A Form of Metabolic-Associated Fatty Liver Disease Associated with a Novel LIPA Variant.

BACKGROUND: The LIPA gene on chromosome 10q23.31 contains 10 exons and encodes lipase A, the lysosomal acid lipase (LAL) containing 399 amino acids. Pathogenic variants in the LIPA result in autosomal recessive Wolman disease and cholesteryl ester storage disease (CESD). Here, we report a novel missense variant (NM_001127605.3:c.928T>A, p.Trp310Arg) of LIPA in an Iranian family with fatty liver disease identified by whole-exome sequencing and confirmed by Sanger sequencing. METHODS: A 28-year-old woman referred with lean NASH cirrhosis and extremely high cholesterol levels. Fatty liver disease was found in six of her family members using vibration-controlled transient elastography (VCTE). Baseline routine laboratory tests were performed and whole-exome sequencing and confirmation by Sanger sequencing were done. RESULTS: The index case had severe dyslipidemia and cirrhosis despite a body mass index of 21.09 kg/m2 . Six other family members had dyslipidemia and fatty liver or cirrhosis. A homozygous missense variant (NM_001127605.3:c.928T>A, p.Trp310Arg) of LIPA which caused LAL-D was found to be associated with fatty liver disease and/or cirrhosis. CONCLUSION: A homozygous missense variant (NM_001127605.3:c.928T>A, p.Trp310Arg) of the LIPA gene which caused LAL-D was found to be associated with dyslipidemia, fatty liver disease and/or cirrhosis in six members of an Iranian family. These results should be confirmed by functional studies and extending the study to at least three families.

RNA-sequencing for transcriptional profiling of whole blood in early stage and metastatic pancreatic cancer patients.

We investigated the transcriptional profile of whole blood in early and metastatic stages of pancreatic cancer (PaC) patients to identify potential diagnostic factors for early diagnosis. Blood samples from 18 participants (6 healthy individuals, 6 patients in early stage (I/II) PaC, and 6 patients in metastatic PaC) were analyzed by RNA-sequencing. The expression levels of identified genes were subsequently compared with their expression in pancreatic tumor tissues based on TCGA data reported in UALCAN and GEPIA2 databases. Overall, 331 and 724 genes were identified as differentially expressed genes in early and metastatic stages, respectively. Of these, 146 genes were shared by early and metastatic stages. Upregulation of PTCD3 and UBA52 genes and downregulation of A2M and ARID1B genes in PaC patients were observed from early stage to metastasis. TCGA database showed increasing trend in expression levels of these genes from stage I to IV in pancreatic tumor tissue. Finally, we found that low expression of PTCD3, A2M, and ARID1B genes and high expression of UBA52 gene were positively correlated with PaC patients survival. We identified a four-gene set (PTCD3, UBA52, A2M, and ARID1B) expressed in peripheral blood of early stage and metastatic PaC patients that may be useful for PaC early diagnosis.

Insights into Organochlorine Pesticides Exposure in the Development of Cardiovascular Diseases: A Systematic Review.

Many human diseases such as cancer, neurological diseases, autism and diabetes are associated with exposure to pesticides, especially organochlorine pesticides. However, pesticide exposure is also associated with cardiovascular disease (CVD) as the leading cause of death worldwide. In this systematic review, results on the link between organochlorine pesticide pollution and CVD were collected from databases (Medline (PubMed), Scopus and Science Direct) in May 2022 from studies published between 2010 and 2022. A total of 24 articles were selected for this systematic review. Sixteen articles were extracted by reviewers using a standardized form that included cross-sectional, cohort, and ecological studies that reported exposure to organochlorine pesticides in association with increased CVD risk. In addition, eight articles covering molecular mechanisms organochlorine pesticides and polychlorinated biphenyls (PCBs) on cardiovascular effects were retrieved for detailed evaluation. Based on the findings of the study, it seems elevated circulating levels of organochlorine pesticides and PCBs increase the risk of coronary heart disease, especially in early life exposure to these pesticides and especially in men. Changes in the regulatory function of peroxisome proliferator-activated γ receptor (PPARγ), reduction of paroxonase activity (PON1), epigenetic changes of histone through induction of reactive oxygen species, vascular endothelial inflammation with miR-expression 126 and miR-31, increased collagen synthesis enzymes in the extracellular matrix and left ventricular hypertrophy (LVH) and fibrosis are mechanisms by which PCBs increase the risk of CVD. According to this systematic review, organochlorine pesticide exposure is associated with increased risk of CVD and CVD mortality through the atherogenic and inflammatory molecular mechanism involving fatty acid and glucose metabolism.

