A novel STAT3/ NFκB p50 axis regulates stromal-KDM2A to promote M2 macrophage-mediated chemoresistance in breast cancer.

BACKGROUND: Lysine Demethylase 2A (KDM2A) plays a crucial role in cancer cell growth, differentiation, metastasis, and the maintenance of cancer stemness. Our previous study found that cancer-secreted IL-6 can upregulate the expression of KDM2A to promote further the transition of cells into cancer-associated fibroblasts (CAFs). However, the molecular mechanism by which breast cancer-secreted IL-6 regulates the expression of KDM2A remains unclear. Therefore, this study aimed to elucidate the underlying molecular mechanism of IL-6 in regulating KDM2A expression in CAFs and KDM2A-mediated paclitaxel resistance in breast cancer. METHODS: The ectopic vector expression and biochemical inhibitor were used to analyze the KDM2A expression regulated by HS-578 T conditioned medium or IL-6 in mammary fibroblasts. Immunoprecipitation and chromatin immunoprecipitation assays were conducted to examine the interaction between STAT3 and NFκB p50. M2 macrophage polarization was assessed by analyzing M2 macrophage-specific markers using flow cytometry and RT-PCR. ESTIMATE algorithm was used to analyze the tumor microenvironment-dominant breast cancer samples from the TCGA database. The correlation between stromal KDM2A and CD163 + M2 macrophages was analyzed using the Pearson correlation coefficient. Cell viability was determined using trypan blue exclusion assay. RESULTS: IL-6 regulates gene expression via activation and dimerization of STAT3 or collaboration of STAT3 and NFκB. However, STAT3, a downstream transcription factor of the IL-6 signaling pathway, was directly complexed with NFκB p50, not NFκB p65, to upregulate the expression of KDM2A in CAFs. Enrichment analysis of immune cells/stromal cells using TCGA-breast cancer RNA-seq data unveiled a positive correlation between stromal KDM2A and the abundance of M2 macrophages. CXCR2-associated chemokines secreted by KDM2A-expressing CAFs stimulated M2 macrophage polarization, which in turn secreted CCL2 to increase paclitaxel resistance in breast cancer cells by activating CCR2 signaling. CONCLUSION: This study revealed the non-canonical molecular mechanism of IL-6 secreted by breast cancer upregulated KDM2A expression in CAFs via a novel STAT3/NFκB p50 axis, which STAT3 complexed with NFκB p50 in NFκB p50 binding motif of KDM2A promoter. KDM2A-expressing CAFs dominantly secreted the CXCR2-associated chemokines to promote M2 macrophage polarization and enhance paclitaxel resistance in breast cancer. These findings underscore the therapeutic potential of targeting the CXCR2 or CCR2 pathway as a novel strategy for paclitaxel-resistant breast cancer.

Host defence peptide LEAP2 contributes to antimicrobial activity in a mustache toad (Leptobrachium liui).

BACKGROUND: The liver-expressed antimicrobial peptide 2 (LEAP2) is essential in host immunity against harmful pathogens and is only known to act as an extracellular modulator to regulate embryonic development in amphibians. However, there is a dearth of information on the antimicrobial function of amphibian LEAP2. Hence, a LEAP2 homologue from Leptobrachium liui was identified, characterized, and chemically synthesized, and its antibacterial activities and mechanisms were determined. RESULTS: In this study, LEAP2 gene (Ll-LEAP2) cDNA was cloned and sequenced from the Chong'an Moustache Toad (Leptobrachium liui). The predicted amino acid sequence of Ll-LEAP2 comprises a signal peptide, a mature peptide, and a prodomain. From sequence analysis, it was revealed that Ll-LEAP2 belongs to the cluster of amphibian LEAP2 and displays high similarity to the Tropical Clawed Frog (Xenopus tropicalis)'s LEAP2. Our study revealed that LEAP2 protein was found in different tissues, with the highest concentration in the kidney and liver of L. liui; and Ll-LEAP2 mRNA transcripts were expressed in various tissues with the kidney having the highest mRNA expression level. As a result of Aeromonas hydrophila infection, Ll-LEAP2 underwent a noticeable up-regulation in the skin while it was down-regulated in the intestines. The chemically synthesized Ll-LEAP2 mature peptide was selective in its antimicrobial activity against several in vitro bacteria including both gram-positive and negative bacteria. Additionally, Ll-LEAP2 can kill specific bacteria by disrupting bacterial membrane and hydrolyzing bacterial gDNA. CONCLUSIONS: This study is the first report on the antibacterial activity and mechanism of amphibian LEAP2. With more to uncover, the immunomodulatory functions and wound-healing activities of Ll-LEAP2 holds great potential for future research.

