Association of early menarche with breast tumor molecular features and recurrence.

BACKGROUND: Early menarche is an established risk factor for breast cancer but its molecular contribution to tumor biology and prognosis remains unclear. METHODS: We profiled transcriptome-wide gene expression in breast tumors (N = 846) and tumor-adjacent normal tissues (N = 666) from women in the Nurses' Health Studies (NHS) to investigate whether early menarche (age < 12) is associated with tumor molecular and prognostic features in women with breast cancer. Multivariable linear regression and pathway analyses using competitive gene set enrichment analysis were conducted in both tumor and adjacent-normal tissue and externally validated in TCGA (N = 116). Subgroup analyses stratified on ER-status based on the tumor were also performed. PAM50 signatures were used for tumor molecular subtyping and to generate proliferation and risk of recurrence scores. We created a gene expression score using LASSO regression to capture early menarche based on 28 genes from FDR-significant pathways in breast tumor tissue in NHS and tested its association with 10-year disease-free survival in both NHS (N = 836) and METABRIC (N = 952). RESULTS: Early menarche was significantly associated with 369 individual genes in adjacent-normal tissues implicated in extracellular matrix, cell adhesion, and invasion (FDR ≤ 0.1). Early menarche was associated with upregulation of cancer hallmark pathways (18 significant pathways in tumor, 23 in tumor-adjacent normal, FDR ≤ 0.1) related to proliferation (e.g. Myc, PI3K/AKT/mTOR, cell cycle), oxidative stress (e.g. oxidative phosphorylation, unfolded protein response), and inflammation (e.g. pro-inflammatory cytokines IFN α and IFN γ ). Replication in TCGA confirmed these trends. Early menarche was associated with significantly higher PAM50 proliferation scores (ß = 0.082 [0.02-0.14]), odds of aggressive molecular tumor subtypes (basal-like, OR = 1.84 [1.18-2.85] and HER2-enriched, OR = 2.32 [1.46-3.69]), and PAM50 risk of recurrence score (ß = 4.81 [1.71-7.92]). Our NHS-derived early menarche gene expression signature was significantly associated with worse 10-year disease-free survival in METABRIC (N = 952, HR = 1.58 [1.10-2.25]). CONCLUSIONS: Early menarche is associated with more aggressive molecular tumor characteristics and its gene expression signature within tumors is associated with worse 10-year disease-free survival among women with breast cancer. As the age of onset of menarche continues to decline, understanding its relationship to breast tumor characteristics and prognosis may lead to novel secondary prevention strategies.

Metformin and other anti-diabetic medication use and breast cancer incidence in the Nurses' Health Studies.

We aimed to examine the association between the use of metformin and other anti-diabetic medications and breast cancer incidence within two large prospective cohort studies. We followed 185,181 women who participated in the Nurses' Health Study (NHS; 1994-2016) and the NHSII (1995-2017), with baseline corresponding to the date metformin was approved for type 2 diabetes (T2D) treatment in the US Information on T2D diagnosis, anti-diabetes medications, and other covariates was self-reported at baseline and repeatedly assessed by follow-up questionnaires every 2 years. Breast cancer cases were self-reported and confirmed by medical record review. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between medication use and breast cancer were estimated using Cox proportional hazards regression models, adjusting for breast cancer risk factors. During 3,324,881 person-years of follow-up, we ascertained 9,192 incident invasive breast cancer cases, of which 451 were among women with T2D. Compared with women without T2D (n = 169,263), neither metformin use (HR = 0.97; 95% CI = 0.81-1.15) nor other anti-diabetic medications use (HR = 1.11; 95% CI = 0.90-1.36) associated with significantly lower breast cancer incidence. Among women with T2D (n = 15,918), compared with metformin never users, metformin ever use was not significantly inversely associated with breast cancer (HR = 0.92; 95% CI = 0.74-1.15). Although we observed that past use of metformin was inversely associated with breast cancer in the T2D population (HR = 0.67; 95% CI = 0.48-0.94), current use (HR = 1.01; 95% CI = 0.80-1.27) and longer duration of metformin use were not associated with breast cancer (each 2-year interval: HR = 1.01; 95% CI = 0.95-1.07). Overall, metformin use was not associated with the risk of developing breast cancer among the overall cohort population or among women with T2D.

