Identification of cell-specific epigenetic patterns associated with chondroitin sulfate treatment response in an endemic arthritis, Kashin-Beck disease.

Aims: To assess the alterations in cell-specific DNA methylation associated with chondroitin sulphate response using peripheral blood collected from Kashin-Beck disease (KBD) patients before initiation of chondroitin sulphate treatment. Methods: Peripheral blood samples were collected from KBD patients at baseline of chondroitin sulphate treatment. Methylation profiles were generated using reduced representation bisulphite sequencing (RRBS) from peripheral blood. Differentially methylated regions (DMRs) were identified using MethylKit, while DMR-related genes were defined as those annotated to the gene body or 2.2-kilobase upstream regions of DMRs. Selected DMR-related genes were further validated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) to assess expression levels. Tensor composition analysis was performed to identify cell-specific differential DNA methylation from bulk tissue. Results: This study revealed 21,060 hypermethylated and 44,472 hypomethylated DMRs, and 13,194 hypermethylated and 22,448 hypomethylated CpG islands for differential global methylation for chondroitin sulphate treatment response. A total of 12,666 DMR-related genes containing DMRs were identified in their promoter regions, such as CHL1 (false discovery rate (FDR) = 2.11 × 10-11), RIC8A (FDR = 7.05 × 10-4), and SOX12 (FDR = 1.43 × 10-3). Additionally, RIC8A and CHL1 were hypermethylated in responders, while SOX12 was hypomethylated in responders, all showing decreased gene expression. The patterns of cell-specific differential global methylation associated with chondroitin sulphate response were observed. Specifically, we found that DMRs located in TESPA1 and ATP11A exhibited differential DNA methylation between responders and non-responders in granulocytes, monocytes, and B cells. Conclusion: Our study identified cell-specific changes in DNA methylation associated with chondroitin sulphate response in KBD patients.

Pilot analysis of tire tread characteristics and associated tire-wear particles in vehicles produced across distinct time periods.

Owing to stringent vehicle emission regulations and the shifting automotive landscape towards clean-energy vehicles, the emission of non-exhaust tire-wear particles and its implications for microplastic contamination have garnered substantial attention, emerging as a focal point of research interest. Unlike traditional source apportionment methods involving direct environmental sampling, this study focuses on the physical and chemical attributes of tire treads, the tread temperature changes, and the tire-wear particle emissions of three light-duty vehicles manufactured between 2011 and 2021. This study advances the understanding of the effects of tire properties on particle emissions, which provides preliminary information on low-wear tires. The results show that tire-wear particle emissions, mainly composed of ultrafine particles in terms of number, heavily depend on the elevated tread temperatures. The change in tread temperature is influenced not only by the initial tread temperature but also by tread pyrolysis characteristics. Ca, Mg, and Zn are abundantly contained in the tire tread and tire-wear particles.

Investigating the causal associations between five anthropometric indicators and nonalcoholic fatty liver disease: Mendelian randomization study.

BACKGROUND: Although the etiology of nonalcoholic fatty liver disease (NAFLD) has not been thoroughly understood, the emerging roles of anthropometric indicators in assessing and predicting the risk of NAFLD have been highlighted by accumulating evidence. AIM: To evaluate the causal relationships between five anthropometric indicators and NAFLD employing Mendelian randomization (MR) design. METHODS: The Anthropometric Consortium provided genetic exposure data for five anthropometric indicators, including hip circumference (HC), waist circumference (WC), waist-to-hip ratio (WHR), body mass index (BMI), and body fat percentage (BF). Genetic outcome data for NAFLD were obtained from the United Kingdom Biobank and FinnGen Consortium. Genome-wide significant single nucleotide polymorphisms were chosen as instrumental variables. Univariable MR (UVMR) and multivariable MR (MVMR) designs with analytical approaches, including inverse variance weighted (IVW), MR-Egger, weighted median (WM), and weighted mode methods, were used to assess the causal relationships between anthropometric indicators and NAFLD. RESULTS: Causal relationships were revealed by UVMR, indicating that a higher risk of NAFLD was associated with a per-unit increase in WC [IVW: odds ratio (OR) = 2.67, 95%CI: 1.42-5.02, P = 2.25 × 10-3], and BF was causally associated with an increased risk of NAFLD (WM: OR = 2.23, 95%CI: 1.07-4.66, P = 0.033). The presence of causal effects of WC on the decreased risk of NAFLD was supported by MVMR after adjusting for BMI and smoking. However, no causal association between BF and NAFLD was observed. In addition, other causal relationships of HC, WHR (BMI adjusted), and BMI with the risk of NAFLD were not retained after FDR correction. CONCLUSION: This study establishes a causal relationship, indicating that an increase in WC is associated with a higher risk of NAFLD. This demonstrates that a suitable decrease in WC is advantageous for preventing NAFLD.

