Leukoaraiosis: Epidemiology, Imaging, Risk Factors, and Management of Age-Related Cerebral White Matter Hyperintensities.

Leukoaraiosis (LA) manifests as cerebral white matter hyperintensities on T2-weighted magnetic resonance imaging scans and corresponds to white matter lesions or abnormalities in brain tissue. Clinically, it is generally detected in the early 40s and is highly prevalent globally in individuals aged >60 years. From the imaging perspective, LA can present as several heterogeneous forms, including punctate and patchy lesions in deep or subcortical white matter; lesions with periventricular caps, a pencil-thin lining, and smooth halo; as well as irregular lesions, which are not always benign. Given its potential of having deleterious effects on normal brain function and the resulting increase in public health burden, considerable effort has been focused on investigating the associations between various risk factors and LA risk, and developing its associated clinical interventions. However, study results have been inconsistent, most likely due to potential differences in study designs, neuroimaging methods, and sample sizes as well as the inherent neuroimaging heterogeneity and multi-factorial nature of LA. In this article, we provided an overview of LA and summarized the current knowledge regarding its epidemiology, neuroimaging classification, pathological characteristics, risk factors, and potential intervention strategies.

Analysis and study of the mechanism of narcotic addiction and withdrawal.

Narcotic drugs refer to drugs that have anesthetic effects on the central nervous system, and they easily produce physical dependence and mental dependence and can be addictive due to continuous use, abuse or unreasonable use. In this paper, bioinformatics and data analysis and mining techniques were used to analyze the methylation differences in transcriptional and clinical data of narcotic addiction in public databases, to explore the mechanism of narcotic addiction, and to mine some norepinephrine drugs. This study confirmed the possibility of using norepinephrine as an auxiliary drug for drug addiction rehabilitation. In addition, we also conducted a similar analysis on the addiction of three drugs. The results showed that the differences in the body caused by the ingestion of opiates and cocaine were significantly greater than those caused by the ingestion of methamphetamine.

Alloferon-1 ameliorates estrogen deficiency-induced osteoporosis through dampening the NLRP3/caspase-1/IL-1ß/IL-18 signaling pathway.

Alloferon-1 is an insect polypeptide that has anti-inflammatory, antitumor and antiviral activity. This study aimed to determine the effects of alloferon-1 on estrogen deficiency-induced osteoporosis and explore the associated mechanism using a murine model of ovariectomy (OVX)-induced osteoporosis. Results showed that alloferon-1 prevented ovariectomy­induced body weight gain, bone loss and bone mineral content reduction, affected biochemical markers of bone turnover, and restored the microstructure of bone trabeculae. Moreover, alloferon-1 suppressed the expression of the ovariectomy­mediated inflammatory cytokines in the vertebrae bone tissues, including nucleotide-binding oligomerization domain-like-receptor family pyrin domain-containing 3 (NLRP3), cysteinyl aspartate specific proteinase-1 (Caspase-1), interleukin 1ß (IL-1ß) and interleukin 18 (IL-18) which were determined by immunofluorescence staining and western blot. Overall, the present study provides evidence for the effectiveness of alloferon-1 against estrogen deficiency-induced osteoporosis, suggesting an alternative drug or an auxiliary modulator for the treatment of postmenopausal osteoporosis (PMOP).

Prediction of immune and targeted drug efficacy in pain-related risk subtypes for bladder cancer patients.

