Combining Gemcitabine-Loaded Macrophage-like Nanoparticles and Erlotinib for Pancreatic Cancer Therapy.

Pancreatic cancer is a lethal malignancy with a dismal prognosis. Gemcitabine is currently used to treat pancreatic cancer, but it is limited by significant toxicity. Clinical trials on the combination of gemcitabine and erlotinib reported unsatisfactory outcomes along with concerns of toxicity. The encapsulation of chemotherapy drugs in polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) can alleviate toxicity through targeted delivery and sustained release. In addition, camouflaging the NPs with a macrophage membrane can evade the immune system and further improve tumor homing. We designed gemcitabine-loaded PLGA NPs with a macrophage membrane coating (MPGNPs) to reduce drug toxicity and increase the accumulation in the tumor. The combination of MPGNPs and erlotinib synergistically inhibited pancreatic cancer cell proliferation in vitro and in vivo by targeting the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling pathways. The MPGNPs were also able to evade phagocytosis and achieve passive targeting to the pancreatic tumors. The combination of MPGNPs and erlotinib showed synergistic anti-tumor efficacy in vitro and in vivo. This study provides a proof-of-concept for treating pancreatic cancer with a combination of MPGNPs and erlotinib.

Gold nanoparticles-loaded anti-miR221 enhances antitumor effect of sorafenib in hepatocellular carcinoma cells.

Objective: Currently, sorafenib is the main systemic chemotherapy drug for advanced stage of hepatocellular carcinoma (HCC). However, emerging data from some clinical HCC patients indicates that sorafenib alone has only moderate antitumor efficacy, and could not inhibit metastasis and progression of disease. MiR-221 plays a role in promoting tumorigenesis in HCC by inhibiting the expression of p27. In this study, we analyzed the synergistic anti-tumor effects of sorafenib and gold nanoparticles-loaded anti-miR221 on HCC cell lines. Methods: Gold nanoparticles-loaded anti-miR221 was investigated and identified by transmission electron microscope, ultraviolet-visible spectroscopy, zeta potential and dynamic light scattering measurements as well as the confocal microscopy and dark-field imaging. Two HCC cell lines were treated with sorafenib and AuNPs-anti-miR221 alone or combination in vitro to investigate the inhibitory effect by CCK-8, live/dead fluorescence staining and colony-forming unit assays. MiR-221/p27/DNMT1 signaling pathway including p27 and DNMT1 was examined by western blot. Results: AuNPs-anti-miR221 can enhance the effect of sorafenib in inhibiting cell proliferation via inactivating miR-221/p27/DNMT1 signaling pathway. Conclusions: Our results demonstrate that sorafenib combined with AuNPs-anti-miR221 treatment does effectively inhibit proliferation of HCC cell lines synergistically. These data suggest the AuNPs-anti-miR221 may be a promising chemosensitizer to sorafenib in the treatment of HCC.

Application of the superior mesenteric artery-first approach in laparoscopic pancreatoduodenectomy: A literature review.

Background: Laparoscopic pancreaticoduodenectomy (LPD) is a complicated surgical procedure that has recently been performed safely. A superior mesenteric artery (SMA)-first approach can allow complete mesopancreas resection, maximizing surgical margins and R0 resection rates. Therefore, the SMA-first approach is recommended. This review is a literature summary of recent updates of the SMA approaches for LPD and informs clinical practice of the advantages of its various approach. Methods: A systematic literature search was performed on the PubMed (MEDLINE) database using truncated word searches and medical subject headings to identify all pertinent published studies. Results: After searching PubMed, 303 studies were identified and reviewed, of which 25 described the SMA-first approach, including the anterior, posterior, right, and left approaches, fully described in 5, 6, 13, and 6 articles, respectively. Conclusions: The SMA-first approach is the standard surgical technique for LPD. This review summarized each SMA-first approach's distinct advantages and indications.

Mutational landscape of TP53 and CDH1 in gastric cancer.

In this editorial we comment on an article published in a recent issue of the World J Gastrointest Surg. A common gene mutation in gastric cancer (GC) is the TP53 mutation. As a tumor suppressor gene, TP53 is implicated in more than half of all tumor occurrences. TP53 gene mutations in GC tissue may be related with clinical pathological aspects. The TP53 mutation arose late in the progression of GC and aided in the final switch to malignancy. CDH1 encodes E-cadherin, which is involved in cell-to-cell adhesion, epithelial structure maintenance, cell polarity, differentiation, and intracellular signaling pathway modulation. CDH1 mutations and functional loss can result in diffuse GC, and CDH1 mutations can serve as independent prognostic indicators for poor prognosis. GC patients can benefit from genetic counseling and testing for CDH1 mutations. Demethylation therapy may assist to postpone the onset and progression of GC. The investigation of TP53 and CDH1 gene mutations in GC allows for the investigation of the relationship between these two gene mutations, as well as providing some basis for evaluating the prognosis of GC patients.