Assessment of bypass patency using transcranial Doppler sonography: correlations with computerized tomography angiography findings in patients with moyamoya disease.

To explore the utility of transcranial Doppler (TCD) findings when assessing bypass patency in patients with Moyamoya disease (MMD). Computed tomography angiography (CTA) and TCD sonography (TCDS) were performed before and after surgery to evaluate bypass patency. The peak systolic flow velocity (PSV) of the superficial temporal artery (STA) and the pulsatility index (PI) were compared between the groups that achieved patency and not, and receiver operating characteristic (ROC) curve analyses were used to define the TCDS criteria revealing patency. This study included 35 hemispheres (15 women; mean age 47 years) with Moyamoya disease who underwent STA-middle carotid artery bypass in our institution between January 2022 and October 2022. The PSV first increased on postoperative days 4-5 and then decreased on postoperative days 6-7 and 7-8. Patients with transient neurological diseases (TNDs), compared to those without, evidenced a significantly lower PSV value (P < 0.05). Compared with the non-patency group, the PSV was higher (P < 0.001) in the patency group. The cutoff values reflecting patency with good sensitivity and specificity were PSV > 49.00; PSV ratio (postoperative/preoperative) > 1.218; PSV ratio (operation side/contralateral side) > 1.082; and PSV ratio (adjusted) > 1.202. In the patency group, the PSV and PI significantly increased (P < 0.001) and decreased (P < 0.001) respectively. Bypass patency can be noninvasively and accurately evaluated via TCDS, affording an objective basis for assessment of the effect of revascularization surgery on patients with MMD.

Parent-child interactions in early life mediating association between prenatal maternal stress and autistic-like behaviors among preschoolers.

A range of studies have shown that prenatal maternal stress (PNMS) exposure is associated with offspring autistic-like behaviors, however the potential pathways remain unexplored. This study aimed to evaluate the mediating role of parent-child interactions in early life in the association between PNMS exposure and preschoolers' autistic-like behaviors. Data from 65,928 child-parent dyads were obtained via a primary caregiver-reported questionnaire administered as part of the Longhua Child Cohort Study. To strengthen confidence in the reliability of the results, the analyses were initially conducted on a random selection of 70% of the total sample, and then validated on the remaining 30% of the sample. Analysis of covariance and multiple linear models were employed to estimate the associations between PNMS exposure, parent-child interactions in early life, and children's autistic-like behaviors. The results showed that PNMS exposure was positively associated with the presence of autistic-like behaviors at preschool age. The total indirect effect of the frequency of positive parent-child interactions in early life accounted for 9.69% or 8.99% of the variance of the association. Our findings indicate that parent-child interactions in early life might function as potential mediators of the association between PNMS and the increased risk of offspring autistic-like behaviors.

C1632 suppresses the migration and proliferation of non-small-cell lung cancer cells involving LIN28 and FGFR1 pathway.