Real-world data on neoadjuvant chemotherapy with dual-anti HER2 therapy in HER2 positive breast cancer.

BACKGROUND: Neoadjuvant chemotherapy with dual-targeted therapy is the standard treatment for human epidermal growth factor 2 (HER2)-positive breast cancer. Although the dual-targeted therapy has significantly improved the pathological complete response (pCR) rate, further investigation is needed to identify biomarkers that predict the response to neoadjuvant therapy. METHODS: This retrospective study analyzed 353 patients with HER2-positive breast invasive ductal carcinoma. The correlation between clinicopathological factors and pCR rate was evaluated. A nomogram was constructed based on the results of the multivariate logistic regression analysis to predict the probability of pCR. RESULTS: The breast pCR (b-pCR) rate was 56.1% (198/353) and the total pCR (t-pCR) rate was 52.7% (186/353). Multivariate analysis identified ER status, PR status, HER2 status, Ki-67 index, and neoadjuvant chemotherapy regimens as independent indicators for both b-pCR and t-pCR. The nomogram had an area under the receiver operating characteristic curve (AUC) of 0.73 (95% CI: 0.68-0.78). According to the nomogram, the t- pCR rate was highest in the ER-PR- HER2-positive patients (131/208) and lowest in the ER + PR + HER2-positive patients (19/73). The subgroup analyses showed that there was no significant difference in pCR rate among the neoadjuvant chemotherapy regimens in ER positive, PR positive, HER2 IHC 2 + , Ki67 index < 30% population. However, for ER-PR-HER2-positive patients, the neoadjuvant chemotherapy regimen has a great influence on the pCR rates. CONCLUSIONS: Patients with ER-negative, PR-negative, HER2 3 + and high KI-67 index were more likely to achieve pCR. THP may be used as an alternative to AC-THP or TCbHP in selected HER2-positive patients.

Breast adipose metabolites mediates the association of tetrabromobisphenol a with breast cancer: A case-control study in Chinese population.

Studies exploring the association of tetrabromobisphenol A (TBBPA) with breast cancer and related mechanisms are limited. To investigate the relationship between TBBPA levels in breast adipose and breast cancer, we carried out case-control research. As well as further examine the mediating role of adipose metabolites between TBBPA and breast cancer using the metabolomics approach. In this study, the concentration of TBBPA was determined utilizing ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) after a solid phase extraction (SPE) pretreatment. High-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) was employed to analyze adipose metabolomics. Evaluation of metabolites linked to TBBPA exposure and breast cancer was performed utilizing mediation analysis. With an estimated OR (95%CI) of 1.153 (1.023, 1.299), TBBPA was firmly linked with breast cancer. We also used propensity score matching analysis and sensitivity analysis to reduce the effect of confounding factors on the results. Metabolomics of adipose suggested significant perturbation in the linoleic acid metabolism pathway. In addition, for PC (16:0/16:0) as phospholipids, a mediation effect on the associations of TBBPA exposure with breast cancer risks was observed (estimated mediation percentage: 56.58%). Understanding the relationship between TBBPA exposure and the risk of breast cancer may be facilitated by the findings, which point to potential mediation metabolites.

The regrouping of Luminal B (HER2 negative), a better discriminator of outcome and recurrence score.