Is there a place for endoscopic management in post-cholecystectomy iatrogenic bile duct injuries?

In this editorial we comment on the article by Emara et al published in the recent issue of the World Journal of Gastrointestinal Surgery. Previously, surgery was the primary treatment for bile duct injuries (BDI). The treatment of BDI has advanced due to technological breakthroughs and minimally invasive procedures. Endoscopic and percutaneous treatments have largely supplanted surgery as the primary treatment for most instances in recent years. Patient management, including the specific technique, is typically impacted by local knowledge and the kind and severity of the injury. Endoscopic therapy is a highly successful treatment for postoperative benign bile duct stenosis and offers superior long-term outcomes compared to surgical correction. Based on the damage features of BDI, therapeutic options include endoscopic duodenal papillary sphincterotomy, endoscopic nasobiliary drainage, and endoscopic biliary stent implantation.

In-situ-formed immunotherapeutic and hemostatic dual drug-loaded nanohydrogel for preventing postoperative recurrence of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a prevalent malignancy characterized by an exceedingly high recurrence rate post-surgery, significantly impairing the prognosis of HCC patients. However, a standard in-care strategy for postoperative therapy is still lacking. Although encouraging results have been obtained in a newly published clinical trial for postoperative therapy by targeting the vascular endothelial growth factor (VEGF) and programmed death ligand 1 (anti-PD-L1), its efficacy remains constrained. Combining a hemostatic hydrogel with a nanoparticle-based drug delivery system presents an opportunity to optimize the antitumor effect. Herein, we developed a nanoplatform, termed HMSN@Sor/aP@Gel, comprising a hemostatic fibrin hydrogel and functionalized hollow mesoporous silica nanoparticles (HMSNs) loaded with sorafenib and anti-PD-L1 for locally administered targeted-immunotherapy to prevent the postoperative recurrence and metastasis of HCC. The antitumor mechanism is grounded in dual inhibition of Ras/Raf/MEK/ERK (MAPK) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathways, synergistically complemented by PD-L1 blockade. HMSN@Sor/aP@Gel facilitates dendritic cell maturation, enhances cytotoxic T-lymphocyte infiltration, promotes the polarization of tumor-associated macrophages to M1 phenotype, induces tumor immunogenic cell death, reverses immunosuppression, and establishes immune memory to counter postoperative recurrence. Animal studies corroborate that HMSN@Sor/aP@Gel-mediated targeted immunotherapy significantly impedes primary and metastatic tumor growth and establishes immune memory to prevent recurrence post-surgery. This investigation presents a promising strategy for postoperative therapy with considerable potential for clinical translation.

Outcomes of laparoscopic pancreaticoduodenectomy using a modified technique：346 cases from a single center.

PURPOSE: To study the outcomes of laparoscopic pancreaticoduodenectomy (LPD) using a modified technique. METHODS: Our center used priority approach of uncinate process and artery in the pancreatectomy and duct to mucosa pancreaticojejunostomy with a single stitch in the pancreaticojejunostomy. Herein, we retrospectively reviewed 346 cases of LPD using modified techniques. Basic characteristics, preoperative outcomes, factors associated with unfavorable postoperative outcome, and mortality of patients undergoing LPD were collected and analyzed. RESULTS: The average operative time was 259.31 (35-425) min. The mean duration of pancreaticojejunostomy anastomosis was 31.97 (16-90) min. The mean intraoperative blood loss was 101.76 (0-1200) ml by estimation. Postoperative complications included 14 cases (4.1%) of bile leakage, 9 cases (2.6%) of delayed gastric emptying, 26 cases (7.5%) of postoperative bleeding, 34 cases (9.9%) of organ space infection, 17 cases (4.9%) of pulmonary infection, and 50 cases (14.5%) of POPF. Three factors including postoperative bleeding (OR = 3.502; P = 0.033), positive lymph node (OR = 3.296; P < 0.001), and postoperative chemotherapy (OR = 0.241; P = 0.008) were significantly associated with death of LPD. CONCLUSIONS: The modified technique for LPD presents safety and reliability. Postoperative bleeding and positive lymph node may be associated with worse overall survival, and postoperative chemotherapy may be associated with better overall survival.

