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PloS One 2024The prevalence of gastrointestinal tumors continues to be significant. To uncover promising therapeutic targets for these tumors, we rigorously executed a Mendelian...
BACKGROUND
The prevalence of gastrointestinal tumors continues to be significant. To uncover promising therapeutic targets for these tumors, we rigorously executed a Mendelian randomization (MR) study to comprehensively screen the blood metabolomes for potential causal mediators of five frequently encountered gastrointestinal tumors (Liver Cancer, Colorectal Cancer, Esophageal Cancer, Gastric Cancer and Pancreatic Cancer).
METHODS
We selected a comprehensive set of 137 distinct blood metabolites derived from three large-scale genome-wide association studies (GWASs) involving a total of 147827 participants of European ancestry. The gastrointestinal tumors-related data were obtained from a GWAS conducted within the Finnish study. Through meticulous MR analyses, we thoroughly assessed the associations between blood metabolites and gastrointestinal tumors. Additionally, a phenome-wide MR (Phe-MR) analysis was employed to investigate the potential on-target side effects of metabolite interventions.
RESULTS
We have identified 1 blood metabolites, namely isovalerylcarnitine (ORlog10: 1.01; 95%CI, 1.01-1.02; P = 1.81×10-7), as the potential causal mediators for liver cancer. However, no potential pathogenic mediators were detected for the other four tumors.
CONCLUSIONS
The current systematic MR analysis elucidated the potential role of isovalerylcarnitine as a causal mediator in the development of liver cancer. Leveraging the power of Phe-MR study facilitated the identification of potential adverse effects associated with drug targets for liver cancer prevention. Considering the weighing of pros and cons, isovalerylcarnitine emerges as a promising candidate for targeted drug interventions in the realm of liver cancer prevention.
Topics: Humans; Gastrointestinal Neoplasms; Metabolome; Genome-Wide Association Study; Mendelian Randomization Analysis; Male; Female; Finland; Carnitine; Middle Aged; Risk Factors; Liver Neoplasms
PubMed: 38814898
DOI: 10.1371/journal.pone.0304574 -
Turkish Journal of Medical Sciences 2023Long noncoding RNAs (lncRNAs) are noncoding RNA molecules with a heterogeneous structure consisting of 200 or more nucleotides. Because these noncoding RNAs are... (Review)
Review
Long noncoding RNAs (lncRNAs) are noncoding RNA molecules with a heterogeneous structure consisting of 200 or more nucleotides. Because these noncoding RNAs are transcribed by RNA polymerase II, they have properties similar to messenger RNA (mRNA). Contrary to popular belief, the term "ncRNA" originated before the discovery of microRNAs. LncRNA genes are more numerous than protein-coding genes. They are the focus of current molecular research because of their pivotal roles in cancer-related processes such as cell proliferation, differentiation, and migration. The incidence of pancreatic cancer (PC) is increasing around the world and research on the molecular aspects of PC are growing. In this review, it is aimed to provide critical information about lncRNAs in PC, including the biological and oncological behaviors of lncRNAs in PC and their potential application in therapeutic strategies and as diagnostic tumor markers.
Topics: Humans; RNA, Long Noncoding; Pancreatic Neoplasms; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic
PubMed: 38813489
DOI: 10.55730/1300-0144.5724 -
World Journal of Gastroenterology May 2024Contrast-enhanced endoscopic ultrasound (CH-EUS) can overcome the limitations of endoscopic ultrasound-guided acquisition by identifying microvessels inside... (Review)
Review
Contrast-enhanced endoscopic ultrasound (CH-EUS) can overcome the limitations of endoscopic ultrasound-guided acquisition by identifying microvessels inside inhomogeneous tumours and improving the characterization of these tumours. Despite the initial enthusiasm that oriented needle sampling under CH-EUS guidance could provide better diagnostic yield in pancreatic solid lesions, further studies did not confirm the supplementary values in cases of tissue acquisition guided by CH-EUS. This review details the knowledge based on the available data on contrast-guided procedures. The indications for CH-EUS tissue acquisition include isoechoic EUS lesions with poor visible delineation where CH-EUS can differentiate the lesion vascularisation from the surrounding parenchyma and also the mural nodules within biliopancreatic cystic lesions, which occur in select cases. Additionally, the roles of CH-EUS-guided therapy in patients whose pancreatic fluid collections or bile ducts that have an echogenic content have indications for drainage, and patients who have nonvisualized vessels that need to be highlighted Doppler EUS are presented. Another indication is represented if there is a need for an immediate assessment of the post-radiofrequency ablation of pancreatic neuroendocrine tumours, in which case CH-EUS can be used to reveal the incomplete tumour destruction.
