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Human Pathology Jun 2024Pancreatic neuroendocrine tumors (PanNETs) comprise a heterogeneous group of neoplasms in terms of biological behavior. This study aims to develop a practical algorithm...
Pancreatic neuroendocrine tumors (PanNETs) comprise a heterogeneous group of neoplasms in terms of biological behavior. This study aims to develop a practical algorithm based on emerging biomarkers, including chromatin-remodeling molecules DAXX/ATRX/H3K36me3, in conjunction with established prognostic factors, such as WHO grade and size. In immunohistochemical analyses, 18 of the 111 (16.2%) primary PanNETs showed DAXX or ATRX loss in a mutually exclusive manner. DAXX/ATRX loss was significantly correlated with higher recurrence risk and better predicted postoperative recurrence than WHO grade. We proposed a novel algorithm for stratifying patients with resectable PanNET into three groups according to recurrence risk: (A) WHO Grade 1 and ≤ 2 cm (very low-risk); for the others, (B) retained DAXX/ATRX (low-risk) and (C) DAXX/ATRX complete/heterogeneous loss (high-risk). Furthermore, we elucidated the intratumoral heterogeneities of PanNETs. Among cases with DAXX or ATRX loss, nine cases demonstrated heterogeneous loss of expression of DAXX/ATRX/H3K36me3. The majority of cases with DAXX/ATRX loss, either homogeneous or heterogeneous loss, showed uniform α-cell-like phenotype (ARX1+/PDX1-). In cases of metastatic or recurrent tumors, the expression pattern was identical to that observed in at least part of the primary tumor. In some instances, the expression pattern differed among different metastatic or recurrent tumors of the same patient. In summary, we propose a clinically useful and practical algorithm for postoperative recurrence risk stratification in PanNETs, by combining DAXX/ATRX status with WHO grade and size. Moreover, our findings highlighted the frequent spatiotemporal heterogeneity of chromatin-remodeling molecule expression in PanNETs with an α-cell phenotype, offering insights into tumorigenesis.
PubMed: 38909708
DOI: 10.1016/j.humpath.2024.06.015 -
Scientific Reports Jun 2024Pancreatic cancer is one of the most aggressive forms of cancer, and treatment options are limited. One therapeutic approach is to use nanoparticles to deliver the...
Pancreatic cancer is one of the most aggressive forms of cancer, and treatment options are limited. One therapeutic approach is to use nanoparticles to deliver the active agent directly to pancreatic cancer cells. Nanoparticles can be designed to specifically target cancer cells, minimizing damage to healthy tissues. Silver nanoparticles have the unique ability to absorb light, especially in the near-infrared (NIR) region. In this study, silver nanoparticles functionalized with IgG molecules were synthesized and administered to pancreatic cancer cell lines. Subsequently, the cells were photo-excited using a 2 W 808 nm laser and further examined in PANC-1 pancreatic cancer cell lines. Flow cytometry and confocal microscopy combined with immunochemical staining were used to examine the interaction between photo-excited silver nanoparticles and pancreatic cancer cells. The photothermal therapy based on IgG-functionalized silver nanoparticles in pancreatic cancer induces dysfunction in the Golgi apparatus, leading to the activation of the caspase-3 apoptotic pathway and ultimately resulting in cellular apoptosis. These findings suggest that our proposed IgG nanoparticle laser treatment could emerge as a novel approach for the therapy of pancreatic cancer.
Topics: Pancreatic Neoplasms; Humans; Silver; Metal Nanoparticles; Immunoglobulin G; Cell Line, Tumor; Photothermal Therapy; Apoptosis; Caspase 3; Phototherapy
PubMed: 38909066
DOI: 10.1038/s41598-024-63142-4 -
Cell Death & Disease Jun 2024TBX3 behaves as a tumor suppressor or oncoprotein across cancer. However, TBX3 function remains undetermined in intrahepatic cholangiocarcinoma (iCCA), a deadly primary...
TBX3 behaves as a tumor suppressor or oncoprotein across cancer. However, TBX3 function remains undetermined in intrahepatic cholangiocarcinoma (iCCA), a deadly primary liver malignancy with few systemic treatment options. This study sought to investigate the impact of TBX3 on iCCA. We found that overexpression of TBX3 strongly inhibited human iCCA cell growth. In the Akt/FBXW7ΔF mouse iCCA model, overexpression of Tbx3 reduced cholangiocarcinogenesis in vivo, while inducible genetic knockout of Tbx3 accelerated iCCA growth. RNA-seq identified MAD2L1 as a downregulated gene in TBX3-overexpressing cells, and ChIP confirmed that TBX3 binds to the MAD2L1 promoter. CRISPR-mediated knockdown of Mad2l1 significantly reduced the growth of two iCCA models in vivo. Finally, we found that TBX3 expression is upregulated in ~20% of human iCCA samples, and its high expression is associated with less proliferation and better survival. MAD2L1 expression is upregulated in most human iCCA samples and negatively correlated with TBX3 expression. Altogether, our findings suggest that overexpression of TBX3 suppresses CCA progression via repressing MAD2L1 expression.