CroReLU: Cross-Crossing Space-Based Visual Activation Function for Lung Cancer Pathology Image Recognition.

Lung cancer is one of the most common malignant tumors in human beings. It is highly fatal, as its early symptoms are not obvious. In clinical medicine, physicians rely on the information provided by pathology tests as an important reference for the final diagnosis of many diseases. Therefore, pathology diagnosis is known as the gold standard for disease diagnosis. However, the complexity of the information contained in pathology images and the increase in the number of patients far outpace the number of pathologists, especially for the treatment of lung cancer in less developed countries. To address this problem, we propose a plug-and-play visual activation function (AF), CroReLU, based on a priori knowledge of pathology, which makes it possible to use deep learning models for precision medicine. To the best of our knowledge, this work is the first to optimize deep learning models for pathology image diagnosis from the perspective of AFs. By adopting a unique crossover window design for the activation layer of the neural network, CroReLU is equipped with the ability to model spatial information and capture histological morphological features of lung cancer such as papillary, micropapillary, and tubular alveoli. To test the effectiveness of this design, 776 lung cancer pathology images were collected as experimental data. When CroReLU was inserted into the SeNet network (SeNet_CroReLU), the diagnostic accuracy reached 98.33%, which was significantly better than that of common neural network models at this stage. The generalization ability of the proposed method was validated on the LC25000 dataset with completely different data distribution and recognition tasks in the face of practical clinical needs. The experimental results show that CroReLU has the ability to recognize inter- and intra-class differences in cancer pathology images, and that the recognition accuracy exceeds the extant research work on the complex design of network layers.

Ataxia telangiectasia mutated inhibitor-loaded copper sulfide nanoparticles for low-temperature photothermal therapy of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, and is ranked the sixth most common neoplasm and the third leading cause of cancer-related deaths. Photothermal therapy (PTT) for thermal ablation of local tumors has recently emerged as a therapeutic strategy. However, the relatively high temperature of over 50 °C may lead to unexpected heat-related damage to tumor-adjacent normal tissues. Herein, we designed and synthesized ataxia telangiectasia mutated (ATM) inhibitor loaded hollow-structured CuS NPs with surface modification with anti-TGF-ß antibody (CuS-ATMi@TGF-ß NPs). CuS-ATMi@TGF-ß NPs are highly photo-stable, can release encapsulated drugs, and increase the temperature to an effective level in a near-infrared (NIR)-responsive manner. Moreover, CuS-ATMi@TGF-ß NPs specifically target tumors and thereby significantly inhibit tumor growth on contribution to synergistic low-temperature PTT and chemotherapy. This system not only achieved low-temperature PTT but also resulted in reduced damage to normal tissues. Modification with anti-TGF-ß antibody enhanced target specificity and immune activation. The combination of PTT and ATM inhibitor showed synergistic effects and significantly attenuated the growth of the HCC via down regulation of heat shock protein (HSP). CuS-ATMi@TGF-ß NPs are a highly promising platform for targeted tumor ablation via hyperthermia-mediated tumor death with minimal damage to normal tissues at a low temperature. STATEMENT OF SIGNIFICANCE: We constructed ataxia telangiectasia mutated (ATM) inhibitor-loaded hollow-structured CuS NPs with surface modification with anti-TGF-ß antibody (CuS-ATMi@TGF-ß NPs). CuS-ATMi@TGF-ß NPs not only achieved low-temperature photothermal therapy (PTT) but also resulted in reduced damage to normal tissues and sufficient biocompatibility. The modification with anti-TGF-ß antibody enhanced targeted specificity, cell endocytosis, and immune activation. In addition, the combination of PTT and ATM inhibitor synergistically attenuated the growth of the HCC via downregulation of heat shock protein (HSP). This study provided proof-of-concept for the ATM inhibitor that mediated low-temperature PTT with a potential for future clinical applications.

