GLIS1 intervention enhances anti-PD1 therapy for hepatocellular carcinoma by targeting SGK1-STAT3-PD1 pathway.

BACKGROUND: GLI-similar 1 (GLIS1) is one of of Krüppel-like zinc finger proteins, which are either stimulators or inhibitors of genetic transcription. Nevertheless, its effects on T cell were elusive. METHODS: In this study, we intend to explore the effects of GLIS1 on modulating the anticancer potency of CD8+ T cells in hepatocellular carcinoma (HCC). The expression of GLIS1 in CD8 peripheral blood mononuclear cell and CD8 tumor-infiltrating lymphocytes of HCC tissues was validated by quantificational real-time-PCR and flow cytometry. The anticancer potency of CD8+ T cells with GLIS1 knock down was confirmed in C57BL/6 mouse model and HCC patient-derived xenograft mice model. GLIS1-/- C57BL/6 mice was applied to explore the effects GLIS1 on tumor immune microenvironment. Chromatin immunoprecipitation and RNA transcriptome sequencing analysis were both performed in GLIS1-knock down of CD8+ T cells. RESULTS: GLIS1 was upregulated in exhausted CD8+ T cells in HCC. GLIS1 downregulation in CD8+ T cells repressed cancer development, elevated the infiltrate ability of CD8+ T cells, mitigated CD8+ T cell exhaustion and ameliorated the anti-PD1 reaction of CD8+ T cells in HCC. The causal link beneath this included transcriptional regulation of SGK1-STAT3-PD1 pathway by GLIS1, thereby maintaining the abundant PD1 expression on the surface of CD8+ T cells. CONCLUSION: Our study revealed that GLIS1 promoted CD8+ T cell exhaustion in HCC through transcriptional regulating SGK1-STAT3-PD1 pathway. Downregulating the expression of GLIS1 in CD8+ T cells exerted an effect with anti-PD1 treatment synergistically, revealing a prospective method for HCC immune therapy.

Idarubicin-loaded biodegradable microspheres enhance sensitivity to anti-PD1 immunotherapy in transcatheter arterial chemoembolization of hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is an image-guided locoregional therapy used for the treatment of patients with primary hepatocellular carcinoma (HCC). However, conventional TACE formulations such as epirubicin-lipiodol emulsion are rapidly dissociated due to the instability of the emulsion, resulting in insufficient local drug concentrations in the target tumor. To overcome these limitations, we used biodegradable Idarubicin loaded microspheres (BILMs), which were prepared from gelatin and carrageenan and could be loaded with Idarubicin (IDA-MS). The morphology and the ability to load and release IDA of BILMs were characterized in vitro. We evaluated tumor changes and side effects after TACE treatment with IDA-MS in VX2 rabbit and C57BL/6 mice HCC models. In addition, the effect of IDA-MS on the tumor immune microenvironment of HCC tumors was elucidated via mass spectrometry and immunohistochemistry. Result showed that IDA-MS was developed as a new TACE formulation to overcome the poor delivery of drugs due to rapid elimination of the anticancer drug into the systemic circulation. We demonstrated in rabbits and mice HCC models that TACE with IDA-MS resulted in significant tumor shrinkage and no more severe adverse events than those observed in the IDA group. TACE with IDA-MS could also significantly enhance the sensitivity of anti-PD1 immunotherapy, improve the expression of CD8+ T cells, and activate the tumor immune microenvironment in HCC. This study provides a new approach for TACE therapy and immunotherapy and illuminates the future of HCC treatment. STATEMENT OF SIGNIFICANCE: Conventional transarterial chemoembolization (TACE) formulations are rapidly dissociated due to the instability of the emulsion, resulting in insufficient local drug concentrations in hepatocellular carcinoma (HCC). To overcome these limitations, we used biodegradable microspheres called BILMs, which could be loaded with Idarubicin (IDA-MS). We demonstrated in rabbits and mice HCC models that TACE with IDA-MS resulted in significant tumor shrinkage and no more severe adverse events than those observed in the IDA group. TACE with IDA-MS could also significantly enhance the sensitivity of anti-PD1 immunotherapy, improve the expression of CD8+ T cells, and activate the tumor immune microenvironment in HCC. This study provides a new approach for TACE therapy and immunotherapy and illuminates the future of HCC treatment.

