Targeting NKG2D/NKG2DL axis in multiple myeloma therapy.

Immune effector cells in patients with multiple myeloma (MM) are at the forefront of many immunotherapy treatments, and several methods have been developed to fully utilise the antitumour potential of immune cells. T and NK cell-derived immune lymphocytes both expressed activating NK receptor group 2 member D(NKG2D). This receptor can identify eight distinct NKG2D ligands (NKG2DL), including major histocompatibility complex class I (MHC) chain-related protein A and B (MICA and MICB). Their binding to NKG2D triggers effector roles in T and NK cells. NKG2DL is polymorphic in MM cells. The decreased expression of NKG2DL on the cell surface is explained by multiple mechanisms of tumour immune escape. In this review, we discuss the mechanisms by which the NKG2D/NKG2DL axis regulates immune effector cells and strategies for promoting NKG2DL expression and inhibiting its release in multiple myeloma and propose therapeutic strategies that increase the expression of NKG2DL in MM cells while enhancing the activation and killing function of NK cells.

Immune profiles to predict bortezomib-based treatment response for multiple myeloma patients.

BACKGROUND: To evaluate the distribution of bone marrow immune cell subsets and their correlation with treatment efficacy in patients with multiple myeloma (MM). METHODS: We analyzed the bone marrow lymphocyte subsets of 186 newly diagnosed MM patients at diagnosis and their correlation with clinical characteristics. In our study, eight-color flow cytometry, a method commonly used to detect plasma cell phenotypes, was used to analyze seven bone marrow immune cell groups by change gate-strategy. RESULTS: First, for all the 7 immune cell groups, the percentage of immature B cells was significantly lower in stage III patients than in stage I patients, while the trend was reversed in memory B cells in both the International Staging System(p = 0.004) and Revised International Staging System(p = 0.018). Second, the percentage of naïve B cells were significantly lower in patients with severe anemia, while the percentage of memory B cells had reversed trend. The percentage of immature B cells were lower in patients with Cr ≥ 2 mg/dL than in patients with Cr < 2 mg/dL. Then we followed the treatment efficacy of 152 patients who received four cycles of induction therapy (bortezomib + dexamethasone or bortezomib + lenalidomide + dexamethasone) and analyzed the relationship between bone marrow lymphocyte subsets at the initial stage and treatment response datasets. We found that both the percentage of B cells(p＜0.001) and immature B(p = 0.002) were increased in patients who achieved very good partial remission(VGPR) after four cycles of induction therapy. The ROC results indicated the combination of the multiple immune subgroups had predictive values (AUC = 0.802, p<0.001) in the treatment effect after four cycles of induction therapy. CONCLUSIONS: Overall, these results suggest that the analysis of lymphocyte subsets along with plasma cell immunophenotyping could be a potential index for determining the prognosis of MM patients.

Cellular immunity in the era of modern multiple myeloma therapy.

Multiple myeloma (MM) is a relapsing clonal plasma cell malignancy and incurable thus far. With the increasing understanding of myeloma, highlighting the critical importance of the immune system in the pathogenesis of MM is essential. The immune changes in MM patients after treatment are associated with prognosis. In this review, we summarize currently available MM therapies and discuss how they affect cellular immunity. We find that the modern anti-MM treatments enhance antitumour immune responses. A deeper understanding of the therapeutic activity of individual drugs offers more effective treatment approaches that enhance the beneficial immunomodulatory effects. Furthermore, we show that the immune changes after treatment in MM patients can provide useful prognostic marker. Analysing cellular immune responses offers new perspectives for evaluating clinical data and making comprehensive predictions for applying novel therapies in MM patients.

Highly Soluble Dimethoxymethyl Tetrathiafulvalene with Excellent Stability for Non-Aqueous Redox Flow Batteries.

