Anti-PD-1/PD-L1 therapy for colorectal cancer: Clinical implications and future considerations.

Colorectal cancer (CRC) is the third most prevalent cancer in the world. The PD-1/PD-L1 pathway plays a crucial role in modulating immune response to cancer, and PD-L1 expression has been observed in tumor and immune cells within the tumor microenvironment of CRC. Thus, immunotherapy drugs, specifically checkpoint inhibitors, have been developed to target the PD-1/PD-L1 signaling pathway, thereby inhibiting the interaction between PD-1 and PD-L1 and restoring T-cell function in cancer cells. However, the emergence of resistance mechanisms can reduce the efficacy of these treatments. To counter this, monoclonal antibodies (mAbs) have been used to improve the efficacy of CRC treatments. mAbs such as nivolumab and pembrolizumab are currently approved for CRC treatment. These antibodies impede immune checkpoint receptors, including PD-1/PD-L1, and their combination therapy shows promise in the treatment of advanced CRC. This review presents a concise overview of the use of the PD-1/PD-L1 blockade as a therapeutic strategy for CRC using monoclonal antibodies and combination therapies. Additionally, this article outlines the function of PD-1/PD-L1 as an immune response suppressor in the CRC microenvironment as well as the potential advantages of administering inflammatory agents for CRC treatment. Finally, this review analyzes the outcomes of clinical trials to examine the challenges of anti-PD-1/PD-L1 therapeutic resistance.

[Emission Inventory of Greenhouse Gas from Urban Wastewater Treatment Plants and Its Temporal and Spatial Distribution in China].

Urban wastewater treatment plants are considered important greenhouse gas resources with massive emissions of carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O) during operation. Based on the emission factor approach of pollutant reduction, the 2014 emission inventory of greenhouse gases (CO2, CH4, and N2O) from urban wastewater treatment plants in China was established. In addition, the temporal and spatial distribution and influencing factors of greenhouse gas emissions were analyzed in this study. The results showed that total emissions of greenhouse gas from urban wastewater treatment plants in China was 7348.60 Gg (CO2-eq) in 2014, which included CO2, CH4, and N2O emissions of 6054.57 Gg, 27.47 Gg (769.08 Gg, CO2-eq), and 1.98 Gg (524.95 Gg, CO2-eq), respectively. The difference in greenhouse gas emissions among provinces was significant:high emissions appeared in the eastern areas of China, low emissions were observed in the northwest, and hardly any emissions were found in Xizang. From 2005 to 2014, annual greenhouse gas emissions from urban sewage treatment plants in China increased by 229.4%, and the rates of CO2, CH4, and N2O increased by 217.9%, 217.9%, and 520.3%, respectively. The regional economic development level and number of wastewater treatment plants were correlated the most with the emissions of greenhouse gasses, and the per-capita protein supply was closely related with the N2O emission.

The Design and Construction of K11: A Novel α-Helical Antimicrobial Peptide.

Amphipathic α-helical antimicrobial peptides comprise a class of broad-spectrum agents that are used against pathogens. We designed a series of antimicrobial peptides, CP-P (KWKSFIKKLTSKFLHLAKKF) and its derivatives, and determined their minimum inhibitory concentrations (MICs) against Pseudomonas aeruginosa, their minimum hemolytic concentrations (MHCs) for human erythrocytes, and the Therapeutic Index (MHC/MIC ratio). We selected the derivative peptide K11, which had the highest therapeutic index (320) among the tested peptides, to determine the MICs against Gram-positive and Gram-negative bacteria and 22 clinical isolates including Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Staphylococcus epidermidis, and Klebsiella pneumonia. K11 exhibited low MICs (less than 10 µg/mL) and broad-spectrum antimicrobial activity, especially against clinically isolated drug-resistant pathogens. Therefore, these results indicate that K11 is a promising candidate antimicrobial peptide for further studies.

Topological and functional discovery in a gene coexpression meta-network of gastric cancer.

Gastric cancer is a leading cause of global cancer mortality, but comparatively little is known about the cellular pathways regulating different aspects of the gastric cancer phenotype. To achieve a better understanding of gastric cancer at the levels of systems topology, functional modules, and constituent genes, we assembled and systematically analyzed a consensus gene coexpression meta-network of gastric cancer incorporating >300 tissue samples from four independent patient populations (the "gastrome"). We find that the gastrome exhibits a hierarchical scale-free architecture, with an internal structure comprising multiple deeply embedded modules associated with diverse cellular functions. Individual modules display distinct subtopologies, with some (cellular proliferation) being integrated within the primary network, and others (ribosomal biosynthesis) being relatively isolated. One module associated with intestinal differentiation exhibited a remarkably high degree of autonomy, raising the possibility that its specific topological features may contribute towards the frequent occurrence of intestinal metaplasia in gastric cancer. At the single-gene level, we discovered a novel conserved interaction between the PLA2G2A prognostic marker and the EphB2 receptor, and used tissue microarrays to validate the PLA2G2A/EphB2 association. Finally, because EphB2 is a known target of the Wnt signaling pathway, we tested and provide evidence that the Wnt pathway may also similarly regulate PLA2G2A. Many of these findings were not discernible by studying the single patient populations in isolation. Thus, besides enhancing our knowledge of gastric cancer, our results show the broad utility of applying meta-analytic approaches to genome-wide data for the purposes of biological discovery.

