) proteins. Their functional and signalling roles in cardiac fibrosis remain poorly understood, despite some evidence of TG2 involvement in abnormal ECM remodelling in heart diseases. In this study, we investigated the role of TG1 and TG2 in mediating fibrotic signalling, collagen cross-linking, and cell proliferation in healthy fibroblasts by siRNA-mediated knockdown. siRNA for TG1, TG2 or negative control was transfected into cultured neonatal rat ventricular fibroblasts and cardiomyocytes. mRNA expression of TGs and profibrotic, proliferation and apoptotic markers was assessed by qPCR. Cell proliferation and soluble and insoluble collagen were determined by ELISA and LC-MS/MS, respectively. TG1 and TG2 were both expressed in neonatal rat cardiomyocytes and fibroblasts before transfection. Other TGs were not detected before and after transfection. TG2 was predominantly expressed and more effectively silenced than TG1. Knocking down TG1 or TG2 significantly modified profibrotic markers mRNA expression in fibroblasts, decreasing connective tissue growth factor (CTGF) and increasing transforming growth factor-ß1 compared to the negative siRNA control. Reduced expression of collagen 3A1 was found upon TG1 knockdown, while TG2 knockdown raised α-smooth muscle actin expression. TG2 knockdown further increased fibroblast proliferation and the expression of proliferation marker cyclin D1. Lower insoluble collagen content and collagen cross-linking were evidenced upon silencing TG1 or TG2. Transcript levels of collagen 1A1, fibronectin 1, matrix metalloproteinase-2, cyclin E2, and BCL-2-associated X protein/B-cell lymphoma 2 ratio were strongly correlated with TG1 mRNA expression, whereas TG2 expression correlated strongly with CTGF mRNA abundance. These findings support a functional and signalling role for TG1 and TG2 from fibroblasts in regulating key processes underlying myocardial ECM homeostasis and dysregulation, suggesting that these isoforms could be potential and promising targets for the development of cardiac fibrosis therapies.

Photolytic Controlled Release Formulation of Methotrexate Loaded in Chitosan/TiO2 Nanoparticles for Breast Cancer.

A new system composed of chitosan nanoparticles loaded with methotrexate (MTX-CS-NPs) and functionalized with photocatalytic TiO2 nanoparticles (TiO2-NPs) was prepared. This system is expected to initiate polymeric rupture of MTX-CS-NPs and subsequently release MTX, upon illumination with UV light. MTX-CS-NPs were prepared and characterized in terms of particle size, charge, polydispersity and drug release before and after coating with TiO2-NPs. The release of MTX in vitro was studied in dark, light and UV light. Finally, coated and uncoated MTX-CS-NPs were studied in vitro using MCF-7 cell line. The functionalized NPs were larger in size, more polydisperse and carried higher positive charges compared to the unfunctionalized NPs. The entrapment efficacy was high reaching 75% and was not affected by coating with MTX-CS-NPs. Further, less than 5% of methotrexate was released after 80 h from uncoated NPs and the release was not enhanced by UV illumination of the particles. In contrast, the release from functionalized NPs was enhanced, reaching 40% after 80 h, as the particles were stroked with UV light and as the amount of TiO2-NPs used in coating increased. Finally, coating the MTX-CS-NPs with TiO2-NPs significantly enhanced their cytotoxicity on MCF-7 cells. The coated MTX-CS-NPs recorded low cell viabilities compared to the other formulations. In conclusion, the drug release of MTX-CS-NPs could be triggered and controlled remotely by coating with TiO2-NPs, which maybe more effective in cancer treatment.

Preparation of Modified Chitosan-based Nanoparticles for Efficient Delivery of Doxorubicin and/or Cisplatin to Breast Cancer Cells.

PURPOSE: The aim is to develop a novel pH-responsive modified chitosan-based nanoparticles system for active loading of doxorubicin (DOX) and triggered intracellular release. METHODS: Nanoparticles were formed in an aqueous medium via ionic interaction between negatively charged chitosan derivative and positively charged DOX at neutral pH and then transformed in situ into cisplatin (CIS) cross-linked nanoparticles through cross-linking the formed micelles via chelation interaction between the negatively charged polymeric carrier and cisplatin. Nanoparticles were characterized in terms of particle size and zeta potential using DLS and TEM. Drug loading efficiency and encapsulation efficiency were determined based on the physio-chemical proprieties of the polymer and the amount of the cross-linking agent. In vitro release studies were performed using the dialysis method at different pHs. Finally, the cytotoxic effects of these nanoparticles were performed against the MCF-7 BrCA cell line under different pHs. RESULTS: The average particle size of polymer alone and DOX nanoparticles was 277.401 ± 13.50 nm and 290.20 ± 17.43 nm, respectively. The zeta potential was -14.6 ± 1.02 mV and -13.2 ± 0.55 mV, respectively, with a low polydispersity index. Drug loading and encapsulation deficiencies were determined, dependent on the amount of the cross-linking agent. In vitro release studies showed that the release of DOX from these nanoparticles was pH-dependent. Moreover, results showed that the cytotoxicity magnitude of DOX-loaded nanoparticles against MCF-7 BrCA cells was higher compared with free DOX. CONCLUSION: These novel pH-sensitive nanoparticles proved to be a promising Nano-drug delivery for tumor-targeted delivery of DOX.

