Prognostic significance of peripheral and tumor-infiltrating lymphocytes in newly diagnosed stage III/IV non-small-cell lung cancer.

Background and aim: Lymphocytes are effector cells that fight cancer by killing tumor cells. Here, we aim to explore the prognostic significance of both peripheral and tumor-infiltrating lymphocytes (TILs) in newly diagnosed stage III/IV non-small-cell lung cancer (NSCLC). Materials and methods: In total, 105 cases of newly diagnosed stage III/IV NSCLC from July 2017 to October 2022 at the Tianjin Beichen Hospital were retrospectively investigated. Peripheral blood samples at the time of diagnosis and tumor tissue slices from these patients were collected. General peripheral blood cell composition and TILs were measured and analyzed via an automatic blood analyzer and immunofluorescence staining analysis. The overall survival (OS) time of all patients was also obtained and analyzed. Results: The median overall survival (mOS) of all patients is 12 months. The 1-, 2-, and 3-year overall survival rates were 60.5, 28.4, and 18.6%, respectively. Peripheral lymphocyte and neutrophil percentages, serum C-reactive protein (CRP) expression, tumor size, and tumor pathology are the prognostic factors of OS for newly diagnosed stage III/IV NSCLC patients. Moreover, patients with high tumor CD4+ and CD8+ T cell infiltration survived significantly longer compared to patients with low tumor CD4+ and CD8+ T cell infiltration (p < 0.0001 and p = 0.011, respectively). Compared to low tumor CD33+ cell infiltration, high tumor CD33+ cell infiltration was associated with worse OS (p = 0.018). High tumor CD8+ T cell infiltration was associated with lower peripheral lymphocyte number, lower serum CRP expression, smaller tumor size, and better tumor pathology (p = 0.012, p = 0.040, p = 0.012, and p = 0.029, respectively). Conclusion: Increased numbers of peripheral lymphocytes, CD33+ cells, CD4+ TILs, and CD8+ TILs were significantly associated with OS in newly diagnosed stage III/IV NSCLC patients, which were positively associated with several basic clinical factors.

Autologous Tumor-Infiltrating Lymphocyte Mono-Therapy Can Rapidly Shrank Tumor in Asian Patient with Stage III/IV Cervical Cancer: Two Cases Report.

Introduction: Tumor-infiltrating lymphocytes (TILs) therapy is one of the most promising adoptive T cell therapies, which has shown great clinical efficacy against several solid malignancies. Nevertheless, clinical response to TILs mono-therapy in Asian patients with recurrent cervical cancer has not been well reported. Case Presentation: Here, we report two patients who were diagnosed with metastatic cervical cancer and tumor progression following multiple conventional treatments. In particular, one of the patients has a history of severe myelosuppression after chemotherapy. The patients received lymphodepletion therapy, which consisted of cyclophosphamide (30mg/kg) for 2 days, followed by Fludarabine (25mg/m2) for 5 days, approximately 24 hr before receiving intravenous autologous TILs infusion. These two patients then received high doses of IL-2 for 10 days with the purpose of maintaining T cell survival and proliferation. Patient 1 experienced clinical partial response (PR) at 6 weeks post TILs infusion and a 33% tumor shrinkage at 12 weeks follow-up, and patient 2 was evaluated as stable disease (SD) at 6 weeks post treatment. Mild and manageable adverse events were observed and soon subsided after the TILs treatment. A time-course study examining the peripheral blood cell count and cytokine secretion demonstrated the persistence of infused TILs and long-term immune response. Conclusion: These results suggest that TILs mono-therapy can be a promising treatment strategy for Asian patients with late-stage metastatic cervical cancer even with severe myelosuppression. TILs infusion can induce persistence and a long-term systematic immune response that reversed peripheral CD4+T and CD8+T percentages implying that TILs infusion increased cytotic T cell responses, which is consistent with clinical responses in these patients. Trial registration number: NCT05366478.

Epidermal Growth Factor Receptor-Targeted Neoantigen Peptide Vaccination for the Treatment of Non-Small Cell Lung Cancer and Glioblastoma.