Topics: Cholangiocarcinoma; T-Box Domain Proteins; Humans; Animals; Mice; Bile Duct Neoplasms; Carcinogenesis; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Cell Proliferation
PubMed: 38909034
DOI: 10.1038/s41419-024-06839-8 -
Medicina 2024Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant inherited disease with an estimated prevalence of 2-10:100 000. The main locations of tumors are...
INTRODUCTION
Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant inherited disease with an estimated prevalence of 2-10:100 000. The main locations of tumors are parathyroid glands (HPT), gastroenteropancreatic tract (GEPT), and anterior pituitary gland (PT). The aim of our investigation was to describe the phenotype and genotype of Argentinian patients with MEN1.
METHODS
A total of 68 index patients diagnosed with at least two of the three main tumors or one tumor and a relative with MEN1, and 84 first-degree relatives were studied. We sequenced the coding region (exons 2-10); the promoter, exon 1; and the flanking intronic regions of the MEN1 gene, following the Sanger method. We used MLPA in index patients without mutation.
RESULTS
Prevalence of tumors: HPT 87.5%, GEPT 49% (p< 0.001). No statistical differences in the prevalence of HPT vs. PT (68%). Prevalence of pathogenic variants: 90% in familial cases and 51% in sporadic cases. Of the different 36 pathogenic variants, 13 (36.2%) were frameshift micro-rearrangement, 8 (22.2%) were missense, 9 (25%) were nonsense, 3 (8.3%) were mutations in splicing sites, 2 (5.5%) were large deletions and, 1 in-frame micro-rearrangement. We found 7 novel pathogenic variants. Thirty-nine percent (n = 33) of first-degree relatives of 23 families were found to be mutation carriers.
CONCLUSION
The phenotype and genotype of Argentinian patients was similar to other MEN1 populations. A high frequency of PT and the identification of seven novel mutations are underscored.
Topics: Humans; Argentina; Male; Multiple Endocrine Neoplasia Type 1; Phenotype; Female; Adult; Genotype; Middle Aged; Adolescent; Young Adult; Child; Aged; Mutation; Child, Preschool; Parathyroid Neoplasms; Proto-Oncogene Proteins
PubMed: 38907957
DOI: No ID Found -
BMC Medical Genomics Jun 2024Collagen (COL) genes, play a key role in tumor invasion and metastasis, are involved in tumor extracellular matrix (ECM)-receptor interactions and focal adhesion...
BACKGROUND
Collagen (COL) genes, play a key role in tumor invasion and metastasis, are involved in tumor extracellular matrix (ECM)-receptor interactions and focal adhesion pathways. However, studies focusing on the diagnostic value of the COL4 family in stomach adenocarcinoma (STAD) are currently lacking.
METHODS
The TCGA database was employed to retrieve the clinical features and RNA sequencing expression profiles of patients with STAD. We conducted an investigation to examine the expression disparities between STAD and adjacent normal tissues. Kaplan-Meier survival analysis was utilized to assess their prognostic significance, while Spearman correlation analysis was employed to determine their association with immune checkpoint genes and immunomodulatory molecules. Furthermore, GO and KEGG analyses were performed on the COL4s-related genes, revealing potential biological pathways through gene set enrichment analysis (GSEA). Subsequently, we explored the extent of immune infiltration of the COL4 family in STAD using the TIMER database. Lastly, the expression levels of the COL4 family in STAD were further validated through quantitative PCR (qPCR) and western blot techniques.
RESULTS
The expression levels of COL4A1/2 were significantly upregulated, while COL4A5/6 were conspicuously downregulated in STAD. The survival analysis revealed that the upregulated COL4s indicated poorer overall survival, first progression and post-progression survival outcomes. Additionally, our findings demonstrated a positive correlation between the expressions of COL4A1/2/3/4 and the infiltration of immune cells, including CD8 + T cells, dendritic cells, macrophages, neutrophils and CD4 + T cells. Further correlation analysis uncovered a favorable association between the expression of COL4A1/2/3/4 and various crucial immunomodulatory molecules, immunological checkpoint molecules, and chemokines. Quantitative PCR analysis confirmed that the expression patterns of COL4A1/3/4/6 genes aligned with the finding from the TCGA database. However, gastric cancer cells exhibited downregulation of COL4A2. Consistently, the protein level of COL4A1 was elevated, whereas the protein level of COL4A2 was reduced in the gastric cancer cell lines.
CONCLUSION
COL4s could potentially serve as biomarkers for diagnosing and predicting the prognosis of STAD.