BACKGROUND: Breast cancer (BC) remains the leading cause of cancer-related deaths worldwide. High recurrence risk Luminal BC receives adjuvant chemotherapy in addition to standard hormone therapy. Considering the heterogeneity of Luminal B BC, a more accurate classification model is urgently needed. METHODS: In this study, we retrospectively reviewed the data of 1603 patients who were diagnosed with HER2-negative breast invasive ductal carcinoma. According to the expression level of PR and Ki-67 index, the Luminal B (HER2-negative) BCs were divided into three groups: ER+PR-Ki67low (ER-positive, PR-negative, and Ki-67 index <20%), ER+PR+Ki67high (ER-positive, PR-positive, and Ki-67 index ≥20%), and ER+PR-Ki67high (ER-positive, PR-negative, and Ki-67 index ≥20%). The cox proportional hazards regression model was used to evaluate the correlation between each variable and outcomes. Besides, discriminatory accuracy of the models was compared using the area under the receiver operating characteristic curve and log-rank χ2 value. RESULTS: The analysis results showed that there was a significant correlation between subtypes using this newly defined classification and overall survival (p < 0.001) and disease-free survival (DFS) (p < 0.001). Interestingly, patients in the ER+PR-Ki67high subgroup have the worst survival outcome in Luminal B (HER2-negative) subtype, similar to Triple-negative patients. Besides, the ER+PR+Ki67high has worse 5-year DFS compared with Luminal A group. There was a significant relationship between the regrouping subtype and the recurrence score index (RI) (p < 0.001). Moreover, the results showed that patients in ER+PR-Ki67high subtype were more likely to have high RI for distance recurrence (RI-DR) and local recurrence (RI-LRR). Our newly defined classification has a better discrimination ability to predict survival outcome and recurrence score of Luminal B (HER2-negative) BC patients, which may help in clinical decision-making for individual treatment.

Perfluoroalkyl substances (PFASs) as risk factors for breast cancer: a case-control study in Chinese population.

BACKGROUND: Perfluoroalkyl substances (PFASs) are a large family of synthetic chemicals, some of which are mammary toxicants and endocrine disruptors. Recent studies have implicated exposure to PFASs as a risk factor for breast cancer in Europe and America. Little is known about the role of PFASs with respect to breast cancer in the Chinese population. METHODS: Participants who were initially diagnosed with breast cancer at Tianjin Medical University Cancer Institute and Hospital between 2012 and 2016 were recruited as cases. The controls were randomly selected from the participants with available blood samples in the Chinese National Breast Cancer Screening Program (CNBCSP) cohort. Ultimately, we enrolled 373 breast cancer patients and 657 controls. Plasma PFASs were measured by an ultra-performance liquid chromatography (UPLC) system coupled to a 5500 Q-Trap triple quadrupole mass spectrometer. A logistic regression model with least absolute shrinkage and selection operator (LASSO) regularization was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the relationships between PFASs and breast cancer. The three most predictive variables in the LASSO model were selected from 17 PFASs, which was based on the optimal penalty coefficient (λ = 0.0218) identified with the minimum criterion. Additionally, Bayesian kernel machine regression (BKMR) and quantile g-computation models were applied to evaluate the associations between separate and mixed exposure to PFASs and breast cancer. RESULTS: Perfluorooctanesulfonic acid (PFOS) exhibited the highest concentration in both the cases and controls. Perfluorooctanoic acid (PFOA) and perfluoro-n-decanoic acid (PFDA) were positively associated with breast cancer, and perfluoro-n-tridecanoic acid (PFTrDA) was negatively associated with breast cancer according to both the continuous-PFASs and the quartile-PFASs logistic regression models. Of note, PFOA was associated with the occurrence of estrogen receptor (ER)-, progesterone receptor (PR)-, and human epidermal growth factor receptor 2 (HER2)-positive breast cancer (ORER+ = 1.47, 95% CI: 1.19, 1.80; ORPR+ = 1.36, 95% CI: 1.09, 1.69; ORHER2 = 1.62, 95% CI: 1.19, 2.21). CONCLUSIONS: Overall, we observed that PFASs were associated with breast cancer in Chinese women. Prospective cohort studies and mechanistic experiments are warranted to elucidate whether these associations are causal.

Breast microbiome associations with breast tumor characteristics and neoadjuvant chemotherapy: A case-control study.