COVID-19 related stress during and one year after the first wave of the pandemic outbreak in China: The role of social support and perceptions of the pandemic.

Introduction: COVID-19 related stress might vary with the pandemic changes, as well as other associated factors. This study aimed to compare the stress level during the first wave of the pandemic outbreak and 1 year later in China, and to explore the differential roles of social support and perceptions of this disease in affecting pandemic-related stress over time. Methods: COVID-19 related stress, social support, and perceptions of the pandemic (perceived threat, perceived protection, and perceived controllability) were measured using the Impact of Event Scale-Revised for COVID-19, the Multidimensional Scale of Perceived Social Support, and the Self-Compiled Scale of COVID-19 Related Perception, respectively. Using an online survey, two independent samples were collected during the first wave of the COVID-19 outbreak (Time 1: March 2020, N = 430) and 1 year later (Time 2: April 2021, N = 512). Results: Levels of COVID-19 related stress and social support were lower at Time 2. Furthermore, at both Time 1 and Time 2, more social support was associated with less stress. Perceived protection and controllability of COVID-19 also mediated the relationship between social support and COVID-19 at both time points. However, the perceived threat of COVID-19 only served as a mediator at Time 1. Conclusion: These results indicate that Chinese people might experience lower COVID-19 related stress as the pandemic progresses. The perceived threat of COVID-19 played a more critical role in stress experienced at Time 1. These findings not only underscore the importance of social support under the context of Chinese society, but also have implications for developing specific interventions targeting different perceptions of COVID-19 to reduce pandemic-related stress during the different waves of this pandemic.

Midazolam exhibits antitumour and enhances the efficiency of Anti-PD-1 immunotherapy in hepatocellular carcinoma.

BACKGROUND: Midazolam (MDZ) is an anaesthetic that is widely used for anxiolysis and sedation. More recently, MDZ has also been described to be related to the outcome of various types of carcinomas. However, how MDZ influences the progression of hepatocellular carcinoma (HCC) and its effects on the biological function and tumour immune microenvironment of this type of tumour remain unknown. METHODS: The effects of MDZ on the proliferation, invasion, and migration of HCC cell lines were examined in vitro using the Cell Counting Kit 8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU), Transwell, and wound healing assays. Additionally, western blotting was employed to confirm that PD-L1 was expressed. Chromatin immunoprecipitation-seq (ChIP-seq) analysis was used to pinpoint the transcriptional regulation regions of NF-κB and programmed death-ligand 1 (PD-L1). A C57BL/6 mouse model was used to produce subcutaneous HCC tumors in order to evaluate the in vivo performance of MDZ. Mass spectrometry was also used to assess changes in the tumour immunological microenvironment following MDZ injection. RESULTS: The HCC-LM3 and Hep-3B cell lines' proliferation, invasion, and migration were controlled by MDZ, according to the results of the CCK8, EdU, Transwell, and wound healing assays. PD-L1 expression was shown by ChIP-seq analysis to be boosted by NF-κB, and by Western blotting analysis, it was shown that MDZ downregulated the expression of NF-κB. Additionally, in vivo tests revealed that intraperitoneal MDZ injections reduced HCC tumor development and enhanced the effectiveness of anti-PD-1 therapy. The CD45+ immune cell proportions were higher in the MDZ group than in the PBS group, according to the mass spectrometry results. Injection of MDZ resulted in a decrease in the proportions of CD4+ T cells, CD8+ T cells, natural killer (NK) cells, monocytes, Tregs, and M2 macrophages and a rise in the proportion of dendritic cells. Additionally, the concentrations of the cytokines IFN-g and TNF-a were noticeably raised whereas the concentrations of the CD8+ T-cell fatigue markers ICOS, TIGIT, and TIM3 were noticeably lowered. CONCLUSION: According to this study, MDZ inhibited the progression of HCC by inhibiting the NF-κB pathway and reducing the exhaustion of CD8+ T cells. In clinical practice, MDZ combined with anti-PD-1 therapy might contribute to synergistically improving the antitumor efficacy of HCC treatment.