Postoperative ctDNA in indicating the recurrence risk and monitoring the effect of adjuvant therapy in surgical non-small cell lung cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) has emerged as a potential novel biomarker to predict molecular residual disease (MRD) in lung cancer after definitive treatment. Herein, we investigated the value of ctDNA in prognosing risk of relapse and monitoring the effect of adjuvant therapy in surgical non-small cell lung cancer (NSCLC). METHODS: We enrolled 58 NSCLC patients in a real-world setting, and 58 tumor tissues and 325 plasma samples were analyzed. Tumor tissues and plasma samples were subjected to targeted next-generation sequencing (NGS) of 1021 cancer-related and ultra-deep targeted NGS covering 338 genes, respectively. RESULTS: ctDNA was detected in 31.0% of cases at the first postoperative time, which was associated with advanced tumor stage, T stage and KEAP1 or GRIN2A mutations in tissues. ctDNA positivity at landmark and longitudinal indicated the shorter disease-free survival. For patients with ctDNA positivity at the first postoperative time, regardless of adjuvant therapy, all patients who were persistently ctDNA positive during postoperative surveillance had disease recurrence. Among the patients who were ctDNA negative, only two patients (15.4%, 2/13) receiving adjuvant therapy relapsed, while one patient (50.0%, 1/2) without adjuvant therapy relapsed. For the first postoperative ctDNA negative patients, the recurrence rate of patients with adjuvant therapy was and higher than without adjuvant therapy (22.6% [7/31] vs. 11.1% [1/9]). The patients who became ctDNA positive may also benefit from intervention therapy. CONCLUSION: Postoperative ctDNA is a prognostic marker, and ctDNA-detection may facilitate personalized adjuvant therapy, and applying adjuvant therapy to the patients with detectable ctDNA could bring clinical benefits for them.

Development and validation of a novel model for predicting the survival of bladder cancer based on ferroptosis-related genes.

The role of ferroptosis, a new form of cell death, in bladder cancer (BC) has not been sufficiently studied. This study aimed to establish a prognostic prediction model for BC patients based on the expression profile of ferroptosis-related genes (FRG). The expression profiles of BC samples with clinical information were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). A total of 80 differentially expressed genes (DEGs) related to FRG were identified among which 37 DEGs were found to have a prognostic value. Eleven genetic markers including SLC2A12, CDO1, JDP2, MAFG, CAPG, RRM2, SLC2A3, SLC3A2, VDAC2, GCH1, and ANGPTL7 were identified through the LASSO regression analysis. The ROC curve analysis showed that the AUC was 0.702, 0.664, and 0.655 for the 1-year, 3-year, and 5-year survival outcomes, respectively. The prediction performance was verified in the TCGA-testing set and external set GSE13507. Multivariate Cox proportional hazards analysis showed that the risk score was an independent prognostic predictor. Moreover, we found differences in gene mutation, gene expression, and immune cell infiltration between the high and low-risk groups of BC patients. Finally, a nomogram was constructed by integrating clinical features and FRG signatures to predict the survival outcomes of BC patients. In addition, the differential expression of FRG mRNA and protein was verified through PCR and HPA online site. The characteristics of 11 FRG genes were examined and a prognostic nomogram for predicting the overall survival of BC was established.

Immunohistochemistry scoring of breast tumor tissue microarrays: A comparison study across three software applications.

