Circulating tumor cell phenotype detection based on epithelial-mesenchymal transition markers combined with clinicopathological risk has potential to better predict recurrence in stage III breast cancer treated with neoadjuvant chemotherapy: a pilot study.

BACKGROUND: The potential value of detecting epithelial-mesenchymal transition (EMT) CTCs in early breast cancer, especially during the neoadjuvant therapy period, requires further investigation. We analyzed dynamic CTC phenotype status, to improve recurrence risk stratification for patients with stage III breast cancers. METHODS: We enrolled 45 patients with stage III breast cancers from 2 clinical trials undergoing neoadjuvant chemotherapy and utilized the CanPatrol CTC enrichment technique pre- and post-chemotherapy to identify CTC phenotypes, including epithelial CTCs, biphenotypic epithelial/mesenchymal CTCs, and mesenchymal CTCs, in peripheral blood samples. Kaplan-Meier analyses were conducted to explore the prognostic value of dynamic change of CTC count and the proportion of CTCs with different phenotypes. Then, redefine the risk stratification based on CTC status and clinicopathological risk in combination. RESULTS: Increased proportion of M + CTCs was a high-risk CTC status that was associated with decreased DFS (HR, 3.584; 95% CI, 1.057-12.15). In a combined analysis with clinicopathological risk, patients with high-risk tumors had an elevated risk of recurrence compared to patients with low-risk tumors (HR, 4.482; 95% CI, 1.246-16.12). The recurrence risk could be effectively stratified by newly defined risk stratification criteria, with 5-year DFS of 100.0%, 77.3%, and 50.0%, respectively, for low-risk, mid-risk, and high-risk patients (P = 0.0077). Finally, in the ROC analysis, the redefined risk stratification demonstrated higher predictive significance with an AUC of 0.7727, compared to CTC status alone (AUC of 0.6751) or clinicopathological risk alone (AUC of 0.6858). CONCLUSION: The proportion of M + CTCs increased after neoadjuvant chemotherapy indicating a higher risk of tumor recurrence. Combining CTC status with clinicopathological risk has potential to redefine the risk stratification of stage III breast cancers and provide improved predictions of relapse.

Adjuvant chemotherapy and survival outcomes in older women with HR+/HER2- breast cancer: a propensity score-matched retrospective cohort study using the SEER database.

OBJECTIVES: This study aimed to investigate the impact of adjuvant chemotherapy (ACT) on survival outcomes in older women with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC). DESIGN: A retrospective cohort study using data from the Surveillance, Epidemiology, and End Results database, which contains publicly available information from US cancer registries. SETTING AND PARTICIPANTS: The study included 45 762 older patients with BC aged over 65 years diagnosed between 2010 and 2015. METHODS: Patients were divided into two groups based on age: 65-79 years and ≥80 years. Propensity score matching (PSM) was employed to balance clinicopathological characteristics between patients who received ACT and those who did not. Data analysis used the χ2 test and Kaplan-Meier method, with a subgroup analysis conducted to identify potential beneficiaries of ACT. OUTCOME MEASURES: Overall survival (OS) and cancer-specific survival (CSS). RESULTS: Due to clinicopathological characteristic imbalances between patients with BC aged 65-79 years and those aged ≥80 years, PSM was used to categorise the population into two groups for analysis: the 65-79 years age group (n=38 128) and the ≥80 years age group (n=7634). Among patients aged 65-79 years, Kaplan-Meier analysis post-PSM indicated that ACT was effective in improving OS (p<0.05, HR=0.80, 95% CI 0.73 to 0.88), particularly in those with advanced disease stages, but did not show a significant benefit in CSS (p=0.09, HR=1.13, 95% CI 0.98 to 1.31). Conversely, for patients aged ≥80 years, ACT did not demonstrate any improvement in OS (p=0.79, HR=1.04, 95% CI 0.79 to 1.36) or CSS (p=0.09, HR=1.46, 95% CI 0.69 to 2.26) after matching. Subgroup analysis also revealed no positive impact on OS and CSS. CONCLUSIONS: Patients with HR+/HER2- BC ≥80 years of age may be considered exempt from ACT because no benefits were found in terms of OS and CSS.

Control of the total orbital angular momentum of light beams propagating through a turbulent medium.