Bladder cancer is a complex disease with high morbidity and mortality rates. At least 430,000 cases are diagnosed annually worldwide. Cancer pain is the most common and distressing symptom in cancer patients. Studies have reported depression, anxiety, and decreased quality of life in survivors of various cancers. The study of pain-related genes in cancer patients may provide a basis for developing targeted drugs for cancer therapy, which could reduce pain and improve quality of life of cancer patients. In this study, the mRNA expression and clinical data of bladder cancer patients were downloaded from public databases. A total of 103 pain-related genes were also downloaded from the public databases. Univariate Cox regression analysis identified 17 pain-related genes that were significantly associated with overall survival. We calculated a pain-related risk score for each patient, constructed a bladder cancer pain risk model, and categorized bladder cancer patients into two risk subtypes. Differences in prognosis, differential gene expression, immune cell signatures, hallmarks, metabolic pathways, and somatic mutations between the different risk subtypes were systematically investigated. Eight drugs associated with bladder cancer risk subtypes were identified. Their differences in the high- and low-risk subtypes of bladder cancer were examined. In addition, the response to immunotherapy was analyzed in patients with different pain-related subtypes. Results revealed significant differences in these characteristics. Finally, a predictive model for pain-related risk subtypes in patients with bladder cancer was established. The study findings provide a reference for prognostication and personalized medical treatment of bladder cancer patients.

Novel structured ADAM17 small-molecule inhibitor represses ADAM17/Notch pathway activation and the NSCLC cells' resistance to anti-tumour drugs.

Background and aims: The outcomes of current treatment for non-small cell lung cancer (NSCLC) are unsatisfactory and development of new and more efficacious therapeutic strategies are required. The Notch pathway, which is necessary for cell survival to avert apoptosis, induces the resistance of cancer cells to antitumour drugs. Notch pathway activation is controlled by the cleavage of Notch proteins/receptors mediated by A disintegrin and metalloproteinase 17 (ADAM17); therefore, ADAM17 is a reliable intervention target for anti-tumour therapy to overcome the drug resistance of cancer cells. This work aims to develop and elucidate the activation of Compound 2b, a novel-structured small-molecule inhibitor of ADAM17, which was designed and developed and its therapeutic efficacy in NSCLC was assessed via multi-assays. Methods and results: A lead compound for a potential inhibitor of ADAM17 was explored via pharmacophore modelling, molecular docking, and biochemical screening. It was augmented by substituting two important chemical groups [R1 and R2 of the quinoxaline-2,3-diamine (its chemical skeleton)]; subsequently, serial homologs of the lead compound were used to obtain anoptimized compound (2b) with high inhibitory activity compared with leading compound against ADAM17 to inhibit the cleavage of Notch proteins and the accumulation of the Notch intracellular domain in the nuclei of NSCLC cells. The inhibitory activity of compound 2b was demonstrated by quantitative polymerase chain reaction and Western blotting. The specificity of compound 2b on ADAM17 was confirmed via point-mutation. Compound 2b enhanced the activation of antitumor drugs on NSCLC cells, in cell lines and nude mice models, by targeting the ADAM17/Notch pathway. Conclusion: Compound 2b may be a promising strategy for NSCLC treatment.

Dynamic interplay between IL-1 and WNT pathways in regulating dermal adipocyte lineage cells during skin development and wound regeneration.

Dermal adipocyte lineage cells are highly plastic and can undergo reversible differentiation and dedifferentiation in response to various stimuli. Using single-cell RNA sequencing of developing or wounded mouse skin, we classify dermal fibroblasts (dFBs) into distinct non-adipogenic and adipogenic cell states. Cell differentiation trajectory analyses identify IL-1-NF-κB and WNT-ß-catenin as top signaling pathways that positively and negatively associate with adipogenesis, respectively. Upon wounding, activation of adipocyte progenitors and wound-induced adipogenesis are mediated in part by neutrophils through the IL-1R-NF-κB-CREB signaling axis. In contrast, WNT activation, by WNT ligand and/or ablation of Gsk3, inhibits the adipogenic potential of dFBs but promotes lipolysis and dedifferentiation of mature adipocytes, contributing to myofibroblast formation. Finally, sustained WNT activation and inhibition of adipogenesis is seen in human keloids. These data reveal molecular mechanisms underlying the plasticity of dermal adipocyte lineage cells, defining potential therapeutic targets for defective wound healing and scar formation.

Disruptive behaviors, antisocial attitudes, and aggression in young offenders: Comparison of Adverse Childhood Experience (ACE) typologies.

