Hepatocellular carcinoma (HCC) is one of the significant threats to human health worldwide, and its conventional treatments have obvious limitations. With the development of nanomedicine, the strategy of integrating multiple therapeutic approaches into a single nanoplatform is expected to lead to more efficient treatment of tumors. This study utilizes the nanomaterial PCN-224 as a carrier, labels it with 177Lu, and modifies its surface with sorafenib (SOR) to construct an integrated diagnostic and therapeutic nanoplatform. The surface modification of SOR not only functions as targeted therapy (TT), but also enhances the active targeting of the nanoparticles and their accumulation at the tumor site. This in vivo distribution could be monitored by dual-modality imaging using fluorescence imaging and SPECT/CT imaging. The long retention allows 177Lu-mediated radioisotope therapy (RIT) to continue working inside the tumor, thereby improving the limitations of photodynamic therapy (PDT), where the depth of light penetration is limited. Additionally, all three therapeutic modalities can act as inducers of immunogenic cell death (ICD), thereby further enhancing the therapeutic effects by activating the immune response. In conclusion, this work designs a combined triple therapy of PDT-RIT-TT to treat HCC through the direct killing effect and the indirect effect of ICD, utilizing multiple synergistic effects to improve the shortcomings of single therapy, and shows promising prospects for clinical application.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with poor prognosis and inadequate response to treatment, such as gemcitabine (Gem), the first-line chemotherapeutic drug. Understanding the molecular determinants that control drug resistance to Gem is critical to predict potentially responsive patients and improve the benefits of Gem therapy. Emerging evidence suggests that certain developmental pathways, such as Hippo signaling, are aberrated and play important roles in Gem resistance in cancers. Although Hippo signaling has been reported to play a role in chemoresistance in cancers, it has not been clarified which specific target gene(s) functionally mediates the effect. In the present study, we found that YAP serves as a potent barrier for the cellular sensitivity of PDAC cells to Gem. We then identified and characterized laminin subunit beta 3 (LAMB3) as a bona fide target of YAP-TEAD4 to amplify YAP signaling via a feedback loop. Such a YAP-LAMB3 axis is critical to induce epithelial-mesenchymal transition and mediate Gem resistance. Taken together, we uncovered that YAP-LAMB3 axis is an important regulator of Gem, thus providing potential therapeutic targets for overcoming Gem resistance in PDAC.

Supplemental Figure S2. TIGAR expression was regulated by TP53 in HepG2 cells.

<p>Supplemental Figure S5. NAC reduced TIGAR knockdown-induced alterations in ROS levels, GSH/GSSH ratio, NADPH levels and cell survival after epirubicin treatment.</p>

<p>Supplemental Figure S1. Epirubicin inhibited cell viability and induced TIGAR expression in A549 cells.</p>

Supplemental Figure S4. Knockdown of TIGAR enhanced epirubicin-induced activation of caspase 3 and apoptosis.

<p>Supplemental Figure S1. Epirubicin inhibited cell viability and induced TIGAR expression in A549 cells.</p>

Objective:To explore the safety and effectiveness of laparoscopy combined with choledochoscope in the treatment of pancreatic duct stones.Methods:Retrospective analysis of clinical data of 8 cases of chronic pancreatitis with pancreatic duct stones treated by laparoscopy combined with choledochoscope in the Department of Hepatobiliary and Pancreatic Surgery of the Second Affiliated Hospital of Soochow University from June 2018 to March 2023, including operation time, postoperative hospital stay, intraoperative bleeding, postoperative complications, residual stones, pain relief, blood sugar status, etc.Results:Among the 8 cases, one case of pancreatic cancer with liver metastasis was found during operation, and the operation was terminated. The other 7 cases successfully completed laparoscopy combined with choledochoscopy+ holmium laser lithotripsy+ Roux-en-Y pancreatojejunostomy. The diameter of pancreatic duct stones (7.64±2.17) mmand pancreatic duct diameters (8.8 ± 2.80) mm were counted. The average surgical time (222±67.5)minutes and the average postoperative hospital stay (16 ± 7.8) days. During the follow-up period (3-64) months, the symptoms of 6 patients were significantly relieved, and no significant abdominal pain occurred; One patient had a history of acute pancreatitis, with a significantly lower frequency of episodes compared to before surgery; All patients showed no obvious recurrence of stones on abdominal CT.Conclusion:Laparoscopy combined with choledochoscopy is a safe and effective method for the treatment of chronic pancreatitis with pancreatic duct stones.

