Perioperative nutritional assessment and management of patients undergoing gastrointestinal surgery.

Malnutrition is a major issue in gastrointestinal perioperative situations, as only 40% of malnourished patients are finally treated. This literature review investigates the inconsistencies regarding the diagnostic approach to both preoperative and postoperative patients and the various underlying causes, as well as the efficiency of the various therapeutic regimens. A literature search was conducted until August 2023 in MEDLINE and Scopus. Clinical studies involving perioperative nutritional assessment in adult gastrointestinal surgery patients during the last 10 years were included in the present review. Finally, 19 articles were included in the study. Preoperative nutritional therapy is increasingly recognized as a key component of surgical care. Malnourished patients who are hospitalized and operated on, have significantly worse clinical results. Gastrointestinal postoperative malnutrition coexists with metabolic stress, as patients usually suffer from minor chronic inflammations; therefore, postoperative malnutrition is the result of a combination of the effects of inflammation and a lack of food intake. Postoperative malnutrition leads to prolonged hospitalizations and hospital complications and therefore the need to treat it is essential. There are many recognized tools for detecting malnutrition. However, all tools showed inconsistent results regarding their validity. Per os feeding after surgery, and dietary supplements when necessary, have been recommended. Therefore, it is very important to reduce malnutrition and define clear strategies towards that direction.

16S rRNA sequencing analysis of the oral and fecal microbiota in colorectal cancer positives versus colorectal cancer negatives in Iranian population.

BACKGROUND: Colorectal cancer (CRC) poses a significant healthcare challenge, accounting for nearly 6.1% of global cancer cases. Early detection, facilitated by population screening utilizing innovative biomarkers, is pivotal for mitigating CRC incidence. This study aims to scrutinize the fecal and salivary microbiomes of CRC-positive individuals (CPs) in comparison to CRC-negative counterparts (CNs) to enhance early CRC diagnosis through microbial biomarkers. MATERIAL AND METHODS: A total of 80 oral and stool samples were collected from Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran, encompassing both CPs and CNs undergoing screening. Microbial profiling was conducted using 16S rRNA sequencing assays, employing the Nextera XT Index Kit on an Illumina NovaSeq platform. RESULTS: Distinct microbial profiles were observed in saliva and stool samples of CPs, diverging significantly from those of CNs at various taxonomic levels, including phylum, family, and species. Saliva samples from CPs exhibited abundance of Calothrix parietina, Granulicatella adiacens, Rothia dentocariosa, and Rothia mucilaginosa, absent in CNs. Additionally, Lachnospiraceae and Prevotellaceae were markedly higher in CPs' feces, while the Fusobacteria phylum was significantly elevated in CPs' saliva. Conversely, the non-pathogenic bacterium Akkermansia muciniphila exhibited a significant decrease in CPs' fecal samples compared to CNs. CONCLUSION: Through meticulous selection of saliva and stool microbes based on Mean Decrease GINI values and employing logistic regression for saliva and support vector machine models for stool, we successfully developed a microbiota test with heightened sensitivity and specificity for early CRC detection.

Genetic Impact of HOTAIR, LINC00951, POLR2E and HULC Polymorphisms in Histopathological and Laboratory Prognostic Factors in Esophageal Cancer in the West: A Case-Control Study.

Long non-coding RNAs' HOTAIR rs920778, LINC00951 rs11752942, POLR2E rs3787016, and HULC rs7763881 are progressively reported having a close genetic affinity with esophageal carcinogenesis in the East. Nonetheless, their correlation with variables already endorsed as significant prognostic factors in terms of staging, guiding treatment and predicting recurrence, metastasis, and survival have yet to be explored. Herein, we investigated their prognostic value by correlating them with clinicopathological and laboratory prognostic markers in esophageal cancer in the West. Formalin-fixed paraffin-embedded tissue specimens from 95 consecutive patients operated on for esophageal cancer between 2014 and 2018 were compared with 121 healthy community controls. HULC was not detected differently in any of the cancer prognostic subgroups. LINC00951 was underrepresented in Ca19.9 elevated subgroup. HOTAIR was more frequent in both worse differentiation grade and positive Signet-Ring-Cell and Ca19.9 subgroups. POLR2E was identified less frequently in Adenocarcinoma, Signet-Ring-Cell, and Diffuse histologies, as well as in Perineural, Lymphovascular, and Perivascular Invasion positive, while it was overrepresented in CEA positive subgroup. These lncRNAs polymorphisms may hold great potential not only as future therapeutic agents but also as novel markers for predictive analysis of esophageal cancer risk, clinical outcome, and survival. Clinical implications of these findings need to be validated with prospective larger sample-size studies.