BACKGROUND: Adverse Childhood Experiences (ACE) are associated with many deleterious outcomes in young offenders. There is a dearth of studies examining its effects on young offenders' antisocial attitudes, disruptive behaviors and aggression, risk factors for delinquency and reoffending. OBJECTIVE: This study examined ACE patterns and their association with the above factors in young offenders. PARTICIPANTS AND SETTING: 1130 youth offenders (964 males; Mage = 17.57 years), provided self-reports on ACEs, antisocial attitudes, disruptive behavior ratings and aggression. METHOD: Latent Class Analysis was performed on 12 self-reported ACEs, followed by Analyses of Covariance on each of the measures. RESULTS: Four classes - Low ACE, Indirect Victims, Abusive Environment, and Polyvictimized - were identified. Polyvictimized youths had the highest levels of conduct problems (M = 70.35, ps < .05) and proactive aggression (M = 0.45, ps < .05) but did not differ from youths in Abusive Environment in reactive aggression (M = 1.02, p = .69), oppositional problems (M = 65.15, p = .18), and antisocial attitudes (M = 26.95, p = .21). Indirect Victims had lower levels of conduct problems (M = 64.80, p < .05) and antisocial attitudes (M = 24.35, p < .05) than Polyvictimized youths but higher levels of these outcomes than the Low ACE group. CONCLUSIONS: Our findings showed that ACEs patterns vary in their effects on antisociality and disruptive behaviors. The novel finding was that childhood victimization does not have to be direct, as indirect victimization significantly impacted factors important to delinquency and reoffending.

Effects of Sodium Dodecyl Sulfate on the Enzyme Catalysis and Conformation of a Recombinant γ-Glutamyltranspeptidase from Bacillus licheniformis.

The study of interactions between proteins and surfactants is of relevance in a diverse range of applications including food, enzymatic detergent formulation, and drug delivery. In spite of sodium dodecyl sulfate (SDS)-induced unfolding has been studied in detail at the protein level, deciphering the conformation-activity relationship of a recombinant γ-glutamyltranspeptidase (BlrGGT) from Bacillus licheniformis remains important to understand how the transpeptidase activity is related to its conformation. In this study, we examined the enzyme catalysis and conformational transition of BlrGGT in the presence of SDS. Enzymatic assays showed that the transpeptidase activity of BlrGGT was greatly affected by SDS in a concentration-dependent manner with approximately 90% inactivation at 6 mM. Native polyacrylamide gel electrophoresis of SDS-treated samples clearly revealed that the heterodimeric enzyme was apparently dissociated into two different subunits at concentrations above 2 mM. The study of enzyme kinetics showed that SDS can act as a mixed-type inhibitor to reduce the catalytic efficiency of BlrGGT. Moreover, the t1/2 value of the enzyme at 55 °C was greatly reduced from 495.1 min to 7.4 min in the presence of 1 mM SDS. The I3/I1 ratio of pyrene excimer fluorescence emission changed around 3.7 mM SDS in the absence of BlrGGT and the inflection point of enzyme samples was reduced to less than 2.7 mM. The Far-UV CD spectrum of the native enzyme had two negative peaks at 208 and 222 nm, respectively; however, both negative peaks increased in magnitude with increasing SDS concentration and reached maximal values at above 4.0 mM. The intrinsic fluorescence spectra of tryptophan further demonstrated that the SDS-induced enzyme conformational transition occurred at approximately 5.1 mM. Tween 20 significantly suppressed the interaction of BlrGGT with SDS by forming mixed micelles at a molar ratio of 1.0. Taken together, this study definitely promotes our better understanding of the relationship between the conformation and catalysis of BlrGGT.

A random forest-based metabolic risk model to assess the prognosis and metabolism-related drug targets in ovarian cancer.

