PCDH11X mutation as a potential biomarker for immune checkpoint therapies in lung adenocarcinoma.

Immune checkpoint inhibitors (ICIs) have achieved impressive success in lung adenocarcinoma (LUAD). However, the response to ICIs varies among patients, and predictive biomarkers are urgently needed. PCDH11X is frequently mutated in LUAD, while its role in ICI treatment is unclear. In this study, we curated genomic and clinical data of 151 LUAD patients receiving ICIs from three independent cohorts. Relations between PCDH11X and treatment outcomes of ICIs were examined. A melanoma cohort collected from five published studies, a pan-cancer cohort, and non-ICI-treated TCGA-LUAD cohort were also examined to investigate whether PCDH11X mutation is a specific predictive biomarker for LUAD ICI treatment. Among the three ICI-treated LUAD cohorts, PCDH11X mutation (PCDH11X-MUT) was associated with better clinical response compared to wild-type PCDH11X (PCDH11X-WT). While in ICI-treated melanoma cohort, the pan-cancer cohort excluding LUAD, and the non-ICI-treated TCGA-LUAD cohort, no significant differences in overall survival (OS) were observed between the PCDH11X-MUT and PCDH11X-WT groups. PCDH11X mutation was associated with increased PD-L1 expression, tumor mutation burden (TMB), neoantigen load, DNA damage repair (DDR) mutations, and hot tumor microenvironment in TCGA-LUAD cohort. Our findings suggested that the PCDH11X mutation might serve as a specific biomarker to predict the efficacy of ICIs for LUAD patients. Considering the relatively small sample size of ICI-treated cohorts, future research with larger cohorts and prospective clinical trials will be essential for validating and further exploring the role of PCDH11X mutation in the context of immunotherapy outcomes in LUAD. KEY MESSAGES: PCDH11X mutation is associated with better clinical response compared to wild type PCDH11X in three ICIs-treated LUAD cohorts. In ICIs-treated melanoma cohort, the pan-cancer cohort excluding LUAD, and non-ICIs-treated TCGA-LUAD cohorts PCDH11X mutation is not associated with better clinical response, suggesting PCDH11X mutation might be a specific biomarker to predict the efficacy of ICIs treatment for LUAD patients. PCDH11X mutation is associated with increased PD-L1 expression, tumor mutation burden, and neoantigen load in TCGA-LUAD cohort. PCDH11X mutation is associated with hot tumor microenvironment in TCGA-LUAD cohort.

Methylation-mediated silencing of PTPRD induces pulmonary hypertension by promoting pulmonary arterial smooth muscle cell migration via the PDGFRB/PLCγ1 axis.

OBJECTIVE: Pulmonary hypertension is a lethal disease characterized by pulmonary vascular remodeling and is mediated by abnormal proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Platelet-derived growth factor BB (PDGF-BB) is the most potent mitogen for PASMCs and is involved in vascular remodeling in pulmonary hypertension development. Therefore, the objective of our study is to identify novel mechanisms underlying vascular remodeling in pulmonary hypertension. METHODS: We explored the effects and mechanisms of PTPRD downregulation in PASMCs and PTPRD knockdown rats in pulmonary hypertension induced by hypoxia. RESULTS: We demonstrated that PTPRD is dramatically downregulated in PDGF-BB-treated PASMCs, pulmonary arteries from pulmonary hypertension rats, and blood and pulmonary arteries from lung specimens of patients with hypoxic pulmonary arterial hypertension (HPAH) and idiopathic PAH (iPAH). Subsequently, we found that PTPRD was downregulated by promoter methylation via DNMT1. Moreover, we found that PTPRD knockdown altered cell morphology and migration in PASMCs via modulating focal adhesion and cell cytoskeleton. We have demonstrated that the increase in cell migration is mediated by the PDGFRB/PLCγ1 pathway. Furthermore, under hypoxic condition, we observed significant pulmonary arterial remodeling and exacerbation of pulmonary hypertension in heterozygous PTPRD knock-out rats compared with the wild-type group. We also demonstrated that HET group treated with chronic hypoxia have higher expression and activity of PLCγ1 in the pulmonary arteries compared with wild-type group. CONCLUSION: We propose that PTPRD likely plays an important role in the process of pulmonary vascular remodeling and development of pulmonary hypertension in vivo .

Development and validation of a blood-based genomic mutation signature to predict the clinical outcomes of atezolizumab therapy in NSCLC.

