JS-K Combined with a Melanin-Based Theranostic Agent: A Novel Sequential Delivery Strategy to Enhance the Near-Infrared Fluorescence Imaging of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5 year survival rate less than 12%. This malignancy is closely related to the unique tumor microenvironment (TME), which is characterized by a hypovascular and hyperdense extracellular matrix, making it difficult for drugs to permeate the tumor center. Near-infrared fluorescence (NIRF) imaging, which has high sensitivity and resolution, may improve the survival rate of PDAC patients. In this study, we first used JS-K (O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl) piperazine-1-yl] diazene-1-ium-1,2-diolate) to specifically dilate blood vessels within the TME of PDAC patients and subsequently injected IR820-PEG-MNPs (IPM NPs) to diagnose and treat orthotopic PDAC. We found that JS-K promoted the accumulation of IPM NPs in orthotopic Pan02 tumor-bearing mice and was able to increase the tumor signal-to-background ratio (SBR) in the orthotopic PDAC area by 41.5%. In addition, surgical navigation in orthotopic Pan02 tumor-bearing mice and complete tumor resection based on fluorescence imaging were achieved with a detection sensitivity of 81.0%. Moreover, we verified the feasibility of the combination of laparoscopy and photothermal ablation (PTA) for the treatment of PDAC. Finally, we demonstrated that IPM NPs had greater affinity for human PDAC tissues than for normal pancreatic tissues ex vivo, preliminarily highlighting the potential for clinical translation of these NPs. In conclusion, we developed and validated a novel sequential delivery strategy that promotes the accumulation of nanoagents in the tumor area and can be used for the diagnosis and treatment of PDAC.

Analysis of the clinical efficacy of laparoscopic middle pancreatectomy in the treatment of benign or low-grade malignant tumors of the pancreas.

Objective: The aim of this study was to investigate the clinical efficacy of laparoscopic middle pancreatectomy in the treatment of benign and junctional tumors of the pancreas. Methods: Retrospective analysis of basic data, tumor diameter, statistical analysis, and evaluation of efficacy-related indicators such as operative time, intraoperative bleeding, pathological findings, postoperative hospital stay, postoperative pancreatic fistula incidence, and pancreatic endocrine function was carried out on 17 patients diagnosed with benign or low-grade malignant tumors of the pancreas and laparoscopic middle pancreatic resection from January 2018 to January 2023 at the First Affiliated Hospital of Hunan Normal University. Results: A total of 17 patients were screened. There were eight males and nine females; mean age was 42.8 ± 17.4 years (range: 15-69 years); BMI was 22.6 ± 2.5 kg/m2 (range: 18.4-27.5 kg/m2), and the tumor size was 3.4 ± 1.2 cm (range: 1.5-5.5 cm). Preoperative glycan antigen CA19-9 was negative and CA125 was negative. Surgical time was 393.2 ± 57.9 min; intraoperative bleeding was 211.7 ± 113.9 ml; tumor diameter size was 3.4 ± 1.2 cm; postoperative admission time was 19.4 ± 7.6 days; postoperative pancreatic fistula (POPF) grading was 17 cases, including nine cases of A-grade fistula, three cases of B-grade fistula, and none of C-grade fistula; postoperative pathology results were five cases of plasmacytoma, three cases of mucinous cystadenoma, four cases of SPN (solid pseudopapillary neoplasm), one case of Intraductal Papillary Mucinous Neoplasm (IPMN), three cases of pancreatic Neuroendocrine Neoplasm (pNEN), one case of inflammatory myofibroblastic osteoblastoma. All cases did not develop pancreatic origin diabetes or exacerbation of previous diabetes, and no cases presented symptoms of exocrine insufficiency such as dyspepsia and diarrhea. Conclusion: Laparoscopic middle pancreatectomy is safe and feasible in the treatment of benign or low-grade malignant tumors in the body of the pancreatic neck and is not accompanied by increased risk of intraoperative and postoperative complications and endocrine dysfunction of the pancreas.

PARP1 controls the transcription of CD24 by ADP-ribosylating the RNA helicase DDX5 in pancreatic cancer.

