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Journal of Nanobiotechnology Jun 2024Chemotherapy and immunotherapy have shown no significant outcome for unresectable pancreatic ductal adenocarcinoma (PDAC). Multi-drug combination therapy has become a...
Chemotherapy and immunotherapy have shown no significant outcome for unresectable pancreatic ductal adenocarcinoma (PDAC). Multi-drug combination therapy has become a consensus in clinical trials to explore how to arouse anti-tumor immunity and meanwhile overcome the poorly tumoricidal effect and the stroma barrier that greatly hinders drug penetration. To address this challenge, a comprehensive strategy is proposed to fully utilize both the ferroptotic vulnerability of PDAC to potently irritate anti-tumor immunity and the desmoplasia-associated focal adhesion kinase (FAK) to wholly improve the immunosuppressive microenvironment via sustained release of drugs in an injectable hydrogel for increasing drug penetration in tumor location and averting systematic toxicity. The injectable hydrogel ED-M@CS/MC is hybridized with micelles loaded with erastin that exclusively induces ferroptosis and a FAK inhibitor defactinib for inhibiting stroma formation, and achieves sustained release of the drugs for up to 12 days. With only a single intratumoral injection, the combination treatment with erastin and defactinib produces further anti-tumor performance both in xenograft and Kras-engineered primary PDAC mice and synergistically promotes the infiltration of CD8 cytotoxic T cells and the reduction of type II macrophages. The findings may provide a novel promising strategy for the clinical treatment of PDAC.
Topics: Animals; Hydrogels; Carcinoma, Pancreatic Ductal; Mice; Pancreatic Neoplasms; Humans; Cell Line, Tumor; Tumor Microenvironment; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Synergism; Micelles; Immunotherapy
PubMed: 38902759
DOI: 10.1186/s12951-024-02646-7 -
BMC Medical Informatics and Decision... Jun 2024Machine Learning (ML) plays a crucial role in biomedical research. Nevertheless, it still has limitations in data integration and irreproducibility. To address these...
BACKGROUND
Machine Learning (ML) plays a crucial role in biomedical research. Nevertheless, it still has limitations in data integration and irreproducibility. To address these challenges, robust methods are needed. Pancreatic ductal adenocarcinoma (PDAC), a highly aggressive cancer with low early detection rates and survival rates, is used as a case study. PDAC lacks reliable diagnostic biomarkers, especially metastatic biomarkers, which remains an unmet need. In this study, we propose an ML-based approach for discovering disease biomarkers, apply it to the identification of a PDAC metastatic composite biomarker candidate, and demonstrate the advantages of harnessing data resources.
METHODS
We utilised primary tumour RNAseq data from five public repositories, pooling samples to maximise statistical power and integrating data by correcting for technical variance. Data were split into train and validation sets. The train dataset underwent variable selection via a 10-fold cross-validation process that combined three algorithms in 100 models per fold. Genes found in at least 80% of models and five folds were considered robust to build a consensus multivariate model. A random forest model was constructed using selected genes from the train dataset and tested in the validation set. We also assessed the goodness of prediction by recalibrating a model using only the validation data. The biological context and relevance of signals was explored through enrichment and pathway analyses using QIAGEN Ingenuity Pathway Analysis and GeneMANIA.
RESULTS
We developed a pipeline that can detect robust signatures to build composite biomarkers. We tested the pipeline in PDAC, exploiting transcriptomics data from different sources, proposing a composite biomarker candidate comprised of fifteen genes consistently selected that showed very promising predictive capability. Biological contextualisation revealed links with cancer progression and metastasis, underscoring their potential relevance. All code is available in GitHub.
CONCLUSION
This study establishes a robust framework for identifying composite biomarkers across various disease contexts. We demonstrate its potential by proposing a plausible composite biomarker candidate for PDAC metastasis. By reusing data from public repositories, we highlight the sustainability of our research and the wider applications of our pipeline. The preliminary findings shed light on a promising validation and application path.
Topics: Humans; Machine Learning; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Biomarkers, Tumor
PubMed: 38902676
DOI: 10.1186/s12911-024-02578-0 -
Scientific Reports Jun 2024Tumor-derived extracellular vesicles (EVs) show great potential as biomarkers for several diseases, including pancreatic cancer, due to their roles in cancer development...
