Egyptian Society of Liver Cancer Recommendation Guidelines for the Management of Hepatocellular Carcinoma.

Globally, hepatocellular carcinoma (HCC) is the fourth most common cause of death from cancer. The prevalence of this pathology, which has been on the rise in the last 30 years, has been predicted to continue increasing. HCC is the most common cause of cancer-related morbidity and mortality in Egypt and is also the most common cancer in males. Chronic liver diseases, including chronic hepatitis C, which is a primary health concern in Egypt, are considered major risk factors for HCC. However, HCC surveillance is recommended for patients with chronic hepatitis B virus (HBV) and liver cirrhosis; those above 40 with HBV but without cirrhosis; individuals with hepatitis D co-infection or a family history of HCC; and Nonalcoholic fatty liver disease (NAFLD) patients exhibiting significant fibrosis or cirrhosis. Several international guidelines aid physicians in the management of HCC. However, the availability and cost of diagnostic modalities and treatment options vary from one country to another. Therefore, the current guidelines aim to standardize the management of HCC in Egypt. The recommendations presented in this report represent the current management strategy at HCC treatment centers in Egypt. Recommendations were developed by an expert panel consisting of hepatologists, oncologists, gastroenterologists, surgeons, pathologists, and radiologists working under the umbrella of the Egyptian Society of Liver Cancer. The recommendations, which are based on the currently available local diagnostic aids and treatments in the country, include recommendations for future prospects.

Multidisciplinary consensus recommendations for management of hepatocellular carcinoma in Middle East and North Africa region.

Hepatocellular carcinoma (HCC) is a growing health concern projected to cross over a million cases worldwide by 2025. HCC presents a significant burden of disease in Middle East and North African (MENA) countries due to a high prevalence of risk factors such as hepatitis C and B infections and rising incidence of non-alcoholic steatohepatitis and non-alcoholic fatty liver disease. In August 2022, an advisory meeting consisting of experts from 5 MENA countries was convened in an attempt to provide consensus recommendations on HCC screening, early diagnosis, current treatment modalities and unmet medical needs in the region. Data were collected from a pre-meeting survey questionnaire and responses analysed and presented during the advisory meeting. This review summarizes the evidence discussed at the meeting and provides expert recommendations on the management of HCC. The 2022 update of Barcelona clinic liver cancer (BCLC) staging and treatment strategy and its implementation in the MENA region was extensively discussed. A key consensus of the expert panel was that multidisciplinary care is crucial to effective patient management that results in better clinical outcomes and overall survival of the patient. The panel recommended the use of predictive and early response biomarkers to guide clinicians in arriving at more effective therapeutic decisions. The experts also emphasized the role of robust screening/surveillance systems, population-based registries, effective referral pathways and standardization of guidelines to ensure the successful management of HCC in the region.

Insights into the possible impact of COVID-19 on the endocrine system.

The novel 2019 coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a highly transmissible and pathogenic coronavirus. Because of the novelty of the COVID-19 pandemic, few data are available on the impact of the SARS-CoV-2 on the different endocrine glands. Previous studies of severe acute respiratory syndrome (SARS) have shown a harmful effect on endocrine function. Notably, the angiotensin-converting enzyme-2 receptor, which is the entry route of coronaviruses to the host cell, is widely expressed in the endocrine organs including testis, endocrine pancreas, thyroid, and adrenal, and pituitary glands. Clinical and biochemical manifestations have been recorded in COVID-19 patients resulting in changes in endocrine activities, which were also recorded during the SARS outbreak in 2003. This review aims to explore the impact of SARS-CoV-2 infection on the function of endocrine glands, based on the latest research in the field.

Therapeutic significance of thymoquinone-loaded chitosan nanoparticles on streptozotocin/nicotinamide-induced diabetic rats: In vitro and in vivo functional analysis.