Depression symptoms and quality of life in patients receiving renal replacement therapy in Jordan: A cross-sectional study.

Patients with chronic illnesses, such as those with chronic kidney disease (CKD) that are undergoing renal replacement therapy (RRT), face significant psychological changes. This descriptive cross-sectional research was carried out to investigate the factors that influence depressive symptoms and quality of life (QoL) in patients with end-stage renal disease. Data were collected from 70 participants undergoing RRT using a self-reported questionnaire that included sociodemographic information, depressive symptoms, disease status, and QoL. The Beck Depression Inventory-II (BDI-II) screening scale was used to measure depressive symptoms and the SF-36 (Medical Outcome Survey-Short Form 36) was used to assess QoL. Participants in the study rated their depressive symptoms as 'minimum (44.3%), 'mild' (20%), 'moderate' (21.4%), and 'severe (14.3%). Furthermore, a shorter duration of dialysis and comorbid conditions were significantly associated with the development of depressive symptoms. Patients on RRT for a longer period of time had lower physical activity scores than patients on dialysis for a shorter period of time. Male participants have a higher mental QoL than female participants, suggesting that the mental aspect of renal disease is less impaired than the physical aspect. The findings of this study are expected to increase awareness of RRT therapy targets and enhance patient outcomes.

Crizotinib induced antitumor activity and synergized with chemotherapy and hormonal drugs in breast cancer cells via downregulating MET and estrogen receptor levels.

MET is a receptor tyrosine kinase known to drive neoplastic transformation and aggressive tumor phenotypes. Crizotinib is an oral multi-targeted tyrosine kinase inhibitor of MET, ALK, RON, and ROS1 kinases. In this study, the anticancer effects of crizotinib on breast cancer cells were investigated in vitro along with the molecular mechanisms associated with these effects. Besides, the antiproliferative effects of crizotinib in combination with chemotherapy, hormonal drugs, and targeted agents were examined. Results showed that crizotinib produced dose-dependent antiproliferative effects in BT-474 and SK-BR-3 breast cancer cells with IC50 values of 1.7 µM and 5.2 µM, respectively. Crizotinib inhibited colony formation of BT-474 cells at low micromolar concentrations (1-5 µM). Immunofluorescence and Western blotting indicated that crizotinib reduced total levels of MET and estrogen receptor (ERα) in BT-474 cells. Also, crizotinib reduced the levels of phosphorylated (active) MET and HER2 in BT-474 cells. The combined treatment of crizotinib with doxorubicin and paclitaxel resulted in synergistic growth inhibition of BT-474 cells with combination index values of 0.46 and 0.35, respectively. Synergy was also observed with the combination of crizotinib with the hormonal drugs 4-hydroxytamoxifen and fulvestrant in BT-474 cells. Alternatively, the combination of crizotinib with lapatinib produced antagonistic antiproliferative effects in both BT-474 and SK-BR-3 cells. Collectively, these findings demonstrate the anticancer effects of crizotinib in breast cancer cells and reveal ERα as a potential therapeutic target of the drug apart from its classical kinase inhibitory activity. Crizotinib could be an appealing option in combination with chemotherapy or hormonal drugs for the management of breast cancer.

Physicians' Attitudes and Ethical Obligations to Pharmacogenetic Testing.