[Application of computerized cognitive behavioral therapy in patients with persistent postural-perceptual dizziness].

Objective:A computerized cognitive behavioral therapy intervention program was constructed for patients with persistent postural-perception dizziness（PPPD） and its effects on dizziness symptoms, negative emotions and balance function were investigated. Methods:A randomized controlled trial design was used to select 86 patients with PPPD who were seen in the Department of Otorhinolaryngology Head and Neck Surgery, First Hospital of Shanxi Medical University from July 2020 to July 2021. Randomly assigned to the control group（43 patients） and the experimental group（43 patients）. The control group was routinely treated with medication and vestibular rehabilitation, while the experimental group underwent computerized cognitive behavioral therapy for a total of 9 sessions over 8 weeks; their dizziness symptoms（DHI）, negative affect（GAD-7, PHQ-9） and balance function（BBS） were compared at baseline, 4 and 8 weeks later. Results:After 4 and 8 weeks of intervention, the improvement of dizziness symptoms and negative mood in both groups had a between-group effect, time effect, and interaction effect（P<0.05）. The improvement of balance function had only a time effect and interaction effect（P<0.05）, and no difference in between-group effect was seen（P>0.05）. Conclusion:Computerized cognitive behavioral therapy can be used as an adjunctive treatment to alleviate patients' dizziness, negative affect, and balance function, but no additional benefit has been seen in terms of balance function improvement.

Inhibition of APOC1 promotes the transformation of M2 into M1 macrophages via the ferroptosis pathway and enhances anti-PD1 immunotherapy in hepatocellular carcinoma based on single-cell RNA sequencing.

Single-cell RNA-sequencing (scRNA-seq) presents better insights into cell behavior in the context of a complex tumor microenvironment by profiling single-cell populations. However, the mechanisms underlying treatment failure in hepatocellular carcinoma (HCC) are poorly understood. In this study, we performed deep scRNA-seq on immune cells under the isolation in peripheral blood, cancer tissues, and nearby common tissues of four HCC cases and two non-cancer controls, and 212,494 cells were included in the analysis. We identified distinct immune cell subtypes, enriched pathways for differential genes, and delineated associated developmentally relevant trajectories. APOC1 was found over-expressed in tumor-associated macrophages (TAMs) of HCC tissues than in normal tissues. Inhibition of APOC1 reversed the M2 phenotype to the M1 phenotype via the ferroptosis pathway in TAMs from HCC. Tumors in APOC1 -/- C57BL/6 mice demonstrated consistent attenuation compared to wild-type (WT) mice. Mass spectrometry results revealed that the relative proportion of M2 macrophages, B cells, and CD4+ T cells in the APOC1 -/- group exhibited a downward expression compared with the WT group, whereas CD8+ T cells, M1 macrophages, and NK cells exhibited an upward trend. Finally, APOC1 was found to be negatively correlated with the expression of PD1/PD-L1 in human HCC samples. In conclusion, the present study demonstrated that inhibiting APOC1 can promote the transformation of M2 macrophages into M1 macrophages via the ferroptosis pathway, thereby reshaping the tumor immune microenvironment and improving the anti-PD1 immunotherapy for HCC, providing a new strategy for improving the therapeutic effect of anti-PD1, and bringing new hope to HCC patients.

Tumor Microenvironment and its Implications for Antitumor Immunity in Cholangiocarcinoma: Future Perspectives for Novel Therapies.

The incidence of cholangiocarcinoma (CCA) has been increasing over the past few years. Although there are surgery, chemotherapy and other conventional treatment methods, the effect is not as expected. At present, immunotherapy has become the research frontier of cancer treatment, and CCA tumor microenvironment (TME) is becoming a hot exploration direction of immunobiology. TME can affect tumor progression through changes in metabolism, secretion and immunity. Accordingly, understanding the role played by immune cells and stromal cells in TME is important for the study of CCA immunotherapy. This review will discuss the interactions between immune cells (including CD8+ T cells, CD4+ T cells, macrophages, natural killer cells, dendritic cells, myeloid suppressor cells, mast cells, and neutrophils) and stromal cells (including cancer-associated fibroblasts, endothelial cells) in the TME of CCA. In addition, we will also discuss current research results on TME of CCA and recent advances in immunotherapy.