The association of dietary intake and plasma fatty acid panel in pancreatic cancer patients: Results from Golestan cohort study.

BACKGROUND & AIMS: High mortality rate of pancreatic cancer (PC) as one of the most common cancers worldwide made it a center of attention for recent researches on its pathology, etiology, screening and early diagnosis. In previous researches, association of dietary intake and plasma levels of fatty acids with risk of pancreatic cancer was investigated. In this study we aimed to evaluate the correlation between dietary and plasma fatty acids in case and control groups. METHODS: From 50,045 adults between 40-75 years old participated in Golestan cohort study, fifty incident cases of PC were diagnosed and 150 controls matched by age, sex and residence place were randomly selected. Dietary intakes and plasma levels of fatty acids was evaluated by validated food-frequency questionnaire (FFQ) and Gas Chromatography - Flame Ionization Detector (GC-FID), respectively. Then, Spearman's correlation was used to measure the correlation between dietary and plasma levels of fatty acids in case and control groups. RESULTS: Among all the fatty acids, there was a significant association between plasma and dietary intake of a few fatty acids including trans fatty acids (TFA), polyunsaturated fatty acids (PUFA), 22:6n-3 and 14:0 only in control group. Only total PUFA intake modified plasma level of some fatty acids in case group. There was no difference between association of desaturase enzymes and fatty acids in case and controls. CONCLUSIONS: Since, plasma levels of fatty acids might be influenced by recent diet, we did not find any specific differences between the associations of plasma levels of fatty acids with dietary intake of fats in case and control groups.

Challenges of cancer immunotherapy and chemotherapy during the COVID-19 pandemic.

People at high risk of morbidity and mortality from coronavirus disease 2019 (COVID-19), including patients dealing with malignancies and patients on immunosuppressive anticancer therapies, need to be followed carefully as the pandemic continues. Challenges in continuing cancer management and patient monitoring are of concern given the importance of timing in cancer therapy. Alternative treatment decisions and priorities are also important considerations. The efficacy and safety of various cancer treatments in patients with COVID-19 are other important considerations. In this systematic review, we summarize the potential risks and benefits of cancer treatments applied to patients with COVID-19 and malignant tumors. Using the PubMed and Scopus databases, we reviewed studies involving cancer therapy and COVID-19 to address the recent discoveries and related challenges of cancer therapy in patients with COVID-19 and cancer.

Diagnostic Significance of Serum Fatty Acid Synthase in Patients with Pancreatic Cancer.

BACKGROUND Pancreatic cancer is considered as the most deadly tumor among gastrointestinal cancers because of its poor prognosis. The frequently deregulated pathway in the cancer cell is associated with an increased expression of various genes, including the synthesis of fatty acids. We aimed to evaluate the level of serum fatty acid synthase (FASN) as a diagnostic marker for early diagnosis of pancreatic cancer. METHODS Serum FASN levels were measured by ELISA in 92 patients with pancreatic adenocarcinomas and in 92 healthy controls. Logistic regression analysis was used to identify independent predictors of certain diagnostic categories. RESULTS Serum FASN levels were significantly higher in patients with pancreatic cancer than in healthy controls (1.35 [0.98-2.3] ng/mL vs 1.04 [0.19-1.34] ng/mL, p < 0.001) and in smokers compared to non-smokers (1.41 [0.79-2.52] ng/mL vs 1.07 [0.21-1.74] ng/mL, p < 0.001). FASN levels and smoking were associated with increased risk of PC (1.54 [1.1- 2.14] ng/mL, p = 0.011 and 5.69 [2.68-12.09] ng/mL, p < 0.001, respectively). CONCLUSION Elevated serum FASN levels in patients with pancreatic cancer indicate the need for the production of large numbers of lipids for the survival and proliferation of human cancer cells and the diagnostic value of FASN as a new diagnostic biomarker.

Cigarette Smoking and Opium Use in Relation to the Oral Microbiota in Iran.