The robustness of the orbital angular momentum (OAM) of light beams propagating in a turbulent medium, e.g., atmosphere, is critical for many applications such as OAM-based free-space optical communications and remote sensing. However, the total OAM of a beam interacting with the turbulent medium inevitably changes. Here, we demonstrate a practical algorithm to control the total OAM of a beam transmitted through a time-evolving, turbulent medium by dynamically modulating the weights of two coherently superimposed OAM modes, which served as the input beam. A cross-OAM matrix is introduced, and applied for checking whether the desired total OAM in the output plane can be achieved. Furthermore, analytical relations between the weights of two input modes and the output total OAM, as well as its modulation range, are established. As a numerical example, we study the behavior of total OAM of the two-mode beam after passing through a thermal convection occurring in an aqueous medium and suggest a possible application of our strategy.

Relationship between oily fish intake and breast cancer based on estrogen receptor status: a Mendelian randomization study.

OBJECTIVE: We used a Mendelian randomization (MR) method in our research to examine the relationship between genetically determined oily fish intake and breast cancer (BC) incidence. METHODS: The summary data pertaining to the oily fish intake were acquired from the UK Biobank, which consisted of a sample size of 460,443 people. Information on BC was received from the Breast Cancer Association Consortium (BCAC). We analyzed the causal connection between oily fish intake and BC incidence using various methods, including inverse variance weighting (IVW). Heterogeneity was investigated using Cochran's Q test. IVW, MR-Egger, and MR-PRESSO methods were used for sensitivity analysis. In addition, a multivariate MR adjusted for body mass index (BMI) and weight was used for further research. RESULTS: Two-sample MR results showed that oily fish intake was negatively associated with total breast cancer (odds ratio (OR) 0.58, 95% confidence interval (CI) 0.39-0.87, IVW method), estrogen receptor-positive (ER +) breast cancer (OR 0.44, 95% CI 0.21-0.93, IVW method), and estrogen receptor-negative (ER-) breast cancer (OR 0.53, 95% CI 0.30-0.93, IVW method). The sensitivity analysis did not observe the presence of heterogeneity and horizontal pleiotropy. In multivariate MR analysis, the negative association between oily fish intake and total breast cancer (P = 0.03) and ER- breast cancer (P = 0.04) risk persisted after adjusting for BMI and body weight. However, no correlation was found in ER + breast cancer (P = 0.30). CONCLUSION: The oily fish intake has a negatively correlated with the incidence of total breast cancer, particularly in the cases of ER- breast cancer. There is a lack of substantial evidence supporting a link between the oily fish intake and the incidence of ER + breast cancer.

Doxorubicin resistance in breast cancer is mediated via the activation of FABP5/PPARγ and CaMKII signaling pathway.

Breast cancer is the most prevalent malignancy among women. Doxorubicin (Dox) resistance was one of the major obstacles to improving the clinical outcome of breast cancer patients. The purpose of this study was to investigate the relationship between the FABP signaling pathway and Dox resistance in breast cancer. The resistance property of MCF-7/ADR cells was evaluated employing CCK-8, Western blot (WB), and confocal microscopy techniques. The glycolipid metabolic properties of MCF-7 and MCF-7/ADR cells were identified using transmission electron microscopy, PAS, and Oil Red O staining. FABP5 and CaMKII expression levels were assessed through GEO and WB approaches. The intracellular calcium level was determined by flow cytometry. Clinical breast cancer patient's tumor tissues were evaluated by immunohistochemistry to determine FABP5 and p-CaMKII protein expression. In the presence or absence of FABP5 siRNA or the FABP5-specific inhibitor SBFI-26, Dox resistance was investigated utilizing CCK-8, WB, and colony formation methods, and intracellular calcium level was examined. The binding ability of Dox was explored by molecular docking analysis. The results indicated that the MCF-7/ADR cells we employed were Dox-resistant MCF-7 cells. FABP5 expression was considerably elevated in MCF-7/ADR cells compared to parent MCF-7 cells. FABP5 and p-CaMKII expression were increased in resistant patients than in sensitive individuals. Inhibition of the protein expression of FABP5 by siRNA or inhibitor increased Dox sensitivity in MCF-7/ADR cells and lowered intracellular calcium, PPARγ, and autophagy. Molecular docking results showed that FABP5 binds more powerfully to Dox than the known drug resistance-associated protein P-GP. In summary, the PPARγ and CaMKII axis mediated by FABP5 plays a crucial role in breast cancer chemoresistance. FABP5 is a potentially targetable protein and therapeutic biomarker for the treatment of Dox resistance in breast cancer.

