The value of combined detection of LDHA and PD-L1 in predicting the efficacy and prognosis of advanced gastric cancer patients treated with PD-1 inhibitor

Background and purpose: The response rate of gastric cancer patients to programmed death-1 (PD-1) inhibitor is relatively low. Establishing a useful efficacy prediction method to screen the superior gastric cancer patients receiving anti-PD-1 therapy could improve the prognosis of patients. This study aimed to explore the value of combined detection of lactate dehydrogenase (LDHA) and programmed death ligand-1 (PD-L1) expressions in predicting the efficacy and prognosis of gastric cancer patients treated with PD-1 inhibitor. Methods: The clinicopathological data of 50 advanced gastric cancer patients treated with PD-1 inhibitor in The First Affiliated Hospital of Wannan Medical College from January 2020 to March 2022 were retrospectively analyzed. The independent risk factors affecting the efficacy of PD-1 inhibitor were analyzed by multivariate logistic regression. The value of combined detection of LDHA and PD-L1 in predicting the efficacy of PD-1 inhibitors in gastric cancer was analyzed by receiver operating characteristic (ROC) curve analysis. Gastric cancer patient survival was analyzed by Kaplan-Meier method. Results: The objective response rate (ORR) of gastric cancer patients receiving PD-1 inhibitor therapy in LDHA low and high expression groups were 59% and 10%, respectively. The disease control rate (DCR) in LDHA low and high expression groups were 83% and 29%, respectively. The difference was statistically significant (P<0.001). Multivariate logistic regression analysis showed that PD-L1 combined positive score (CPS)<5 and LDHA high expression were independent risk factors affecting the efficacy of PD-1 inhibitor in gastric cancer (P<0.05). ROC curve analysis showed that combined detection of LDHA and PD-L1 had good predictive value for the efficacy of PD-1 inhibitor in gastric cancer [area under curve (AUC) was 0.951]. Kaplan-Meier survival analysis showed that gastric cancer patients with low LDHA expression and PD-L1 CPS≥5 had longer overall survival (OS, P=0.003) and progression-free survival (PFS, P<0.001) after receiving PD-1 inhibitor therapy. Conclusion: Low LDHA expression and PD-L1 CPS≥5 were positively correlated with the efficacy of PD-1 inhibitor in gastric cancer. Gastric cancer patients with low LDHA expression and PD-L1 CPS≥5 significantly had prolonged OS and PFS after receiving PD-1 therapy. Therefore, the combined detection of LDHA and PD-L1 expressions has good value in predicting the efficacy and evaluating prognosis of advanced gastric cancer patients treated with PD-1 inhibitor

A unified construction of weightwise perfectly balanced Boolean functions

At Eurocrypt 2016, Méaux et al. presented FLIP, a new family of stream ciphers {that aimed to enhance the efficiency of homomorphic encryption frameworks. Motivated by FLIP, recent research has focused on the study of Boolean functions with good cryptographic properties when restricted to subsets of the space $\mathbb{F}_2^n$. If an $n$-variable Boolean function has the property of balancedness when restricted to each set of vectors with fixed Hamming weight between $1$ and $n-1$, it is a weightwise perfectly balanced (WPB) Boolean function. In the literature, a few algebraic constructions of WPB functions are known, in which there are some constructions that use iterative method based on functions with low degrees of 1, 2, or 4. In this paper, we generalize the iterative method and contribute a unified construction of WPB functions based on functions with algebraic degrees that can} be any power of 2. For any given positive integer $d$ not larger than $m$, we first provide a class of $2^m$-variable Boolean functions with a degree of $2^{d-1}$. Utilizing these functions, we then present a construction of $2^m$-variable WPB functions $g_{m;d}$. In particular, $g_{m;d}$ includes four former classes of WPB functions as special cases when $d=1,2,3,m$. When $d$ takes other integer values, $g_{m;d}$ has never appeared before. In addition, we prove the algebraic degree of the constructed WPB functions and compare the weightwise nonlinearity of WPB functions known so far in 8 and 16 variables