Cigarettes and opium contain chemicals and particulate matter that may modify the oral microbiota. This study aimed to investigate the association between cigarette and opium use with the oral microbiota. A total of 558 participants were recruited from Iran between 2011 and 2015. Individuals were categorized as never cigarette nor opium users, ever cigarette-only smokers, ever opium-only users, and ever both cigarette and opium users. Participants provided saliva samples for 16S rRNA gene sequencing. Logistic regression, microbiome regression-based kernel association test (MiRKAT), and zero-inflated beta regression models were calculated. For every increase in 10 observed amplicon sequence variants (ASVs), the odds for being a cigarette-only smoker, opium-only user, and both user compared to never users decreased by 9% (odds ratio [OR] = 0.91; 95% confidence interval [95% CI] = 0.86 to 0.97), 13% (OR = 0.87; 95% CI = 0.75 to 1.01), and 12% (OR = 0.88; 95% CI = 0.80 to 0.96), respectively. The microbial communities differed by cigarette and opium use as indicated by MiRKAT models testing the three beta-diversity matrices (P < 0.05 for all). Three genera were less likely and one genus was more likely to be detected in cigarette-only smokers or opium-only users than in never users. The relative abundance of the phylum Actinobacteria (never, 14.78%; both, 21.20%) was higher and the phyla Bacteroidetes (never, 17.63%; both, 11.62%) and Proteobacteria (never, 9.06%; both, 3.70%) were lower in users of both cigarettes and opium, while the phylum Firmicutes (never, 54.29%; opium, 65.49%) was higher in opium-only users. Cigarette and opium use was associated with lower alpha-diversity, overall oral microbiota community composition, and both the presence and relative abundance of multiple taxa. IMPORTANCE Cigarette smoking and opium use are associated with periodontal disease caused by specific bacteria such as Porphyromonas gingivalis, which suggests a link between cigarette smoking and opium use and the oral microbiota. Alterations of the oral microbiota in cigarette smokers compared to nonsmokers have been reported, but this has not been studied across diverse populations. Additionally, the association of opium use with the oral microbiota has not been investigated to date. We conducted this study to investigate differences in the oral microbiota between ever users of cigarettes only, opium only, and both cigarettes and opium and never users of cigarettes and opium in Iran. Lower alpha-diversity, distinct overall oral microbial communities, and the presence and relative abundance of multiple taxa have been found for users of cigarettes and/or opium.

Dehydroepiandrosterone modulates oxidative DNA damage in pancreatic cancer: A case-control study.

BACKGROUND AND AIM: Dehydroepiandrosterone (DHEA) has a protective role against several types of cancer, although its mechanisms of action are still unknown, it may be related to the antioxidant effect of DHEA. We hypothesized that DHEA has a preventive effect on the formation of the 8-hydroxy-2'-deoxyguanosine (8-OHdG) DNA adduct in pancreatic cancer patients. METHODS: Serum DHEAs were quantified by the ELISA method in 50 pancreatic cancer patients with histopathological diagnosis of adenocarcinoma and 50 matched controls. The amount of 8-OHdG was assessed in peripheral blood leukocyte extracted DNA using a 32P-DNA postlabeling technique. RESULTS: Pancreatic cancer patients had lower serum DHEA levels than healthy controls, although it did not differ significantly. Instead, the 8-OHdG DNA adduct was significantly higher in the case than in the control (P = <0.001). Remarkably, the negative correlation between 8-OHdG and DHEA was distinguished between cases (P = 0.025, r = -0.315) but not in controls (P = 0.078, r = -0.250). In the crude and corrected estimate for pancreatic cancer risk, a significant protective effect of DHEA against pancreatic cancer was found with increasing DHEA when 8-OHdG is greater than its median (adjusted OR = 0, 79, 95% confidence intervals [CI]: 0.66-0.94). Similarly, a lower risk of pancreatic cancer was observed in the third tertile of DHEA (adjusted OR = 0.05, 95% CI: 0.004-0.69). CONCLUSIONS: These results indicate that serum DHEA reduces the risk of pancreatic cancer with an anti-DNA damage effect. Hence, the influence of DHEA to prohibit the accumulation of 8-OHdG may be one of its physiological functions.

Dietary intake of fatty acids and risk of pancreatic cancer: Golestan cohort study.

