Ticks Resist Skin Commensals with Immune Factor of Bacterial Origin.

Ticks transmit a diverse array of microbes to vertebrate hosts, including human pathogens, which has led to a human-centric focus in this vector system. Far less is known about pathogens of ticks themselves. Here, we discover that a toxin in blacklegged ticks (Ixodes scapularis) horizontally acquired from bacteria-called domesticated amidase effector 2 (dae2)-has evolved to kill mammalian skin microbes with remarkable efficiency. Secreted into the saliva and gut of ticks, Dae2 limits skin-associated staphylococci in ticks while feeding. In contrast, Dae2 has no intrinsic ability to kill Borrelia burgdorferi, the tick-borne Lyme disease bacterial pathogen. These findings suggest ticks resist their own pathogens while tolerating symbionts. Thus, just as tick symbionts can be pathogenic to humans, mammalian commensals can be harmful to ticks. Our study underscores how virulence is context-dependent and bolsters the idea that "pathogen" is a status and not an identity.

ATP-Dependent Dynamic Protein Aggregation Regulates Bacterial Dormancy Depth Critical for Antibiotic Tolerance.

Cell dormancy is a widespread mechanism used by bacteria to evade environmental threats, including antibiotics. Here we monitored bacterial antibiotic tolerance and regrowth at the single-cell level and found that each individual survival cell shows different "dormancy depth," which in return regulates the lag time for cell resuscitation after removal of antibiotic. We further established that protein aggresome-a collection of endogenous protein aggregates-is an important indicator of bacterial dormancy depth, whose formation is promoted by decreased cellular ATP level. For cells to leave the dormant state and resuscitate, clearance of protein aggresome and recovery of proteostasis are required. We revealed that the ability to recruit functional DnaK-ClpB machineries, which facilitate protein disaggregation in an ATP-dependent manner, determines the lag time for bacterial regrowth. Better understanding of the key factors regulating bacterial regrowth after surviving antibiotic attack could lead to new therapeutic strategies for combating bacterial antibiotic tolerance.

Lipopolysaccharide transport regulates bacterial sensitivity to a cell wall-degrading intermicrobial toxin.

Gram-negative bacteria can antagonize neighboring microbes using a type VI secretion system (T6SS) to deliver toxins that target different essential cellular features. Despite the conserved nature of these targets, T6SS potency can vary across recipient species. To understand the functional basis of intrinsic T6SS susceptibility, we screened for essential Escherichia coli (Eco) genes that affect its survival when antagonized by a cell wall-degrading T6SS toxin from Pseudomonas aeruginosa, Tae1. We revealed genes associated with both the cell wall and a separate layer of the cell envelope, lipopolysaccharide, that modulate Tae1 toxicity in vivo. Disruption of genes in early lipopolysaccharide biosynthesis provided Eco with novel resistance to Tae1, despite significant cell wall degradation. These data suggest that Tae1 toxicity is determined not only by direct substrate damage, but also by indirect cell envelope homeostasis activities. We also found that Tae1-resistant Eco exhibited reduced cell wall synthesis and overall slowed growth, suggesting that reactive cell envelope maintenance pathways could promote, not prevent, self-lysis. Together, our study reveals the complex functional underpinnings of susceptibility to Tae1 and T6SS which regulate the impact of toxin-substrate interactions in vivo.

Genome-wide identification, stress- and hormone-responsive expression characteristics, and regulatory pattern analysis of Scutellaria baicalensis SbSPLs.