Associations of long non-coding RNAs HOTAIR, LINC00951, POLR2E and HULC polymorphisms with the risk of esophageal and esophagogastric junction cancer in a western population: a case-control study.

BACKGROUND: The incidence of single-nucleotide-polymorphisms with malignant potential in esophageal cancer tissues has only been sparsely investigated in the west. Hence, we explored the contribution of four long non-coding RNAs' polymorphisms HOTAIR rs920778, LINC00951 rs11752942, POLR2E rs3787016 and HULC rs7763881 in esophageal cancer susceptibility. METHODS AND RESULTS: Formalin-fixed paraffin-embedded tissue specimens from 95 consecutive patients operated for esophageal/esophagogastric junction carcinoma during 25/03/2014-25/09/2018 were processed. Demographic data, histopathological parameters, surgical and oncological outcomes were collected. DNA findings of the abovementioned population were compared with 121 healthy community controls. Both populations were of European/Greek ancestry. Sixty-seven patients underwent Ivor Lewis/McKeown esophagectomy for either squamous cell esophageal carcinoma (N = 6) or esophageal/esophagogastric junction Siewert I or II adenocarcinoma (N = 61). Twenty-eight patients were subjected to extended total gastrectomy for esophagogastric junction Siewert III adenocarcinoma. Neither LINC00951 rs11752942 nor HULC rs7763881 polymorphisms were detected more frequently in esophageal cancer patients compared with healthy community subjects. A significantly higher presence of HOTAIR rs920778 TT genotype in esophagogastric junction Siewert I/II adenocarcinoma was identified. POLR2E rs3787016 C allele and CC genotypes were overrepresented in the control group, and when found in esophageal cancer carriers were associated with earlier disease stages, as well as with minor lymph node involvement and lesser metastatic potential. CONCLUSIONS: HOTAIR rs920778 may serve as a potential therapeutic suppression target, while POLR2E rs3787016 may represent a valuable biomarker to evaluate esophageal cancer predisposition and predict treatment response and prognosis. Clinical implications of these findings need to be verified with further prospective studies with larger sample-size.

Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.

Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10-6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10-5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.

Inflammation and Immunity Gene Expression Patterns and Machine Learning Approaches in Association with Response to Immune-Checkpoint Inhibitors-Based Treatments in Clear-Cell Renal Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer. Despite the rapid evolution of targeted therapies, immunotherapy with checkpoint inhibition (ICI) as well as combination therapies, the cure of metastatic ccRCC (mccRCC) is infrequent, while the optimal use of the various novel agents has not been fully clarified. With the different treatment options, there is an essential need to identify biomarkers to predict therapeutic efficacy and thus optimize therapeutic approaches. This study seeks to explore the diversity in mRNA expression profiles of inflammation and immunity-related circulating genes for the development of biomarkers that could predict the effectiveness of immunotherapy-based treatments using ICIs for individuals with mccRCC. Gene mRNA expression was tested by the RT2 profiler PCR Array on a human cancer inflammation and immunity crosstalk kit and analyzed for differential gene expression along with a machine learning approach for sample classification. A number of mRNAs were found to be differentially expressed in mccRCC with a clinical benefit from treatment compared to those who progressed. Our results indicate that gene expression can classify these samples with high accuracy and specificity.

RediScore: Prospective validation of a pipeline for homologous recombination deficiency analysis.