Topics: Stomach Neoplasms; Humans; Adenocarcinoma; Prognosis; Collagen Type IV; Gene Expression Regulation, Neoplastic; Male; Female; Biomarkers, Tumor; Middle Aged; Kaplan-Meier Estimate
PubMed: 38907304
DOI: 10.1186/s12920-024-01934-3 -
Medicine Jun 2024To explore the relationships between gastrointestinal radiation injuries of pancreatic cancer patients treated with TOMO and dose-volume histogram parameters... (Observational Study)
Observational Study
To explore the relationships between gastrointestinal radiation injuries of pancreatic cancer patients treated with TOMO and dose-volume histogram parameters prospectively. Seventy patients with pancreatic cancer who underwent TOMO were enrolled in this prospective study from February 2015 to May 2020. The clinical and dose-volume histogram parameters of the patients were collected. The optimal dose parameters for gastrointestinal radiation ulcers were confirmed based on the receiver operating characteristic curve (ROC) and the area below the ROC curve. Acute gastrointestinal tract toxic and side effect and injury grading correlation analyzed by Kruskal-Wallis rank sum test. Gastrointestinal injury often occurs during radiotherapy for pancreatic cancer, as observed using gastroscopy. The main adverse reactions were radioactive gastrointestinal inflammation (58.5%), radioactive gastrointestinal ulcers (41.4%), active bleeding (10%), newly-developed gastric retention (8.6%), and gastric varices (5.7%). As for the stomach, Dmean and V10 were related to radiation ulcer injury. ROC curve indicated that for stomach a Dmean of 13.39 Gy (area under ROC curves = 0.74, P = .048) and a V10 of 72.21% (area = 0.74, P = .048) was the tolerated dose for the injury of stomach radiation ulcer. As for duodenum, aV20 and aV25 are related to radiation ulcer injury. ROC curve indicated that aV20 of 22.82 cm3 (area = 0.68, P = .025) and aV25 of 32.04 cm3 (area = 0.66, P < .047) was the tolerated dose for the injury of duodenum radiation ulcer. The acute gastrointestinal tract toxic and side effects have no significant correlation with injury grading under gastroscope. Dmean > 13.39 Gy and V10 > 72.21% were the key dosimetric indices for predicting radiation-induced gastric ulcer, and aV20 > 22.82 cm3 and aV25 > 32.04 cm3 were for duodenal. Gastrointestinal reactions cannot be used as an overall basis for the diagnosis of gastrointestinal injury, and gastroscopy is recommended as a review item after radiotherapy.
Topics: Humans; Male; Female; Pancreatic Neoplasms; Middle Aged; Prospective Studies; Aged; Radiation Injuries; Gastroscopy; Radiotherapy Dosage; Radiotherapy, Intensity-Modulated; Adult; ROC Curve; Aged, 80 and over
PubMed: 38905414
DOI: 10.1097/MD.0000000000038469 -
Ugeskrift For Laeger Jun 2024This is a case report of a 70-year-old woman with possible cholestyramine-induced bowel perforation. She had a prior history of pancreaticoduodenectomy for pancreatic...
This is a case report of a 70-year-old woman with possible cholestyramine-induced bowel perforation. She had a prior history of pancreaticoduodenectomy for pancreatic cancer with a daily intake of cholestyramine. She underwent emergency laparotomy for small bowel perforation twice. Subsequent pathology reports showed crystal depositions in the small bowel wall. Leasions spread out on the small bowel and the omentum during the second surgery were thought to be carcinomatosis. However, the pathology report showed no malignant cells but plenty of crystal depositions as seen with cholestyramine intake.
Topics: Humans; Aged; Female; Intestinal Perforation; Cholestyramine Resin; Intestine, Small; Pancreaticoduodenectomy; Anticholesteremic Agents; Pancreatic Neoplasms
PubMed: 38904283
DOI: 10.61409/V02240109 -
Diabetes & Vascular Disease Research 2024A pharmacoepidemiological study to assess VTE risk factors in a diabetes-rich population.
A pharmacoepidemiological nested case-control study of risk factors for venous thromboembolism with the focus on diabetes, cancer, socioeconomic group, medications, and comorbidities.
OBJECTIVES
A pharmacoepidemiological study to assess VTE risk factors in a diabetes-rich population.
METHODS
The study comprised 299,590 individuals. We observed 3450 VTEs and matched them with 15,875 controls using a nested case-control approach and collected data on comorbidities and prescriptions. By multivariable conditional logistic regression, we calculated ORs with 95%CIs for comorbidities and medications to evaluate their associations with VTE.
