Neurotransmitter system gene variants as biomarkers for the therapeutic efficacy of rTMS and SSRIs in obsessive-compulsive disorder.

Purpose: This study aims to examine the potential influence of RS4680 (COMT), RS16965628 (SLC6A4), and RS1019385 (GRIN2B) polymorphisms on the therapeutic response to repetitive transcranial magnetic stimulation (rTMS) and selective serotonin reuptake inhibitors (SSRIs) in individuals with obsessive-compulsive disorder (OCD). Patients and methods: Thirty-six untreated outpatients diagnosed with OCD were recruited and allocated to active or sham rTMS groups for two weeks. The mean age of the participants was 31.61, with 17 males (47.22%) and 19 females (52.78%). Peripheral blood samples (5 mL) were collected from each participant using ethylenediaminetetraacetic acid (EDTA) vacuum tubes for genotyping purposes, clinical evaluation was taken place at baseline and second week. Results: The A allele of RS4680, C allele of RS16965628, and GG allele of RS1019385 were identified as potential bio-markers for predicting treatment response to OCD treatments (rTMS & SSRIs). Conclusion: Those genes may serve as bio-markers for the combined treatment of rTMS and SSRIs in OCD. The finding hold promise for further research and the potential implementation of precision treatment of OCD. Clinical trial registration: https://www.chictr.org.cn, identifier ChiCTR1900023641.

In vivo efficacy of phage cocktails against carbapenem resistance Acinetobacter baumannii in the rat pneumonia model.

Acinetobacter baumannii, an opportunistic pathogen, poses a significant threat in intensive care units, leading to severe nosocomial infections. The rise of multi-drug-resistant strains, particularly carbapenem-resistant A. baumannii, has created formidable challenges for effective treatment. Given the prolonged development cycle and high costs associated with antibiotics, phages have garnered clinical attention as an alternative for combating infections caused by drug-resistant bacteria. However, the utilization of phage therapy encounters notable challenges, including the narrow host spectrum, where each phage targets a limited subset of bacteria, increasing the risk of phage resistance development. Additionally, uncertainties in immune system dynamics during treatment hinder tailoring symptomatic interventions based on patient-specific states. In this study, we isolated two A. baumannii phages from wastewater and conducted a comprehensive assessment of their potential applications. This evaluation included sequencing analysis, genome classification, pH and temperature stability assessments, and in vitro bacterial inhibition assays. Further investigations involved analyzing histological and cytokine alterations in rats undergoing phage cocktail treatment for pneumonia. The therapeutic efficacy of the phages was validated, and transcriptomic studies of rat lung tissue during phage treatment revealed crucial changes in the immune system. The findings from our study underscore the potential of phages for future development as a treatment strategy and offer compelling evidence regarding immune system dynamics throughout the treatment process.IMPORTANCEDue to the growing problem of multi-drug-resistant bacteria, the use of phages is being considered as an alternative to antibiotics, and the genetic safety and application stability of phages determine the potential of phage application. The absence of drug resistance genes and virulence genes in the phage genome can ensure the safety of phage application, and the fact that phage can remain active in a wide range of temperatures and pH is also necessary for application. In addition, the effect evaluation of preclinical studies is especially important for clinical application. By simulating the immune response situation during the treatment process through mammalian models, the changes in animal immunity can be observed, and the effect of phage therapy can be further evaluated. Our study provides compelling evidence that phages hold promise for further development as therapeutic agents for Acinetobacter baumannii infections.

LAMC2 regulates the proliferation, invasion, and metastasis of gastric cancer via PI3K/Akt signaling pathway.