Digital pathology can efficiently assess immunohistochemistry (IHC) data on tissue microarrays (TMAs). Yet, it remains important to evaluate the comparability of the data acquired by different software applications and validate it against pathologist manual interpretation. In this study, we compared the IHC quantification of 5 clinical breast cancer biomarkers-estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and cytokeratin 5/6 (CK5/6)-across 3 software applications (Definiens Tissue Studio, inForm, and QuPath) and benchmarked the results to pathologist manual scores. IHC expression for each marker was evaluated across 4 TMAs consisting of 935 breast tumor tissue cores from 367 women within the Nurses' Health Studies; each women contributing three 0.6-mm cores. The correlation and agreement between manual and software-derived results were primarily assessed using Spearman's ρ, percentage agreement, and area under the curve (AUC). At the TMA core-level, the correlations between manual and software-derived scores were the highest for HER2 (ρ ranging from 0.75 to 0.79), followed by ER (0.69-0.71), PR (0.67-0.72), CK5/6 (0.43-0.47), and EGFR (0.38-0.45). At the case-level, there were good correlations between manual and software-derived scores for all 5 markers (ρ ranging from 0.43 to 0.82), where QuPath had the highest correlations. Software-derived scores were highly comparable to each other (ρ ranging from 0.80 to 0.99). The average percentage agreements between manual and software-derived scores were excellent for ER (90.8%-94.5%) and PR (78.2%-85.2%), moderate for HER2 (65.4%-77.0%), highly variable for EGFR (48.2%-82.8%), and poor for CK5/6 (22.4%-45.0%). All AUCs across markers and software applications were ≥0.83. The 3 software applications were highly comparable to each other and to manual scores in quantifying these 5 markers. QuPath consistently produced the best performance, indicating this open-source software is an excellent alternative for future use.

Omega-3 Polyunsaturated Fatty Acids, Gut Microbiota, Microbial Metabolites, and Risk of Colorectal Adenomas.

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are thought to protect against colorectal adenoma (CRA) development. We aimed to further understand the underlying mechanisms by examining the relationships between ω-3 PUFAs and the gut microbiota on CRAs. We assessed the mucosal microbiota via bacterial 16S rRNA sequencing among 217 CRA cases and 218 controls who completed PUFA intake questionnaires. The overall microbial composition was assessed by α-diversity measurements (diversity, richness, and evenness). Global metabolomics was conducted using a random subset of case−control pairs (n = 50). We compared microbiota and metabolite signatures between cases and controls according to fold change (FC). Odds ratios (OR) and confidence intervals (CI) were estimated from logistic regression for associations of ω-3 PUFAs and the microbiota with CRAs. We observed an inverse association between overall ω-3 PUFA intake and CRAs, especially for short-chain ω -3 PUFAs (OR = 0.45, 95% CI: 0.21, 0.97). Such inverse associations were modified by bacterial evenness (p-interaction = 0.03). Participants with higher levels (FC > 2) of bile acid-relevant metabolites were more likely to have CRAs than the controls, and the correlation between bile acids and bacterial diversity differed by case−control status. Our findings suggest that ω-3 PUFAs are inversely associated with CRA development, and the association may be modified by gut microbiota profiles.

Loss of PTEN Expression, PIK3CA Mutations, and Breast Cancer Survival in the Nurses' Health Studies.

BACKGROUND: The relationships between PTEN loss and/or PIK3CA mutation and breast cancer prognosis remain controversial. We aim to examine the associations in large epidemiologic cohorts. METHODS: We followed women with invasive breast cancer from the Nurses' Health Studies with available data on tumor PTEN expression (n = 4,111) and PIK3CA mutation (n = 2,930). PTEN expression was evaluated by IHC and digitally scored (0%-100%). Pyrosequencing of six hotspot mutations of PIK3CA was performed. RESULTS: We found loss of PTEN expression (≤10%) occurred in 17% of cases, and PIK3CA mutations were detected in 11% of cases. After adjusting for clinical and lifestyle factors, PTEN loss was not associated with worse breast cancer-specific mortality among all samples [HR, 0.85; 95% confidence intervals (CI), 0.71-1.03] or among estrogen receptor (ER)-positive tumors (HR, 0.99; 95% CI, 0.79-1.24). However, among ER-negative tumors, PTEN loss was associated with lower breast cancer-specific mortality (HR, 0.68; 95% CI, 0.48-0.95). PIK3CA mutation was not strongly associated with breast cancer-specific mortality (HR, 0.89; 95% CI, 0.67-1.17). Compared with tumors without PTEN loss and without PIK3CA mutation, those with alterations (n = 540) were not at higher risk (HR, 1.07; 95% CI, 0.86-1.34). However, women with both PTEN loss and PIK3CA mutation (n = 38) were at an increased risk of breast cancer-specific mortality (HR, 1.65; 95% CI, 0.83-3.26). CONCLUSIONS: In this large epidemiologic study, the PTEN-mortality association was more pronounced for ER-negative tumors, and the joint PTEN loss and PIK3CA mutation may be associated with worse prognosis. IMPACT: Further studies with a larger sample of ER-negative tumors are needed to replicate our findings and elucidate underlying mechanisms.

