Exposure to particulate matter 2.5 leading to lung microbiome disorder and the alleviation effect of Auricularia auricular-judae polysaccharide.

OBJECTIVES: The aim of the paper is to explore the role of lung microbiome disorder in lung tissue injury induced by exposure to particulate matter with a maximum diameter of 2.5 µm (PM2.5) and the alleviation effect of Auricularia auricular-judae polysaccharide (AAP). MATERIAL AND METHODS: Sprague Dawley rats were given PM2.5 suspension at a dose of 20 mg/l twice a week for 8 weeks. Then, 100 mg/kg or 200 mg/kg of AAP was administered to the rats after PM2.5 exposure. The bronchoalveolar lavage fluid (BALF) and lung tissue samples were collected at the end of the experiment. The BALF was meant to detect changes in lung microbiome by 16S sequences and cluster analysis, with the application of the principal component analysis and the partial least squares discriminant analysis. The levels of interferon-γ (IFN-γ), and interleukin (IL)-4, IL-8, and IL-10 in lung tissue were detected by the enzyme-linked immunosorbent assay method. The pathological changes in lung tissue were observed by hematoxylin and eosin staining. RESULTS: After PM2.5 exposure, the alveolar septum was widened, and the structures of alveolar walls were destroyed. There was inflammatory cells infiltration in the alveolar space and the interstitial space. Alpha diversity in BALF showed that the Chao1, ACE, Simpson, and Shannon values were increased, and the lung microbiome analysis revealed that the relative abundance of Firmicutes and Clostridium increased, while the relative abundance of Bacteroidetes and Akkermansia decreased. The contents of IFN-γ and IL-8 in lung tissue increased while the content of IL-10 decreased. After the administration of AAP, the alveolar structure damage was alleviated, and the interstitial hemorrhage, edema, and inflammatory cells infiltration were reduced. The Chao1 and ACE values decreased, and the taxonomic abundance values of Akkermansia were much higher. Simultaneously, the contents of IFN-γ, IL-4, and IL-8 decreased, and the content of IL-10 increased. CONCLUSIONS: It was found that PM2.5 resulted in lung microbiome disorder, which might lead to the inflammation of lung tissue. It was also revealed that AAP could alleviate the inflammatory damage of lung tissue induced by PM2.5. Int J Occup Med Environ Health. 2022;35(6):651-64.

TRAF4 Inhibits the Apoptosis and Promotes the Proliferation of Breast Cancer Cells by Inhibiting the Ubiquitination of Spindle Assembly-Associated Protein Eg5.

Tumor necrosis factor receptor associated factor 4 (TRAF4) is a RING domain E3 ubiquitin ligase that mediates the ubiquitination of various proteins and plays an important role in driving tumor progression. By studying the relationship between TRAF4 and Eg5, a member of the kinesin family that plays a critical role in spindle assembly, we demonstrated that TRAF4 regulated Eg5 ubiquitination and contributed to Eg5-mediated breast cancer proliferation and inhibited breast cancer apoptosis. TRAF4 and Eg5 were both highly expressed in breast cancer and their protein level was positively correlated. Relying on its Zinc fingers domain, TRAF4 interacted with Eg5 in the cytoplasm of breast cancer cells. TRAF4 was a mitosis-related protein, and by up-regulating the protein level of Eg5 TRAF4 participated in spindle assembly. Loss of TRAF4 resulted in monopolar spindles formation, but loss of function could be rescued by Eg5. Relying on its RING domain, TRAF4 up-regulated Eg5 protein levels by inhibition of Eg5 ubiquitination, thus stabilizing Eg5 protein level during mitosis. Furthermore, we found that Smurf2, a TRAF4-targeted ubiquitination substrate, mediated the regulation of Eg5 ubiquitination by TRAF4. TRAF4 inhibited the interaction between Smurf2 and Eg5, and down-regulated the protein level of Smurf2 by promoting its ubiquitination, thereby inhibited the Smurf2-catalyzed ubiquitination of Eg5 and up-regulated Eg5 protein levels. We also demonstrate that TRAF4 plays an important role in promoting cell proliferation and in inhibiting cell apoptosis induced by Eg5. In summary, our study suggests a new direction for investigating the role of TRAF4 in driving breast cancer progression.