Topics: Humans; Contrast Media; Pancreatic Neoplasms; Endosonography; Pancreas; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Ultrasonography, Interventional; Drainage; Pancreatic Diseases
PubMed: 38813054
DOI: 10.3748/wjg.v30.i17.2311 -
Frontiers in Bioscience (Landmark... May 2024The F-box protein (FBXO) family plays a key role in the malignant progression of tumors. However, the biological functions and clinical value of the FBXO family in liver...
OBJECTIVE
The F-box protein (FBXO) family plays a key role in the malignant progression of tumors. However, the biological functions and clinical value of the FBXO family in liver cancer remain unclear. Our study comprehensively assessed the clinical value of the FBXO family in hepatocellular carcinoma (HCC) and constructed a novel signature based on the FBXO family to predict prognosis and guide precision immunotherapy.
METHODS
The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases were utilized to investigate the expression characteristics and prognostic value of the FBXO family in HCC. A predictive model based on the FBXO family using TCGA database; and its predictive ability was validated using the ICGC database. Further analyses revealed that this predictive model can independently predict the overall survival (OS) rate of patients with HCC. We further analyzed the association of this predictive model with signaling pathways, clinical pathological features, somatic mutations, and immune therapy responses. Finally, we validated the biological functions of cyclin F () through experiments.
RESULTS
A predictive model involving three genes (, , and ) was constructed, effectively identifying high and low-risk patients with differences in OS, clinicopathological characteristics, somatic mutations, and immune cell infiltration status. Additionally, knock-down of in HCC cell lines reduced cell proliferation , suggesting that may be a potential therapeutic target for HCC.
CONCLUSIONS
The predictive model based on the FBXO family can effectively predict OS and the immune therapy response in HCC. Additionally, is a potential therapeutic target for HCC.
Topics: Humans; Liver Neoplasms; Carcinoma, Hepatocellular; F-Box Proteins; Prognosis; Male; Female; Cell Line, Tumor; Middle Aged; Gene Expression Regulation, Neoplastic; Cyclins; Biomarkers, Tumor; Cell Proliferation; Databases, Genetic
PubMed: 38812312
DOI: 10.31083/j.fbl2905202 -
Frontiers in Bioscience (Landmark... May 2024Gastric cancer (GC) is frequently diagnosed at advanced stages, when cancer cells have already metastasized. Therefore, patients with GC have a low survival rate and...
BACKGROUND
Gastric cancer (GC) is frequently diagnosed at advanced stages, when cancer cells have already metastasized. Therefore, patients with GC have a low survival rate and poor prognosis even after treatment.
METHODS
We downloaded GC-related RNA sequencing (RNA-Seq) data, copy number variation (CNV) data, and clinical data for bioinformatics analysis to screen prognostic genes of GC. Single-sample gene set enrichment analysis and survival analyses were performed on the RNA-Seq data, and differential and correlation analyses were conducted on the CNV data to obtain CNV-driven differentially expressed genes (DEGs). Prognostic genes were identified through univariate Cox analyses of the CNV-driven DEGs, combined with the clinical data. () was finally selected for verification after functional and survival analyses of the prognostic genes.
