In cancer-immunity cycle, the immune checkpoint PD1 and its ligand PDL1 act as accomplices to help tumors resist to immunity-induced apoptosis and promote tumor progression. Immunotherapy targeting PD1/PDL1 axis can effectively block its pro-tumor activity. Anti-PD1/PDL1 therapy has achieved great success in the past decade. However, only a subset of patients showed clinical responses. Most of the patients can not benefit from anti-PD1/PDL1 therapy. Furthermore, a large group of responders would develop acquired resistance after initial responses. Therefore, understanding the mechanisms of resistance is necessary for improving anti-PD1/PDL1 efficacy. Currently, researchers have identified primary resistance mechanisms which include insufficient tumor immunogenicity, disfunction of MHCs, irreversible T cell exhaustion, primary resistance to IFN-γ signaling, and immunosuppressive microenvironment. Some oncogenic signaling pathways also contribute to the primary resistance. Under the pressure applied by anti-PD1/PDL1 therapy, tumors experience immunoediting and preserve beneficial mutations, upregulate the compensatory inhibitory signaling and induce re-exhaustion of T cells, all of which may attenuate the durability of the therapy. Here we explore the underlying mechanisms in detail, review biomarkers that help identifying responders among patients and discuss the strategies that may relieve the anti-PD1/PDL1 resistance.

Immunotherapy is a currently popular treatment strategy for cancer patients. Although recent developments in cancer immunotherapy have had significant clinical impact, only a subset of patients exhibits clinical response. Therefore, understanding the molecular mechanisms of immunotherapy resistance is necessary. The mechanisms of immune escape appear to consist of two distinct tumor characteristics: a decrease in effective immunocyte infiltration and function and the accumulation of immunosuppressive cells in the tumor microenvironment. Several host-derived factors may also contribute to immune escape. Moreover, inter-patient heterogeneity predominantly results from differences in somatic mutations between cancers, which has led to the hypothesis that differential activation of specific tumor-intrinsic pathways may explain the phenomenon of immune exclusion in a subset of cancers. Increasing evidence has also shown that tumor-intrinsic signaling plays a key role in regulating the immunosuppressive tumor microenvironment and tumor immune escape. Therefore, understanding the mechanisms underlying immune avoidance mediated by tumor-intrinsic signaling may help identify new therapeutic targets for expanding the efficacy of cancer immunotherapies.

Tumor‐associated macrophages (TAMs), key immune cells in the tumor microenvironment, are shown to be closely correlated with the progression of non‐small cell lung cancer (NSCLC). Cancer stem cells (CSCs) can contribute to NSCLC progression as well. We aimed to clarify whether TAMs promote the progression of NSCLC by mainly affecting the activities of CSCs. We found that TAM‐like cells promoted CSC‐like properties in NSCLC cells in vitro, which was mediated by TAM‐derived IL‐10. TAM‐derived IL‐10 promoted CSC‐like properties of NSCLC cells through JAK1/STAT1/NF‐κB/Notch1 signaling. Blockade of IL‐10/JAK1 signaling inhibited TAM‐mediated NSCLC tumor growth in vivo, and the TAM‐mediated expression of CSC‐related and mesenchymal‐related genes in NSCLC. Lastly, expression levels of these signaling molecules were significantly correlated with survival of NSCLC patients. Therefore, IL‐10/JAK1 signaling might be a potential therapeutic target for NSCLC treatment.

Complex interactions between the immune system and tumor cells exist throughout the initiation and development of cancer. Although the immune system eliminates malignantly transformed cells in the early stage, surviving tumor cells evade host immune defense through various methods and even reprogram the anti-tumor immune response to a pro-tumor phenotype to obtain unlimited growth and metastasis. The high proliferation rate of tumor cells increases the demand for local nutrients and oxygen. Poorly organized vessels can barely satisfy this requirement, which results in an acidic, hypoxic, and glucose-deficient tumor microenvironment. As a result, lipids in the tumor microenvironment are activated and utilized as a primary source of energy and critical regulators in both tumor cells and related immune cells. However, the exact role of lipid metabolism reprogramming in tumor immune response remains unclear. A comprehensive understanding of lipid metabolism dysfunction in the tumor microenvironment and its dual effects on the immune response is critical for mapping the detailed landscape of tumor immunology and developing specific treatments for cancer patients. In this review, we have focused on the dysregulation of lipid metabolism in the tumor microenvironment and have discussed its contradictory roles in the tumor immune response. In addition, we have summarized the current therapeutic strategies targeting lipid metabolism in tumor immunotherapy. This review provides a comprehensive summary of lipid metabolism in the tumor immune response.