Tumor-derived extracellular vesicles (EVs) show great potential as biomarkers for several diseases, including pancreatic cancer, due to their roles in cancer development and progression. However, the challenge of utilizing EVs as biomarkers lies in their inherent heterogeneity in terms of size and concentration, making accurate quantification difficult, which is highly dependent on the isolation and quantification methods used. In our study, we compared three EV isolation techniques and two EV quantification methods. We observed variations in EV concentration, with approximately 1.5-fold differences depending on the quantification method used. Interestingly, all EV isolation techniques consistently yielded similar EV quantities, overall size distribution, and modal sizes. In contrast, we found a notable increase in total EV amounts in samples from pancreatic cancer cell lines, mouse models, and patient plasma, compared to non-cancerous conditions. Moreover, individual tumor-derived EVs exhibited at least a 3-fold increase in several EV biomarkers. Our data, obtained from EVs isolated using various techniques and quantified through different methods, as well as originating from various pancreatic cancer models, suggests that EV profiling holds promise for the identification of unique and cancer-specific biomarkers in pancreatic cancer.
Topics: Pancreatic Neoplasms; Extracellular Vesicles; Humans; Biomarkers, Tumor; Animals; Mice; Cell Line, Tumor; Epithelial Cell Adhesion Molecule; Glypicans; Integrin alphaV
PubMed: 38902362
DOI: 10.1038/s41598-024-65209-8 -
Scientific Reports Jun 2024This study aimed to confirm urinary protein fragments in relation to the presence of pancreatic ductal adenocarcinoma (PDAC) via a C-terminal proteomics strategy using...
This study aimed to confirm urinary protein fragments in relation to the presence of pancreatic ductal adenocarcinoma (PDAC) via a C-terminal proteomics strategy using exploratory and validation cohorts. Urinary fragments were examined by iTRAQ-labelling of tryptic peptides and concentrations of C-terminal fragments were evaluated. Only the urinary CD276 fragment showed a fold change (FC) of > 1.5 with a significant difference of P < 0.01 between healthy (H) and PDAC participants in both the exploratory (H, n = 42; PDAC, n = 39) and validation cohorts (H, n = 36; resectable PDAC, n = 28). The sensitivity and specificity of the CD276 fragment for diagnosing resectable PDAC were 75% and 89%, respectively, in the validation cohort. Postoperative urinary levels of the CD276 fragment were low as compared to those before surgery (n = 18, P < 0.01). Comprehensive C-terminus proteomics identified an increase in the urinary CD276 fragment level as a feature of patients with PDAC. The urinary CD276 fragment is a potential biomarker for detecting resectable PDAC.
Topics: Humans; Pancreatic Neoplasms; Proteomics; Female; Male; Biomarkers, Tumor; Aged; B7 Antigens; Middle Aged; Carcinoma, Pancreatic Ductal
PubMed: 38902359
DOI: 10.1038/s41598-024-65093-2 -
Nature Communications Jun 2024Functionally characterizing the genetic alterations that drive pancreatic cancer is a prerequisite for precision medicine. Here, we perform somatic CRISPR/Cas9...
Functionally characterizing the genetic alterations that drive pancreatic cancer is a prerequisite for precision medicine. Here, we perform somatic CRISPR/Cas9 mutagenesis screens to assess the transforming potential of 125 recurrently mutated pancreatic cancer genes, which revealed USP15 and SCAF1 as pancreatic tumor suppressors. Mechanistically, we find that USP15 functions in a haploinsufficient manner and that loss of USP15 or SCAF1 leads to reduced inflammatory TNFα, TGF-β and IL6 responses and increased sensitivity to PARP inhibition and Gemcitabine. Furthermore, we find that loss of SCAF1 leads to the formation of a truncated, inactive USP15 isoform at the expense of full-length USP15, functionally coupling SCAF1 and USP15. Notably, USP15 and SCAF1 alterations are observed in 31% of pancreatic cancer patients. Our results highlight the utility of in vivo CRISPR screens to integrate human cancer genomics and mouse modeling for the discovery of cancer driver genes with potential prognostic and therapeutic implications.