Hybrid membrane camouflaged copper sulfide nanoparticles for photothermal-chemotherapy of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Biomimetic nanoparticles (NPs) coated with cell membranes show enhanced biocompatibility and specificity for homotypic cells, and have gained considerable attention for targeted anti-tumor therapy. We constructed cancer cell-macrophage hybrid membrane-coated near infrared (NIR)-responsive hollow copper sulfide nanoparticles encapsulating sorafenib and surface modified with anti-VEGFR (CuS-SF@CMV NPs). These CuS-SF@CMV NPs expressed the characteristic membrane proteins of both cancer cells and macrophages, and selectively accumulated in cancer cells in vitro and tumors in vivo, compared to the CuS NPs. In addition, the CuS-SF@CMV NPs achieved synergistic photo-thermal and chemotherapy in cancer cells upon NIR irradiation, with 94.3% inhibition of tumor growth in a murine hepatoma model. While the initial increase in temperature rapidly killed the tumor cells, sorafenib and the anti-VEGFR antibody sustained the tumor killing effect by respectively inhibiting tumor cell proliferation and angiogenesis via the Ras/Raf/MEK/ERK and PI3K/AKT pathways. Taken together, the CuS-SF@CMV NPs have immune evasion, tumor cell targeting and drug loading capacities, along with an inherent photo-thermal conversion ability, making them ideal for synergistic photo-thermal/chemo therapy against HCC. STATEMENT OF SIGNIFICANCE: We created cancer cell-macrophage hybrid membrane-coated hollow CuS NPs encapsulating sorafenib and surface modified with anti-VEGFR antibodies (CuS-SF@CMV). These CuS-SF@CMV NPs enhanced synergistic PTT and chemotherapy against hepatoma cells through homotypic cell targeting, immune escape and inhibition of a tumorigenic signaling pathway. A long-term inhibition of tumor growth and metastasis was achieved owing to the rapid destruction of the cancer cells through photo-thermal conversion by the CuS NPs, and sustained clearance of the tumor cells by sorafenib and anti-VEGFR antibodies. Our findings suggest that CuS-SF@CMV NPs present great treating effects in preclinical models of HCC, providing the framework for further study in clinical trials to improve patient outcome in hepatocellular carcinoma.

Clinical Value of lncRNA LUCAT1 Expression in Liver Cancer and its Potential Pathways.

BACKGROUND AND AIMS: Emerging studies indicate that long noncoding RNAs (lncRNAs) play a role as prognostic markers in many cancers, including liver cancer. Here, we focused on the lncRNA lung cancer-associated transcript 1 (LUCAT1) for liver cancer prognosis. METHODS: RNA-seq and phenotype data were downloaded from the Cancer Genome Atlas (TCGA). Chisquare tests were used to evaluate the correlations between LUCAT1 expression and clinical features. Survival analysis and Cox regression analysis were used to compare different LUCAT1 expression groups (optimal cutoff value determined by ROC). The log-rank test was used to calculate the p-value of the Kaplan-Meier curves. A ROC curve was used to evaluate the diagnostic value. Gene Set Enrichment Analysis (GSEA) was performed, and competing endogenous RNA (ceRNA) networks were constructed to explore the potential mechanism. RESULTS: Data mining of the TCGA -Liver Hepatocellular Carcinoma (LIHC) RNA-seq data of 371 patients showed the overexpression of LUCAT1 in cancerous tissue. High LUCAT1 expression was associated with age (p=0.007), histologic grade (p=0.009), T classification (p=0.022), and survival status (p=0.002). High LUCAT1 patients had a poorer overall survival and relapse-free survival than low LUCAT1 patients. Multivariate analysis identified LUCAT1 as an independent risk factor for poor survival. The ROC curve indicated modest diagnostic performance. GSEA revealed the related signaling pathways, and the ceRNA network uncovered the underlying mechanism. CONCLUSION: High LUCAT1 expression is an independent prognostic factor for liver cancer.

Low CYP24A1 mRNA expression and its role in prognosis of breast cancer.

Breast cancer is the most common malignant cancer in women. CYP24A1 expression regulates cellular response to vitamin D, which has antitumor effects against breast cancer. This study aimed to identify the correlation between CYP24A1 mRNA expression and prognosis of breast cancer. This study enrolled 1102 patients, including 1090 females and 12 males, from TCGA-BRCA cohort. The Cancer Genome Atlas database was used to study CYP24A1 mRNA expression in breast cancer, and Chi-squared tests were performed to test the correlation between clinical features and CYP24A1 expression. The prognostic value of CYP24A1 in breast cancer was assessed using Kaplan-Meier curves and Cox analysis. Low CYP24A1 expression was associated with age, molecular subtype, ER, PR, HER2, menopause status, N classification, vital status, overall survial and relapse-free survival. CYP24A1 presented a moderate diagnostic ability in breast cancer. Furthermore, low CYP24A1 expression was correlated with poor prognosis. CYP24A1 was an independent risk factor for breast cancer. CYP24A1 plays an important role in prognosis of breast cancer. CYP24A1 has the potential to be a biomarker, especially in predicting prognosis.