Background: Commensal microbiota have been proven to colonize the mammary gland, but whether their composition is altered in patients with breast cancer (BC) remains elusive. This study intends to explore the breast microbiome differences between benign and malignant diseases and to investigate the impact of neoadjuvant chemotherapy (NAC) on the breast microbiota in patients with BC. Methods: Breast normal adipose tissues (NATs) were collected from 79 patients with BC and 15 controls between July 2019 and November 2021. The BC group consisted of 29 patients who had received NAC and 50 who were non-NAC patients. Participants diagnosed with benign breast disease were recruited as controls. 16S rRNA gene sequencing was used to analyze the bacterial diversity of NATs. Results: The community structure of the NAT microbiome was significantly different between the BC and control groups. Proteobacteria decreased (47.40% versus 39.74%), whereas Firmicutes increased (15.71% versus 25.33%) in patients with BC when compared with that in control tissues. Nine genera were enriched in BC NATs, and four genera levels increased in the control group. The associations between differential bacterial genera and breast tumor grade were calculated by Spearman's correlation. The results showed that tumor grade was positively associated with the relative abundance of Streptococcus and negatively related to Vibrio, Pseudoalteromonas, RB41, and Photobacterium. Moreover, menopause was associated with the microbiota composition change of non-NAC BC patients and related to the significant reduction in the abundance level of Pseudoalteromonas, Veillonella, and Alcaligenes. In addition, NAC was related to the beta diversity of patients with BC and associated with the decrease of Clostridium_sensu_stricto_7 and Clostridium_sensu_stricto_2 in postmenopausal patients. Of note, Tax4Fun functional prediction analysis revealed that the metabolic state was more exuberant in the BC group with upregulating of multiple metabolism-related pathways. Conclusion: Our results offer new insight into the relationship between NAC and breast microbiota and help to better characterize the breast microbial dysbiosis that occurs in patients with BC. Further epidemiological studies with larger sample size and well-designed animal experiments are required to elucidate the role of breast microbiota in the therapeutic outcome of BC.

China 6 moving average window method for real driving emission evaluation: Challenges, causes, and impacts.

The light-duty moving average window (MAW) method, used for China 6 real driving emission (RDE) calculation, is quite complex with various boundaries. Previous research noticed that the MAW might underestimate the calculation results, while the reasons for this underestimation haven't been studied systematically. With 29 vehicles tested in 10 cities and different boundaries applied for calculation, this study quantitively analyzed the problem, causes, and impacts of the light-duty MAW method. The instantaneous utilization factor (IUF) is proposed for reason analysis. The current MAW method could weaken the supervision of real driving tests as more than 75% of the tests underestimated MAW results, with the largest underestimation being around 100%. The data exclusion could lead to biased MAW results. But without the exclusion, the MAW result couldn't always get an increase due to the IUF and window weighting factor variation. With the extended factors removed, the MAW result bias is significantly reduced. The MAW will lead to a lower IUF of the data at the start/end of the tests, and when the cold-start data is considered, this low utilization must be noticed. The effect from the data exclusion, extended factors, and the window characteristics are closely coupled and they should be taken into consideration simultaneously to consummate the calculation method. The current drift-check progress couldn't effectively monitor the portable emission measurement system (PEMS), especially during the tests. The MAW result might lead to unreasonable emission limits and the emission inventory. Relevant policy based on these results might be implausible.

Particle number emissions from fully warmed gasoline vehicles at various ambient temperatures.

Road vehicles have become the primary source of fine particles in many large cities. Vehicle hot-start PN emissions at various ambient temperatures were studied previously. Still, these studies used the same rolling resistance setting at different ambient temperatures and the tests at various ambient temperatures have similar PN emissions. Vehicles get larger resistance at cold ambient temperatures, so this experimental setting (same resistance at various ambient temperatures) is beyond the natural conditions. To evaluate how ambient temperatures affect the PN emissions from fully warmed vehicles, two vehicles were tested at four ambient temperatures: -10 °C, 0 °C, 23 °C, and 40 °C. Vehicle resistance variations under different ambient temperatures were taken into consideration. The observed results proved that PN emission would significantly deteriorate under cold conditions even when the vehicles are thoroughly warmed. The PN emission factor at -10 °C could be six times higher than at 23 °C. The deteriorated PN emission is caused by enhanced fuel enrichment and GPF regeneration, and larger vehicle resistance under cold ambient temperatures is the underlying reason for the increased PN emission. For the first time, this study proved that PN emission from fully warmed vehicles would significantly deteriorate when the ambient temperature decreases. The results could be used for emission models, inventory, and regulations.

