Assessment of the Anterior Loop and Pattern of Entry of Mental Nerve Into the Mental Foramen: A Radiographic Study of Panoramic Images.

INTRODUCTION: The precise location of the mental foramina is an essential landmark in planning the position of dental implants in the anterior mandible. Injury to inferior alveolar nerve during anterior mandibular implant surgery causes altered sensation which greatly affects patient satisfaction. METHODS: In this study, we assessed the prevalence of anterior loop of mental nerve and the pattern of entry of mental nerve into the mental foramen. Three hundred panoramic radiographs (600 hemimandibles) obtained from records maintained in the Department of Oral Medicine and Radiology were randomly selected for the study. The radiographs were evaluated by two independent observers for the pattern of entry of mental nerve into the mental foramen on either side of the mandible and for the presence or absence of anterior loop of mental nerve. RESULTS: The most prevalent pattern of mental nerve observed was Straight pattern which totals to 67.5% followed by Anterior loop pattern (18.8%) and then the Perpendicular pattern (13.7%). There was no significant association between the gender and subtypes of looping pattern on the left and right side and a highly significant association between the side of the mandible and loop pattern was observed by Chi square test. CONCLUSION: The Anterior loop pattern of mental nerve has been found in 18.8% of the population suggesting to accurate planning with three-dimensional imaging techniques to avoid injury to mental nerve during dental implant placement and other surgical procedure involving the interforaminal region of the mandible.

Citalopram, an antipsychotic agent, induces G1/G0 phase cell cycle arrest and promotes apoptosis in human laryngeal carcinoma HEP-2 cells.

Human laryngeal squamous carcinoma (LSCC) is a common malignant tumor in the head and neck. Despite the recently developed therapies for the treatment of LSCC, patients' overall survival rate still did not enhance remarkably; this highlights the need to formulate alternative strategies to develop novel treatments. The antitumor effects of antidepressant drugs such as citalopram have been reported on several cancer cells; however, they have yet to be investigated against LSCC. The current study was directed to explore the possible antitumor effects of citalopram on human laryngeal carcinoma cell lines (HEP-2). HEP-2 cells were cultured and treated with different doses of citalopram (50-400 µM) for 24, 48, and 72 h. The effects of citalopram on the viability of cancer cells were determined by the MTT assay. In addition, apoptosis and cell cycle analysis were performed by flow cytometry. Moreover, evaluation of the expression of proapoptotic and apoptotic proteins, such as cytochrome c, cleaved caspases 3 and 9, Bcl-2, and BAX, was performed by western blotting analysis. Our results revealed that citalopram significantly suppressed the proliferation of HEP-2 cells through the upregulation of p21 expression, resulting in the subsequent arrest of the cell cycle at the G0/G1 phase. Furthermore, citalopram treatment-induced HEP-2 cell apoptosis; this was indicated by the significant increase of cytochrome c, cleaved caspases 3 and 9, and BAX protein expression. On the contrary, Bcl-2 protein expression was significantly downregulated following treatment with citalopram. The ultrastructure studies were in accordance with the protein expression findings and showed clear signs of apoptosis with ring chromatin condensation upon treatment with citalopram. These findings suggest that citalopram's anti-tumor activities on HEP-2 cells entailed stimulation of the intrinsic apoptotic pathway, which was mediated via Bcl-2 suppression.

Novel phloretin-based combinations targeting glucose metabolism in hepatocellular carcinoma through GLUT2/PEPCK axis of action: in silico molecular modelling and in vivo studies.

Hepatocellular carcinoma (HCC) is commonly associated with disturbances in glucose metabolism and enhanced glycolysis. However, a controversial role for gluconeogenesis was reported to be tumor-promoting and tumor-suppressive. We investigated novel anti-HCC treatments through either the simultaneous inhibition of glycolysis and gluconeogenesis by "phloretin" and "sodium meta-arsenite", respectively (Combination 1); or the concurrent inhibition of glycolysis and induction of gluconeogenesis by phloretin and dexamethasone, respectively, (combination 2). A total of 110 Swiss albino mice were divided into eleven groups, HCC was induced by N, N-dimethyl-4-aminoazobenzene. We have measured the expression of the glucose transporter 2 (GLUT2), Phosphoenolpyruvate carboxykinases (PEPCK), Caspase-3, Beclin 1, Cyclin D1, and cytokeratin 18 genes; blood glucose and ATP levels; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Furthermore, in silico molecular docking was performed to investigate the potential drug-receptor interactions. Histologically, the phloretin-based combinations resulted in a significant regression of malignant tissue compared to various treatments. GLUT2 and PEPCK mRNA analysis indicated successful off/on modulation of glycolysis and gluconeogenesis. Docking confirmed the potent binding between phloretin, sodium meta-arsenite, and dexamethasone with GLUT2, PEPCK, and Retinoid X Receptor Alpha, respectively. Molecularly, Combination 2 resulted in the highest reduction in cyclin D1, cytokeratin 18, and Beclin 1 expression contemporaneously with the upregulation in Caspase-3 levels. Biochemically, both combinations caused a significant reduction in ATP levels, ALT, and AST activity compared to the other groups. In conclusion, we propose two novel phloretin-based combinations that can be used in treating HCC through the regulation of glucose metabolism and ATP production.