Non-aqueous redox flow batteries (RFBs) are highly attractive for grid-scale energy storage applications because of their independent design of energy and power, high energy density and efficiency, easy maintenance, and potentially low cost. In order to develop active molecules with large solubility, excellent electrochemical stability, and high redox potential for a non-aqueous RFB catholyte, herein, two flexible methoxymethyl groups had been attached to a famous redox-active tetrathiafulvalene (TTF) core. The strong intermolecular packing of the rigid TTF unit was effectively depressed, leading to a dramatically improved solubility of up to 3.1 M in conventional carbonate solvents. The performance of the obtained dimethoxymethyl TTF (DMM-TTF) was studied in a semi-solid RFB system with Li foil as the counter electrode. When using porous Celgard as the separator, the hybrid RFB with 0.1 M DMM-TTF had two high discharge plateaus at 3.20 and 3.52 V and a low capacity retention of 30.7% after 100 cycles at 5 mA cm-2. Replacing Celgard with a permselective membrane, the capacity retention was increased to 85.4%. Further increasing the concentration of DMM-TTF to 1.0 M and current density to 20 mA cm-2, the hybrid RFB exhibited a high volumetric discharge capacity of 48.5 A h L-1 and an energy density of 154 W h L-1. The capacity was maintained at 72.2% after 100 cycles (10.7 days). The great redox stability of DMM-TTF was revealed by UV-vis and 1H NMR tests and verified by density functional theory calculations. Therefore, the methoxymethyl group is an excellent group to increase the solubility while maintaining the redox capability of TTF for high-performance non-aqueous RFBs.

Study on the Effect of EZH2 Inhibitor Combined with TIGIT Monoclonal Antibody against Multiple Myeloma Cells.

EZH2, a member of the polycomb repressive complex 2, induces trimethylation of the downstream gene at the histone three lysine 27 (H3K27me3) position to inhibit tumor cell proliferation. Here, we showed that the apoptosis rate and apoptotic protein expression increased after EZH2 inhibition, whereas key molecules of the NF-κB signaling pathway and the downstream target genes were inhibited. Additionally, the expression of CD155, a TIGIT high-affinity ligand in multiple myeloma (MM) cells, was decreased by the mTOR signaling pathway. Furthermore, the combination of EZH2 inhibitor and TIGIT monoclonal antibody blockade enhanced the anti-tumor effect of natural killer cells. In summary, the EZH2 inhibitor not only plays an anti-tumor role as an epigenetic drug, but also enhances the anti-tumor effect of the TIGIT monoclonal antibody by affecting the TIGIT-CD155 axis between NK cells and MM cells, thus providing new ideas and theoretical basis for the treatment of MM patients.

Pneumocystis jirovecii diagnosed by next-generation sequencing of bronchoscopic alveolar lavage fluid: A case report and review of literature.

BACKGROUND: The advent of molecular targeted agents and immune checkpoint inhibitors has greatly improved the treatment of advanced renal cell carcinoma (RCC), thus significantly improving patient survival. The incidence of rare drug-related adverse events has gained increased attention. CASE SUMMARY: We report a patient with advanced RCC treated with multiple lines of molecular targeted agents and immune checkpoint inhibitors, who developed a pulmonary infection after treatment with everolimus in combination with lenvatinib. Determining the pathogenic organism was difficult, but it was eventually identified as Pneumocystis jirovecii by next-generation sequencing (NGS) of bronchoscopic alveolar lavage fluid (BALF) and successfully treated with trimethoprim-sulfamethoxazole. CONCLUSION: Rare pulmonary infections caused by molecular targeted agents are not uncommon in clinical practice, but their diagnosis is difficult. Evaluating BALF with NGS is a good method for rapid diagnosis of such infections.

Efficacy of Melatonin for Insomnia in Children with Autism Spectrum Disorder: A Meta-analysis.

AIM: This study aimed to evaluate the effectiveness of melatonin in treating insomnia in children with autism spectrum disorder (ASD). METHODS: Comprehensive searches were conducted in the PubMed, EMBASE, and Web of Science databases from their inception to April 20, 2022. Data were extracted and assessed for quality by two researchers. Statistical analysis was performed using the Stata 15.0 software. RESULTS: Four studies including 238 patients were included. The results showed that compared with the control group, melatonin could shorten the sleep-onset latency (standardized mean difference [SMD] = - 1.34, 95% CI: -2.19 to -0.48), reduce the number of awakenings (SMD = -2.35, 95% CI: -4.62 to -0.08), and prolong the total sleep time (SMD = 1.42, 95% CI: 0.5-2.33) in children with ASD. CONCLUSION: Melatonin has a certain effect on relieving sleep disturbances in children with ASD, which can shorten sleep latency, reduce the number of awakenings, and prolong total sleep time. Larger studies are required to verify this hypothesis.

BSA-AIE Nanoparticles with Boosted ROS Generation for Immunogenic Cell Death Immunotherapy of Multiple Myeloma.