The mini-subvastus approach could offer faster recovery, less pain and shorter hospital stays without compromising the principles of proper prosthesis position and limb alignment compared with the medial parapatellar approach.

Low frequency pulsed electromagnetic field (LFPEMF) has been shown to provide anti-inflammatory and antioxidative effects. However, there are no reports on whether LFPEMF can treat spinal cord injury (SCI) and its therapeutic mechanism. Therefore, this study was conducted to investigate whether LFPEMF can promote the recovery of neurological function after SCI in rats and its therapeutic mechanism. Basso-Beattie-Bresnahan (BBB) score and transcranial magnetic motor-evoked potentials (tcMMEPs) were recorded to assess the recovery of neurological function. Hematoxylin and eosin (HE) staining and luxol fast blue (LFB) staining were performed to assess the severity of SCI. Immunofluorescence (IF) staining and western blotting (WB) were performed to assess the differentiation of oligodendrocyte precursor cells (OPCs) into oligodendrocytes (OLs). Toluidine blue (TB) staining was performed to assess remyelination. WB and enzyme-linked immunosorbent assays (ELISA) were performed to assess the expression of neurotrophins and inflammatory factors. Our results showed that following stimulation by LFPEMF, there were significant improvements in BBB scores, tcMMEP amplitudes, the extent of the damage, and reduced demyelination in rats after SCI. The mature OLs, the number of well-myelinated fibers, and the myelin sheath thickness significantly increased in rats stimulated by LFPEMF after SCI. The expression of neurotrophins significantly increased, and the expression of inflammatory factors significantly decreased in rats stimulated by LFPEMF after SCI. Therefore, we suggest that LFPEMF can promote the recovery of neurological function in rats after SCI by improving the differentiation of OPCs into OLs and promoting remyelination, as well as by inhibiting inflammation and promoting neurotrophic effects. ß

Nonunion and C1-C2 instability of odontoid fractures usually result from delayed diagnosis and inappropriate treatment. However, the available treatment options for odontoid fractures remain controversial. The authors evaluated the effectiveness of internal screw fixation via the C1 and C2 pedicle in cases of old odontoid fractures. This retrospective study included 21 patients with old odontoid fractures (13 men and 8 women; mean age, 46.5 years; range, 24-69 years). Internal screw fixation via the C1 and C2 pedicle was performed in all patients. Fracture reduction and C1-C2 fusion were assessed with imaging. The neck pain visual analog scale score and cervical spinal cord functional Japanese Orthopaedic Association score (for those who had cervical spinal cord injury) were used to evaluate the effectiveness of treatment. Postoperative complications were recorded. Postoperative imaging showed that the C1-C2 dislocation was satisfactorily repositioned in all patients. Bone fusion was observed 1 year after surgery in all patients. No loosening or breaking of internal fixation occurred. The preoperative neck pain visual analog scale score was 5.9±1.5 and improved significantly to 1.8±0.8 after surgery (P<.001). The Japanese Orthopaedic Association score in patients with cervical spinal injury (n=14) was 9.2±1.9 and also significantly improved to 13.8±1.9 at the last follow-up examination (P<.001), with an average improvement rate of 61.0%. No iatrogenic vertebral artery injury or severe spinal cord injury occurred. Screw fixation via the C1 and C2 pedicle was found to be an effective and safe surgical approach for the treatment of old odontoid fractures with C1-C2 dislocation or instability.

Abstract:A high-temperature oil-paper insulation system offers an opportunity to improve the overloading capability of distribution transformers facing seasonal load variation. A high-temperature electrical insulation system (EIS) was chosen due to thermal calculation based on a typical loading curve on the China Southern Power Grid. In order to evaluate candidate high-temperature insulation systems, Nomex ® T910 (aramid-enhanced cellulose) immersed in FR3 (natural ester) was investigated by a dual-temperature thermal aging test compared with a conventional insulation system, Kraft paper impregnated with mineral oil. Throughout the thermal aging test, mechanical, chemical, and dielectric parameters of both paper and insulating oil were investigated in each aging cycle. The thermal aging results determined that the thermal class of the FR3-T910 insulation system meets the request of overloading transformer needs.