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The cell of origin and the development of breast cancer are not fully elucidated in BRCA1 mutation carriers, especially for estrogen receptor (ER)–positive breast cancers. Here, we performed single-cell RNA sequencing (RNA-seq) on 82,122 cells isolated from the breast cancer tissues and adjacent or prophylactic normal breast tissues from four BRCA1 mutation carriers and three noncarriers. Whole-exome sequencing was performed on breast tumors from the four BRCA1 mutation carriers; for validation, bulk RNA-seq was performed on adjacent normal breast tissues from eight additional BRCA1 mutation carriers and 14 noncarriers. Correlation analyses suggested that breast cancers in BRCA1 mutation carriers might originate from luminal cells. The aberrant luminal progenitor cells with impaired differentiation were significantly increased in normal breast tissues in BRCA1 mutation carriers compared with noncarriers. These observations were further validated by the bulk RNA-seq data from additional BRCA1 mutation carriers. These data suggest that the cell of origin of basal-like breast tumors (ERneg) in BRCA1 mutation carriers might be luminal progenitor cells. The expression of TP53 and BRCA1 was decreased in luminal progenitor cells from normal breast tissue in BRCA1 mutation carriers, which might trigger the basal/mesenchymal transition of luminal progenitors and might result in basal-like tumor development. Furthermore, ERhigh luminal tumors might originate from mature luminal cells. Our study provides in-depth evidence regarding the cells of origin of different breast cancer subtypes in BRCA1 mutation carriers. Significance: Single-cell RNA-seq data indicate that basal-like breast cancer (ERneg) might originate from luminal progenitors, and ERhigh luminal breast cancer might originate from mature luminal cells in BRCA1 mutation carriers.

Characterizing the pathogenicity of BRCA1 variants of uncertain significance (VUSs) is a major bottleneck in clinical management of BRCA1-associated breast cancer. Saturation genome editing (SGE) was recently reported as an innovative laboratory-based approach to assess the pathogenicity of BRCA1 variants. We combined clinical phenotypes and SGE score to identify the pathogenicity of BRCA1 VUSs detected in a cohort of 8,085 breast cancer patients. According to SGE function score, 33 out of 144 BRCA1 VUSs detected were classified into “loss of function” (n = 13), “intermediate” (n = 2), and “functional” (n = 18) groups. Compared with non-carriers, “loss of function” VUS carriers (n = 19) presented significantly worse clinicopathological characteristics. These included younger age at breast cancer diagnosis (44.4 years vs. 51.2 years, P = 0.01), stronger family history of any cancer (57.9% vs. 32.3%, P = 0.017) especially breast or ovarian cancer (47.4% vs. 9.3%, P

Whether adding carboplatin to standard neoadjuvant chemotherapy improves survival in BRCA1/2-mutated triple-negative breast cancer (TNBC) is unknown. In this retrospective study, we aimed to explore the efficacy of anthracycline-taxane (A-T)-based or anthracycline-taxane/carboplatin (A-TP)-based neoadjuvant chemotherapy in BRCA1/2-mutated TNBC. A total of 1585 operable primary breast cancer patients were treated with either neoadjuvant A-T (n = 886) or A-TP regimen (n = 699). BRCA1 and BRCA2 germline mutations were determined in all subjects. Pathological complete response (pCR), recurrence-free survival (RFS), distant recurrence-free survival (DRFS) and overall survival (OS) were estimated. Of the entire cohort, 102 patients (6.4%) carried a pathogenic BRCA1/2 germline mutation. After a median follow-up of 81 months, no significant differences in survival between the A-T and A-TP arms were found in the entire cohort. However, among 288 TNBC patients, BRCA1/2 mutation carriers had significantly better survival when treated with the A-TP regimen than with the A-T regimen (5-year RFS: 82.6% vs 47.9%; P = .024; 5-year DRFS: 88.5% vs 46.9%; P = .010; 5-year OS: 88.2% vs 49.9%; P = .036). Multivariate analyses revealed that the A-TP regimen was a significantly favourable factor for RFS and DRFS and showed a trend towards better OS when compared with the A-T regimen in BRCA1/2-mutated TNBC (RFS: adjusted hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.06-0.91, P = .035; DRFS: HR, 0.17; 95% CI, 0.03-0.80; P = .025; OS: HR, 0.29; 95% CI, 0.06-1.49; P = .14). Our study suggested that BRCA1/2-mutated TNBC patients gain a survival benefit when carboplatin is added to standard A-T-based neoadjuvant chemotherapy.