OBJECTIVES: Gastric cancer (GC) is a prevalent malignant tumor widely distributed globally, exhibiting elevated incidence and fatality rates. The gene LAMC2 encodes the laminin subunit gamma-2 chain and is found specifically in the basement membrane of epithelial cells. Its expression is aberrant in multiple types of malignant tumors. This research elucidated a link between LAMC2 and the clinical characteristics of GC and investigated the potential involvement of LAMC2 in GC proliferation and advancement. MATERIALS AND METHODS: LAMC2 expressions were detected in GC cell lines and normal gastric epithelial cell lines via qRT-PCR. Silencing and overexpression of the LAMC2 were conducted by lentiviral transfection. A xenograft mouse model was also developed for in vivo analysis. Cell functional assays were conducted to elucidate the involvement of LAMC2 in cell growth, migration, and penetration. Further, immunoblotting was conducted to investigate the impact of LAMC2 on the activation of signal pathways after lentiviral transfection. RESULTS: In the findings, LAMC2 expression was markedly upregulated in GC cell lines as opposed to normal gastric epithelial cells. In vitro analysis showed that sh-LAMC2 substantially inhibited GC cell growth, migration, and invasion, while oe-LAMC2 displayed a contrasting effect. Xenograft tumor models demonstrated that oe-LAMC2 accelerated tumor growth via high expression of Ki-67. Immunoblotting analysis revealed a substantial decrease in various signaling pathway proteins, PI3K, p-Akt, and Vimentin levels upon LAMC2 knockdown, followed by increased E-cadherin expression. Conversely, its overexpression exhibited contrasting effects. Besides, epithelial-mesenchymal transition (EMT) was accelerated by LAMC2. CONCLUSION: This study provides evidence indicating that LAMC2, by stimulating signaling pathways, facilitated EMT and stimulated the progression of GC cells in laboratory settings and mouse models. Research also explored that the abnormal LAMC2 expression acts as a biomarker for GC.

SSF-DDI: a deep learning method utilizing drug sequence and substructure features for drug-drug interaction prediction.

BACKGROUND: Drug-drug interactions (DDI) are prevalent in combination therapy, necessitating the importance of identifying and predicting potential DDI. While various artificial intelligence methods can predict and identify potential DDI, they often overlook the sequence information of drug molecules and fail to comprehensively consider the contribution of molecular substructures to DDI. RESULTS: In this paper, we proposed a novel model for DDI prediction based on sequence and substructure features (SSF-DDI) to address these issues. Our model integrates drug sequence features and structural features from the drug molecule graph, providing enhanced information for DDI prediction and enabling a more comprehensive and accurate representation of drug molecules. CONCLUSION: The results of experiments and case studies have demonstrated that SSF-DDI significantly outperforms state-of-the-art DDI prediction models across multiple real datasets and settings. SSF-DDI performs better in predicting DDI involving unknown drugs, resulting in a 5.67% improvement in accuracy compared to state-of-the-art methods.

Serotonin syndrome caused by a CYP2C19-mediated interaction between low-dose escitalopram and clopidogrel: a case report.

Background: Serotonin syndrome has been recognized as a serious adverse reaction to antidepressants and is characterized by sudden or severe autonomic nerve dysfunction and neuromuscular symptoms. Without an accurate diagnosis and prompt treatment, serotonin syndrome progresses rapidly and can be life-threatening. It is usually related to the dose of 5-hydroxytryptamine drugs, and the dose is the basis for diagnosis. Therefore, serotonin syndrome induced by low-dose antidepressants rarely occurs, and clinicians are more likely to misdiagnose patients who take low-dose antidepressants with similar symptoms. Here, we present a case study of serotonin syndrome caused by a relatively low dose of escitalopram, which is not common in past references. Case summary: The patient was a 74-year-old Asian woman with a 42-year history of schizophrenia. After 6 weeks of antidepressant treatment, our patient presented with characteristic myoclonus in the lower limbs and closed eyes with fluttering. Initially, she was misdiagnosed with neuroleptic malignant syndrome (NMS) due to antipsychotic medication and was treated accordingly, even with discontinuation of clozapine. However, her symptoms persisted, and then therapeutic drug monitoring was initiated with the involvement of a clinical pharmacist. Eventually, she was diagnosed with serotonin syndrome due to escitalopram levels reaching the warning level. Subsequently, the patient's treatment was modified, and her clinical outcome was satisfactory without any other serious adverse reactions. Gene detection was also performed, and a cytochrome P450 enzyme (CYP) 2C19-mediated interaction between low-dose escitalopram and clopidogrel seems to be a possible mechanism. Conclusion: Data on this is extremely scarce, and to the best of our knowledge, serotonin syndrome caused by low-dose antidepressants has not yet been discussed to any great extent in the literature. Our case provides more clinical experience in the treatment of serotonin syndrome.

