Identification of RESP18 Gene Mutations Linked to Hereditary Non-Syndromic Cleft Lip and Palate in a Southern Chinese Family.

BACKGROUND Non-syndromic cleft lip with cleft palate (NSCLP) is one of the most common congenital birth defects worldwide; it causes lifelong problems and imposes burdens on patients and their families. This study aimed to describe the genomic analysis and identification of de novo regulated endocrine-specific protein 18 (RESP18) rs2385404 and rs2385405 gene polymorphisms associated with NSCLP in a southern Chinese family and to improve prevention, treatment, and prognosis of NSCLP. MATERIAL AND METHODS We performed a genome-wide association study (GWAS) to investigate the association of NSCLP phenotype with gene mutation. We investigated a 5-persons NSCLP family to screen the genetic variation of Han nationality in southern Chinese. Whole-genome sequencing (WGS) was used to detect all candidate genetic variants, and whole-exome sequencing (WES) was implemented to further verify mutations. The Clinical Variation Data Base (ClinVar) was employed for screening gene mutations. Finally, Sanger sequencing was applied to verify gene variations. RESULTS The combined analysis of WGS, WES, and ClinVar showed that a total of 9 variation positions overlapped among the 3 study cohorts. Sanger sequencing verified Glu amino acid variation in 2 mutation sites (rs2385404, rs2385405) from the RESP18 gene, which caused abnormal RESP18 function and was associated with hereditary NSCLP. CONCLUSIONS The combined genomic results showed that 2 mutations (rs2385404 and rs2385405) of the RESP18 gene were related to NSCLP in the family. The RESP18 gene may play an important role in the etiology and pathogenesis of cleft lip and palate.

TGFß2 Promotes the Construction of Fibrotic and Immunosuppressive Tumor Microenvironment in Pancreatic Adenocarcinoma: A Comprehensive Analysis.

Pancreatic adenocarcinoma (PAAD) was characterized by dense fibrotic stroma and immunosuppressive tumor microenvironment (TME). TGFß signaling pathways are highly activated in human cancers. However, the role of TGFß2 in TME of PAAD remains to be elucidated. In this study, we showed that TGFß2 was expressed at a relatively high level in PAAD tissues or cancer cells. Moreover, its high expression predicted unfavorable prognosis. In PAAD, gene set enrichment analysis showed that TGFß2 correlated positively with leukocyte transendothelial migration, but negatively with aerobic metabolism, including oxidative phosphorylation. Results in Tumor and Immune System Interaction Database showed that TGFß2 correlated with the infiltration of tumor-associated macrophages (TAMs), which could be attributed to that TGFß2 promote CCL2 expression in PAAD. Moreover, correlation analysis showed that TGFß2 could trigger cancer-associated fibroblasts (CAFs) activation in PAAD. The drug sensitivity analysis may indicate that patients with TGFß2 high expression have higher sensitivity to chemotherapeutics, but the sensitivity to targeted drugs is still controversial. TGFß2 could promote expansion of CAFs and infiltration of TAMs, thus participating in the construction of a fibrotic and immunosuppressive TME in PAAD. Targeting TGFß2 could be a promising therapeutic approach, which needs to be elucidated by clinical and experimental evidences.

Advances in laser therapies for the scar. / ç˜¢ç—•çš„æ¿€å ‰æ²»ç–—è¿›å±•.

Scars are classified into 5 types: Superficial scars, hypertrophic scars, atrophic scars, depressed scars, and keloid. These types are primarily characterized by abnormal production of fibroblasts and collagen, as well as the disorderly arrangement of connective tissue. Laser treatment for scars involves the coordinated activation of various signaling pathways and cytokines. However, the exact pathological mechanism for scar formation remains unclear, leading to a lack of radical treatment. Recently, laser treatment has gained popularity as a new minimally invasive approach for scar treatment. The emergence of new theories such as fractional, picosecond laser, and laser-assisted drug delivery has led to continuous advance in laser treatment. Up to now, it has been developed numerous novel treatments, including combined with drug, physical, and other treatments, which have shown superior therapeutic effects. In order to optimize laser treatment in the future, it is crucial to combine new materials with postoperative care. This will help clinicians develop more comprehensive treatment strategies. Therefore, it is important to explore treatment options that have broader applicability.

Molecular targets and mechanisms of different aberrant alternative splicing in metastatic liver cancer.

Metastasis remains a major challenge in the successful management of malignant diseases. The liver is a major site of metastatic disease and a leading cause of death from gastrointestinal malignancies such as colon, stomach, and pancreatic cancers, as well as melanoma, breast cancer, and sarcoma. As an important factor that influences the development of metastatic liver cancer, alternative splicing drives the diversity of RNA transcripts and protein subtypes, which may provide potential to broaden the target space. In particular, the dysfunction of splicing factors and abnormal expression of splicing variants are associated with the occurrence, progression, aggressiveness, and drug resistance of cancers caused by the selective splicing of specific genes. This review is the first to provide a detailed summary of the normal splicing process and alterations that occur during metastatic liver cancer. It will cover the role of alternative splicing in the mechanisms of metastatic liver cancer by examining splicing factor changes, abnormal splicing, and the contribution of hypoxia to these changes during metastasis.

Integrated mRNA- and miRNA-sequencing analyses unveil the underlying mechanism of tobacco pollutant-induced developmental toxicity in zebrafish embryos.