Chemoresistance and migration represent major obstacles in the therapy of non-small-cell lung cancer (NSCLC), which accounts for approximately 85% of lung cancer patients in clinic. In the present study, we report that the compound C1632 is preferentially distributed in the lung after oral administration in vivo with high bioavailability and limited inhibitory effects on CYP450 isoenzymes. We found that C1632 could simultaneously inhibit the expression of LIN28 and block FGFR1 signalling transduction in NSCLC A549 and A549R cells, resulting in significant decreases in the phosphorylation of focal adhesion kinase and the expression of matrix metalloproteinase-9. Consequently, C1632 effectively inhibited the migration and invasion of A549 and A549R cells. Meanwhile, C1632 significantly suppressed the cell viability and the colony formation of A549 and A549R cells by inhibiting DNA replication and inducing G0/G1 cell cycle arrest. Interestingly, compared with A549 cells, C1632 possesses the same or even better anti-migration and anti-proliferation effects on A549R cells, regardless of drug resistance. In addition, C1632 also displayed the capacity to inhibit the growth of A549R xenograft tumours in mice. Altogether, these findings reveal the potential of C1632 as a promising anti-NSCLC agent, especially for chemotherapy-resistant NSCLC treatment.

Association between prenatal exposure to indoor air pollution and autistic-like behaviors among preschool children.

Indoor air pollution is a recognized risk factor for a range of negative health outcomes. This study aimed to investigate the association between maternal prenatal exposure to indoor air pollution and the presence of autistic-like behaviors among preschool children. Data were obtained from the Longhua Child Cohort Study in 2017, in which we enrolled a total of 65 317 preschool children. Associations between maternal exposure to four sources of indoor air pollution (e.g., cooking, environmental tobacco smoke (ETS), mosquito coils, and home decoration) during pregnancy and preschool children's autistic traits were analyzed using multivariate logistic regression. Our results showed that maternal exposure to indoor air pollution from four different sources during pregnancy was associated with the presence of children's autistic-like behaviors. There was dose-response relationship between the accumulative exposure to the four different indoor air pollution sources and the risk of autistic-like behaviors. Furthermore, we found a significant additive interaction between prenatal exposure to both cooking and mosquito coil incense on the risk of autistic-like behaviors. Maternal prenatal exposure to the indoor air pollution from four sources might increase with the risk of autistic-like behaviors being present among preschool children, with an additive interaction effect between some pollution sources.

Reproduction disrupts stem cell homeostasis in testes of aged male Drosophila via an induced microenvironment.

Stem cells rely on instructive cues from their environment. Alterations in microenvironments might contribute to tissue dysfunction and disease pathogenesis. Germline stem cells (GSCs) and cyst stem cells (CySC) in Drosophila testes are normally maintained in the apical area by the testicular hub. In this study, we found that reproduction leads to accumulation of early differentiating daughters of CySCs and GSCs in the testes of aged male flies, due to hyperactivation of Jun-N-terminal kinase (JNK) signaling to maintain self-renewal gene expression in the differentiating cyst cells. JNK activity is normally required to maintain CySCs in the apical niche. A muscle sheath surrounds the Drosophila testis to maintain its long coiled structure. Importantly, reproduction triggers accumulation of the tumor necrosis factor (TNF) Eiger in the testis muscle to activate JNK signaling via the TNF receptor Grindelwald in the cyst cells. Reducing Eiger activity in the testis muscle sheath suppressed reproduction-induced differentiation defects, but had little effect on testis homeostasis of unmated males. Our results reveal that reproduction in males provokes a dramatic shift in the testicular microenvironment, which impairs tissue homeostasis and spermatogenesis in the testes.

Analyzing the gonadal transcriptome of the frog Hoplobatrachus rugulosus to identify genes involved in sex development.