Role of skeletal muscle satellite cells in the repair of osteoporotic fractures mediated by ß-catenin.

BACKGROUND: Osteoporosis is a metabolic disease, and osteoporotic fracture (OPF) is one of its most serious complications. It is often ignored that the influence of the muscles surrounding the fracture on the healing of OPF. We aimed to clarify the role of skeletal muscle satellite cells (SMSCs) in promoting OPF healing by ß-catenin, to improve our understanding of SMSCs, and let us explore its potential as a therapeutic target. METHODS: Skeletal muscles were obtained from control non-OPF or OPF patients for primary SMSCs culture (n = 3, 33% females, mean age 60 ± 15.52). Expression of SMSCs was measured. In vivo, 3-month-old female C57BL/6 mice underwent OVX surgery. Three months later, the left tibia fracture model was again performed. The control and the treatment group (n = 24, per group, female). The treatment group was treated with an agonist (osthole). Detection of SMSCs in muscles and fracture healing at 7, 14, and 28 three time points (n = 8, 8, 8, female). To further clarify the scientific hypothesis, we innovatively used Pax7-CreERT2/+ ;ß-cateninfx/fx transgenic mice (n = 12, per group, male). Knock out ß-catenin in SMSC to observe the proliferation and osteogenic differentiation of SMSCs, and OPF healing. In vitro primary cells of SMSCs from 3-month-old litter-negative ß-cateninfx/fx transgenic mice. After adenovirus-CRE transfection, the myogenic and osteogenic differentiation of SMSC was observed. RESULTS: We find that human SMSCs reduced proliferation and osteogenic differentiation in patients with OPF (-38.63%, P < 0.05). And through animal experiments, it was found that activation of ß-catenin promoted the proliferation and osteogenic differentiation of SMSC at the fracture site, thereby accelerating the healing of the fracture site (189.47%, P < 0.05). To prove this point of view, in the in vivo Pax7-CreERT2/+ ;ß-cateninfx/fx transgenic mouse experiment, we innovatively found that knocking out ß-catenin in SMSC will cause a decrease in bone mass and bone microstructure, and accompanied by delayed fracture healing (-35.04%, P < 0.001). At the same time, through in vitro SMSC culture experiments, it was found that their myogenic (-66.89%, P < 0.01) and osteogenic differentiation (-16.5%, P < 0.05) ability decreased. CONCLUSIONS: These results provide the first practical evidence for a direct contribution of SMSCs to promote the healing of OPF with important clinical implications as it may help in the treatment of delayed healing and non-union of OPFs, and mobilization of autologous stem cell therapy in orthopaedic applications.

Diabetes Risk Reduction Diet and Survival after Breast Cancer Diagnosis.

Type II diabetes is associated with poor breast cancer prognosis. To study the association between a diabetes risk reduction diet (DRRD) and survival following breast cancer, we followed 8,482 women with breast cancer from two large cohort studies. Information on diet and other factors was repeatedly measured in validated questionnaires every two to four years. The DRRD includes 9 components: higher intakes of cereal fiber, coffee, nuts, whole fruits and polyunsaturated/saturated fat ratio; and lower glycemic index, trans fat, sugar-sweetened beverages, and red meat. Cumulative average DRRD score was calculated using repeated measures of postdiagnostic diet. Deaths were assessed by family members or via National Death Index. Multivariable-adjusted HRs and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. During a median of 14 years of follow-up since diagnosis, 2,600 deaths occurred among participants, 1,042 of which were due to breast cancer. Women with higher postdiagnostic DRRD score had a 20% lower risk of breast cancer-specific mortality (top vs. bottom quintile HR = 0.80; 95% CI = 0.65-0.97; P trend = 0.02) and 34% lower risk of all-cause mortality (HR = 0.66; 95% CI = 0.58-0.76; P trend < 0.0001). Compared with women who consistently had lower score (≤median) before and after diagnosis, those whose score improved from low to high had a lower risk of breast cancer-specific mortality (HR = 0.77; 95% CI = 0.62-0.95) and overall mortality (HR = 0.85; 95% CI = 0.74-0.97). These findings demonstrate that greater adherence to DRRD was associated with better survival, suggesting postdiagnosis dietary modification consistent with type II diabetes prevention may be important for breast cancer survivors. SIGNIFICANCE: This study suggests that greater adherence to the diabetes risk reduction diet after diagnosis associates with improved survival outcomes among a large number of breast cancer survivors.