Development of a prognostic model for anoikis and identifies hub genes in hepatocellular carcinoma.

Considering the high fatality of hepatocellular carcinoma (HCC), current prognostic systems are insufficient to accurately forecast HCC patients' outcomes. In our study, nine anoikis­related genes (PTRH2, ITGAV, ANXA5, BIRC5, BDNF, BSG, DAP3, SKP2, and EGF) were determined to establish a risk scoring model using LASSO regression, which could be validated in ICGC dataset. Kaplan-Meier curves and time-dependent receiver operating characteristic (ROC) curve analysis confirmed the risk score possessed an accurate predictive value for the prognosis of HCC patients. The high-risk group showed a higher infiltration of aDCs, macrophages, T-follicular helper cells, and Th2 cells. Besides, PD-L1 was significantly higher in the high-risk group compared to the low-risk group. Several anoikis­related genes, such as ANX5, ITGAV, BDNF and SKP2, were associated with drug sensitivity in HCC. Finally, we identified BIRC5 and SKP2 as hub genes among the nine model genes using WGCNA analysis. BIRC5 and SKP2 were over-expressed in HCC tissues, and their over-expression was associated with poor prognosis, no matter in our cohort by immunohistochemical staining or in the TCGA cohort by mRNA-Seq. In our cohort, BIRC5 expression was highly associated with the T stage, pathologic stage, histologic grade and AFP of HCC patients. In general, our anoikis-related risk model can enhance the ability to predict the survival outcomes of HCC patients and provide a feasible therapeutic strategy for immunotherapy and drug resistance in HCC. BIRC5 and SKP2 are hub genes of anoikis­related genes in HCC.

Association of high-risk comorbidity with overall survival among patients with gastric cancer and its sex-specific differences in China: a retrospective observational cohort study.

BACKGROUND: Concomitant diseases often occur in cancer patients and are important in decision-making regarding treatments. However, information regarding the prognostic relevance of comorbidities for mortality risk is still limited among Chinese gastric cancer (GC) patients. This study aimed to investigate the association between comorbidities and 3-year mortality risk. METHODS: This retrospective study enrolled 376 GC patients undergoing radical gastrectomy at the Affiliated Zhongshan Hospital of Dalian University from January 2011 to December 2019. Demographic and clinicopathological information and treatment outcomes were collected. Patients were divided into low-, moderate- and high-risk comorbidity groups based on their Charlson Comorbidity Index (CCI) and age-adjusted CCI (ACCI) scores. Kaplan-Meier survival and Cox regression analyses were used to examine 3-year overall survival (OS) and mortality risk for each group. RESULTS: The median follow-up time was 43.5 months, and 40.2% (151/376) of GC patients had died at the last follow-up. There were significant differences in OS rates between ACCI-based comorbidity groups (76.56; 64.51; 54.55%, log-rank P = 0.011) but not between CCI-based comorbidity groups (log-rank P = 0.16). The high-risk comorbidity group based on the ACCI remained a significant prognostic factor for 3-year OS in multivariate analysis, with an increased mortality risk (hazard ratio [HR], 1.99; 95% CI, 1.15-3.44). Subgroup analysis revealed that this pattern only held for male GC patients but not for female patients. CONCLUSION: The present study suggested that high-risk comorbidities were significantly associated with a higher mortality risk, particularly in Chinese male GC patients. Moreover, the ACCI score was an independent prognostic factor of long-term mortality.

