Background: Hilar cholangiocarcinoma (HC) is a highly aggressive malignancy with a poor prognosis, highlighting the urgent need to elucidate its molecular drivers. This study aimed to systematically identify and functionally validate key genes and pathways driving HC pathogenesis. Methods: RNA sequencing (RNA-seq) was performed on paired primary HC tumors and matched adjacent non-tumorous tissues to identify differentially expressed genes (DEGs). Subsequent bioinformatic analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction (PPI) network construction, were conducted to characterize the functional landscape and identify hub genes. Transwell assays and orthotopic metastatic models were used to investigate the functions of Contactin-1 (CNTN1) in HC invasion in vitro and metastasis in vivo. Results: RNA-seq analysis identified 35 DEGs in HC, mainly involved in cell adhesion, cytoskeletal regulation, and axon development. PPI network analysis identified six hub genes, including CNTN1, NCAM1, PLP1, GPM6B, SLC1A3, and PMP2. Furthermore, we demonstrated that CNTN1, a neuronal membrane glycoprotein, was markedly up-regulated in HC at both mRNA and protein levels, and its elevated expression correlated with poor prognosis. Gain- and loss-of-function studies demonstrated that CNTN1 promotes HC cell invasion in vitro and metastasis in vivo. Mechanistically, CNTN1 exerts its pro-invasive effects by activating the PI3K-AKT signaling pathway and inducing epithelial-mesenchymal transition (EMT). Conclusions: Our integrated analysis identifies CNTN1 as a critical oncogenic driver in HC, promoting metastasis through PI3K-AKT-mediated EMT. These findings nominate CNTN1 as a potential prognostic biomarker and therapeutic target in HC.

Background: Sunitinib remains an important VEGFR-targeted therapy for advanced clear cell renal cell carcinoma (ccRCC), but acquired resistance frequently limits its clinical benefit. The molecular mechanisms underlying sunitinib resistance remain insufficiently understood. Methods: Sunitinib-resistant ccRCC models were generated by serial in vivo selection using Caki-1 and 786-O xenografts. Transcriptomic profiling, integration with GSE76068, and siRNA-based screening were performed to identify candidate resistance drivers. DERL3 expression and function were validated using qRT-PCR, Western blot, immunohistochemistry, gain- and loss-of-function assays, xenograft models, and mechanistic analyses of endoplasmic reticulum stress, ROS, and apoptosis. Results: Serial in vivo selection established stable sunitinib-resistant Caki-1-SR and 786-O-SR cells with markedly increased IC50 values. Integrated transcriptomic analysis identified six consistently upregulated genes in resistant models and GSE76068, among which DERL3 knockdown most strongly restored sunitinib sensitivity. DERL3 was upregulated in resistant ccRCC cells and clinical resistant specimens. High intratumoral DERL3 expression was associated with poor response to neoadjuvant sunitinib and shorter progression-free and overall survival. Functionally, DERL3 overexpression increased sunitinib resistance in vitro and in vivo, whereas DERL3 silencing restored drug sensitivity. Mechanistically, DERL3 depletion activated pro-apoptotic endoplasmic reticulum stress, increased ROS accumulation, and enhanced caspase-dependent apoptosis. Suppression of endoplasmic reticulum stress reduced ROS generation and apoptosis induced by DERL3 knockdown. In resistant xenografts, DERL3-targeted inhibition enhanced the antitumor efficacy of sunitinib. Conclusions: DERL3 is a clinically relevant driver of acquired sunitinib resistance in ccRCC. Targeting DERL3 may restore sunitinib sensitivity by reactivating pro-apoptotic endoplasmic reticulum stress and ROS-dependent apoptosis.

