Molecular Medicine最新文献

Recurrent pregnancy loss (RPL) profoundly impacts not only the physical health but also the psychological well-being of women. Despite its profound effects, the underlying pathophysiological mechanisms of RPL remain largely elusive, with few discernible warning signs. Lymphocyte activation gene-3 (LAG-3) is a crucial immune checkpoint that modulates immune responses during infection and tumor. In the present study, we examined the expression of LAG-3 on CD4⁺T cells during pregnancy via cytometry by time-of-flight and flow cytometry. Our findings revealed a higher frequency of LAG-3⁺ decidual CD4⁺T (dCD4⁺T) cells in response to trophoblasts during normal pregnancy. This specific LAG-3⁺ subset of dCD4⁺T cells was found to produce a greater number of anti-inflammatory cytokines. Notably, blocking LAG-3 was highly effective in inhibiting the production of anti-inflammatory cytokines, which is detrimental to the maintenance of pregnancy. A decrease in the number of LAG-3⁺dCD4⁺T cells was correlated with miscarriage. Interestingly, the RNA level of LAG-3 (data analyzed from the two published single-cell databases) remained stable in RPL. Palmitoylation might play a role in regulating LAG-3 expression during RPL, as the palmitoylation of LAG-3⁺dCD4⁺T cells was increased in RPL. Additionally, the general palmitoylation inhibitor 2-bromopalmitate was found to upregulate LAG-3 expression on dCD4⁺T cells both in vitro and in vivo. Collectively, these findings highlighted the significant roles of LAG-3 in regulating the function of dCD4⁺T cell and maintaining normal pregnancy. Furthermore, they suggested that lower LAG-3 expression on dCD4⁺T cells could serve as a potential biomarker for diagnosis of RPL.

Background: Previous studies have suggested that, after acquisition of t(11;14), mantle cell lymphoma (MCL) pathogenesis may proceed via several different genetic second hits, which may shape different mutational profiles of clinically manifest lymphoma. The most prevalent second hit in MCL includes ATM aberrations, accounting for about half of patients with newly diagnosed MCL. As ATM and TP53 mutations tend to be exclusive in MCL, we retrospectively analyzed the prognostic role of ATM deletions and/or mutations in patients with newly diagnosed MCL, both in the entire cohort and in a subcohort of patients with wild-type TP53.

Methods: To investigate deletions and mutations of ATM and TP53 in newly diagnosed MCL, we used fluorescence in situ hybridization and next-generation sequencing. To assess relationships between variables, non-parametric (Spearman) and chi-square tests were used. The Kruskal-Wallis test was used to analyze differences in continuous variables between two groups of patients. For survival analyses, the standard Kaplan-Meier estimator and log-rank test were employed. Univariate and multivariate Cox proportional hazard models were used to examine the prognostic value of various factors on patient survival.

Results: We analyzed 187 patients with MCL (a median follow-up of 3.6 years). Eighty-one (43%) and 75 (40%) patients had ATM and TP53 aberrations, respectively. Of note, three (9%) patients with mutated ATM harbored a germline mutation. Patients with TP53 aberration had shorter survival rates. Although ATM deletion did not correlate with progression-free survival (PFS) in the entire cohort, it was associated with shorter PFS (hazard ratio 2.25, p = 0.01) in patients with wild-type TP53. A higher frequency of ATM deletion correlated with shorter PFS. Patients with ATM mutation (and wild-type TP53) had a trend toward better PFS (albeit not statistically significant). Moreover, patients with a higher variant allele frequency of ATM mutation tended to have longer PFS.

Conclusions: ATM deletion is an important predictor of prognosis in MCL patients and should be routinely examined, especially in those with wild-type TP53. In contrast, an isolated ATM mutation may predict a better prognosis in the context of standard immunochemotherapy.

Background: Seven female individuals with multiple congenital anomalies, developmental delay and/or intellectual disability have been found to have a genetic variant of uncertain significance in the mediator complex subunit 12 gene (MED12 c.3412C>T, p.Arg1138Trp). The functional consequence of this genetic variant in disease is undetermined, and insight into disease mechanism is required.

Methods: We identified a de novo MED12 p.Arg1138Trp variant in a female patient and compared disease phenotypes with six female individuals identified in the literature. To investigate affected biological pathways, we derived two induced pluripotent stem cell (iPSC) lines from the patient: one expressing wildtype MED12 and the other expressing the MED12 p.Arg1138Trp variant. We performed neural disease modelling, transcriptomics and protein analysis, comparing healthy and variant cells.

Results: When comparing the two cell lines, we identified altered gene expression in neural cells expressing the variant, including genes regulating RNA polymerase II activity, transcription, pre-mRNA processing, and neural development. We also noted a decrease in MED12L expression. Pathway analysis indicated temporal delays in axon development, forebrain differentiation, and neural cell specification with significant upregulation of pre-ribosome complex gene pathways.

Conclusion: In a human neural model, expression of MED12 p.Arg1138Trp altered neural cell development and dysregulated the pre-ribosome complex providing functional evidence of disease aetiology and mechanism in MED12-related disorders.

The galactoside-binding galectin-3 is a multi-mode promoter in a broad range of cancers, as well as in the pathogenesis of inflammation and fibrosis-associated diseases. It is currently a hotly pursued therapeutic target in those disease areas. Several carbohydrate-based galectin-3 inhibitors have recently demonstrated encouraging results in early phase clinical trials. This study reports the discovery of two synthetic, non-carbohydrate, small molecule compounds (named K2 an L2) as potent galectin-3 inhibitors. K2 and L2 share the same molecular composition with difference of one -NH2 group located at para (K2) or meta (L2) position at one of its aromatic rings. These novel compound inhibitors were shown to bind to galectin-3 on the canonical S-face of galectin-3 carbohydrate-recognition domain. Their binding was shown to alter galectin-3 conformation and significantly inhibit galectin-3-mediated activities in cancer cell adhesion, invasion, angiogenesis and macrophage secretion of pro-inflammatory cytokines min vitro, and markedly reduce galectin-3-mediated tumour growth and metastasis in vivo in mice as well as in chick embryos. Moreover, these novel galectin-3 inhibitors showed no detectable cytotoxicity and no genotoxicity. K2 and L2 therefore represent a unique class of novel galectin-3 inhibitors that can effectively inhibit galectin-3-mediated activities in vitro and in vivo. The discovery of these non-carbohydrate galectin-3 inhibitors offers significant promises to the development of galectin-3-targeted therapeutic drugs for the treatment of cancer and other galectin-3-mediated pathologies such as inflammation and fibrosis-associated diseases.