<p>Legends for Supplemental Figures S1-S5</p>

Transplantation of splenic tissue is a rare condition that usually occurs after splenic trauma and splenectomy. It usually requires surgery for diagnosis and treatment. A 38-year-old Asian male with familial hemolytic disease underwent laparoscopic splenectomy for a traumatic rupture of the spleen one year prior. The patient developed middle-upper abdominal pain without any obvious cause, radiating to the back and chest seven months prior to presentation. The condition improved with conservative treatment but the patient experienced recurrent episodes. Abdominal CT suggested multiple gallstones in the gallbladder that changed after splenectomy and multiple nodules in the original splenic area; thus, transplantation of splenic tissue was considered. MRI suggested thick gall bladder bile, multiple stones and cholecystitis, and the spleen was not observed (the patient underwent laparoscopic splenectomy at our hospital one year previously due to traumatic splenic rupture); furthermore, there were multiple abnormal signal foci in the splenic area, so the possibility of spleen implantation was considered. Considering the patient's family history of a hereditary hemolytic disease, laparoscopic cholecystectomy was performed simultaneously with laparoscopic accessory splenectomy. The final pathological report revealed chronic cholecystitis, mixed calculi, red pulp dilation, hyperemia and bleeding in round tissue with blood clot formation and acute and chronic inflammatory cell infiltration. Clinicians must bear in mind the possibility of splenosis after splenic trauma and its image variations.

Background : Natural products often have novel frameworks and unique mechanisms, It is an important way to develop new anti-tumor drugs.The paper explored the effect of Icariin on HepG2 cell apoptosis and cell cycle arrest. Material and methods : Human liver cancer HepG2 cells were studied. The biological activity of Icariin on HepG2 cells was comprehensively investigated. The mechanism was preliminarily explored from the aspects of proliferation, cell cycle, and apoptosis. Results : Icariin showed significant inhibitory effect on cell proliferation after administration, and the effect was time-and-concentration-dependent. Annexin V-PI detection showed that, after 48 hours of administration of Icariin at different concentrations, the apoptosis rate of HepG2 cells increased in a concentration-dependent manner. The results of Hoechst 33342 staining showed that, after 48 hours of intervention with Icariin at different concentrations, HepG2 cells appeared densely stained and granular fluorescence, characterizing apoptosis. In the JC-1 mitochondrial membrane potential experiment, Icariin was found to destroy cell mitochondrial membrane potential and induce HepG2 cell apoptosis. After 48 h administration of Icariin at different concentrations, Bcl-2 and survivin proteins were down-regulated, and Bax was up-regulated, both in a concentration-dependent manner. PI single staining combined with flow cytometry to detect cell cycle results showed that, Icariin can induce G2/M phase arrest of HepG2 cells, and is time-and-concentration-dependent. Western Blot detection revealed that Icariin can down-regulate the cycle-related proteins Cyclin B and CDK1 in a concentration-dependent manner, and also significantly down-regulate the expressions of p-AKT, AKT, p-ERK and ERK proteins. Conclusion : Icariin is a selectively potential active compound that can treat liver cancer. The paper provided theoretical basis and experimental support for the clinical application of Icariin in the drug treatment of liver cancer. It is necessary to further study the antitumor effect of Icariin, explore and find the target, and provide higher selectivity for the treatment of liver cancer by Icariin.

Background: To study the role of TP53-induced glycolysis and apoptosis regulator (TIGAR) in hepatocellular carcinoma (HCC) and drug resistance. Methods: HCC cells (HepG2 and SMMC7721) were used in this study. Fura 2-AM was used to assess cytosolic free Ca 2+ concentrations ([Ca 2+ ]i) within the two HCC cell lines. Nimodipine (NMDP), a Ca 2+ antagonist, was used to reduce cytosolic [Ca 2+ ]i level. Proliferation of HCC was measured using cell counting kit-8 (CCK-8). The roles of TIGAR and Ca 2+ in drug resistance of HCC cells were assessed using epirubicin (Epi), 5-fluorouracil (5-FU), or cisplatinum (DDP). Results: Knockdown of TIGAR significantly suppressed cell viability, reduced [Ca 2+ ]i, restrained protein expression of Ca 2+ -activated cysteine proteinases (Calpain1 and 2), as well as blocked the activation of nuclear factor kappa B (NF-κB) through an increase of cytoplasmic NF-κB and reduction of nuclear NF-κB. However, overexpression of TIGAR (oeTIGAR) resulted in the opposite. Evidence also shows that oeTIGAR suppressed the sensitivity of HCC to Epi, which was retarded by NMDP as an additional treatment. TIGAR interference could enhance the sensitivity of HCCs with high TIGAR expression to drugs. Conclusions: TIGAR promoted HCC progression and induced drug resistance, and the mechanism involved was [Ca 2+ ]i-mediated activation of Calpain 1 and 2 and NF-κB signaling.