Aim: Hepatocellular carcinoma (HCC) remains a formidable worldwide health challenge, characterized by inadequate treatment efficacy and unsatisfactory clinical prognosis. Our previous study implicated LINC01607 in lenvatinib resistance, but its role in HCC progression and ferroptosis-associated vulnerability remains unclear. Methods: LINC01607 expression was examined in HCC patient samples and The Cancer Genome Atlas datasets. Cellular, animal, and patient-derived organoid (PDO) models were used to evaluate its biological function. RNA sequencing, ferroptosis-related assays, rescue experiments, and drug-sensitivity analyses were performed to explore associated downstream pathways. Results: LINC01607 was upregulated in HCC tissues and associated with aggressive clinicopathological features and poor survival. Functional assays showed that LINC01607 promoted HCC cell proliferation, migration, invasion, tumor growth, and metastasis. LINC01607 depletion induced ferroptosis-associated changes, including increased lipid peroxidation, glutathione depletion, and Fe2+ accumulation under ferroptotic stress, which were partially reversed by ferroptosis inhibitors. LINC01607 knockdown also enhanced sensitivity to RSL3 and sorafenib, while ferrostatin-1 partially rescued the increased sorafenib sensitivity. RNA sequencing and rescue experiments suggested involvement of the p62-Keap1-Nrf2 pathway. LINC01607 depletion was associated with reduced SQSTM1/p62, Nrf2, and ferroptosis-resistance proteins, whereas p62 overexpression partially reversed these effects and Nrf2 knockdown abrogated the rescue. In xenograft and PDO models, LINC01607 depletion improved the response to sorafenib. Conclusion: LINC01607 contributes to HCC progression and ferroptosis-associated therapy resistance, at least in part through the p62-Keap1-Nrf2 pathway, supporting further investigation of LINC01607 as a potential therapeutic target.

Hepatoprotective regimens are frequently used during chemotherapy for breast cancer, but their effects on oncologic outcomes remain unclear. S-adenosylmethionine (SAMe), a universal methyl donor, may influence treatment response through epigenetic and epitranscriptomic regulations. We retrospectively analyzed data from 1013 consecutive women with primary breast cancer treated at Zhengzhou University People’s Hospital between January 1, 2018 and January 1, 2020, and who underwent surgery followed by standard adjuvant chemotherapy. Overall survival (OS) and disease-free survival (DFS) were compared across hepatoprotective regimens. Propensity score matching (1:2) was performed to balance baseline characteristics between SAMe-treated and untreated patients. Receiver operating characteristic (ROC) analysis identified the optimal exposure threshold for recurrence discrimination, and survival was further assessed according to SAMe exposure duration using Cox proportional hazards models. Transcriptomic data from the Cancer Transcriptome Relationships Database (CTR-DB) were analyzed for SAMe-related pathways. In an exploratory neoadjuvant cohort (n = 62), intratumoral SAMe levels, m6A/m5C/m7G signals and METTL3/METTL14 expression were quantified in post-treatment tumor tissues. SAMe exposure during adjuvant chemotherapy was associated with shorter OS and DFS than other or no hepatoprotectants (both P < 0.05). After matching, prolonged SAMe exposure (≥ 14days) remained associated with worse OS and DFS than non-SAMe exposure (both P < 0.05), and this association persisted after multivariable adjustment. CTR-DB analyses revealed enrichment of methionine metabolism and RNA methylation-related pathways in non-responsive tumours. In the neoadjuvant cohort, tumours from patients with poor radiologic response showed higher intratumoral SAMe levels, stronger m6A signals, and higher METTL3 and METTL14 expression. Higher m6A levels were also associated with poorer MRI-based response. Prolonged SAMe exposure during chemotherapy was associated with poorer treatment response and worse survival. Transcriptomic and tissue-level findings further support a possible link with altered m6A methylation. These results indicate that a cautious and standardized approach to SAMe use during chemotherapy may help limit treatment resistance and improve long-term outcomes.