Health prevention intervention for chronic tissue fibrosis: Based on the specific expression of CCL19/21 + mast cell.

Chronic tissue fibrosis is a common pathological feature of connective tissue diseases and malignant tumors, and its prevention has been a major focus of relevant research.However, the details of the mechanism of action of tissue-colonizing immune cells in fibroblast migration are unclear. In this study, connective tissue disease tissue specimens and solid tumor specimens were selected to observe the relationship between mast cells and interstitial fibrosis and the expression characteristics of mast cells. Our findings suggest that the number of mast cells in the tissue correlates with the degree of pathological fibrosis and that mast cells specifically express the chemokines CCL19 and CCL21, especially CCL19. CCR7+ fibroblasts are highly expressed in mast cell clusters. The mast cell line HMC-1 regulates CD14+ monocyte-derived fibroblasts via CCL19. In disease tissue fibrosis, mast cell activation may increase the expression of chemokines, especially CCL19, in the tissue, thereby inducing a large number of CCR7-positive fibroblasts to migrate to specific tissues. This study lays a foundation for the mechanism of tissue fibrosis and provides evidence for the mechanism by which mast cells induce fibroblast migration.Through the experimental results of this paper, we can combine the induction factors of chronic tissue fibrosis and put forward targeted health prevention strategies.

Repeatability and reproducibility of a new fully automatic measurement optical low coherence reflectometry biometer and agreement with swept-source optical coherence tomography-based biometer.

AIMS: To assess the repeatability and reproducibility of the ocular measurements obtained with the Suoer SW-9000 µm Plus, a new fully automatic biometer based on optical low coherence reflectometry (OLCR) biometer, and to compare them to those obtained by a swept-source optical coherence tomography (SS-OCT)-based biometer. METHODS: This prospective study consisted of 115 eyes of 115 healthy subjects. The measurements were taken by the two optical biometers in random order. The measured parameters were axial length (AL), central corneal thickness (CCT), aqueous depth (AQD), anterior chamber depth (ACD), mean keratometry (Km), lens thickness (LT) and corneal diameter (CD). To evaluate the intraobserver repeatability and interobserver reproducibility, the within-subject SD, test-retest variability, coefficient of variation (CoV) and intraclass correlation coefficient (ICC) were adopted. The Bland-Altman plot was drawn to assess the agreement. RESULTS: The repeatability and reproducibility of all parameters for the new device were excellent (ICC>0.960 and CoV<0.71%). The Bland-Altman plots showed high agreement between the OLCR-based and SS-OCT-based devices for AL, CCT, AQD, ACD, Km and LT, with narrow 95% limit of agreements (LoAs) (-0.08 mm to 0.06 mm, -15.91 µm to -1.01 µm, -0.09 mm to 0.09 mm, -0.09 mm to 0.08 mm, -0.47 D to 0.35 D, -0.05 mm to 0.16 mm, respectively) and moderate agreement for CD (95% LoA: -0.67 mm to -0.01 mm). CONCLUSIONS: The new Suoer SW-9000 µm Plus biometer showed excellent repeatability and reproducibility. All the parameters obtained by this biometer were similar to those measured by SS-OCT-based biometer.

Corneal Higher-Order Aberrations Measurements: Precision of SD-OCT/Placido Topography and Comparison with a Scheimpflug/Placido Topography in Eyes After Small-Incision Lenticule Extraction.