To overcome the low bioavailability of lipophilic free thymoquinone (TQ), this study aims to evaluate a novel oral formula of TQ-loaded chitosan nanoparticles (TQ-CsNPs) for the effective treatment of diabetes. The XRD, FTIR, FESEM, HRTEM, and dynamic light scattering were all conducted on the prepared formula. The release pattern of TQ, cytotoxicity against MRC-5 cell line (human lung fibroblast cells), and antidiabetic activity on streptozotocin/nicotinamide (STZ/NA) rat model of diabetes were investigated. The results confirmed the formation of TQ-CsNPs with an entrapment efficiency of 75.7 ± 6.52 %, a mean Zetasizer distribution of 84.25 nm, and an average particle size of about 50 nm. After 24 h, the percentage of free TQ-cumulative release was approximately 35.8 %, whereas TQ-CsNPs showed a sustained release pattern of 78.5 %. The investigated formula was not toxic to normal lung cells, and more efficient in ameliorating the altered glycemia, dyslipidemia, inflammation, and oxidative stress induced by STZ/NA than free TQ, blank CsNPs, and metformin-HCl (as a reference drug). Additionally, TQ-CsNPs restored the normal pancreatic islets' configuration and morphometry, suggesting a potent insulinotropic action. In conclusion, the antidiabetic efficacy of TQ was improved by engaging TQ with CsNPs as an excellent nanoplatform to enhance the oral bioavailability of TQ.

Activated-memory T cells influence naïve T cell fate: a noncytotoxic function of human CD8 T cells.

T cells are endowed with the capacity to sense their environment including other T cells around them. They do so to set their numbers and activation thresholds. This form of regulation has been well-studied within a given T cell population - i.e., within the naïve or memory pool; however, less is known about the cross-talk between T cell subsets. Here, we tested whether memory T cells interact with and influence surrounding naïve T cells. We report that human naïve CD8 T cells (TN) undergo phenotypic and transcriptional changes in the presence of autologous activated-memory CD8 T cells (TMem). Following in vitro co-culture with activated central memory cells (TCM), ~3% of the TN acquired activation/memory canonical markers (CD45RO and CD95) in an MHC-I dependent-fashion. Using scRNA-seq, we also observed that ~3% of the TN acquired an activated/memory signature, while ~84% developed a unique activated transcriptional profile hybrid between naïve and activated memory. Pseudotime trajectory analysis provided further evidence that TN with an activated/memory or hybrid phenotype were derived from TN. Our data reveal a non-cytotoxic function of TMem with potential to activate autologous TN into the activated/memory pool. These findings may have implications for host-protection and autoimmunity that arises after vaccination, infection or transplantation.

HOTAIR and THRIL Long Non Coding RNAs and Their Target Genes in Rheumatoid Arthritis patients.

Background: Rheumatoid arthtritis (RA) is a chronic systemic inflammatory autoimmune disease characterized by irreversible joint damage and deformity. The aim of this study is to investigate THRIL and HOTAIR serum expression and their target genes in Egyptian RA patients and to evaluate their relationship to the clinico-pathological data. Methods: The present study included fifty-two RA patients and fifty-six healthy controls. RA patients were classified according to DAS28 score. All subjects were subjected to full history taking and clinical examination. Quantitative real time PCR was done to estimate the expression levels of serum THRIL and HOTAIR as well as their target genes tumor necrosis factor alpha (TNF-α) and metalloproteinase 2 (MMP-2) were estimated by ELISA techniques. Results: Results revealed that both THRIL and HOTAIR were statistically over expressed in RA patients compared to healthy group with p-value< 0.05. Results showed as well that the target genes for those long-non coding RNAs, TNF-α and MMP-2, were also significantly higher in RA patients compared to healthy controls. Conclusion: Both THRIL and HOTAIR associated with their target genes, can be considered as diagnostic markers for RA.

Cinnamaldehyde mitigates placental vascular dysfunction of gestational diabetes and protects from the associated fetal hypoxia by modulating placental angiogenesis, metabolic activity and oxidative stress.

