Targeted Delivery of Gemcitabine for Precision Therapy of Cholangiocarcinoma Using Hyaluronic Acid-Modified Metal-Organic Framework Nanoparticles.

Chemotherapy is widely recognized as an important approach for the treatment of cholangiocarcinoma. Gemcitabine (GEM) has been considered a first-line drug for treating cholangiocarcinoma due to its ability to effectively inhibit the proliferation, migration, and invasion of liver cancer cells. However, the systemic toxicity, premature degradation, and lack of tumor-targeting properties of GEM limit its application in cholangiocarcinoma chemotherapy. Additionally, precise targeted delivery of GEM is necessary to align with the current concept of precision medicine. In this study, considering the overexpression of hyaluronic acid (HA) receptors (CD44) on cholangiocarcinoma cells, we designed GEM@ZIF-67-HA NPs by loading GEM onto ZIF-67 and modifying its surface with HA. The structure, size, morphology, and elemental composition of GEM@ZIF-67-HA were analyzed using transmission electron microscopy, Fourier transform infrared spectroscopy, ζ-potential, and isothermal adsorption. Cell toxicity experiments demonstrated that GEM@ZIF-67-HA NPs not only reduced cytotoxicity to normal cells but also effectively inhibited the viability of two types of cholangiocarcinoma tumor cells. In a subcutaneous tumor model, GEM@ZIF-67-HA significantly suppressed tumor growth. The tumor-targeting and controllable properties of GEM@ZIF-67-HA NPs hold promise for further development in the strategy of precise targeted therapy for cholangiocarcinoma.

Anatomic Variation of the Cystic Artery: New Findings and Potential Implications.

Purpose: To determine the anatomy of the cystic artery by dual-source CT, and correlate imaging findings with those patients who had laparoscopic cholecystectomy (LC). Materials and Methods: Following institutional review board approval, a total of 289 consecutive patients (204 men and 85 women) were evaluated with CT for abdominal pain, including 55 patients subsequently underwent LC. Location of the cystic artery termination, distance between the cystic artery origin and the gallbladder, and angle between the cystic artery and its parent artery were evaluated by two radiologists. The laparoscopic surgical video record (gold standard) was similarly evaluated by a surgeon. Results: A total of 256 cystic arteries in the 247 patients were included. Cystic artery terminations are predominately found in ventral Calot triangle plane (50.8%, type II). Cystic artery origin immediately adjacent to the gallbladder surface was seen in 11/256 (4.3%). Zero angle between the cystic artery and its parent artery was found in 17 of 256 cystic arteries (6.6%). The cystic arteries and the Calot triangle were depicted in 49 patients (95% confidence interval: 85%, 97%). For all 49 patients, CT imaging findings were consistent with surgical video records. No case involved vascular and biliary injury occurred. Conclusions: Given the large number of LC performed each year, better knowledge of anatomic variation of the cystic artery could potentially prevent arterial injury and bile duct injury, particularly for patients with unusual anatomy.

Anti-PD-1, anti-VEGF, and temozolomide therapy in a patient with recurrent glioblastoma: a case report.

BACKGROUND: Patients suffering from postoperative recurrent glioblastoma have an extremely unfavorable outcome because there are no proven therapeutic options. The median overall survival for those with relapsed glioblastoma after surgery is only 7.5 months.Case presentation: Between March 2015 and October 2019, a 44-year-old female patient with recurrent glioblastoma was treated by our medical team. After several failed rounds of therapy, the patient was subsequently treated with the anti-programmed death (PD)-1 antibody nivolumab, anti-vascular endothelial growth factor (VEGF) antibody bevacizumab, and cytotoxic agent temozolomide. RESULTS: The patient showed a sustainable complete response to the regimen. To date, there have been no serious toxic side effects. As of October 2019 (the last follow-up), the patient has been in complete remission for 17 months since recurrence. CONCLUSION: The experience of this complicated case indicates the possible application of immune checkpoint inhibitors, anti-angiogenesis agents, and cytotoxic reagents for recurrent glioblastoma. The administration of this three-agent regimen appears safe and effective. However, further clinical trials are warranted.