SQUAMOSA PROMOTER BINDING PROTEIN-LIKEs (SPLs) encode plant-specific transcription factors that regulate plant growth and development, stress response, and metabolite accumulation. However, there is limited information on Scutellaria baicalensis SPLs. In this study, 14 SbSPLs were identified and divided into 8 groups based on phylogenetic relationships. SbSPLs in the same group had similar structures. Abscisic acid-responsive (ABRE) and MYB binding site (MBS) cis-acting elements were found in the promoters of 8 and 6 SbSPLs. Segmental duplications and transposable duplications were the main causes of SbSPL expansion. Expression analysis based on transcriptional profiling showed that SbSPL1, SbSPL10, and SbSPL13 were highly expressed in roots, stems, and flowers, respectively. Expression analysis based on quantitative real-time polymerase chain reaction (RT‒qPCR) showed that most SbSPLs responded to low temperature, drought, abscisic acid (ABA) and salicylic acid (SA), among which the expression levels of SbSPL7/9/10/12 were significantly upregulated in response to abiotic stress. These results indicate that SbSPLs are involved in the growth, development and stress response of S. baicalensis. In addition, 8 Sba-miR156/157 s were identified, and SbSPL1-5 was a potential target of Sba-miR156/157 s. The results of target gene prediction and coexpression analysis together indicated that SbSPLs may be involved in the regulation of L-phenylalanine (L-Phe), lignin and jasmonic acid (JA) biosynthesis. In summary, the identification and characterization of the SbSPL gene family lays the foundation for functional research and provides a reference for improved breeding of S. baicalensis stress resistance and quality traits.

Minimal residual disease profiling predicts pathological complete response in esophageal squamous cell carcinoma.

Accurate presurgical prediction of pathological complete response (pCR) can guide treatment decisions, potentially avoiding unnecessary surgeries and improving the quality of life for cancer patients. We developed a minimal residual disease (MRD) profiling approach with enhanced sensitivity and specificity for detecting minimal tumor DNA from cell-free DNA (cfDNA). The approach was validated in two independent esophageal squamous cell carcinoma (ESCC) cohorts. In a cohort undergoing neoadjuvant, surgical, and adjuvant therapy (NAT cohort), presurgical MRD status precisely predicted pCR. All MRD-negative cases (10/10) were confirmed as pCR by pathological evaluation on the resected tissues. In contrast, MRD-positive cases included all the 27 non-pCR cases and only one pCR case (10/10 vs 1/28, P < 0.0001, Fisher's exact test). In a definitive radiotherapy cohort (dRT cohort), post-dRT MRD status was closely correlated with patient prognosis. All MRD-negative patients (25/25) remained progression-free during the follow-up period, while 23 of the 26 MRD-positive patients experienced disease progression (25/25 vs 3/26, P < 0.0001, Fisher's exact test; progression-free survival, P < 0.0001, log-rank test). The MRD profiling approach effectively predicted the ESCC patients who would achieve pCR with surgery and those likely to remain progression-free without surgery. This suggests that the cancer cells in these MRD-negative patients have been effectively eliminated and they could be suitable candidates for a watch-and-wait strategy, potentially avoiding unnecessary surgery.

The role of DGAT1 and DGAT2 in regulating tumor cell growth and their potential clinical implications.

Lipid metabolism is widely reprogrammed in tumor cells. Lipid droplet is a common organelle existing in most mammal cells, and its complex and dynamic functions in maintaining redox and metabolic balance, regulating endoplasmic reticulum stress, modulating chemoresistance, and providing essential biomolecules and ATP have been well established in tumor cells. The balance between lipid droplet formation and catabolism is critical to maintaining energy metabolism in tumor cells, while the process of energy metabolism affects various functions essential for tumor growth. The imbalance of synthesis and catabolism of fatty acids in tumor cells leads to the alteration of lipid droplet content in tumor cells. Diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2, the enzymes that catalyze the final step of triglyceride synthesis, participate in the formation of lipid droplets in tumor cells and in the regulation of cell proliferation, migration and invasion, chemoresistance, and prognosis in tumor. Several diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2 inhibitors have been developed over the past decade and have shown anti-tumor effects in preclinical tumor models and improvement of metabolism in clinical trials. In this review, we highlight key features of fatty acid metabolism and different paradigms of diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2 activities on cell proliferation, migration, chemoresistance, and prognosis in tumor, with the hope that these scientific findings will have potential clinical implications.

High-dose ascorbate exerts anti-tumor activities and improves inhibitory effect of carboplatin through the pro-oxidant function pathway in uterine serous carcinoma cell lines.