Gestational diabetes mellitus (GDM) is a major pregnancy-related disorder with an increasing prevalence worldwide. GDM is associated with altered placental vascular functions and has severe consequences for fetal growth. There is no commonly accepted medication for GDM due to safety considerations. Actions of the currently limited therapeutic options focus exclusively on lowering the blood glucose level without paying attention to the altered placental vascular reactivity and remodelling. We used the fat-sucrose diet/streptozotocin (FSD/STZ) rat model of GDM to explore the efficacy of cinnamaldehyde (Ci; 20 mg/kg/day), a promising antidiabetic agent for GDM, and glyburide/metformin-HCl (Gly/Met; 0.6 + 100 mg/kg/day), as a reference drug for treatment of GDM, on the placenta structure and function at term pregnancy after their oral intake one week before mating onward. Through genome-wide transcriptome, biochemical, metabolome, metal analysis and histopathology we obtained an integrated understanding of their effects. GDM resulted in maternal and fetal hyperglycemia, fetal hyperinsulinemia and placental dysfunction with subsequent fetal anemia, hepatic iron deficiency and high serum erythropoietin level, reflecting fetal hypoxia. Differentially-regulated genes were overrepresented for pathways of angiogenesis, metabolic transporters and oxidative stress. Despite Ci and Gly/Met effectively alleviated the maternal and fetal glycemia, only Ci offered substantial protection from GDM-associated placental vasculopathy and prevented the fetal hypoxia. This was explained by Ci's impact on the molecular regulation of placental angiogenesis, metabolic activity and redox signaling. In conclusion, Ci provides a dual impact for the treatment of GDM at both maternal and fetal levels through its antidiabetic effect and the direct placental vasoprotective action. Lack of Gly/Met effectiveness to restore it's impaired functionality demonstrates the vital role of the placenta in developing efficient medications for GDM.

Highly Efficient Visible-Light-Induced Photocatalytic Hydrogen Production via Water Splitting using FeCl3 -Based Ionic Liquids as Homogeneous Photocatalysts.

The ionic liquid (IL) 1-octyl-3-methylimidazolium bromide/FeCl3 [OMIM]Br/FeCl3 was prepared with three molar ratios of [OMIM]Br/FeCl3 (0.5 : 1, 1 : 1, and 2 : 1), and fully characterized through 1 H and 13 C NMR, Fourier-transform IR, and Raman spectroscopic techniques. The optical properties of the prepared [OMIM]Br/FeCl3 ILs were revealed via diffuse reflectance and photoluminescence spectra. The photocatalytic activity of [OMIM]Br/FeCl3 ILs as homogenous photocatalysts were investigated towards hydrogen generation from methanol/water mixtures under visible light irradiation. The FeCl3 -based IL with [OMIM]Br/FeCl3 molar ratio of 1 : 1 exhibited the highest visible light photocatalytic activity with a hydrogen productivity of 243.2 mmol h-1 g-1 and a hydrogen purity of 95.5 %; such a high hydrogen yield and purity was reported for the first time. It was proposed that [OMIM] Br acted as an electron acceptor, which delayed the electron-hole pair recombination of FeCl3 . Also, [OMIM] Br could capture the produced carbon dioxide that is released with hydrogen gas. Additionally, [OMIM] Br/FeCl3 could be reused six times with nearly the same photocatalytic activity. These outstanding credits in terms of hydrogen generation rate and purity plus the economic feasibility, through several cycles of reuse, could certify such an IL as a promising photocatalyst for employment in water splitting. This paper suggests ways forward for research to develop the use of ILs as efficient and effective photocatalysts for hydrogen generation via water splitting.

Evolution of Plasmodium falciparum drug resistance genes following artemisinin combination therapy in Sudan.