Effect of short-term high fat diet on resistin levels and expression of autophagy-related genes in the cartilage of male rats.

Obesity is a significant risk factor for the development of knee osteoarthritis (KOA). However, the precise molecular mechanisms linking obesity to OA remain unclear. In the present study, we investigated the effect of short-term high-fat diet (HFD) on the development of OA and the possible role of the adipokine resistin and autophagy-related genes in mediating this effect. Thirty adult male Wistar rats were equally divided into 2 groups: control and obese groups. Body mass index (BMI), levels of lipid profile, glucose, insulin and HOMA-IR index were significantly higher in the obese group compared with control. Our results revealed significantly higher serum and cartilage resistin levels with a significant increase in the mRNA expressions of toll-like receptor 4 (TLR4), matrix metalloproteinase-9 (MMP-9) and interleukin-1ß (IL-1ß) as well as protein levels of IL-1ß, matrix metalloproteinase-13 (MMP-13), ADAMTS 5 (aggrecanase-2) and caspase-3 in the cartilage of obese rats. The HFD induced a significant upregulation of autophagy related 5 (ATG5), beclin-1 and light chain 3 (LC3) mRNA expressions and a significant downregulation of mammalian target of rapamycin (mTOR) expression in cartilage. The protein levels of cartilage ATG5 were also significantly elevated in HFD-fed group. In conclusion, we suggested that increased levels of resistin and expression of autophagy-related genes may contribute in part, to OA development in HFD-fed rats. This provides a novel insight into the early molecular changes in the cartilage associated with obesity.

Mathematical and deep learning analysis based on tissue dielectric properties at low frequencies predict outcome in human breast cancer.

BACKGROUND: The early detection of human breast cancer represents a great chance of survival. Malignant tissues have more water content and higher electrolytes concentration while they have lower fat content than the normal. These cancer biochemical characters provide malignant tissue with high electric permittivity (ε´) and conductivity (σ). OBJECTIVE: To examine if the dielectric behavior of normal and malignant tissues at low frequencies (α dispersion) will lead to the threshold (separating) line between them and find the threshold values of capacitance and resistance. These data are used as input for deep learning neural networks, and the outcomes are normal or malignant. METHODS: ε´ and σ in the range of 50 Hz to 100 KHz for 15 human malignant tissues and their corresponding normal ones have been measured. The separating line equation between the two classes is found by mathematical calculations and verified via support vector machine (SVM). Normal range and the threshold value of both normal capacitance and resistance are calculated. RESULTS: Deep learning analysis has an accuracy of 91.7%, 85.7% sensitivity, and 100% specificity for instant and automatic prediction of the type of breast tissue, either normal or malignant. CONCLUSIONS: These data can be used in both cancer diagnosis and prognosis follow-up.

Poly-Tobacco Use among Young Adult Waterpipe Smokers: Insights from University Students in Three Eastern Mediterranean Countries.

INTRODUCTION: There is a tendency of waterpipe smokers to advance their practice toward concurrent use (poly-tobacco use) of other tobacco products and nicotine delivery systems. This study investigated poly-tobacco use among waterpipe smokers, and its effect on their quit intention. METHODS: Descriptive cross-sectional design was utilized to recruit a convenience sample of university students who used waterpipe in three East Mediterranean countries. Using an internet-based survey, data were collected regarding participants' demographics, use of alternative tobacco products and nicotine delivery systems, and waterpipe quitting profile. Results: A total of 2290 students agreed to participate, among which 1116 (45.3%) reported using at least one tobacco product beside waterpipe. Poly-tobacco use was highest (61.1%) in Egypt, followed by Jordan (45.1%) and Palestine (33.1%). Across countries, cigarettes were the most common product (45.2%, n = 924) followed by cigar (18.6%, n = 374) and e-shisha (17.5%, n = 353). Conversely, the least reported product was smokeless tobacco (7.5%, n = 151) preceded by regular pipe (9.5%, n = 193). Participants who were males (OR = 2.83, 95% CI: 2.18-3.65), older (22-29 years) (OR = 1.15, 95% CI: 1.09-1.22), unemployed (OR = 1.58, 95% CI: 1.22-2.04), and those who initiated waterpipe at a younger age (OR = 0.87, 95% CI: 0.87-0.91) had higher odds of being poly-smokers. Poly-tobacco users were significantly more resistant to quit waterpipe. Conclusion: This study demonstrates poly-tobacco use as a rising phenomenon among waterpipe smokers and highlights the necessity for initiating advanced interventions to help waterpipe poly-tobacco users quit this dangerous type of addiction. Various country-specific programs are needed considering the various products used by the users.