Oral delivery of liraglutide-loaded Poly-N-(2-hydroxypropyl) methacrylamide/chitosan nanoparticles: Preparation, characterization, and pharmacokinetics.

The delivery of peptides or protein drugs via the oral route has always presented a significant challenge. Here, nanoparticles for the oral delivery of liraglutide are prepared. The nanoparticles are composed of the biodegradable carrier materials chitosan and poly-N-(2-hydroxypropyl) methacrylamide (pHPMA). In addition, CSKSSDYQC (CSK) and hemagglutinin-2 (HA2) are introduced into the particles to improve the in vivo bioavailability of liraglutide. The size of the nanoparticles is less than 200 nm, and the encapsulation efficiency is approximately 80%. Compared with the subcutaneously injected liraglutide solution group (100%), the relative bioavailability of the nanoparticle group modified with CSK and HA2 reached 10.12%, which is 2.53 times that of the oral liraglutide solution group. In vivo imaging results showed that pHPMA/HA2-CSK chitosan nanoparticles (pHPMA/HA-CCNPs) are retained in the gastrointestinal tract for up to 12 h, which is beneficial for oral absorption. CSK and HA2 modified pHPMA/chitosan nanoparticles significantly improved liraglutide oral bioavailability and therefore have the potential to be applied for oral administration of peptides and proteins.

Synchronous multiple primary lung cancers with shared EGFR mutation but differential imaging findings and pathological subtypes: A case report.

Lung cancer is a leading cause of cancer mortality worldwide. As the incidence of lung cancer increases in recent years, the number of patients diagnosed with synchronous multiple primary lung cancers (SMPLC) is also rising. SMPLC diagnosis is often made based on the clinical course, imaging findings, and histologic and molecular features. Standard lobectomy is the main therapeutic modality for SMPLC. Because maximum retention of lung function is essential, sublobectomy is also a commonly used surgical strategy when appropriate. The question is how to optimize the sequence of lobectomy and sublobectomy for patients with SMPLC. Thoracoscope lobectomy for the primary lesion plus sublobectomy for the secondary lesions is the most commonly used approach. Here we present a case of SMPLC with sublobectomy followed by lobectomy.

Corrigendum: Alleviation of Synovial Inflammation of Juanbi-Tang on Collagen-Induced Arthritis and TNF-Tg Mice Model.

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Use of Baidu Index to Track Chinese Online Behavior and Interest in Kidney Stones.

BACKGROUND AND AIM: Baidu, currently the top online search tool in China, has developed an internet search trends gathering and analysis tool called the Baidu Index. The aim of this study was to explore the value of the Baidu Index for monitoring online kidney stones-related information-seeking behavior and understanding of population features and priorities in China. MATERIALS AND METHODS: The Baidu Index was queried using the term "kidney stones" for the period 2014-2018. The search volume was recorded as well as a demand graph, with a geographic and demographic distribution. For surgical treatment modalities, the medical term "extracorporeal shock wave lithotripsy (ESWL)" was analyzed and then compared to the term "kidney stone surgery" to assess changes. RESULTS: The search trend for the term "kidney stones" remained sustained growth over time. Searches were mostly presented by the age 20-49, in males in the south of China. The demand graph indicated that the diagnosis, followed by the treatment, and dietary control of kidney stones had received the most attention. The search volume related to ESWL showed a similar increasing trend, but was searched with a greater volume than the term "kidney stone surgery" for most of the last 5 years. CONCLUSION: The Baidu Index is a useful tool to track online health information-seeking behavior of internet users in China. The geographic and demographic characteristics in kidney stones seem to be reflected in online search trend data to some extent.