BACKGROUND: Malaria control efforts in Sudan rely heavily on case management. In 2004, health authorities adopted artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria. However, some recent surveys have reported ACT failure and a prevalent irrational malaria treatment practice. Here we examine whether the widespread use of ACT and failure to adhere to national guidelines have led to the evolution of drug resistance genes. METHODS: We genotyped known drug resistance markers (Pfcrt, Pfmdr-1, Pfdhfr, Pfdhps, Pfk13 propeller) and their flanking microsatellites among Plasmodium falciparum isolates obtained between 2009 and 2016 in different geographical regions in Sudan. Data were then compared with published findings pre-ACT (1992-2003). RESULTS: A high prevalence of Pfcrt76T, Pfmdr-1-86Y, Pfdhfr51I, Pfdhfr108N, Pfdhps37G was observed in all regions, while no Pfk13 mutations were detected. Compared with pre-ACT data, Pfcrt-76T and Pfmdr-1-86Y have decayed, while Pfdhfr-51I, Pfdhfr-108N and Pfdhps-437G strengthened. Haplotypes Pfcrt-CVIET, Pfmdr-1-NFSND/YFSND, Pfdhfr-ICNI and Pfdhps-SGKAA predominated in all sites. Microsatellites flanking drug resistance genes showed lower diversity than neutral ones, signifying high ACT pressure/selection. CONCLUSIONS: Evaluation of P. falciparum drug resistance genes in Sudan matches the drug deployment pattern. Regular monitoring of these genes, coupled with clinical response, should be considered to combat the spread of ACT resistance.

Can mesenchymal stem cells pretreated with platelet-rich plasma modulate tissue remodeling in a rat with burned skin?

Our aim was to study the effect of platelet-rich plasma (PRP) on the proliferation of bone-marrow-derived mesenchymal stem cells (BM-MSCs) and to investigate their roles in the healing of experimental burn injury and the possible mechanism of action. Our work was divided into in-vitro and in-vivo studies. The in-vitro study included untreated MSCs and MSCs treated with PRP. Levels of TGF-ß and cell proliferation were assessed. In the in-vivo study, 72 rats were distributed equally among 6 groups: control, burn, burn with MSCs, burn with PRP, burn with both MSCs and PRP, and burn with MSCs pretreated with PRP. On the 7th and 20th day after injury, the serum levels of transforming growth factor beta (TGF-ß) and tumor necrosis factor alpha (TNF-α), as well as interleukin-10 (IL-10) levels in skin tissue were measured by ELISA; histopathology and gene expression of MMP-1, TIMP-2, Ang-1, Ang-2, and vimentin by real-time PCR were performed in all groups. In vitro: proliferation of MSCs and TGF-ß increased in the PRP-treated group compared with the control group. In vivo: Ang-1, Ang-2, and vimentin were upregulated, whereas MMP-1 and TIMP-2 were downregulated. TGF-ß and IL-10 were increased, whereas TNF-α was decreased in all treated groups with more significance in MSCs and PRP on day 20. Histopathology of burn skin was improved in all treated groups, particularly in MSCs pretreated with PRP 20 days post-burn.

Cinnamaldehyde potentially attenuates gestational hyperglycemia in rats through modulation of PPARγ, proinflammatory cytokines and oxidative stress.

Cinnamon has a history of use for medicinal purposes and its major benefits have been linked to cinnamaldehyde. The present study aimed to investigate the hypoglycemic action of cinnamaldehyde against fatty-sucrosed diet/streptozotocin (FSD/STZ)-rat model of gestational diabetes. Female albino rats were divided into three groups. Group I fed with normal diet (ND) while group II and III were fed with FSD for eight weeks (five weeks pre-gestational and three weeks gestational). Rats of group III were administered with a daily oral dose of 20mg/kg cinnamaldehyde one week before mating onward. At the 7th day of gestation, FSD-fed rats were injected intraperitoneally with STZ (25mg/kg b.wt.) to induce gestational diabetes. Pre-mating treatment of cinnamaldehyde controls hyperphagia and glucose intolerance during the gestational period than in diabetic rats. It also reduced levels of fructosamine, total cholesterols, triglycerides, leptin, tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA) and nitric oxide (NO), while it significantly increased levels of high-density lipoprotein (HDL)-cholesterol, adiponectin, liver glycogen, reduced glutathione (GSH) and catalase activity at term pregnancy. In addition, cinnamaldehyde administration up-regulated the mRNA expression of peroxisome proliferated activated receptor-gamma (PPARγ) and also ameliorated the number of viable fetuses, implantation loss sites, fetal glucose and insulin levels. In conclusion, cinnamaldehyde has safe hypoglycemic action on gestational diabetes by potentiating insulin secretion and sensitivity through activating the antioxidant defense system, suppressing pro-inflammatory cytokines production, upregulating PPARγ gene expression and alleviating the reproductive performance.