Identification of Genetic Variants Associated With Myocardial Infarction in Saudi Arabia.

The genetic variants associated with various genetic disorders have not been identified decisively in Saudi Arabia. Among these variants, six known for their association with coronary artery disease or myocardial infarction (MI) were studied on Saudi patients. Reference single nucleotide polymorphisms (SNPs) of these variants are rs5174, rs11591147, rs2259816, rs111245230, rs3782886 and rs2259820, referring to genes LRP8, PCSK9, HNF1A, SVEP1, BRAP and HNF1A, respectively. The analysis employed polymerase chain reaction panel coupled with mini-sequencing (SNapShot multiplex system) in order to identify these variants. A total of 100 MI patients and 103 healthy control individuals participated in this study. The six variants (SNPs) were evaluated for the risk of developing MI in the Saudi patients. Analysis of allele frequencies indicated that A allele of rs11591147 variant can be a protective allele, thus, is associated with the decreased risk of MI in Saudi individuals. Rare allele of rs111245230 variant (e.g., C allele) was extremely reduced, while rare allele of rs3782886 variant (e.g., G allele) does not exist in the ethnic signature of the Saudi population. This study elucidates the possible prediction of risk factors associated with severe diseases in Saudi population utilizing SNapShot multiplex system.

Fam83F induces p53 stabilisation and promotes its activity.

p53 is one of the most important tumour suppressor proteins currently known. It is activated in response to DNA damage and this activation leads to proliferation arrest and cell death. The abundance and activity of p53 are tightly controlled and reductions in p53's activity can contribute to the development of cancer. Here, we show that Fam83F increases p53 protein levels by protein stabilisation. Fam83F interacts with p53 and decreases its ubiquitination and degradation. Fam83F is induced in response to DNA damage and its overexpression also increases p53 activity in cell culture experiments and in zebrafish embryos. Downregulation of Fam83F decreases transcription of p53 target genes in response to DNA damage and increases cell proliferation, identifying Fam83F as an important regulator of the DNA damage response. Overexpression of Fam83F also enhances migration of cells harbouring mutant p53 demonstrating that it can also activate mutant forms of p53.

Whole exome sequencing of a consanguineous family identifies the possible modifying effect of a globally rare AK5 allelic variant in celiac disease development among Saudi patients.

Celiac disease (CD), a multi-factorial auto-inflammatory disease of the small intestine, is known to occur in both sporadic and familial forms. Together HLA and Non-HLA genes can explain up to 50% of CD's heritability. In order to discover the missing heritability due to rare variants, we have exome sequenced a consanguineous Saudi family presenting CD in an autosomal recessive (AR) pattern. We have identified a rare homozygous insertion c.1683_1684insATT, in the conserved coding region of AK5 gene that showed classical AR model segregation in this family. Sequence validation of 200 chromosomes each of sporadic CD cases and controls, revealed that this extremely rare (EXac MAF 0.000008) mutation is highly penetrant among general Saudi populations (MAF is 0.62). Genotype and allelic distribution analysis have indicated that this AK5 (c.1683_1684insATT) mutation is negatively selected among patient groups and positively selected in the control group, in whom it may modify the risk against CD development [p<0.002]. Our observation gains additional support from computational analysis which predicted that Iso561 insertion shifts the existing H-bonds between 400th and 556th amino acid residues lying near the functional domain of adenylate kinase. This shuffling of amino acids and their H-bond interactions is likely to disturb the secondary structure orientation of the polypeptide and induces the gain-of-function in nucleoside phosphate kinase activity of AK5, which may eventually down-regulates the reactivity potential of CD4+ T-cells against gluten antigens. Our study underlines the need to have population-specific genome databases to avoid false leads and to identify true candidate causal genes for the familial form of celiac disease.