This study aimed to compare the effect of BCT versus mastectomy on the recurrence and survival of different-aged patients, and to investigate whether effects of BCT versus mastectomy on survival of young patients were consistent with those of old patients. Data on women with primary invasive breast cancer between 2007 and 2011 were extracted from the institutional database of Breast Center. Disparities in hormone receptor, tumor size, lymph node status, and Her-2 status between BCT and mastectomy groups were adjusted using the propensity score (PS) adjustment method. Patients were divided by age into two groups (≤ 40 years and > 40 years). We assessed proportions of local recurrence (LR), distant disease-free survival (DDFS), disease-free survival (DFS), and breast cancer-specific survival (BCSS) in different-aged groups; this assessment was further stratified by surgical treatment. A total of 2964 patients were included; 565 (19%) were aged ≤ 40 years. In the entire cohort, hazard ratios (HR) of BCT versus mastectomy for DDFS and DFS were 0.56 (P = 0.029) and 0.55 (P = 0.008), respectively. After PS adjustment, there was no significant difference between BCT and mastectomy in LR, DDFS, DFS and BCSS in the young age group. In the old age group, women who underwent BCT exhibited improved DDFS (HR 0.57, 95% CI 0.39–0.84, P = 0.004). BCT did not significantly affect survival outcomes of young patients with breast cancer. Superior survival of BCT compared to mastectomy was observed only in old patients.

To compare outcomes in patients with human epidermal growth factor receptor-2 (HER2)-positive breast cancer who received either dose-dense neoadjuvant chemotherapy (NAC) with trastuzumab or standard-interval chemotherapy with trastuzumab. Patients with HER2-positive breast cancer who received NAC, including epirubicin and cyclophosphamide followed by paclitaxel with trastuzumab were included. Patients were divided into either the dose-dense or standard-interval group. We compared pathologic complete remission (pCR), distant disease-free survival (DDFS), event-free survival (EFS), and breast cancer-specific survival (BCSS) between the two groups. Two hundred (49.6%) patients received dose-dense NAC, and 203 (50.4%) received standard-interval NAC. The pCR rate was 38.4% in the dose-dense group and 29.2% in the standard-interval group (P = 0.052). In patients with lymph node (LN) metastases, the LN pCR rate was 70.9% in the dose-dense group and 56.5% in the standard-interval group (P = 0.037). After a median follow-up of 54.6 months, dose-dense chemotherapy presented an improvement on DDFS (hazard ratio [HR] = 0.49, 95% confidence interval [CI]: 0.19–1.28, EFS (HR = 0.54, 95% CI: 0.24–1.21), and BCSS (HR = 0.41, 95% CI: 0.11–1.51), but the difference was not significant. Compared with standard-interval chemotherapy, dose-dense chemotherapy resulted in a superior 5-year DDFS (100% vs. 75.3%, P = 0.017) and 5-year EFS (96.9% vs. 78.3%, P = 0.022) in patients younger than 40 years. HER2-positive patients can achieve a higher LN pCR rate with dose-dense NAC than with standard-interval NAC with trastuzumab. Better survival may also be achieved with dose-dense chemotherapy with trastuzumab than with standard-interval chemotherapy with trastuzumab among young patients (age ≤ 40 years).