Background Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with high mortality worldwide. Accumulating researches have indicated that long non‑coding RNAs (lncRNAs) are involved in varies human cancers, including HCC. Nevertheless, the specific molecular mechanism of lncRNA lysyl oxidase like 1 antisense RNA 1 (LOXL1-AS1) in HCC is still unclear. Methods LOXL1-AS1 expression was tested via qRT-PCR in HCC cells. Functional and mechanism assays were respectively done to evaluate the biological functions of HCC cells and the potential interaction of LOXL1-AS1 and other factors. Results We discovered that LOXL1-AS1 was high expressed in HCC cells. Inhibition of LOXL1-AS1 repressed cell proliferation, migration and invasion, but enhanced cell apoptosis in HCC. Further, miR-3614-5p was proven to be sponged by LOXL1-AS1. Additionally, Yin Yang 1 (YY1) was proven as the target gene of miR-3614-5p, and YY1 depletion could repress HCC cell malignant behaviors. YY1 could also transcriptionally activate LOXL1-AS1 expression. In rescue assays, we confirmed that overexpression of YY1 or miR-3614-5p inhibition could reverse the suppressive effects of LOXL1-AS1 silence on the malignant behaviors of HCC cells. Conclusion In short, LOXL1-AS1/miR-3614-5p/YY1 forms a positive loop in modulating HCC cell malignant behaviors.

The nuclear receptor-binding SET domain 3 (NSD3) catalyzes methylation of histone H3 at lysine 36 (H3K36), and promotes malignant transformation and progression of human cancer. Its expression, potential functions and underlying mechanisms in pancreatic cancer are studied. Bioinformatics studies and results from local human tissues show that NSD3 is upregulated in human pancreatic cancer tissues, which is correlated with poor overall survival. In primary and established pancreatic cancer cells, NSD3 silencing (by shRNAs) or CRISPR/Cas9-induced NSD3 knockout potently inhibited cell proliferation, migration and invasion, while provoking cell cycle arrest and apoptosis. Conversely, ectopic expression of NSD3-T1232A mutation significantly accelerated proliferation, migration, and invasion of pancreatic cancer cells. H3K36 dimethylation, expression of NSD3-dependent genes ( Prkaa2 , Myc , Irgm1 , Adam12 , and Notch3 ), and mTOR activation (S6K1 phosphorylation) were largely inhibited by NSD3 silencing or knockout. In vivo, intratumoral injection of adeno-associated virus (AAV)-packed NSD3 shRNA potently inhibited pancreatic cancer xenograft growth in nude mice. These results suggest that elevated NSD3 could be an important driver for the malignant progression of pancreatic cancer.

目的 探讨骨髓母细胞增生症病毒癌基因同源物样2(MYB proto-oncogene like 2,MYBL2)在透明细胞性肾细胞癌(clear cell renal cell carcinoma,ccRCC)中的表达及其与临床病理特征的相关性.方法 应用qRT-PCR法检测ccRCC及癌旁正常肾组织中MYBL2 mRNA的表达水平;运用免疫组化法观察MYBL2蛋白表达,分析其表达与临床病理特征及预后的关系;利用TCGA数据库进一步验证MYBL2 mRNA的表达及其与患者预后的关系.通过计算Pearson相关系数获得与MYBL2表达显著相关的基因,且对这些基因进行GO分析.结果 与正常肾组织相比,MYBL2 mRNA在ccRCC组织中高表达(P=0.020),MYBL2蛋白在ccRCC组织中高表达(P=0.004),且其表达与远处转移相关(P=0.025).MYBL2蛋白高表达是ccRCC患者的不良预后因素.TCGA数据库分析结果进一步证实,MYBL2 mRNA在ccRCC中的表达高于正常肾组织(P<0.001),且MY-BL2基因高表达ccRCC患者的生存时间显著缩短(P<0.001).相关系数及GO分析显示,ccRCC组织中,MYBL2相关基因明显富集在ATP酶活性、丝氨酸/苏氨酸激酶活性、有丝分裂细胞周期转变的调控等功能簇.结论 MYBL2在ccRCC中高表达,可能参与了ccRCC的发生、发展和转归.