The epidermal growth factor receptor (EGFR) plays crucial roles in several important biological functions such as embryogenesis, epithelial tissue development, and cellular regeneration. However, in multiple solid tumor types overexpression and/or activating mutations of the EGFR gene frequently occur, thus hijacking the EGFR signaling pathway to promote tumorigenesis. Non-small cell lung cancer (NSCLC) tumors in particular often contain prevalent and shared EGFR mutations that provide an ideal source for public neoantigens (NeoAg). Studies in both humans and animal models have confirmed the immunogenicity of some of these NeoAg peptides, suggesting that they may constitute viable targets for cancer immunotherapies. Peptide vaccines targeting mutated EGFR have been tested in multiple clinical trials, demonstrating an excellent safety profile and encouraging clinical efficacy. For example, the CDX-110 (rindopepimut) NeoAg peptide vaccine derived from the EGFRvIII deletion mutant in combination with temozolomide and radiotherapy has shown efficacy in treating EGFRvIII-harboring glioblastoma multiforme (GBM) patients undergone surgery in multiple Phase I and II clinical trials. Furthermore, pilot clinical trials that have administered personalized NeoAg peptides for treating advanced-stage NSCLC patients have shown this approach to be a feasible and safe method to increase antitumor immune responses. Amongst the vaccine peptides administered, EGFR mutation-targeting NeoAgs induced the strongest T cell-mediated immune responses in patients and were also associated with objective clinical responses, implying a promising future for NeoAg peptide vaccines for treating NSCLC patients with selected EGFR mutations. The efficacy of NeoAg-targeting peptide vaccines may be further improved by combining with other modalities such as tyrosine kinase or immune checkpoint inhibitor (ICI) therapy, which are currently being tested in animal models and clinical trials. Herein, we review the most current basic and clinical research progress on EGFR-targeted peptide vaccination for the treatment of NSCLC and other solid tumor types.

A dissected LMO2 functional analysis and clinical relevance in brain gliomas.

Brain glioma is one of the cancer types with worst prognosis, and LMO2 has been reported to play oncogenic functions in brain gliomas. Herein, analysis of datasets from The Cancer Genome Atlas (TCGA) indicated that higher LMO2 level in patient samples indicated worse prognosis in lower grade gliomas (LGG) but not glioblastoma multiforme (GBM). Further, in tumor tissues consisting of a variety of cell types, LMO2 level indicated intratumoral endothelium and pattern recognition receptor (PRR) response in both LGGs and GBMs, and additionally indicated cytotoxic T-lymphocyte, M2 macrophage infiltration and fibroblast specifically in LGGs. Moreover, only in LGGs these aspects were significantly associated with patient survival, in either risky or protective manner, and these dissected associations can give a better prediction on patient prognosis than LMO2 alone. This study not only provided more detailed understandings of LMO2 functional representatives in brain gliomas but also demonstrated that dealing with certain gene (LMO2 in this study) in transcriptome data with the Weighted Gene Co-Expression Network Analysis (WGCNA) method was a robust strategy for dissecting exact and reasonable gene functions/associations in a complicated tumor environment.

Facile synthesis of Mn-doped MoS2 nanosheets on carbon nanotubes as efficient electrocatalyst for hydrogen evolution reaction.

As a substitute of Pt-based catalysts, MoS2-based catalysts have been widely used in hydrogen evolution reaction, but the inherent low conductivity, limited active edges, self-stacking and agglomeration still hinder their activities. In this work, Mn-doped MoS2 nanosheets were vertically anchored on carbon nanotubes (CNTs) by the one-step hydrothermal reaction, in which Mn-O-C/Mo-O-C was considered as a bridge between Mn-MoS2 and CNTs. The doping of the Mn element enables the spreading of MoS2 on CNTs and the rapid escape of hydrogen bubbles from the electrode, while conductive CNTs with hydrophilicity can accelerate the electron transport process between the electrolyte and the material. With an overpotential of 150 mV at a current density of -10 mA cm-2 and a Tafel slope of 39 mV dec-1, this material exhibited excellent catalytic hydrogen evolution activity, which could open the path for designing commercial electrocatalysts.

Study on Umbilical Cord-Matrix Stem Cells Transplantation for Treatment of Acute Traumatic Brain Injury in Rats.

AIM: To evaluate the effect of umbilical cord derived mesenchymal stem cells (UC-MSCs) transplantation on traumatic brain injury (TBI). MATERIAL AND METHODS: UC-MSCs were isolated from human umbilical cord and TBI rat model was constructed. 30 male SD rats were randomly divided into 3 groups: control group, TBI group and MSCs transplantation group. Rats in MSCs group received the injection of a total of 1.5 C- 106 MSCs (25 I»l) via ventricle at operated ventricular coordinates (0 at bregma, 1.5 mm at lateral, 1.1 mm at behind, 4.5 mm in depth). RESULTS: 80% confluence of cells was formed from tissue at day 10 and the amount of CD90, CD73, CD105 positive cells increased correspondingly. In TBI model, clear hyperemia, edema and obvious infiltration of inflammatory cells in brain tissue were found. However, the manifestations were alleviated after the treatment of MSCs. In MSCs group, GFP in the brain tissue and the area around the vessels were found after the injection, while the expression levels of micro-vessel density (MVD), brain-derived neurotrophic factor (BDNF) and glial fibrillary acidic protein (GFAP) were elevated. CONCLUSION: UC-MSCs transplantation for treatment of acute TBI could effectively reduce the injury and improve the vascular reconstruction.

Phenformin and metformin inhibit growth and migration of LN229 glioma cells in vitro and in vivo.