[Corrigendum) RNA interference­mediated FANCF silencing sensitizes OVCAR3 ovarian cancer cells to adriamycin through increased adriamycin­induced apoptosis dependent on JNK activation.

After the publication of the article, an interested reader drew to the authors' attention that there appeared to be a pair of overlapping data panels in Fig. 4C on p. 1726 [specifically, the 'Untransfected' and 'Control shRNA' data panels for the ADM (24 h) experiments]. The authors have consulted their original data, and have realized that this figure was inadvertently assembled incorrectly. Furthermore, they have noticed that Fig. 1 on p. 1724 also contained errors that arose during its assembly; essentially, several of the data panels in Fig. 1C, showing the detection of FANCD2 focus formation via immunofluorescence experiments, were selected inappropriately. The corrected versions of Figs. 1 and 4, containing the corrected data panels for Figs. 1C and 4C respectively, are shown on the next page. Note that these errors did not affect the results or the conclusions reported in this work. The authors all agree to this Corrigendum, and are grateful to the Editor of Oncology Reports for allowing them to have the opportunity to correct these mistakes. Lastly, the authors apologize to the readership for any inconvenience these errors may have caused. [Oncology Reports 29: 1721­1729, 2013; DOI: 10.3892/or.2013.2295].

Household Water Access, Dietary Diversity and Nutritional Status among Preschoolers in Poor, Rural Areas of Central and Western China.

Poor child feeding and childhood malnutrition are major public health problems in rural central and western China, with little evidence about their environmental determinants. This study aimed to investigate whether household water access is associated with dietary diversity and nutritional outcomes. We analyzed the cross-sectional data of 3727 children aged 6 to 59 months in rural central and western China, applying multivariate linear and logistic models to estimate the effect of water access on children's anthropometric indices, hemoglobin, and dietary diversity. We found that unimproved water access was linked to a lower likelihood of achieving dietary diversity (OR = 0.65, 95% CI 0.44 to 0.98, p = 0.039); lower height-for-age z-score (ß = −0.34, 95% CI −0.49 to −0.19, p < 0.001) and hemoglobin concentration (ß = −2.78, 95% CI −5.16 to −0.41, p = 0.022); higher odds of stunting (OR = 1.50, 95% CI 1.01 to 2.25, p = 0.047) and anemia (OR = 1.34, 95% CI 1.02 to 1.77, p = 0.037). The associations between water access and nutritional outcomes were not explained by dietary diversity and were stronger in children who did not receive iron supplementation. These findings provide evidence for designing water-based nutritional interventions in China.

Ajuba Overexpression Promotes Breast Cancer Chemoresistance and Glucose Uptake through TAZ-GLUT3/Survivin Pathway.

The LIM protein Ajuba has been implicated in the development of human cancers. To date, its expression pattern and biological significance in breast cancers (BC) have not been fully investigated. In the current study, we examined Ajuba protein levels in 93 invasive ductal carcinoma specimens by immunohistochemistry. The Ajuba expression level was elevated in breast cancer tissue compared with normal tissue. Ajuba overexpression is correlated with advanced tumor-node-metastasis (TNM) stage, positive node status, and adverse patient outcomes. The Ajuba protein level was also higher in BC cell lines compared to normal breast epithelial cell line MCF-10A. Ectopically expressed Ajuba in MCF-7 cells stimulated in vitro and in vivo cell growth, invasion, cell cycle progression, and decreased paclitaxel-induced apoptosis. RNA-sequencing (RNA-seq) followed by gene set enrichment analysis (GSEA) analysis showed that Ajuba overexpression regulated the Hippo signaling pathway. Ajuba overexpression also increased glucose uptake and increased expression of TAZ, GLUT3, and Survivin. TAZ knockdown abolished the role of Ajuba on GLUT3 and Survivin induction. The ChIP assay showed that TEAD4, a major TAZ binding transcription factor, could bind to the GLUT3 and Survivin promoter regions. In conclusion, our data demonstrated that elevated Ajuba expression is correlated with poor BC prognosis and regulated malignant behavior through TAZ-GLUT3/Survivin signaling in BC cells.

