Unveiling the promise of PD1/PD-L1: A new dawn in immunotherapy for cholangiocarcinoma.

Cholangiocarcinoma (CCA), a rare yet notably aggressive cancer, has experienced a surge in incidence in recent years. Presently, surgical resection remains the most effective curative strategy for CCA. Nevertheless, a majority of patients with CCA are ineligible for surgical removal at the time of diagnosis. For advanced stages of CCA, the combination of gemcitabine and cisplatin is established as the standard chemotherapy regimen. Despite this, treatment efficacy is often hindered by the development of resistance. In recent times, immune checkpoint inhibitors, particularly those that block programmed death 1 and its ligand (PD1/PD-L1), have emerged as promising strategies against a variety of cancers and are being increasingly integrated into the therapeutic landscape of CCA. A growing body of research supports that the use of PD1/PD-L1 monoclonal antibodies in conjunction with chemotherapy may significantly improve patient outcomes. This article seeks to meticulously review the latest studies on PD1/PD-L1 involvement in CCA, delving into their expression profiles, prognostic significance, contribution to oncogenic processes, and their potential clinical utility.

Impacts of prothioconazole and prothioconazole-desthio on bile acid and glucolipid metabolism: Upregulation of CYP7A1 expression in HepG2 cells.

As an efficient triazole fungicide, prothioconazole (PTC) is widely used for the prevention and control of plant fungal pathogens. It was reported that the residues of PTC and prothioconazole-desthio (PTC-d) have been detected in the environment and crops, and the effects of PTC-d may be higher than that of PTC. Currently, PTC and PTC-d have been proven to induce hepatic metabolic disorders. However, their toxic effects on cellular bile acid (BA) and glucolipid metabolism remain unknown. In this study, HepG2 cells were exposed to 1-500 µM of PTC or PTC-d. High concentrations of PTC and PTC-d were found to induce cytotoxicity; thus, subsequent experimental exposure was conducted at concentrations of 10-50 µM. The expression levels of CYP7A1 and TG synthesis-related genes and levels of TG and total BA were observed to increase in HepG2 cells. Molecular docking analysis revealed direct interactions between PTC or PTC-d and CYP7A1 protein. To further investigate the underlying mechanisms, PTC and PTC-d were treated to HepG2 cells in which CYP7A1 expression was knocked down using siCYP7A1. It was observed that PTC and PTC-d affected the BA metabolism process and regulated the glycolipid metabolism process by promoting the expression of CYP7A1. In summary, we comprehensively analyzed the effects and mechanisms of PTC and PTC-d on cellular metabolism in HepG2 cells, providing theoretical data for evaluating the safety and potential risks associated with these substances.

Primary intra-abdominal paraganglioma: A case report.

BACKGROUND: Paragangliomas are rare neuroendocrine tumors. We hereby report a case of a localized paraganglioma found in the abdominal cavity, and review the relevant literature to improve the understanding of this disease. CASE SUMMARY: A 29-year-old Chinese female patient was referred to our hospital due to an abdominal mass found on physical examination. Imaging revealed a mass in the left upper abdomen, suggestive of either a benign stromal tumor or an ectopic accessory spleen. Laparoscopic radical resection was subsequently performed, and histopathological analysis confirmed the diagnosis of a paraganglioma. The patient was followed up 3 months post-operation, and reported good recovery with no metastasis. CONCLUSION: Radical resection can effectively treat intra-abdominal paragangliomas, with few side effects and low recurrence risk. In addition, early and accurate diagnosis and timely intervention are essential for the prognosis of this disease.

Hsa_circular RNA_0001013 exerts oncogenic effects in gastric cancer through the microRNA-136-TWSG1 axis.