Early and late hepatocellular carcinoma (HCC) recurrences, which are driven by residual and de novo tumors, respectively, differ in biology and potential treatment susceptibility. The effectiveness of adjuvant PD-1 inhibitors (aPD-1) across these distinct recurrence patterns remains unclear. A total of 3436 cases were included from 9 centers in China. Among these, 1662 patients (2019–2023) were propensity score-matched to compare the effects of aPD-1 versus active surveillance on survival outcomes. Machine learning (ML) models were trained on 1774 patients (2014–2018) to predict early recurrence (≤ 2 years). The efficacy of aPD-1 was further assessed in ML-predicted subgroups, using a 2-year landmark analysis to evaluate its effect on recurrence etiology. The logistic regression model achieved the best performance, with an AUC of 0.818 in the test set. Patients classified as high risk showed significantly poorer disease-free survival (DFS) and overall survival. aPD-1 significantly improved DFS in high-risk patients (HR 0.69, 95

INTRODUCTION:Aggressive pathologic features are closely associated with early recurrence of hepatocellular carcinoma (HCC), and the association between vessels encapsulating tumor clusters (VETC) and poor prognosis has received increasing attention. OBJECTIVES:This study aimed to investigate the role of adjuvant Sintilimab (AS) with or without Lenvatinib (ASL) compared to active monitoring (AM) in high-risk HCC, with emphasis on VETC-positive subtypes. METHODS:Patients identified as being at high risk for recurrence and who had undergone either AM, AS, or ASL were retrospectively enrolled from four medical centers. Propensity score matching (PSM) was adopted to minimize bias. Digital spatial profiling (DSP) and multiplex immunofluorescence (mIF) were employed to elucidate the molecular underpinnings of VETC-positive HCC. RESULTS:This study included 620 patients with a median follow-up of 46.9 months. After PSM, 135 patients were allocated to each cohort. Both the AS and ASL regimens significantly prolonged median disease-free survival compared to AM (26.0 and 59.2 months vs. 12.2 months, respectively; p < 0.001). Critically, subgroup analysis revealed that the benefit of AS was absent in VETC-positive HCC (p = 0.681), whereas ASL demonstrated a substantial reduction in recurrence (p = 0.001). This specific efficacy of Lenvatinib against VETC-positive HCC was further corroborated by data from first-line treatment for recurrent disease and an independent neoadjuvant therapy cohort. Mechanistically, DSP revealed that VETC-positive tumors possess an immunosuppressive microenvironment, characterized by downregulated antigen presentation and impoverished CD8+ T cell infiltration. This immune contexture was validated by mIF, which confirmed sparse CD8+ T cells alongside enriched CD4+ and regulatory T cells in VETC-positive HCC. CONCLUSIONS:This study validates VETC-positive HCC as a distinct entity with a high risk of postoperative recurrence and validates the combination of PD-1 inhibitors with Lenvatinib as its preferred therapeutic strategy.

BACKGROUND:Intrahepatic cholangiocarcinoma (ICC) is a challenging cancer with an increasing incidence. The Phase III TOPAZ-1/KEYNOTE-966 study demonstrated chemo-immunotherapy (CIT) as a significant advancement, potentially replacing traditional chemotherapy for advanced biliary tract cancer. Ferroptosis is a crucial process that affects cancer cell survival and therapy resistance. Although AKT hyperactivation is prevalent in numerous cancers, including ICC, its role in ferroptosis resistance remains unclear. This study explored whether targeting ferroptosis can enhance CIT response rates, specifically in ICC patients with AKT hyperactivation. METHODS:In vivo metabolic CRISPR screening in a KrasG12D/Tp53-/- ICC mouse model was used to identify primary regulators of ferroptosis during CIT (gemcitabine, cisplatin, and anti-mouse programmed cell death 1 ligand 1). Phosphoenolpyruvate carboxykinase 1 (PCK1) was assessed for its role in ferroptosis and treatment resistance in preclinical models under AKT activation levels. Molecular and biochemical techniques were used to explore PCK1-related resistance mechanisms in AKT-hyperactivated ICC. RESULTS:Under AKT hyperactivation condition, phosphorylated PCK1 (pPCK1) promoted metabolic reprogramming, enhancing ubiquinol and menaquinone-4 synthesis through the mevalonate (MVA) pathway. This cascade was mediated by the pPCK1-pLDHA-SPRINGlac axis. Inhibiting PCK1 phosphorylation or using simvastatin significantly augmented CIT efficacy in preclinical models. Clinical data further indicated that phosphorylated AKT (pAKT)-pPCK1 levels might serve as a biomarker to predict CIT response in ICC. CONCLUSION:This study identified the pAKT-pPCK1-pLDHA-SPRINGlac axis as a novel mechanism driving ferroptosis resistance in AKT-hyperactivated ICC by associating glycolytic activation with MVA flux reprogramming. Targeting this axis, potentially through statin-based therapies, may offer a strategy to sensitize ICC cells to ferroptosis and improve treatment outcomes.