Tumors harboring homologous recombination deficiency (HRD) are considered optimal candidates for poly(ADP-ribose) polymerase 1 (PARP) inhibitor treatment. Such deficiency can be detected by analyzing breast cancer type (BRCA)1/2 gene mutations, as well as mutations in other genes of the homologous recombination pathway. The algorithmic measurement of the HRD effect by identifying genomic instability (GI) has been used as biomarker. As compared with the direct measurement of somatic gene alterations, this approach increases the number of patients who could benefit from PARP inhibitor treatment. In the present study, the performance of the Oncoscan CNV assay, accompanied by appropriate bioinformatic algorithms, was evaluated for its performance in GI calculation and was compared with that of a validated next-generation sequencing (NGS) test (myChoice HRD test). In addition, the clinical utility of the GI score (GIS) and BRCA1/2 tumor analysis were investigated in a cohort of 444 patients with ovarian cancer. For that reason, single nucleotide polymorphism (SNP) arrays and appropriate bioinformatics algorithms were used to calculate GIS in 29 patients with ovarian cancer with known GIS status using a validated NGS test. Furthermore, BRCA1/2 analysis results were compared between the aforementioned assay and the amplicon-based Oncomine™ BRCA Research Assay. BRCA1/2 analysis was performed in 444 patients with ovarian cancer, while GIS was calculated in 175 BRCA1/2-negative cases. The bioinformatics algorithm developed for GIS calculation in combination with NGS BRCA1/2 analysis (RediScore), and the OncoscanR pipeline exhibited a high overall agreement with the validated test (93.1%). In addition, the Oncomine NGS assay had a 100% agreement with the validated test. The BRCA1/2 mutation frequency was 26.5% in the examined patients with ovarian cancer. GIS was positive in 40% of the BRCA1/2-negative cases. The RediScore bioinformatics algorithm developed for GIS calculation in combination with NGS BRCA1/2 analysis is a viable and effective approach for HRD calculation in patients with ovarian cancer, offering a positive prediction for PARP inhibitor responsiveness in 55% of the patients.

The Utility of NGS Analysis in Homologous Recombination Deficiency Tracking.

Several tumor types have been efficiently treated with PARP inhibitors (PARPis), which are now approved for the treatment of ovarian, breast, prostate, and pancreatic cancers. The BRCA1/2 genes and mutations in many additional genes involved in the HR pathway may be responsible for the HRD phenomenon. The aim of the present study was to investigate the association between genomic loss of heterozygosity (gLOH) and alterations in 513 genes with targeted and immuno-oncology therapies in 406 samples using an NGS assay. In addition, the %gLOHs of 24 samples were calculated using the Affymetrix technology in order to compare the results obtained via the two methodologies. HR variations occurred in 20.93% of the malignancies, while BRCA1/2 gene alterations occurred in 5.17% of the malignancies. The %LOH was highly correlated with alterations in the BRCA1/2 genes, since 76.19% (16/21) of the BRCA1/2 positive tumors had a high %LOH value (p = 0.007). Moreover, the LOH status was highly correlated with the TP53 and KRAS statuses, but there was no association with the TMB value. Lin's concordance correlation coefficient for the 24 samples simultaneously examined via both assays was 0.87, indicating a nearly perfect agreement. In conclusion, the addition of gLOH analysis could assist in the detection of additional patients eligible for treatment with PARPis.

A scan of all coding region variants of the human genome, identifies 13q12.2-rs9579139 and 15q24.1-rs2277598 as novel risk loci for pancreatic ductal adenocarcinoma.

Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (P = 2.46 × 10-9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (P = 1.53 × 10-6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of genome-wide association studies (GWASs) in light of functional data.

Exploring the Neandertal legacy of pancreatic ductal adenocarcinoma risk in Eurasians.