The main obstacle of multiple myeloma (MM) therapy is the compromised immune microenvironment, which leads to MM relapses and extramedullary disease progression. In this study, a novel strategy is reported of enhanced immunogenic cell death (ICD) immunotherapy with aggregation-induced emission (AIE) photosensitizer-loaded bovine serum albumin (BSA) nanoparticles (referred as BSA/TPA-Erdn), which can activate T cells, convert the cold tumor to hot, and reverse T cell senescence to restore the immune microenvironment for MM treatment. Loading AIE photosensitizer into the hydrophobic domain of BSA proteins significantly immobilizes the molecular geometry, which massively increases reactive oxygen species (ROS) generation and elicits a promising ICD immune response. Employing a NOD-SCID IL-2receptor gamma null mice model with MM patients' monocytes, it is shown that BSA/TPA-Erdn can simulate human dentric cell maturation, activate functional T lymphocytes, and increase additional polarization and differentiation signals to deliver a promising immunotherapy performance. Intriguingly, for the first time, it is shown that BSA/TPA-Erdn can greatly reverse T cell senescence, a main challenge in treating MM. Additionally, BSA/TPA-Erdn can effectively recruit more functional T lymphocytes into MM tumor. As a consequence, BSA/TPA-Erdn restores MM immune microenvironment and shows the best MM tumor eradication performance, which shall pave new insights for MM treatment in clinical practices.

Adenosinergic axis and immune checkpoint combination therapy in tumor: A new perspective for immunotherapy strategy.

There are two figures and one table in this review, the review consists of 5823 words, without the description of figures and table, but including references. Tumor cells escape anti-tumor immune responses in various ways, including functionally shaping the microenvironment through the secretion of various chemokines and, cytokines. Adenosine is a powerful immunosuppressive metabolite, that is frequently elevated in the extracellular tumor microenvironment (TME). Thus, it has recently been proposed as a novel antitumor immunoassay for targeting adenosine- generating enzymes, such as CD39, CD73, and adenosine receptors. In recent years, the discovery of the immune checkpoints, such as programmed cell death 1(PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4), has also greatly changed treatment methods and ideas for malignant tumors. Malignant tumor immunotherapy has been developed from point-to-point therapy targeting immune checkpoints, combining different points of different pathways to create a therapy based on the macroscopic immune regulatory system network. This article reviews the theoretical basis of the adenosine energy axis and immune checkpoint combined therapy for malignant tumors and the latest advances in malignant tumors.

The efficacy of Shenghua Decoction supplementation after early medical abortion: A meta-analysis of randomized controlled trials.

AIMS: Shenghua Decoction (SHD) is a well-known classic herbal formula documented in traditional Chinese medicine (TCM) that has been widely applied during the postpartum period in Chinese communities for several years. We conducted this systematic review and meta-analysis to explore the influence of SHD as an adjuvant treatment for early medical abortion using a combination of mifepristone followed by misoprostol. METHODS: This systematic review and meta-analysis was reported using 2020 PRISMA guidelines. Eight databases were searched from their establishment to February 28, 2022, for randomized controlled trials (RCTs): PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, the Chinese BioMedical database, the Chinese Scientific Journal Database, and the Wanfang database. The Grading of Recommendations Assessment, Development, and Evaluation estimated the quality of evidence. RESULTS: Sixteen RCTs involving 3016 patients were included in the meta-analysis. Overall, compared with no treatment as the control group after early medical abortion, patients treated with SHD were associated with a higher complete abortion rate (RR: 1.14; 95% CI: 1.10 - 1.18; P < 0.01, I2 = 26%, moderate quality), lower incomplete abortion rate (RR: 0.31; 95% CI: 0.24 - 0.41; P < 0.01, I2 = 0%, moderate quality), and lower viable pregnancy rate (RR: 0.26; 95% CI: 0.11 - 0.62; P < 0.01, I2 = 0%, moderate quality). Additionally, SHD supplementation was associated with reduced the induction-abortion time, duration of vaginal bleeding and menstrual recovery time. CONCLUSION: Our findings suggest that SHD supplementation may be beneficial for women seeking a medical abortion before the 7-week gestational period and no adverse events in the experimental group were reported. However, the methodological quality of the included RCTs was unsatisfactory, and therefore it is necessary to further verify the effectiveness of SHD using standardized studies of rigorous design.