INTRODUCTION: The aim of this study was to evaluate the measurements of corneal higher-order aberrations (HOAs) obtained by a new anterior segment optical coherence tomography (OCT) technique combined with a Placido topographer (the MS-39 device) in eyes with prior small-incision lenticule extraction (SMILE) and compare them to the measurements obtained by a Scheimpflug camera combined with a Placido topographer (the Sirius device). METHODS: A total of 56 eyes (56 patients) were included in this prospective study. Corneal aberrations were analyzed for the anterior, posterior, and total cornea surfaces. Within-subject standard deviation (Sw), test-retest repeatability (TRT), and intraclass correlation coefficient (ICC) were used to assess the intraobserver repeatability and interobserver reproducibility. The differences were evaluated by paired t-test. Bland-Altman plots and 95% limits of agreement (95% LoA) were used to evaluate the agreement. RESULTS: High repeatability was observed for anterior and total corneal parameters, with Sw value < 0.07, TRT ≤ 0.16, and ICCs > 0.893, but not trefoil. For the posterior corneal parameters, ICCs varied from 0.088 to 0.966. Regarding interobserver reproducibility, all Sw values were ≤ 0.04 and TRT ≤ 0.11. ICCs ranged from 0.846 to 0.989, from 0.432 to 0.972, and from 0.798 to 0.985 for the anterior, total, and posterior corneal aberrations parameters, respectively. The mean difference in all aberrations was ≤ 0.05 µm. All parameters showed a narrow 95% LoA. CONCLUSION: The MS-39 device achieved high precision in both anterior and total corneal measurements; the precision of posterior corneal higher-order RMS, astigmatism II, coma, and trefoil was lower. The two technologies used by the MS-39 and Sirius devices can be used interchangeably for measuring corneal HOAs after SMILE.

Elevated Sera IL-6 and NK-T Cells Associated With Increased Pathological Complete Response in HER2-positive Breast Cancer With Carboplatin-based Neoadjuvant Therapy.

Context: Neoadjuvant therapy is the primary treatment for stage II to III breast cancer (BC). The heterogeneity of BC challenges the identification of effective neoadjuvant regimens and of the related sensitive populations. Objective: The study intended to explore the predictive role of inflammatory cytokines, immune-cell subsets, and tumor-infiltrating lymphocytes (TILs) for the accomplishment of the pathological complete response (pCR) after a neoadjuvant regimen. Design: The research team conducted a phase II, single-armed, open-label trial. Setting: The study took place at the Fourth Hospital of Hebei Medical University in Shijiazhuang, Hebei, China. Participants: Participants were 42 patients at the hospital receiving treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) between November 2018 and October 2021. Intervention: Participants received neoadjuvant therapy of six cycles of docetaxel, carboplatin, and trastuzumab (TCbH). Outcome Measures: The research team: (1) measured 13 cytokines and immune-cell populations in peripheral blood prior to neoadjuvant therapy administration; (2) measured TILs in tumor tissues; (3) analyzed correlations among biomarkers and pCR. Results: Of the 42 participants, 18 achieved pCR (42.9%) after the neoadjuvant therapy, with 37 having an overall response rate (ORR) of 88.1%. All participants experienced at least one short-term adverse event. The most common toxicity was leukopenia, with 33 participants (78.6%), while no cardiovascular dysfunction occurred. Compared with the non-pCR group, the pCR group had higher serum levels of tumor necrosis factor alpha (TNF-ɑ), with P = .013; interleukin 6 (IL-6), with P = .025; and IL-18, with P = .0004. Univariate analysis showed that IL-6 (OR, 3.429; 95% CI,1.838-6.396; P = .0001) had a significant correlation with pCR. Participants in the pCR group had a higher level of natural killer T (NK-T) cells (P = .009) and a lower ratio of cluster of differentiation 4 (CD4):CD8 (P = .0014) before neoadjuvant therapy. Univariate analysis linked a high population of NK-T cells (OR, 0.204; 95% CI,0.052-0.808; P = .018), a low CD4:CD8 ratio (OR, 10.500; 95% CI, 2.475-44.545; P = .001), and TILs expression (OR, 0.192; 95% CI, 0.051-0.731; P = .013) to pCR. Conclusions: Immunological factors, including IL-6, NK-T cells, CD4+ T versus CD8+ T ratio, and TILs expression were significant predictors for response to TCbH neoadjuvant therapy with carboplatin.

Therapeutic effects of atorvastatin on doxorubicin-induced hepatotoxicity in rats via antioxidative damage, anti-inflammatory, and anti-lipotoxicity.