The PARP1 protein plays a key role in DNA damage repair and ADP-ribosylation to regulate gene expression. Strategies to target PARP1 have rapidly been developed for cancer treatment. However, the role of the innate immune response in targeted anti-PARP1 therapy remains poorly understood. In this work, we aimed to elucidate the regulatory mechanism underlying the immunogenicity of PARP1 and explore efficient therapeutic strategies to enhance the antitumor effect of PARP inhibitors. The relationships between PARP1 expression and immunosuppressive factors were examined by qRTPCR and immunoblot analysis. DNA pull-down, chromatin immunoprecipitation-quantitative PCR (ChIPqPCR) and luciferase reporter assays were employed to reveal the mechanism by which the expression of the immune checkpoint regulator CD24 is regulated by PARP1. Phagocytosis assays and pancreatic cancer animal models were applied to evaluate the therapeutic effect of simultaneous disruption of PARP1 and the antiphagocytic factor CD24. Upregulation of the innate immunosuppressive factor CD24 was observed in pancreatic cancer during PARP1 inhibition. The activating effect of targeting CD24 on macrophage phagocytosis was verified. Then, we showed that PARP1 attenuated the transcription of CD24 by ADP-ribosylating the transcription factor DDX5 in pancreatic cancer. Combined blockade of PARP1 and the antiphagocytic factor CD24 elicited a synergetic antitumor effect in pancreatic cancer. Our research provided evidence that combination treatment with PARP inhibitors and CD24 blocking monoclonal antibodies (mAbs) could be an effective strategy to improve the clinical therapeutic response in pancreatic cancer.

Prognostic value of KRAS subtype in patients with PDAC undergoing radical resection.

Objective: To explore the frequency distribution of KRAS mutant subtypes in patients with resectable PDAC in China and then evaluate the prognostic value of different KRAS subtypes in patients with PDAC undergoing radical resection. Methods: The clinicopathological data and gene test reports of 227 patients undergoing PDAC radical surgery at Hunan Provincial People's Hospital from 1 January 2016 to 1 January 1 2020 were retrospectively evaluated. There were 118 men (52%) and 109 women (48%). The mean age was 58.8 ± 10.3 years. After univariate analysis of the clinicopathological factors (sex, age, presence or absence of underlying disease, location of the primary tumour, tumour TNM stage, T stage, N stage, presence or absence of vascular invasion, presence or absence of nerve invasion, surgical margin, KRAS mutation subtype), variables with P < 0.1 were included in the multivariate Cox regression model analysis, and the log-rank sum test and Kaplan-Meier curves were used to assess the correlation of the KRAS mutation subtype with the overall survival time. Results: KRAS mutations were detected in 184 of 227 patients (81.1%) (G12D: 66; G12V: 65; G12R: 27; Q61:26) and were not detected in 43 patients (18.9%). KRAS mutations were associated with tumour differentiation (P = 0.001), TNM stage (P = 0.013), and T stage (P < 0.001). Multivariate Cox regression model analysis showed that N stage, surgical margin, tumour differentiation, and KRAS-G12D mutation were independent prognostic factors for DFS and OS. Patients with the KRAS-G12D subtype had shorter OS with a median OS of 12 months (HR: 0.55, CI: 0.39-0.77, P < 0.001), and patients with KRAS wild-type had longer OS with a median OS of 19 months (HR: 0.57, CI: 0.42-0.76, P < 0.001). Conclusion: KRAS wild-type individuals are more prevalent in the Chinese population than in European or American populations. Patients undergoing surgery had a reduced percentage of tumors with KRAS-G12D. When determining the prognosis of individuals with radically resected PDAC, reference markers for KRAS mutation subtypes can be employed.

KRAS as a Key Oncogene in the Clinical Precision Diagnosis and Treatment of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors, with a 5-year survival rate of less than 10%. At present, the comprehensive treatment based on surgery, radiotherapy and chemotherapy has encountered a bottleneck, and targeted immunotherapy turns to be the direction of future development. About 90% of PDAC patients have KRAS mutations, and KRAS has been widely used in the diagnosis, treatment, and prognosis of PDAC in recent years. With the development of liquid biopsy and gene testing, KRAS is expected to become a new biomarker to assist the stratification and prognosis of PDAC patients. An increasing number of small molecule inhibitors acting on the KRAS pathway are being developed and put into the clinic, providing more options for PDAC patients.