Selinexor synergizes with azacitidine to eliminate myelodysplastic syndrome cells through p53 nuclear accumulation.

Myelodysplastic syndromes (MDS) are clonal malignancies of multipotent hematopoietic stem cells, characterized by ineffective hematopoiesis leading to cytopenia. Hypomethylating agents, including azacitidine, have been used for treating MDS with some success; however, the overall survival rate remains poor and, therefore, finding new therapies is necessary. Selinexor, which exerts anticancer effects against some hematologic tumors, is a nuclear export protein inhibitor that blocks cell proliferation and induces apoptosis in various cancer cell lines. We investigated the effects of combined selinexor and azacitidine administration on two MDS cell lines, namely SKM-1 and MUTZ-1. Cells were subjected to a proliferation assay, and the effects of each drug alone, and in combination, were compared. Changes in apoptosis and the cell cycle between groups were also analyzed. Western blotting was conducted to identify the underlying mechanism of action of combined selinexor and azacitidine therapy. The results revealed that the combination of selinexor and azacitidine synergistically inhibited MDS cell proliferation and arrested the cell cycle at the G2/M phase. This combination also promoted MDS cell apoptosis and enhanced p53 accumulation in the nucleus, thereby allowing p53 to be activated and to function as a tumor suppressor. Overall, our results indicate that the combination of selinexor and azacitidine may be a promising approach for treating MDS.

Jasmonates Alleviate the Harm of High-Temperature Stress During Anthesis to Stigma Vitality of Photothermosensitive Genetic Male Sterile Rice Lines.

Using photothermosensitive genic male sterile (PTSGMS) rice (Oryza sativa L.) lines to produce hybrids can obtain great heterosis. However, PTSGMS rice lines exhibit low stigma vitality when high-temperature (HT) stress happens during anthesis. Jasmonates (JAs) are novel phytohormones and play vital roles in mediating biotic and abiotic stresses. Little is known, however, if and how JAs could alleviate the harm of HT stress during anthesis to the stigma vitality of PTSGMS lines. This study investigated the question. Two PTSGMS lines and one restorer line of rice were pot-grown and subjected to normal temperature and HT stress during anthesis. The stigma exertion rate, sigma fresh weight, stigma area, contents of JAs, hydrogen peroxide (H2O2), and ascorbic acid (AsA), activity of catalase in stigmas, and the number of pollens germinated on the stigma of PTSGMS lines were determined. The results showed that a rice line with higher JAs content in the stigma under HT stress showed lower H2O2 content, higher AsA content and catalase activity in stigmas, larger stigma area, heavier stigma fresh weight, more pollens germinated on the stigma, and higher fertilization and seed-setting and rates. Applying methyl JAs during anthesis to rice panicles decreased the accumulation of reactive oxygen species and enhanced stigma vitality, thereby increasing fertilization and seed-setting rates of the hybrids of PTSGMS rice lines under HT stress. The results demonstrate that JAs attenuate the injury of HT stress to the stigma vitality of PTSGMS rice lines through enhancing antioxidant ability.

Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes.

The gut microbiota benefits humans via short-chain fatty acid (SCFA) production from carbohydrate fermentation, and deficiency in SCFA production is associated with type 2 diabetes mellitus (T2DM). We conducted a randomized clinical study of specifically designed isoenergetic diets, together with fecal shotgun metagenomics, to show that a select group of SCFA-producing strains was promoted by dietary fibers and that most other potential producers were either diminished or unchanged in patients with T2DM. When the fiber-promoted SCFA producers were present in greater diversity and abundance, participants had better improvement in hemoglobin A1c levels, partly via increased glucagon-like peptide-1 production. Promotion of these positive responders diminished producers of metabolically detrimental compounds such as indole and hydrogen sulfide. Targeted restoration of these SCFA producers may present a novel ecological approach for managing T2DM.

Diagnostic value of elevated serum miRNA-143 levels in sepsis.