Background The status of axillary lymph nodes (ALNs) is one of the important factors in decision-making for breast cancer treatment. Physical examination (PE) has long been the main, or even the only, means of clinical staging for ALNs in breast cancer. However, the sensitivity and accuracy of PE remains unsatisfactory. The results from this study suggest that axillary ultrasonography (US) should replace PE as a standard method for the clinical staging of ALNs in breast cancer. Methods Consecutive and nonselective breast cancer patients treated between September 2018 and November 2018 in our center were enrolled in the study. Comparisons of ALN results between PE/US and pathological results were conducted and the difference in sensitivity, specificity and accuracy between PE and US were tested by McNemar chi-square test. Results A total of 123 patients were enrolled into the study. Their ages ranged from 28 to 76 years with a median age of 53 ± 10. There were 83 ALN positive cases and 40 ALN negative cases confirmed pathologically. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value of PE and US were 54.2%, 90.0%, 65.9%, 91.8%, 48.7% versus 86.8%, 72.5%, 82.1%, 86.8%, 72.5%, respectively. The sensitivity and accuracy of US was significantly higher than that of PE (P = 0.004 and P = 0.002). Conclusion The results of this study demonstrated that US is superior in evaluating ALNs when compared with PE and that US should replace PE as the standard method for the clinical staging of ALNs in breast cancer.

Background Myasthenia gravis (MG) is an autoimmune diseases characterized by fatigue and weakness of skeletal muscles. B-lymphocyte-activating factor (BAFF), an essential factor for B cell differentiation and development, is important in the progression of MG. The current study aimed to investigate the association between single nucleotide polymorphism rs2893321 in BAFF with MG susceptibility in Chinese Han population. Methods One hundred forty-nine patients with MG and 148 healthy controls were recruited. Using improved multiple ligase detection reaction technology, the polymorphisms of rs2893321 between groups and among MG subgroups have been compared. Results A significant differences between the MG group and the healthy control group was observed. Additionally, rs2893321 was found to be associated with gender and age in patients with MG. Conclusion Genetic variations of rs2893321 in BAFF might be associated with susceptibility to MG in the Chinese Han population.

BRCA1/2 genes are the most frequently germline mutated DNA‐repair genes, and the survival of BRCA1/2 carriers has been extensively explored in breast cancer. However, the prevalence of germline mutations in non‐BRCA1/2 DNA‐repair genes and the survival of carriers are largely unknown in a large cohort of unselected breast cancer patients. Germline mutations in 16 DNA‐repair genes were determined using a multigene panel in 7657 BRCA1/2‐negative breast cancer patients who were unselected for family history of cancer or age at diagnosis. Among the 7657 BRCA1/2‐negative breast cancer patients, 257 (3.4%) carried at least 1 pathogenic germline mutation in the 16 DNA‐repair genes. The prevalence of DNA‐repair gene mutations was significantly higher in familial breast cancers (5.2%, P = 0.002) and early‐onset breast cancers (diagnosed at and before the age of 40) (4.5%, P = 0.003) than that of sporadic breast cancers (2.9%) (diagnosed above age of 40), respectively. The DNA‐repair gene mutation carriers were significantly more likely to have a larger tumor (P = 0.04) and axillary lymph node metastasis (P = 0.03). Moreover, DNA‐repair gene mutation was an independent unfavorable factor for recurrence‐free survival (adjusted hazard ratio [HR] = 1.38, 95% CI: 1.00‐1.91, P = 0.05) and disease‐specific survival (adjusted HR=1.63, 95% CI: 1.04‐2.57, P = 0.03) in this cohort. Overall, 3.4% of BRCA1/2‐negative breast cancer patients carried germline mutations in the 16 DNA‐repair genes, and the DNA‐repair gene mutation carriers exhibited an aggressive phenotype and had poor survival compared with noncarriers., In this study, we determined germline mutations in 16 DNA‐repair genes in a large cohort of 7657 BRCA1/2‐negative breast cancer patients. We observed that 3.4% of patients harbored at least 1 pathogenic mutation in DNA‐repair genes in this cohort; moreover, the DNA‐repair gene mutation carriers exhibited an aggressive phenotype and had poor survival compared with noncarriers.