OBJECTIVE: Uterine serous carcinoma is a highly aggressive non-endometrioid subtype of endometrial cancer with poor survival rates overall, creating a strong need for new therapeutic strategies to improve outcomes. High-dose ascorbate (vitamin C) has been shown to inhibit cell proliferation and tumor growth in multiple preclinical models and has shown promising anti-tumor activity in combination with chemotherapy, with a favorable safety profile. We aimed to study the anti-tumor effects of ascorbate and its synergistic effect with carboplatin on uterine serous carcinoma cells. METHODS: Cell proliferation was evaluated by MTT and colony formation assays in ARK1, ARK2 and SPEC2 cells. Cellular stress, antioxidant ability, cleaved caspase 3 activity and adhesion were measured by ELISA assays. Cell cycle was detected by Cellometer. Invasion was measured using a wound healing assay. Changes in protein expression were determined by Western immunoblotting. RESULTS: High-dose ascorbate significantly inhibited cell proliferation, caused cell cycle arrest, induced cellular stress, and apoptosis, increased DNA damage, and suppressed cell invasion in ARK1 and SPEC2 cells. Treatment of both cells with 1 mM N-acetylcysteine reversed ascorbate-induced apoptosis and inhibition of cell proliferation. The combination of ascorbate and carboplatin produced significant synergistic effects in inhibiting cell proliferation and invasion, inducing cellular stress, causing DNA damage, and enhancing cleaved caspase 3 levels compared to each compound alone in both cells. CONCLUSIONS: Ascorbate has potent antitumor activity and acts synergistically with carboplatin through its pro-oxidant effects. Clinical trials of ascorbate combined with carboplatin as adjuvant treatment of uterine serous carcinoma are worth exploring.

Intermittent energy restriction inhibits tumor growth and enhances paclitaxel response in a transgenic mouse model of endometrial cancer.

OBJECTIVE: Overweight/obesity is the strongest risk factor for endometrial cancer (EC), and weight management can reduce that risk and improve survival. We aimed to establish the differential benefits of intermittent energy restriction (IER) and low-fat diet (LFD), alone and in combination with paclitaxel, to reverse the procancer effects of high-fat diet (HFD)-induced obesity in a mouse model of EC. METHODS: Lkb1fl/flp53fl/fl mice were fed HFD or LFD to generate obese and lean phenotypes, respectively. Obese mice were maintained on a HFD or switched to a LFD (HFD-LFD) or IER (HFD-IER). Ten weeks after induction of endometrial cancer, mice in each group received paclitaxel or placebo for 4 weeks. Body and tumor weights; tumoral transcriptomic, metabolomic and oxylipin profiles; and serum metabolic hormones and chemocytokines were assessed. RESULTS: HFD-IER and HFD-LFD, relative to HFD, reduced body weight; reversed obesity-induced alterations in serum insulin, leptin and inflammatory factors; and decreased tumor incidence and mass, often to levels emulating those associated with continuous LFD. Concurrent paclitaxel, versus placebo, enhanced tumor suppression in each group, with greatest benefit in HFD-IER. The diets produced distinct tumoral gene expression and metabolic profiles, with HFD-IER associated with a more favorable (antitumor) metabolic and inflammatory environment. CONCLUSION: In Lkb1fl/flp53fl/fl mice, IER is generally more effective than LFD in promoting weight loss, inhibiting obesity-related endometrial tumor growth (particularly in combination with paclitaxel), and reversing detrimental obesity-related metabolic effects. These findings lay the foundation for further investigations of IER as an EC prevention and treatment strategies in overweight/obesity women.

ASH2L Controls Ureteric Bud Morphogenesis through the Regulation of RET/GFRA1 Signaling Activity in a Mouse Model.