A Protective Role for RHOJ in NonSmall Cell Lung Cancer Based on Integrated Bioinformatics Analysis.

RHOJ is a small G protein characterized by its abundant expression in endothelial cells. Existing research has documented a link between abnormal RHOJ expression and carcinogenesis. This research aims to investigate the protective role of RHOJ in nonsmall cell lung cancer (NSCLC). In this study, Cancer Genome Atlas database and Gene Expression Omnibus were collected to analyze RHOJ expression and gene regulation networks in NSCLC. Oncomine™ and Gene Expression Profiling Interactive Analysis tools were first utilized to analyze RHOJ expression, and then cBioPortal was employed for identification of RHOJ alterations and associated functional networks. To identify differential RHOJ expression, LinkedOmics was used, which also served to analyze Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. Besides, the target networks of kinases factors were explored using gene enrichment analysis. Our results suggested that lower expression of RHOJ was observed in patients with NSCLC compared with normal people. Low expression of this gene is linked to functional networks involving cytoskeleton, adhesion, infection, and Ras signaling pathways. Functional network analysis suggested that RHOJ regulates the Staphylococcus aureus infection, AGE-RAGE signaling pathway, and DNA and RNA damage. In conclusion, the results in this study demonstrated that data mining is an effective approach that can uncover information about RHOJ expression and potential regulatory networks in NSCLC, thus laying the groundwork for future studies of a similar kind.

IL-10 in vitro could enhance IFNγ expression and suppress PD-1 expression in CD8 T cells from esophageal cancer patients.

IL-10 is commonly regarded as an immunoregulatory cytokine, but accumulating evidence suggests that IL-10 may promote CD8 T cell expansion and proliferation. In this study, tumor infiltrating (TI) and peripheral blood (PB) CD8 T cells were collected from esophageal cancer patients. Interestingly, IL-10 concentration in the tumor microenvironment increased with advancing tumor stage, while TI CD8 T cell-mediated IL-10 production decreased with advancing tumor stage. By flow cytometry, three distinctive subsets, including IL-10+IFNγ-, IL-10+IFNγ+, and IL-10-IFNγ+, could be observed in TI CD8 T cells. The former two subsets were present at much higher frequency in stage I and stage II patients than in stage III patients. IL-10+IFNγ+ TI CD8 T cells presented significantly higher IFNγ and lower PD-1 expression than the IL-10-IFNγ+ TI CD8 T cells. PB CD8 T cells, on the other hand, produced little IL-10 but potent IFNγ upon stimulation. Interestingly, intermediate level of exogenous IL-10 could significantly elevate the expression of IFNγ by PB CD8 T cells, while high level of exogenous IL-10 resulted in reduced expression of IFNγ by PB CD8 T cells. Exogenous IL-10 could not significantly reduce the frequencies of PD-1+ PB CD8 T cells, but significantly reduced the MFI of PD-1 in the PB CD8 T cells, especially in stage III patients. Together, this investigation demonstrated that IL-10 enhanced IFNγ expression and suppressed PD-1 expression in PB and TI CD8 T cells; however, the frequency of IL-10-expressing TI CD8 T cells decreased with increasing severity in esophageal cancer.

Effects of pilose antler peptide on bleomycin-induced pulmonary fibrosis in mice.

The aim of present study was to evaluate the effects of the pilose antler peptide (PAP) on bleomycin (BLM)-induced lung fibrosis. The lung wet-to-dry weight (W/D) ratio and myeloperoxidase (MPO) activity were measured. The serum levels of super-oxide dismutase (SOD), malondialdehyde (MDA) were examined. Then the contents of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and IL-6 were determined using ELISA method. Furthermore, the protein expressions of Rho, ROCK1, p-IκB, IκB, p-NF-κB, NF-κB in lung tissues were detected by western blot analysis. As a result, PAP markedly decreased pulmonary W/D ratio, lung MPO activity and relieved lung histopathological changes. In addition, PAP increased the level of SOD and reduced the levels of MDA, TNF-α, IL-1ß, IL-6 in serum of BLM-stimulated mice. In addition, PAP remarkably inhibited the protein levels of ROCK/NF-κB pathway. In conclusion, our results showed that PAP exhibited protective effects on pulmonary fibrosis via the regulation of ROCK/NF-κB pathway.