Oxaliplatin/5-fluorouracil (OXA/5-FU)-based hepatic artery infusion chemotherapy (HAIC) represents a promising strategy against advanced hepatocellular carcinoma (HCC), yet acquired resistance frequently impedes its efficacy. Here, we identify lactylation of IGF2BP3 at lysine 76 (IGF2BP3-K76lac) as a key driver of HAIC resistance. IGF2BP3-K76lac overexpression enhances chemoresistance in vitro and in vivo. Mechanistically, lactylation at IGF2BP3 K76 strengthens its affinity for m6A-modified FSP1 mRNA, upregulating FSP1 and conferring ferroptosis resistance. Blocking of IGF2BP3-K76lac bolsters OXA/5-FU-induced ferroptosis, disrupts antioxidant defenses, and curbs tumor growth. Moreover, PARK7 functions as a lactyltransferase to facilitate IGF2BP3-K76lac via increasing the binding of lactate at IGF2BP3-K76 site. Finally, blocking antibody targeting IGF2BP3-K76lac was shown to work synergistically with OXA/5-FU to restore chemosensitivity. Taken together, our findings reveal a critical role for the PARK7-IGF2BP3-K76lac-FSP1 axis in HAIC resistance, highlighting IGF2BP3-K76lac as a potential therapeutic target in HCC.

Therapeutic options for large or locally advanced hepatocellular carcinoma (HCC) have limited efficacy. This study investigated the efficacy and safety of drug-eluting beads trans-arterial chemo-embolization (dTACE), portal vein embolization (PVE), tyrosine kinase inhibitor (TKI), and immune checkpoint inhibitors (ICI) compared to Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) for large or locally advanced HCC. Data regarding clinicopathological details, safety, and oncological outcomes were reviewed for the quadruple therapy (dTACE-PVE-TKI-ICI) and compared with ALPPS. From 2019 to 2020, 10 patients with large or locally advanced HCC underwent future remnant liver (FRL) modulation (dTACE-PVE-TKI-ICI: 5; ALPPS: 5). All five dTACE-PVE-TKI-ICI cases responded well, with patients #4 and #5 achieving complete tumor necrosis. The overall response rate (ORR) was 5/5. Patients #1–4 underwent hepatectomy, while #5 declined surgery due to complete tumor necrosis. Mean FRL volume increased by 75.3

Acquired resistance remains a bottleneck for molecular-targeted therapy in advanced hepatocellular carcinoma (HCC). Metabolic adaptation and epigenetic remodeling are recognized as hallmarks of cancer that may contribute to acquired resistance. In various lenvatinib-resistant models, increased glycolysis leads to lactate accumulation and lysine lactylation of IGF2BP3. This lactylation is crucial for capturing PCK2 and NRF2 mRNAs, thereby enhancing their expression. This process reprograms serine metabolism and strengthens the antioxidant defense system. Additionally, altered serine metabolism increases the availability of methylated substrates, such as S-adenosylmethionine (SAM), for N6-methyladenosine (m6A) methylation of PCK2 and NRF2 mRNAs. The lactylated IGF2BP3-PCK2-SAM-m6A loop maintains elevated PCK2 and NRF2 levels, enhancing the antioxidant system and promoting lenvatinib resistance in HCC. Treatment with liposomes carrying siRNAs targeting IGF2BP3 or the glycolysis inhibitor 2-DG restored lenvatinib sensitivity in vivo. These findings highlight the connection between metabolic reprogramming and epigenetic regulation and suggest that targeting metabolic pathways may offer new strategies to overcome lenvatinib resistance in HCC.