SIGNIFICANCE STATEMENT: Causes of congenital anomalies of the kidney and urinary tract (CAKUT) remain unclear. The authors investigated whether and how inactivation of Ash2l -which encodes a subunit of the COMPASS methyltransferase responsible for genome-wide histone H3 lysine K4 (H3K4) methylation-might contribute to CAKUT. In a mouse model, inactivation of Ash2l in the ureteric bud (UB) lineage led to CAKUT-like phenotypes. Removal of ASH2L led to deficient H3K4 trimethylation, which slowed cell proliferation at the UB tip, delaying budding and impairing branching morphogenesis. The absence of ASH2L also downregulated the expression of Ret , Gfra1 , and Wnt11 genes involved in RET/GFRA1 signaling. These findings identify ASH2L-mediated H3K4 methylation as an upstream epigenetic regulator of signaling crucial for UB morphogenesis and indicate that deficiency or dysregulation of these processes may lead to CAKUT. BACKGROUND: Ureteric bud (UB) induction and branching morphogenesis are fundamental to the establishment of the renal architecture and are key determinants of nephron number. Defective UB morphogenesis could give rise to a spectrum of malformations associated with congenital anomalies of the kidney and urinary tract (CAKUT). Signaling involving glial cell line-derived neurotrophic factor and its receptor rearranged during transfection (RET) and coreceptor GFRA1 seems to be particularly important in UB development. Recent epigenome profiling studies have uncovered dynamic changes of histone H3 lysine K4 (H3K4) methylation during metanephros development, and dysregulated H3K4 methylation has been associated with a syndromic human CAKUT. METHODS: To investigate whether and how inactivation of Ash2l , which encodes a subunit of the COMPASS methyltransferase responsible for genome-wide H3K4 methylation, might contribute to CAKUT, we inactivated Ash2l specifically from the UB lineage in C57BL/6 mice and examined the effects on genome-wide H3K4 methylation and metanephros development. Genes and epigenome changes potentially involved in these effects were screened using RNA-seq combined with Cleavage Under Targets and Tagmentation sequencing. RESULTS: UB-specific inactivation of Ash2l caused CAKUT-like phenotypes mainly involving renal dysplasia at birth, which were associated with deficient H3K4 trimethylation. Ash2l inactivation slowed proliferation of cells at the UB tip, delaying budding and impairing UB branching morphogenesis. These effects were associated with downregulation of Ret , Gfra1 , and Wnt11 , which participate in RET/GFRA1 signaling. CONCLUSIONS: These experiments identify ASH2L-dependent H3K4 methylation in the UB lineage as an upstream epigenetic regulator of RET/GFRA1 signaling in UB morphogenesis, which, if deficient, may lead to CAKUT.

[Banxia Xiexin Decoction inhibiting colitis-associated colorectal cancer infected with Fusobacterium nucleatum by regulating Wnt/ß-catenin pathway].

This paper investigates the intervention effect and mechanism of Banxia Xiexin Decoction(BXD) on colitis-associated colorectal cancer(CAC) infected with Fusobacterium nucleatum(Fn). C57BL/6 mice were randomly divided into a control group, Fn group, CAC group [azoxymethane(AOM)/dextran sulfate sodium salt(DSS)](AOM/DSS), model group, and BXD group. Except for the control and AOM/DSS groups, the mice in the other groups were orally administered with Fn suspension twice a week. The AOM/DSS group, model group, and BXD group were also injected with a single dose of 10 mg·kg~(-1) AOM combined with three cycles of 2.5% DSS taken intragastrically. The BXD group received oral administration of BXD starting from the second cycle until the end of the experiment. The general condition and weight changes of the mice were monitored during the experiment, and the disease activity index(DAI) was calculated. At the end of the experiment, the colon length and weight of the mice in each group were compared. Hematoxylin-eosin(HE) staining was used to observe the pathological changes in the colon tissue. Enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of interleukin(IL)-2, IL-4, and IL-6 inflammatory factors in the serum. Immunohistochemistry(IHC) was used to detect the expression of Ki67, E-cadherin, and ß-catenin in the colon tissue. Western blot was used to detect the protein content of Wnt3a, ß-catenin, E-cadherin, annexin A1, cyclin D1, and glycogen synthase kinase-3ß(GSK-3ß) in the colon tissue. The results showed that compared with the control group, the Fn group had no significant lesions. The mice in the AOM/DSS group and model group had decreased body weight, increased DAI scores, significantly increased colon weight, and significantly shortened colon length, with more significant lesions in the model group. At the same time, the colon histology of the model group showed more severe adenomas, inflammatory infiltration, and cellular dysplasia. The levels of IL-4 and IL-6 in the serum were significantly increased, while the IL-2 content was significantly decreased. The IHC results showed low expression of E-cadherin and high expression of Ki67 and ß-catenin in the model group, with a decreased protein content of E-cadherin and GSK-3ß and an increased protein content of Wnt3a, ß-catenin, annexin A1, and cyclin D1. After intervention with BXD, the body weight of the mice increased; the DAI score decreased; the colon length increased, and the tumor decreased. The histopathology showed reduced tumor proliferation and reduced inflammatory infiltration. The levels of IL-6 and IL-4 in the serum were significantly decreased, while the IL-2 content was increased. Meanwhile, the expression of E-cadherin was upregulated, and that of Ki67 and ß-catenin was downregulated. The protein content of E-cadherin and GSK-3ß increased, while that of Wnt3a, ß-catenin, annexin A1, and cyclin D1 decreased. In conclusion, BXD can inhibit CAC infected with Fn, and its potential mechanism may be related to the inhibition of Fn binding to E-cadherin, the decrease in annexin A1 protein level, and the regulation of the Wnt/ß-catenin pathway.