RESULTS
expression was lower in paracancer tissue than in GC tissue, and lower in GES-1 gastric epithelial cells than in GC cells. The cell culture supernatants from -knockdown GC cells were collected and used to culture human umbilical vein endothelial cells (HUVECs). It was observed that enhanced the activity, metastasis, invasion, and angiogenesis of GC cells; promoted the epithelial-mesenchymal transition (EMT) of GC cells; and impacted the Ras-associated protein 1 (Rap1)/mitogen-activated protein kinase (MAPK) pathway. To further explore the involvement of the Rap1/MAPK pathway in GC development, a pathway activator was added to GC cells with knockdown of expression. This pathway activator not only enhanced the activity, invasion, and migration of GC cells but also promoted the EMT and blood vessel formation.
CONCLUSIONS
regulates the angiogenesis and EMT of GC cells through the Rap1/MAPK pathway, thus influencing the onset and progression of GC.
Topics: Stomach Neoplasms; Humans; Epithelial-Mesenchymal Transition; Neovascularization, Pathologic; Cell Line, Tumor; Prognosis; Gene Expression Regulation, Neoplastic; MAP Kinase Signaling System; Human Umbilical Vein Endothelial Cells; Shelterin Complex; Male; Female; Telomere-Binding Proteins; DNA Copy Number Variations; Cell Movement; rap1 GTP-Binding Proteins; Angiogenesis
PubMed: 38812308
DOI: 10.31083/j.fbl2905177 -
Journal of Experimental & Clinical... May 2024Intrahepatic cholangiocarcinoma (ICCA) is a heterogeneous group of malignant tumors characterized by high recurrence rate and poor prognosis. Heterochromatin Protein 1α...
BACKGROUND
Intrahepatic cholangiocarcinoma (ICCA) is a heterogeneous group of malignant tumors characterized by high recurrence rate and poor prognosis. Heterochromatin Protein 1α (HP1α) is one of the most important nonhistone chromosomal proteins involved in transcriptional silencing via heterochromatin formation and structural maintenance. The effect of HP1α on the progression of ICCA remained unclear.
METHODS
The effect on the proliferation of ICCA was detected by experiments in two cell lines and two ICCA mouse models. The interaction between HP1α and Histone Deacetylase 1 (HDAC1) was determined using Electrospray Ionization Mass Spectrometry (ESI-MS) and the binding mechanism was studied using immunoprecipitation assays (co-IP). The target gene was screened out by RNA sequencing (RNA-seq). The occupation of DNA binding proteins and histone modifications were predicted by bioinformatic methods and evaluated by Cleavage Under Targets and Tagmentation (CUT & Tag) and Chromatin immunoprecipitation (ChIP).
RESULTS
HP1α was upregulated in intrahepatic cholangiocarcinoma (ICCA) tissues and regulated the proliferation of ICCA cells by inhibiting the interferon pathway in a Signal Transducer and Activator of Transcription 1 (STAT1)-dependent manner. Mechanistically, STAT1 is transcriptionally regulated by the HP1α-HDAC1 complex directly and epigenetically via promoter binding and changes in different histone modifications, as validated by high-throughput sequencing. Broad-spectrum HDAC inhibitor (HDACi) activates the interferon pathway and inhibits the proliferation of ICCA cells by downregulating HP1α and targeting the heterodimer. Broad-spectrum HDACi plus interferon preparation regimen was found to improve the antiproliferative effects and delay ICCA development in vivo and in vitro, which took advantage of basal activation as well as direct activation of the interferon pathway. HP1α participates in mediating the cellular resistance to both agents.
CONCLUSIONS
HP1α-HDAC1 complex influences interferon pathway activation by directly and epigenetically regulating STAT1 in transcriptional level. The broad-spectrum HDACi plus interferon preparation regimen inhibits ICCA development, providing feasible strategies for ICCA treatment. Targeting the HP1α-HDAC1-STAT1 axis is a possible strategy for treating ICCA, especially HP1α-positive cases.