Elevated expression of CDK4 in lung cancer

<p/> <p>Background</p> <p>The aim of the present study was to analyze the expression of Cyclin-dependent kinase 4 (<it>CDK4</it>) in lung cancer and its correlation with clinicopathologic features. Furthermore, the involvement of <it>CDK4</it>-mediated cell cycle progression and its molecular basis were investigated in the pathogenesis of lung cancer.</p> <p>Methods</p> <p>Using immunohistochemistry analysis, we analyzed <it>CDK4 </it>protein expression in 89 clinicopathologically characterized lung cancer patients (59 males and 30 females) with ages ranging from 36 to 78 years and compared them to 23 normal lung tissues. Cases with cytoplasmic and nuclear <it>CDK4 </it>immunostaining score values greater than or equal to 7 were regarded as high expression while scores less than 7 were considered low expression. The correlation between the expression level of <it>CDK4 </it>and clinical features was analyzed. Furthermore, we used lentiviral-mediated shRNA to suppress the expression of CDK4 and investigate its function and molecular mechanism for mediating cell cycle progression.</p> <p>Results</p> <p>The expression level of <it>CDK4 </it>protein was significantly increased in lung cancer tissues compared to normal tissues (<it>P </it>< 0.001). In addition, high levels of <it>CDK4 </it>protein were positively correlated with the status of pathology classification (<it>P </it>= 0.047), lymph node metastasis (<it>P </it>= 0.007), and clinical stage (<it>P </it>= 0.004) of lung cancer patients. Patients with higher <it>CDK4 </it>expression had a markedly shorter overall survival time than patients with low <it>CDK4 </it>expression. Multivariate analysis suggested the level of <it>CDK4 </it>expression was an independent prognostic indicator (<it>P </it>< 0.001) for the survival of patients with lung cancer. Use of lentiviral-mediated shRNA to inhibit the expression of <it>CDK4 </it>in lung cancer cell line A549 not only inhibited cell cycle progression, but also dramatically suppressed cell proliferation, colony formation, and migration. Furthermore, suppressing <it>CDK4 </it>expression also significantly elevated the expression of cell cycle regulator <it>p21</it></p> <p>Conclusion</p> <p>Overexpressed <it>CDK4 </it>is a potential unfavorable prognostic factor and mediates cell cycle progression by regulating the expression of <it>p21 </it>in lung cancer</p

CDK13 RNA Over-Editing Mediated by ADAR1 Associates with Poor Prognosis of Hepatocellular Carcinoma Patients

Background/Aims: Aberrant RNA editing, mediated by adenosine deaminases acting on RNA (ADAR), serves as a post-transcriptional event participating in tumorigenesis and prognosis. However, the RNA editing profiles during HCC progression and their clinical correlations remain unclear. Methods: Multiple tissue samples were collected from an advanced HCC patient. RNA-seq was performed to obtain the RNA editing profiles for each sample. Two RNA editing sites from CDK13 were further validated in 60 HCC patients; and their potential regulatory mechanisms were investigated. Results: In-depth analysis of the RNA-seq data revealed a significant number of editing sites (632-816) in coding regions for each tissue sample, showing branched evolution during tumorigenesis and metastasis. Two editing sites (Q103R and K96R) in CDK13 showed significant over-editing in tumor, and these phenomenon were validated in 60 HCC patients. Furthermore, the clinicopathological analysis revealed that these CDK13 over-editing sites were positively associated with TNM, PVTT and poor prognosis. In addition, the editing level of these sites were significantly correlated with the expression of ADAR1. Loss of function assays further proved that these CDK13 over-editing sites were mediated by ADAR1 in HCC cells. Conclusions: CDK13 RNA over-editing sites mediated by ADAR1 may serve as novel cancer driver events in HCC progression

