Evaluating the progression to abnormal thyrotropin in euthyroid preconception women: a population-based study.

BACKGROUND: Abnormal preconception thyrotropin levels were associated with fecundability and adverse fetomaternal outcomes, however, little is known regarding the natural change of serum thyrotropin in euthyroid preconception women. Thus, we performed a population-based study to evaluate the progression to abnormal thyrotropin in euthyroid preconception women. METHODS: This retrospective cohort study used data from the National Free Prepregnancy Checkups Project (NFPCP) collected between 2010 and 2020. Female Han Chinese participants aged 20-49 years who had two repeated NFPCP participations with a time interval of 1.5-3.0 years, confirmed non-pregnant status within this duration, and normal thyrotropin levels during their first participation were included for the analysis of thyrotropin abnormalities during the second NFPCP examination. Data were analyzed between June 1 and October 1, 2023. RESULTS: This study included 186,095 euthyroid women of reproductive age (mean ± SD, 26.72 ± 4.70 years) whose preconception thyrotropin levels were between 0.37 and 4.87 mIU/L. The median follow-up time was 2.13 (IQR, 1.85-2.54) years. A total of 8,497 (4.57%) women developed abnormal thyrotropin, including 4,118 (2.21%) subnormal thyrotropin and 4,379 (2.35%) supranormal thyrotropin. Compared with the reference group (thyrotropin 1.01-2.00 mIU/L), the lower baseline thyrotropin group had greater risk of developing subnormal thyrotropin, and the higher baseline thyrotropin group had greater risk of developing supranormal thyrotropin. Moreover, the restricted cubic spline analysis revealed a U-shaped dose-response association of baseline thyrotropin levels or thyrotropin multiples of the median (MOM) levels against risk of subnormal thyrotropin in the follow-up, and a J-shaped dose-response association against risk of supranormal thyrotropin levels in the follow-up. We further found that baseline thyrotropin outside of 1.43-1.93 mIU/L or baseline thyrotropin MOM outside 0.59-1.36 would hava a higher risk of developing of abnormal thyrotropin. CONCLUSIONS: Both low and high baseline thyrotropin were associated with a significantly increased risk of developing abnormal thyrotropin outcomes. The optimal preconception baseline thyrotropin levels may be between 1.43 mIU/L and 1.93 mIU/L or baseline thyrotropin MoM between 0.59 and 1.36 to minimize progression toward abnormal thyrotropin after 1.5-3.0 years. These findings may help with counseling of preconception thyroid function monitoring.

High expression of LOC541471, GDAP1, SOD1, and STK25 is associated with poor overall survival of patients with acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is an aggressive heterogeneous hematological malignancy with remarkably heterogeneous outcomes. This study aimed to identify potential biomarkers for AML risk stratification via analysis of gene expression profiles. METHODS: RNA sequencing data from 167 adult AML patients in the Cancer Genome Atlas (TCGA) database were obtained for overall survival (OS) analysis, and 52 bone marrow (BM) samples from our clinical center were used for validation. Additionally, siRNA was used to investigate the role of prognostic genes in the apoptosis and proliferation of AML cells. RESULTS: Co-expression of 103 long non-coding RNAs (lncRNAs) and mRNAs in the red module that were positively correlated with European Leukemia Network (ELN) risk stratification and age was identified by weighted gene co-expression network analysis (WGCNA). After screening by uni- and multivariate Cox regression, Kaplan-Meier survival, and protein-protein interaction analysis, four genes including the lncRNA LOC541471, GDAP1, SOD1, and STK25 were incorporated into calculating a risk score from coefficients of the multivariate Cox regression model. Notably, GDAP1 expression was the greatest contributor to OS among the four genes. Interestingly, the risk score, ELN risk stratification, and age were independent prognostic factors for AML patients, and a nomogram model constructed with these factors could illustrate and personalize the 1-, 3-, and 5-year OS rates of AML patients. The calibration and time-dependent receiver operating characteristic curves (ROCs) suggested that the nomogram had a good predictive performance. Furthermore, new risk stratification was developed for AML patients based on the nomogram model. Importantly, knockdown of LOC541471, GDPA1, SOD1, or STK25 promoted apoptosis and inhibited the proliferation of THP-1 cells compared to controls. CONCLUSIONS: High expression of LOC541471, GDAP1, SOD1, and STK25 may be biomarkers for risk stratification of AML patients, which may provide novel insight into evaluating prognosis, monitoring progression, and designing combinational targeted therapies.

BET bromodomain inhibition rescues PD-1-mediated T-cell exhaustion in acute myeloid leukemia.