Intimate Partner Violence against Women Living in Inadequate Conditions in Sub-Saharan Africa: A Meta-Analysis of Demographic and Health Survey Data.

Intimate partner violence (IPV) against women is a major public health problem and is widespread in sub-Saharan Africa (SSA). However, little is known about its environmental determinants. This study aimed to investigate whether inadequate living conditions are associated with IPV victimization in women in SSA. We analyzed cross-sectional data for 102,714 women in 25 SSA countries obtained from the Demographic and Health Surveys Program. Logistic regression was used to estimate the country-specific effects of inadequate living conditions (housing with at least one of four characteristics of unimproved water, unimproved sanitation, insufficient space, and unfinished materials) on multiple forms of IPV. Random effects meta-analysis was used to combined the country-specific estimates. We found an association between inadequate living conditions and a higher likelihood of experiencing any (OR = 1.12, 95% CI 1.03 to 1.23, p = 0.012), sexual (OR = 1.18, 95% CI 1.05 to 1.34, p = 0.008), emotional (OR = 1.12, 95% CI 1.02 to 1.23, p = 0.023), and physical (OR = 1.15, 95% CI 1.03 to 1.28, p = 0.010) IPV. The associations were stronger for rural and less-educated women. These findings suggest that future research to establish a causal link between living conditions and IPV and to elucidate the underlying pathways is crucial to design IPV interventions in SSA.

Housing environment and early childhood development in sub-Saharan Africa: A cross-sectional analysis.

BACKGROUND: The influence of the safety and security of environments on early childhood development (ECD) has been under-explored. Although housing might be linked to ECD by affecting a child's health and a parent's ability to provide adequate care, only a few studies have examined this factor. We hypothesized that housing environment is associated with ECD in sub-Saharan Africa (SSA). METHODS AND FINDINGS: From 92,433 children aged 36 to 59 months who participated in Multiple Indicator Cluster Survey (MICS) in 20 SSA countries, 88,271 were tested for cognitive and social-emotional development using the Early Childhood Development Index (ECDI) questionnaire and were thus included in this cross-sectional analysis. Children's mean age was 47.2 months, and 49.8% were girls. Children were considered developmentally on track in a certain domain if they failed no more than 1 ECDI item in that domain. In each country, we used conditional logistic regression models to estimate the association between improved housing (housing with finished building materials, improved drinking water, improved sanitation facilities, and sufficient living area) and children's cognitive and social-emotional development, accounting for contextual effects and socioeconomic factors. Estimates from each country were pooled using random-effects meta-analyses. Subgroup analyses were conducted by the child's gender, maternal education, and household wealth quintiles. On-track cognitive development was associated with improved housing (odds ratio [OR] = 1.15, 95% CI 1.06 to 1.24, p < 0.001), improved drinking water (OR = 1.07, 95% CI 1.00 to 1.14, p = 0.046), improved sanitation facilities (OR = 1.15, 95% CI 1.03 to 1.28, p = 0.014), and sufficient living area (OR = 1.06, 95% CI 1.01 to 1.10, p = 0.018). On-track social-emotional development was associated with improved housing only in girls (OR = 1.14, 95% CI 1.04 to 1.25, p = 0.006). The main limitations of this study included the cross-sectional nature of the datasets and the use of the ECDI, which lacks sensitivity to measure ECD outcomes. CONCLUSIONS: In this study, we observed that improved housing was associated with on-track cognitive development and with on-track social-emotional development in girls. These findings suggest that housing improvement in SSA may be associated not only with benefits for children's physical health but also with broader aspects of healthy child development.