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Colorectal carcinoma (CRC) is one of the most common cancers, and is associated with a poor clinical outcome. The key genes and potential prognostic markers in colorectal carcinoma remain to be identified and explored for clinical application. DNA expression/methylation profiles were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed/methylated genes (DEGs and DEMs). A total of 255 genes and 372 genes were identified as being up-regulated and down-regulated, respectively, in GSE113513, GSE81558, and GSE89076. There were a total of 3350 hypermethylated genes and 443 hypomethylated genes identified in GSE48684. Twenty genes were found to be hypermethylated as well as down-regulated, and a functional enrichment analysis revealed that these genes were mainly involved in cancer-related pathways. Among these 20 genes, GPM6A, HAND2 and C2orf40 were related to poor outcomes in cancer patients based on a survival analysis. Concurrent decreases of GPM6A, HAND2 and C2orf40 protein expression were observed in highly-differentiated colorectal carcinoma tissues, and higher expression levels were found in undifferentiated or minimally-differentiated colorectal carcinoma tissues. In conclusion, 20 genes were found to be downregulated and hypermethylated in CRC, among which GPM6A, HAND2 and C2orf40 were explored for their potential prognostic value.

目的 分析杂交技术治疗腹壁复杂切口疝的临床疗效.方法 回顾性分析2015年7月至2018年7月,苏州大学附属第二医院采用杂交技术修补腹壁复杂切口疝61例患者的临床资料.结果 61例复杂切口疝患者手术顺利,其中巨大切口疝46例,疝环缺损(14.46±2.22)cm,复发疝9例,造口旁疝6例,手术时间(140.74±43.24)min,术中出血(59.02±35.20)ml,术后疼痛评分(3.97±0.91)分,术后住院时间(7.54±2.88)d.术后随访12～48个月,术后出现血清肿2例,切口感染1例,慢性疼痛2例,无死亡及复发病例.结论 杂交技术修补腹壁复杂切口疝是一种安全、可靠的手术方式,值得临床推广.

Background: Pancreatic Ductal Adenocarcinoma (PDAC) is the most common form of pancreatic cancer and leading causes of pancreatic cancer death because of most PDAC patients with advanced unresectable disease at that time, which is remarkably resistant to all forms of chemotherapy and radiotherapy. Objective: PDAC increases the social and patient's family burden. However, the PDAC pathogenesis is not identified. We are trying to uncover the underlying mechanism in the future. Methods: In our research, the drug-resistant cell line was successfully induced in the vitro by progressive concentrations of Afatinib, which we named it as BxPC3-AR. Results: It has been observed that the effect of autophagy was on the resistance of BxPC3-AR to Afatinib. Conclusion: It has been confirmed that autophagy plays a certain role in BxPC3-AR resistance to Afatinib. Our findings provide a new perspective on the role of autophagy in pancreatic ductal adenocarcinoma.

Background Circular RNAs (circRNAs) play an important role in the tumorigenesis of pancreatic cancer. However, the expression profiles and roles of circRNAs in pancreatic cancer remain largely unknown. Methods To identify differentially expressed circRNAs (DEcircRNAs) between pancreatic cancer and matched normal tissues, bioinformatics analysis was performed. Hsa_circ_0000069 was identified by 0.bioinformatics analysis. In addition, the level of hsa_circ_0000069 in pancreatic cancer tissues and cell lines, and pancreatic cancer cell-derived exosomes were assessed using RT-qPCR assay. Results The expression of hsa_circ_0000069 was markedly upregulated in pancreatic cancer tissues and cell lines. SCL/TAL1 interrupting locus (STIL) is the parent gene for hsa_circ_0000069, and its high expression was related to poor overall survival in patients with pancreatic cancer. In addition, downregulation of hsa_circ_0000069 markedly suppressed STIL expression, induced the apoptosis and cell cycle arrest, and inhibited the proliferation, migration and invasion in pancreatic cancer cells. Moreover, hsa_circ_0000069 knockdown inhibited the growth of xenograft pancreatic cancer tumors in vivo. Furthermore, human pancreatic duct epithelial cells (HPDE) are capable of internalizing SW1990 cell-derived exosomes, allowing the transfer of hsa_circ_0000069. Significantly, SW1990 cell-derived exosomes promoted the proliferation, migration and cell cycle progression of HPDE cells, whereas exosomes with downregulated hsa_circ_0000069 suppressed the proliferation, migration and cell cycle progression of HPDE cells, by suppressing STIL expression. Conclusion Our results suggest that hsa_circ_0000069 knockdown could inhibit pancreatic cancer tumorigenesis and exosomes with downregulated hsa_circ_0000069 could suppress HPDE cell malignant transformation. Collectively, hsa_circ_0000069 might be a therapeutic target for the treatment of pancreatic cancer.