Sustained expression of programmed cell death receptor-1 (PD-1) is correlated with the exhaustion of T cells, and blockade of the PD-1 pathway is an effective immunotherapeutic strategy for treating various cancers. However, response rates are limited, and many patients do not achieve durable responses. Thus, it is important to seek additional strategies that can improve anticancer immunity. Here, we report that the bromodomain and extraterminal domain (BET) inhibitor JQ1 inhibits PD-1 expression in Jurkat T cells, primary T cells, and T-cell exhaustion models. Furthermore, JQ1 dramatically impaired the expression of PD-1 and T-cell immunoglobulin mucin-domain-containing-3 (Tim-3) and promoted the secretion of cytokines in T cells from patients with acute myeloid leukemia (AML). In line with that, BET inhibitor-treated CD19-CAR T and CD123-CAR T cells have enhanced anti-leukemia potency and resistant to exhaustion. Mechanistically, BRD4 binds to the NFAT2 and PDCD1 (encoding PD-1) promoters, and NFAT2 binds to the PDCD1 and HAVCR2 (encoding Tim-3) promoters. JQ1-treated T cells showed downregulated NFAT2, PD-1, and Tim-3 expression. In addition, BET inhibitor suppressed programmed death-ligand 1 (PD-L1) expression and cell growth in AML cell lines and in primary AML cells. We also demonstrated that JQ1 treatment led to inhibition of leukemia progression, reduced T-cell PD-1/Tim-3 expression, and prolonged survival in MLL-AF9 AML mouse model and Nalm6 (B-cell acute lymphoblastic leukemia cell)-bearing mouse leukemia model. Taken together, BET inhibition improved anti-leukemia immunity by regulating PD-1/PD-L1 expression, and also directly suppressed AML cells, which provides novel insights on the multiple effects of BET inhibition for cancer therapy.

The role of NFAT in the pathogenesis and targeted therapy of hematological malignancies.

The nuclear factor of activated T cells (NFAT) family is well known for the survival of hemopoietic cells and plays an important role in the immune response. In recent decades, NFAT alteration was discovered in hematological malignancies, suggesting that targeted NFAT therapy may be a promising strategy for the treatment of hematological malignancies. In this review, we present an overview of the NFAT signaling pathway in lymphocytes as well as aberrant NFAT in hematological malignancies. Moreover, therapeutically targeting NFAT in hematological malignancies is also discussed in this review.

Physalin B inhibits cell proliferation and induces apoptosis in undifferentiated human gastric cancer HGC-27 cells.

BACKGROUND: Physalin B (PB) from Physalis angulata L. (Solanaceae) is a naturally occurring secosteroid with multiple biological activities, including anti-inflammatory and anticancer activity. However, PB's effects and mechanisms in human gastric cancer (GC) cells are not well characterized. METHODS: The undifferentiated GC cell line HGC-27 and semi-differentiated GC cell line SGC-7901 were treated with PB. Cell counting kit-8 (CCK-8) and colony formation assays were performed to evaluate cell viability. Apoptosis and the cell cycle were assessed by Annexin V/PI and PI/RNase DNA staining assays, respectively, and Western blotting was used to evaluate the expression of a protein. RESULTS: PB significantly inhibited the proliferation of HGC-27 cells in a dose- and time-dependent manner. Moreover, PB induced G0/G1 cycle arrest and caspase-dependent apoptosis of HGC-27 cells. Cleaved caspases 8, 3, and 7, poly(ADP)-ribose polymerase (PARP), and the cyclin-dependent kinase (CDK) inhibitor p-Chk2 was induced by PB in HGC-27 cells, while the cell cycle-related proteins cyclin D1, cyclin D3, CDK4, CDK6, cyclin E, and phosphorylated retinoblastoma tumor suppressor protein (p-Rb) were downregulated in a dose-dependent manner. CONCLUSIONS: PB inhibits proliferation via cyclin-dependent kinase and induces caspase-dependent apoptosis in HGC-27 cells, suggesting that PB might be a novel and effective agent for undifferentiated GC therapy.

[Research Advances in the Mechanisms of BRD4 and Its Inhibitors in Hematologic Malignancies--Review].

Bromodomain-containing protein 4 (BRD4) is one of the most important members in the bromodomain and extra terminal domain(BET) family, it plays an important role in cellular physiology in human body, such as cell cycles, cell proliferation, and immune response. Recent studies have shown that BRD4 is associated with occurrence and development of acute myeloblastic leukemia, multiple myeloma and lymphoma. The mechanisms of BRD4 in hematologic malignancies including the regulation of c-Myc expression, and participation of the composition of super-enhancer, etc. At present, many kinds of inhibitors have been developed to target inhibit BRD4 for therapy in hematologic malignancies, and some of BRD4 inhibitors have entered phase Ⅱ clinical trials, which suggested that BRD4 inhibitors are expected to become new therapeutic agents for hematologic malignancies. In this review, the research advance of BRD4 and BRD4 inhibitors in hematologic malignancies was summarized briefly.