Association of iron supplementation and deworming with early childhood development: analysis of Demographic and Health Surveys in ten low- and middle-income countries.

PURPOSE: We assessed the associations of iron supplementation and deworming separately or combined with improved early childhood development (ECD) status. METHODS: Cross-sectional data were analyzed for 29,729 children aged 36-59 months surveyed using the Demographic and Health Surveys in ten low- and middle-income countries, where iron supplementation and deworming are recommended by the World Health Organization. In each country, we estimated linear regression models for the effects of iron supplementation and deworming individually or combined on the Early Childhood Development Index (ECDI) z score, and whether this association differed between various ECD domains and the sex and residence of the child. Estimates were pooled using random-effects meta-analyses. RESULTS: Compared with receiving neither of the two interventions, iron supplementation plus deworming was associated with an increased ECDI z score (ß = 0.13, 95% confidence interval (CI) 0.03-0.22, p = 0.009), particularly in rural residences. However, iron supplementation and deworming, individually, were not associated with the ECDI z score. Iron supplementation plus deworming was associated with higher odds of on-track development in literacy-numeracy (OR = 1.57, 95% CI 1.24-2.01, p < 0.001) and learning domains (OR = 1.27, 95% CI 1.09-1.48, p = 0.003), but not with development in the social-emotional and physical domains. CONCLUSION: Iron supplementation plus deworming, particularly for populations who are more susceptible to iron deficiency and intestinal worm infections, could be an important intervention for improving ECD. These findings may inform the argument for the necessity of implementing iron supplementation and deworming for preschool-age children.

Association between Household Crowding and Violent Discipline and Neglect of Children: Analysis of Multiple Indicator Cluster Surveys in 26 Low- and Middle-Income Countries.

The influence of household crowding on physical and mental health has been well documented. However, research on the influence of household crowding on violent discipline and neglect of children is scarce. Therefore, we aimed to investigate whether household crowding was associated with violent discipline and neglect of children in low- and- middle-income countries (LMICs). Cross-sectional data for 280,005 and 73,030 children in 26 LMICs surveyed using the Multiple Indicator Cluster Survey were analyzed for (1) violent discipline and (2) neglect, respectively. In each country, we used logistic regression models to estimate the effects of household crowding on multiple forms of violent discipline and stimulation activities (as a proxy of the level of child neglect). Estimates were pooled using random effects meta-analyses. After adjusting for confounding variables, household crowding was associated with higher odds of any violent discipline (odds ratio (OR) = 1.09, 95% CI 1.03 to 1.15, p = 0.002) and lower odds of engaging in four or more stimulation activities (OR = 0.88, 95% CI 0.83 to 0.94, p < 0.001). The associations were stronger for urban children and children living in low- and lower-middle-income countries. The findings suggest that screenings and interventions aimed at reducing the effects of household crowding might be effective in preventing and controlling violent discipline and neglect of children in LMICs.

Prognostic Value and Influence of Receptor Conversion on Treatment Regimen in Metastatic Breast Cancer at the First Time of Recurrence.

PURPOSE: At the first time of metastatic breast cancer recurrence, conversion of the receptors status may occur between primary lesions and metastatic lesions, including the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Whether the decision of the treatment regimen is based on the primary receptor status or that of metastatic lesions is still unclear. METHODS: This study enrolled 411 female patients with a diagnosis of metastatic breast cancer at the first time of recurrence to explore the influence of receptor conversion on prognosis prediction and treatment regimen of patients with metastatic breast cancer. RESULTS: ER and PR changes from negative to positive are both prognostic factors for patients with breast cancer. Patients receiving endocrine therapy showed a better survival after recurrence than those using chemotherapy alone in the ER or PR Prim- Met+ subgroup. Patients in the HER2 Prim- Met+ subgroup using HER2-targeted therapy in multilines showed a post-recurrence survival advantage. In the bone re-biopsy subgroup, the PR change from positive to negative appeared to be more frequent than at other re-biopsy sites. CONCLUSIONS: Patients with metastatic breast cancer should perform re-biopsy to clarify the receptor status of the first metastatic lesions, which may provide clinicians valuable evidence to conduct treatments with higher precision.