Doxorubicin (DOX), is a high efficiency anthracycline antitumor drug. However, the clinical application of DOX is limited mainly by dose-related adverse drug reactions. Currently, the therapeutic effects of Atorvastatin (ATO) on DOX-induced hepatotoxicity were studied in vivo. The results indicated that DOX impaired hepatic function, as measured by an increased levels of liver weight index and serum concentrations of aspartate transaminase and alanine transaminase, as well as alteration of hepatic histology. In addition, DOX increased the serum levles of triglyceride (TG) and nonestesterified fatty acid. ATO prevented these changes. Mechanical analysis revealed that ATO restored the changes of malondialdehyde, reactive oxygen radical species, glutathione peroxidase and manganese superoxide dismutase. Additionally, ATO inhibited the increased expression levels of nuclear factor-kappa B and interleukin 1ß, hence suppressing inflammation. Meanwhile, ATO inhibited cell apoptosis by dramatically decreasing the Bax/Bcl-2 ratio. In addition, ATO mitigated the lipidtoxicity by inhibiting the adipolysis of TG and accelerating hepatic lipid metabolism. Taken together, the results suggest ATO has therapeutic effect on DOX-induced hepatotoxicity via inhibition of oxidative damage, inflammatory and apoptosis. In addition, ATO attenuates DOX-induced hyperlipidemia via modulation of lipid metabolism.

PDPN positive CAFs contribute to HER2 positive breast cancer resistance to trastuzumab by inhibiting antibody-dependent NK cell-mediated cytotoxicity.

Trastuzumab is a humanized monoclonal antibody, and has been clinical employed to treat human epidermal growth factor receptor 2 (HER2) positive breast cancer. However, drug resistance to trastuzumab remains a challenge due to the generally uncharacterized interactive immune responses within the tumor tissue. In this study, by means of single-cell sequencing, we identified a novel podoplanin-positive (PDPN+) cancer-associated fibroblasts (CAFs) subset, which was enriched in trastuzumab resistant tumor tissues. Furthermore, we found that PDPN+ CAFs promote resistance to trastuzumab in HER2+ breast cancer by secreting immunosuppressive factors indoleamine 2,3-dioxygenase 1 (IDO1) as well as tryptophan 2,3-dioxygenase 2 (TDO2), thereby suppressing antibody-dependent cell-mediated cytotoxicity (ADCC), which was mediated by functional NK cells. A dual inhibitor IDO/TDO-IN-3 simultaneously targeting IDO1 and TDO2 showed a promising effect on reversing PDPN+ CAFs-induced suppression of NK cells mediated ADCC. Collectively, a novel subset of PDPN+ CAFs was identified in this study, which induced trastuzumab resistance in breast cancer of HER2+ status via inhibiting ADCC immune response mediated by NK cells, hinting that PDPN+ CAFs could be a novel target of treatment to increase the sensitivity of HER2+ breast cancer to trastuzumab.

Metastasis patterns and prognosis in young breast cancer patients: A SEER database analysis.

Background: There are few studies on young patients with metastatic breast cancer (MBC). This study aims to explore the metastasis pattern and prognosis of young patients with MBC. Methods: A total of 6,336 MBC patients diagnosed in the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015 were selected. They were divided into two age groups: the younger group (≤40 years old) and the older group (>40 years old). χ2 test was used to compare clinicopathological characteristics. Survival differences were compared by Kaplan-Meier analysis. Cox regression models were used to determine the prognostic factors affecting survival. Propensity score matching (PSM) was performed to balance the effects of baseline clinicopathological differences. Results: Finally, 494 patients (7.8%) who are ≤40 years old and 5,842 patients (92.2%) who are >40 years old were included. In the younger group, the proportion of liver metastasis was significantly higher than that in the older group; the proportion of lung metastasis was significantly lower than that of the older group. Kaplan-Meier analysis showed that the younger group had the best prognosis and the older group had the worst. Youth is an independent protective factor for overall survival (OS). In the younger group, liver metastasis had the best prognosis among all metastatic sites, and the HER2-enriched subtype had the best prognosis among all subtypes. Conclusions: The disease in young MBC patients is more aggressive but has a better prognosis, especially in liver metastases and the HER2-enriched subtypes.

Real-world study of trastuzumab and pertuzumab combined with chemotherapy in neoadjuvant treatment for patients with HER2-positive breast cancer.