Tobacco pollutants are prevalent in the environment, leading to inadvertent exposure of pregnant females. Studies of these pollutants' toxic effects on embryonic development have not fully elucidated the potential underlying mechanisms. Therefore, in this study, we aimed to investigate the developmental toxicity induced by cigarette smoke extract (CSE) at concentrations of 0.25, 1, and 2.5% using a zebrafish embryo toxicity test and integrated transcriptomic analysis of microRNA (miRNA) and messenger RNA (mRNA). The findings revealed that CSE caused developmental toxicity, including increased mortality and decreased incubation rate, in a dose-dependent manner. Moreover, CSE induced malformations and apoptosis, specifically in the head and heart of zebrafish larvae. We used mRNA and miRNA sequencing analyses to compare changes in the expression of genes and miRNAs in zebrafish larvae. The bioinformatics analysis indicates that the mechanism underlying CSE-induced developmental toxicity was associated with compromised genetic material damage repair, deregulated apoptosis, and disturbed lipid metabolism. The enrichment analysis and RT-qPCR show that the ctsba gene plays a crucial function in embryo developmental apoptosis, and the fads2 gene mainly regulates lipid metabolic toxicity. The results of this study improve the understanding of CSE-induced developmental toxicity in zebrafish embryos and contribute insights into the formulation of novel preventive strategies against tobacco pollutants during early embryonic development.

Roles and mechanisms of aberrant alternative splicing in melanoma - implications for targeted therapy and immunotherapy resistance.

BACKGROUND: Despite advances in therapeutic strategies, resistance to immunotherapy and the off-target effects of targeted therapy have significantly weakened the benefits for patients with melanoma. MAIN BODY: Alternative splicing plays a crucial role in transcriptional reprogramming during melanoma development. In particular, aberrant alternative splicing is involved in the efficacy of immunotherapy, targeted therapy, and melanoma metastasis. Abnormal expression of splicing factors and variants may serve as biomarkers or therapeutic targets for the diagnosis and prognosis of melanoma. Therefore, comprehensively integrating their roles and related mechanisms is essential. This review provides the first detailed summary of the splicing process in melanoma and the changes occurring in this pathway. CONCLUSION: The focus of this review is to provide strategies for developing novel diagnostic biomarkers and summarize their potential to alter resistance to targeted therapies and immunotherapy.

Neoadjuvant Therapy for Locally Advanced Esophageal Cancers.

Esophageal carcinoma is one of the most aggressive malignant diseases. At present, neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy are regarded as the standard modalities for the treatments of locally advanced esophageal cancers based on several landmark trials. However, the optimal regimen, radiation dose, and surgical intervals are uncertain and the rate of recurrence after neoadjuvant therapy is high. Patients receiving neoadjuvant therapy and reaching a pathological complete response have been reported to have a better survival benefit and a fewer recurrence risk than those non-pathological complete responses. Nevertheless, less than half of patients will reach a pathological complete response after neoadjuvant therapy, and the methods to evaluate the efficacy after neoadjuvant therapy accurately are limited. Immune checkpoint inhibitors have been recommended for the treatments of advanced esophageal cancers. Recently, research has been beginning to evaluate the safety and efficacy of immunotherapy combined with neoadjuvant therapy. Here, we will review and discuss the development of the neoadjuvant therapy of locally advanced esophageal cancers and unsolved clinical problems.

Role of Rho guanine nucleotide exchange factors in non-small cell lung cancer.

Conventionally, Rho guanine nucleotide exchange factors (GEFs) are known activators of Rho guanosine triphosphatases (GTPases) that promote tumorigenesis. However, the role of Rho GEFs in non-small cell lung cancer (NSCLC) remains largely unknown. Through the screening of 81 Rho GEFs for their expression profiles and correlations with survival, four of them were identified with strong significance for predicting the prognosis of NSCLC patients. The four Rho GEFs, namely ABR, PREX1, DOCK2 and DOCK4, were downregulated in NSCLC tissues compared to normal tissues. The downregulation of ABR, PREX1, DOCK2 and DOCK4, which can be attributfed to promoter methylation, is correlated with poor prognosis. The underexpression of the four key Rho GEFs might be related to the upregulation of MYC signaling and DNA repair pathways, leading to carcinogenesis and poor prognosis. Moreover, overexpression of ABR was shown to have a tumor-suppressive effect in PC9 and H1703 cells. In conclusion, the data reveal the unprecedented role of ABR as tumor suppressor in NSCLC. The previously unnoticed functions of Rho GEFs in NSCLC will inspire researchers to investigate the distinct roles of Rho GEFs in cancers, in order to provide critical strategies in clinical practice.

Rho GTPases in cancer radiotherapy and metastasis.

Despite treatment advances, radioresistance and metastasis markedly impair the benefits of radiotherapy to patients with malignancies. Functioning as molecular switches, Rho guanosine triphosphatases (GTPases) have well-recognized roles in regulating various downstream signaling pathways in a wide range of cancers. In recent years, accumulating evidence indicates the involvement of Rho GTPases in cancer radiotherapeutic efficacy and metastasis, as well as radiation-induced metastasis. The functions of Rho GTPases in radiotherapeutic efficacy are divergent and context-dependent; thereby, a comprehensive integration of their roles and correlated mechanisms is urgently needed. This review integrates current evidence supporting the roles of Rho GTPases in mediating radiotherapeutic efficacy and the underlying mechanisms. In addition, their correlations with metastasis and radiation-induced metastasis are discussed. Under the prudent application of Rho GTPase inhibitors based on critical evaluations of biological contexts, targeting Rho GTPases can be a promising strategy in overcoming radioresistance and simultaneously reducing the metastatic potential of tumor cells.