Hallmarks of the tumour microenvironment of gliomas and Its interaction with emerging immunotherapy modalities

Gliomas are aggressive, primary central nervous system tumours arising from glial cells. Glioblastomas are the most malignant. They are known for their poor prognosis or median overall survival. The current standard of care is overwhelmed by the heterogeneous, immunosuppressive tumour microenvironment promoting immune evasion and tumour proliferation. The advent of immunotherapy with its various modalities—immune checkpoint inhibitors, cancer vaccines, oncolytic viruses and chimeric antigen receptor T cells and NK cells—has shown promise. Clinical trials incorporating combination immunotherapies have overcome the microenvironment resistance and yielded promising survival and prognostic benefits. Rolling these new therapies out in the real-world scenario in a low-cost, high-throughput manner is the unmet need of the hour. These will have practice-changing implications to the glioma treatment landscape. Here, we review the immunobiological hallmarks of the TME of gliomas, how the TME evades immunotherapies and the work that is being conducted to overcome this interplay

Exosomes in the diagnosis and treatment of renal cell cancer

Renal cell carcinoma (RCC) is the most prevalent type of kidney cancer originating from renal tubular epithelial cells, with clear cell RCC comprising approximately 80% of cases. The primary treatment modalities for RCC are surgery and targeted therapy, albeit with suboptimal efficacies. Despite progress in RCC research, significant challenges persist, including advanced distant metastasis, delayed diagnosis, and drug resistance. Growing evidence suggests that extracellular vesicles (EVs) play a pivotal role in multiple aspects of RCC, including tumorigenesis, metastasis, immune evasion, and drug response. These membrane-bound vesicles are released into the extracellular environment by nearly all cell types and are capable of transferring various bioactive molecules, including RNA, DNA, proteins, and lipids, aiding intercellular communication. The molecular cargo carried by EVs renders them an attractive resource for biomarker identification, while their multifarious role in the RCC offers opportunities for diagnosis and targeted interventions, including EV-based therapies. As the most versatile type of EVs, exosomes have attracted much attention as nanocarriers of biologicals, with multi-range signaling effects. Despite the growing interest in exosomes, there is currently no widely accepted consensus on their subtypes and properties. The emerging heterogeneity of exosomes presents both methodological challenges and exciting opportunities for diagnostic and clinical interventions. This article reviews the characteristics and functions of exosomes, with a particular reference to the recent advances in their application to the diagnosis and treatment of RCC

Cardiorespiratory and sedation evaluation of the combination of dexmedetomidine-butorphanol-midazolam or detomidine butorphanol-midazolam in collared peccaries (Pecari tajacu)

The study compared the cardiorespiratory, hemogasometric and sedative effects of the combination of midazolam (0.41mg/kg) and butorphanol (0.31mg/kg) plus detomidine (157μg/kg) (DTMB) or dexmedetomidine (36μg/kg) (DXMB) in collared peccaries. Collared peccaries (n= 20) were divided into two groups, either DTMB or DXMB. The variables (FC, f, PAM, SpO2, EtCO2 and TR) were evaluated after application of the drugs. Sedation was assessed by visual analogue scale, muscle relaxation, posture and auditory response. ANOVA followed by paired t-test (parametric) and Mann Whitney Rank Sum Test (non-parametric) with P< 0.05 were performed. No statistical difference was observed for the latency period. A significant increase was observed between groups for the variables f, PAM and SpO2 with higher values for DTMB and EtCO2 with higher values for DXMB. The two groups presented a reduction in HR and lactate concentration, and an increase in bicarbonate concentration. SpO2 remained below 90% throughout the experiment in both groups. The animals of the two groups presented deep sedation and maximum muscle relaxation. It is concluded that the two protocols tested provided adequate sedation and could be indicated for chemical containment of collared peccaries.A presente pesquisa comparou os efeitos cardiorrespiratórios, hemogasométricos e sedativos da associação midazolam (0,41mg/kg) e butorfanol (0,31mg/kg) acrescida de detomidina (157μg/kg) (DTMB) ou dexmedetomidina (36μg/kg) (DXMB) em catetos. Catetos adultos (n=20) foram distribuídos em dois grupos, DTMB ou DXMB. As variáveis (FC, f, PAM, SpO2, EtCO2 e TR) foram avaliadas após aplicação dos fármacos. A sedação foi avaliada por meio de escala analógica visual, relaxamento muscular, postura e resposta auditiva. Foi realizada ANOVA, seguida de teste t pareado (paramétricos) e teste de Mann-Whitney rank-sum test (não paramétricos), com P<0,05. Não foi observada diferença estatística entre os grupos para o período de latência. Observou-se diferença significativa entre grupos para as variáveis f, PAM e SpO2, com maiores valores para DTMB, e EtCO2, com maiores valores para DXMB. Os dois grupos apresentaram redução da FC e da concentração de lactato, bem como aumento da concentração de bicarbonato. A SpO2 permaneceu abaixo de 90%, durante todo o período experimental, nos dois grupos estudados. Os animais dos dois grupos apresentaram sedação profunda e relaxamento muscular máximo. Conclui-se que os dois protocolos testados proporcionaram adequada sedação, podendo ser indicados para contenção química de catetos adultos