BACKGROUND: Gastric cancer (GC) is one of the leading malignancies of the digestive system. Circular RNAs (circRNAs) are well-established to play critical regulatory roles in GC development. The current study sought to explore the effects and regulatory mechanism of circ_0001013 in the course of GC. METHODS: First, differential circRNAs and related mechanisms in GC were predicted by microarray analysis. Circ_0001013, microRNA (miR)-136, and TWSG1 expression patterns were subsequently detected in GC clinical samples and cells using RT-qPCR. The relationship among circ_0001013, miR-136, and TWSG1 was further assessed by dual-luciferase reporter assay, biotin-coupled probe pull-down assay, and biotin-coupled miRNA capture. Based on gain- and loss-of-function assays, GC cell proliferation, migration, invasion, and the cell cycle and apoptosis were also measured by 5-ethynyl-2'-deoxyuridine (EdU) assay, scratch test, Transwell assay, and flow cytometry, respectively. Moreover, the effect of circ_0001013 on tumor growth was detected by tumor xenografting in nude mice. RESULTS: Circ_0001013 was predicted to be up-regulated in GC by microarray profiling, which was confirmed by RT-qPCR detection in GC tissues and cells. miR-136 was poorly expressed, and TWSG1 was highly expressed in GC tissues. Mechanistically, circ_0001013 bound to miR-136, which negatively targeted TWSG1 in the GC cells. Silencing circ_0001013 or TWSG1 or over-expressing miR-136 led to decreased GC cell proliferation, migration, invasion, and cell cycle arrest and enhanced apoptosis. Furthermore, silencing circ_0001013 resulted in diminished TWSG1 expression and inhibited transplanted tumor growth in the nude mice. CONCLUSION: Collectively, our findings indicated that circ_0001013 increased TWSG1 expression by binding to miR-136, thereby exerting oncogenic effects in GC.

Supplementation of tea polyphenols in sludge Fenton oxidation improves sludge dewaterability and reduces chemicals consumption.

The Fenton oxidation improves sludge dewatering but faces notable technical and economic challenges, including a narrow acidic pH range, slow reduction of Fe(III), and the use of high doses of chemicals. Herein, we used a natural polyhydroxyphenol tea polyphenols (TP), as an iron redox conversion enhancer, to mitigate these issues. Compared with the classical Fenton process at pH 3.0, the process with TP (33.8 mg/g dry solids (DS)) improved sludge dewaterability at pH 7.5 in a Fenton-like system with faster Fe(II)/Fe(III) cycling and two times lower consumption of the Fenton reagent. Sludge capillary suction time and specific resistance to filtration decreased from 70 s to 22 s and from 2.7 × 1013 m/kg to 5.2 × 1011 m/kg, respectively, while the required doses of Fe(II) and H2O2 were cut to 25 mg/g DS and 31.2 mg/g DS. Mechanistically, TP could bond readily with Fe(II)/Fe(III) at neutral pH to form stable complexes with complexation constants of 34 ± 161 M-1 and 52 ± 70 M-1, respectively, and reduce part of the Fe(III) to Fe(II) simultaneously. This maintained sufficient soluble Fe in the sludge and boosted efficient conversion of Fe(II)/Fe(III) to yield more hydroxyl radicals (•OH). Subsequently, •OH oxidation resulted in the decomposition of biopolymers with a molecular weight of 108 Da (e.g., 58.2% of polysaccharides and 31.6% of proteins in tightly bound extracellular polymeric substances) into small molecules and disintegration of bioflocs into smaller particles with increased porosity, contact angle, and cell lysis; these changes helped reduce bound water content and improved sludge dewaterability. In addition, the TP-mediated Fenton process disinfected fecal coliforms in the sludge and preserved the sludge organic matters. This work proposes a new paradigm for developing cost-effective sludge dewatering technologies that relies on the synergistic effects of plant polyphenols and advanced oxidation processes.

Parental exposure to 3-methylcholanthrene before gestation adversely affected the endocrine system and spermatogenesis in male F1 offspring.