BACKGROUND: The genomes of present-day non-Africans are composed of 1-3% of Neandertal-derived DNA as a consequence of admixture events between Neandertals and anatomically modern humans about 50-60 thousand years ago. Neandertal-introgressed single nucleotide polymorphisms (aSNPs) have been associated with modern human disease-related traits, which are risk factors for pancreatic ductal adenocarcinoma (PDAC), such as obesity, type 2 diabetes, and inflammation. In this study, we aimed at investigating the role of aSNPs in PDAC in three Eurasian populations. RESULTS: The high-coverage Vindija Neandertal genome was used to select aSNPs in non-African populations from 1000 Genomes project phase 3 data. Then, the association between aSNPs and PDAC risk was tested independently in Europeans and East Asians, using existing GWAS data on more than 200 000 individuals. We did not find any significant associations between aSNPs and PDAC in samples of European descent, whereas, in East Asians, we observed that the Chr10p12.1-rs117585753-T allele (MAF = 10%) increased the risk to develop PDAC (OR = 1.35, 95%CI 1.19-1.54, P = 3.59 × 10-6), with a P-value close to a threshold that takes into account multiple testing. CONCLUSIONS: Our results show only a minimal contribution of Neandertal SNPs to PDAC risk.

Functional MOF-Based Materials for Environmental and Biomedical Applications: A Critical Review.

Over the last ten years, there has been a growing interest in metal-organic frameworks (MOFs), which are a unique category of porous materials that combine organic and inorganic components. MOFs have garnered significant attention due to their highly favorable characteristics, such as environmentally friendly nature, enhanced surface area and pore volume, hierarchical arrangements, and adjustable properties, as well as their versatile applications in fields such as chemical engineering, materials science, and the environmental and biomedical sectors. This article centers on examining the advancements in using MOFs for environmental remediation purposes. Additionally, it discusses the latest developments in employing MOFs as potential tools for disease diagnosis and drug delivery across various ailments, including cancer, diabetes, neurological disorders, and ocular diseases. Firstly, a concise overview of MOF evolution and the synthetic techniques employed for creating MOFs are provided, presenting their advantages and limitations. Subsequently, the challenges, potential avenues, and perspectives for future advancements in the utilization of MOFs in the respective application domains are addressed. Lastly, a comprehensive comparison of the materials presently employed in these applications is conducted.

Analysis of glucocorticoid receptor and microRNAs expression in pathological renal tissues.

Glucocorticoid receptor (GR) is expressed in normal renal podocytes; however, its expression differs among renal diseases. The expression of GR as well as its epigenetic regulators microRNA (miR)30a, miR24 and miR370 was studied in the renal tissues of patients with systemic lupus nephritis (LN), minimal changes disease (MCD) and pauci-immune glumeronephritis (PIN). A total of 51 patients undergoing renal biopsy and 22 nephrectomised controls with no history of parenchymal renal disease were recruited from the Clinic of Nephrology and Renal Transplantation of General Laikon hospital between November 2016 and March 2019. All patients were newly-diagnosed and they were naïve of any treatment. The mRNA and protein expression were analyzed through reverse transcription-quantitative PCR and immunohistochemistry respectively. Written consent was obtained from all participants. GR mRNA expression was significantly reduced in all pathological samples compared with the 'normal' renal tissues used as controls (P=0.023 for LN, P=0.05 for MCD and P=0.004 for PIN). Similarly, GR protein expression was lower in all pathological samples (>6 GR positive podocytes/glomerulus in 50% of patients with LN and MCD and 18% with PIN) compared with controls (>6 positive podocytes/glomerulus in all the controls). PIN samples presented significantly lower GR mRNA and protein expression compared with LN and MCD samples. No significant differences were observed in the miR30a expression when comparing pathological with 'normal' renal samples. miR24 and miR370 expression demonstrated statistically significant difference in all pathological compared with 'normal' tissues. Moreover, GR expression was not significantly associated with either LN disease activity score or the response to the treatment. GR and miR24 expression was significantly reduced whereas miR370 significantly increased in all pathological compared with 'normal' renal tissues implying their protentional role in nephritis pathogenesis and treatment. Analysis of larger samples are required for more robust statistical analysis.

Prolonged impact of anti-cancer therapy on endothelial function and arterial stiffness in breast cancer patients.