Preoperative sarcopenia combined with prognostic nutritional index predicts long-term prognosis of radical gastrectomy with advanced gastric cancer: a comprehensive analysis of two-center study.

PURPOSE: This study aims to investigate the predictive value of the combined index smni(skeletal muscle index (SMI)-prognostic nutrition index(PNI)) for the postoperative survival of patients with advanced gastric cancer(AGC). METHODS: 650 patients with AGC from two centers (290 cases from the First Affiliated Hospital of Dalian University and 360 points from the Fujian Medical University Union Hospital) were selected as the study subjects based on unified screening criteria. Clinical data, preoperative abdominal CT images, results of hematology-related examinations, tumor-related characteristics, and surgical and follow-up data of the patients were collected and organized. The L3 vertebral level muscle area was measured using computer-assisted measurement techniques, and the skeletal muscle index(SMI) was calculated based on this measurement. The prognostic nutrition index (PNI) was calculated based on serum albumin and lymphocyte count indicators. The Kaplan-Meier survival analysis of data from the First Affiliated Hospital was used to determine that SMI and PNI are significantly correlated with the postoperative survival rate of patients with advanced gastric cancer. Based on this, a novel combined index smni was fitted and stratified for risk. Cox proportional hazards regression analysis was used to determine that the index smni is an independent prognostic risk factor for patients with AGC after surgery. The ROC curve was used to describe the predictive ability of the new combined index and its importance and predictive power in predicting postoperative survival of patients with AGC, which was verified in the data of Fujian Medical University Union Hospital. RESULT: The Kaplan-Meier curve analysis of the combined indicator smni Is clearly associated with long-term survival(3-year OS (P < 0.001) and DSS (P < 0.001)), univariate analysis and multivariate analysis showed that smni was an independent prognostic risk factor, The ROC curve for the first center 3-year OS(AUC = 0.678), DSS(AUC = 0.662) show good predictive ability and were validated in the second center. CONCLUSION: The combined index smni has a good predictive ability for the postoperative survival rate of patients with AGC and is expected to provide a new reference basis and more accurate and scientific guidance for the postoperative management and treatment of patients with AGC.

Identification of VIPR2 rare and common variants in the Chinese Han population with schizophrenia.

Introduction: Schizophrenia is a severe and chronic psychiatric disorder with hereditary risk up to 80% as previous studies indicated. Several researches have demonstrated a significant association between schizophrenia and microduplications that overlap the vasoactive intestinal peptide receptor 2 gene (VIPR2). Methods: To further investigate potential causal VIPR2 gene variants, all exons and un-translated portions of the VIPR2 gene were sequenced using amplicon targeted resequencing in 1804 Chinese Han patients with schizophrenia and 996 healthy counterparts in the present study. Results: Nineteen rare non-synonymous mutations and 1 frameshift deletion was identified for schizophrenia, among which 5 variants have never been reported so far. Frequencies of rare non-synonymous mutations were significantly different between the two groups. Specifically, the non-synonymous mutation rs78564798 (Pallele = 0.006) as well as two rare variations in the VIPR2 gene's introns (rs372544903, Pallele = 0.026 and a novel mutation, chr7:159034078, GRCh38, Pallele = 0.048) were significantly associated with schizophrenia. Discussion: Our findings add new evidence that the functional and probable causative variants of VIPR2 gene may play an important role in susceptibility to schizophrenia. Further studies on validations of VIPR2's function in the etiology of schizophrenia are warranted.

Protective efficacy of a recombinant enterotoxin antigen in a maternal immunization model and the inhibition of specific maternal antibodies to neonatal oral vaccination.