Corticosteroids compromise survival in glioblastoma.

Glioblastoma is the most common and most aggressive primary brain tumour. Standard of care consists of surgical resection followed by radiotherapy and concomitant and maintenance temozolomide (temozolomide/radiotherapy→temozolomide). Corticosteroids are commonly used perioperatively to control cerebral oedema and are frequently continued throughout subsequent treatment, notably radiotherapy, for amelioration of side effects. The effects of corticosteroids such as dexamethasone on cell growth in glioma models and on patient survival have remained controversial. We performed a retrospective analysis of glioblastoma patient cohorts to determine the prognostic role of steroid administration. A disease-relevant mouse model of glioblastoma was used to characterize the effects of dexamethasone on tumour cell proliferation and death, and to identify gene signatures associated with these effects. A murine anti-VEGFA antibody was used in parallel as an alternative for oedema control. We applied the dexamethasone-induced gene signature to The Cancer Genome Atlas glioblastoma dataset to explore the association of dexamethasone exposure with outcome. Mouse experiments were used to validate the effects of dexamethasone on survival in vivo Retrospective clinical analyses identified corticosteroid use during radiotherapy as an independent indicator of shorter survival in three independent patient cohorts. A dexamethasone-associated gene expression signature correlated with shorter survival in The Cancer Genome Atlas patient dataset. In glioma-bearing mice, dexamethasone pretreatment decreased tumour cell proliferation without affecting tumour cell viability, but reduced survival when combined with radiotherapy. Conversely, anti-VEGFA antibody decreased proliferation and increased tumour cell death, but did not affect survival when combined with radiotherapy. Clinical and mouse experimental data suggest that corticosteroids may decrease the effectiveness of treatment and shorten survival in glioblastoma. Dexamethasone-induced anti-proliferative effects may confer protection from radiotherapy- and chemotherapy-induced genotoxic stress. This study highlights the importance of identifying alternative agents such as vascular endothelial growth factor antagonists for managing oedema in glioblastoma patients. Beyond the established adverse effect profile of protracted corticosteroid use, this analysis substantiates the request for prudent and restricted use of corticosteroids in glioblastoma.

Prevalence of human papilloma virus (HPV) and its genotypes in cervical specimens of Egyptian women by linear array HPV genotyping test.