BACKGROUND: The tiger frog (Hoplobatrachus rugulosus) is listed as a national Class II protected species in China. In the context of global warming, the sex ratio of amphibians will be affected, and the development of the population will be limited. Therefore, considering the potential for a decrease in the number of amphibians, studying sex evolution and molecular regulation of gonadal development in H. rugulosus, phenomenon that are currently unclear, is of great significance. RESULTS: Here, H. rugulosus was used to explore the mechanisms regulating gonadal development in amphibians. Illumina HiSeq 3000 was used to sequence the gonadal transcriptome of male and female H. rugulosus at two growth stages to identify genes related to gonadal development and analyze expression differences in the gonads. This analysis indicated that cyp17α, hsd3ß, hsd11ß1, cyp19α, and hsd17ß12 perform vital functions in sex development in amphibians. Specifically, the expression of cyp3α, cyp17α, hsd3ß, hsd11ß1, sox2, sox9, sox30, soat, cyp19α, hsd17ß12, and hspα1s was correlated with gonadal development and differentiation in H. rugulosus, as determined using the quantitative reverse transcriptase-polymerase chain reaction. CONCLUSION: Significant differences were found in the gonadal gene expression levels in H. rugulosus of both sexes, and we identified a steroid hormone synthesis pathway in this species and analyzed related gene expression, but the changes during sex differentiation were still unclear. To our knowledge, this report presents the first analysis of the H. rugulosus gonadal transcriptome and lays the foundation for future research.

Lysine demethylase 2A expression in cancer-associated fibroblasts promotes breast tumour growth.

BACKGROUND: Our previous study demonstrated that lysine demethylase 2A (KDM2A) enhances stemness in breast cancer cells. This demethylase is also highly expressed in cancer-associated fibroblasts (CAFs). However, its clinical significance is unclear. METHODS: The expression of KDM2A in CAFs was studied using immunohistochemical staining and its association with clinicopathological features and patient's survival was tested. Overexpression and knockdown strategies were used to investigate KDM2A-regulated genes in fibroblasts. Senescent cells were detected by using ß-galactosidase staining. The in vivo tumour-promoting activity of stromal KDM2A was confirmed by animal study. RESULTS: Increase of stromal KDM2A is associated with advanced tumour stage and poor clinical outcome in breast cancer patients. Cancer-derived cytokines stimulated KDM2A expression in normal fibroblasts and transformed them into CAFs. Upregulation of KDM2A induced p53-dependent senescence in fibroblasts and enhanced the release of cytokines, which reciprocally promoted cancer cell proliferation. Additionally, KDM2A upregulated programmed death-ligand 1 (PD-L1) expression via transcriptional activation in fibroblasts. Knockdown of KDM2A completely abolished the tumour-promoting activity of CAFs on breast tumour growth in vivo and diminished PD-L1 expression in the stroma of tumour tissues. CONCLUSIONS: Stromal KDM2A plays an oncogenic role in breast cancer and inhibition of KDM2A reduces fibroblast senescence and suppresses tumour growth.

Screen time and autistic-like behaviors among preschool children in China.

Screen time is becoming increasingly common in daily life. Early and excessive screen use has raised growing concerns for children's neuropsychological development. The purpose of this study was to evaluate the association between exposure to screen time in early life and the presence of autistic-like behaviors among preschool children. 29,461 child-caregiver dyads at kindergartens in Longhua New District of Shenzhen, China, were enrolled in this cross-sectional study. Information concerning socio-demographic characteristics, frequency and duration of children's electronic screen exposure for each year since birth, and autistic-like behaviors (measured by the Autism Behavior Checklist) were collected using a self-administered structured questionnaire completed by the primary caregivers. A series of logistic regression models assessed the association between screen time and autistic-like behaviors. Results indicated that younger initial age, longer daily screen time and longer cumulative years of screen exposure since birth were associated with the presence of autistic-like behaviors at preschool age. The risk was enhanced with the increase of both daily screen time and cumulative years of screen exposure during preschool period. Moreover, the cross-over analysis indicated that the first three years following birth might be a sensitive period for children when screen exposure increases the risk of experiencing autistic-like behaviors. In conclusion, our study implied that screen exposure in early life might increase the occurrence of autistic-like behaviors among preschoolers. These findings support the need for early interventions into preschoolers' screen use, however longitudinal studies are necessary to further confirm the causal relationship between early screen time and the incidence of later autistic-like behaviors among preschool children.