CircPAK1 promotes the progression of hepatocellular carcinoma via modulation of YAP nucleus localization by interacting with 14-3-3ζ.

BACKGROUND: Circular RNA (circRNA), a new class of non-coding RNA, has obvious correlations with the occurrence and development of many diseases, including tumors. This study aimed to investigate the potential roles of circPAK1 in hepatocellular carcinoma (HCC). METHODS: High-throughput sequencing was performed on 3 pairs of HCC and matched normal tissues to determine the upregulated circRNAs. The expression level of circPAK1 was detected by qRT-PCR in HCC and paired with normal liver tissue samples. The effects of circPAK1 on proliferation, invasion, metastasis and apoptosis of HCC cells were evaluated by in vitro and in vivo experiments. We also constructed Chitosan/si-circPAK1 (CS/si-circPAK1) nanocomplexes using Chitosan material to evaluate its in vivo therapeutic effect on HCC. High-throughput sequencing, RNA-sequencing, RNA probe pull-down, RNA immunoprecipitation and Co-Immunoprecipitation assays were performed to explore the relationship between circPAK1, 14-3-3ζ, p-LATS1 and YAP. Exosomes isolated from lenvatinib-resistant HCC cell lines were used to evaluate the relationship between exosomal circPAK1 and lenvatinib resistance. RESULTS: CircPAK1, a novel circRNA, is highly expressed in HCC tumor tissues and cell lines as well as correlated with poor outcomes in HCC patients. Functionally, circPAK1 knockdown inhibited HCC cell proliferation, migration, invasion and angiogenesis while circPAK1 overexpression promoted HCC progression. The tumor-promoting phenotypes of circPAK1 on HCC were also confirmed by animal experiments. Importantly, the application of CS/si-circPAK1 nanocomplexes showed a better therapeutic effect on tumor growth and metastasis. Mechanistically, circPAK1 enhanced HCC progression by inactivating the Hippo signaling pathway, and this kind of inactivation is based on its competitively binding of 14-3-3 ζ with YAP, which weakens the recruitment and cytoplasmic fixation of 14-3-3 ζ to YAP, thus promoting YAP nucleus localization. Additionally, circPAK1 could be transported by exosomes from lenvatinib-resistant cells to sensitive cells and induce lenvatinib resistance of receipt cells. CONCLUSION: CircPAK1 exerts its oncogenic function by competitively binding 14-3-3 ζ with YAP, thus promoting YAP nucleus localization, leading to the inactivation of a Hippo signaling pathway. Exosomal circPAK1 may drive resistance to lenvatinib, providing a potential therapeutic target for HCC patients.

Over-Expression of GUSB Leads to Primary Resistance of Anti-PD1 Therapy in Hepatocellular Carcinoma.

Immunotherapy treatments, particularly immune checkpoint blockade, can result in benefits in clinical settings. But many pre-clinical and clinical studies have shown that resistance to anti-PD1 therapy frequently occurs, leading to tumor recurrence and treatment failure, including in patients with hepatocellular carcinoma (HCC). In this study, 10 patients with HCC were remedied with anti-PD1, and pre-treatment biopsy samples were sequenced for 289 nanostring panel RNA to compare responsive and non-responsive tumors to identify possible pretreatment biomarkers or targets of anti-PD1 therapeutic responses. Fortunately, the expression of ß-Glucuronidase (GUSB) in the non-responding tumors was found to be remarkably higher than that in responding tumors. Results of the cell counting kit 8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU), transwell, wound healing test, and flow cytometry showed that GUSB facilitated proliferation, invasion, as well as migration of human HCC cells and downregulated PD-L1 expression by promoting miR-513a-5p. Additionally, as a GUSB inhibitor, amoxapine can reduce the progression of human HCC cells, and was an effective treatment for HCC and improved the sensitivity of anti-PD1 therapy. In summary, this study reveals that increased GUSB downregulates PD-L1 expression by promoting miR-513a-5p, leading to primary resistance to anti-PD1 treatment in HCC, and amoxapine enhances the sensitivity of anti-PD1 therapy by inhibiting GUSB, providing a new strategy and method for improving the efficacy of anti-PD1 therapy and bringing new prospects for therapy of HCC.