Menopausal hormone therapy use and long-term all-cause and cause-specific mortality in the Long Island Breast Cancer Study Project.

Previous studies have observed a reduced mortality risk associated with menopausal hormone therapy (MHT) use among breast cancer survivors. We sought to clarify whether such association could be explained by tumor heterogeneity, specific causes of death, confounding from comorbidities or health behaviors, and a comparison group of women without breast cancer. We interviewed 1508 women newly diagnosed with first primary breast cancer in 1996 to 1997 (~3 months after diagnosis), and 1556 age-matched women without breast cancer, about MHT use history. The National Death Index was used to ascertain vital status after a median of 17.6 years of follow-up (N = 597 deaths for breast cancer subjects). Multivariable-adjusted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs) for all-cause mortality, and cause-specific HR (cHR) for breast cancer and cardiovascular disease (CVD). The Fine-Gray model was used to account for competing causes of death. Among women with breast cancer, ever vs never MHT use was inversely associated with all-cause (HR = 0.77, 95%CI = 0.62-0.95), breast cancer-specific (cHR = 0.69, 95%CI = 0.48-0.98), and CVD-specific mortality (cHR = 0.57, 95%CI = 0.38-0.85). Difference of the association was observed in breast cancer-specific mortality according to hormone receptor status (negative tumors: cHR = 0.44, 95%CI = 0.19-1.01; positive tumors: cHR = 0.96, 95%CI = 0.60-1.53). Among the comparison group, we observed similar, but more modest inverse associations for all-cause and CVD-specific mortality. MHT use was inversely associated with mortality after breast cancer, even after accounting for competing causes of death and multiple confounders, and was evident among women without breast cancer. Potential heterogeneity by hormone receptor status requires more study.

Urinary Estrogen Metabolites and Long-Term Mortality Following Breast Cancer.

BACKGROUND: Estrogen metabolite concentrations of 2-hydroxyestrone (2-OHE1) and 16-hydroxyestrone (16-OHE1) may be associated with breast carcinogenesis. However, no study has investigated their possible impact on mortality after breast cancer. METHODS: This population-based study was initiated in 1996-1997 with spot urine samples obtained shortly after diagnosis (mean = 96 days) from 683 women newly diagnosed with first primary breast cancer and 434 age-matched women without breast cancer. We measured urinary concentrations of 2-OHE1 and 16-OHE1 using an enzyme-linked immunoassay. Vital status was determined via the National Death Index (n = 244 deaths after a median of 17.7 years of follow-up). We used multivariable-adjusted Cox proportional hazards to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the estrogen metabolites-mortality association. We evaluated effect modification using likelihood ratio tests. All statistical tests were two-sided. RESULTS: Urinary concentrations of the 2-OHE1 to 16-OHE1 ratio (>median of 1.8 vs ≤median) were inversely associated with all-cause mortality (HR = 0.74, 95% CI = 0.56 to 0.98) among women with breast cancer. Reduced hazard was also observed for breast cancer mortality (HR = 0.73, 95% CI = 0.45 to 1.17) and cardiovascular diseases mortality (HR = 0.76, 95% CI = 0.47 to 1.23), although the 95% confidence intervals included the null. Similar findings were also observed for women without breast cancer. The association with all-cause mortality was more pronounced among breast cancer participants who began chemotherapy before urine collection (n = 118, HR = 0.42, 95% CI = 0.22 to 0.81) than among those who had not (n = 559, HR = 0.98, 95% CI = 0.72 to 1.34; P interaction = .008). CONCLUSIONS: The urinary 2-OHE1 to 16-OHE1 ratio may be inversely associated with long-term all-cause mortality, which may depend on cancer treatment status at the time of urine collection.

Diabetes and cardiovascular disease mortality among a population-based cohort of women with and without breast cancer.