Background: We aim to investigate the prevalence, patterns, risk factors, and outcomes of peritoneal metastases (PM) after curative laparoscopic hepatectomy (LH) for hepatocellular carcinoma (HCC).Methods: A multicenter cohort of 2,138 HCC patients who underwent curative LH from August 2010 to December 2016 from seven hospitals in China was retrospectively analyzed. The incidence of PM following LH was evaluated and compared with that in open hepatectomy (OH) after 1:1 propensity score matching (PSM).Results: PM prevalence was 5.1% (15/295) in the early period [2010-2013], 2.6% (47/1,843) in the later period [2014-2016], and 2.9% (62/2,138) in all LH patients, which was similar to 4.0% (59/1,490) in the OH patients. The recurrence patterns, timing, and treatment did not significantly vary between the LH and OH patients (P>0.05). Multivariate logistic regression revealed that tumor diameter >5 cm, non-anatomical resection, presence of microvascular invasion, and lesions <2 cm from major blood vessels were independent risk factors of PM after LH. Of the 62 cases with PM, 26 (41.9%) had PM only, 34 (54.9%) had intrahepatic recurrence (IHR) and PM, and 2 (3.2%) had synchronous extraperitoneal metastases (EPM). Patients with resectable PM had a 5-year overall survival (OS) of 65.0% compared to 9.0% for unresectable PM (P=0.001).Conclusions: The prevalence, patterns and independent risk factors of PM were identified for HCC patients after LH. LH was not associated with increased incidence of PM in HCC patients for experienced surgeons. Surgical re-excision of PM was associated with prolonged survival.

OBJECTIVE:To establish global benchmark outcomes indicators for laparoscopic right posterior sectionectomies (L-RPSs)/H67. BACKGROUND:Minimally invasive liver resections have seen an increase in uptake in recent years. Over time, challenging procedures such as L-RPS/H67 are also increasingly adopted. METHODS:This is a post hoc analysis of a multicenter database of 854 patients undergoing minimally invasive RPS in 57 international centers in 4 continents between 2015 and 2021. There were 651 pure L-RPS and 160 robotic RPS. Sixteen outcome indicators of low-risk L-RPS cases were selected to establish benchmark cutoffs. The 75th percentile of individual center medians for a given outcome indicator was set as the benchmark cutoff. RESULTS:There were 573 L-RPS/H67 performed in 43 expert centers, of which 254 L-RPS/H67 (44.3%) cases qualified as low-risk benchmark cases. The benchmark outcomes established for operation time, open conversion rate, blood loss ≥500 mL, blood transfusion rate, postoperative morbidity, major morbidity, 90-day mortality, and textbook outcome after L-RPS were 350.8 minutes, 12.5%, 53.8%, 22.9%, 23.8%, 2.8%, 0%, and 4%, respectively. CONCLUSIONS:The present study established the first global benchmark values for L-RPS/H6/7. The benchmark provided an up-to-date reference of the best achievable outcomes for surgical auditing and benchmarking.

Background: High rate of recurrence impaired the prognosis of hepatocellular carcinoma (HCC) after surgery. We aimed to explore the safety and efficacy of neoadjuvant drug-eluting bead transarterial chemoembolization (DTACE) and tislelizumab therapy for resectable or borderline resectable HCC. Methods: 41 HCC patients received neoadjuvant therapy and surgery were respectively enrolled. The safety and efficacy of the neoadjuvant therapy were assessed. The prognosis was evaluated and compared with that of 41 matched HCC patients who received surgery alone. Results: 36 (87.8%) patients had adverse events (AEs) and only one patient had a grade 3/4 of ALT elevated. All patients performed surgery successfully and no severe postoperative complications occurred. The objective response rate (ORR) was 56.1% and 87.8% based on RECIST 1.1 and mRECIST, respectively. 15 (36.6%) patients had radiological complete tumor necrosis and the disease control rate (DCR) was 100%. The pathological complete response (pCR) and major pathological response (MPR) was 13 (31.7%) and 18 (43.9%), respectively. The incidence of microvascular invasion (MVI) was 4.9% in neoadjuvant therapy patients, compared with 64.9% before propensity score matching (PSM) and 60.9% after PSM for surgery alone patients. Neoadjuvant therapy patients had a significant better prognosis than surgery alone patients (recurrence-free survival p = 0.041, overall survival p = 0.006). Conclusions: Our preliminary results suggest the neoadjuvant D-TACE and tislelizumab therapy is safe and benefit to the pathological results and prognosis for patients with resectable or borderline resectable HCC.