BACKGROUND: As pancreatic cancer (PC) is a malignancy with poor prognosis, finding strategies for its prevention became a notable priority. Among all the factors influencing the risk of PC, dietary items especially fats are considered as the most modifiable risk factors.This study is designed to assess the associations of dietary intake of fatty acids with the risk of PC incidence. METHODS: A total of 50,045 adults between 40 and 75 years old participated in this cohort study in 2004-2008 and were followed up to the present. Intakes of fatty acids was evaluated by validated food-frequency questionnaire (FFQ). Cox proportional hazards regression model was used to estimate hazard ratio (HR) with 95 % confidence interval of differing levels of dietary intakes of fatty acids for incidence of PC. RESULTS: At the end of follow-up period, 76 cases of PC were identified and 46,904 participants without history of cancer, acute kidney disorders, fibrosis and cirrhosis were included in the study. Dietary total saturated fatty acids (SFAS) was associated with PC risk (HR = 1.05 (1.01-1.09), Ptrend=0.01), whereas dietary total monounsaturated fatty acids (MUFAS) was inversely associated with the risk of PC (HR = 0.92 (0.86-0.99), Ptrend=0.04). Dietary total polyunsaturated fatty acids (PUFAS) did show a protective but not significant association with the risk of PC (HR = 0.91(0.84-1.00), Ptrend=0.05). CONCLUSIONS: The amount of total fat intake is not a risk factor for PC in our study and focusing on the intake of specific fatty acids becomes more striking. Unsaturated fatty acids including PUFAS and especially MUFAS are considered as protective dietary factors in PC prevention. In contrast, total SFAS is positively associated with the increased risk of PC. However, very long chain and odd-chain saturated fatty acids intake may be protective against PC.

Circulating plasma fatty acids and risk of pancreatic cancer: Results from the Golestan Cohort Study.

BACKGROUND & AIMS: Pancreatic cancer (PC) with a dismal prognosis is considered as a fatal malignancy, attracting the scientists' attention to study its causes and pathogenesis pathways. Given the lack of enough evidence and conflicting findings about the association of PC risk with plasma fatty acids, we aimed to explore the associations of circulating plasma fatty acids with the risk of PC in a cohort study. METHODS: From about 50,000 subjects participated in this cohort study in 2004-2008, fifty incident cases of PC were recruited and 150 controls matched by age, sex and residence place (urban/rural) were randomly selected. The plasma fatty acids composition was measured by gas chromatography with Flame Ionization Detector (GC-FID) in plasma samples collected at the baseline of cohort study. Multivariable conditional logistic regression was used to estimate OR (with 95% CI) of PC risk associated with plasma levels of fatty acids considering known potential risk factors for PC. RESULTS: Our findings showed that total saturated fatty acids and total industrial trans fats were not associated with the risk of PC; whereas, statistically significant inverse associations were found between high plasma levels of total mono-unsaturated fatty acids (MUFAs), omega-3 and ruminant trans fatty acids with the risk of PC [ORQ1-Q4 = 0.31 (0.11-0.89), OR Q2-Q1 = 0.30 (0.10-0.91) and ORQ2-Q1 = 0.15 (0.04-0.49), respectively]. Omega-6 fatty acids especially high plasma levels of Arachidonic acid was positively associated with the risk of PC [ORQ1-Q3 = 11.07 (3.50-35.02)]. CONCLUSION: Except for the plasma circulating whole fats, the levels of different classes of fats may significantly change pancreatic cancer susceptibility. Unsaturated fatty acids including omega-3-PUFA and MUFA are considered as protective biomarkers in PC prevention. On the contrary, omega-6-fatty acids are positively associated with the risk of PC.

Heritability for stroke: Essential for taking family history.

BACKGROUND: There are many well-established factors that influence the risk of stroke including blood pressure, diabetes, low socioeconomic status and smoking, however, the shared genetic resource in members of a family effect on stroke predisposition. Genome-wide association studies (GWAS) have demonstrated evidence of a shared genetic source in stroke risk. This review considered the influence of family history as one of the main risk factors in stroke according to the literature. METHODS: Literature review was obtained by searching for the key words "stroke", "family history" and "stroke gene" in PubMed. An overview has been made on the topics: relevance of stroke family history, family history assessment tools and specific candidate genes for stroke. RESULTS: Family history of stroke is an important risk factor for the development of cerebrovascular diseases in addition to stroke subtypes in relatives who have reached the questionnaire and pedigree. While variation in a small number of loci showed Mendelian inheritance of stroke phenotypes, the genetic variations in several stroke risk loci are shared with multiple related vascular traits. CONCLUSION: This study highlighted the importance of family history in stroke phenotypes and current related genetics information. Increasing awareness of the importance of family history in stroke has the advantage of preventing exposure to stroke with health care.

