Immune Checkpoint and Tumor Therapy

Cancer immunotherapy employing immune checkpoint inhibitors (ICI) has revolutionized the tumor therapy far beyond their impressing clinical effects. Immune checkpoint therapy (ICT), which is directly involved in different immunosuppressive mechanisms at tumor sites, has been thoroughly studied. Nevertheless, the “off-target” effects of ICIs following systemic administration is still challenging. In addition, the clinical response rate of ICT is still unsatisfactory in that only a few patients hold lasting benefits. In this chapter, the mechanism of most widely used ICIs, including those based on CTLA-4 and PD-1/PD-L1, has been introduced. The approaches to enhancing the efficacy of ICT have been highlighted, namely improving targeted delivery of ICI by employing nanotechnology, modulating the immunosuppressive tumor microenvironment (TME), and combining ICT with other therapies. We hope advanced strategies summarized in this chapter would further inspire the development of ICT to boost their effectiveness while minimize unwanted side effects

Identification of novel immune-related targets mediating disease progression in acute pancreatitis

IntroductionAcute pancreatitis (AP) is an inflammatory disease with very poor outcomes. However, the order of induction and coordinated interactions of systemic inflammatory response syndrome (SIRS) and compensatory anti-inflammatory response syndrome (CARS) and the potential mechanisms in AP are still unclear.MethodsAn integrative analysis was performed based on transcripts of blood from patients with different severity levels of AP (GSE194331), as well as impaired lung (GSE151572), liver (GSE151927) and pancreas (GSE65146) samples from an AP experimental model to identify inflammatory signals and immune response-associated susceptibility genes. An AP animal model was established in wild-type (WT) mice and Tlr2-deficient mice by repeated intraperitoneal injection of cerulein. Serum lipase and amylase, pancreas impairment and neutrophil infiltration were evaluated to assess the effects of Tlr2 in vivo.ResultsThe numbers of anti-inflammatory response-related cells, such as M2 macrophages (P = 3.2 × 10–3), were increased with worsening AP progression, while the numbers of pro-inflammatory response-related cells, such as neutrophils (P = 3.0 × 10–8), also increased. Then, 10 immune-related AP susceptibility genes (SOSC3, ITGAM, CAMP, FPR1, IL1R1, TLR2, S100A8/9, HK3 and MMP9) were identified. Finally, compared with WT mice, Tlr2-deficient mice exhibited not only significantly reduced serum lipase and amylase levels after cerulein induction but also alleviated pancreatic inflammation and neutrophil accumulation.DiscussionIn summary, we discovered SIRS and CARS were stimulated in parallel, not activated consecutively. In addition, among the novel susceptibility genes, TLR2might be a novel therapeutic target that mediates dysregulation of inflammatory responses during AP progression

Conformational Transition Pathway in the Inhibitor Binding Process of Human Monoacylglycerol Lipase

Human monoacylglycerol lipase (MGL) catalyzes the hydrolysis of 2-arachidonoylglycerol to arachidonic and glycerol, which plays a pivotal role in the normal biological processes of brain. Co-crystal structure of the MGL in complex with its inhibitor, compound 1, shows that the helix α4 undergoes large-scale conformational changes in response to the compound 1 binding compared to the apo MGL. However, the detailed conformational transition pathway of the helix α4 in the inhibitor binding process of MGL has remained unclear. Here, conventional molecular dynamics (MD) and nudged elastic band (NEB) simulations were performed to explore the conformational transition pathway of the helix α4. Conventional MD simulations unveiled that the compound 1 induced the closed conformation of the active site of MGL, reduced the conformational flexibility of the helix α4, and elicited the large-scale conformational rearrangement of the helix α4, leading to the complete folding of the helix α4. Moreover, NEB simulations revealed that the conformational transition pathway of helix α4 underwent an almost 180° counter-clockwise rotation of the helix α4. Our computational results advance the structural and mechanistic understanding of the inhibitory mechanism

Immune Checkpoint and Tumor Therapy

Cancer immunotherapy employing immune checkpoint inhibitors (ICI) has revolutionized the tumor therapy far beyond their impressing clinical effects. Immune checkpoint therapy (ICT), which is directly involved in different immunosuppressive mechanisms at tumor sites, has been thoroughly studied. Nevertheless, the “off-target” effects of ICIs following systemic administration is still challenging. In addition, the clinical response rate of ICT is still unsatisfactory in that only a few patients hold lasting benefits. In this chapter, the mechanism of most widely used ICIs, including those based on CTLA-4 and PD-1/PD-L1, has been introduced. The approaches to enhancing the efficacy of ICT have been highlighted, namely improving targeted delivery of ICI by employing nanotechnology, modulating the immunosuppressive tumor microenvironment (TME), and combining ICT with other therapies. We hope advanced strategies summarized in this chapter would further inspire the development of ICT to boost their effectiveness while minimize unwanted side effects.</jats:p

Gastrointestinal bleeding as an initial manifestation in asymptomatic multiple myeloma: A case report and review of the literature

Multiple myeloma (MM) is an uncommon type of malignant hematological neoplasm which, besides primarily involving the bone marrow, has a potent tendency to involve other organs and to present with various clinical manifestations. Involvement of the gastrointestinal (GI) system, particularly presenting with GI hemorrhage, in the course of MM is extremely rare. In the present study, we report a case of a middle-aged male who initially demonstrated GI bleeding and was finally diagnosed with MM. Further laboratory examinations, including analysis of globulin in the blood, bone marrow aspiration and radiogram, supported this diagnosis. This case may promote the possible involvement of plasma cell myeloma in the differential diagnosis of patients with unexplained and refractory GI bleeding. In this study we also present a thorough review of the literature with regard to the association between MM and GI hemorrhage

Reducing energy consumption of heat pumps by introducing a thermal energy storage system

We proposed a short-term thermal energy storage system by applying Phase Change Materials (PCMs) in air ducts connected to an indoor air conditioning unit within a ceiling space. PCM tubes were arranged in a staggered layout in the air duct and cooled by chilled air from the air conditioning unit during “charging” mode, whereas the PCM tubes released cold energy to the room space without operation of the compressor during “discharging” mode. The charging mode allowed for an increase in the partial load ratio of the heat pump to prevent low-efficiency operation at <20% load, which can increase seasonal energy efficiency. We constructed an energy simulation program, where the heat exchange coefficient between the PCM tubes and air was varied with airflow rate and the temperature difference between the PCM and air, in accordance with results from CFD analysis. Switching between the charging and discharging modes was based on the outlet temperature (Tout) and 30% of the rated capacity of the indoor unit (Lr). The heat balance between the charging and discharging modes was improved by this change to the system control. A higher load factor and higher COP resulted in a 7.6% reduction in energy consumption