The role of surgery on locoregional treatment of patients with breast cancer newly diagnosed with ipsilateral supraclavicular lymph node metastasis.

Background: Radiotherapy is a practical locoregional treatment approach for women with breast cancer who show ipsilateral supraclavicular lymph node metastasis (ISLNM) on diagnosis. However, there is controversy around the role of supraclavicular lymph node dissection. Therefore, we aimed to study the significance of supraclavicular surgery based on radiotherapy. Patients and Methods: We retrospectively reviewed the data of 142 patients with breast cancer who presented with isolated ISLNM and received radiotherapy between the years 2000 and 2016. We also defined the effect of surgery on locoregional treatment of these patients by analyzing the prognostic factors for recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). Results: We observed that, of the 142 patients, 104 who received radiotherapy underwent supraclavicular lymph node dissection. Also, among the study group, the progesterone receptor (PR) status (P = 0.044) and the number of axillary lymph nodes (ALNs) involved (P = 0.002) were significant independent predictors of RFS. Also, tumor size (P = 0.007), PR (P < 0.001), and number of ALNs (P < 0.001) were independent predictors of DMFS and were statistically significant. Also, PR was an independent prognostic factor of OS (P = 0.033), whereas the supraclavicular surgery was not an independent prognostic factor for RFS, DMFS, and OS. Furthermore, our study focused on 92 patients with negative estrogen receptors (ERs). The result showed that supraclavicular surgery was statistically significant for RFS (P = 0.023); no significant differences in DMFS and OS were found between patients who received supraclavicular surgery and those who did not. Conclusion: Radiotherapy may be the primary locoregional treatment approach for patients with breast cancer who present with newly diagnosed ISLNM. Additionally, supraclavicular surgery may be more appropriate for patients with negative ER who received radiotherapy.

Developing Hybrid Machine Learning Models to Determine the Dynamic Modulus (E*) of Asphalt Mixtures Using Parameters in Witczak 1-40D Model: A Comparative Study.

To characterize the dynamic modulus (E*) of the asphalt mixtures more accurately, a comparative study was shown in this paper, combining six ML models (BP, SVM, DT, RF, KNN, and LR) with the novelly developed MBAS (modified BAS, beetle antennae search) algorithm to check the potential to replace the empirical model. The hyperparameter tuning process of the six ML models by the proposed MBAS algorithm showed satisfactory results. The calculation and evaluation process demonstrated fast convergence and significantly lower values of RMSE for the five ML models (BP, SVM, DT, RF, and KNN) to determine the E* of the asphalt mixtures. Comparing the performances of the six ML models in the prediction of the E* by the statistical coefficients and Monte Carlo simulation, the RF model showed the highest accuracy, efficiency, and robustness.

Assessment of ethanol blended fuels for gasoline vehicles in China: Fuel economy, regulated gaseous pollutants and particulate matter.

The government of China has announced an ambitious plan to expand the mandatory use of ethanol blended gasoline fuels by 2020. Given the dissimilarity in fuel properties between China and other countries with ethanol blending practices, it is necessary to assess the energy and environmental impacts of ethanol blending. In this study, we prepared two types of ethanol blended fuels (E10, with ethanol contents of approximately 10%) with lower contents of aromatics (ELA) and olefins (ELO), respectively, compared with the market China 5 gasoline. Nine in-use gasoline vehicles varying by manufacturer, engine technology, model year, and emission standard level were analyzed using a chassis dynamometer, which followed the Worldwide Harmonized Light Vehicles Test Cycle (WLTC). Two major positive effects from using E10 fuels could be observed in this study. First, tested turbocharged gasoline direct injection (GDI) vehicles could gain reductions in CO2 emission, fuel consumption and energy consumption by switching to the higher-octane-number ELO. This finding, along with the engine development trends in the automotive industry (e.g., downsizing and higher compression ratio), may have a synergistic effect to deliver greater energy efficiency in the future. Second, the two ethanol blended fuels could be more effective in reducing the particle mass (PM) and particle number (PN) emissions than the levels of using China 5 gasoline. Notably, the benefit of using ELO was more significant, with average emission reductions of 35% for the PM and of 44% for the PN. However, ELA and ELO possibly increased emissions of gaseous pollutants for certain vehicles in the study, but the intra-vehicle differences between the various fuel groups were not statistically significant (not significant, p > 0.05, t-test). We suggest that more measurements under various environmental conditions and comprehensive air quality simulations should be conducted to better understand the environmental impacts of ethanol blending in China.

