TIGIT, a novel immune checkpoint therapy for melanoma.

Melanoma is the most aggressive and deadliest type of skin cancer. In the last 10 years, immune checkpoint blockades (ICBs) including PD-1/PD-L1 and CTLA-4 inhibitor has been shown to be effective against melanoma. PD-1/PD-L1 and CTLA-4 inhibitors have shown varying degrees of drug resistance in the treatment of melanoma patients. Furthermore, the clinical benefits of ICBs are also accompanied by severe immune toxicity. Therefore, there is an urgent need to develop new immune checkpoint inhibitors to optimize melanoma therapy and reduce cytotoxicity. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) is thought to activate inhibitory receptors in T cells, natural killer (NK) cells, and regulatory T cells (Tregs), and has become a promising target for immunotherapy. Studies have found that TIGIT can be detected in different stages of melanoma, which is closely related to the occurrence, development, and prognosis of melanoma. This review mainly describes the immunosuppressive mechanism of TIGIT and its role in antitumor immunity of melanoma, so as to provide new ideas and schemes for the clinical treatment of melanoma with targeted TIGIT.

Ginger (Zingiber officinale Roscoe) preparations for prophylaxis of postoperative nausea and vomiting: A Bayesian network meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginger has been proposed for prevention of postoperative nausea and vomiting (PONV), however it remains equivocal whether ginger can be an alternative option and which certain preparation is optimal for PONV prophylaxis. AIM OF THE STUDY: We conducted a network meta-analysis (NMA) to compare and rank relative efficacy for PONV control among all available ginger preparations collected in the databases. METHODS: Eligible records were identified by retrieving Medline (via Pubmed), Embase, Web of Science, CENTRAL, CNKI, WHO ICTRP and ClinicalTrials.gov for randomized controlled trials that investigated the efficacy of ginger therapies for the prophylaxis of PONV. A bayesian NMA within random-effects models was implemented. Certainty of evidence for estimates was investigated following GRADE framework. We prospectively registered the protocol (CRD 42021246073) in PROSPERO. RESULTS: Eighteen publications comprising 2199 participants with PONV were identified. Ginger oil (RR [95%CI], 0.39 [0.16, 0.96]) appeared to have the highest probability of being ranked best to decrease the incidence of postoperative vomiting (POV), with statistical significance compared with placebo, based on high to moderate confidence in estimates. With regard to reducing postoperative nausea (PON), statistically superiority was not observed in ginger regimens compared with placebo based on moderate to low certainty of evidence. Reduction in antemetic use and nausea intensity were noticed in ginger powder and oil. Ginger was significantly associated with better efficacy for Asian, older age, higher dosage, preoperative administration, hepatobiliary and gastrointestinal surgery. CONCLUSIONS: Ginger oil appeared to be superior to other ginger treatments for the prophylaxis of POV. With regard to reducing PON, ginger preparations indicated no obvious advantages.

Surface-engineered nanoparticles in cancer immune response and immunotherapy: Current status and future prospects.

Cancer immunotherapy is a therapeutic strategy to inhibit tumor growth and metastasis by intervening in the immune response process. Strategies applied to cancer immunotherapy mainly include blocking immune checkpoints, adoptive transfer of engineered immune cells, cytokine therapy, cancer vaccines, and oncolytic virus infection. However, many factors, such as off-target side effects, immunosuppressive cell infiltration and/or upregulation of immune checkpoint expression, cancer cell heterogeneity, and lack of antigen presentation, affect the therapeutic effect of immunotherapy on cancer. To improve the efficacy of targeted immunotherapy and reduce off-target effects, over the past two decades, nanoparticle delivery platforms have been increasingly used in tumor immunotherapy. However, nanoparticles are still subject to biological barriers and biodistribution challenges, which limit their overall clinical potential. This has prompted a series of engineered nanoparticles to overcome specific obstacles and transfer the accumulation of payloads to tumor-infiltrating immune cells. In recent years, new techniques and chemical methods have been employed to modify or functionalize the surfaces of nanoparticles. This review discusses the recent progress of surface-engineered nanoparticles in inducing tumor immune responses and immunotherapy, as well as future directions for the development of next-generation nanomedicines.

Recent Progress in Bio-Responsive Drug Delivery Systems for Tumor Therapy.

Spatially- and/or temporally-controlled drug release has always been the pursuit of drug delivery systems (DDSs) to achieve the ideal therapeutic effect. The abnormal pathophysiological characteristics of the tumor microenvironment, including acidosis, overexpression of special enzymes, hypoxia, and high levels of ROS, GSH, and ATP, offer the possibility for the design of stimulus-responsive DDSs for controlled drug release to realize more efficient drug delivery and anti-tumor activity. With the help of these stimulus signals, responsive DDSs can realize controlled drug release more precisely within the local tumor site and decrease the injected dose and systemic toxicity. This review first describes the major pathophysiological characteristics of the tumor microenvironment, and highlights the recent cutting-edge advances in DDSs responding to the tumor pathophysiological environment for cancer therapy. Finally, the challenges and future directions of bio-responsive DDSs are discussed.

Tumor-Acidity Responsive Polymeric Nanoparticles for Targeting Delivery of Angiogenesis Inhibitor for Enhanced Antitumor Efficacy With Decreased Toxicity.

Various nanocarriers with tumor targeting ability and improved pharmacokinetic property have been extensively utilized to reduce the toxicity of existing clinical chemotherapeutics. Herein, we showed that by encapsulating angiogenesis inhibitor anlotinib into polymeric nanoparticles, we could significantly decrease its in vivo toxicity. The introduction of pH-responsiveness into the nanocarrier further enhanced its anti-tumor activity. Systemic administration of the anlotinib-loaded nanocarrier into mice bearing A549 and 4T1 subcutaneous tumor received a higher tumor growth suppression and metastasis inhibition without detectable side effects. This strategy offers a promising option to improve the patient compliance of anlotinib.