Inhibition of BCL11B induces downregulation of PTK7 and results in growth retardation and apoptosis in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive subtype of leukemia with poor prognosis, and biomarkers and novel therapeutic targets are urgently needed for this disease. Our previous studies have found that inhibition of the B-cell leukemia/lymphoma 11B (BCL11B) gene could significantly promote the apoptosis and growth retardation of T-ALL cells, but the molecular mechanism underlying this effect remains unclear. This study intends to investigate genes downstream of BCL11B and further explore its function in T-ALL cells. We found that PTK7 was a potential downstream target of BCL11B in T-ALL. Compared with the healthy individuals (HIs), PTK7 was overexpressed in T-ALL cells, and BCL11B expression was positively correlated with PTK7 expression. Importantly, BCL11B knockdown reduced PTK7 expression in T-ALL cells. Similar to the effects of BCL11B silencing, downregulation of PTK7 inhibited cell proliferation and induced apoptosis in Molt-4 cells via up-regulating the expression of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and p27. Altogether, our studies suggest that PTK7 is a potential downstream target of BCL11B, and downregulation of PTK7 expression via inhibition of the BCL11B pathway induces growth retardation and apoptosis in T-ALL cells.

Regulation of PD-1 in T cells for cancer immunotherapy.

Study of the molecular mechanisms underlying cancer immune escape is one of the core issues in immuno-oncology research. Cancer cells can evade T cell cytotoxicity by exploiting the upregulation of T cell inhibitory receptors on T cells and their ligands on cancer cells. These upregulated proteins include the inhibitory receptor programmed cell-death protein 1 (PD-1) and its ligand programmed cell death 1 ligand 1 (PD-L1), which can induce T cell exhaustion and reduce T cell activation. Characterizing PD-1 regulation will help to elucidate the molecular mechanisms underlying T cell exhaustion and improve cancer treatment. Recent studies have found that tumor cells regulate PD-1 during gene transcription, post-transcriptional regulation, and post-translational modification and influence the effects of the anticancer immune response by targeting PD-1. In this review,we summarize the mechanisms of PD-1 regulation in T cells.

Transcriptome-Based Co-Expression of BRD4 and PD-1/PD-L1 Predicts Poor Overall Survival in Patients With Acute Myeloid Leukemia.

Positive response to PD-1/PD-L1 blockades was observed in the treatment of solid tumors. However, the clinical response to PD-1/PD-L1 blockade varied in patients with acute myeloid leukemia (AML). It is thought that there are factors other than PD-1 and PD-L1 that may affect the effect of immunotherapy. This study explored the impact of transcriptome-based co-expression of bromodomain containing 4 (BRD4) and PD-1/PD-L1 on the overall survival (OS) of patients with AML, in order to understand whether BRD4 would affect the effect of PD-1/PD-L1 blockades. Bone marrow samples from 59 AML patients in our clinical center and data of 176 patients from the Cancer Genome Atlas (TCGA) database were used for OS analysis and validation. It was found that increased expression of BRD4 was associated with poor OS in AML patients. Moreover, co-expression of BRD4 with PD-1 or PD-L1 was related to poor OS. The co-expression of BRD4 and PD-L1 was better than BRD4 and PD-1 for OS prediction. Furthermore, co-expression of BRD4 and PD-L1 was positively correlated with high tumor mutation burden, which contributed to poor OS in AML patients. Additionally, the co-expression of BRD4 and PD-L1 was associated with poor OS in non-acute promyelocytic leukemia patients with intermediate/high risk or under 60 years. Our results suggest that transcriptome-based co-expression of BRD4 and PD-L1 is a predictor for poor OS in AML patients, which might provide novel insight into designing combinational targeted therapy for AML.

Caveolin-1 deficiency protects pancreatic ß cells against palmitate-induced dysfunction and apoptosis.

Lipotoxicity leads to insulin secretion deficiency, which is among the important causes for the onset of type 2 diabetes mellitus. Thus, the restoration of ß-cell mass and preservation of its endocrine function are long-sought goals in diabetes research. Previous studies have suggested that the membrane protein caveolin-1 (Cav-1) is implicated in ß-cell apoptosis and insulin secretion, however, the underlying mechanisms still remains unclear. Our objective is to explore whether Cav-1 depletion protects pancreatic ß cells from lipotoxicity and what are the underlying mechanisms. In this study, we found that Cav-1 silencing significantly promoted ß-cell proliferation, inhibited palmitate (PA)-induced pancreatic ß-cell apoptosis and enhanced insulin production and secretion. These effects were associated with enhanced activities of Akt and ERK1/2, which in turn downregulated the expression of cell cycle inhibitors (FOXO1, GSK3ß, P21, P27 and P53) and upregulated the expression of Cyclin D2 and Cyclin D3. Subsequent inhibition of PI3K/Akt and ERK/MAPK pathways abolished Cav-1 depletion induced ß-cell mass protection. Furthermore, under PA induced endoplasmic reticulum (ER) stress, Cav-1 silencing significantly reduced eIF2α phosphorylation and the expression of ER stress-responsive markers BiP and CHOP, which are among the known sensitizers of lipotoxicity. Our findings suggest Cav-1 as potential target molecule in T2DM treatment via the preservation of lipotoxicity-induced ß-cell mass reduction and the attenuation of insulin secretion dysfunction.