Reduced expression of EphB2 that parallels invasion and metastasis in colorectal tumours.

EphB2, a receptor tyrosine kinase regulated by the beta-catenin/Tcf4 complex, is expressed in the proliferative compartment of mouse intestine and regulates bidirectional migration of intestinal precursor cells in the crypt-villus axis through repulsive interaction with Ephrin-B ligands. Recently, it has been shown that reduction of EphB activity accelerates colon tumour progression in the Apc(Min/+) mice. In this study, we examined the expression of EphB2 in normal colon, adenomas, primary colorectal cancers (CRCs), lymph node metastases and liver metastases using immunohistochemistry on tissue microarrays. In addition, EphB2 was overexpressed in SW480 colon cancer cells to study its effect in vitro. We found that EphB2 was expressed in 100% of normal colon crypt base cells, 78% of adenomas, 55.4% of primary CRCs, 37.8% of lymph node metastases and 32.9% of liver metastases (all differences were statistically significant at P < 0.001 compared with primary CRCs). Patients with CRCs that lose EphB2 expression had more advanced tumour stage (P = 0.005), poor differentiation (P < 0.001), poor overall survival (P = 0.005) and disease-free survival (P = 0.001), with the latter being independent of tumour stage. In vitro studies showed that overexpression of EphB2 inhibited colon cancer cell growth in colony formation assay and activation of EphB2 receptor inhibited colon cancer cell adhesion and migration. Our data demonstrated a progressive loss of EphB2 expression in each critical step of colon carcinogenesis, including the onset of invasion, dedifferentiation and metastasis which are paralleled by adverse patient outcome. EphB2 may achieve its tumour suppressor function through regulation of cell survival, adhesion and migration.

[Dynamic expression of antigen MG7 in the gastric cancer and gastric precancerous lesions].

OBJECTIVE: To study the kinetics of MG7 expression in the process of gastric cancer development. METHODS: The expression level of antigen MG7 on gastric mucosa in 406 cases was determined by immunohistochemical techniques. The classification of intestinal metaplasia of gastric mucosa was determined by histochemistry techniques on gastric mucosa in 82 cases. RESULTS: The positive rates of MG7 expression in normal gastric mucosa, intestinal metaplasia and dysplasia of gastric mucosa and gastric cancer all increased gradually (P < 0.01). The positive rates of MG7 expression in superficial gastritis, atrophic gastritis and gastric cancer increased in sequence (P < 0.01). The positive rate of antigen MG7 expression in III intestinal metaplasia of gastric mucosa was significantly different with I and II intestinal metaplasia (P < 0.05). CONCLUSIONS: MG7 was quite specific in gastric cancer thus could be used as a good index in the screening of gastric cancer. Patients with III intestinal metaplasia of gastric mucosa, atrophic gastritis and dysplasia of gastric mucosa should be closely followed in order to improve the early detection on gastric cancer. It seemed that MG7 was clinically valuable in the dynamic follow-up of gastric precursors.

Expression of gastric cancer-associated MG7 antigen in gastric cancer, precancerous lesions and H. pylori -associated gastric diseases.

AIM: To investigate the relationship between the antigen MG7 antigen expression and gastric cancer as well as precancerous condition; to study the relationship between the MG7 antigen expression and H. pylori infection in benign gastric lesions in order to find out the effect of H. pylori infection on the process of gastric cancer development. METHODS: The level of MG7 antigen expression was determined by immunohistochemical method in 383 gastric biopsied materials. The intestinal metaplasia was determined by histochemistry method. The H. pylori infection was determined by HE stain, PCR and ELISA in 291 specimens, among which only 34 cases of H. pylori-associated gastric lesions were followed up. RESULTS: The positive rate of MG7 expression in normal gastric mucosa, intestinal metaplasia, dysplasia and gastric cancer increased gradually in ascending order (P<0.01). The positive rate of MG7 antigen expression in type III intestinal metaplasia of gastric mucosa was higher than that of type I and II intestinal metaplasia, being highly significant (P<0.05).The positive rate of MG7 antigen expression in superficial gastritis, atrophic gastritis and gastric cancer increased gradually (11.9 %, 64.8 %, 91.2 %, P<0.01). There was no significant difference between H. pylori-negative and H. pylori-positive intestinal metaplasia, atrophic gastritis and dysplasia of gastric epithelium in the positive rate of MG7 antigen expression. There was no expression of MG7 antigen in H. pylori-negative superficial gastritis. The positive rate of MG7 expression in H. pylori-positive superficial gastritis was 20.5 %, and the difference between them was significant (P<0.05). During following up, one of the three H. pylori negative cases turned positive again, and its MG7 antigen expression turned to be stronger correspondingly. 3 of 31 H. pylori positive cases were detected as early gastric cancer, among which one with "+++" MG7 antigen expression was diminished after H. pylori eradication. CONCLUSION: MG7 antigen expression is highly specific in gastric cancer and can be used as a good marker for screening of gastric cancer; type III intestinal metaplasia, atrophic gastritis and dysplasia should be followed up and MG7 antigen expression has high clinical value in the dynamic follow-up study; although the positive -MG7 in positive -H. pylori superficial gastritis show benign morphology in features, there is still the potential risk of developing into gastric cancer, hence special attention should be paid to those showing increasing MG7 antigen expression.