Association of the Synapse-Associated Protein 97 (SAP97) Gene Polymorphism With Neurocognitive Function in Schizophrenic Patients

The SAP97 gene is located in the schizophrenia susceptibility locus 3q29, and it encodes the synaptic scaffolding protein that interacts with the N-methyl-D-aspartate (NMDA) receptor, which is presumed to be dysregulated in schizophrenia. In this study, we genotyped a single-nucleotide polymorphism (SNP) (rs3915512) in the SAP97 gene in 1114 patients with schizophrenia and 1036 healthy-matched controls in a Han Chinese population through the improved multiplex ligation detection reaction (imLDR) technique. Then, we analyzed the association between this SNP and the patients' clinical symptoms and neurocognitive function. Our results showed that there were no significant differences in the genotype and allele frequencies between the patients and the controls for the rs3915512 polymorphism. However, patients with the rs3915512 polymorphism TT genotype had higher neurocognitive function scores (list learning scores, symbol coding scores, category instances scores and controlled oral word association test scores) than the subjects with the A allele (P = 4.72 × 10−5, 0.027, 0.027, 0.013, respectively). Our data are the first to suggest that the SAP97 rs3915512 polymorphism may affect neurocognitive function in patients with schizophrenia

Schizophrenia plausible protective effect of microRNA-137 is potentially related to estrogen and prolactin in female patients

BackgroundSchizophrenia (SCZ) is a serious chronic mental disorder. Our previous case–control genetic association study has shown that microRNA-137 (miR-137) may only protect females against SCZ. Since estrogen, an important female sex hormone, exerts neuroprotective effects, the relationship between estrogen and miR-137 in the pathophysiology of SCZ was further studied in this study.MethodsGenotyping of single-nucleotide polymorphism rs1625579 of miR-137 gene in 1,004 SCZ patients and 896 healthy controls was conducted using the iMLDR assay. The effect of estradiol (E2) on the miR-137 expression was evaluated on the human mammary adenocarcinoma cell line (MCF-7) and the mouse hippocampal neuron cell line (HT22). The relationships between serum E2, prolactin (PRL), and peripheral blood miR-137 were investigated in 41 SCZ patients and 43 healthy controls. The miR-137 and other reference miRNAs were detected by real-time fluorescent quantitative reverse transcription-PCR.ResultsBased on the well-known SNP rs1625579, the distributions of protective genotypes and alleles of the miR-137 gene were not different between patients and healthy controls but were marginally significantly lower in female patients. E2 upregulated the expression of miR-137 to 2.83 and 1.81 times in MCF-7 and HT22 cells, respectively. Both serum E2 and blood miR-137 were significantly decreased or downregulated in SCZ patients, but they lacked expected positive correlations with each other in both patients and controls. When stratified by sex, blood miR-137 was negatively correlated with serum E2 in female patients. On the other hand, serum PRL was significantly increased in SCZ patients, and the female patients had the highest serum PRL level and a negative correlation between serum PRL and blood miR-137.ConclusionThe plausible SCZ-protective effect of miR-137 may be female specific, of which the underlying mechanism may be that E2 upregulates the expression of miR-137. This protective mechanism may also be abrogated by elevated PRL in female patients. These preliminary findings suggest a new genetic/environmental interaction mechanism for E2/miR-137 to protect normal females against SCZ and a novel E2/PRL/miR-137-related pathophysiology of female SCZ, implying some new antipsychotic ways for female patients in future

NEDD9 Is a Positive Regulator of Epithelial-Mesenchymal Transition and Promotes Invasion in Aggressive Breast Cancer