As one of the most common gynecologic malignant tumors, ovarian cancer is usually diagnosed at an advanced and incurable stage because of its early asymptomatic onset. Increasing research into tumor biology has demonstrated that abnormal cellular metabolism precedes tumorigenesis, therefore it has become an area of active research in academia. Cellular metabolism is of great significance in cancer diagnostic and prognostic studies. In this study, we integrated The Cancer Genome Atlas dataset with multiple Gene Expression Omnibus ovarian cancer datasets, identified 17 metabolic pathways with prognostic values using the random forest algorithm, constructed a metabolic risk scoring model based on metabolic pathway enrichment scores, and classified patients with ovarian cancer into two subtypes. Then, we systematically investigated the differences between different subtypes in terms of prognosis, differential gene expression, immune signature enrichment, Hallmark signature enrichment, and somatic mutations. As well, we successfully predicted differences in sensitivity to immunotherapy and chemotherapy drugs in patients with different metabolic risk subtypes. Moreover, we identified 5 drug targets associated with high metabolic risk and low metabolic risk ovarian cancer phenotypes through the weighted correlation network analysis and investigated their roles in the genesis of ovarian cancer. Finally, we developed an XGBoost classifier for predicting metabolic risk types in patients with ovarian cancer, producing a good predictive effect. In light of the above study, the research findings will provide valuable information for prognostic prediction and personalized medical treatment of patients with ovarian cancer.

Alloferon-1 ameliorates acute inflammatory responses in λ-carrageenan-induced paw edema in mice.

Alloferon-1 have been proposed as an effective peptide to enhance antitumoral immunity, antiviral defense and anti-inflammatory activity. This work aimed to assess anti-inflammatory effects of alloferon-1 against acute inflammation and histopathological deformations in λ-carrageenan-induced paw edema in mice. Systemic pretreatment with alloferon-1 (22.0 mg/kg) intraperitoneally injected mice showed a significant reduction in paw thickness and vascular permeability. Alloferon-1 prevented λ-carrageenan-evoked exudation and the neutrophil influx to the mouse pleura and the neutrophil migration into carrageenan-stimulated mouse air pouches based on the histopathological changes in the paw tissues. Administration of alloferon-1 also suppressed the expression of the inflammatory cytokines in the inflamed paw tissues such as tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein 1 (MCP1), interleukin-5 (IL-5), etc. detected by Luminex liquid chip. Collectively, the present study provides evidences for the marked anti-inflammatory effects of alloferon-1 which might represent new therapeutic options for the treatment of acute inflammatory diseases.

Deep learning-based transcription factor activity for stratification of breast cancer patients.

Transcription factors directly bind to DNA and regulate the expression of the gene, causing epigenetic modification of the DNA. They often mediate epigenetic parameters of transcriptional and posttranscriptional mechanisms, and their expression activities can be used to characterize genomic aberrations in cancer cell. In this study, the activity profile of transcription factors inferred by VIPER algorithm. The autoencoder model was applied for compressing the transcription factor activity profile for obtaining more useful transformed features for stratifying patients into two different breast cancer subtypes. The deep learning-based subtypes exhibited superior prognostic value and yielded better risk-stratification than the transcription factor activity-based method. Importantly, according to transformed features, a deep neural network was constructed to predict the subtypes, and achieved the accuracy of 94.98% and area under the ROC curve of 0.9663, respectively. The proposed subtypes were found to be significantly associated with immune infiltration, tumor immunogenicity and so on. Furthermore, the ceRNA network was constructed for the breast cancer subtypes. Besides, 11 master regulators were found to be associated with patients in cluster 1. Given the robustness performance of our deep learning model over multiple breast cancer cohorts, we expected this model may be useful in the area of prognosis prediction and lead some possibility for personalized medicine in breast cancer patients.

Morphometric Relationships, Growth and Condition Factors of Critically Endangered Chinese Pangolin (Manis pentadactyla).