A mathematical prediction model incorporating molecular subtype for risk of non-sentinel lymph node metastasis in sentinel lymph node-positive breast cancer patients: a retrospective analysis and nomogram development.

BACKGROUND: Molecular subtype of breast cancer is associated with sentinel lymph node status. We sought to establish a mathematical prediction model that included breast cancer molecular subtype for risk of positive non-sentinel lymph nodes in breast cancer patients with sentinel lymph node metastasis and further validate the model in a separate validation cohort. METHODS: We reviewed the clinicopathologic data of breast cancer patients with sentinel lymph node metastasis who underwent axillary lymph node dissection between June 16, 2014 and November 16, 2017 at our hospital. Sentinel lymph node biopsy was performed and patients with pathologically proven sentinel lymph node metastasis underwent axillary lymph node dissection. Independent risks for non-sentinel lymph node metastasis were assessed in a training cohort by multivariate analysis and incorporated into a mathematical prediction model. The model was further validated in a separate validation cohort, and a nomogram was developed and evaluated for diagnostic performance in predicting the risk of non-sentinel lymph node metastasis. Moreover, we assessed the performance of five different models in predicting non-sentinel lymph node metastasis in training cohort. RESULTS: Totally, 495 cases were eligible for the study, including 291 patients in the training cohort and 204 in the validation cohort. Non-sentinel lymph node metastasis was observed in 33.3% (97/291) patients in the training cohort. The AUC of MSKCC, Tenon, MDA, Ljubljana, and Louisville models in training cohort were 0.7613, 0.7142, 0.7076, 0.7483, and 0.671, respectively. Multivariate regression analysis indicated that tumor size (OR = 1.439; 95% CI 1.025-2.021; P = 0.036), sentinel lymph node macro-metastasis versus micro-metastasis (OR = 5.063; 95% CI 1.111-23.074; P = 0.036), the number of positive sentinel lymph nodes (OR = 2.583, 95% CI 1.714-3.892; P < 0.001), and the number of negative sentinel lymph nodes (OR = 0.686, 95% CI 0.575-0.817; P < 0.001) were independent statistically significant predictors of non-sentinel lymph node metastasis. Furthermore, luminal B (OR = 3.311, 95% CI 1.593-6.884; P = 0.001) and HER2 overexpression (OR = 4.308, 95% CI 1.097-16.912; P = 0.036) were independent and statistically significant predictor of non-sentinel lymph node metastasis versus luminal A. A regression model based on the results of multivariate analysis was established to predict the risk of non-sentinel lymph node metastasis, which had an AUC of 0.8188. The model was validated in the validation cohort and showed excellent diagnostic performance. CONCLUSIONS: The mathematical prediction model that incorporates five variables including breast cancer molecular subtype demonstrates excellent diagnostic performance in assessing the risk of non-sentinel lymph node metastasis in sentinel lymph node-positive patients. The prediction model could be of help surgeons in evaluating the risk of non-sentinel lymph node involvement for breast cancer patients; however, the model requires further validation in prospective studies.

miR-190 suppresses breast cancer metastasis by regulation of TGF-ß-induced epithelial-mesenchymal transition.