Iva xanthiifolia leaf extract reduced the diversity of indigenous plant rhizosphere bacteria.

BACKGROUND: Iva xanthiifolia, native to North America, is now widely distributed in northeastern China and has become a vicious invasive plant. This article aims to probe the role of leaf extract in the invasion of I. xanthiifolia. METHODS: We collected the rhizosphere soil of Amaranthus tricolor and Setaria viridis in the invasive zone, the noninvasive zone and the noninvasive zone treated with extract from I. xanthiifolia leaf, and obtained I. xanthiifolia rhizosphere soil in the invasive zone. All wild plants were identified by Xu Yongqing. I. xanthiifolia (collection number: RQSB04100), A. tricolor (collection number: 831,030) and S. viridis (collection number: CF-0002-034) are all included in Chinese Virtual Herbarium ( https://www.cvh.ac.cn/index.php ). The soil bacterial diversity was analyzed based on the Illumina HiSeq sequencing platform. Subsequently, taxonomic analysis and Faprotax functional prediction were performed. RESULTS: The results showed that the leaf extract significantly reduced the diversity of indigenous plant rhizosphere bacteria. A. tricolor and S. viridis rhizobacterial phylum and genus abundances were significantly reduced under the influence of I. xanthiifolia or its leaf extract. The results of functional prediction showed that bacterial abundance changes induced by leaf extracts could potentially hinder nutrient cycling in native plants and increased bacterial abundance in the A. tricolor rhizosphere related to aromatic compound degradation. In addition, the greatest number of sensitive Operational Taxonomic Units (OTUs) appeared in the rhizosphere when S. viridis was in response to the invasion of I. xanthiifolia. It can be seen that A. tricolor and S. viridis have different mechanisms in response to the invasion of I. xanthiifolia. CONCLUSION: I. xanthiifolia leaves material has potential role in invasion by altering indigenous plant rhizosphere bacteria.

LRPPRC regulates malignant behaviors, protects mitochondrial homeostasis, mitochondrial function in osteosarcoma and derived cancer stem-like cells.