BACKGROUND: The association of human papillomavirus (HPV) with cervical cancer is well established. AIM: To investigate HPV genotype distribution and co-infection occurrence in cervical specimens from a group of Egyptian women. METHODS: A group of 152 women with and without cervical lesions were studied. All women had cervical cytology and HPV testing. They were classified according to cytology into those with normal cytology, with squamous intraepithelial lesions (SIL) and invasive squamous cell carcinoma (SCC). Cervical samples were analyzed to identify the presence of HPV by PCR, and all positive HPV-DNA samples underwent viral genotype analysis by means of LINEAR ARRAY HPV Genotyping assay. RESULTS: A total of 26 HPV types with a prevalence of 40.8 % were detected. This prevalence was distributed as follows: 17.7 % among cytologically normal females, 56.5, 3.2, and 22.6 % among those with LSIL, HSIL and invasive SCC respectively. Low-risk HPV types were detected in 81.8 % of the cytologically-normal women, in 5.7 % of those in LSIL women, and in 14.3 % of infections with invasive SCC, while no low-risk types were detected in HSIL. High-risk HPV types were detected in 18.2 % of infections in the cytologically normal women, 14.3 % of infections in LSIL, and in 21.4 % of invasive lesions. The probable and possible carcinogenic HPV were not detected as single infections. Mixed infection was present in 80 % of women with LSIL, in 100 % of those with HSIL, and in 64.3 % of those with invasive SCC. This difference was statistically significant. HPV 16, 18 and 31 were the most prevalent HR HPV types, constituting 41.9, 29.03 and 12.9 % respectively, and HPV 6, 62 and CP6108 were the most prevalent LR HPV types constituting 11.3, 9.7 and 9.7 % respectively. CONCLUSION: These data expand the knowledge concerning HPV prevalence and type distribution in Egypt which may help to create a national HPV prevention program. HPV testing using the LINEAR ARRAY HPV Genotyping assay is a useful tool when combined with cytology in the diagnosis of mixed and non-conventional HPV viral types.

Menstrual patterns and disorders among secondary school adolescents in Egypt. A cross-sectional survey.

BACKGROUND: To our knowledge, no large population - based studies have been performed on the topic of menstrual patterns among Egyptian adolescent in recent years. The aims of this study were to identify menstrual patterns and associated disorders as well as the sources of menstrual health knowledge among Egyptian adolescents. METHODS: A cross-sectional survey. A total of 800 questionnaires were administered to post-menarcheal Egyptian adolescents attending secondary schools in Giza, Egypt, from September 1, 2012, to December 1, 2013. Participants were asked to respond to a semi-structured questionnaire on menstrual health awareness. The questionnaire included items on girl's socio-demographic and menstrual pattern characteristics, concerning their age at menarche, menstrual cycle length and regularity, duration and amount of flow, type and severity of pain related to menstruation, need for analgesia; and symptoms suggestive of premenstrual syndrome (PMS) Main Outcome Measure: description of menstrual patterns, disorders and source of knowledge. RESULTS: Four hundred twelve (51.5 %) out of 800 adolescents completed the questionnaire. The mean age of the girls was 14.67 ± 1.7 years. Mean age at menarche was 12.49 ± 1.20 years. 382 respondents reported various menstrual disorders, giving a prevalence rate of 95 %. Dysmenorrhea was the most prevalent (93 %) menstrual disorder in our sample, followed by PMS (65 %), and abnormal cycle lengths (43 %). Menstrual disorders interfered with social and academic life of 33 and 7.7 % of respondents respectively. Most participants lacked menstrual health knowledge and only 8.9 % of girls reported consulting a physician. CONCLUSION: To the best of our knowledge, this is one of the largest studies on menstrual pattern and disorders among Egyptian adolescent girls. Our Findings of the present study are consistent with other studies and reported higher than expected prevalence of menstrual disorders.

Screening for Chlamydia trachomatis in Egyptian women with unexplained infertility, comparing real-time PCR techniques to standard serology tests: case control study.

BACKGROUND: To study the prevalence of Chlamydia infection in women with primary and secondary unexplained infertility using ELISA technique for antibody detection and real time, fully automated PCR for antigen detection and to explore its association with circulating antisperm antibodies (ASA). METHODS: A total of 50 women with unexplained infertility enrolled in this case control study and a control group of 44 infertile women with a known cause of infertility. Endocervical specimens were collected for Chlamydia antigen detection using PCR and serum samples for antibodies detection. Circulating anti-sperm antibodies were detected using sperm antibody Latex Agglutination tests. RESULTS: The overall prevalence of Chlamydial infection in unexplained infertility cases as detected by both ELISA and PCR was 40 % (20/50). The prevalence of current Chlamydial genital infection as detected by real-time PCR was only 6.0 % (3/50); two of which were also IgM positive. Prevalence of ASA was 6.0 % (3/50); all were sero-negative for anti-C.trachomatis IgM and were PCR negative. CONCLUSION: The incidence of Chlamydial infection in Egyptian patients with unexplained infertility is relatively high. In the setting of fertility investigations; screening for anti. C.trachomatis antibodies using ELISA, and treatment of positive cases should be considered. The presence of circulating ASA does not correlate with the presence of old or current Chlamydia infection in women with unexplained infertility.