The compound 3-methylcholanthrene (3-MC) is an environmental pollutant belonging to the PAHs, which reportedly have the potential to disrupt the endocrine systems of animals. In the present study, 4-week-old male and female mice were given 3-MC through their diet at a dose of 0.5 mg/kg of chow for 6 weeks before pregnancy. The first filial (F1) generation offspring of exposed or unexposed parental mice were sacrificed at the age of 5 or 10 weeks (F1-5 W or F1-10 W), and the potential effects on the F0 and F1 offspring were evaluated. The results showed that the serum and testicular testosterone (T) levels and the genes involved in T synthesis in F0 males and male F1-5 W individuals born from female mice exposed to 3-MC were significantly decreased. In addition, histological analysis suggested that exposure to 3-MC significantly disrupted testicular morphology in F0 mice and in the offspring of female mice exposed to 3-MC. Further investigation revealed that genes involved in spermatogenesis, such as Phosphoglycerate kinase 2 (Pgk2), Glial cell derived neurotrophic factor (Gdnf), Myeloblastosis oncogene (Myb), DEAD box helicase 4 (Ddx4) and KIT proto-oncogene receptor tyrosine kinase (Kit), were suppressed in these mice. However, the adverse effects of parental 3-MC exposure on the adolescent mice were mitigated when they grew to adulthood, which was verified by studies on F1-10 W mice. Our results suggest that female exposure to 3-MC has the potential to disrupt the endocrine system and spermatogenesis in male offspring; nevertheless, the adverse effects might be mitigated with age.

The prognostic value of intratumoral and peritumoral tumor-infiltrating FoxP3+Treg cells in of pancreatic adenocarcinoma: a meta-analysis.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) are major participants in the tumor microenvironment. The prognostic value of TILs in patients with pancreatic cancer is still controversial. METHODS: The aim of our meta-analysis was to determine the impact of FoxP3+Treg cells on the survival of pancreatic cancer patients. We searched for related studies in PubMed, EMBASE, Ovid, and Cochrane Library from the time the databases were established to Mar 30, 2017. We identified studies reporting the prognostic value of FoxP3+Treg cells in patients with pancreatic cancer. Overall survival (OS) and disease-free survival (DFS)/progression-free survival (PFS)/relapse-free survival (RFS) were investigated by pooling the data. The pooled hazard ratios (HRs) with 95% confidence intervals (95% CI) were used to evaluate the association between FoxP3+Treg cells and survival outcomes of pancreatic cancer patients. A total of 972 pancreatic cancer patients from 8 studies were included in our meta-analysis. RESULTS: High levels of infiltration with FoxP3+Treg cells were significantly associated with poor OS (HR=2.13; 95% CI 1.64-2.77; P<0.05) and poor DFS/PFS/RFS (HR=1.70; 95% CI 1.04 ~ 2.78; P< 0.05). Similar results were also observed in the peritumoral tissue; high levels of FoxP3+Treg cells were associated with poor OS (HR =2.1795% CI, CI 1.50-3.13). CONCLUSION: This meta-analysis indicated that high levels of intratumoral or peritumoral FoxP3+Treg cell infiltration could be recognized as a negative factor in the prognosis of pancreatic cancer.

Clinical prognostic value of circulating tumor cells in the treatment of pancreatic cancer with gemcitabine chemotherapy.

Pancreatic cancer (PC) is a highly malignant tumor type with a high early metastasis rate and no obvious symptoms. Gemcitabine is a first-line chemotherapeutic drug for PC. Since there is no distinct method to determine the efficacy of chemotherapy with gemcitabine in patients with PC, the purpose of the present study was to determine whether positivity for circulating tumor cells (CTCs) in patients with advanced PC is associated with response to gemcitabine chemotherapy and to explore whether CTCs may be used as a predictor of prognosis of patients with advanced PC undergoing chemotherapy. First, immunomagnetic microspheres (magnetic beads; MIL) were prepared to detect CTCs. The patients' clinical characteristics and survival data, as well as efficacy and adverse effects of chemotherapy, were prospectively obtained and their association with CTCs was analyzed. The results indicated that CTC-positive patients with advanced PC had a higher probability of developing resistance to gemcitabine chemotherapy than CTC-negative patients. Survival in the CTC-negative group was significantly higher than in the CTC-positive group (χ2=14.58, P<0.001). CTC-positive patients with advanced PC also had shorter progression-free survival (PFS) after chemotherapy with gemcitabine (P=0.01). In conclusion, CTC-positive patients with PC are more likely to develop gemcitabine resistance, have poor PFS and low incidence of thrombocytopenia. CTCs are expected to become a prognostic indicator for chemotherapy response in patients with PC.