The role of long-acting hematopoietic growth factor in supporting dose-dense chemotherapy and minimizing hematologic toxicity has not been established. We investigated the efficacy and safety of once-per-cycle pegfilgrastim in breast cancer patients receiving neoadjuvant dose-dense epirubicin and cyclophosphamide (ddEC). Newly diagnosed stage I to III breast cancer patients received four cycles of ddEC (E, 100 mg/m2 and C, 600 mg/m2 every 2 weeks) and 6 mg of subcutaneous pegfilgrastim on day 2 of each cycle. The primary endpoint was to evaluate the incidence of chemotherapy delay. Secondary endpoints include the incidences of febrile neutropenia (FN) and grade 3/4 neutropenia during the four ddEC cycles. A total of 240 patients were enrolled and 913 ddEC cycles were administered in the study. Chemotherapy delay occurred in 15 patients (6.3% of patients, 95% CI 3.2–9.4%) for 17 cycles (1.9% of cycles, 95% CI 1.0–2.8%). The most frequent cause of chemotherapy delay was transaminase elevation (10 patients, 12 cycles). A total of 12 patients (5.0%, 95% CI 2.2–7.8%) developed 13 episodes of FN. Of the 221 patients that completed four ddEC cycles with pegfilgrastim support, 209 patients (94.6%, 95% CI 91.6–97.6%) had a 100% relative dose intensity (RDI). A RDI ≥ 85% was achieved in 217 of 221 patients (98.2%, 95% CI 96.5–99.9%). Bone pain of any grade was recorded in 85 of 220 evaluable patients (38.6%, 95% CI 32.2–45.0%). Pegfilgrastim is effective and safe in facilitating four cycles of neoadjuvant ddEC, with low incidences of chemotherapy delay and febrile neutropenia.

Background: We investigated the effects of risk factors on the incidence of local recurrence (LR) in patients who underwent breast-conserving treatment (BCT) for primary breast cancer at a single institution in China from 1999 to 2011. Methods: Patient outcomes were compared with respect to LR, ipsilateral breast tumor recurrence (IBTR), distant disease-free survival (DDFS), and disease-free survival (DFS). Additionally, the risk factors for relapse after BCT were studied. Results: The 2028 patients with invasive breast cancer included in this study were followed for a median of 95 months, during which the 8-year LR, IBTR, DDFS, and DFS rates were 2.6%, 3.0%, 93.7%, and 91.3%, respectively. Lymph node involvement, the human epidermal growth factor receptor 2 (HER2) status, and the use of computed tomography (CT) information during boost field planning were identified as significant predictors of LR and IBTR. Notably, use of the surgical scar for tumor bed identification during boost field planning was associated with a higher adjusted risk of LR, compared with the use of CT. By contrast, the neoadjuvant chemotherapy (NAC) was not an independent predictor of LR (hazard ratio of no NAC vs. NAC, 0.63; 95% confidence interval, 0.33-1.19; P = 0.157). In a multivariate analysis, the age at diagnosis, tumor diameter, lymph node involvement, HER2-positive status, and use of CT information during boost field planning were identified as significant factors affecting DFS. Conclusions: The use of CT information during boost field planning could reduce the risk of LR among patients undergoing BCT. Neoadjuvant and adjuvant treatments for breast cancer did not show the significant difference in respect to the outcome of LR.

