B and T lymphocyte attenuator (BTLA) is a newly identified immune checkpoint molecular belonging to the CD28 immunoglobulin superfamily. However, the expression and clinical value of BTLA in skin cutaneous melanoma (SKCM) has not been widely characterized. We found that BTLA levels were upregulated in metastatic melanoma compared to normal skin tissues and primary melanoma. Higher BTLA was also correlated with improved prognosis in SKCM based on several datasets. The multivariate Cox regression model revealed that BTLA was an independent survival indicator in metastatic melanoma. Tumor microenvironment analysis indicated BTLA was positively associated with the infiltrating levels of different immune cells and the activity of the anti-cancer immunity cycle. Importantly, BTLA accurately predicted the outcome of melanoma patients treated with MAGE-A3 blocker or first-line anti-PD-1. The present findings disclose that BTLA is a reliable biomarker for prognosis and immunotherapeutic response and might contribute to developing novel SKCM immunological treatment strategies.

No abstract

Background Research has shown that Poly-ADP-ribose polymerases 1 (PARP-1) is a potential therapeutic target in the clinical treatment of breast cancer. An increasing number of studies have focused on the development of highly selective inhibitors that target PARP-1 over PARP-2, its closest isoform, to mitigate potential side effects. However, due to the highly conserved and similar binding sites of PARP-1 and PARP-2, there is a huge challenge for the discovery and design of PARP-1 inhibitors. Recently, it was reported that a potent PARP-1 inhibitor named NMS-P118 exhibited greater selectivity to PARP-1 over PARP-2 compared with a previously reported drug (Niraparib). However, the mechanisms underlying the effect of this inhibitor remains unclear. Methods In the present study, classical molecular dynamics (MD) simulations and accelerated molecular dynamics (aMD) simulations combined with structural and energetic analysis were used to investigate the structural dynamics and selective mechanisms of PARP-1 and PARP-2 that are bound to NMS-P118 and Niraparib with distinct selectivity. Results The results from classical MD simulations indicated that the selectivity of inhibitors may be controlled by electrostatic interactions, which were mainly due to the residues of Gln-322, Ser-328, Glu-335, and Tyr-455 in helix αF. The energetic differences were corroborated by the results from aMD simulations. Conclusion This study provides new insights about how inhibitors specifically bind to PARP-1 over PARP-2, which may help facilitate the design of highly selective PARP-1 inhibitors in the future.

No abstract

Thyroid cancer is a disease with an extremely high incidence rate and is divided into papillary, follicular, medullary, and undifferentiated thyroid cancers. Among them, papillary carcinoma is the most common subtype. We assessed expression of ETNK2 in public databases and found that ETNK2 is upregulated in PTC. Cohort and RNA sequencing data were used to verify this discovery. To further determine the relationship between ETNK2 and papillary thyroid carcinoma, we performed an in vitro experiment. In a PTC cell line, silencing ETNK2 inhibited cell proliferation, weakened cell migration and invasion ability, promoted apoptosis, and blocked the cell cycle. In addition, western blotting suggested that ETNK2 is related to the HIPPO pathway and may activate the EMT pathway through the HIPPO pathway to promote the development of thyroid cancer. These results revealed that ETNK2 is related to the occurrence and development of papillary thyroid carcinoma, suggesting that ETNK2 may be an oncogene associated with PTC.