Morphometric relationships and condition factors are crucial to quickly understanding the fitness and well-being of animals. Total length (cm) and bodyweight (g) of 282 (male = 167 and female = 115) pangolins were accounted for in this study which was received and rehabilitated in Pingtung Rescued Center, Pingtung and Endemic Species Research Institute, Nantou, Taiwan. The allometric equation; W = aLb was used to estimate the length-weight relationships where R2 = 0.70, a = 0.61, and b = 1.98. The ratio of total body length and tail length was between 1.1 and 2.7. Pangolins exhibited negative allometric growth (b < 3) as their length increased. The average relative condition factor (KR) was 1.04, indicating a state of good health for rescued individuals. However, Fulton condition factor (KF) and KR fluctuated in different months but was significantly heavier during the wet seasons. This study recommended to release healthy animals with KF of 0.8 or higher back into the wild in order to increase their survival rate. The study, thus will be helpful to promote standardized guidelines for conducting physical measurements and understanding health status. Additionally, it will support the recovery of this threatened species by husbandry and diet management in ex-situ and in-situ conservation.

Integrated multi-cohorts for characterizing the immunogenomic landscape and predicting drug response in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the breast cancer subtype with the highest fatality rate, and it seriously threatens women's health. Recent studies found that the level of immune cell infiltration in TNBC was associated with tumor progression and prognosis. However, due to practical constraints, most of these TNBC immune infiltration studies only used a small number of patient samples and a few immune cell types. Therefore, it is necessary to integrate more TNBC patient samples and immune cell types to comprehensively study immune infiltration in TNBC to contribute to the prognosis and treatment of patients. In this study, 12 TNBC datasets were integrated and an extensive collection of 182 gene sets with immune-related signatures were included to comprehensively investigate tumor immune microenvironment of TNBC. A single sample gene set enrichment analysis was performed to calculate the infiltration score of each immune-related signature in each patient, and an immune-related risk scoring model for TNBC was constructed to accurately assess patient prognosis. Significant differences were found in immunogenomic landscape between different immune risk subtypes. In addition, the immunotherapy response and chemotherapy drug sensitivity of patients with different immune risk subtypes were also analyzed. The results showed that there were significant differences in these characteristics. Finally, a prediction model for immune risk subtypes of TNBC patients was constructed to accurately predict patients with unknown subtypes. Based on the aforementioned findings, we believed that the immune-related risk score constructed in this study can assist in providing personalized medicine to TNBC patients.

Activation and thermal stabilization of a recombinant γ-glutamyltranspeptidase from Bacillus licheniformis ATCC 27811 by monovalent cations.

The regulation of enzyme activity through complexation with certain metal ions plays an important role in many biological processes. In addition to divalent metals, monovalent cations (MVCs) frequently function as promoters for efficient biocatalysis. Here, we examined the effect of MVCs on the enzymatic catalysis of a recombinant γ-glutamyltranspeptidase (BlrGGT) from Bacillus licheniformis ATCC 27,811 and the application of a metal-activated enzyme to L-theanine synthesis. The transpeptidase activity of BlrGGT was enhanced by Cs+ and Na+ over a broad range of concentrations with a maximum of 200 mM. The activation was essentially independent of the ionic radius, but K+ contributed the least to enhancing the catalytic efficiency. The secondary structure of BlrGGT remained mostly unchanged in the presence of different concentrations of MVCs, but there was a significant change in its tertiary structure under the same conditions. Compared with the control, the half-life (t1/2) of the Cs+-enriched enzyme at 60 and 65 °C was shown to increase from 16.3 and 4.0 min to 74.5 and 14.3 min, respectively. The simultaneous addition of Cs+ and Mg2+ ions exerted a synergistic effect on the activation of BlrGGT. This was adequately reflected by an improvement in the conversion of substrates to L-theanine by 3.3-15.1% upon the addition of 200 mM MgCl2 into a reaction mixture comprising the freshly desalted enzyme (25 µg/mL), 250 mM L-glutamine, 600 mM ethylamine, 200 mM each of the MVCs, and 50 mM borate buffer (pH 10.5). Taken together, our results provide interesting insights into the complexation of MVCs with BlrGGT and can therefore be potentially useful to the biocatalytic production of naturally occurring γ-glutamyl compounds. KEY POINTS: • The transpeptidase activity of B. licheniformis Î³-glutamyltranspeptidase can be activated by monovalent cations. • The thermal stability of the enzyme was profoundly increased in the presence of 200 mM Cs+. • The simultaneous addition of Cs+and Mg2+ions to the reaction mixture improves L-theanine production.