BACKGROUND: Malignant glioma is refractory to conventional treatment, highlighting a need to develop novel efficacious therapies. Biguanides, a class of oral antidiabetic drug, have been thought to inhibit proliferation and metastasis in a variety of cancers. PURPOSE: The objective of this study was to investigate the affections of biguanides, phenformin (Phen) and metformin (Met), on growth and migration of glioma cells LN229 in vitro and in vivo. METHODS: Glioma cells LN229 were treated with Phen or Met, then cell proliferation and death were evaluated by MTT assay and PI stain, and cell cycle were evaluated using flow cytometric analysis, meantime wound healing assay and transwell migration assay were performed to detect cell migration ability. In addition, LN229 were injected in thigh of nude mice, and the mice were treated with Phen or Met to detect the effect of Phen and Met in vivo. RESULTS: Phen and Met could significantly inhibit cell growth through inhibiting cell proliferation, promoting cell death and disturbing cell cycle, and these drugs also could inhibit cell colony formation in glioma cells LN229 in vitro. Meanwhile, both Phen and Met could significantly inhibit cell migration of LN229 in vitro, through effecting the expression of E-cadherin and Vimentin. In addition, both Phen and Met inhibited the growth and migration of LN229 in a tumor xenograft model. Furthermore, Phen and Met were associated with the increased level of ROS of cell mitochondrial, and ROS inhibitor NAC could significantly rescue the cell death induced by Phen and Met. CONCLUSION: Phen and Met displayed powerful antitumor effects of LN229, and our findings powerfully suggest the possibility of Phen and Met being used as an adjuvant agent in the treatment of glioma patients.

Neuroprotective effects of genistein on SH-SY5Y cells overexpressing A53T mutant α-synuclein.

Genistein, a potent antioxidant compound, protects dopaminergic neurons in a mouse model of Parkinson's disease. However, the mechanism underlying this action remains unknown. This study investigated human SH-SY5Y cells overexpressing the A53T mutant of α-synuclein. Four groups of cells were assayed: a control group (without any treatment), a genistein group (incubated with 20 µM genistein), a rotenone group (treated with 50 µM rotenone), and a rotenone + genistein group (incubated with 20 µM genistein and then treated with 50 µM rotenone). A lactate dehydrogenase release test confirmed the protective effect of genistein, and genistein remarkably reversed mitochondrial oxidative injury caused by rotenone. Western blot assays showed that BCL-2 and Beclin 1 levels were markedly higher in the genistein group than in the rotenone group. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling revealed that genistein inhibited rotenone-induced apoptosis in SH-SY5Y cells. Compared with the control group, the expression of NFE2L2 and HMOX1 was significantly increased in the genistein + rotenone group. However, after treatment with estrogen receptor and NFE2L2 channel blockers (ICI-182780 and ML385, respectively), genistein could not elevate NFE2L2 and HMOX1 expression. ICI-182780 effectively prevented genistein-mediated phosphorylation of NFE2L2 and remarkably suppressed phosphorylation of AKT, a protein downstream of the estrogen receptor. These findings confirm that genistein has neuroprotective effects in a cell model of Parkinson's disease. Genistein can reduce oxidative stress damage and cell apoptosis by activating estrogen receptors and NFE2L2 channels.

Trigeminal Cardiac Reflex Caused by Onyx Embolization of Intracranial Dural Arteriovenous Fistula.

Trigeminocardiac reflex (TCR) is a reflexive response of bradycardia, hypotension and gastric hypermotility which is observed upon mechanical stimulation in the distribution of the trigeminal nerve. Previous articles have described TCR during intracranial operations, ophthalmic surgery, microcompression of the trigeminal ganglion and radiofrequency lesioning of the trigeminal ganglion. TCR may occur during transarterial embolization of dural arteriovenous fistula (DAVF) with Onyx, leading to a significant decrease in heart rate under a standard anesthetic protocol. TCR may also occur due to chemical stimulus of dimethyl sulfoxide (DMSO) in transvenous Onyx embolization of dural cavernous sinus fistula. Slow rate of injection may give DMSO enough time to dissipate in the blood stream which is important for the prevention of toxicity. This report confirms that the reflex was blunted by the anticholinergic effects of atropine and there was no harm to patients if stopped immediately.

MicroRNA-873 (miRNA-873) inhibits glioblastoma tumorigenesis and metastasis by suppressing the expression of IGF2BP1.

Glioblastoma multiforme (GBM) is known as a highly malignant brain tumor with a poor prognosis, despite intensive research and clinical efforts. In this study, we observed that microRNA-873 (miR-873) was expressed at low levels in GBM and that the overexpression of miR-873 dramatically reduced the cell proliferation, migration, and invasion of GBM cells. Our further investigations of the inhibition mechanism indicated that miR-873 negatively affected the carcinogenesis and metastasis of GBM by down-regulating the expression of IGF2BP1, which stabilizes the mRNA transcripts of its target genes. These results demonstrate that miR-873 may constitute a potential target for GBM therapy.