TRAF4, a new substrate of SIAH1, participates in chemotherapy resistance of breast cancer cell by counteracting SIAH1-mediated downregulation of ß-catenin.

PURPOSE: TRAF4 plays an important role in the development and progression of breast cancer, but its impact on chemotherapy resistance is as yet, however, poorly understood. METHODS: Western blotting, immunoprecipitation, and immunofluorescence staining were used to identify and verify that TRAF4 was a novel substrate of SIAH1 and prevented SIAH1-mediated ß-catenin degradation. Cell proliferation analysis and Flow cytometry analysis were utilized to detect TRAF4's function on the growth-inhibitory effect of etoposide. Immunohistochemistry was used to detect the expression of TRAF4, SIAH1, and ß-catenin. Statistical analysis was used to analyze the relationships between them with clinical parameters and curative effect of chemotherapy pathologically. RESULTS: Our results suggested that TRAF4 prevents SIAH1-mediated ß-catenin degradation. TRAF4 was a novel substrate of SIAH1 and the TRAF domain of TRAF4 was critical for binding to SIAH1. TRAF4 reduced the growth-inhibitory effect of etoposide via reducing the number of S-phase cells and suppressing cell apoptosis. Concordantly, we found that breast cancer patients with a low-TRAF4 expression benefited most from chemotherapy, who had higher tumor volume reduction rate and better pathological response, while, the high-TRAF4 expression group had lower tumor volume reduction rate and poor pathological response. CONCLUSIONS: TRAF4 was a novel substrate of SIAH1 and prevented SIAH1-mediated ß-catenin degradation, which explains the protective effect of TRAF4 on ß-catenin during cell stress and links TRAF4 to chemotherapy resistance in tumors. These findings implicated a novel pathway for the oncogenic function of TRAF4.

Mixed granulosa-Sertoli sex cord-stromal tumor of the testis: clinical, ultrasonic and histopathological features: a case report.

Testicular sex cord-stromal tumors are less common in men, while mixed sex cord-stromal tumors (MSCSTs) are rarer. Recently, we found a MSCST in an adult male testis [adult granulosa cell tumor (AGCT) with Sertoli cell tumor]. He was admitted to the hospital based on "left testicular bloating and dull pain for 20 years and aggravating for 10 days". Routine examination of color Doppler ultrasound showed a size of approximately 1.09 cm × 0.79 cm in the left testis with a low echo area, clear outline, and color flow in it. The patient underwent a radical left orchiectomy to remove the tumor. Pathological results showed that the tumor was diagnosed as testicular MSCST (AGCT with Sertoli cell tumor). He was in good health after the operation and showed no signs of recurrence or metastasis after 6 months of follow-up. We summarized the clinical, ultrasonic, and histopathological characteristics of this case. And immunohistochemical staining was very important in the pathological diagnosis of testicular MSCSTs, which can distinguish different tumor types. MSCSTs were usually mixed Sertoli-Leydig cell tumors, while this case is a MSCST of AGCT with Sertoli cell tumor, which is unique from other cases. Moreover, in this case, the doctors could not clearly diagnose the tumor through pre-operative physical, ultrasonic and laboratory examinations until the postoperative pathological examination. This further reflected the importance of pathological examination in the diagnosis of such tumors.

FAM53A Affects Breast Cancer Cell Proliferation, Migration, and Invasion in a p53-Dependent Manner.