Optimizing sludge dewatering with a combined conditioner of Fenton's reagent and cationic surfactant.

Enhancing sludge dewatering is of importance in reducing environmental burden and disposal costs. In this work, a cationic surfactant, cetyl trimethyl ammonium bromide (CTAB), was combined with Fenton's reagent for sludge dewatering. Results show that the Fenton-CTAB conditioning significantly promotes the sludge dewatering. Using combined techniques of response surface methodology and uniform design, dosages of Fe2+, H2O2, and CTAB for water content response were optimized to be 89, 276, and 233 mg/g dry solids (DS), respectively. The water content of sludge decreased from 79.0% to 66.8% under the optimal conditions. Compared with cationic polyacrylamide, the Fenton-CTAB system exhibited superior sludge dewatering performance. To gain insights into the mechanisms involved in sludge dewatering, the effects of Fenton-CTAB conditioning on the composition of extracellular polymeric substances (EPS) and the morphology of the sludge flocs were investigated. The decomposition of EPS into some dissolved organics and the release of proteins in tightly bound EPS facilitated the conversion of bound water to free water and further reduced the water content of sludge cake. After conditioning, morphology of sludge showed aggregation. Overall, the enhanced sludge dewatering by Fenton-CTAB treatment provides an efficient way for management of sewage sludge.

Evaluation of the sensitivity of Microhyla fissipes tadpoles to aqueous cadmium.

Cadmium (Cd) exposure is harmful to amphibians in natural environments and the Cd concentration is a key parameter in water monitoring. Cd pollution has been a severe issue in the Yangtze River and its southern reaches in recent years. Acute toxicity assays were employed to determine the tolerance limits of Cd for Microhyla fissipes tadpoles and five different concentrations of Cd (0, 50, 100, 200 and 300 µg/L) were involved to detect its chronic effects on metamorphosis, growth, locomotion, genotoxicity and enzymatic activities of M. fissipes tadpoles. The results showed that the 24-h and 48-h LC50 values of Cd on M. fissipes tadpoles were 2591.3 µg/L and 1567.9 µg/L, respectively, and the presumable non-lethal concentration obtained was 172.2 µg/L. During the 70-day chronic toxicity assays, Cd showed negative impacts on survival, growth, metamorphosis and the frequency of erythrocytes nuclear abnormality of M. fissipes tadpoles. However, the Cd exposure caused the increased body size and condition of tadpoles at complete metamorphosis (GS46). The tadpoles exposed to 200 µg/L of Cd exhibited degraded locomotor performance at GS46. Weight increments of tadpoles were inhibited at Day 14 and massive deaths were observed over the next 14 days. The enzymatic activities of tadpoles experienced a shock response stage (GS30-GS35) and a complete recovery stage (GS36-GS41) in all treatments. However, the enzymatic activities (except alkaline phosphatase) of tadpoles at GS46 increased after Cd exposure, especially at high concentrations. In summary, Cd is a threat to M. fissipes tadpoles as that causes reduced fitness.

[Transdermal characteristics and mechanism of asiaticoside nanoemulsions and asiaticoside nanoemulsions-based gels].