ETEC (enterotoxigenic Escherichia coli) infection is the leading cause of profuse watery diarrhea in mammals, especially among pre-weaning and post-weaning piglets in swine industry. Maternal immunization is a current rational strategy for providing protection to susceptive piglets and reducing the incidence of ETEC-associated diarrhea. Here we evaluated the protective efficiency of a recombinant antigen (MBP-SLS) fused by major enterotoxin subunits (STa-LTB-STb) via a maternal immunization model, and the impacts of maternal antibodies to neonatal oral vaccination were also investigated in the neonates. The high titers of specific IgG and sIgA in pups shown that the maternal antibodies could be transferred passively. Furthermore, the increases of IL-6 and IL-10 cytokines in breast milk and pup serum indicated that immunization on mother could effectively boost the immune system of neonates. Newborn rats from immunized mothers showed a 70% survival rate after ETEC infection. However, the mucosal immune responses of neonates were inhibited by the high level of maternal specific antibodies. Among the oral-vaccinated neonates, born from mock-immunized rats reached the highest survival after ETEC challenge. Collectively, the fusion MBP-SLS antigen could effectively induce strong immune responses in rats during pregnancy and the pups could receive passive protection through specific antibodies transferred via milk and placenta. However, the specific maternal antibodies exhibited an inhibition effect on the mucosal immune responses in offspring.

Oncogenic role and potential regulatory mechanism of fatty acid binding protein 5 based on a pan-cancer analysis.

As one member of fatty acid binding proteins (FABPs), FABP5 makes a contribution in the occurrence and development of several tumor types, but existing analysis about FABP5 and FABP5-related molecular mechanism remains limited. Meanwhile, some tumor patients showed limited response rates to current immunotherapy, and more potential targets need to be explored for the improvement of immunotherapy. In this study, we made a pan-cancer analysis of FABP5 based on the clinical data from The Cancer Genome Atlas database for the first time. FABP5 overexpression was observed in many tumor types, and was statistically associated with poor prognosis of several tumor types. Additionally, we further explored FABP5-related miRNAs and corresponding lncRNAs. Then, miR-577-FABP5 regulatory network in kidney renal clear cell carcinoma as well as CD27-AS1/GUSBP11/SNHG16/TTC28-AS1-miR-22-3p-FABP5 competing endogenous RNA regulatory network in liver hepatocellular carcinoma were constructed. Meanwhile, Western Blot and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) analysis were used to verify miR-22-3p-FABP5 relationship in LIHC cell lines. Moreover, the potential relationships of FABP5 with immune infiltration and six immune checkpoints (CD274, CTLA4, HAVCR2, LAG3, PDCD1 and TIGIT) were discovered. Our work not only deepens the understanding of FABP5's functions in multiple tumors and supplements existing FABP5-related mechanisms, but also provides more possibilities for immunotherapy.

One-step salting-out extraction of bacteriophage from its infection broth of Acinetobacter baumannii.

Phages as a potential alternative antibiotic for multidrug-resistant bacterial infections are receiving great attention worldwide. However, the traditional separation and purification of phage are cumbersome, time-consuming, costly and inefficient. In this study, phage phiAB9 for multidrug-resistant Acinetobacter baumannii was separated and purified by a simple and cost-saving one-step salting-out extraction (SOE). Several kinds of salts and organic solvents without effect on phage survival were chosen to form the SOE systems, and the composition of SOE systems were optimized according to the phage recovery rate and impurity removal rate. After one-step SOE by an optimal system composed of 18% (w/w) ammonium citrate and 40% (w/w) ethyl acetate, the recovery rate of phage in the middle phase could reach to 90.82%, and most proteins (99.57%), cells (97.98%) and endotoxin (84.08%) were well removed, with a concentration factor of 210 and the purification factors of phage to proteins, cells and endotoxin were 303.64, 133.55 and 5.36, respectively. Comparing with two-step SOE and traditional aqueous two-phase extraction, one-step SOE may be an available method for the separation and purification of phages.