Clinical trials have shown that trastuzumab (H) and pertuzumab (P) combined with chemotherapy as neoadjuvant therapy increased pathological complete response (pCR) rate of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, date in China in the real world are currently limited. Clinical data from patients with HER2-positive breast cancer who received HP combined with chemotherapy as neoadjuvant therapy at 2 institutions from March 2019 to February 2022 were retrospectively analyzed. Adverse reactions were evaluated using CTCAE version 5.0. The primary endpoint was total pathologic complete response (tpCR; ypT0/isypN0), and the secondary endpoints were breast pathologic complete response (bpCR; ypT0/is) and axillary pathologic complete response (apCR; ypN0). Factors influencing tpCR were also analyzed. A total of 302 patients were included in the analysis, of which 145 were treated with H + P + taxane + carboplatin (TcbHP), 94 with H + P + taxane (THP) and 63 with sequential anthracycline and cyclophosphamide, followed by H + P + taxane (AC-THP). The overall tpCR rate was 64.9%, and those of TcbHP, THP, and AC-THP were 73.1%, 52.1%, and 65.1%, respectively. The tpCR rate of the hormone receptor (HR) negative group (80.3%) was higher than that of the HR positive group (52.1%). The overall bpCR rate was 73.5% and the apCR rate was 75.8%. In the univariate analysis, HR, HER2 status and treatment regimen were related factors that affected tpCR. In the multivariate analysis, HR, HER2 status and treatment regimen were independent predictors of tpCR (P < .001, P < .001 and P = .009). The levels 3 and 4 toxicities rates of TcbHP were slightly higher than those of THP and AC-THP. HP combined with chemotherapy has achieved a high pCR rate. The TcbHP regimen had the highest pCR. HR-negative tumors demonstrated a higher pCR. HR, HER2 status and treatment regimen were independent predictors of tpCR. The adverse reactions are controllable.

The expression landscape of FOXP3 and its prognostic value in breast cancer.

Background: Forkhead Box Protein 3 (FOXP3), as an essential marker of regulatory T cell (Treg) development, is reportedly overexpressed in invasive breast carcinoma (BRCA) and could be a potential prognostic factor for BRCA. However, the biological function of FOXP3 in BRCA is still unclear. In this study, we comprehensively explored the expression landscape of FOXP3 and its prognostic value in BRCA. Methods: FOXP3 transcriptomic expression data were mainly obtained from The Cancer Genome Atlas (TCGA). The Kaplan-Meier plotter and receiver operating characteristic (ROC) curve were used to assess the prognostic and diagnostic value of FOXP3 in BRCA. UALCAN, cBio-Portal, and MethSurv were used to evaluate the genomic variation of FOXP3. Gene set enrichment analysis (GSEA) was performed to explore the FOXP3 pathways involved in BRCA. Morover, we detected the expression of FOXP3 in 123 BRCA specimens and 5 BRCA cell lines to verify the biological value of FOXP3 in BRCA. The Kaplan-Meier method was adopted for the overall survival (OS) analysis, and a Cox proportional hazards model was used to estimate the hazard ratio (HR) for OS. Results: FOXP3 was more highly expressed in BRCA than in normal tissues (2.808±1.020 vs. 1.409±0.656, P<0.001), and overexpressed FOXP3 was associated with a better prognosis. The ROC curve demonstrated a significant diagnostic value of FOXP3 in BRCA (area under the ROC curve, AUC: 0.877). Genomic analysis revealed that promoter hypomethylation of FOXP3 may be the underlying mechanism of FOXP3's upregulation in BRCA. GSEA found that FOXP3 coexpressed genes were mainly involved in the Toll-like receptor pathway, JAK/STAT pathway, cell cycle, and apoptosis. Moreover, high FOXP3 expression was an independent protective factor for OS in our 123 BRCA tissues (HR: 0.367; P=0.036). In vitro, we found that FOXP3 knockdown with siRNA promoted migration and invasion in MCF-7 cells. Conclusions: This study demonstrated that FOXP3 shows prognostic and diagnostic value for BRCA. We provided evidence that promoter hypomethylation and a high expression of FOXP3 were both related to a favorable prognosis in BRCA, which maybe associated with the Toll-like receptor pathway, JAK/STAT pathway, cell cycle, and apoptosis.

ROCK inhibitor fasudil reduces the expression of inflammatory factors in LPS-induced rat pulmonary microvascular endothelial cells via ROS/NF-κB pathway.