INTRODUCTION: Despite the increased utilization of pharmacogenetic (PGt) testing to guide drug therapy, little is known about the ethical challenges posed by the use of these genetic tools. METHODS: This cross-sectional study aimed to address ethical issues related to ancillary genetic information, consent forms, and potential confidentiality breaches from physicians' perspectives. A questionnaire was administered to all practicing physicians working in KAUH. RESULTS: Almost 49% and 65% of physicians were willing to recommend PGt testing for adult and pediatric patients, respectively. The findings showed that physicians attitudes towards the clinical utility of PGt testing became more preceptive. The majority (73.7%) indicated that PGt testing should not be treated as other routine laboratory tests. The finding also focused on potential conflicts regarding ancillary genetic information, in which 78.8% indicated that they would like to preserve the confidentiality and privacy of the patients and only 14.4% of physicians did not feel obligated to let patients know about any future risk that might be uncovered using PGt testing. The findings showed that collecting both verbal and written consents was imperative prior to testing. Seriousness and predictability of the diseases were reported to be legitimate circumstances that allow disclosure of genetic information. DISCUSSION: Unless the field of PGt testing addresses the ethical challenges that might be encountered during PGt treatment, these issues might influence its acceptance in routine clinical settings. Establishing a minimal set of ethical standards may help emphasize the role of physicians and thus facilitate the implementation of PGt tests.

Fresh Pomegranate Juice Decreases Fasting Serum Erythropoietin in Patients with Type 2 Diabetes.

Pomegranate juice (PJ) has been recognized to have various biological benefits in several pathological conditions. One such benefit is the augmentation of hemoglobin level and the number of erythrocytes in the human body. Here, we assessed the short-term effect of fresh PJ on the level of Erythropoietin (EPO) in patients with type 2 diabetes (T2D) compared to healthy individuals. Blood samples from 59 participants with T2D and 30 healthy individuals were collected after a 12-hour fast and 3 hours after administration of fresh PJ at 1.5 mL per kg body weight. Serum glucose was measured by standard method and commercially available chemiluminescent immunoassay kits were used to determine serum EPO concentration. Mean changes in serum EPO levels 3 hours after ingesting PJ and before the juice ingestion (EPO response to PJ) for both diabetic and healthy participants were -2.002 ± 0.541 vs. - 0.041 ± 0.214, respectively (P = 0.0087). This EPO response to PJ was found not to be correlated with age (P = 0.6622) and gender (P = 0.5354) for patients with T2D, while a negative correlation (P = 0.0183) between EPO response to PJ and fasting serum glucose concentrations was observed in these patients. In conclusion, fresh PJ reduced serum EPO level in patients with T2D, but not in healthy individuals, 3 hours after ingesting the juice. The EPO response to PJ was found to be negatively correlated with fasting serum glucose, but not with age and gender, of patients with T2D. This trial is registered with ClinicalTrials.gov Identifier. NCT03902288.

Immunomodulatory effect of statins on Regulatory T Lymphocytes in human colorectal cancer is determined by the stage of disease.

Colorectal cancer (CRC) is a public health problem worldwide and in Jordan. Statins are cholesterol lowering agents. Beyond their effects, statins use has been reported to reduced risk of several malignances, including CRC. This study aimed to assess the effect of statins on CRC by studying cellular infiltration of Regulatory T Lymphocytes (Tregs) into CRC tissues and their effect on Transforming growth factor beta 1 (TGF-ß1) level and on angiogenesis. Fourty seven specimens (25 statins users vs. 22 non-users) were used. Immunohistochemistry was performed to study Tregs infiltration using their marker, fork head transcription factor, and angiogenesis using CD31 as a marker. TGF-ß1 levels were measured using ELISA. Results revealed that statins use was associated with more Tregs infiltration, less angiogenesis but no difference in TGF-ß1 content in tumor tissue. When results were further stratified according to stage of disease, more Tregs infiltration was significantly noticed in advanced disease but not in early disease. In addition, more angiogenesis inhibition was noticed in early disease but not in advanced disease. Same stage-dependence wasn't noticed with TGF-ß1 expression. In early disease, reduction of angiogenesis mediated by statins might lead to reduction of tumor aggressiveness. On the other hand, Tregs infiltration into tumor mediated by statins might reduce cancer aggressiveness in advanced disease. These results suggest that statins might be used in the treatment of CRC.

Investigating the Effect of Demographics, Clinical Characteristics, and Polymorphism of MDR-1, CYP1A2, CYP3A4, and CYP3A5 on Clopidogrel Resistance.

Clopidogrel is an antiplatelet agent that is indicated for cardiovascular emergencies and procedures. The drug, however, is subject to response variability leading to therapy resistance. In this research, we explored the demographic, clinical, and genetic factors associated with clopidogrel resistance. Data analysis among our 280 subjects receiving clopidogrel showed some risk factors that are significantly associated with clopidogrel resistance compared with responders. Those were: female sex (P = 0.021), advanced age (P = 0.011), obesity (P = 0.002), and higher body mass index (P = 0.008) and higher platelets count (P = 0.002). However, known polymorphisms of MDR-1, CYP1A2, CYP3A4, and CYP3A5 were not associated with treatment resistance when compared to responders to clopidogrel therapy. Knowledge about such risk factors might provide recommendation in the future about starting doses or monitoring recommendations.