To prepare the asiaticoside nanoemulsions (ASI-NEs) and asiaticoside nanoemulsions-based gels (ASI-NBGs), compare them with the commercial cream of asiaticoside (ASI-C) in terms of transdermal characteristics, and investigate the transdermal mechanism of ASI-NEs and ASI-NBGs. Their transdermal characteristics were studied by using Franz diffusion cells. The effect of topical ASI-NEs and ASI-NBGs on ultrastructure of rabbit skin was evaluated by using HE staining method. The localization and the permeation pathway of asiaticoside were visually investigated by using laser scanning confocal microscope (CLSM). The transdermal studies in vitro showed that the cumulative amount of ASI permeated from ASI-NEs and ASI-NBGs at 12 h after application were (3 504.30±180.93), (1 187.40±128.88) µg·cm⁻² respectively, 6.57, 2.23 times of that in the control group of ASI-C; the drug deposition of ASI-NEs and ASI-NBGs in skin was (159.48±7.47), (120.53±5.71) µg·cm⁻² respectively, 5.93, 4.48 times of that of ASI-C. HE staining of the rabbit skin after application of ASI-NEs and ASI-NBGs showed that the epidermis structure was basically intact; stratum corneum was loosed and the keratin fragment was increased; at the same time, the gap of prickle cell was increased and the basal cells were arranged loosely. The study of CLSM showed that significant percutaneous enhancer effect was observed for ASI-NEs after the topical application of 6 h, as the fluorescent compound was penetrated in the dermis and diffused uniformly. The fluorescence area and the integral optical density (IOD) were 28.81, 32.51 times of that in the FITC aqueous solution group, respectively. The fluorescent preparations showed strong fluorescence in the epidermis, but weak in deeper layers; with the increase of treatment time, the fluorescence in deeper layer was increased and stronger in skin appendages. The prepared ASI-NEs and ASI-NBGs have good transdermal characteristics and the transdermal mechanism is related to breaking the ultrastructure of stratum corneum and penetrating by the path of skin adnexa.

Isolation and Characterization of Phosphate-Solubilizing Bacteria from Mushroom Residues and their Effect on Tomato Plant Growth Promotion.

Phosphorus is a major essential macronutrient for plant growth, and most of the phosphorus in soil remains in insoluble form. Highly efficient phosphate-solubilizing bacteria can be used to increase phosphorus in the plant rhizosphere. In this study, 13 isolates were obtained from waste mushroom residues, which were composed of cotton seed hulls, corn cob, biogas residues, and wood flour. NBRIP solid medium was used for isolation according to the dissolved phosphorus halo. Eight isolates produced indole acetic acid (61.5%), and six isolates produced siderophores (46.2%). Three highest phosphate-dissolving bacterial isolates, namely, M01, M04, and M11, were evaluated for their beneficial effects on the early growth of tomato plants (Solanum lycopersicum L. Wanza 15). Strains M01, M04, and M11 significantly increased the shoot dry weight by 30.5%, 32.6%, and 26.2%, and root dry weight by 27.1%, 33.1%, and 25.6%, respectively. Based on 16S rRNA gene sequence comparisons and phylogenetic positions, strains M01 and M04 belonged to the genus Acinetobacter, and strain M11 belonged to the genus Ochrobactrum. The findings suggest that waste mushroom residues are a potential resource of plant growth-promoting bacteria exhibiting satisfactory phosphate-solubilizing for sustainable agriculture.

Identification of Up- and Down-Regulated Proteins in Pemetrexed-Resistant Human Lung Adenocarcinoma: Flavin Reductase and Calreticulin Play Key Roles in the Development of Pemetrexed-Associated Resistance.

Drug resistance is one of the major causes of cancer chemotherapy failure. In the current study, we used a pair of lung adenocarcinoma cell lines, A549 and the pemetrexed-resistant A549/PEM cells, as a model to monitor resistance-dependent cellular responses and identify potential therapeutic targets. By means of 2D differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS), we investigated the global protein expression alterations induced by pemetrexed treatment and resistance. The proteomic result revealed that pemetrexed exposure obviously altered the expression of 81 proteins in the A549 cells, whereas no significant response was observed in the similarly treated A549/PEM cells, hence implying an association between these proteins and the drug-specific response. Moreover, 72 proteins including flavin reductase and calreticulin demonstrated differential expression between the A549 and A549/PEM cells, indicating baseline resistance. Additional tests employed siRNA silencing, protein overexpression, cell viability analysis, and analysis of apoptosis to examine and confirm the potency of flavin reductase and calreticulin proteins in the development of pemetrexed resistance. In summary, by using a proteomic approach, we identified numerous proteins, including flavin reductase and calreticulin, involved in pemetrexed drug resistance-developing mechanisms. Our results provide useful diagnostic markers and therapeutic candidates for pemetrexed-resistant lung cancer treatment.