PURPOSE: We investigated whether the relationship between diabetes and all-cause and CVD-related mortality differed between women with and without breast cancer among a cohort drawn from the same source population. METHODS: We interviewed 1,363 women newly diagnosed with breast cancer in 1996-1997, and 1,358 age-matched women without breast cancer, to assess history of physician-diagnosed diabetes. All-cause (n = 631) and CVD-specific mortality (n = 234) was determined by the National Death Index through 2009. We estimated multivariable-adjusted hazard ratios (HRs) for the rates of all-cause and CVD-specific mortality and, to account for competing causes of death, and subdistribution HRs (sHRs) for risk of CVD-related death. RESULTS: Among women with and without breast cancer, respectively, diabetes was associated with: all-cause mortality [HR (95% CI) 1.52 (1.13, 2.05) and 2.17 (1.46, 3.22)]; CVD-specific deaths [1.74 (1.06, 2.84) and 2.06 (1.11, 3.84)]; and risk of CVD-related death [sHR 1.36 (0.81, 2.27) and 1.79 (0.94, 3.40)]. Differences in effect estimates between women with and without breast cancer did not reach statistical significance (p-interaction > 0.10). CONCLUSION: We found that the positive association between a history of physician-diagnosed diabetes and risk of all-cause and CVD-related mortality is of similar magnitude among a population-based cohort of women with or without breast cancer.

Alleviation of Synovial Inflammation of Juanbi-Tang on Collagen-Induced Arthritis and TNF-Tg Mice Model.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is primarily characterized by synovial inflammation. In this study, we found that a traditional Chinese decoction, Juanbi-Tang (JBT), JBT attenuated the symptoms of collagen-induced arthritis (CIA) mice and in tumor necrosis factor transgenic (TNF-Tg) mice by attenuating the arthritis index and hind paw thickness. According to histopathological staining of ankle sections, JBT significantly decreased the area of inflammation and reduced bone destruction of ankle joints in both these two types of mice. Moreover, decreased tartaric acid phosphatase-positive osteoclasts were observed in the JBT group compared with those found in the control group. We also revealed that JBT suppressed monocytes and T cells as well as the production of CCL2, CCR6, and CXCR3 ligands. We next used high-performance liquid chromatography to investigate the components and pharmacological properties of this classical herbal medicine in traditional Chinese medicine. Based on network pharmacology, we performed computational prediction simulation of the potential targets of JBT, which indicated the NF-kappa B pathway as its target, which was confirmed in vitro. JBT suppressed the production of pro-inflammatory cytokines including interleukin-6 (IL-6) and IL-8, and inhibited the expression of matrix metalloproteinase 1 in fibroblast-like synoviocytes derived from RA patients (MH7A cells). Furthermore, JBT also suppressed the phosphorylation of p38, JNK, and p65 in TNF-α-treated MH7A cells. In summary, this study proved that JBT could inhibit synovial inflammation and bone destruction, possibly by blocking the phosphorylation of NF-kappa B pathway-mediated production of proinflammatory effectors.

Quantitative expression of MMPs 2, 9, 14, and collagen IV in LCIS and paired normal breast tissue.

Certain matrix metalloproteinases (MMPs) have the ability to degrade collagen IV, a main component of the breast lobular basement membrane. In this cross-sectional study, we evaluated expression of MMPs 2, 9, and 14 and collagen IV in LCIS and adjacent normal breast tissue among LCIS patients without invasive breast cancer to determine whether expression differed between benign and preinvasive breast epithelial tissue. A total of 64 LCIS patients, diagnosed 2004-2014, were included; 44 had sufficient paired normal tissue for analysis. Marker epithelial expression was measured using immunofluorescence and quantified using the H score (MMPs) or pixel intensity (collagen IV). Associations were evaluated using the Spearman correlation or the Wilcoxon signed-rank test. In LCIS and normal tissue, there was a strong correlation between MMP2 and MMP14 expression (LCIS r = 0.69, normal r = 0.81, both P < 0.01). Other pairwise correlations were moderate to weak (range: LCIS r = 0.32-0.47, normal r = 0.19-0.32). For all markers, expression was lower in LCIS vs. normal tissue (all P ≤ 0.05). In sum, collagenase MMPs were expressed in normal breast and LCIS lesions of LCIS patients. However, expression was not higher in LCIS compared with normal tissue, suggesting collagenase MMP expression does not increase as breast tissue gains a more proliferative phenotype.