OBJECTIVES: We designed this study to develop a blood-based genomic mutation signature (bGMS) model for predicting the efficacy of atezolizumab therapy in non-small cell lung cancer (NSCLC) in a non-invasive manner. MATERIALS AND METHODS: Patients with NSCLC treated with atezolizumab from POPLAR and OAK clinical trials were included in our study. OAK cohort was defined as the training group, and POPLAR cohort was defined as the validation group. LASSO Cox regressions were applied to the training group to develop the gene mutation signature model to predict the overall survival (OS). Then the model was validated in the validation group. The combined impact of bGMS and other factors was explored with multivariable Cox regression. RESULTS: A bGMS risk model including 15 genes was established to classify patients into high-bGMS and low-bGMS groups. High-bGMS patients had shorter overall survival (OS) and progression-free survival (PFS) compared with low-bGMS in both training cohort (OS 7.9 vs. 19.9 months, p < 0.0001; PFS 1.7 vs. 4 months, p = 0.011) and validation cohort (OS 8.4 vs. 18.6 months, p = 0.0019; PFS 1.5 vs. 4.4 months, p = 0.013). The bGMS was superior to the blood tumor mutation burden (bTMB), LAF-bTMB, MSAF, PD-L1 expression, and a 5-genomic mutation signature in predicting OS for patients receiving atezolizumab. In addition, low-bGMS patients receiving atezolizumab therapy had a better OS rate compared with those receiving docetaxel therapy in both training (P < 0.0001) and validation groups (P = 0.018). Multivariate Cox regression analysis showed that bGMS was an independent prognostic factor on OS and PFS for patients receiving atezolizumab. Furthermore, a nomogram was developed to combine bGMS with the clinical characteristics to improve the predictive power further. CONCLUSION: bGMS could predict OS benefit for patients with NSCLC receiving atezolizumab therapy. BGMS and other non-invasive clinical characteristics can be combined to develop a more accurate model.

A novel tonicity-responsive microRNA miR-23a-5p modulates renal cell survival under osmotic stress through targeting heat shock protein 70 HSPA1B.

There is growing evidence that microRNAs (miRNAs) are implicated in cellular adaptation to osmotic stress, but the underlying osmosignaling pathways are still not completely understood. In this study, we found that a passenger strand miRNA, miR-23a-5p, was significantly downregulated in response to high NaCl treatment in mouse inner medullary collecting duct cells (mIMCD3) through an miRNA profiling assay. The decrease of miR-23a-5p is hypertonicity-dependent and osmotolerant cell type-specific. Knockdown of miR-23a-5p increased cellular survival and proliferation in mIMCD3. In contrast, miR-23a-5p overexpression repressed cell viability and proliferation under hypertonic stress. RNA deep-sequencing revealed that a heat shock protein 70 (HSP70) isoform, HSP70 member 1B (HSPA1B), was significantly increased under hypertonic treatment. Based on the prediction analysis by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and TargetScan, and a further validation via a dual-luciferase assay, HSPA1B was identified as a potential target of miR-23a-5p. Overexpressed miR-23a-5p suppressed HSPA1B, whereas downregulated miR-23a-5p promoted HSPA1B expression in mIMCD3. In addition, an in vivo study demonstrated that there is a reverse correlation between the levels of miR-23a-5p and HSPA1B in mouse renal inner medulla (papilla) that is exposed to extremely high osmolality. In summary, this study elucidates that passenger strand miR-23a-5p is a novel tonicity-responsive miRNA. The downregulation of miR-23a-5p facilitates cellular adaptation to hypertonic stress in mammalian renal cells through modulating HSPA1B.

Direct S-Poly(T) Plus assay in quantification of microRNAs without RNA extraction and its implications in colorectal cancer biomarker studies.

BACKGROUND: Advances in microRNAs (miRNAs) biomarkers have generated disease markers with potential clinical values. However, none of these published results have been applied in clinic until today. The main reason could be the lack of simple but robust miRNA measurements. METHODS: We built up a simple but ultrasensitive RT-qPCR protocol, Direct S-Poly(T) Plus assay, for detecting miRNAs without RNA purification. In this study, the method was optimized and compared with other RNA purification-based miRNA assays, and the sensitivity was tested. Using Direct S-Poly(T) Plus method, seven potential miRNA biomarkers of colorectal cancer were validated. RESULTS: It is possible to detect approximately 100 miRNAs with minimal plasma inputs (20 µl) and time (~ 140 min) with this approach. The sensitivity of this method was 2.7-343-fold higher than that of the stem-loop method, and comparable with S-Poly(T) plus method. 7 validated miRNA biomarkers of colorectal cancer by Direct S-Poly(T) plus assay could discriminate colorectal cancer stage I from healthy individuals, and promised satisfactory discrimination with the area under receiver operating characteristic (ROC) curve ranging from 0.79 to 0.94 (p value < 0.001). CONCLUSIONS: This simple and robust protocol may have strong impact on the development of specific miRNAs as biomarkers in clinic.

Advances in Biomarker Studies in Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is a neurological and developmental condition that begins early in childhood and lasts throughout life. The epidemiology of ASD is continuously increasing all over the world with huge social and economical burdens. As the etiology of autism is not completely understood, there is still no medication available for the treatment of this disorder. However, some behavioral interventions are available to improve the core and associated symptoms of autism, particularly when initiated at an early stage. Thus, there is an increasing demand for finding biomarkers for ASD. Although diagnostic biomarkers have not yet been established, research efforts have been carried out in neuroimaging and biological analyses including genomics and gene testing, proteomics, metabolomics, transcriptomics, and studies of the immune system, inflammation, and microRNAs. Here, we will review the current progress in these fields and focus on new methods, developments, research strategies, and studies of blood-based biomarkers.