Characterized the diversity of ABCB1 subtypes in immunogenomic landscape for predicting the drug response in breast cancer.

ABCB1 is an important gene that closely related to analgesic tolerance to opioids, and plays an important role in their postoperative treatment. Recent studies have demonstrated that ABCB1 genotype is significantly associated with the chemico-resistance and chemical sensitivity in breast cancer patients. So, it is become very important to investigate the important role of ABCB1 for predicting drug response in breast cancer patients. In this study, by conducting the Cox proportional hazards regression analysis in breast cancer patients, significant differences were found in prognosis between the ABCB1 high- and low-expression subtypes. Meanwhile, by using immune infiltration profiles as well as transcriptomics datasets, the ABCB1 high subtype was found to be significantly enriched in many immune-related KEGG pathways and biological processes, and was characterized by the high infiltration levels of immune cell types. Furthermore, bioinformatics inference revealed that the ABCB1 subtypes were associated with the therapeutic effect of immunotherapy, which would be important for patient prognosis. In conclusion, these findings may provide useful help for recognizing the diversity between ABCB1 subtypes in tumor immune microenvironment, and may unravel prognosis outcomes and immunotherapy utility for ABCB1 in breast cancer.

Silibinin Alleviates Muscle Atrophy Caused by Oxidative Stress Induced by Cisplatin through ERK/FoxO and JNK/FoxO Pathways.

Cisplatin (DDP), a widely used chemotherapeutic drug in cancer treatment, causes oxidative stress, resulting in cancer cachexia and skeletal muscle atrophy. This study investigated the effects and activity of silibinin (SLI) in reducing DDP-induced oxidative stress and skeletal muscle atrophy in vivo and in vitro. SLI alleviated weight loss, food intake, muscle wasting, adipose tissue depletion, and organ weight reduction induced by DDP and improved the reduction of grip force caused by DDP. SLI can attenuated the increase in reactive oxygen species (ROS) levels, the decrease in Nrf2 expression, the decrease in the fiber cross-sectional area, and changes in fiber type induced by DDP. SLI regulated the ERK/FoxO and JNK/FoxO pathways by downregulating the abnormal increase in ROS and Nrf2 expression in DDP-treated skeletal muscle and C2C12 myotube cells. Further, SLI inhibited the upregulation of MAFbx and Mstn, the downregulation of MyHC and MyoG, the increase in protein degradation, and the decrease of protein synthesis. The protective effects of SLI were reversed by cotreatment with JNK agonists and ERK inhibitors. These results suggest that SLI can reduce DDP-induced skeletal muscle atrophy by reducing oxidative stress and regulating ERK/FoxO and JNK/FoxO pathways.

Simultaneous electro-optic spectral switching and Q switching in a dual-wavelength Nd:YVO4 laser based on an aperiodic optical superlattice lithium niobate.

We report the demonstration of an electro-optic (EO) switchable dual-wavelength (1064- and 1342-nm) Nd:YVO4 laser based on an aperiodically poled lithium niobate (APPLN) chip whose domain structure is designed using aperiodic optical superlattice (AOS) technology. The APPLN works as a wavelength-dependent EO polarization-state controller in the polarization-dependent laser gain system to enable switching among multiple laser spectra simply by voltage control. When the APPLN device is driven by a voltage-pulse train modulating between a VHQ (in which target laser lines obtain gain) and a VLQ (in which laser lines are gain suppressed), the unique laser system can produce Q-switched laser pulses at dual wavelengths 1064 and 1342 nm, single wavelength 1064 nm, and single wavelength 1342 nm, as well as their non-phase-matched sum-frequency and second-harmonic generations at VHQ = 0, 267, and 895 V, respectively. A laser can benefit from such a novel, to the best of our knowledge, simultaneous EO spectral switching and Q switching mechanisms to increase its processing speed and multiplexity for versatile applications.