A Novel Prognostic Scoring Model for Myelodysplastic Syndrome Patients With SF3B1 Mutation.

The outcomes of myelodysplastic syndrome (MDS) patients with SF3B1 mutation, despite identified as a favorable prognostic biomarker, are variable. To comprehend the heterogeneity in clinical characteristics and outcomes, we reviewed 140 MDS patients with SF3B1 mutation in Zhejiang province of China. Seventy-three (52.1%) patients diagnosed as MDS with ring sideroblasts (MDS-RS) following the 2016 World Health Organization (WHO) classification and 118 (84.3%) patients belonged to lower risk following the revised International Prognostic Scoring System (IPSS-R). Although clonal hematopoiesis-associated mutations containing TET2, ASXL1 and DNMT3A were the most frequent co-mutant genes in these patients, RUNX1, EZH2, NF1 and KRAS/NRAS mutations had significant effects on overall survival (OS). Based on that we developed a risk scoring model as IPSS-R×0.4+RUNX1×1.1+EZH2×0.6+RAS×0.9+NF1×1.6. Patients were categorized into two subgroups: low-risk (L-R, score <= 1.4) group and high risk (H-R, score > 1.4) group. The 3-year OS for the L-R and H-R groups was 91.88% (95% CI, 83.27%-100%) and 38.14% (95% CI, 24.08%-60.40%), respectively (P<0.001). This proposed model distinctly outperformed the widely used IPSS-R. In summary, we constructed and validated a personalized prediction model of MDS patients with SF3B1 mutation that can better predict the survival of these patients.

Treatment of patients with cancer using PD­1/PD­L1 antibodies: Adverse effects and management strategies (Review).

In 2020, there were an estimated 19.3 million new cancer cases and close to 10 million cancer deaths worldwide. Cancer remains one of the leading causes of death. In recent years, with the continuous improvement of our understanding of tumor immunotherapy, immunotherapeutics, such as immune checkpoint inhibitors, have gradually become a hot spot for tumor treatment. Amongst these, programmed cell death protein 1/programmed cell death protein ligand 1 (PD­1/PD­L1) related inhibitors, such as nivolumab and pembrolizumab, atezolizumab, avelumab and durvalumab have been shown to exhibit a high level of efficacy in several types of tumors. It has been confirmed that these inhibitors play an important role in the anti­tumor process, significantly improving the survival rate of patients and delaying the progress of the underlying cancer. However, its method of therapeutic interference and potential for damaging the immune system has caused concern regarding its suitability. As these adverse effects are caused by an immune response to endogenous tissues, they are designated as immune­related adverse events (irAEs). In this review, the typical irAEs reported in recent years and the management strategies adopted are highlighted, to serve as a reference in assessing the clinical response to these adverse reactions.

MGP promotes CD8+ T cell exhaustion by activating the NF-κB pathway leading to liver metastasis of colorectal cancer.