Evaluation of the Effect of Uremic Serum on Hepatic Reductase Functional Expression.

BACKGROUND: The nonrenal clearance of drugs mediated by hepatic reduction is selectively altered by kidney disease. This study evaluated the influence of uremic serum on the expression and activity of reductase enzymes. METHODS: Human hepatocellular carcinoma cells (HepG2) were incubated with 5% pooled serum collected from patients with hemodialysis (pre- and post-dialysis session) or control subjects. The mRNA expression of various aldo-keto (AKR1C) and carbonyl (CBR) reductases were measured. Reductase metabolic activity was assessed in human liver cytosol or HepG2 cells using naltrexone as a substrate. RESULTS: Incubation of cells with pre-dialysis serum resulted in significant upregulation of AKR1C4 (by 63.2%) and CBR1 (by 34.6%) versus control serum. This increase was not observed for AKR1C1 and CBR1 with serum collected post-dialysis. While uremic serum had no effect on reductase activity, some instances with differences in metabolite formation among individual's pre- and post-dialysis samples were observed. CONCLUSION: Although uremic serum can upregulate mRNA expression of several reductases, this effect was not observed at the activity level. Future studies are necessary to improve our understanding of the mechanistic effects of impaired kidney function on drug reduction.

Knowledge and Awareness of Colorectal Cancer Early Warning Signs and Risk Factors among University Students in Jordan.

In the present study, we aimed to assess the level of awareness regarding CRC warning signs and risk factors among undergraduate students. A cross-sectional survey using standardized questionnaire developed by the Cancer Research Center in the UK was carried out in three different public universities in Jordan including Jordan University of Science and Technology, Yarmouk University, and AL al-Bayt University over a 5-month period. Volunteers were asked about their knowledge regarding CRC symptoms, risk factors, and their behaviors regarding seeking medical advice. Findings revealed that response rate was 80.1%. Vast majority of responders were female (70.9%) and 18.2% of them were studying medical-related specialties. Regarding CRC symptoms, 14.3% of responders experienced poor knowledge, 52.9% have fair knowledge, and 32.8% have good knowledge. Abdominal pain was the most recognized warning signs where 70.8% of responders could recall it. In addition, risk factors awareness was lower than warning signs awareness. About 36.1% of responders have poor knowledge, 47.4% had fair knowledge, and 16.5% had good knowledge. Unhealthy diet was the most recognized risk factor where 32.3% of responders could recall it. Moreover, females were more aware regarding CRC symptoms. Similar findings were obtained for participants who were aged 20 years or more and for those who had previous experience of cancer. Students who were studying medical-related specialties were more aware of both CRC symptoms and risk factors than those who studying other specialties. Furthermore, regarding time to seek medical attention we found that 60.6% of volunteers would seek medical advice within 1 week of noticing CRC symptoms and 12% would seek it within 2 weeks. The mean duration for seeking medical advice was found to be 1.9 weeks. University students' awareness level of CRC is poor, and therefore, extended attention should be attempted to enhance the awareness of CRC via continuous education programs, lectures, or campaigns to encourage the early detection CRC.

A mini-review of c-Met as a potential therapeutic target in melanoma.

Melanoma is the third highest rated cancer in prevalence. Surgery, radiotherapy and targeted/biological therapies in addition to chemotherapy are available options for management of this cancer. Met is an appealing target for management of this type of cancer, since it targets many cancer vital processors, such as angiogenesis, cell growth, scattering and differentiation. In this review, we provide an overview about pathway abnormalities associated with melanoma. We also provide a summary about the events involved in Met signaling and related signaling molecules. We also show the evidence of the importance of Met signaling pathway as a target in cancer management. We also summarize clinical evidence about the use of Met signaling in management of cancer and summarize available trials related to targeting Met in other cancers.

Changes in the expression and protein level of matrix metalloproteinases after exposure to waterpipe tobacco smoke.