Topics: Pancreatic Neoplasms; Humans; Animals; CRISPR-Cas Systems; Mice; Cell Line, Tumor; Ubiquitin-Specific Proteases; Mutation; Gene Expression Regulation, Neoplastic; Deoxycytidine; Gemcitabine
PubMed: 38902237
DOI: 10.1038/s41467-024-49450-3 -
Oncotarget Jun 2024
Topics: Humans; Pancreatic Neoplasms; ATP-Binding Cassette Transporters; Carcinoma, Pancreatic Ductal; Molecular Targeted Therapy; Antineoplastic Agents; Animals
PubMed: 38900606
DOI: 10.18632/oncotarget.28597 -
Integrative Cancer Therapies 2024(SM) is a commonly used herb in traditional Chinese medicine (TCM) and has been used in the treatment of pancreatic cancer to relieve the symptom of "blood stasis and...
CONTEXT
(SM) is a commonly used herb in traditional Chinese medicine (TCM) and has been used in the treatment of pancreatic cancer to relieve the symptom of "blood stasis and toxin accumulation." Tanshinones (Tan), the main lipophilic constituents extracted from the roots and rhizomes of SM, have been reported to possess anticancer functions in several cancers. But the mechanism of how the active components work in pancreatic cancer still need to be clarified.
OBJECTIVE
In this study, we aimed to investigate the therapeutic potential of Tan in pancreatic cancer and elucidate the underlying mechanisms.
MATERIALS AND METHODS
The viabilities of PANC-1 and Bxpc-3 cells were determined by MTT assay, after treatment with various concentrations of Tan. The apoptotic cells were quantified by annexin V-FITC/PI staining and DAPI staining assays. The expression of relative proteins was used western blotting. Tumor growth was assessed by subcutaneously inoculating cells into C57BL/6 mice.
RESULTS
Our experiments discovered that Tan effectively suppressed pancreatic cancer cell proliferation and promoted apoptosis. Mechanistically, we propose that Tan enhances intracellular ROS levels by activating the AKT/FOXO3/SOD2 signaling pathway, ultimately leading to apoptosis in pancreatic cancer cells. In vivo assay showed the antitumor effect of Tan.
CONCLUSION
Tan, a natural compound from , was found to effectively suppress pancreatic cancer cell proliferation and promote apoptosis both in vitro and in vivo. Mechanistically, we propose a positive feedback loop mechanism. These findings provide valuable insights into the molecular pathways driving pancreatic cancer progression.
Topics: Pancreatic Neoplasms; Salvia miltiorrhiza; Abietanes; Apoptosis; Animals; Humans; Forkhead Box Protein O3; Mice; Proto-Oncogene Proteins c-akt; Signal Transduction; Cell Line, Tumor; Reactive Oxygen Species; Plant Extracts; Mice, Inbred C57BL; Cell Proliferation
PubMed: 38899834
DOI: 10.1177/15347354241258961 -
World Journal of Gastroenterology Jun 2024Pancreatic cancer (PC) is associated with some of the worst prognoses of all major cancers. Thymoquinone (TQ) has a long history in traditional medical practice and is...
BACKGROUND
Pancreatic cancer (PC) is associated with some of the worst prognoses of all major cancers. Thymoquinone (TQ) has a long history in traditional medical practice and is known for its anti-cancer, anti-inflammatory, anti-fibrosis and antioxidant pharmacological activities. Recent studies on hypoxia-inducible factor-1α (HIF-1α) and PC have shown that HIF-1α affects the occurrence and development of PC in many aspects. In addition, TQ could inhibit the development of renal cancer by decreasing the expression of HIF-1α. Therefore, we speculate whether TQ affects HIF-1α expression in PC cells and explore the mechanism.
AIM
To elucidate the effect of TQ in PC cells and the regulatory mechanism of HIF-1α expression.
METHODS
Cell counting kit-8 assay, Transwell assay and flow cytometry were performed to detect the effects of TQ on the proliferative activity, migration and invasion ability and apoptosis of PANC-1 cells and normal pancreatic duct epithelial (hTERT-HPNE) cells. Quantitative real-time polymerase chain reaction and western blot assay were performed to detect the expression of HIF-1α mRNA and protein in PC cells. The effects of TQ on the HIF-1α protein initial expression pathway and ubiquitination degradation in PANC-1 cells were examined by western blot assay and co-immunoprecipitation.