Sensor data fusion for body state estimation in a bipedal robot and its feedback control application for stable walking.

We report on a sensor data fusion algorithm via an extended Kalman filter for estimating the spatial motion of a bipedal robot. Through fusing the sensory information from joint encoders, a 6-axis inertial measurement unit and a 2-axis inclinometer, the robot's body state at a specific fixed position can be yielded. This position is also equal to the CoM when the robot is in the standing posture suggested by the detailed CAD model of the robot. In addition, this body state is further utilized to provide sensory information for feedback control on a bipedal robot with walking gait. The overall control strategy includes the proposed body state estimator as well as the damping controller, which regulates the body position state of the robot in real-time based on instant and historical position tracking errors. Moreover, a posture corrector for reducing unwanted torque during motion is addressed. The body state estimator and the feedback control structure are implemented in a child-size bipedal robot and the performance is experimentally evaluated.

Retrospective study of oral and maxillofacial lesions in older Taiwanese patients.

OBJECTIVE: The aim was to provide information regarding oral and maxillofacial (OMF) lesions in an older Taiwanese population. BACKGROUND: The rate of increase of older people in Taiwan is expected to be rapid. OMF lesions are very frequent in the older population, but no studies have been performed on these lesions in Taiwan. MATERIALS AND METHODS: OMF cases (between 2000 and 2011) in geriatric patients (≥60 years of age) with records of age, sex and histological diagnoses were retrieved from the Oral Pathology Department of our institution. These lesions were classified into four main categories: tumour/tumour-like reactive lesions, cystic/pseudocystic lesions, inflammatory/infective lesions and other miscellaneous lesions. RESULTS: Six thousand seven hundred and twenty-six lesions were collected from a total of 39 503 OMF lesions in older Taiwanese patients in this study. Most of these lesions were distributed in the inflammatory/infective group, followed by tumour/tumour-like reactive lesions. Squamous cell carcinoma was the most common lesion, and, additionally, there was a high frequency of oral potentially malignant disorders. CONCLUSIONS: The present study showed trends similar to previous reports from other countries. However, some detailed information was different, perhaps due to the different criteria and different geographic distribution. Worthy of note, our results indicated that screening for oral potentially malignant disorder and oral malignancy in the older population is essential.

Cancer/stroma interplay via cyclooxygenase-2 and indoleamine 2,3-dioxygenase promotes breast cancer progression.

INTRODUCTION: Expression of indoleamine 2,3-dioxygenase (IDO) in primary breast cancer increases tumor growth and metastasis. However, the clinical significance of stromal IDO and the regulation of stromal IDO are unclear. METHODS: Metabolomics and enzyme-linked immunosorbent assay (ELISA) were used to study the effect of cyclooxygenase-2 (COX-2)-overexpressing breast cancer cells on IDO expression in co-cultured human breast fibroblasts. Biochemical inhibitors and short-hairpin RNA (shRNA) were used to clarify how prostaglandin E2 (PGE2) upregulates IDO expression. Associations of stromal IDO with clinicopathologic parameters were tested in tumor specimens. An orthotopic animal model was used to examine the effect of COX-2 and IDO inhibitors on tumor growth. RESULTS: Kynurenine, the metabolite generated by IDO, increases in the supernatant of fibroblasts co-cultured with COX-2-overexpressing breast cancer cells. PGE2 released by cancer cells upregulates IDO expression in fibroblasts through an EP4/signal transducer and activator of transcription 3 (STAT3)-dependent pathway. Conversely, fibroblast-secreted kynurenine promotes the formation of the E-cadherin/Aryl hydrocarbon receptor (AhR)/S-phase kinase-associated protein 2 (Skp2) complex, resulting in degradation of E-cadherin to increase breast cancer invasiveness. The enhancement of motility of breast cancer cells induced by co-culture with fibroblasts is suppressed by the IDO inhibitor 1-methyl-tryptophan. Pathological analysis demonstrates that upregulation of stromal IDO is a poor prognosis factor and is associated with of COX-2 overexpression. Co-expression of cancer COX-2 and stromal IDO predicts a worse disease-free and metastasis-free survival. Finally, COX-2 and IDO inhibitors inhibit tumor growth in vivo. CONCLUSION: Integration of metabolomics and molecular and pathological approaches reveals the interplay between cancer and stroma via COX-2, and IDO promotes tumor progression and predicts poor patient survival.