Expression screening using a Medaka cDNA library identifies evolutionarily conserved regulators of the p53/Mdm2 pathway.

BACKGROUND: The p53 tumor suppressor protein is mainly regulated by alterations in the half-life of the protein, resulting in significant differences in p53 protein levels in cells. The major regulator of this process is Mdm2, which ubiquitinates p53 and targets it for proteasomal degradation. This process can be enhanced or reduced by proteins that associate with p53 or Mdm2 and several proteins have been identified with such an activity. Furthermore, additional ubiquitin ligases for p53 have been identified in recent years. Nevertheless, our understanding of how p53 abundance and Mdm2 activity are regulated remains incomplete. Here we describe a cell culture based overexpression screen to identify evolutionarily conserved regulators of the p53/Mdm2 circuit. The results from this large-scale screening method will contribute to a better understanding of the regulation of these important proteins. METHODS: Expression screening was based on co-transfection of H1299 cells with pools of cDNA's from a Medaka library together with p53, Mdm2 and, as internal control, Ror2. After cell lysis, SDS-PAGE/WB analysis was used to detect alterations in these proteins. RESULTS: More than one hundred hits that altered the abundance of either p53, Mdm2, or both were identified in the primary screen. Subscreening of the library pools that were identified in the primary screen identified several potential novel regulators of p53 and/or Mdm2. We also tested whether the human orthologues of the Medaka genes regulate p53 and/or Mdm2 abundance. All human orthologues regulated p53 and/or Mdm2 abundance in the same manner as the proteins from Medaka, which underscores the suitability of this screening methodology for the identification of new modifiers of p53 and Mdm2. CONCLUSIONS: Despite enormous efforts in the last two decades, many unknown regulators for p53 and Mdm2 abundance are predicted to exist. This cross-species approach to identify evolutionarily conserved regulators demonstrates that our Medaka unigene cDNA library represents a powerful tool to screen for these novel regulators of the p53/Mdm2 pathway.

Pineal gland plays a role in gonadal development after eyelids separation in puppies / La glándula pineal juega un rol en el desarrollo gonadal luego de la separación de los párpados en cachorros

Several functional and morphological studies have been conducted on the pineal gland in many mammalian species; however, no published reports are available on the role of pineal gland on the gonadal development before and after eyelids separation in puppies. Therefore, this study aimed to trace the postnatal histo-morphological changes in the pineal gland and gonads of puppies before (2, 10 and 11 days old) and after (25, 35 and 40 days old) eyelids separation in an attempt to investigate the possible role of pineal gland on the gonadal development. In general, the differentiation of pineal cells, interstitial endocrine cells of testes and stromal ovarian cells coincides with the start of eyelids separation in puppies. Histological examination of stained pineal and gonadal slices of puppies after eyelids separation revealed a remarkable differentiation of pinealocytes and testicular interstitial endocrine cells, as well as presence of some evidence of folliculogenesis in ovary. Surprisingly, melatonin receptor (MT1) protein expression levels were significantly increased in the ovaries and testes of puppies after eyelids separation. Moreover, the mRNA and protein expression of AANAT, a rate-limiting enzyme in melatonin biosynthesis, was notably increased in the pineal gland of opened eyes puppies. Our results suggest an increase of melatonin production from the pineal gland of opened eyes puppies and this could play a vital role in the developmental changes observed in the gonads of these puppies.

Diversos estudios morfológicos y funcionales han sido realizados sobre la glándula pineal en distintas especies de mamíferos. Sin embargo, no hay informes publicados acerca del rol de la glándula pineal en el desarrollo gonadal antes y después de la separación de los párpados en cachorros. Este estudio tuvo como objetivo trazar los cambios histo-morfológicos postnatales en la glándula pineal y las gónadas de los cachorros antes (2, 10 y 11 días de edad) y después (25, 35 y 40 días de edad) de la separación de los párpados, en un intento por investigar el posible rol de la glándula pineal en el desarrollo gonadal. En general, la diferenciación de los pinealocitos, células intersticiales endocrinas de los testículos y las células estromales del ovario coincide con el inicio de la separación de los párpados en cachorros. El examen histológico de glándula pineal y los cortes gonadales de los cachorros, después de la separación de los párpados, reveló una notable diferenciación de los pinealocitos y las células intersticiales endocrinas testiculares, así como la posible evidencia de foliculogénesis en el ovario. Sorprendentemente, en el receptor de melatonina (MT1) los niveles de expresión de proteínas fueron significativamente superiores en los ovarios y los testículos de los cachorros después de la separación de los párpados. Además, el ARNm y la expresión de la proteína AANAT, una enzima limitante de la velocidad en la biosíntesis de la melatonina, aumentaron notablemente en la glándula pineal de los cachorros con los ojos abiertos. Nuestros resultados sugieren que existe un aumento de la producción de melatonina por parte de la glándula pineal en los cachorros con los ojos abiertos, lo que podría jugar un rol vital en los cambios evolutivos observados enlas gónadas de estos cachorros.