Epithelial to mesenchymal transition (EMT) plays an important role in many biological processes. The latest studies revealed that aggressive breast cancer, especially the triple-negative breast cancer (TNBC) subtype was frequently associated with apparent EMT, but the mechanisms are still unclear. NEDD9/HEF1/Cas-L is a member of the Cas protein family and was identified as a metastasis marker in multiple cancer types. In this study, we wished to discern the role of NEDD9 in breast cancer progression and to investigate the molecular mechanism by which NEDD9 regulates EMT and promotes invasion in triple-negative breast cancer. We showed that expression of NEDD9 was frequently upregulated in TNBC cell lines, and in aggressive breast tumors, especially in TNBC subtype. Knockdown of endogenous NEDD9 reduced the migration, invasion and proliferation of TNBC cells. Moreover, ectopic overexpression of NEDD9 in mammary epithelial cells led to a string of events including the trigger of EMT, activation of ERK signaling, increase of several EMT-inducing transcription factors and promotion of their interactions with the E-cadherin promoter. Data presented in this report contribute to the understanding of the mechanisms by which NEDD9 promotes EMT, and provide useful clues to the evaluation of the potential of NEDD9 as a responsive molecular target for TNBC chemotherapy

Genetic Variability of TCF4 in Schizophrenia of Southern Chinese Han Population: A Case-Control Study

Objective: Schizophrenia is thought to be a neurodevelopmental disorder. As a key regulator in the development of the central nervous system, transcription factor 4 (TCF4) has been shown to be involved in the pathogenesis of schizophrenia. The aim of our study was to assay the association of TCF4 single nucleotide polymorphisms (SNPs) with schizophrenia and the effect of these SNPs on phenotypic variability in schizophrenia in Southern Chinese Han Population.Methods: Four SNPs (rs9960767, rs2958182, rs4309482, and rs12966547) of TCF4 were genotyped in 1137 schizophrenic patients and 1035 controls in a Southern Chinese Han population using the improved multiplex ligation detection reaction (iMLDR) technique. For patients with schizophrenia, the severity of symptom phenotypes was analyzed by the five-factor model of the Positive and Negative Symptom Scale (PANSS). Cognitive function was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS) scale.Results: The results showed that the genotypes and alleles of the three SNPs (rs2958182, rs4309482, and rs12966547) were not significantly different between the control group and the case group (all P &gt; 0.05). rs9960767 could not be included in the statistics for the extremely low minor allele frequency. However, the genotypes of rs4309482 shown a potential risk in the positive symptoms (P = 0.04) and excitement symptoms (P = 0.04) of the five-factor model of PANSS, but not survived in multiple test correction. The same potential risk was shown in the rs12966547 in positive symptoms of the PANSS (P = 0.03).Conclusion: Our results failed to find the associations of SNPs (rs2958182, rs4309482, and rs12966547) in TCF4 with schizophrenia in Southern Chinese Han Population

Genome-Wide Analysis of Histone H3 Lysine9 Modifications in Human Mesenchymal Stem Cell Osteogenic Differentiation

Mesenchymal stem cells (MSCs) possess self-renewal and multi-lineage differentiation potentials. It has been established that epigenetic mechanisms such as histone modifications could be critical for determining the fate of stem cells. In this study, full human genome promoter microarrays and expression microarrays were used to explore the roles of histone modifications (H3K9Ac and H3K9Me2) upon the induction of MSC osteogenic differentiation. Our results revealed that the enrichment of H3K9Ac was decreased globally at the gene promoters, whereas the number of promoters enriched with H3K9Me2 was increased evidently upon osteogenic induction. By a combined analysis of data from both ChIP-on-chip and expression microarrays, a number of differentially expressed genes regulated by H3K9Ac and/or H3K9Me2 were identified, implicating their roles in several biological events, such as cell cycle withdraw and cytoskeleton reconstruction that were essential to differentiation process. In addition, our results showed that the vitamin D receptor played a trans-repression role via alternations of H3K9Ac and H3K9Me2 upon MSC osteogenic differentiation. Data from this study suggested that gene activation and silencing controlled by changes of H3K9Ac and H3K9Me2, respectively, were crucial to MSC osteogenic differentiation