Association Plasma Aß42 Levels with Alzheimer's Disease and Its Influencing Factors in Chinese Elderly Population.

Background and Purpose: Intracerebral Aß protein deposition is an important pathological mechanism of Alzheimer's disease (AD) and is one of the indicators of early diagnosis of AD. However, invasive lumbar puncture and Aß PET are difficult to perform in primary units, resulting delays in early diagnosis of AD. In recent years, it has been found that plasma Aß can reflect the pathological state of AD in early stage, but the results are not consistent. The objective of this study was to explore the association between plasma Aß42 levels and AD cognitive impairment and its influencing factors in Chinese elderly population, so as to provide guidance for the clinical application of plasma Aß42 as a blood biomarker of AD. Methods: This is a cross-sectional study based on the community population. Plasma samples were collected from 604 healthy controls (HC), 508 mild cognitive impairment (MCI) and 202 dementia with Alzheimer's type (DAT) patients from three cities. We analyzed the correlation between plasma Aß42 levels and cognitive function and the influence of confounding factors on the relationship between plasma Aß42 levels and AD. The independent influencing factors of plasma Aß42 levels were determined by covariance and linear regression analysis. Results: Our results suggest that there is a special linear relationship between plasma Aß42 and cognitive impairment of AD in Chinese elderly population, with Aß42 levels slightly decreased in early AD and significantly increased in moderate-to-severe AD (P<0.01). There are many factors influencing the association between plasma Aß42 levels and AD cognitive impairment, and sample source, gender and BMI are independent influencing factors of plasma Aß42. Conclusion: This indentifies that plasma Aß42 may be a peripheral biomarker for AD screening in Chinese elderly population, but it is necessary to establish standardized detection methods and establish different demarcation criteria for various influencing factors.

Promoter Specific Methylation of SSTR4 is Associated With Alcohol Dependence in Han Chinese Males.

Alcohol dependence (AD), a disease can be affected by environmental factors with epigenetic modification like DNA methylation changes, is one of the most serious and complex public health problems in China and worldwide. Previous findings from our laboratory using the Illumina Infinium Human Methylation450 BeadChip suggested that methylation at the promoter of SSTR4 was one of the major form of DNA modification in alcohol-dependent populations. To investigate whether DNA methylation levels of the SSTR4 promoter influence alcohol-dependent behaviors, genomic DNA was extracted from the peripheral blood sample of 63 subjects with AD and 65 healthy controls, and pyrosequencing was used to verify the results of BeadChip array. Linear regression was used to analyze the correlation between the methylation levels of SSTR4 promoter and the scores of alcohol dependence scales. Gene expression of SSTR4 in brain tissue was obtained from the Genotype-Tissue Expression (GTEx) project and Human Brain Transcriptome database (HBT). We found the methylation levels of SSTR4 in AD group were significantly lower than healthy controls (two-tailed t-test, t = 14.723, p < 0.001). In addition, only weak to moderate correlations between the methylation levels of the SSTR4 promoter region and scale scores of Alcohol Use Disorders Identification Test (AUDIT), Life Events Scale (LES) and Wheatley Stress Profile (WSS) based on linear regression analyses (AUDIT: R 2 = 0.35, p < 0.001; LES: R 2 = 0.27, p < 0.001; WSS: R 2 = 0.49, p < 0.001). The hypomethylated status of SSTR4 may involve in the development of AD and increase the risk of AD persistence in Han Chinese males.

Long non-coding RNA OIP5-AS1 promotes cell proliferation and aerobic glycolysis in gastric cancer through sponging miR-186.