The Effect of Vitamin D on Serum Asymmetric Dimethylarginine in Patients with Mild to Moderate Ulcerative Colitis.

Purpose: In inflammatory bowel disease increased asymmetric dimethylarginine (ADMA) levels could inhibit nitric oxide (NO) synthase. Vitamin D may increase activity and expression of endothelial NO synthase, which could be done through its possible mechanism of decreasing ADMA levels. The aim of this study is to investigate the possible effect of Vitamin D3 on serum ADMA levels in ulcerative colitis (UC) patients. Methods: Ninety mild to moderate UC patients were randomized. Each patient received one single muscular injection of 300,000 IU (7500 µg) Vitamin D3 (Vitamin D group) or 1 ml normal saline (Placebo group). At baseline and 90 days after the intervention measurements were done. Data were analyzed using independent t-test and analysis of covariance. Baseline correlations were assessed by Pearson and Spearman correlation coefficients. Results: Following data analysis of 86 participants (40 in placebo and 46 in vitamin D group), there was no correlation between baseline ADMA with baseline vitamin D, ESR and hs-CRP at baseline (p = 0.77) and at the end of study (p = 0.82). Serum ADMA levels were not statistically different between two groups. Adjustment for baseline ADMA levels and baseline body mass index (BMI) did not change the results. With subgroup analyses based on gender and vitamin D level no statistical differences in ADMA levels between two groups were found. Conclusions: In this study, we found no significant changes in serum ADMA levels 3 months following a high dose vitamin D administration in mild to moderate UC patients. Further studies in vitamin D deficient patients are needed.

Oral microbial community composition is associated with pancreatic cancer: A case-control study in Iran.

BACKGROUND: Oral microbiota may be related to pancreatic cancer risk because periodontal disease, a condition linked to multiple specific microbes, has been associated with increased risk of pancreatic cancer. We evaluated the association between oral microbiota and pancreatic cancer in Iran. METHODS: A total of 273 pancreatic adenocarcinoma cases and 285 controls recruited from tertiary hospitals and a specialty clinic in Tehran, Iran provided saliva samples and filled out a questionnaire regarding demographics and lifestyle characteristics. DNA was extracted from saliva and the V4 region of the 16S rRNA gene was PCR amplified and sequenced on the MiSeq. The sequencing data were processed using the DADA2 plugin in QIIME 2 and taxonomy was assigned against the Human Oral Microbiome Database. Logistic regression and MiRKAT models were calculated with adjustment for potential confounders. RESULTS: No association was observed for alpha diversity with an average of 91.11 (standard deviation [SD] 2.59) sequence variants for cases and 89.42 (SD 2.58) for controls. However, there was evidence for an association between beta diversity and case status. The association between the Bray-Curtis dissimilarity and pancreatic cancer was particularly strong with a MiRKAT P-value of .000142 and specific principal coordinate vectors had strong associations with cancer risk. Several specific taxa were also associated with case status after adjustment for multiple comparisons. CONCLUSION: The overall microbial community appeared to differ between pancreatic cancer cases and controls. Whether these reflect differences evident before development of pancreatic cancer will need to be evaluated in prospective studies.

Metabolomics analysis of the saliva in patients with chronic hepatitis B using nuclear magnetic resonance: a pilot study.

OBJECTIVES: Hepatitis B virus infection causes chronic disease such as cirrhosis and hepatocellular carcinoma. The metabolomics investigations have been demonstrated to be related to pathophysiologic mechanisms in many disorders such as hepatitis B infection. The aim of this study was to investigate the saliva metabolic profile of patients with chronic hepatitis B infection and to identify underlying mechanisms as well as potential biomarkers associated with the disease. MATERIALS AND METHODS: Saliva from 16 healthy subjects and 20 patients with chronic hepatitis B virus were analyzed by nuclear magnetic resonance (NMR). Then, multivariate statistical analysis was performed to identify discriminative metabolites between two groups. RESULTS: A set of metabolites were detected, including propionic acid, putrescine, acetic acid, succinic acid, tyrosine, lactic acid, butyric acid, pyruvic acid, 4-pyridoxic acid and 4-hydroxybenzoic acid, which in combination with one another could accurately distinguish patients from healthy controls. Our results clearly demonstrated altered metabolites are involved in nine metabolic pathways. CONCLUSION: Metabolomics has the potential to be considered as a novel clinical tool for hepatitis B diagnosis while contributing to a comprehensive understanding of disease mechanisms.