BACKGROUND: Leucine-rich pentatricopeptide repeat containing (LRPPRC) is a potential oncogene in multiple tumor types, including lung adenocarcinoma, esophageal squamous cell carcinoma and gastric cancer. LRPPRC exerts its tumor-promoting effects mainly by regulating mitochondrial homeostasis and inducing oxidative stress. However, the exact role and mechanisms by which LRPPRC acts in osteosarcoma and osteosarcoma-derived cancer stem-like cells (CSCs), which potentially critically contribute to recurrence, metastasis and chemoresistance, are still largely unclear. METHODS: LRPPRC level in osteosarcoma cells and CSCs were detected by western blot. Effects of LRPPRC on CSCs were accessed after LRPPRC knockdown by introducing lentivirus containing shRNA targeting to LRPPRC mRNA. RESULTS: we found that LRPPRC was highly expressed in several osteosarcoma cell lines and that LRPPRC knockdown inhibited malignant behaviors, including proliferation, invasion, colony formation and tumor formation, in MG63 and U2OS cells. Enriched CSCs derived from MG63 and U2OS cells presented upregulated LRPPRC levels compared to parental cells (PCs), and LRPPRC knockdown markedly decreased the sphere-forming capacity. These findings demonstrate that LRPPRC knockdown decreased stemness in CSCs. Consistent with a previous report, LRPPRC knockdown decreased the expression levels of FOXM1 and its downstream target genes, including PRDX3, MnSOD and catalase, which are responsible for scavenging reactive oxygen species (ROS). Expectedly, LRPPRC knockdown increased the accumulation of ROS in osteosarcoma and osteosarcoma-derived CSCs under hypoxic conditions due to the decrease in ROS scavenging proteins. Moreover, LRPPRC knockdown sensitized osteosarcomas and CSCs against carboplatin, a ROS-inducing chemoagent, and promoted apoptosis. Furthermore, LRPPRC knockdown significantly decreased the mitochondrial membrane potential, disturbed mitochondrial homeostasis and led to mitochondrial dysfunction. CONCLUSION: Taken together, these findings indicated that LRPPRC exerts critical roles in regulating mitochondrial homeostasis, mitochondrial function and tumorigenesis in osteosarcomas and osteosarcoma-derived CSCs. This suggests that LRPPRC might be a promising therapeutic target for osteosarcomas.

TRIM11, a new target of p53, facilitates the migration and invasion of nasopharyngeal carcinoma cells.

BACKGROUND: Although tripartite motif-containing protein 11 (TRIM11) is known to be associated with a variety of cancers, its role in nasopharyngeal carcinoma (NPC) is unclear. METHODS AND RESULTS: To investigate the role of TRIM11 in NPC, TRIM11 was stably overexpressed in 6-10B and CNE2 cells with lentiviral vectors and knocked down in S18 and 5-8F cells using the CRISPR/Cas9 system. Transwell assays and wound-healing assays revealed that TRIM11 facilitated the migration and invasion of NPC cells. Mechanistically, we found that p53 inhibits TRIM11 expression by binding to its promoter. CONCLUSIONS: TRIM11 may serve as a potential diagnostic marker for NPC and has a certain therapeutic value.

Impacts of calcium peroxide on phosphorus and tungsten releases from sediments.

In this study, CaO2 was used as a capping material to control the release of Phosphate (P) and tungsten (W) from the sediment due to its oxygen-releasing and oxidative properties. The results revealed significant decreases in SRP and soluble W concentrations after the addition of CaO2. The mechanisms of P and W adsorption by CaO2 were mainly chemisorption and ligand exchange mechanisms. In addition, the results showed significant increases in HCl-P and amorphous and poorly crystalline(oxyhydr)oxides bound W after the addition of CaO2. The highest reduction rates of sediment SRP and soluble W release were 37 and 43%, respectively. Furthermore, CaO2 can promote the redox of iron (Fe) and manganese (Mn). On the other hand, a significant positive correlation was observed between SRP/soluble W and soluble Fe (II) and between SRP/soluble W and soluble Mn, indicating that the effects of CaO2 on Fe and Mn redox play a crucial role in controlling P and W releases from sediments. However, the redox of Fe plays a key role in controlling sediment P and W release. Therefore, CaO2 addition can simultaneously inhibit sediment internal P and W release.

Prognostic value of consolidation-to-tumor ratio on computed tomography in NSCLC: a meta-analysis.