The combination of camrelizumab and apatinib obtained ongoing partial remission for a patient with osimertinib-resistant non-small cell lung cancer: case report.

Extensive clinical studies have indicated that the epidermal growth factor receptor (EGFR)- tyrosine kinase inhibitors (TKIs) can significantly improve the survival rate of patients with EGFRmutation-positive malignancies. However, acquired resistance to the third-generation EGFR-TKI osimertinib is an intractable obstacle for many clinical oncologists. The resistance mechanism of osimertinib is very complicated, and the individual treatment varies greatly. We present the case of a 76-year-old woman with advanced non-small cell lung cancer (NSCLC) with EGFR L858R mutation, as well as multiple lung metastases and multiple liver metastases. The patient's lung lesions progressed after almost 2 years of treatment with Osimertinib. Due to poor physical condition, she could not tolerate chemotherapy or invasive examination. A next-generation sequencing (NGS) panel of a plasma sample showed missense mutations of KRAS (G12S), MET (D1028Y), AR (S697P), LRP1B (S2662C) with allelic frequencies of 0.6%, 0.5%, 0.2%, 0.2%, respectively), 2 nonsense mutations [ZNF521 (E307*), MET (Q42*), with allelic frequencies of 0.5%, 0.3%, respectively], and a splicing mutation in FAT1 (c.3266-1G>C) with an allelic frequency of 0.5%. After treatment with camrelizumab (200 mg fortnightly) combined with small dose of apatinib (125 mg qd), the patient's lung lesions were successfully overcome with significant reduction and necrosis formation. And the patient's symptoms were significantly relieved and was well tolerated. To our knowledge, this is the first report on the successful treatment of such patients. It indicated a promising treatment option in the clinic to the NSCLC with osimertinib resistance.

Effects of Parecoxib on Pain Threshold and Inflammatory Factors IL-1ß, IL-6 and TNF-𝜶 in Spinal Cord of Rats with Bone Cancer Pain.

OBJECTIVE: To investigate the effects of parecoxib on pain threshold and inflammatory factors interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in spinal cord of rats with bone cancer pain. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: Department of Oncology, Shengjing Hospital of China Medical University, China, from March 2017 to May 2018. METHODOLOGY: Twenty-four healthy female Sprague-Dawley rats were selected and the bone cancer pain model was inoculated with W256 breast cancer cell into the bone marrow. Rats with bone cancer pain were randomly divided into the model group and the parecoxib group on the 7th day postoperation, with 12 rats in each group. Another 12 rats were taken as the control group. Rats in the parecoxib group were given intraperitoneal injection of parecoxib (8 mg/kg) for 10 consecutive days since the 15th day after operation. Mechanical pain threshold, thermal pain threshold, and the levels of inflammatory factors IL-1ß, IL-6 and TNF-α in spinal cord of rats in each group were compared. RESULTS: On the 14th postoperative day, mechanical pain threshold and thermal pain threshold of rats in the model group and the parecoxib group were significantly decreased compared with those in the control group (p<0.001). After 5 and 10 days of administration, mechanical and thermal pain threshold of rats in the parecoxib group were significantly higher than those in the model group and the control group (p<0.001). After 10 days of administration, levels of IL-1ß, IL-6 and TNF-α in spinal cord of the model group were higher than those of the control group (p<0.001); and levels of IL-1ß, IL-6 and TNF-α in spinal cord of the parecoxib group were significantly lower than those in the model group and the control group (p<0.001). CONCLUSION: Parecoxib can alleviate hyperalgesia in rats with bone cancer pain, increase pain threshold and inhibit the up-regulation of inflammatory factors in the spinal cord. Parecoxib may achieve analgesic effects by down-regulating the expression of IL-1ß, IL-6 and TNF-α in the spinal cord.

Current evidences on XPC polymorphisms and breast cancer susceptibility: a meta-analysis.

Published data on the association between three polymorphisms (Lys939Gln, Ala499Val, and PAT±) of Xeroderma Pigmentosum group C (XPC) and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Crude ORs with 95% CIs were used to assess the strength of association between them. A total of 11 studies including 5,090 cases and 5,214 controls were involved in this meta-analysis. For XPC Lys939Gln polymorphism, no obvious associations were found for all genetic models when all studies were pooled into the meta-analysis (Lys/Gln vs. Lys/Lys: OR = 1.00, 95% CI 0.92-1.10; Gln/Gln vs. Lys/Lys: OR = 0.96, 95% CI 0.84-1.09; dominant model: OR = 0.99, 95% CI 0.91-1.08; and recessive model: OR = 0.97, 95% CI 0.86-1.09). In the subgroup analysis by ethnicity or study design, still no obvious associations were found. For XPC Ala499Val polymorphism, also no obvious associations were found for all genetic models when all studies were pooled into the meta-analysis (Val/Ala vs. Ala/Ala: OR = 0.91, 95% CI 0.79-1.05; Val/Val vs. Ala/Ala: OR = 1.07, 95% CI 0.80-1.44; dominant model: OR = 0.93, 95% CI 0.81-1.06; and recessive model: OR = 1.11, 95% CI 0.84-1.48). For XPC PAT± polymorphism, obvious associations were found for recessive model when all studies were pooled into the meta-analysis (OR = 1.41, 95% CI 1.05-1.89). In conclusion, this meta-analysis suggests that the XPC PAT± polymorphism allele may be a low-penetrant risk factor for developing breast cancer.