INTRODUCTION: Long non-coding RNAs (lncRNAs) play vital roles in tumour initiation and progression. LncRNA OIP5-AS1 is a potential oncogene in many types of human malignancies, but its biological functions in gastric cancer (GC) remain to be further elucidated. MATERIAL AND METHODS: The expression levels of OIP5-AS1 and miR-186 in GC tissues and cell lines were detected by RT-qPCR analysis. CCK-8 assay and colony formation assay were performed to investigate the proliferation of GC cells in vitro, and a nude mouse tumour model was established to validate the role of OIP5-AS1 in GC tumorigenesis in vivo. The glucose consumption and lactate production of GC cells were detected by ELISA assay. Interaction between OIP5-AS1 and miR-186 was determined using dual luciferase reporter assay. RESULTS: The results demonstrated that OIP5-AS1 was upregulated in GC tissues and cell lines and that its high expression was notably correlated with aggressive clinicopathological features of GC patients. Functionally, knockdown of OIP5-AS1 inhibited GC cell proliferation and enhanced cell apoptosis in vitro, and inhibited GC xenograft growth in vivo. In addition, knockdown of OIP5-AS1 reduced the glucose consumption and lactate production in GC cells. In particular, OIP5-AS1 may function as a ceRNA for miR-186, and inhibition of miR-186 blocks the effects of OIP5-AS1 knockdown on aerobic glycolysis in GC cells. CONCLUSIONS: Accordingly, our findings suggested that the OIP5-AS1/miR-186 axis might be considered as a potential therapeutic target for GC patients.

An image super-resolution reconstruction model based on fractional-order anisotropic diffusion equation.

The image denoising model based on anisotropic diffusion equation often appears the staircase effect while image denoising, and the traditional super-resolution reconstruction algorithm can not effectively suppress the noise in the image in the case of blur and serious noise. To tackle this problem, a novel model is proposed in this paper. Based on the original diffusion equation, we propose a new method for calculating the adaptive fidelity term and its coefficients, which is based on the relationship between the image gradient and the diffusion function. It is realized that the diffusion speed can be slowed down by adaptively changing the coefficient of the fidelity term, and it is proved mathematically that the proposed fractional adaptive fidelity term will not change the existence and uniqueness of the solution of the original model. At the same time, washout filter is introduced as the control item of the model, and a new model of image super-resolution reconstruction and image denoising is constructed. In the proposed model, the order of fractional differential will be determined adaptively by the local variance of the image. And we give the numerical calculation method of the new model in the frequency domain by the method of Fourier transform. The experimental results show that the proposed algorithm can better prevent the staircase effect and achieve better visual effect. And by introducing washout filter to act as the control of the model, the stability of the system can be improved and the system can converge to a stable state quickly.

Alteration in the mRNA expression profile of the autophagy-related mTOR pathway in schizophrenia patients treated with olanzapine.

BACKGROUND: The mammalian target of rapamycin protein (mTOR) signaling pathway is involved in the pathogenesis of schizophrenia and the mechanism of extrapyramidal adverse reactions to antipsychotic drugs, which might be mediated by an mTOR-dependent autophagy impairment. This study aimed to examine the expression of mTOR pathway genes in patients with schizophrenia treated with olanzapine, which is considered an mTOR inhibitor and autophagy inducer. METHODS: Thirty-two patients with acute schizophrenia who had been treated with olanzapine for four weeks (average dose 14.24 ± 4.35 mg/d) and 32 healthy volunteers were recruited. Before and after olanzapine treatment, the Positive and Negative Syndrome Scale (PANSS) was used to evaluate the symptoms of patients with schizophrenia, and the mRNA expression levels of mTOR pathway-related genes, including MTOR, RICTOR, RAPTOR, and DEPTOR, were detected in fasting venous blood samples from all subjects using real-time quantitative PCR. RESULTS: The MTOR and RICTOR mRNA expression levels in patients with acute schizophrenia were significantly decreased compared with those of healthy controls and further significantly decreased after four weeks of olanzapine treatment. The DEPTOR mRNA expression levels in patients with acute schizophrenia were not significantly different from those of healthy controls but were significantly increased after treatment. The expression levels of the RAPTOR mRNA were not significantly different among the three groups. The pairwise correlations of MTOR, DEPTOR, RAPTOR, and RICTOR mRNA expression levels in patients with acute schizophrenia and healthy controls were significant. After olanzapine treatment, the correlations between the expression levels of the DEPTOR and MTOR mRNAs and between the DEPTOR and RICTOR mRNAs disappeared. CONCLUSIONS: Abnormalities in the mTOR pathway, especially DEPTOR and mTORC2, might play important roles in the autophagy mechanism underlying the pathophysiology of schizophrenia and effects of olanzapine treatment.