BACKGROUND: Although several studies have confirmed the prognostic value of the consolidation to tumor ratio (CTR) in non-small cell lung cancer (NSCLC), there still remains controversial about it. METHODS: We systematically searched the PubMed, Embase, and Web of Science databases from inception to April, 2022 for eligible studies that reported the correlation between CTR and prognosis in NSCLC. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were extracted and pooled to assess the overall effects. Heterogeneity was estimated by I2 statistics. Subgroup analysis based on the cut-off value of CTR, country, source of HR and histology type was conducted to detect the sources of heterogeneity. Statistical analyses were performed using STATA version 12.0. RESULTS: A total of 29 studies published between 2001 and 2022 with 10,347 patients were enrolled. The pooled results demonstrated that elevated CTR was associated with poorer overall survival (HR = 1.88, 95% CI 1.42-2.50, P < 0.01) and disease-free survival (DFS)/recurrence-free survival (RFS)/progression-free survival (PFS) (HR = 1.42, 95% CI 1.27-1.59, P < 0.01) in NSCLC. According to subgroup analysis by the cut-off value of CTR and histology type, both lung adenocarcinoma and NSCLC patients who had a higher CTR showed worse survival. Subgroup analysis stratified by country revealed that CTR was a prognostic factor for OS and DFS/RFS/PFS in Chinese, Japanese, and Turkish patients. CONCLUSIONS: In NSCLC patients with high CTR, the prognosis was worse than that with low CTR, indicating that CTR may be a prognostic factor.

Inhibition of CDK1 by RO-3306 Exhibits Anti-Tumorigenic Effects in Ovarian Cancer Cells and a Transgenic Mouse Model of Ovarian Cancer.

Ovarian cancer is the deadliest gynecological malignancy of the reproductive organs in the United States. Cyclin-dependent kinase 1 (CDK1) is an important cell cycle regulatory protein that specifically controls the G2/M phase transition of the cell cycle. RO-3306 is a selective, ATP-competitive, and cell-permeable CDK1 inhibitor that shows potent anti-tumor activity in multiple pre-clinical models. In this study, we investigated the effect of CDK1 expression on the prognosis of patients with ovarian cancer and the anti-tumorigenic effect of RO-3306 in both ovarian cancer cell lines and a genetically engineered mouse model of high-grade serous ovarian cancer (KpB model). In 147 patients with epithelial ovarian cancer, the overexpression of CDK1 was significantly associated with poor prognosis compared with a low expression group. RO-3306 significantly inhibited cellular proliferation, induced apoptosis, caused cellular stress, and reduced cell migration. The treatment of KpB mice with RO-3306 for four weeks showed a significant decrease in tumor weight under obese and lean conditions without obvious side effects. Overall, our results demonstrate that the inhibition of CDK1 activity by RO-3306 effectively reduces cell proliferation and tumor growth, providing biological evidence for future clinical trials of CDK1 inhibitors in ovarian cancer.

A comparison of the role of aggression in the association between hostile interpretation bias and antisocial personality features between young offenders and university students.

BACKGROUND: Antisocial personality features in adolescents are frequently associated with delinquency and constitute the problem that most concerns the criminal justice system and the public. Hostile interpretation bias has been identified as a candidate for explaining emergent adolescent antisocial personality problems and aggression, but it is unclear whether offenders and non-offenders show differences in the relationships between hostile interpretation bias, aggression and antisocial personality features. AIMS: To compare relationships between hostile interpretation bias and a personality measure between incarcerated teenagers and first year university students and to explore aggression and criminal history as mediating or moderating variables. METHODS: Fifty-three 16-18-year-old incarcerated male offenders and 69 17-20-year-old male university students were recruited, the former through institutional staff and the latter by online advert only. Individuals in both groups self-rated, in private, on the Word and Sentence Association Paradigm-hostile (WSAP), The Ambiguous Intentions Hostility Questionnaire (AIHQ), Hostility Interpretation Bias Task (HIBT) as tests for hostile interpretation bias, and on the Buss-Perry Aggression Questionnaire and on Hyler's Personality Disorder Questionnaire (PDQ-4). Among the students, criminal history was assessed by a self-reported binary question. LASSO regressions were used to test inter-relationships between hostile interpretation bias and aggression or antisocial personality traits. Mediation and moderation were tested using MPLUS 7.4. RESULTS: The WSAP and AIHQ, as measures of self-reported hostility bias, had relationships with self-reported aggression (Pearson r 0.24-0.58, p < 0.001) and with antisocial personality features (r 0.36-0.50, p < 0.001), the HIBT did not. Aggression scores mediated the relationship between hostile interpretation bias and antisocial personality features. Furthermore, the relationship between hostile interpretation bias and aggression was stronger among the young offenders (estimates 0.43-0.75) than among the university students without criminal history (estimates 0.13-0.36). CONCLUSIONS: Hostile interpretation bias appears to promote antisocial personality features by increasing an individual's aggression, regardless of social status, although the effect was much stronger among the young offenders. To reduce young people's antisocial personality features, future studies should perhaps focus on evaluating strategies to reduce hostile bias or prevent it from being expressed in aggressive behaviours.