Topics: Cholangiocarcinoma; Humans; Chromobox Protein Homolog 5; Histone Deacetylase 1; Mice; Animals; STAT1 Transcription Factor; Bile Duct Neoplasms; Chromosomal Proteins, Non-Histone; Cell Line, Tumor; Cell Proliferation; Male; Gene Expression Regulation, Neoplastic; Female
PubMed: 38812060
DOI: 10.1186/s13046-024-03070-3 -
Radiation Oncology (London, England) May 2024Local treatment options for locally recurrent pancreatic adenocarcinoma (LR-PAC) are limited, with median survival time (MST) of 9-13 months (mos) following recurrence....
BACKGROUND
Local treatment options for locally recurrent pancreatic adenocarcinoma (LR-PAC) are limited, with median survival time (MST) of 9-13 months (mos) following recurrence. MRI-guided stereotactic body radiation therapy (MRgSBRT) provides the ability to dose escalate while sparing normal tissue. Here we report on the early outcomes of MRgSBRT for LR-PAC.
METHODS
Patients with prior resection of pancreatic adenocarcinoma with local recurrence treated with MRgSBRT at a single tertiary referral center from 5-2021 to 2-2023 were identified from our prospective database. MRgSBRT was delivered to 40-50 Gy in 4-5 fractions with target and OAR delineation per institutional standards. Endpoints included local control per RECIST v1.1, distant failure, overall survival (OS), and acute and chronic toxicities per Common Terminology Criteria for Adverse Events, v5.
RESULTS
Fifteen patients with LR-PAC were identified with median follow-up of 10.6 mos (2.8-26.5 mos) from MRgSBRT. There were 8 females and 7 males, with a median age of 69 years (50-83). One patient underwent neoadjuvant radiation for 50.4 Gy in 28 fractions followed by resection, and one underwent adjuvant radiation for 45 Gy in 25 fractions prior to recurrence. MRgSBRT was delivered a median of 18.8 mos (3.5-52.8 mos) following resection. OS following recurrence at 6 and 12 mos were 87% and 51%, respectively, with a median survival time of 14.1 mos (3.2-27.4 mos). Three patients experienced local failure at 5.9, 7.8, and 16.6 months from MgSBRT with local control of 92.3% and 83.9% at 6 and 12 months. 10 patients experienced distant failure at a median of 2.9 mos (0.3-6.7 mos). Grade 1-2 acute GI toxicity was noted in 47% of patients, and chronic GI toxicity in 31% of patients. No grade > 3 toxicities were noted.
CONCLUSIONS
This is the first report on toxicity and outcomes of MRgSBRT for LR-PAC in the literature. MRgSBRT is a safe, feasible treatment modality with the potential for improved local control in this vulnerable population. Future research is necessary to better identify which patients yield the most benefit from MRgSBRT, which should continue to be used with systemic therapy as tolerated.
TRIAL REGISTRATION
Jefferson IRB#20976, approved 2/17/21.
Topics: Humans; Male; Pancreatic Neoplasms; Female; Aged; Radiosurgery; Middle Aged; Adenocarcinoma; Neoplasm Recurrence, Local; Aged, 80 and over; Magnetic Resonance Imaging; Radiotherapy, Image-Guided; Survival Rate; Prospective Studies; Retrospective Studies
PubMed: 38812040
DOI: 10.1186/s13014-024-02457-y -
BMC Cancer May 2024Pancreatic cancer, a highly fatal malignancy, has shown a global rise in the incidence and mortality rates. However, these rates vary significantly across different...
Pancreatic cancer, a highly fatal malignancy, has shown a global rise in the incidence and mortality rates. However, these rates vary significantly across different regions worldwide. This study aims to assess the incidence and mortality of pancreatic cancer in Saudi Arabia. We collected the data from 16 annual cancer incidence reports in Saudi Arabia for the study period (2005-2020) and from the WHO's IARC Global Cancer Observatory website. Although the burden of pancreatic cancer in Saudi Arabia is relatively lower compared to global rates, the disease incidence has shown a steady increase over the study period, in addition to regional variations within the country. The disease predominantly affects the elderly population, aged 50 years and above in both genders, with males exhibiting higher rates than females. Further studies are required to identify the potential risk factors for pancreatic cancer in the Saudi population.