Lenvatinib is a standard therapy option for advanced hepatocellular carcinoma (HCC), but resistance limits clinical benefits. In this study, we identified inhibition of ROS levels and reduced redox status in Lenvatinibresistant HCC. Integrating RNA-seq with unbiased whole-genome CRISPR-Cas9 screen analysis indicated LINC01607 regulated the P62 to enhance drug resistance by affecting mitophagy and antioxidant pathways. Underlying mechanisms were investigated both in vitro and in vivo. We initially confirmed that LINC01607, as a competing endogenous RNA (ceRNA) competing with mirRNA-892b, triggered protective mitophagy by upregulating P62, which reduced ROS levels and promoted drug resistance. Furthermore, LINC01607 was proved to resist oxidative stress by regulating the P62-Nrf2 axis, which transcriptionally regulated the expression of LINC01607 to form a positive feedback loop. Finally, silencing LINC01607 combined with Lenvatinib reversed resistance in animal and patient-derived organoid models. In conclusion, we proposed a novel mechanism of Lenvatinib resistance involving ROS homeostasis. This work contributed to understanding redox homeostasisrelated drug resistance and provided new therapeutic targets and strategies for HCC patients.

Cancer stem cells (CSCs) are a minority population of cancer cells with stemness and multiple differentiation potentials, leading to cancer progression and therapeutic resistance. However, the concrete mechanism of CSCs in hepatocellular carcinoma (HCC) remains obscure. We found that in advanced HCC tissues, collagen I was upregulated, which is consistent with the expression of its receptor DDR1. Accordingly, high collagen I levels accompanied by high DDR1 expression are associated with poor prognoses in patients with HCC. Collagen I-induced DDR1 activation enhanced HCC cell stemness in vitro and in vivo. Mechanistically, DDR1 interacts with CD44, which acts as a co-receptor that amplifies collagen I-induced DDR1 signaling, and collagen I-DDR1 signaling antagonized Hippo signaling by facilitating the recruitment of PP2AA to MST1, leading to exaggerated YAP activation. The combined inhibition of DDR1 and YAP synergistically abrogated HCC cell stemness in vitro and tumorigenesis in vivo. A radiomic model based on T2 weighted images can noninvasively predict collagen I expression. These findings reveal the molecular basis of collagen I-DDR1 signaling inhibiting Hippo signaling and highlight the role of CD44/DDR1/YAP axis in promoting cancer cell stemness, suggesting that DDR1 and YAP may serve as novel prognostic biomarkers and therapeutic targets in HCC.

对于需要手术切除的肝脏良恶性疾病,由于其位置侵及肝脏重要管道,难以在体切除.在移植技术的基础上,离体(或半离体)肝切除方法可以完成在体切除风险极大的外科手术.鉴于其高度复杂性及安全性问题,离体肝切除术较外科其他手术进展缓慢.近年来,随着肝脏外科手术技术及器官移植学理论的进步,离体肝切除术取得较大进展.但缺乏临床实践规范及国际共识,限制其临床推广.

Objective:To investigate the value of tumor budding in the clinicopathology and prognosis of pancreatic neuroendocrine tumors.Methods:The Cliniccal data of 105 pancreatic neuroendocrine tumor patients underwent resection in Henan Provincial People's Hospital from Jan 2010 to Dec 2016 were retrospectively analyzed. Tumor budding was calculated through hematoxylin-eosin (HE) and immunohistochemical stained slides. Based on the receiver operating characteristic curve (ROC), the number of tumor budding ≥10 was defined as the high-grade budding group, and <10 as the low-grade budding group. Multiple analysis was performed to determine the relationship between tumor budding and clinicopathology as well as prognosis.Results:High-grade budding group was observed in 35 cases and low-grade group in 70. High-grade budding were more common in tumors with advanced T stage, high risk of lymphatic metastasis, preoperative liver metastasis, vascular invasion and postoperative recurrence (respectively χ 2=9.043, 4.286, 10.130, 12.090, 9.260, all P<0.05). Multivariate COX regression analysis showed that tumor budding ( P=0.018), tumor grade ( P=0.026), preoperative liver metastasis ( P=0.042), vascular invasion( P=0.048) was independent risk factors predicting poor prognosis. Conclusion:Tumor budding is highly correlated with clinicopathological parameters which reflect the aggressiveness of pancreatic neuroendocrine tumor, it is also an important prognostic factor.

