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Nuclear factors TOX and TOX2 upregulate TIM3 expression and lead to T-cell exhaustion in malignancies. Here, we demonstrate two distinct TIM3 expression patterns (high & low) with high TOX and TOX2 levels in T-cell acute lymphoblastic leukemia (T-ALL) specimens and cell lines. However, the mechanisms regulated by TOX and TIM3 signaling in leukemogenesis are unclear. We found that TOX and TOX2 proteins each directly upregulated HAVCR2 transcription, while the cellular localization of TOX2 was different in Jurkat and MOLT3 cells (nucleus) and lymphoblastic cell T2 and normal T cells (cytoplasm). Nuclear TOX and TOX2 formed a protein complex and repressed HAVCR2 promoter activity by recruiting transcriptional corepressor LCOR and deacetylase HDAC3. The nuclear-cytosol translocation of TOX2 was deacetylation-dependent and cooperatively mediated by deacetylase Sirt1 and kinase TBK1. Radiation damage induced TOX2 nuclear translocation and decreased Sirt1, TIM3, and caspase 1 expression in normal T cells. Accordingly, knockdown of TOX, TOX2 or LCOR; HDAC3 inhibition; or TIM3 overexpression induced Jurkat cell apoptosis in vitro and slow growth in vivo. Thus, our findings demonstrate a novel regulatory mechanism involving TOX-TOX2 and the TIM3 pathway in the leukemogenesis of T-ALL.
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Polycystic ovary syndrome (PCOS) is one of the most prevalent gynecological endocrine conditions affecting reproductive women. It can feature a variety of symptoms, such as obesity, insulin resistance, skin conditions, and infertility. Women with PCOS are susceptible to illnesses including mood disorders, diabetes, hypertension, and dyslipidemia. Among them, depression is the most common in PCOS and has a detrimental effect on quality of life. Depression may occasionally develop due to the pathological traits of PCOS, but its exact pathogenesis in PCOS have eluded researchers to date. Therefore, there is an urgent need to explore the pathogenesis and treatments of depression in PCOS. The present review discusses the epidemiology of depression in PCOS, potential pathogenic mechanisms underlying PCOS and depression, as well as some potential factors causing depression in PCOS, including obesity, insulin resistance, hyperandrogenism, inflammation, and infertility. Meanwhile, some common treatment strategies for depression in PCOS, such as lifestyle intervention, acupuncture, oral contraceptive pills, psychological intervention, and insulin-sensitizer, are also reviewed. To fully understand the pathogenesis and treatment of depression in PCOS, a need remains for future large-scale multi-center randomized controlled trials and in-depth mechanism studies. Appeared originally in Front Psychiatry 2022; 13:1001484.
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Objective: To evaluate the effectiveness of different acupuncture treatments for mammary gland hyperplasia (MGH) using a network meta-analysis. Methods: Several databases were searched without language restrictions from 2000 to February 2023, including PubMed, Embase, Web of Science, Cochrane Library, China Science and Technology Journal Database, China Biology Medicine Database, Wanfang Database, China National Knowledge Infrastructure Database, and other professional websites and gray literature. Inclusion criteria were adult women diagnosed with MGH; intervention measures included acupuncture and related therapies; the control group was treated with simple drugs; and the research type was a randomized controlled trial (RCT). The primary outcomes were treatment effectiveness and estradiol and progesterone levels. Secondary outcomes were breast lump size and visual analog scale (VAS) score of breast pain. Exclusion criteria were studies unrelated to MGH, incorrect study populations, control measures or interventions, incomplete data, non-RCTs, case reports, and animal experiments. Cochrane tools were used to assess the risk of bias. The R software (x64 version 4.2.1), Review Manager 5.3 software and STATA 16.0 software were used for data analysis. Results: Following a rigorous screening process, data extraction, and quality assessment, 48 eligible RCTs encompassing 4,500 patients with MGH and 16 interventions were included. The results indicated that acupuncture, alone or in combination with traditional Chinese or Western medicine, had better therapeutic effects than conventional therapy. In terms of effectiveness, warm needle acupuncture was the best choice (94.6%). Bloodletting pricking was the most effective method (85.7%) for lowering progesterone levels. Bloodletting pricking was the most effective method (98.3%) for lowering estradiol levels. Manual acupuncture combined with traditional Chinese medicine was the most effective (74.5%) treatment to improve the size of the breast lump. Warm needle acupuncture was the most effective (69.8%) in improving the VAS score. Conclusion: Acupuncture therapy was more effective in treating MGH than drug therapy alone, and warm needle acupuncture and bloodletting pricking were the two best options. However, larger sample sizes and high-quality RCTs are required.
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Background: CD5-positive (CD5+) non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB DLBCL) is heterogeneous with a poor prognosis. For refractory DLBCL, the median overall survival was only 6.3 months. Therefore, there is a need for approaches to elongate the survival in this subgroup of relapsed DLBCL patients. Case Description: Here, we present a rare case of a 72-year-old patient with stage IV CD5+ non-GCB DLBCL with myeloid differentiation primary response 88 (MYD88) and cluster of differentiation 79B (CD79B) comutations. Zanubrutinib and rituximab therapy was initially administered until disease progression. Subsequently, zanubrutinib plus rituximab together with attenuated standard chemotherapy (miniCHOP) was applied and a notable response was observed. The patient tolerated the treatment well and exhibited a complete response in lung for about 5 months. Afterwards, the patients experienced relapse in the brain and started programmed death protein 1 (PD-1) regimens of toripalimab plus lenalidomide, which also exhibited a good response with decreased lesions in brain after half-year treatment. However, the patient experienced relapse again in the brain 3 months later and started chemotherapy with methotrexate plus rituximab. The patient had survived for over 2 years since the initial diagnosis of stage IV DLBCL and has continued to survive after experiencing a relapse in the brain for approximately 11 months till now. Conclusions: These findings suggest that toripalimab may be a new therapeutic option for central nervous system recurrence in refractory CD5+ DLBCL with MYD88 and CD79B comutation. Further clinical trials are warranted to confirm these results.