Matrix Gla protein (MGP) was originally reported as a physiological suppressor of ectopia calcification and has also been reported to be associated with cancer. However, the relation between the biological functions of MGP and the immune response in colorectal cancer (CRC) remains unclear. Here, we investigated the regulatory role of MGP in the immune microenvironment of CRC. MGP expression in CRC samples was assessed by single-cell RNA sequencing and the Gene Expression Omnibus (GEO) database, and confirmed by quantitative real-time Polymerase Chain Reaction (qRT-PCR) and immunohistochemistry analysis of human CRC samples. The effect of MGP on proliferation and invasion of CRC cells was evaluated by in vitro assays involving MGP knockdown and overexpression. Luciferase reporter assay and chromatin immunoprecipitation (ChIP)-qPCR assay were performed to identify transcriptional regulatory sites of the nuclear factor kappa-B (NF-κB) and programmed cell death ligand 1 (PD-L1). In vivo experiments were performed in mouse model of CRC liver metastasis established via spleen injection. The results revealed that MGP was significantly upregulated in cancer cell clusters from the primary CRC or liver metastases, compared with that in the corresponding paracancerous tissues via single-cell RNA sequencing. MGP enriched intracellular free Ca2+ levels and promoted NF-κB phosphorylation, thereby activated PD-L1 expression to promote CD8+ T cell exhaustion in CRC. The luciferase reporter assay and ChIP-qPCR assay indicated that the transcriptional regulation of NF-κB upregulated PD-L1 expression. In vivo, MGP inhibition significantly decreased the rate of CRC liver metastasis, which was further reduced after combined therapy with αPD1 (anti-PD1). In conclusions, this study revealed that MGP can facilitate CD8+ T cell exhaustion by activating the NF-κB pathway, leading to liver metastasis of CRC. The combination of MGP knockdown and αPD1 can synergistically resist liver metastasis of CRC.

COVID-19 Related Stress and Mental Health Outcomes 1 Year After the Peak of the Pandemic Outbreak in China: the Mediating Effect of Resilience and Social Support.

Background: COVID-19 outbreak have a long-term negative impact on mental health. Meanwhile, it may also provide opportunities for positive outcomes (e.g., post-traumatic growth). Resilience and social support could serve as psychological resources to protect individuals against the detrimental effects of the COVID-19 crisis and enable people to develop positive changes during challenging times. Objective: By testing the roles of resilience and social support in the relationship between COVID-19 related stress and negative mental health outcomes (depression and anxiety), as well as the relationship between COVID-19 related stress and positive mental health outcomes (post-traumatic growth, PTG), this study aimed to investigate the psychological mechanisms involved in different mental health outcomes induced by COVID-19. Methods: An online survey was conducted 1 year after the peak of the COVID-19 outbreak (from April to August 2021) in China. The survey includes demographic questionnaires and six scales: the Impact of Event Scale-Revised for COVID-19 (IES-RC), the 10-item Connor-Davidson Resilience Scale (CD-RISC-10), the Perceived Social Support Scale (PSSS), the Center for Epidemiological Studies Depression Scale (CES-D), the Generalized Anxiety Disorder scale (GAD-7) and the Posttraumatic Growth Inventory (PTGI). The structural equation model (SEM) was used to evaluate the relations and mechanisms between COVID-19 related stress and resilience, social support in depression, anxiety, and PTG. Results: A total of 771 Chinese subjects completed the questionnaire, including 416 (54%) females. COVID-19 related stress was associated with anxiety (P < 0.001), PTG (P < 0.001), and depression (P < 0.001). Resilience was related to depression (P < 0.001), anxiety (P < 0.001), and PTG (P < 0.001). Social support was associated with depression (P < 0.001), anxiety (P < 0.001), and PTG (P < 0.001). Under SEM analysis, resilience mediated the effects of COVID-19 related stress on depression and post-traumatic growth. Social support mediated the impacts of COVID-19 related stress on post-traumatic growth, depression, and anxiety. The path coefficients of the mediation effects were statistically significant. Conclusions: The current findings suggest that COVID-19 related stress has a double-edged effect on mental health. Depression, anxiety, and PTG coexist in Chinese individuals 1 year after the peak of the pandemic. Resilience and social support serve as important protective factors of mental health, safeguard people from the negative mental health outcomes of the COVID-19, and promote PTG.

Tegaserod Maleate Inhibits Breast Cancer Progression and Enhances the Sensitivity of Immunotherapy.