Family with sequence similarity 53-member A (FAM53A) is an uncharacterized protein with a suspected but unclear role in tumorigenesis. In this study, we examined its role in breast cancer. Immunohistochemical staining of specimens from 199 cases of breast cancer demonstrated that FAM53A levels were negatively correlated with p53 status. In the p53 wild-type breast cancer cell line MCF-7, FAM53A overexpression inhibited cell migration, invasion, and proliferation, downregulated the expression of Snail, cyclin D1, RhoA, RhoC, and MMP9, and decreased mitogen-activated protein kinase kinase (MEK) and extracellular-signal regulated kinase (ERK) phosphorylation. Concurrently, it upregulated E-cadherin and p21 expression levels. Interestingly, opposite trends were observed in the p53-null breast cancer cell line MDA-MB-231. The MEK inhibitor PD98059 reduced the biological effects of FAM53A knockdown in MCF-7 cells and FAM53A overexpression in MDA-MB-231 cells, suggesting that FAM53A affects breast cancer through the MEK-ERK pathway. Silencing TP53 in MCF-7 cells and stably expressing wild-type p53 in MDA-MB-231 cells confirmed that the effects of FAM53A signaling through the MEK/ERK pathway depended on the p53 status of the cells. These results suggest that FAM53A acts as a tumor suppressor in p53-positive breast cancer by modulating the MEK-ERK pathway, but may be a potential candidate for targeted anticancer therapies in p53-negative breast cancer.

TRIM59 overexpression correlates with poor prognosis and contributes to breast cancer progression through AKT signaling pathway.

TRIM59 has been recently implicated in the carcinogenesis of several cancers such as lung cancer, gastric cancer, and bladder cancer. However, its expression pattern and clinical significance has not been investigated in human breast cancer. In the present study, we examined TRIM59 protein expression in 95 cases of breast cancer tissues using immunohistochemistry. We found that TRIM59 was upregulated in 42 out of 95 cases and correlated with TNM stage (P = 0.0056), lymph node metastasis (P = 0.0088) and poor prognosis (P = 0.0092). Importantly, TRIM59 level was higher in triple-negative breast cancer (TNBC) (P = 0.0157). Expression of TRIM59 protein was also upregulated in breast cancer cell lines compared to normal MCF-10A cell line. TRIM59 plasmid and shRNA transfection was performed in MCF-7 and SK-BR-3 cells respectively. TRIM59 overexpression promoted cell proliferation, invasion, migration, cell cycle transition, and paclitaxel resistance, whereas TRIM59 depletion showed the opposite results. Further analysis showed that TRIM59 overexpression upregulated expression of cyclinA, cyclinE, Bcl-xl, Bcl-2, p-AKT, and downregulated expression of p21, p27, p53. AKT inhibitor treatment abolished the effect of TRIM59 on Bcl-2 expression. TRIM59 overexpression also upregulated the level of p53 ubiquitination. In conclusion, TRIM59 overexpression correlates with poor prognosis and promotes malignant behavior through regulation of AKT pathway in human breast cancer.

Prognostic impact of total and tyrosine phosphorylated GIV/Girdin in breast cancers.

Gα-interacting vesicle-associated protein (GIV, aka Girdin) is a guanine exchange factor (GEF) for the trimeric G protein Gαi and a bona fide metastasis-related gene that serves as a platform for amplification of tyrosine-based signals via G-protein intermediates. Here we present the first exploratory biomarker study conducted on a cohort of 187 patients with breast cancer to evaluate the prognostic role of total GIV (tGIV) and tyrosine phosphorylated GIV (pYGIV) across the various molecular subtypes. A Kaplan-Meier analysis of recurrence-free survival showed that the presence of tGIV, either cytoplasmic or nuclear, carried poor prognosis, but that nuclear tGIV had a greater prognostic impact (P = 0.007 in early and P = 0.0048 in late clinical stages). Activated pYGIV in the cytoplasm had the greatest prognostic impact in late clinical stages (P = 0.006). Furthermore, we found that the prognostic impacts of cytoplasmic pYGIV and nuclear tGIV were additive (hazard ratio 19.0548; P = 0.0002). Surprisingly, this additive effect of nuclear tGIV/cytoplasmic pYGIV was observed in human epidermal growth factor receptor 2-positive tumors (hazard ratio 16.918; P = 0.0005) but not in triple-negative breast cancers. In triple-negative breast cancers, tGIV and cytoplasmic pYGIV had no prognostic impact; however, membrane-association of pYGIV carried a poor prognosis (P = 0.026). Both tGIV and pYGIV showed no correlation with clinical stage, tumor size, pathologic type, lymph node involvement, and BRCA1/2 status. We conclude that immunocytochemical detection of pYGIV and tGIV can serve as an effective prognosticator. On the basis of the differential prognostic impact of tGIV/pYGIV within each molecular subtype, we propose a diagnostic algorithm. Further studies on larger cohorts are essential to rigorously assess the effectiveness and robustness of this algorithm in prognosticating outcome among patients with breast cancer.-Dunkel, Y., Diao, K., Aznar, N., Swanson, L., Liu, L., Zhu, W., Mi, X.-Y., Ghosh, P. Prognostic impact of total and tyrosine phosphorylated GIV/Girdin in breast cancers.