Waterpipe smoking has become a worldwide epidemic with health consequences that only now are beginning to be understood fully. Because waterpipe use involves inhaling a large volume of toxicant-laden smoke that can cause inflammation, some health consequences may include inflammation-mediated lung injury. Excess matrix metalloproteinase expression is a key step in the etiology of toxicant exposure-driven inflammation and injury. In this study, changes in the level and mRNA of major matrix metalloproteinases (MMP-1, -9, and -12) in the lungs of mice following exposure to waterpipe smoke were investigated. Balb/c mice were exposed to waterpipe smoke for one hour daily, over a period of 2 or 8 weeks. Control mice were exposed to fresh air only. ELISA and real-time PCR techniques were used to determine the protein and mRNA levels of MMP-1, -9, and -12 in the lungs. Our findings showed that MMP-1, -9, and -12 levels in the lung significantly increased after both 2 (p < 0.05) and 8 weeks (p < 0.01) exposures. Similarly, RT-PCR findings showed that mRNA of those proteinases significantly increased following 2 (p < 0.01) and 8 weeks (p < 0.001) exposures. In conclusion, waterpipe smoking is associated strongly with lung injury as measured by elevation in the expression of MMPs in the lung tissue.

Targeting Src-mediated Tyr216 phosphorylation and activation of GSK-3 in prostate cancer cells inhibit prostate cancer progression in vitro and in vivo.

Recent studies suggest a positive correlation between glycogen synthase kinase-3 (GSK-3) activation and tumor growth. Currently, it is unclear how both Akt that inhibits GSK-3 and active GSK-3 are maintained concurrently in tumor cells. We investigated the role of GSK-3 and the existence of an Akt-resistant pathway for GSK-3 activation in prostate cancer cells. Our data show that Src, a non-receptor tyrosine kinase is responsible for Y216GSK-3 phosphorylation leading to its activation even when Akt is active. Experiments involving mouse embryonic fibroblasts lacking cSrc, Yes and Fyn, as well as Src activity modulation in prostate cancer cells with constitutively active (CA-Src) and dominant negative Src (DN-Src) plasmids demonstrated the integral role of Src in Y216GSK-3 phosphorylation and activity modulation. Inhibition of GSK-3 with SB415286 in PC3 cells resulted in impaired motility, proliferation and colony formation. Treatment of PC3 cells with the Src inhibitor dasatinib reduced Y216GSK-3 phosphorylation and inhibited proliferation, invasion and micrometastasis in vitro. Dasatinib treatment of athymic nude mice resulted in impaired growth of PC3 cell tumor xenograft. Together, we provide novel insight into the Src-mediated Y216GSK-3 phosphorylation and activation in prostate cancer cells and reveal the potential benefits of targeting Src-GSK-3 axis using drugs such as dasatinib.

An audit on public awareness of depression symptoms in Jordan.

OBJECTIVES: Depression is a common mental health disorder. The aim of this study is to determine the level of public awareness regarding this illness, its symptoms, associated factors, available forms of treatment, and the attitude towards depressed people. METHODS: A self administered questionnaire was filled in by approximately 5000 individuals selected from various regions of Jordan. RESULTS: The majority of participants thought that depression is a treatable condition that can affect patient at any age, and may be controlled by the will power. Loss of interest in things and presence of negative feelings were the most commonly recognized symptoms of depression, while, unemployment and poverty were found to be the most recognized risk factors for depression. In addition, most participants considered support from family and friends (93.6%) as well as exercise (80.4%) to be the best available forms of depression treatment. Respondents found it acceptable to work, make friends with, or marry depressed individuals. The first choice persons for seeking help by most participants were family members and friends (49.8%). CONCLUSION: Collectively, the level of awareness of depression was acceptable. However, further efforts are necessary to establish public educational programs related to depression in order to raise awareness regarding the disease.

Suppression of interactions between prostate tumor cell-surface integrin and endothelial ICAM-1 by simvastatin inhibits micrometastasis.

Cancer micrometastasis relies on the ability of cancer cells to secrete angiogenic modulators, to interact with the vascular endothelium, and to overcome the resistance offered by the endothelial-barrier. Being an essential step prior to metastasis, blockage of micrometastasis can have potential applications in cancer therapy and metastasis prevention. Due to poorly known molecular mechanisms leading to micrometastasis, developing therapeutic strategies to target prostate cancer utilizing drugs that block micrometastasis is far from reality. Here, we demonstrate the potential benefits of simvastatin in the inhibition of prostate cancer micrometastasis and reveal the novel molecular mechanisms underlying this process. First, we showed that simvastatin inhibited the ability of human PC3 prostate cancer cells for transendothelial migration in vitro. Second, our data indicated that simvastatin modulates the expression of tumor-derived factors such as angiopoietins and VEGF-A at the mRNA and protein levels by the PC3 cells, thus preventing endothelial-barrier disruption. Third, simvastatin directly activated endothelial cells and enhances endothelial-barrier resistance. Apart from this, our study revealed that simvastatin-mediated effect on PC3 micrometastasis was mediated through inhibition of integrin αv ß3 activity and suppression of interaction between prostate cancer cell integrin αv ß3 with endothelial ICAM-1.