Quercetin-induced cardioprotection against doxorubicin cytotoxicity.

BACKGROUND: Cancer has continually been the leading cause of death worldwide for decades. Thus, scientists have actively devoted themselves to studying cancer therapeutics. Doxorubicin is an efficient drug used in cancer therapy, but also produces reactive oxygen species (ROS) that induce severe cytotoxicity against heart cells. Quercetin, a plant-derived flavonoid, has been proven to contain potent antioxidant and anti-inflammatory properties. Thus, this in vitro study investigated whether quercetin can decrease doxorubicin-induced cytotoxicity and promote cell repair systems in cardiomyocyte H9C2 cells. RESULTS: Proteomic analysis and a cell biology assay were performed to investigate the quercetin-induced responses. Our data demonstrated that quercetin treatment protects the cardiomyocytes in a doxorubicin-induced heart damage model. Quercetin significantly facilitated cell survival by inhibiting cell apoptosis and maintaining cell morphology by rearranging the cytoskeleton. Additionally, 2D-DIGE combined with MALDI-TOF MS analysis indicated that quercetin might stimulate cardiomyocytes to repair damage after treating doxorubicin by modulating metabolic activation, protein folding and cytoskeleton rearrangement. CONCLUSION: Based on a review of the literature, this study is the first to report detailed protective mechanisms for the action of quercetin against doxorubicin-induced cardiomyocyte toxicity based on in-depth cell biology and proteomic analysis.

A retrospective comparison of the location and diameter of the inferior alveolar canal at the mental foramen and length of the anterior loop between American and Taiwanese cohorts using CBCT.

PURPOSE: The aim was to retrospectively compare the measurements of the location and size of the inferior alveolar canal at the mental foramen and the length of the anterior loop between two cohorts of Americans and Taiwanese using cone-beam computed tomography (CBCT). METHODS: CBCT was performed with an I-CAT(®) Cone-Beam 3D Dental Imaging System and reconstructed into multiple-plane views to measure two populations. RESULTS: There was no statistically significant difference (P = 0.2681) in the distance from the mental foramen to the inferior border of the mandible (mandibular border height) between Americans (9.84 ± 2.01 mm) and Taiwanese (10.13 ± 1.66 mm). No significant difference was found (p = 0.1161) in the inferior alveolar canal diameter between these two cohorts (2.26 ± 0.67 and 2.13 ± 0.47 mm, respectively). However, the anterior loop length of Taiwanese (7.61 ± 1.81 mm) was significantly longer than that of Americans (6.22 ± 1.68 mm) (P < 0.0001). CONCLUSION: Our study indicated that (1) the location of mental foramen of Americans was closer to the inferior border of the mandible than Taiwanese; (2) the diameter of the inferior alveolar canal of Americans was larger than Taiwanese; (3) the anterior loop of Taiwanese was longer than Americans. These differences may be, at least partly, due to the racial influence and this information may possess potential valuable clinical relevance.