BACKGROUND: Breast cancer (BC) is the most commonly diagnosed cancer in women worldwide. The challenge in managing this heterogeneous malignancy is that BC is highly aggressive and is always associated with chemical resistance, radiation resistance, hormone therapy resistance, and targeted therapy resistance. Therefore, there is an urgent need to find effective drugs to treat BC. METHODS: Based on the Selleck drug library approved by FDA, we screened 800 drugs for anti-BC cells and found that tegaserod maleate (TM), a 5-hydroxytryptamine 4-receptor (HTR4) partial agonist had the best anti-BC effect, which was further verified. The effects of different concentrations of TM on cell proliferation, invasion, and migration were evaluated in vitro using CCK8, plate cloning, transwell, and scratch assays. The UALCAN database, Kaplan-Meier Plotter database, Human Protein Atlas, and GEPIA2 were used to explore the correlation between HTR4 expression and BC patients' clinicopathological data as well as immune response. In vivo experiments demonstrated the effect of the TM and immunotherapy drug (anti-PD1/anti-TIGIT) combination on BC tumor growth in mice. RESULTS: TM significantly inhibited the proliferation, invasion, and migration of BC cells, and the higher the concentration, the better the inhibition effect. HTR4 was significantly downregulated in BC tissues compared to paracancerous tissues. The downregulation of HTR4 was correlated with clinicopathological data and positively correlated with BC prognosis. Interestingly, the GEPIA2 database suggested that there was a strong positive correlation between the expression of HTR4 and effector T cells, effector memory T cells, and exhausted T cells. In vitro experiments showed that TM, anti-PD1, and anti-TIGIT could all inhibit the growth and weight of BC tumors as compared with the control group. However, when anti-PD1 or anti-TIGIT was used simultaneously with TM, the inhibition of tumors significantly exceeded that in the control group. Moreover, the combination of anti-TIGIT and TM has the best inhibitory effect. CONCLUSION: TM inhibited the progression of breast cancer, and its combination with anti-TIGIT could effectively inhibit tumor growth and improve the sensitivity of immunotherapy in breast cancer.

Current Perspectives on B Lymphocytes in the Immunobiology of Hepatocellular Carcinoma.

Immune cells infiltrating tumors are capable of significantly impacting carcinogenesis through cancer promotion and anticancer responses. There are many aspects of hepatocellular carcinoma (HCC) related T lymphocytes that are undergoing extensive studies, whereas the effect exerted by B lymphocytes remains a less researched area. In this study, the latest research on the effect of B lymphocytes as they infiltrate tumors in relation to HCC is presented. Their prognosis-related importance is analyzed, along with their function in the tumor microenvironment (TME), as well as the way that B cell biology can be employed to help create a B cell therapy strategy for HCC.

Multiple myeloma secondary to acute lymphoblastic leukemia: A case report.

RATIONALE: Acute lymphoblastic leukemia (ALL) secondary to multiple myeloma (MM) is rare. Here we report a rare case of secondary ALL transformed from MM. PATIENT CONCERNS: A 64-year-old woman was diagnosed as MM IgG light chain type in 2001. She achieved complete remission after 2 cycles of therapy, and received maintenance therapy with thalidomide. The patient suffered from MM relapse in September 2011. Bone marrow examination showed that the percentage of primary lymphocytes was 59%, indicating ALL-L2 (Pre-B-ALL). The patient reached complete remission after 1 cycle of chemotherapy, and has been maintained for more than 6 years. DIAGNOSES: Immunophenotyping analysis revealed that the abnormal cell population accounted for approximately 66% which expressed HLA-DR, CD4, CD22, CD33, CD34, and cCD79a. These results indicated acute B lymphoblastic leukemia. Chromosome presented 47, XX, +5, -7, +19. Leukemia fusion gene analysis demonstrated positive EVI1 and negative IgH and TCR gene rearrangement. INTERVENTIONS: The patient accepted 1 cycle of VDCLP chemotherapy and reached complete remission, followed with consolidation therapies with VDCLP, MA, CAG and other chemotherapy regimens. OUTCOMES: This patient has maintained CR1 of ALL for more than 6 years. LESSONS: Even secondary lymphoblastic leukemia has been rarely reported in patients with MM, we still need perform bone marrow examination, flow cytology, and gene tests, especially during maintenance therapy.