RESULTS
Diabetes (aOR 2.16; 95%CI 1.99-2.34), inflammatory bowel disease (1.84; 1.27-2.66), and severe psychiatric disorders (1.72; 1.43-2.05) had the strongest associations among the non-cancer comorbidities. Pancreatic (12.32; 7.11-21.36), stomach (8.57; 4.07-18.03), lung and bronchus (6.26; 4.16-9.43), and ovarian (6.72; 2.95-15.10) cancers were ranked as high-risk for VTE. Corticosteroids, gabapentinoids, psychotropic drugs, risedronic acid, and pramipexole were most strongly associated (aOR exceeding 1.5) with VTE. Insulin (3.86; 3.33-4.47) and sulphonylureas (2.62; 2.18-3.16) had stronger associations than metformin (1.65; 1.49-1.83). Statins and lercanidipine (0.78; 0.62-0.98) were associated with a lowered risk of VTE.
CONCLUSIONS
In this cohort, with 50% diabetes prevalence, pancreatic, stomach, lung and bronchus, and ovarian cancers were strongly associated with VTE. Corticosteroids, gabapentinoids, and psychotropic medications had the strongest associations with VTE among medications. This may be valuable for generating hypotheses for the further research. Lercanidipine may be a novel protective medication against VTE.
Topics: Humans; Female; Risk Factors; Male; Case-Control Studies; Neoplasms; Middle Aged; Aged; Comorbidity; Venous Thromboembolism; Pharmacoepidemiology; Risk Assessment; Diabetes Mellitus; Adult; Socioeconomic Factors; Social Determinants of Health
PubMed: 38904171
DOI: 10.1177/14791641241236894 -
International Journal of Biological... 2024Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options. As a first-line treatment for advanced HCC, Lenvatinib has been applicated in...
Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options. As a first-line treatment for advanced HCC, Lenvatinib has been applicated in clinic since 2018. Resistance to Lenvatinib, however, has severely restricted the clinical benefits of this drug. Therefore, it is urgent to explore the potential resistance mechanisms of Lenvatinib and identify appropriate methods to reduce resistance for the treatment of HCC. We identified SAHA, a HDAC inhibitor, to have effective anti-tumor activity against Lenvatinib-resistant HCC organoids by screening a customized drug library. Mechanism analysis revealed that SAHA upregulates PTEN expression and suppresses AKT signaling, which contributes to reversing Lenvatinib resistance in liver cancer cells. Furthermore, combinational application of Lenvatinib and HDAC inhibitor or AKT inhibitor synergistically inhibits HCC cell proliferation and induces cell apoptosis. Finally, we confirmed the synergistic effects of Lenvatinib and SAHA, or AZD5363 in primary liver cancer patient derived organoids. Collectively, these findings may enable the development of Lenvatinib combination therapies for HCC.
Topics: Quinolines; Phenylurea Compounds; Humans; Carcinoma, Hepatocellular; Histone Deacetylase Inhibitors; Liver Neoplasms; Proto-Oncogene Proteins c-akt; Cell Line, Tumor; Apoptosis; Cell Proliferation; Animals; Vorinostat; Drug Synergism; Mice; Drug Resistance, Neoplasm
PubMed: 38904018
DOI: 10.7150/ijbs.93375 -
International Journal of Biological... 2024Pancreatic ductal adenocarcinoma (PDAC) poses significant challenges in terms of prognosis and treatment. Recent research has identified splicing deregulation as a new...
Pancreatic ductal adenocarcinoma (PDAC) poses significant challenges in terms of prognosis and treatment. Recent research has identified splicing deregulation as a new cancer hallmark. Herein, we investigated the largely uncharacterized alternative splicing profile and the key splicing factor SF3B1 in PDAC pancreatic cells and tissues as a potential discovery source of plausible drug targets and new predictive biomarkers of clinical outcome. The research involved a transcriptome-wide analysis, comparing profiles of splicing profiles in PDAC primary cells with normal ductal cells. This revealed more than 400 significant differential splicing events in genes involved in regulation of gene expression, primarily related to mRNA splicing, and metabolism of nucleic acids. PDAC cultures were highly sensitive to the SF3B1 modulators, E7107 and Pladienolide-B, showing IC50s in the low nanomolar range. These compounds induced apoptosis, associated to induction of the MCL-1/S splice variant. and reduced cell migration, associated to RON mis-splicing. In an orthotopic mouse model, E7107 showed promising results. Furthermore, we evaluated SF3B1 expression in specimens from 87 patients and found a significant association of SF3B1 expression with progression-free and overall survival. In conclusion, SF3B1 emerges as both a potential prognostic factor and therapeutic target in PDAC, impacting cell proliferation, migration, and apoptosis. These findings warrant future studies on this new therapeutic strategy against PDAC.
Topics: Humans; RNA Splicing Factors; Pancreatic Neoplasms; Animals; Mice; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Epoxy Compounds; Prognosis; Phosphoproteins; Macrolides; Apoptosis; RNA Splicing; Alternative Splicing; Female; Cell Movement
PubMed: 38904016
DOI: 10.7150/ijbs.92671