Ccr4-not regulates RNA polymerase I transcription and couples nutrient signaling to the control of ribosomal RNA biogenesis.

Ribosomal RNA synthesis is controlled by nutrient signaling through the mechanistic target of rapamycin complex 1 (mTORC1) pathway. mTORC1 regulates ribosomal RNA expression by affecting RNA Polymerase I (Pol I)-dependent transcription of the ribosomal DNA (rDNA) but the mechanisms involved remain obscure. This study provides evidence that the Ccr4-Not complex, which regulates RNA Polymerase II (Pol II) transcription, also functions downstream of mTORC1 to control Pol I activity. Ccr4-Not localizes to the rDNA and physically associates with the Pol I holoenzyme while Ccr4-Not disruption perturbs rDNA binding of multiple Pol I transcriptional regulators including core factor, the high mobility group protein Hmo1, and the SSU processome. Under nutrient rich conditions, Ccr4-Not suppresses Pol I initiation by regulating interactions with the essential transcription factor Rrn3. Additionally, Ccr4-Not disruption prevents reduced Pol I transcription when mTORC1 is inhibited suggesting Ccr4-Not bridges mTORC1 signaling with Pol I regulation. Analysis of the non-essential Pol I subunits demonstrated that the A34.5 subunit promotes, while the A12.2 and A14 subunits repress, Ccr4-Not interactions with Pol I. Furthermore, ccr4Δ is synthetically sick when paired with rpa12Δ and the double mutant has enhanced sensitivity to transcription elongation inhibition suggesting that Ccr4-Not functions to promote Pol I elongation. Intriguingly, while low concentrations of mTORC1 inhibitors completely inhibit growth of ccr4Δ, a ccr4Δ rpa12Δ rescues this growth defect suggesting that the sensitivity of Ccr4-Not mutants to mTORC1 inhibition is at least partially due to Pol I deregulation. Collectively, these data demonstrate a novel role for Ccr4-Not in Pol I transcriptional regulation that is required for bridging mTORC1 signaling to ribosomal RNA synthesis.

Prevalence and Pattern of Third Molar Impaction: A retrospective study of radiographs in Oman.

OBJECTIVES: The aim of this retrospective study was to investigate the prevalence and pattern of third molar impaction in patients between 19-26 years old attending Sultan Qaboos University Hospital (SQUH) in Muscat, Oman. METHODS: The study reviewed 1,000 orthopantomograms (OPGs) of patients attending the Oral Health Department of SQUH between October 2010 and April 2011. Patients were evaluated to determine the prevalence of third molar impaction, angulation, level of eruption and associated pathological conditions. RESULTS: Of the study population, 543 (54.3%) OPGs showed at least one impacted third molar. The total number of impacted molars was 1,128. The most common number of impacted third molars was two (41%). The most common angulation of impaction in the mandible was the mesioangular (35%) and the most common level of impaction in the mandible was level A. Of the 388 bilateral occurrences of impacted third molars, 377 were in the mandible. There was no significant difference in the frequency of impaction between the right and left sides of both jaws. Pathological conditions associated with impacted lower third molars were found in 18%, of which 14% were associated with a radiographic radiolucency of more than 2.5 mm, and 4% of impacted lower third molars were associated with dental caries. CONCLUSION: This study found that more than half of Omani adult patients ranging in age from 19-26 years had at least one impacted third molar.

MicroRNA-21 promotes glioblastoma tumorigenesis by down-regulating insulin-like growth factor-binding protein-3 (IGFBP3).