INTRODUCTION:The poorly differentiated pancreatic adenocarcinoma (PDAC) is an extremely lethal neoplasm without effective biomarkers for early detection and prognosis prediction, which is characteristically unresponsive to chemotherapeutic regimens. This study aims at searching for key genes which could be applied as novel prognostic biomarkers and therapeutic targets in PDAC.METHODS:Clinical samples were collected and a comprehensive differential analysis of seven PDAC samples by integrating RNA-seq data of tumor tissues and matched normal tissues from both our cohort and gene expression profiling interactive analysis (GEPIA) were performed to discover potential prognostic genes in PDAC. Pathway enrichment analysis was carried out to determine the biological function of PDAC differentially expressed genes (DEGs), and protein-protein interaction (PPI) network was constructed for functional modules analysis. Real-time PCR was performed to validate expression of hub genes.RESULTS:A total of 126 PDAC-specific expressed genes identified from seven PDAC samples were predominantly enriched in cell adhesion, integral component of membrane, signal transduction and chemical carcinogenesis, IL-17 signaling pathway, indicating that obtained genes might play a unique role in PDAC tumorigenesis. Furthermore, survival analysis revealed that five genes (CEACAM5, KRT6A, KRT6B, KRT7, KRT17) which exhibited high expression levels in tumor tissues were obviously correlated with the prognosis of PDAC patients and KRT7 was positively correlated with KRT6A, KRT6B, KRT17 expression. In addition, real-time PCR demonstrated that the expression level of the hub genes was consistent with RNA-seq analysis.DISCUSSION:The current study suggested that CEACAM5, KRT6A, KRT6B, KRT7, and KRT17 may represent novel prognostic biomarkers as well as novel therapeutic targets for poorly differentiated PDAC.

目的 探讨吲哚菁绿(indocyanine green,ICG)荧光显像在腹腔镜解剖性肝切除术(lap-aroscope anatomical hepatectomy,LAH)中的临床应用价值.方法 回顾性分析2018年1月至2019年12月在郑州大学人民医院(河南省人民医院)行L A H的85例原发性肝癌病人的临床资料.其中43例行常规LAH(对照组),42例在吲哚菁绿荧光显像指导下行LAH(观察组).比较两组病人术中术后相关指标.结果 对照组和观察组在年龄、性别、肝功能储备、手术切除范围、手术时间、术后病理、术后肝功能、术后并发症发生及随访结果比较,差异均无统计学意义(均P>0.05).与对照组相比,观察组术中出血量减少,术后C反应蛋白峰值降低,术后住院时间减少,差异均有统计学意义(均P<0.05).结论 ICG荧光显像指导LAH是一种安全有效的手术方法,值得推广应用.

Abstract HDAC6 regulates the expression and activity of various tumor-related proteins, but currently there is no selective inhibitor targeting HDAC6 for clinical application. In order to discover novel HDAC6 inhibitors, virtual screening methods comprised of pharmacophore based virtual screening, molecular docking and molecular dynamics (MD) simulations were employed. 15 molecules were obtained after virtual screening. After in vitro bioassays, two of the hits showed inhibition activity against HDAC6, among which the inhibition activity of G1 to HDAC6 reached 81% at concentration of 20 μM. In addition, the inhibitory activity against HDAC1 and HDAC10 demonstrated that G1 and G10 were highly selective to HDAC6. The analysis of the binding modes of G1 and G10 provides a reference for further development of highly active HDAC6 inhibitors. Communicated by Ramaswamy H. Sarma