BACKGROUND: Cardiotoxicity restricts anthracycline and trastuzumab treatment of Human Epidermal Growth Factor Receptor 2 positive early breast cancer. Endothelial dysfunction and arteriosclerosis are significant cardiovascular risk factors. OBJECTIVES: We studied the effect of anthracycline-based chemotherapy, with or without trastuzumab, on endothelium and arteriosclerosis in patients with breast cancer. METHODS: In this case-control study, 52 women with breast cancer and 104 women without breast cancer were examined longitudinally up to 15 months following (in the breast cancer group) initiation of chemotherapy. Arterial stiffness was evaluated through pulse wave velocity (PWV), while endothelial function via flow-mediated dilatation (FMD) at baseline (T0), 3 (T1), 6 (T2), and 15 (T3) months later. RESULTS: There was no difference between subjects with breast cancer and control in PWV and FMD at baseline. Longitudinally, participants with breast cancer exhibited considerable impairment of PWV and FMD compared to the control group (p for interaction <0.001 for both parameters). In breast cancer patients, there was a significant increase from T0 to T3 in PWV (7.43 ± 1.68 m/s vs. 8.18 ± 2.00 m/s, p = 0.01) and decrease in FMD (6.95 ± 2.86% vs. 5.03 ± 2.83%, p = 0.006). The addition of trastuzumab in the treatment did not have any effect on PWV (p = 0.74) or FMD (p = 0.91). CONCLUSIONS: In patients with breast cancer, there is progression of endothelial dysfunction and arteriosclerosis up to 15 months following initiation of anthracycline-based chemotherapy. Trastuzumab has no additive effect on endothelial function or arterial stiffness.

The Role of EMT-Related lncRNAs in Ovarian Cancer.

Ovarian cancer (OC) is one of the deadliest cancers worldwide; late diagnosis and drug resistance are two major factors often responsible for high morbidity and treatment failure. Epithelial-to-mesenchymal transition (EMT) is a dynamic process that has been closely linked with cancer. Long non-coding RNAs (lncRNAs) have been also associated with several cancer-related mechanisms, including EMT. We conducted a literature search in the PubMed database in order to sum up and discuss the role of lncRNAs in regulating OC-related EMT and their underlying mechanisms. Seventy (70) original research articles were identified, as of 23 April 2023. Our review concluded that the dysregulation of lncRNAs is highly associated with EMT-mediated OC progression. A comprehensive understanding of lncRNAs' mechanisms in OC will help in identifying novel and sensitive biomarkers and therapeutic targets for this malignancy.

Novel Multi-Responsive Hyperbranched Polyelectrolyte Polyplexes as Potential Gene Delivery Vectors.

In this work, we investigate the complexation behavior of poly(oligo(ethylene glycol)methyl methacrylate)-co-poly(2-(diisopropylamino)ethyl methacrylate), P(OEGMA-co-DIPAEMA), hyperbranched polyelectrolyte copolymers, synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization, with short-linear DNA molecules. The synthesized hyperbranched copolymers (HBC), having a different chemical composition, are prepared in order to study their ability to bind with a linear nucleic acid at various N/P ratios (amine over phosphate groups). Specifically, the three pH and thermo-responsive P(OEGMA-co-DIPAEMA) hyperbranched copolymers were able to form polyplexes with DNA, with dimensions in the nanoscale. Using several physicochemical methods, such as dynamic and electrophoretic light scattering (DLS, ELS), as well as fluorescence spectroscopy (FS), the complexation process and the properties of formed polyplexes were explored in response to physical and chemical stimuli such as temperature, pH, and ionic strength. The mass and the size of polyplexes are shown to be affected by the hydrophobicity of the copolymer utilized each time, as well as the N/P ratio. Additionally, the stability of polyplexes in the presence of serum proteins is found to be excellent. Finally, the multi-responsive hyperbranched copolymers were evaluated regarding their cytotoxicity via in vitro experiments on HEK 293 non-cancerous cell lines and found to be sufficiently non-toxic. Based on our results, these polyplexes could be useful candidates for gene delivery and related biomedical applications.

The PANcreatic Disease ReseArch (PANDoRA) consortium: Ten years' experience of association studies to understand the genetic architecture of pancreatic cancer.