An Increased Level of Aryl Hydrocarbon Receptor in Patients with Pancreatic Cancer.

BACKGROUND Aryl-carbon receptor (AhR), a ligand-activated transcription factor, is best known for its ability to mediate the effects of environmental toxins such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. AhR is expressed in several tumor cells and regulates the expression of genes in the signal transduction pathways. In this study, we examined the soluble levels of AhR in patients with pancreatic cancer. METHODS 123 samples, including 59 (48%) samples of pancreatic ductal adenocarcinoma based on histological evidence and 64 (52%) healthy control samples, were evaluated to determine plasma levels of AhR by Enzyme-linked immunoassay. RESULTS The median of AhR among patients was 0.280 ng/mL, which differed considerably from 0.07 ng/mL in the control group (p < 0.001). Significant differences of the AhR were observed between the plasma samples of the patients compared with the healthy group, with respect to male sex (p < 0.001), age groups (p = 0.001), diabetic status (p < 0.001), body mass index (BMI) categories (p = 0.035), and constantly smokers (p < 0.001). We also observed significant differences between the level of AhR expression between men and women (p = 0.01) and ever to never smokers (p = 0.009) in the case group. In addition, the age of 65 and a BMI of 25 or less were significant factors in plasma AhR levels ([1.61 95%CI 1.08-2.38] and [1.84 95%CI 1.22-2.77], respectively). CONCLUSION The results of this study can add diagnostic information to pancreatic cancer involving AhR and the potential efficacy of this receptor in therapeutic strategies.

Vitamin D Decreases Beck Depression Inventory Score in Patients with Mild to Moderate Ulcerative Colitis: A Double-Blind Randomized Placebo-Controlled Trial.

The prevalence of depression in inflammatory bowel disease (IBD) is significantly more than in controls. Some studies assessed the link between vitamin D and depression. The aim of this study was to assess the effect of vitamin D on Beck Depression Inventory (BDI) score in ulcerative colitis (UC) patients. In this double-blind randomized controlled trial, 90 mild to moderate UC patients were assigned to receive a single injection of 300,000 IU vitamin D3 or 1 ml normal saline as placebo. At baseline and 3 months later, measurements of BDI score and serum 25-OH-vitamin D3 were done. Data were compared by independent sample t test, Mann-Whitney U test, and analysis of covariance (ANCOVA). Baseline BDI scores were not statistically different between the two groups (p = .4); scores decreased in the vitamin D group after the intervention (p = .023). Further subgroup analysis regarding baseline serum vitamin D levels and adjusted for baseline BDIs revealed lowering effect of vitamin D on BDI scores only in subgroup with baseline serum vitamin D levels equal to or higher than 30 ng/ml (p < .001). In this study, there was a statistically significant reduction in BDI score in mild to moderate UC patients 3 months after 300,000 IU vitamin D3 injection. Subgroup analysis showed that patients with sufficient baseline vitamin D may benefit from supplementation more than vitamin D-deficient patients, which indicates that higher serum vitamin D levels may be needed for its antidepressant effect.

Mutations in Known and Novel cancer Susceptibility Genes in Young Patients with Pancreatic Cancer.

BACKGROUND: Pancreatic cancer is the fourth most common cause of mortality due to cancer, globally. It has a poor prognosis and is usually diagnosed at later stages when tumor resection is not possible. Heritability for pancreatic cancer is relatively high and clinically significant. METHODS: A group of 24 pancreatic cancer patients with young age at onset, from a referral hospital in Tehran University of Medical Sciences were screened for mutations in 710 cancer relevant genes using next generation sequencing technology. RESULTS: Two patients had pathogenic mutations in known pancreatic cancer susceptibility genes, BRCA1/2. Two other patients also had potentially pathogenic mutations in 2 novel candidate genes including PARP4 and EXO1. CONCLUSION: BRCA1/2 genes are the most commonly mutated pancreatic cancer susceptibility genes that should be considered in all pancreatic cancer cases with young age at onset or a family history of cancer. PARP4 and EXO1 also are potential candidate genes for susceptibility to pancreatic cancer. Identifying the hereditary cases of pancreatic cancer will help to offer more targeted treatments to the patients and also to prevent cancer in family members who might be a mutation carrier.