Despite advances in surgery, imaging, chemotherapy, and radiation, patients with glioblastoma multiforme (GBM), the most common histological subtype of glioma, have an especially dismal prognosis; >70% of GBM patients die within 2 years of diagnosis. In many human cancers, the microRNA miR-21 is overexpressed, and accumulating evidence indicates that it functions as an oncogene. Here, we report that miR-21 is overexpressed in human GBM cell lines and tumor tissue. Moreover, miR-21 expression in GBM patient samples is inversely correlated with patient survival. Knockdown of miR-21 in GBM cells inhibited cell proliferation in vitro and markedly inhibited tumor formation in vivo. A number of known miR-21 targets have been identified previously. By microarray analysis, we identified and validated insulin-like growth factor (IGF)-binding protein-3 (IGFBP3) as a novel miR-21 target gene. Overexpression of IGFBP3 in glioma cells inhibited cell proliferation in vitro and inhibited tumor formation of glioma xenografts in vivo. The critical role that IGFBP3 plays in miR-21-mediated actions was demonstrated by a rescue experiment, in which IGFBP3 knockdown in miR-21KD glioblastoma cells restored tumorigenesis. Examination of tumors from GBM patients showed that there was an inverse relationship between IGFBP3 and miR-21 expression and that increased IGFBP3 expression correlated with better patient survival. Our results identify IGFBP3 as a novel miR-21 target gene in glioblastoma and suggest that the oncogenic miRNA miR-21 down-regulates the expression of IGFBP3, which acts as a tumor suppressor in human glioblastoma.

Synthesis and in vitro evaluation of novel 1,2,3,4-tetrahydroisoquinoline derivatives as potent antiglioma agents.

Glioblastoma Multiforme (GBM) continues to demand improved chemotherapeutic solutions. In order to discover novel chemotherapeutic agents for GBM, we identified novel tetrahydroisoquinoline (THI) analogs as antiglioma agents. The present study reports the design, synthesis and in vitro evaluation of new THI derivatives in four established human glioma cell lines (T98, U87, LN18 and A172). Our structure activity relationship (SAR) studies revealed that the important modification of the carbon linker between the biphenyl and THI ring yielded EDL-360 (12) as a potent antiglioma agent (LN18; IC50: 5.42 ± 0.06 µM) and is considered to be our new lead drug candidate for further preclinical studies.

EDL-360: A Potential Novel Antiglioma Agent.

Glioma is a brain tumor that arises from glial cells or glial progenitor cells, and represents 80% of malignant brain tumor incidence in the United States. Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor malignancy with fewer than 8% of patients with GBM surviving for more than 3 years. Over the past 10 years, despite improvement in diagnosis and therapies for cancer, the survival rate for high-grade glioma patients remains dismal. The main focus of our research is to identify potent novel antiglioma small molecules. We previously showed that EDL-360, a tetrahydroisoquinoline (THIQ) analog, as being highly cytotoxic to human glioma cell cultures. Here we show that EDL-360 significantly induced apoptosis in human glioma cell lines (U87 and LN18). However, in normal astrocytic cells, EDL-360 induced a modest G0/G1 cell cycle arrest but did not induce apoptosis. In an attempt to enhance EDL-360 induced cell death, we tested simultaneous treatment with EDL-360 and embelin (an inhibitor of the anti-apoptotic protein, XIAP). We found that, glioma cells had significant lower viability when EDL-360 and embelin were used in combination when compared to EDL-360 alone. We also used combination treatment of EDL-360 with decylubiquinone (dUb), a caspase-9 inhibitor, and found that the combination treatment induced a significant cell death when compared to treatment with EDL-360 alone. This is the first report that suggests that dUb has anticancer activity, and perhaps acts as a XIAP inhibitor. Finally, our in vivo data showed that EDL-360 treatment induced a partial regression in glioma tumorigenesis and induced cell death in the treated tumors as shown by H&E staining. Taken together these data suggests that EDL-360 has a potential therapeutic application for treating glioma, especially when combined with XIAP inhibitors.