BACKGROUND: Breast cancer is the most common cancer among women worldwide and metastasis is the leading cause of death among patients with breast cancer. The transforming growth factor-ß (TGF-ß) pathway plays critical roles during breast cancer epithelial-mesenchymal transition (EMT) and metastasis. SMAD2, a positive regulator of TGF-ß signaling, promotes breast cancer metastasis through induction of EMT. METHODS: The expression of miR-190 and SMAD2 in breast cancer tissues, adjacent normal breast tissues and cell lines were determined by RT-qPCR. The protein expression levels and localization were analyzed by western blotting and immunofluorescence. ChIP and dual-luciferase report assays were used to validate the regulation of ZEB1-miR-190-SMAD2 axis. The effect of miR-190 on breast cancer progression was investigated both in vitro and in vivo. RESULTS: miR-190 down-regulation is required for TGF-ß-induced EMT. miR-190 suppresses breast cancer metastasis both in vitro and in vivo by targeting SMAD2. miR-190 expression is down-regulated and inversely correlates with SMAD2 in breast cancer samples, and its expression level was associated with outcome in patients with breast cancer. Furthermore, miR-190 is transcriptionally regulated by ZEB1. CONCLUSIONS: Our data uncover the ZEB1-miR-190-SMAD2 axis and provide a mechanism to explain the TGF-ß network in breast cancer metastasis.

The combined pN stage and breast cancer subtypes in breast cancer: a better discriminator of outcome can be used to refine the 8th AJCC staging manual.

BACKGROUND: pN stage and breast cancer subtypes (BCS) are both well-recognized prognostic indicators. Our previous work has highlighted that patients even with the same pN stage exhibited a significant survival difference in different BCS. Given this achievement, we hypothesized that a statistical interaction might exist between pN stage and BCS. The aim of this retrospective cohort study was to compare the prognostic value of the combined pN stage and BCS (pNnew stage) with either pN stage or BCS alone, and to determine if this combined new stage could serve as an alternative discriminator of outcome. METHODS: We combined pN stage and BCS to create a new variable named pNnew stage and then divided it into four groups: pN0new, pN1new, pN2new, and pN3new. Survival analysis was performed with the use of the Kaplan-Meier method and the log-rank test was used for univariate analysis. For multivariate analysis, cox proportional hazard models were applied, allowing for the estimation of disease-free survival (DFS). To assess discriminatory accuracy of the models, we compared the area under the receiver-operating characteristic curve (AUROC), the Akaike information criterion (AIC), and the Bayesian information criterion (BIC) values. Then, we used this pNnew stage to generate a TNnewM staging system according to the 7th AJCC staging system. RESULTS: A statistical interaction between pN stage and BCS was found. In multivariate survival analysis, the pNnew stage has been confirmed as an independent prognostic variable of 5-year DFS. The pNnew stage, with a smaller AIC or BIC value and larger AUROC, was a more powerful predictor of DFS than either pN stage or BCS alone. Results were validated in a separate cohort of patients. The TNnewM stage proposed in our present study was found comparable to the new 8th AJCC edition which includes anatomic T, N, and M plus tumor grade and the status of the biomarkers Her-2, ER, and PR with respect to prognostic value for breast cancer patients. CONCLUSIONS: The pNnew stage (combined pN stage and BCS) appears to be a more powerful predictor and discriminator for the outcome of breast cancer, as compared to pN stage or BCS alone, and the TNnewM stage may serve as a simple, easy-to-use alternative to the 8th AJCC edition staging manual.

Endoscopic sentinel lymph node biopsy and endoscopic axillary lymphadenectomy without liposuction in patients with early stage breast cancer.