OBJECTIVE: To evaluate serum micro RNA-143 (miR-143) levels in patients with sepsis or non-infectious systemic inflammatory response syndrome (SIRS), and investigate its possible diagnostic or prognostic value. METHODS: Serum was obtained from patients with sepsis or SIRS and healthy control subjects. Relative miR-143 expression was determined using quantitative real time polymerase chain reaction. The diagnostic and prognostic value of serum miR-143 was evaluated. RESULTS: Serum miR-143 levels were significantly higher in patients with sepsis (n = 103) than patients with SIRS (n = 95) and healthy controls (n = 40). There were significant positive correlations between serum miR-143 level and SOFA and APACHE II scores in patients with sepsis (r = 0.794 and r = 0.825, respectively). Serum miR-143 had a sensitivity of 78.6% and specificity of 91.6% for distinguishing between sepsis and SIRS. There was no association between serum miR-143 and 28-day survival in patients with sepsis. CONCLUSION: Serum miR-143 is elevated in patients with sepsis, and may be a useful biomarker for distinguishing between sepsis and SIRS.

Assessment and prognostic analysis of EGFR mutations or/and HER2 overexpression in Uygur's Non-small Cell Lung Cancer.

AIM: The epidermal growth factor receptor (EGFR) mutations and human epidermal growth factor receptor HER-2/neu (HER2) have been established roles in the signal transduction pathways leading to cell growth and differentiation. The present study focus on the significance of EGFR mutations combined with HER2 overexpression on survival outcomes in Non-small Cell Lung Cancer patients in Uygur population. METHODS: A total of 111 consecutive Uygurods: A total of 111 consecutive Cell Lung Cancer under went lung Cell Lung biopsy or surgery at the Affiliated Tumor Hospital of Xin Jiang Medical University between March 2009 and January 2013 were included in this retrospective study. All the patients included had received gefitinib 250 mg once daily. The HER2 expression were evaluated by immunohistochemical staining with score of membranous staining being 0 = none, 1 = weak, 2 = 10-30% cells, 3≥30% cells stained, and Real-time PCR techniques were conducted to detect mutations of EGFR through 21 kinds of human EGFR gene mutation detection kits. A retrospective review of the medical records was analyzed to determine the correlation between the presence of EGFR mutations combined with HER2 overexpression and clinicopathological factors. RESULTS: The overall rate of EGFR mutation was 10.81% (n = 12), which mainly involved exons 19 (83.33%, n = 10), 21 (16.67%, n = 2). The overall rate of HER2 overexpression was 21.62% (n = 24). EGFR mutation combined with HER2 overexpression analysis was performed in 111 patients, with an overall rate of 5.41% (n = 6). Median progression-free survival and overall survival were significantly longer in the EGFR mutations group than in the wild type group (PFS: 10.0±1.5 versus 3.8±1.4 months, P = 0.000; OS: 27.3±2.9 versus 19.1±4.7 months, P = 0.000). The ORR in patients with HER2 overexpression was 29.17%, and 13.80% in those patients with HER2 negative, but no significant difference (P = 0.121). The median PFS and OS in HER2 positive group showed no significant difference compared with HER2 negative group (PFS: 4.7±1.2 months versus 3.9±1.6 months, P = 0.085; OS: 20.5±2.4 versus 19.2±2.6 months, P = 0.094). As regarding to ORR, PFS and OS, EGFR mutations combined with HER2 overexpression patients showed no superior efficacy to gefitinib treatment compared with EGFR mutations combined with HER2 negative. CONCLUSION: In Uygur population, progression-free survivals were improved in Non-small Cell Lung Cancer with EGFR mutations. HER2 overexpression provided a poor prognostic factor in Non-small Cell Lung Cancer.

Expression of osteopontin in non-small cell lung cancer and correlative relation with microvascular density.

BACKGROUND AND OBJECTIVE: Lung cancer is one of the malignant diseases which most seriously threat humansurvival and development. This study aimed to assess osteopontin (OPN) expression in non-small cell lung cancer (NSCLC) and any relationship with clinicopathological features. METHODS: Immunohistochemistry was used to determine OPN expression and microvascular density (MVD) in 120 cases of NSCLC also undergoing clinical assessment. RESULTS: Moderately positive expression of OPN was found in 34.6% (41/120) and strong expression in 47.5% (57/120) of the NSCLCs; OPN expression in carcinomas was higher than in pericarcinoma tissues (P<0.05). While no obvious association was observed with NSCLC patient age, gender, maximum diameter of the tumor and pathological type, OPN expression was more commonly detected in poorly differentiated carcinoma tissue and lymph node metastasis as well as at advanced clinical stage (P<0.05); OPN expression in cancer tissue was positively correlated with MVD (r = 0.839, P = 0.000). CONCLUSION: OPN plays an important role in promoting tumor angiogenesis and progress of NSCLCs and has the possibility to become the new target for therapy.