The expression and clinical prognostic value of protein phosphatase 1 catalytic subunit beta in pancreatic cancer.

Pancreatic cancer (PAAD) is a common malignancy with a poor survival rate. The identification of novel biomarkers could improve clinical outcomes for patients with PAAD. Here we evaluated the expression and clinical significance of PPP1CB in PAAD. PPP1CB expression was higher in PAAD tissue than in matched paracancerous tissue (P < 0.05). We predicted a network of regulatory targets and protein interaction partners of PPP1CB, and identified a PPI network consisting of 39 node genes. The expression of 33 node genes was higher in PAAD tissue than in matching paracancerous tissue. High expression of the node genes ACTN4, ANLN, CLTB, IQGAP1, SPTAN1, and TMOD3 was associated with improved overall survival (P < 0.05). SiRNA knockdown of PPP1CB significantly reduced the migration and invasion of PAAD cells. A PPP1CB immunohistochemical staining was performed using a tissue microarray (TMA), consisting of tumor samples collected from 91 patients with PAAD (88 of which contained matched paracancerous tissues). The expression of PPP1CB in PAAD was significantly higher than in the matched paracancerous tissue, (P = 0.016). High PPP1CB expression was associated with patient sex (P = 0.048), alcohol use (P = 0.039), CEA (P= 0.038), N stage (P = 0.001), and invasion of nerve (P = 0.036). Furthermore, high PPP1CB expression was associated with significantly poorer overall survival (P = 0.022). Our data demonstrate that PPP1CB is associated with the migration and invasion of PAAD cells, and may be useful as an independent prognostic indicator for clinical outcome in patients with PAAD.

Myo-inositol mediates reactive oxygen species-induced programmed cell death via salicylic acid-dependent and ethylene-dependent pathways in apple.

As a versatile compound, myo-inositol plays vital roles in plant biochemistry and physiology. We previously showed that exogenous application of myo-inositol had a positive role in salinity tolerance in Malus hupehensis Rehd. In this study, we used MdMIPS (the rate-limiting gene of myo-inositol biosynthesis) transgenic apple lines to gain new insights into the physiological role of myo-inositol in apple. Decreasing myo-inositol biosynthesis in apple lines by RNA silencing of MdMIPS1/2 led to extensive programmed cell death, which manifested as necrosis of both the leaves and roots and, ultimately, plant death. Necrosis was directly caused by the excessive accumulation of reactive oxygen species, which may be closely associated with the cell wall polysaccharide-mediated increase in salicylic acid and a compromised antioxidant system, and this process was enhanced by an increase in ethylene production. In addition, a high accumulation of sorbitol promoted necrosis. This synergetic interplay between salicylic acid and ethylene was further supported by the fact that increased myo-inositol accumulation significantly delayed leaf senescence in MdMIPS1-overexpressing apple lines. Taken together, our results indicated that apple myo-inositol regulates reactive oxygen species-induced programmed cell death through salicylic acid-dependent and ethylene-dependent pathways.

MdUGT88F1-Mediated Phloridzin Biosynthesis Regulates Apple Development and Valsa Canker Resistance.

In apple (Malus domestica), the polyphenol profile is dominated by phloridzin, but its physiological role remains largely elusive. Here, we used MdUGT88F1 (a key UDP-glucose:phloretin 2'-O-glucosyltransferase gene) transgenic apple lines and Malus spp. germplasm to gain more insight into the physiological role of phloridzin in apple. Decreasing phloridzin biosynthesis in apple lines by RNA silencing of MdUGT88F1 led to a series of severe phenotypic changes that included severe stunting, reduced internode length, spindly leaf shape, increased stem numbers, and weak adventitious roots. These changes were associated directly with reduced lignin levels and disorders in cell wall polysaccharides. Moreover, compact organization of tissues and thickened bark enhanced resistance to Valsa canker (caused by the fungus Valsa mali), which was associated with lignin- and cell wall polysaccharide-mediated increases of salicylic acid and reactive oxygen species. Phloridzin was also assumed to be utilized directly as a sugar alternative and a toxin accelerator by V. mali in apple. Therefore, after infection with V. mali, a higher level of phloridzin slightly compromised resistance to Valsa canker in MdUGT88F1-overexpressing apple lines. Taken together, our results shed light on the importance of MdUGT88F1-mediated biosynthesis of phloridzin in the interplay between plant development and pathogen resistance in apple trees.