Acetaminophen (N-acetyl-p-aminophenol, APAP) is one of the most common antipyretic analgesics used to treat common ailments throughout the world. Recently, APAP has been frequently detected in wastewater effluent and groundwater, resulting in potential risks to the environment. Current methods for eliminating APAP are complicated and cost-prohibitive. This study examined APAP degradation by ultraviolet-C (UV-C) and UV-C irradiation combined with activated sludge (UV/AS) to evaluate potential applications in wastewater treatment. The results of this study indicate that UV-C irradiation reached an APAP degradation efficiency of more than 52% and a degradation rate of 0.0012–0.0013 min−1 during 720 min of exposure, while the initial APAP concentration exhibited only a nominal effect on the degradation rate. However, the UV/AS treatment demonstrated an APAP degradation rate that was 9.6 times the rate of the UV-C-only treatment, with a degradation efficiency of 99% over the same UV irradiation period. The results further indicated that APAP photolysis efficiency was more effective when applied to sterilized AS than when applied to unsterilized AS. Finally, excessive dosage of both AS and humic acid inhibited APAP photolysis efficiency.

Myasthenia gravis (MG) is a cell-dependent autoimmune disease commonly associated with thymic pathology. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) has been associated with gene regulation and alternative splicing. It has shown relationship with proliferation, apoptosis, migration, and invasion. In this study, we found that MALAT-1 expression was downregulated in MG. The level of the miR-338-3p was increased in peripheral blood mononuclear cells from MG patients compared with those from control subjects. MALAT-1 competed for binding to miR-338-3p with male-specific lethal 2 (MSL2) in luciferase reporter assays. We confirmed the MALAT-1-miR-338-3p-MSL2 interaction network in MG in vitro. Thus, MALAT-1 directly induced MSL2 expression in MG by acting as a competing endogenous RNA for miR-338-3p, suggesting that it may serve as a therapeutic target for MG treatment.

PURPOSE To investigate the association between the HER2 germline mutation Ala270Ser (A270S), located in HER2 extracellular domain, and survival in breast cancer patients. METHODS HER2 germline mutation A270S was identified in 5395 consecutive patients with operable primary breast cancer using direct Sanger sequencing analysis. Survival curves for patients with HER2 A270S mutation were compared using the Kaplan-Meier method with log-rank test. RESULTS We identified that 31 cases carried HER2 germline mutation A270S in 5395 patients (0.6%, 31/5395). The HER2 A270S mutation was significantly associated with recurrence-free survival (RFS) and distant recurrence-free survival (DRFS) in the entire cohort of 5395 patients (RFS, unadjusted hazard ratio [HR] = 2.23; 95% confidence interval [CI] = 1.00-5.00; P= 0.045; DRFS, unadjusted HR = 2.80; 95% CI = 1.25-6.28; P= 0.009). Among the HER2-negative patients (n= 3825), those with the HER2 A270S mutation had a significantly worse RFS (unadjusted HR = 3.19; 95% CI = 1.42-7.16; P= 0.003) and DRFS (unadjusted HR = 3.98; 95% CI = 1.77-8.96; P< 0.001) than did those with wild type. Moreover, the A270S mutation remained an independent unfavorable factor for RFS and DRFS in the HER2-negative patients (RFS, HR = 3.30; 95% CI = 1.34-8.10; P= 0.009; DRFS, HR = 4.26; 95% CI = 1.73-10.47; P= 0.002). CONCLUSIONS Breast cancer patients with the HER2 germline mutation A270S had a worse survival, especially in HER2-negative patients. Therefore, HER2-negative patients with a HER2 germline mutation A270S might be potential candidates for HER2-targeted therapy.