BACKGROUND: Inflammation plays a major role in the pulmonary artery hypertension (PAH) and the acute lung injury (ALI) diseases. The common feature of these complications is the dysfunction of pulmonary microvascular endothelial cells (PMVECs). Fasudil, the only Rho kinase (ROCK) inhibitor used in clinic, has been proved to be the most promising new drug for the treatment of PAH, with some anti-inflammatory activity. Therefore, in the present study, the effect of fasudil on lipopolysaccharide (LPS)-induced inflammatory injury in rat PMVECs was investigated. METHODS: LPS was used to make inflammatory injury model of rat PMVECs. Thereafter, the mRNA and protein expression of pro-inflammatory factors was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) assay respectively. Intracellular reactive oxygen species (ROS) levels were measured by the confocal laser scanning system. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and the content of malondialdehyde (MDA) were determined by using commercial kits according to the manufacturer's instructions. Western blot assay was used to detect the protein expression of nuclear factor kappa B (NF-κB) p65. RESULTS: Fasudil effectively prevented inflammatory injury induced by LPS, which is manifested by the decrease of pro-inflammatory cytokines interleukin-6 (IL-6) and monocyte chenotactic protein-1 (MCP-1). Meanwhile, fasudil dramatically reduced the levels of ROS and MDA, and also elevated the activities of SOD and GSH-Px. Furthermore, the nuclear translocation of NF-κB p65 induced by LPS was also suppressed by fasudil. Additionally, the ROS scavengers N-Acetylcysteine (N-Ace) was also found to inhibit the nuclear translocation of NF-κB and the mRNA expression of IL-6 and MCP-1 induced by LPS, which suggested that ROS was essential for the nuclear translocation of NF-κB. CONCLUSIONS: The present study revealed that fasudil reduced the expression of inflammatory factors, alleviated the inflammatory and oxidative damage induced by LPS in rat PMVECs via ROS-NF-κB signaling pathway.

Survival outcomes of autologous breast reconstruction after mastectomy: A matched case-control study.

Background: Due to the lack of strong evidence-based medical evidence, the relationship between autologous breast reconstruction (ABR) after mastectomy and long-term prognosis is unclear. This study aims to explore if ABR after mastectomy is associated with the prognosis of breast cancer (BC) patients based on the data from the Surveillance, Epidemiology, and End Results (SEER) database. Methods: We collected data for all cases diagnosed with BC who underwent or did not undergo ABR after mastectomy from 2010-2015 in the SEER database. The primary outcome of our study was overall survival (OS) and cancer specific survival (CSS). The Propensity Score-Matched (PSM) analysis was used to eliminate the effects of non-random statistics, setting the caliper as 0.0001 to balance the baseline variables within the groups. Chi-square test, Kaplan-Meier method, univariate and multivariate cox regression analysis were used to analyze the data and subgroup analysis was performed to find the subgroups of people who might benefit from ABR. Result: Of 27893 eligible patients, 11038 patients were matched. The cohort consisted of 5519 (50%) ABR patients and 5519 (50%) non-ABR patients after PSM. After PSM, on multivariate cox regression analysis, ABR still exerted a significant influence on the OS (hazard ratio (HR), 0.83, P< 0.05). However, no statistical difference was shown on CSS (HR, 0.93, P = 0.31). Kaplan-Meier survival analysis showed ABR group had better OS (P = 0.001), but similar CSS (P = 0.174) between ARB and mastectomy groups. Subgroup analysis showed that after matching, those with 50-59 years old, earlier stages of disease, without a marital partner and living in urban areas had better OS after ABR. Conclusions: ABR after mastectomy was associated with better OS, but not affect CSS.

Marfan Syndrome With Recurrent Lower Left Posterior Toothache as the First Symptom: A Report on a Rare Case.

Marfan syndrome (MFS) is a life-threatening connective tissue disorder that affects multiple organs and systems. We report a case of MFS with recurrent lower left posterior toothache as the first symptom. A 23-year-old Asian man walked into the dental emergency room with a chief complaint of recurrent spontaneous and intermittent toothache in his lower left posterior tooth region, mimicking acute symptomatic pulpitis. He self-reported a relatively healthy medical status without any hereditary disease. However, his disproportionately elongated body structure, high myopia, and positive wrist sign were immediately recognizable. Although there were no remarkable findings on the dental examination, pectus carinatum deformity and abnormal blood pressure were later detected. He was immediately referred to a cardiologist in a medical hospital. The timely diagnosis of MFS and early surgical intervention helped to avoid severe lethal consequences. The symptoms of toothache completely resolved after surgery.