On the potential role of intestinal microbial community in hepatocarcinogenesis in chronic hepatitis B.

The chronic infection of hepatitis B virus (HBV) is the most potent risk factor for the development of cirrhosis and hepatocellular carcinoma (HCC). The association of intestinal microbiota alteration with progressive liver disease has been investigated in recent studies. Overgrowth of potentially pathogenic bacteria of gram-negative species and, in particular, a significant increase in the fecal count of Escherichia coli (E. coli) are characterized in the presence of HCC. This study was conducted to describe the characteristics of the intestinal microbiota related to the presence of HCC in HBV-carrier patients. The available literature indicates the colonization of E. coli as principal source of portal vein lipopolysaccharide (LPS), in the gut may contribute to the carcinogenesis process by inducing chronic inflammation. This understanding could help to predict the clinical outcomes in HBV-carrier patients and innovative strategies to reduce the virulence of liver disease from intestinal dysbiosis.

Significant SNPs Related to Telomere Length and Hepatocellular Carcinoma Risk in Chronic Hepatitis B Carriers

Chronic hepatitis B virus (HBV) infection increases the risk of developing cirrhosis and hepatocellular carcinoma (HCC) with suspected interactions between virus replication and host immune responses. A number of reports have suggested that telomerase function may be involved in chronic hepatitis B (CHB) pathogenesis, but positive or negative associations with HCC risk remain for discussion. Mean telomere length is an indicator of biological aging and it has been reported that reduction in NBV carriers compared to normal individuals. In somatic cells, telomeres contain simple, tandemly repeated G-rich sequences that frequently are reduced by 50 to 200 base pairs at each cell division. Several genome-wide association studies (GWAS) in diverse ethnic populations have revealed eleven single nucleotide polymorphisms (SNPs) linked to telomere length. Two of these, rs398652 and rs621559, have prognostic value and could be used as genetic markers. This review describes current knowledge concerning telomerase activity and telomere length as well as significant polymorphisms in HBV-related HCC patients. In particular, to cast light on genotype-phenotype interactions, we used SNPnexus to evaluate effects of the two SNPs on risk of disease and complex disorders.

Kaempferol increases apoptosis in human acute promyelocytic leukemia cells and inhibits multidrug resistance genes.

Acute promyelocytic leukemia (APL) is one of the most life-threatening hematological malignancies. Defects in the cell growth and apoptotic pathways are responsible for both disease pathogenesis and treatment resistance. Therefore, pro-apoptotic agents are potential candidates for APL treatment. Kaempferol is a flavonoid with antioxidant and anti-tumor properties. This study was designed to investigate the cytotoxic, pro-apoptotic, and differentiation-inducing effects of kaempferol on HL-60 and NB4 leukemia cells. Resazurin assay was used to determine cell viability following treatment with kaempferol (12.5-100 µM) and all-trans retinoic acid (ATRA; 10 µM; used as a positive control). Apoptosis and differentiation were also detected using propidium iodide and NBT staining techniques, respectively. Furthermore, the expression levels of genes involved in apoptosis (PI3 K, AKT, BCL2, BAX, p53, p21, PTEN, CASP3, CASP8, and CASP9), differentiation (PML-RAR and HDAC1), and multi-drug resistance (ABCB1 and ABCC1) were determined using quantitative real-time PCR. The protein expressions of Bax/Bcl2 and casp3 were confirmed using Western blot. The results showed that kaempferol decreased cell viability and increased subG1 population in the tested leukemic cells. This effect was associated with decreased expression of Akt, BCL2, ABCB1, and ABCC1 genes, while the expression of CASP3 and BAX/BCL-2 ratio were significantly increased at both gene and protein levels. Kaempferol promoted apoptosis and inhibited multidrug resistance in a concentration-dependent manner, without any differential effect on leukemic cells. In conclusion, this study suggested that kaempferol may be utilized as an appropriate alternative for ATRA in APL patients.