[Clinical efficacy and quality of life evaluation of BPPV by different reduction methods].

OBJECTIVE: Comparative analysis of the clinical curative effect of manipulative reduction and TRV- CRP treatment of BPPV, comfort degree during reset and quality of life improvement. METHOD: One hundred and thirty-two patients with BPPV were randomly divided into two groups ,one group underwent the traditional manip- ulative reduction, the other group with TRV-CRP. DRI and VAS was evaluated in the pre and after treatment and evaluation of the efficacy was conducted. The results of two groups were compared. RESULT: The effective rate of manipulative reduction after a week treatment was 89. 23% and TRV-CRP.was 98. 51%, which was higher in TRV-CRP group than that of the manipulation reduction group(P<0. 05). The comfort degree of the manipulation reduction group was 4. 54±2. 48,higher than the TRV-CRP group which was 5. 48±1. 44 (P<0. 05). The score of DHI showed no significant difference before treatment between manipulation reduction group and TRV-CRP group(P>0. 05), the score of the two groups were decreased after a week of reduction, but the improvement of TRV-CRP group was higher than that of manipulation reduction group(P<0. 05). CONCLUSION: The success rate of TRV-CRP was higher than that of manipulative reduction,but manipulative reduction comfort degree was higher than TRV-CRP, the two methods can both improve the quality of life of patients with BPPV. TRV-CRP has many advantages over manipulative reduction, but manipulative reduction is simple with low cost, and the effect is still a great advantage. In clinical work, we should reasonable combine the two methods,so as to improve the cure rate of RPPV.

Changes in cerebral hemodynamics during a sleep-deprived video-electroencephalogram in healthy children.

This study investigates the cerebral hemodynamic changes during a routine sleep-deprived video-electroencephalogram (SD-VEEG) in healthy children. Forty-two children with normal intelligence were examined. The children were 5-14 years of age, and their electroencephalograms (EEGs) were within the normal range. Each subject was deprived of a routine night's sleep and then examined during non-drug-induced sleep in the daytime. The awake and sleep stages were evaluated using EEGs, according to the American Academy of Sleep Medicine. Stable transcranial Doppler ultrasound (TCD) tracings through real-time TCD-VEEG monitoring were recorded. The mean systolic cerebral blood flow velocity (CBFV), diastolic CBFV, pulsatility index and resistance index of each artery were analyzed for 30 s per stage. A multivariate analysis of variance was conducted to compare the hemodynamic parameters for the awake stage versus light sleep and deep sleep stages. Non-rapid eye movement sleep was associated with an increased CBFV in the middle (164.38 ± 27.28) and anterior cerebral artery (131.81 ± 21.55) during light sleep (stages N1 and N2) (P = 0.0001), a reduced systolic CBFV in all vascular arteries (LMCA, 138.73 ± 20.64; LACA, 108.33 ± 22.33; LPCA, 83.9 ± 18.6) during deep sleep (stage N3) compared with light sleep (P = 0.0001), and a sustained increased PI (LMCA, 0.92 ± 0.13; LACA, 0.964 ± 0.18) during deep sleep (P < 0.05). These findings indicate distinct cerebral hemodynamic alterations during SD-VEEG in children. This study utilized real-time TCD-VEEG monitoring during SD-EEG to further investigate neurovascular coupling in interictal epileptic discharges and understand its potential influence on cognition in the developing brain.

[On analysis of interrelation of the composition, structure and crack problem of plastics slice material].

In this paper, we analyse the composition, structure and property of two kinds of slice materials by FTIR spectrometer, X-ray fluorometer and tension test device. Results show that: 1) K thin slice consists of PVC resin, plasticizer(15.5%) and a little additive. Its structures look like woollen blanket. Its property is good. 2) L thin slice consists of PVC resin, the plasticier (13.2%), CaCO3 (6.59%) and little additive. There is a little crack on its structure. On these bases, the rupture problem of thin slice is discussed by the theory of the freedom volume and of the boundary chemistry. Research shows that the keys to question are the composition of the thin slices and the quantity of plasticizer.