MiR-107 down-regulates SIAH1 expression in human breast cancer cells and silencing of miR-107 inhibits tumor growth in a nude mouse model of triple-negative breast cancer.

We have reported that SIAH1 is down-regulated and associated with apoptosis and invasion in human breast cancer. However, the molecular mechanisms leading to SIAH1 down-regulation remain to be elucidated. Here, we demonstrated that miR-107 directly down-regulates SIAH1 expression in human breast cancer cells. Over- expression of miR-107 reduced SIAH1 expression, promoted human breast cancer cell proliferation, colony formation, migration and invasion, and inhibited apoptosis. On the contrary, silencing of miR-107 increased SIAH1 expression and inhibited the tumor growth of MDA-MB-231 cells, a kind of triple-negative breast cancer (TNBC) cells, in vitro and in vivo. Our results reveal that miR-107 is an upstream regulator for SIAH1 down-regulation in human breast cancer cells and miR-107 provides a potential effective target for the treatment of TNBC.

Giant cell rich osteosarcoma of the mandible with abundant spindle cells and osteoclast-like giant cells mimicking malignancy in giant cell tumor.

Giant cell rich osteosarcoma is a relatively unusual histological form of osteosarcoma, common lesion usually presenting in the long bones of the appendicular skeleton. The occurrence in the mandible is exceptional rare. Histologically, this tumor tends to be a highly anaplastic, pleomorphic tumor in which the tumor cells may be: plasmacytoid, fusiform, ovoid, small round cells, clear cells, mono-or multinucleated giant cells, or, spindle cells. Herein, we present a case with the sternum and first thoracic vertebra metastasis from primary giant cell rich osteosarcoma of the mandible in a 28 year-old Chinese female. The tumor was predominantly composed of abundant spindle cells with marked atypia and numerous osteoclast-like giant cells reminiscent of malignancy in giant cell tumor. The unusual histological appearance can pose a great diagnostic challenge. It may be easily misdiagnosed, especially if the specimen is limited or from fine-needle aspiration.

Expression, correlation, and prognostic value of TRAF2 and TRAF4 expression in malignant plural effusion cells in human breast cancer.

BACKGROUND: TRAF2 and TRAF4, members of the tumor necrosis factor receptor- associated factor family of intracellular signal transduction proteins, are associated with breast cancer progression and metastasis. METHODS: We collected malignant serous effusion cells from the patients with breast cancer (n = 46). Cell blocks prepared from plural effusions (n = 46) and primary breast cancer (n = 50), lymph node metastases (n = 50), and normal breast tissue specimens (n = 30). The immunohistochemistry was performed for the detection of TRAF2 and TRAF4 expression with the correlation of their expression with clinicopathological parameters and survival rate analyzed. RESULTS: Compared with normal breast tissues, TRAF2 expression was upregulated, and nuclear TRAF4 expression was downregulated in malignant pleural effusion cells, primary tumors, and lymph node metastases (P < 0.05). Multivariate analysis revealed TRAF2 expression in pleural effusions was associated with the molecular/pathological type, venous invasion, and lymph node metastasis, while nuclear TRAF4 expression was associated with age, tumor size, venous invasion, and lymph node metastasis, clinical staging, molecular/pathological subtype and p53 status (P < 0.05). There was a significant positive correlation between TRAF2 and TRAF4 expression levels in malignant pleural effusion cells (r = 0.937; P < 0.01). Kaplan-Meire analysis demonstrated a close correlation of TRAF2 and TRAF4 expression in malignant pleural effusion cells with cumulative overall survival (P < 0.05). CONCLUSION: TRAF2 and nuclear TRAF4 expression in malignant pleural effusion cells may represent potential prognostic factors and biomarkers of invasion and metastasis in breast cancer.