Effects of antiatherosclerosis in carotid artery by RNAi-mediated silencing of MCP-1 expression.

BACKGROUND: Our objective was to identify the effects of MCP-1 siRNA in vivo transfection in an atherosclerosis model on local expression of MCP-1 and pathogenesis of atherosclerosis. METHODS: Carotid atherosclerosis was induced in 28 New Zealand white rabbits. Rabbits were divided into three groups randomly: RNAi group, model group, and blank plasmid group. siRNA-expressing vector was transfected to blood vessels by liposomes. The carotid arteries were processed for morphological evaluation. Local expression of MCP-1 was detected by immunohistochemistry, RT-PCR, and Western blot. RESULTS: On hematoxylin and eosin-stained sections, partial endothelial cells detached while intimae were less thickened in the RNAi group compared to the model and blank plasmid groups; the I:M ratio was significantly reduced to 1.46 in the RNAi group compared to the model and blank plasmid groups (5.55 and 5.27, respectively). The results of immunohistochemistry showed that MCP-1 expression was less colorized and less positive in the RNAi group. RT-PCR and Western blot showed reduced expression in the RNAi group than in the model and blank plasmid groups. There were highly positive correlations between semiquantitative RT-PCR and the I:M ratio (r = 0.968). CONCLUSION: Expression of MCP-1 was successfully inhibited by transfecting MCP-1 siRNA expression plasmid to the carotid artery, and the progression of atherosclerosis was restricted by RNAi-mediated silencing of MCP-1 expression.

[Construction of adenoviral vector encoding Calponin-1 siRNA and its effect on human myometrium cells in vitro].

OBJECTIVE: To investigate the effect of Calponin-1 suppression on human myometrium cells through adenovirus mediated siRNA. METHODS: Human uterine smooth muscle tissues were digested with enzymes, cultured and confirmed with immunocytochemistry. Adenovirus siRNA-Calponin-1 plasmid was transfected into primary cultured uterine smooth muscle cells in vitro. The expressions of Calponin-1 mRNA and protein were analyzed by RT-PCR and Western blot, respectively. RESULTS: The pAdEasy-pShuttle-U6-Calponin-1 siRNA plasmid was successfully constructed, and Calponin-1 siRNA mediated by recombinant adenovirus resulted in markedly reduced expression of Calponin-1 mRNA and protein in human myometrium cells. The gray values of Calponin-1 mRNA in the uterine smooth muscle cells in the experimental, blank control, and empty vector groups were 316.3+/-39.2, 1048.5+/-126.4 and 1027.2+/-127.5, respectively. The gray values of Calponin-1 protein were 323.3+/-43.2, 1021.5+/-143.4, and 1019.2+/-144.5, respectively. The difference between the experimental group and the blank control group as well as the empty vector group was significant (P< 0.05). There was no significant difference between the empty vector group and the blank control group (P>0.05). CONCLUSION: The pAdEasy-pShuttle-U6-Calponin-1 siRNA plasmid can inhibit the expression of Calponin-1 in human myometrium cells in vitro, which may be a useful approach to determine the role of Calponin-1 in delivery.

[Progress in genetic modification of vascular prostheses and its significance in molecular reconstruction].

OBJECTIVE: To summarize the current progress in the genetic modification of vascular prostheses and to look forward to the future of genetic modification in vascular prostheses. METHODS: PubMed online search with the key words of "vascular prostheses, gene" was undertaken to identify articles about the genetic modification of vascular prostheses. Then these articles were reviewed and summarized. RESULTS: To improve long-term patency of vascular prostheses, various genes were transfected into seeded cells. The anti thrombosis activity of local vessels increased. CONCLUSION: Progresses in tissue engineering and molecular biology make possible endothelialization and genetic modification of vascular prostheses. However, because most relevant researches are still basic experiments, further study is needed before clinical application.