Topics: Humans; Saudi Arabia; Pancreatic Neoplasms; Male; Female; Incidence; Middle Aged; Aged; Risk Factors; Adult
PubMed: 38811942
DOI: 10.1186/s12885-024-12401-8 -
BMC Cancer May 2024Pancreatic ductal adenocarcinoma (PDAC) ranks among the deadliest types of cancer, and it will be meaningful to search for new biomarkers with prognostic value to help...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) ranks among the deadliest types of cancer, and it will be meaningful to search for new biomarkers with prognostic value to help clinicians tailor therapeutic strategies.
METHODS
Here we tried to use an advanced optical imaging technique, multiphoton microscopy (MPM) combining second-harmonic generation (SHG) and two-photon excited fluorescence (TPEF) imaging, for the label-free detection of PDAC tissues from a cohort of 149 patients. An automated image processing method was used to extract collagen features from SHG images and the Kaplan-Meier survival analysis and Cox proportional hazards regression were used to assess the prognostic value of collagen signatures.
RESULTS
SHG images clearly show the different characteristics of collagen fibers in tumor microenvironment. We gained eight collagen morphological features, and a Feature-score was derived for each patient by the combination of these features using ridge regression. Statistical analyses reveal that Feature-score is an independent factor, and can predict the overall survival of PDAC patients as well as provide well risk stratification.
CONCLUSIONS
SHG imaging technique can potentially be a tool for the accurate diagnosis of PDAC, and this optical biomarker (Feature-score) may help clinicians make more approximate treatment decisions.
Topics: Humans; Carcinoma, Pancreatic Ductal; Prognosis; Female; Male; Collagen; Pancreatic Neoplasms; Middle Aged; Aged; Second Harmonic Generation Microscopy; Biomarkers, Tumor; Kaplan-Meier Estimate; Microscopy, Fluorescence, Multiphoton; Adult; Tumor Microenvironment
PubMed: 38811917
DOI: 10.1186/s12885-024-12412-5 -
Scientific Reports May 2024Addressing the significant level of variability exhibited by pancreatic cancer necessitates the adoption of a systems biology approach that integrates molecular data,...
Addressing the significant level of variability exhibited by pancreatic cancer necessitates the adoption of a systems biology approach that integrates molecular data, biological properties of the tumors, medical images, and clinical features of the patients. In this study, a comprehensive multi-omics methodology was employed to examine a distinctive collection of patient dataset containing rapid autopsy tumor and normal tissue samples as well as longitudinal imaging with a focus on pancreatic cancer. By performing a whole exome sequencing analysis on tumor and normal tissues to identify somatic gene variants and a radiomic feature analysis to tumor CT images, the genome-wide association approach established a connection between pancreatic cancer driver genes and relevant radiomic features, enabling a thorough and quantitative assessment of the heterogeneity of pancreatic tumors. The significant association between sets of genes and radiomic features revealed the involvement of genes in shaping tumor morphological heterogeneity. Some results of the association established a connection between the molecular level mechanism and their outcomes at the level of tumor structural heterogeneity. Because tumor structure and tumor structural heterogeneity are related to the patients' overall survival, patients who had pancreatic cancer driver gene mutations with an association to a certain radiomic feature have been observed to experience worse survival rates than cases without these somatic mutations. Furthermore, the association analysis has revealed potential gene mutations and radiomic feature candidates that warrant further investigation in future research endeavors.
Topics: Humans; Pancreatic Neoplasms; Mutation; Exome Sequencing; Phenotype; Genome-Wide Association Study; Male; Female; Tomography, X-Ray Computed
PubMed: 38811597
DOI: 10.1038/s41598-024-62741-5