Replication of GWAS Coding SNPs Implicates MMEL1 as a Potential Susceptibility Locus among Saudi Arabian Celiac Disease Patients.

Celiac disease (CD), a gluten intolerance disorder, was implicated to have 57 genetic susceptibility loci for Europeans but not for culturally and geographically distinct ethnic populations like Saudi Arabian CD patients. Therefore, we genotyped Saudi CD patients and healthy controls for three polymorphisms, that is, Phe196Ser in IRAK1, Trp262Arg in SH2B3, and Met518Thr in MMEL1 genes. Single locus analysis identified that carriers of the 518 Thr/Thr (MMEL1) genotype conferred a 1.6-fold increased disease risk compared to the noncarriers (OR = 2.6; 95% CI: 1.22-5.54; P < 0.01). This significance persisted even under allelic (OR = 1.55; 95% CI: 1.05-2.28; P = 0.02) and additive (OR = 0.35; 95% CI: 0.17-0.71; P = 0.03) genetic models. However, frequencies for Trp262Arg (SH2B3) and Phe196Ser (IRAK1) polymorphisms were not significantly different between patients and controls. The overall best MDR model included Met518Thr and Trp262Arg polymorphisms, with a maximal testing accuracy of 64.1% and a maximal cross-validation consistency of 10 out of 10 (P = 0.0156). Allelic distribution of the 518 Thr/Thr polymorphism in MMEL1 primarily suggests its independent and synergistic contribution towards CD susceptibility among Saudi patients. Lack of significant association of IRAK and SH2B3 gene polymorphisms in Saudi patients but their association in European groups suggests the genetic heterogeneity of CD.

Gas chromatographic determination of amino acid enantiomers in bottled and aged wines.

Free L- and D-amino acids were determined by chiral GC-MS in 26 wines, comprising white wines, red wines, ice wines and sparkling wines. The aim of the work was to investigate whether quantities and pattern of D-amino acids, in particular D-proline, correlate with the storage time of bottled wines. The relative quantities with respect to the corresponding L-enantiomer ranged in white wines from 0.4 to 3.9% D-Ala, 0.9-8.3% D-Asx, and 0.5-8.9% D-Glx, in red wines from 2.9 to 10.6% D-Ala, 2.2-10.9% D-Asx, and 3.9-7.4% D-Glx, and in sparkling wines from 2.2 to 9.8% D-Ala, 2.1-4.4% D-Asx and 1.3-6.1% D-Glx. Low relative quantities of 0.3-0.7% D-Pro were detected in three white wines stored for more than 20 years and did not exceed 0.2% D-Pro in two red wines stored for 10 and 20 years, respectively. An ice wine stored for 24 years contained 0.9% D-Pro, 6.4% D-Glx, 3.0% D-Asp and 1.5% D-Ala. The data confirm the presence of D-amino acids in wines. They do not provide evidence for a correlation between the storage time of bottled wines and quantities of D-amino acids.

Survival and recurrence in nonmycosis fungoides primary cutaneous lymphoma.

PURPOSE: To evaluate overall and relapse-free survival (RFS) in patients with nonmycosis fungoides (non-MF) primary cutaneous lymphoma (PCL). METHODS: Thirty-eight patients with PCL excluding cases of MF treated between 1993 and 2006 were analyzed retrospectively. Survival statistics were estimated by the methods of Kaplan and Meier, and univariate and multivariate significance testing were performed by Cox regression analysis. RESULTS: The median follow-up was 34.6 months (range, 2-138.3 months). The overall survival for the entire study population, at 5 and 10 years, was 97% and 78%, respectively. The RFS for the entire study population, at 5 and 10 years, was 30% and 22%, respectively. For those who received radiotherapy (RT) as a component of their initial therapy, the RFS at 5 and 10 years was 48% and 36%, respectively. Among those receiving RT who relapsed, the site of relapse was out-of-field in 82% of the cases. In our multivariate analysis, only RT as a component of the initial therapy and the absence of bulky disease had a statistically significant improvement in RFS (P = 0.01 and <0.01, respectively). CONCLUSION: RT improves the local control and RFS of patients with non-MF PCL.