Identification and Characterization of Paramyosin from Cyst Wall of Metacercariae Implicated Protective Efficacy against Clonorchis sinensis Infection

Human clonorchiasis has been increasingly prevalent in recent years and results in a threat to the public health in epidemic regions, motivating current strategies of vaccines to combat Clonorchis sinensis (C. sinensis). In this study, we identified C. sinensis paramyosin (CsPmy) from the cyst wall proteins of metacercariae by proteomic approaches and characterized the expressed recombinant pET-26b-CsPmy protein (101 kDa). Bioinformatics analysis indicated that full-length sequences of paramyosin are conserved in helminthes and numerous B-cell/T-cell epitopes were predicted in amino acid sequence of CsPmy. Western blot analysis showed that CsPmy was expressed at four life stages of C. sinensis, both cyst wall proteins and soluble tegumental components could be probed by anti-CsPmy serum. Moreover, immunolocalization results revealed that CsPmy was specifically localized at cyst wall and excretory bladder of metacercaria, as well as the tegument, oral sucker and vitellarium of adult worm. Both immunoblot and immunolocalization results demonstrated that CsPmy was highly expressed at the stage of adult worm, metacercariae and cercaria, which could be supported by real-time PCR analysis. Both recombinant protein and nucleic acid of CsPmy showed strong immunogenicity in rats and induced combined Th1/Th2 immune responses, which were reflected by continuous high level of antibody titers and increased level of IgG1/IgG2a subtypes in serum. In vaccine trials, comparing with control groups, both CsPmy protein and DNA vaccine exhibited protective effect with significant worm reduction rate of 54.3% (p<0.05) and 36.1% (p<0.05), respectively. In consistence with immune responses in sera, elevated level of cytokines IFN-γ and IL-4 in splenocytes suggested that CsPmy could induce combined cellular immunity and humoral immunity in host. Taken together, CsPmy could be a promising vaccine candidate in the prevention of C. sinensis regarding its high immunogenicity and surface localization

Avaliação cardiorrespiratória e de sedação da associação de dexmedetomidina-butorfanol-midazolam ou detomidina-butorfanol-midazolam em catetos (Pecari tajacu)

RESUMO A presente pesquisa comparou os efeitos cardiorrespiratórios, hemogasométricos e sedativos da associação midazolam (0,41mg/kg) e butorfanol (0,31mg/kg) acrescida de detomidina (157μg/kg) (DTMB) ou dexmedetomidina (36μg/kg) (DXMB) em catetos. Catetos adultos (n=20) foram distribuídos em dois grupos, DTMB ou DXMB. As variáveis (FC, f, PAM, SpO2, EtCO2 e TR) foram avaliadas após aplicação dos fármacos. A sedação foi avaliada por meio de escala analógica visual, relaxamento muscular, postura e resposta auditiva. Foi realizada ANOVA, seguida de teste t pareado (paramétricos) e teste de Mann-Whitney rank-sum test (não paramétricos), com P&lt;0,05. Não foi observada diferença estatística entre os grupos para o período de latência. Observou-se diferença significativa entre grupos para as variáveis f, PAM e SpO2, com maiores valores para DTMB, e EtCO2, com maiores valores para DXMB. Os dois grupos apresentaram redução da FC e da concentração de lactato, bem como aumento da concentração de bicarbonato. A SpO2 permaneceu abaixo de 90%, durante todo o período experimental, nos dois grupos estudados. Os animais dos dois grupos apresentaram sedação profunda e relaxamento muscular máximo. Conclui-se que os dois protocolos testados proporcionaram adequada sedação, podendo ser indicados para contenção química de catetos adultos.</jats:p