Enhanced Mechanical Properties of Metallic Glass Thin Films via Modification of Structural Heterogeneity.

The structure of Cu50Zr50 and Co56Ta35B9 metallic glass thin films (MGTF) was effectively tailored via various applied substrate temperatures by means of the magnetron sputtering technology. Obviously enhanced hardness and elastic modulus are achieved by different compositional MGTFs by increasing the substrate temperature. Compared with the CuZr MGTFs, the CoTaB MGTF deposited at 473 K displays the smaller strain-rate sensitivity exponent, m, and a weaker spectrum intensity based on the nanoindentation creep test, suggesting its better creep resistance. In addition, the STZ volume of the CoTaB MGTF significantly decreases after depositing at higher temperature. According to the nano-scratch analysis, the CoTaB MGTF at the substrate temperatures of 473 K performs the shallower scratch width and the larger H3/E2 value, indicating its better tribological property.

Preliminary adipose removal did not prevent diet-induced metabolic disorders in mice.

BACKGROUND: Obesity is a fundamental factor in metabolic disorders such as hyperlipidemia, insulin resistance, fatty liver, and atherosclerosis. However, effective preventive measures are still lacking. This study aimed to investigate different surgical protocols for removing partial adipose tissue before the onset of obesity and determine whether, and by which protocol, preliminary adipose removal could exert potent preventive effects against diet-induced metabolic disorders. METHODS: Male low-density lipoprotein receptor (LDL-R) knockout (KO) mice were randomly divided into four groups and subjected to epididymal fat removal (Epi-FR) surgery, subcutaneous fat removal (suQ-FR) surgery, both subcutaneous and epididymal fat removal (Epi + suQ-FR) surgery, or sham-operation. After 1 week of recovery, all mice were given a high-fat diet (HFD) for 10 weeks to induce metabolic disorders. RESULTS: In the Epi-FR group and the sham-operated group, the mean numbers of the residual subcutaneous fat were 28.59 mg/g and 18.56 mg/g, respectively. The expression of relative genes such as Pparg, Cebpa, Dgat2, Fabp4 and Cd36 in the residual subcutaneous fat increased 2.62, 3.90, 3.11, 2.06, 1.78 times in the Epi-FR group compared with that in the sham-operated group. Whereas in the other fat-removal groups, the residual fat depots had no significant change in either size or gene expression, as compared with those of the sham-operated group. Plasma lipid and glucose levels and insulin sensitivity, as detected by the glucose tolerance test, were not significantly alleviated in the three fat removal groups. Liver mass or lipid content was not attenuated in any of the three fat removal groups. The atherosclerosis burdens in the entire inner aorta and aortic root did not decrease in any of the three fat removal groups. CONCLUSIONS: Our data suggest that removal of epididymal adipose or subcutaneous adipose alone or in combination before the onset of obesity did not protect against hyperlipidemia, insulin resistance, fatty liver, or atherosclerosis in LDL-R KO mice fed with a HFD. Hence, adipose removal possibly does not represent a potential approach in preventing obesity-related metabolic disorders in the obesity-susceptible population.

Periodontal Regeneration of Teeth with Radicular Developmental Groove after Intentional Replantation: Two Case Reports.

Our case reports probe whether intentional replantation is a feasible and successful treatment for teeth with radicular developmental groove. Radicular developmental groove is an anatomical malformation that often leads to combined periodontal-endodontic lesion. Treatment of complex radicular groove presents a great challenge to the operator. Two cases of periodontal compromised teeth with this developmental anomaly were treated with intentional replantation and followed up for 2 years. The teeth were asymptomatic and functional. The periodontal probing depths decreased from original 10 mm to 2-3 mm. The receded gingival papillae associated with the teeth was regenerated two years after intentional replantation. With careful case selection and treatment planning, intentional replantation may be a predictable alternative treatment modality for the combined endodontic-periodontal lesion accompanied with radicular developmental groove.