Biological role of matrix stiffness in tumor growth and treatment.

In recent years, the biological role of changes in physical factors in carcinogenesis and progression has attracted increasing attention. Matrix stiffness, also known as ECM stress, is a critical physical factor of tumor microenvironment and remains alternating during carcinogenesis as a result of ECM remodeling through activation of cancer-associated fibroblasts and extracellular collagen accumulation, crosslinking and fibrosis. Different content and density of extracellular collagen in ECM endows matrix with varying stiffness. Physical signals induced by matrix stiffness are transmitted to tumor cells primarily by the integrins receptor family and trigger a series of mechanotransduction that result in changes in tumor cell morphology, proliferative capacity, and invasive ability. Importantly, accumulating evidence revealed that changes in matrix stiffness in tumor tissues greatly control the sensitivity of tumor cells in response to chemotherapy, radiotherapy, and immunotherapy through integrin signaling, YAP signaling, and related signaling pathways. Here, the present review analyzes the current research advances on matrix stiffness and tumor cell behavior with a view to contributing to tumor cell growth and treatment, with the hope of improving the understanding of the biological role of matrix stiffness in tumors.

Genetically predicted testosterone and cancers risk in men: a two-sample Mendelian randomization study.

OBJECTIVE: In observational studies, testosterone has been reported to be associated with some types of cancers. However, the direction and magnitude of the causal association between testosterone and different types of cancer remain unclear. This Mendelian randomization study assessed the causal associations of total testosterone (TT) and bioavailable testosterone (BT) with cancer risk in men. METHODS: We performed two-sample Mendelian randomization using publicly available GWAS summary statistics to investigate the genetically causal association between testosterone and the risk of 22 kinds of cancers in men. Causal estimates were calculated by the inverse variance weighted method. We also performed additional sensitivity tests to evaluate the validity of the casualty. RESULTS: Genetically predicted BT level were significantly associated with an increased risk of prostate cancer [odds ratio (OR) = 1.17 95% confidence interval (CI): 1.09-1.26, P = 2.51E-05] in the MR analysis with the IVW method. TT was found to be the suggestive protective factor against stomach cancer (OR = 0.66, 95% CI: 0.48-0.93, P = 0.0116) as well as pancreatic cancer (OR = 0.59, 95% CI: 0.36-0.96, P = 0.0346). A suggestive association was found between TT and the occurrence of small intestine cancer (OR = 1.0004, 95% CI: 1.0001-1.0007, P = 0.0116). However, testosterone had no significant association with other cancers. CONCLUSION: This study investigated the role of testosterone in the development of prostate cancer, stomach cancer, pancreatic cancer, and small intestine cancer but found no strong association with the other cancers in men.

Pull the plug: Anti-angiogenesis potential of natural products in gastrointestinal cancer therapy.

Gastrointestinal cancer (GIC), including gastric cancer and colorectal cancer, is a common malignant tumor originating from the gastrointestinal epithelium. Although the pathogenesis of GIC has not been fully elucidated, angiogenesis is recognized as the key pathological basis for the growth, invasion and metastasis of cancer cells, and GIC angiogenesis is closely related to vascular endothelial growth factor family, hypoxia-inducible factor family, fibroblast growth factor family and matrix metalloproteinase family. Recently, many natural products have shown a wide range of pharmacological biological activities against GIC. In this review, the effects and mechanisms of natural compounds on the angiogenesis of gastric and colorectal cancer were summarized. The results show that some natural compounds, especially gallic catechin gallate, astragaloside and curcumin, can effectively inhibit angiogenesis; the HIF-1α/VEGF, COX-2/PGE2, HGF/c-Met and PI3K/Akt/mTOR are involved in these inhibition effects. This review examines the anti-angiogenesis potential of natural products in the GIC treatment and provides clues to the development of vascular targeted agents.