BACKGROUND: Our purpose was to present a new method of endoscopic sentinel lymph node biopsy (ESLNB) and endoscopic axillary lymphadenectomy (EALND) without liposuction for treating early-stage breast cancer, and compare results with traditional open dissection. METHODS: The medical records of patients with early-stage breast cancer who underwent EALND/ESLNB without liposuction or traditional open dissection between March 2015 and September 2016 were retrospectively reviewed. Outcomes between the 2 groups were compared. RESULTS: A total 65 patients with a mean age of 41.2 ± 9.3 years (range, 23-60 years) were included. Thirty-three patients underwent traditional open lymph node dissection and 32 patients underwent endoscopic treatment. The 2 groups were similar with respect to age, body mass index (BMI), menopausal status, tumor location, and tumor disease stage (all, p > 0.05). The mean operating time was significantly higher in the endoscopic group (91.2 vs. 75.2 min, p = 0.022), while the mean blood loss was significantly lower (28.7 vs. 37.0 ml, p = 0.034). The mean number of SLNs harvested in the open (2.4 ± 1.6) and the endoscopic (2.3 ± 1.4) groups were not different (p = 0.829), with a sentinel lymph node retrieval rate of 80%. The mean number of axillary lymph nodes harvested in the open (13.8 ± 3.3) and the endoscopic (13.3 ± 3.1) groups were not different (p = 0.457). Scars were minimal in the endoscopic group. CONCLUSION: ESLNB and EALND without liposuction for early-stage breast cancer is feasible, has a low complication rate, a lymph node harvest rate similar to that of open dissection, and has good cosmetic results. Future studies, however, are required to evaluate oncological outcomes.

Clinicopathological characteristics and prognosis of metaplastic carcinoma of the breast.

Metaplastic carcinoma of the breast (MBC) is a rare and heterogeneous type of neoplasm. Knowledge about its clinical characteristics, prognostic significance and optimal treatment modalities is fragmentary and controversial. The present retrospective study aimed to investigate the prognostic value of the clinicopathological features and different therapeutic strategies in MBC. For this purpose, the medical records of 69 MBC patients subjected to surgical resection for MBC at the Tianjin Medical University Cancer Institute and Hospital (Tianjin, China) were reviewed. A total of 69 MBC cases were followed up for 9-139 months. The 5-year disease-free survival (DFS) rate was 52.2% and the overall survival (OS) rate was 60.2%. Survival analysis revealed that large tumor size and lymph node (LN) metastases were correlated with shortened 5-year DFS and OS rates. In addition, chemotherapy significantly improved the prognosis of patients with LN metastasis, while radiation therapy (RT) significantly improved the 5-year OS and DFS rates of MBC patients with tumors ≥5 cm or with >4 metastatic LNs. In conclusion, MBC is a clinically aggressive subtype of breast cancer associated with a large tumor size. Chemotherapy may be recommended for certain subtypes of MBC with LN positivity, and RT may be a component of multimodality therapy for some MBC patients.

Downregulation of delta-aminolevulinate dehydratase is associated with poor prognosis in patients with breast cancer.

Delta-aminolevulinate dehydratase (ALAD) catalyzes the second step in the biosynthesis of heme and is also an endogenous inhibitor of the 26S proteasome. The role of ALAD in breast cancer progression is still unclear. In this study, we found that the expression of ALAD was downregulated in breast cancer tissues compared with adjacent normal breast tissues. Enhanced ALAD expression was associated with a favorable outcome in patients with breast cancer. Overexpression of ALAD suppresses breast cancer cell proliferation and invasion and inhibits the epithelial-mesenchymal transition phenotype. Furthermore, we found that ALAD regulates transforming growth factor-ß-mediated breast cancer progression. This finding suggests that ALAD might be a potential biomarker for breast cancer that suppresses breast cancer progression by regulating transforming growth factor-ß-mediated epithelial-mesenchymal transition.

The prognostic value of node status in different breast cancer subtypes.

Nodal metastases and breast cancer subtypes (BCS) are both well-recognized prognostic indicators. However, the association between nodal metastases and BCS, and the prognostic value of nodal metastases in different BCS are still remains unclear. Our aim was to investigate the association between nodal metastases and BCS, and the prognostic value of nodal metastases in the different BCS.We found that the breast cancer subtype was closely associated with the pN stage. pN stage and breast cancer subtype were significantly associated with disease-free survival. The subgroup analysis showed that the patients in higher pN stage had a poor outcome than patients in lower pN stage in each breast cancer subtype. Furthermore, when the analysis was stratified by breast cancer subtype, we found that even in the same pN stage (pN0-pN2), there was significant survival difference among patients in different BCS, and Luminal A breast cancer patients had the best survival outcome. However, there were no significant survival difference between Luminal A patients and other breast cancer subtype when patients in pN3 stage. Thus, our study suggested that both lymph node status and molecular subtype played important roles in the outcome of breast cancer patients and they cannot replace each other.