RAD50 is a highly conserved DNA double-strand break (DSB) repair gene. However, the associations between RAD50 germline mutations and the survival and risk of breast cancer have not been fully elucidated. Here, we aimed to investigate the clinical impact of RAD50 germline mutations in a large cohort of unselected breast cancer patients. In our study, RAD50 germline mutations were determined using next-generation sequencing in 7657 consecutive unselected breast cancer patients without BRCA1/2 mutations. We also screened for RAD50 recurrent mutations (L719fs, K994fs, and H1269fs) in 5000 healthy controls using Sanger sequencing. We found that 26 out of 7,657 (0.34%) patients had RAD50 pathogenic mutations, and 16 patients carried one of the three recurrent mutations (L719fs, n = 6 cases; K994fs, n = 5 cases; and H1269fs, n = 5 cases); the recurrent mutation rate was 0.21%. The frequency of the three recurrent mutations in the 5,000 healthy controls was 0.18% (9/5,000). These mutations did not confer an increased risk of breast cancer in the studied patients [odds ratios (OR), 1.16; 95% confidence interval (CI), 0.51-2.63; p = 0.72]. Nevertheless, multivariate analysis revealed that RAD50 pathogenic mutations were an independent unfavourable predictor of recurrence-free survival (RFS) [adjusted hazard ratio (HR) 2.66; 95% CI, 1.18-5.98; p = 0.018] and disease-specific survival (DSS; adjusted HR 4.36; 95% CI, 1.58-12.03; p = 0.004) in the entire study cohort. Our study suggested that RAD50 germline mutations are not associated with an increased risk of breast cancer, but patients with RAD50 germline mutations have unfavourable survival compared to patients without these mutations.

Cell-cycle-checkpoint kinase 2 (CHEK2) is an important moderate-penetrance breast cancer predisposition gene; however, recurrent CHEK2 mutations found in Caucasian women are very rare in Chinese population. We investigated the mutation spectrum and clinical relevance of CHEK2 germline mutations in Chinese breast cancer patients. The entire coding regions and splicing sites of CHEK2 were screened in 7657 Chinese BRCA1/2-negative breast cancer patients, using 62-gene panel-based sequencing. Out of 7657 BRCA1/2-negative breast cancer patients, 26 (0.34%) carried CHEK2 pathogenic germline mutations. Most of these mutations (92.3%, 24/26) were nonsense or frameshift mutations; 84.6% (22/26) of them were in forkhead-associated (FHA) or kinase domains. Of the 18 types of CHEK2 mutations we found, 61.1% (11/18) of were novel mutations and two recurrent mutations (Y139X and R137X) were found in this cohort. Patients with CHEK2 mutations were significantly more likely to have family histories of breast and/or ovarian cancer (23.1% vs. 8.6%, p = 0.022) and family histories of any cancer (50.0% vs. 31.6%, p = 0.044); and were significantly more likely to have lymph node-positive (53.8% vs. 27.3%, p = 0.002) and progesterone receptor (PR)-positive (88.5% vs. 64.5%, p = 0.011) breast cancers. Among Chinese breast cancer patients, the CHEK2 germline mutation rate is approximately 0.34% and two specific mutations (Y139X and R137X) are recurrent. Patients with CHEK2 mutations are significantly more likely to have family histories of cancer, and to develop lymph node-positive and/or PR-positive breast cancers.

It is well known that BRCA1 and BRCA2 play a central role in DNA repair, but the relationship between BRCA1 and BRCA2 mRNA expression and response to neoadjuvant chemotherapy in sporadic breast cancer patients has not been well established. Here, we investigate the association between BRCA1 or BRCA2 mRNA expression levels and pathological response in 674 BRCA1/2 mutation-negative breast cancer patients who received neoadjuvant chemotherapy. BRCA1 and BRCA2 mRNA expression were assessed using quantitative real-time polymerase chain reaction in core biopsy breast cancer tissue obtained prior to the initiation of neoadjuvant chemotherapy. A total 129 patients (19.1%) achieved pathological complete response (pCR) after neoadjuvant chemotherapy. Among patients treated with anthracycline-based chemotherapy (n = 531), BRCA1 mRNA low expression patients had a significantly higher pCR rate than intermediate or high BRCA1 mRNA expression groups (24.6% vs 16.8% or 14.0%, P = .031) and retained borderline significance (OR = 1.54, 95% CI = 0.93-2.56, P = .094) in multivariate analysis. Among the 129 patients who received a taxane-based regimen, pCR rate showed no differences in BRCA1 low, intermediate, and high mRNA level subgroups (19.6%, 26.8% and 21.4%, respectively; P = .71). BRCA2 mRNA level was not associated with pCR rate in the anthracyline-based treated subgroup (P = .60) or the taxane-based regimen subgroup (P = .82). Taken together, our findings suggested that BRCA1 mRNA expression could be used as a predictive marker in BRCA1/2 mutation-negative breast cancer patients who received neoadjuvant anthracycline-based treatment.