Pancreatic cancer has an incidence that almost matches its mortality. Only a small number of risk factors and 33 susceptibility loci have been identified. so Moreover, the relative rarity of pancreatic cancer poses significant hurdles for research aimed at increasing our knowledge of the genetic mechanisms contributing to the disease. Additionally, the inability to adequately power research questions prevents small monocentric studies from being successful. Several consortia have been established to pursue a better understanding of the genetic architecture of pancreatic cancers. The Pancreatic disease research (PANDoRA) consortium is the largest in Europe. PANDoRA is spread across 12 European countries, Brazil and Japan, bringing together 29 basic and clinical research groups. In the last ten years, PANDoRA has contributed to the discovery of 25 susceptibility loci, a feat that will be instrumental in stratifying the population by risk and optimizing preventive strategies.

Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma.

INTRODUCTION: Only a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate. MATERIALS AND METHODS: We scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase. RESULTS: The C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10-8 in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of the RCCD1 antisense (RCCD1-AS1) gene which, when expressed, decreases the expression of the RCC1 domain-containing (RCCD1) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase of RCCD1 gene expression, made possible by the inactivity of RCCD1-AS1. CONCLUSION: We identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.

The Role of HIF1-related Genes and Non-coding RNAs Expression in Clear Cell Renal Cell Carcinoma.

BACKGROUND/AIM: Renal cell carcinoma is one of the three most common malignant urologic tumors, with clear cell renal cell carcinoma (ccRCC) representing its most common subtype. Although nephrectomy can radically cure the disease, a large percentage of patients is diagnosed when metastatic sites are present and thus alternative, pharmaceutical approaches need to be sought. Since HIF1 up-regulates the transcription of genes that range from metabolic enzymes to non-coding RNAs, and is a key molecule of ccRCC pathogenesis, this study aimed to investigate the expression ALDOA, SOX-6, and non-coding RNAs (mir-122, mir-1271, and MALAT-1) in samples from ccRCC patients. PATIENTS AND METHODS: Tumor and adjacent normal tissue samples from 14 patients with ccRCC were harvested. Expression of ALDOA, mir-122, mir-1271, and MALAT-1 mRNA was estimated using real time PCR, whereas the expression of SOX-6 protein was investigated using immunohistochemistry. RESULTS: Up-regulation of HIF1 was observed, accompanied with up-regulation of ALDOA, MALAT-1, and mir-122. On the contrary, the expression of mir-1271 was found to be reduced, a finding that can be attributed to a potential MALAT-1 sponge function. Furthermore, SOX-6 protein levels (a transcription factor with tumor suppressing properties) were also reduced. CONCLUSION: The observed dysregulated expression levels highlight the importance of ALDOA, MALAT-1, mir-122, mir-1271, and SOX-6, which remain less studied than the known and well-studied HIF1 pathways of VEGF, TGF-α, and EPO. Furthermore, inhibition of the up-regulated ALDOA, mir-122, and MALAT-1 could be of therapeutic interest for selected ccRCC patients.

Genetic and non-genetic risk factors for early-onset pancreatic cancer.

BACKGROUND: Early-onset pancreatic cancer (EOPC) represents 5-10% of all pancreatic ductal adenocarcinoma (PDAC) cases, and the etiology of this form is poorly understood. It is not clear if established PDAC risk factors have the same relevance for younger patients. This study aims to identify genetic and non-genetic risk factors specific to EOPC. METHODS: A genome-wide association study was performed, analysing 912 EOPC cases and 10 222 controls, divided into discovery and replication phases. Furthermore, the associations between a polygenic risk score (PRS), smoking, alcohol consumption, type 2 diabetes and PDAC risk were also assessed. RESULTS: Six novel SNPs were associated with EOPC risk in the discovery phase, but not in the replication phase. The PRS, smoking, and diabetes affected EOPC risk. The OR comparing current smokers to never-smokers was 2.92 (95% CI 1.69-5.04, P = 1.44 × 10-4). For diabetes, the corresponding OR was 14.95 (95% CI 3.41-65.50, P = 3.58 × 10-4). CONCLUSION: In conclusion, we did not identify novel genetic variants associated specifically with EOPC, and we found that established PDAC risk variants do not have a strong age-dependent effect. Furthermore, we add to the evidence pointing to the role of smoking and diabetes in EOPC.