Synthetic lethality and synergetic effect: the effective strategies for therapy of IDH-mutated cancers.

Mutant isocitrate dehydrogenase 1/2 (mIDH1/2) gain a novel function for the conversion of α-ketoglutarate (α-KG) to oncometabolite R-2-hydroxyglutarate (R-2-HG). Two molecular entities namely enasidenib (AG-221) and ivosidenib (AG-120) targeting mIDH2 and mIDH1 respectively, have already been approved by FDA for the treatment of relapsed/refractory acute myeloid leukemia (R/R AML). However, the low responses, drug-related adverse effects, and most significantly, the clinically-acquired resistance of AG-221 and AG-120 has shown great influence on their clinical application. Therefore, searching for novel therapeutic strategies to enhance tumor sensitivity, reduce drug-related side effects, and overcome drug resistance have opened a new research field for defeating IDH-mutated cancers. As the effective methods, synthetic lethal interactions and synergetic therapies are extensively investigated in recent years for the cure of different cancers. In this review, the molecules displaying synergetic effects with mIDH1/2 inhibitors, as well as the targets showing relevant synthetic lethal interactions with mIDH1/2 are described emphatically. On these foundations, we discuss the opportunities and challenges for translating these strategies into clinic to combat the defects of existing IDH inhibitors.

Association Analysis of Polymorphisms in BIN1, MC1R, STARD6 and PVRL2 with Mild Cognitive Impairment in Elderly Carrying APOE ε4 Allele.

BACKGROUND: Apolipoprotein (APOE) ε4 is recognized as an independent risk factor for mild cognitive impairment (MCI). However, not everyone with the ε4 allele develops MCI, suggesting that other susceptibility genes exist. This study aimed to identify MCI susceptibility genes, including BIN1, MC1R, STARD6, and PVRL2, in elderly Han Chinese and to verify their association with APOE ε4 allele in MCI onset. METHODS: To determine whether polymorphisms in BIN1 (rs6733839, rs7561528), MC1R (rs2228479), STARD6 (rs10164112), and PVRL2 (rs6859) occurred in elderly MCI patients carrying APOE ε4 allele, we carried out a case-control study including 285 MCI patients and 326 healthy controls. RESULTS: Statistically significant differences in the proportion of APOE ε4 carriers, and BESCI, ADAS-cog, and CNT scores existed between the NC and MCI groups (all P < 0.01). Frequencies of the rs10164112 T and rs6859 A alleles were significantly higher in the latter than in the former (P = 0.01; 0.029). However, no significant differences in allele and genotype distribution of BIN1 (rs6733839, rs7561528) and MC1R (rs2228479) existed between samples in our two groups (all P > 0.05). When stratified by APOE ε4 status (carriers/non-carriers), genotype frequencies of BIN1 rs7561528, STARD6 rs10164112, and PVRL2 rs6859 among the four groups (NCε4+, NCε4-, MCIε4+, MCIε4-) were significantly different. Additionally, our results suggest a significant association between MCI and BIN1 rs7561528, STARD6 rs10164112, and PVRL2 rs6859 (all P<0.05) in elderly carriers. CONCLUSION: This suggests that among the Han Chinese, MCI in elderly APOE ε4 carriers may be related to the BIN1 (rs7561528), STARD6 (rs10164112) and PVRL2 (rs6859). Genotype AA of rs7561528 and TT of rs10164112 might be protective factors against MCI in elderly APOE ε4 carriers.