The Hedgehog signalling pathway mediates drug response of MCF-7 mammosphere cells in breast cancer patients.

BCSCs (breast cancer stem cells) have been shown to be resistant to chemotherapy. However, the mechanisms underlying BCSC-mediated chemoresistance remain poorly understood. The Hh (Hedgehog) pathway is important in the stemness maintenance of CSCs. Nonetheless, it is unknown whether the Hh pathway is involved in BCSC-mediated chemoresistance. In the present study, we cultured breast cancer MCF-7 cells in suspension in serum-free medium to obtain BCSC-enriched MCF-7 MS (MCF-7 mammosphere) cells. We showed that MCF-7 MS cells are sensitive to salinomycin, but not paclitaxel, distinct from parent MCF-7 cells. The expression of the critical components of Hh pathway, i.e., PTCH (Patched), SMO (Smoothened), Gli1 and Gli2, was significantly up-regulated in MCF-7 MS cells; salinomycin, but not paclitaxel, treatment caused a remarkable decrease in expression of those genes in MCF-7 MS cells, but not in MCF-7 cells. Salinomycin, but not paclitaxel, increased apoptosis, decreased the migration capacity of MCF-7 MS cells, accompanied by a decreased expression of c-Myc, Bcl-2 and Snail, the target genes of the Hh pathway. The salinomycin-induced cytotoxic effect could be blocked by Shh (Sonic Hedgehog)-mediated Hh signalling activation. Inhibition of the Hh pathway by cyclopamine could sensitize MCF-7 MS cells to paclitaxel. In addition, salinomycin, but not paclitaxel, significantly reduced the tumour growth, accompanied by decreased expression of PTCH, SMO, Gli1 and Gli2 in xenograft tumours. Furthermore, the expression of SMO and Gli1 was positively correlated with the expression of CD44+ / CD24-, and the expression of SMO and Gli1 in CD44+ / CD24- tissues was associated with a significantly shorter OS (overall survival) and DFS (disease-free survival) in breast cancer patients receiving chemotherapy.

Cytoplasmic TRAF4 contributes to the activation of p70s6k signaling pathway in breast cancer.

Tumor necrosis factor receptor associated factor 4 (TRAF4) is an important adaptor protein that plays a significant role in several signaling pathways. By studying the relationship between TRAF4 and 70 kDa ribosomal protein S6 kinase (p70s6k) in vivo, we demonstrated that cytoplasmic TRAF4 was correlated with the activation of p70s6k in breast cancer. Moreover, we found that cytoplasmic TRAF4 expression in breast cancer patients was significantly associated with a poor prognosis. To determine the exact mechanism, we analyzed the interaction between TRAF4 and p70s6k and identified the Zinc fingers domain of TRAF4 was responsible for their interaction in MCF7 cells. Furthermore, we found that activation of p70s6k/S6 signaling pathway by TRAF4 requires the mammalian target of rapamycin (mTOR) activity; TRAF4 acted as a sensitizer. Tumor necrosis factor receptor associated factor 2 (TRAF2), as a binding partner of TRAF4, could also promoted activation of p70s6k signaling via upregulating cytoplasm expression of TRAF4 and played a critical role in TNFa-induced activation of p70s6k/S6 pathway. Finally, we demonstrated p70s6k/S6 signaling pathway played an important role in the promoting function of TRAF4 on cell proliferation. In summary, our work suggests a new direction for understanding the oncogenic function of TRAF4 in breast cancer.