The Predictive Validity of Three Youth Violence Assessment Instruments: The SAVRY, VRS-YV, and SAPROF-YV.

This study examined the predictive validity of three assessment instruments for violent youth, the SAVRY, the VRS-YV, and the SAPROF-YV. Files relating to a sample of 233 young male offenders aged between 12 and 18 years were retrospectively reviewed to score each instrument, with reoffending data extracted from prison, community and juvenile justice records. The analysis showed that all three assessments predicted general (any) reoffending better than violent and non-violent reoffending, with higher rates of predictive validity for the SAVRY and VRS-YV Total Scores. There were, however, only small to moderate effect sizes at 1- and 3-year follow up periods for all three instruments in predicting all types of reoffending. The SAPROF-YV had a small effect size for the prediction of violent reoffending and did not add incrementally to the predictive validity (for violent reoffending) of the SAVRY or VRS-YV.

Liquid Biopsy, ctDNA Diagnosis through NGS.

Liquid biopsy with circulating tumor DNA (ctDNA) profiling by next-generation sequencing holds great promise to revolutionize clinical oncology. It relies on the basis that ctDNA represents the real-time status of the tumor genome which contains information of genetic alterations. Compared to tissue biopsy, liquid biopsy possesses great advantages such as a less demanding procedure, minimal invasion, ease of frequent sampling, and less sampling bias. Next-generation sequencing (NGS) methods have come to a point that both the cost and performance are suitable for clinical diagnosis. Thus, profiling ctDNA by NGS technologies is becoming more and more popular since it can be applied in the whole process of cancer diagnosis and management. Further developments of liquid biopsy ctDNA testing will be beneficial for cancer patients, paving the way for precision medicine. In conclusion, profiling ctDNA with NGS for cancer diagnosis is both biologically sound and technically convenient.

Suppression of Tumorigenicity 5 Ameliorates Tumor Characteristics of Invasive Breast Cancer Cells via ERK/JNK Pathway.

BACKGROUND: Suppression of tumorigenicity 5 (ST5) has been considered as a tumor suppressor gene in HeLa tumor cells. However, its role in the progression of breast cancer remains vague. METHODS: Online database analysis was determined by Oncomine and Breast Cancer Gene-Expression Miner v4.4 (bc-GenExMiner v4.4). Tumor biology behaviors were measured by MTT assay, wound healing model, Transwell and Flow cytometry assays. Methylation-specific PCR (MSP) was employed to detect promoter methylation. RESULTS: Low level of ST5 was observed in breast cancer specimens, particularly in recurrent, invasive breast cancer cases compared to para-carcinoma tissue or non-invasive breast cancer. The downregulation of ST5 was also proved in MDA-MB-231 and SKBR3 cell lines with a high invasive capability as compared to MCF-7 cell with a low invasive capability. ST5 was negatively associated with pathological stages of breast cancer. ST5-downregulation promoted, while ST5-upregulation inhibited the progression of cell proliferation, cell cycle and migration of MDA-MB-231 cells. Additionally, ST5 knockdown inhibited, whereas ST5 overexpression promoted apoptosis of MDA-MB-231 cells. However, ST5 modification, either upregulation or downregulation, had no significant impact on tumor behaviors of MCF-7 cells. Mechanistically, ST5 protein ablation activated, while ST5-upregulation repressed the activities of phosphorylated ERK1/2 and JNK, and subsequently the expression of c-Myc. PD98059-mediated ERK1/2 inhibition abolished the stimulatory effects of ST5-depletion on ERK1/2/JNK/c-Myc signaling axis, and ST5 depletion-mediated cell over-proliferation and migration. Of note, ST5 reduction in invasive breast cancer cells should implicate in the hypermethylation of ST5 promoter region. CONCLUSION: Our findings suggest that ST5 potentially acts as a tumor suppressor gene in invasive breast cancer through regulating ERK/JNK signaling pathway and provide a novel insight for breast cancer treatment.