RESULTS
TQ significantly inhibited proliferative activity, migration, and invasion ability and promoted apoptosis of PANC-1 cells; however, no significant effects on hTERT-HPNE cells were observed. TQ significantly reduced the mRNA and protein expression levels of HIF-1α in PANC-1, AsPC-1, and BxPC-3 cells. TQ significantly inhibited the expression of the HIF-1α initial expression pathway (PI3K/AKT/mTOR) related proteins, and promoted the ubiquitination degradation of the HIF-1α protein in PANC-1 cells. TQ had no effect on the hydroxylation and von Hippel Lindau protein mediated ubiquitination degradation of the HIF-1α protein but affected the stability of the HIF-1α protein by inhibiting the interaction between HIF-1α and HSP90, thus promoting its ubiquitination degradation.
CONCLUSION
The regulatory mechanism of TQ on HIF-1α protein expression in PC cells was mainly to promote the ubiquitination degradation of the HIF-1α protein by inhibiting the interaction between HIF-1α and HSP90; Secondly, TQ reduced the initial expression of HIF-1α protein by inhibiting the PI3K/AKT/mTOR pathway.
Topics: Benzoquinones; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; HSP90 Heat-Shock Proteins; Pancreatic Neoplasms; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases; Cell Line, Tumor; Signal Transduction; Cell Proliferation; Apoptosis; Cell Movement; Phosphatidylinositol 3-Kinases; Gene Expression Regulation, Neoplastic; Neoplasm Invasiveness
PubMed: 38899332
DOI: 10.3748/wjg.v30.i21.2793 -
World Journal of Clinical Cases Jun 2024The diagnosis of pancreatic cancer associates an appalling significance. Detection of preinvasive stage of pancreatic cancer will ameliorate the survival of this deadly...
The diagnosis of pancreatic cancer associates an appalling significance. Detection of preinvasive stage of pancreatic cancer will ameliorate the survival of this deadly disease. Premalignant lesions such as Intraductal Papillary Mucinous Neoplasms or Mucinous Cystic Neoplasms of the pancreas are detectable on imaging exams and this permits their management prior their invasive development. Pancreatic intraepithelial neoplasms (PanIN) are the most frequent precursors of pancreatic adenocarcinoma (PDAC), and its particular type PanIN high-grade represents the malignant non-invasive form of PDAC. Unfortunately, PanINs are not detectable on radiologic exams. Nevertheless, they can associate indirect imaging signs which would rise the diagnostic suspicion. When this suspicion is established, the patient will be enrolled in a follow-up strategy that includes performing of blood test and serial imaging test such as computed tomography or magnetic resonance imaging, which will cost in the best-case scenario a burden of healthcare systems, and potential mortality in the worst-case scenario when the patient underwent resection surgery, worthless when there is no moderate or high grade dysplasia in the final histopathology. This issue will be avoid having at its disposal a diagnostic technique capable of detecting high-grade PanIN lesions, such is the cytology of pancreatic juice obtained by nasopancreatic intubation. Herein, we review the possibility of detection of early malignant lesions before they become invasive PADC.
PubMed: 38898835
DOI: 10.12998/wjcc.v12.i17.2935 -
World Journal of Clinical Cases Jun 2024Function-preserving pancreatectomy can improve the long-term quality of life of patients with benign or low-grade malignant tumors, such as intraductal papillary...
BACKGROUND
Function-preserving pancreatectomy can improve the long-term quality of life of patients with benign or low-grade malignant tumors, such as intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms. However, there is limited literature on laparoscopic spleen-preserving total pancreatectomy (L-SpTP) due to technical difficulties.
CASE SUMMARY
Patient 1 was a 51-year-old male diagnosed with IPMN based on preoperative imaging, showing solid nodules in the pancreatic head and diffuse dilation of the main pancreatic duct with atrophy of the distal pancreas. We performed L-SpTP with preservation of the splenic vessels, and the postoperative pathology report revealed IPMN with invasive carcinoma. Patient 2 was a 60-year-old male with multiple cystic lesions in the pancreatic head and body. L-SpTP was performed, and intraoperatively, the splenic vein was injured and required ligation. Postoperative pathology revealed a mucinous cystic tumor of the pancreas with low-grade dysplasia. Both patients were discharged on postoperative day 7, and there were no major complications during the perioperative period.
CONCLUSION
We believe that L-SpTP is a safe and feasible treatment for low-grade malignant pancreatic tumors, but more case studies are needed to evaluate its safety, efficacy, and long-term outcomes.
PubMed: 38898831
DOI: 10.12998/wjcc.v12.i17.3206