Pregnane X receptor is associated with unfavorable survival and induces chemotherapeutic resistance by transcriptional activating multidrug resistance-related protein 3 in colorectal cancer.

BACKGROUND: Although chemotherapy represents a predominant anti-cancer therapeutic modality, drug treatment efficacy is often limited due to the development of resistant tumor cells. The pregnane X receptor (PXR) affects chemotherapeutic effects by regulating targets involved in drug metabolism and transportation, but the regulatory mechanism is poorly understood. METHODS: Oxaliplatin (L-OHP) content in tumor cells was analyzed by mass cytometry. The roles of PXR on cancer cell proliferation, apoptosis and tumor growth with L-OHP-treated were investigated by MTS, colony formation, flow cytometry and xenograft tumor assays. Luciferase reporter, Chromatin-immunoprecipitation and Site-directed mutagenesis were evaluated the mechanisms. The PXR and multidrug resistance-related protein 3 (MRP3) expressions were examined by western blot, RT-PCR or immunohistochemistry of TMA. Kaplan-Meier and Cox regression were adopted to analyze the prognostic value of PXR in colorectal cancer (CRC). RESULTS: PXR over-expression significantly increased oxaliplatin (L-OHP) transport capacity with a reduction of its content and repressed the effects of L-OHP on tumour cell proliferation and apoptosis. Conversely, PXR knockdown augments L-OHP-mediated cellular proliferation and apoptosis. Moreover, PXR significantly reduced the therapeutic effects of L-OHP on tumor growth in nude mice. Further studies indicated a positive correlation between PXR and MRP3 expression and this finding was confirmed in two independent cohorts. Significantly increased MRP3 expression was also found in PXR over-expressing cell lines. Mechanistically, PXR could directly bind to the MRP3 promoter, activating its transcription. The PXR binding sites were determined to be at -796 to -782bp (CTGAAGCAGAGGGAA) and the key binding sites were the "AGGGA" (-787 to -783bp) on the MRP3 promoter. Accordingly, blockade of MRP3 diminishes the effects on drug resistance of PXR. In addition, PXR expression is significantly associated with poor overall survival and represents an unfavorable and independent factor for male or stage I + II CRC patient prognosis. CONCLUSIONS: PXR is a potential biomarker for predicting outcome and activates MRP3 transcription by directly binding to its promoter resulting in an increased L-OHP efflux capacity, and resistance to L-OHP or platinum drugs in CRC. Our work reveals a novel and unique mechanism of drug resistance in CRC.

Decreased expression of C10orf10 and its prognostic significance in human breast cancer.

Breast cancer is a common malignant tumor, which severely threatens the health of women with an increasing incidence in many countries. Here, we identified C10orf10 as a novel differentially expression gene using expression microarray screening. The expression analysis indicated that C10orf10 was frequently decreased in human breast cancers compared to noncancerous breast tissues (81/95, P = 0.0063). Kaplan-Meier analysis indicated that patients with low C10orf10 expression showed a poorer prognosis both in mRNA (n = 1115, P = 0.0013) and protein (n = 100, P = 0.003) levels. Univariate and multivariate analysis showed that the C10orf10 expression was an independent prognostic factor for overall survival of breast cancer patients. Further analysis revealed that low expression of C10orf10 was an unfavorable factor for the prognosis of the patients who were luminal A, luminal B, Her2+ subtypes, at histological grade 2, lymph node negative and ER positive. Our data provided the first evidence that C10orf10 expression was frequently decreased in breast cancer tissues, and low expression of C10orf10 may be an important prognostic factor for poorer survival time of breast cancer patients.