Purpose: The prevalence of mutations in cancer susceptibility genes such as BRCA1 and BRCA2 and other cancer susceptibility genes and their clinical relevance are largely unknown among a large series of unselected breast cancer patients in the Chinese population. Experimental Design: A total of 8,085 consecutive unselected Chinese breast cancer patients were enrolled. Germline mutations in 46 cancer susceptibility genes were detected using a 62-gene panel. Results: Pathogenic mutations were identified in 9.2% of patients among the 8,085 unselected breast cancer patients. Of these, 5.3% of patients carried a BRCA1 or BRCA2 mutation (1.8% in BRCA1 and 3.5% in BRCA2), 2.9% carried other breast cancer susceptibility genes (BOCG) and 1.0% carried another cancer susceptibility genes. Triple-negative breast cancers had the highest prevalence of BRCA1/2 mutations (11.2%) and other BOCG mutations (3.8%) among the four molecular subgroups, whereas ER−/PR−HER2+ breast cancers had the lowest mutations in BRCA1/2 (1.8%) and BOCG (1.6%). In addition, BRCA1 mutation carriers had a significant worse disease-free survival [unadjusted hazard ratio (HR) 1.60; 95% confidence interval (CI) 1.10–2.34; P = 0.014] and disease-specific survival (unadjusted HR 1.96; 95% CI, 1.03–3.65; P = 0.040) than did non-carriers, whereas no significant difference in survival was found between BRCA2 mutation carriers and non-carriers. Conclusions: 9.2% of breast cancer patients carry a pathogenic mutation in cancer susceptibility genes in this large unselected series. Triple-negative breast cancers have the highest prevalence of mutations in BRCA1 /2 and other breast cancer susceptibility genes among the four molecular subgroups, whereas ER−/PR−HER2+ breast cancers had the lowest mutations in these genes. Clin Cancer Res; 23(20); 6113–9. ©2017 AACR.

Summary It is well documented that HER2 overexpression/amplification is associated with the poor survival in breast cancer patients. However, it is largely unknown whether HER2 somatic mutations are associated with the survival in HER2-negative breast cancer patients. Here, we identified HER2 somatic mutations in tumors from 1,348 unselected breast cancer patients by sequencing the entire HER2 coding region. All these mutations were tested for in corresponding blood samples to determine whether they were somatic or germline mutations. We further investigated the associations between the HER2 somatic mutations and recurrence-free survival (RFS) and distant recurrence-free survival (DRFS) in this cohort of patients. We found that 27 of 1,348 (2.0%) of these patients carried a HER2 somatic mutation. In vitro experiments demonstrated that some of novel mutations and those with unknown functions increased HER2 activity. HER2 status was available for 1,306 patients, and the HER2 somatic mutation rates in HER2-positive (n=353) and HER2-negative breast cancers (n=953) were 1.4% and 2.3%, respectively. Among the HER2-negative patients, those with a HER2 somatic mutation had a significantly worse recurrence-free survival (unadjusted hazard ratio [HR] =2.67; 95% confidence interval [CI]: 1.25-5.72, P=0.002) and distant recurrence-free survival (unadjusted HR=2.50; 95% CI: 1.10-5.68, P=0.004) than those with wild-type HER2. Taken together, our findings suggested that HER2 somatic mutations occur at a higher frequency in HER2-negative breast cancer, and HER2-negative breast cancer patients with these mutations have poor survival. Therefore, HER2-negative patients with a HER2 somatic mutation are potentially good candidates for HER2-targeted therapy. This article is protected by copyright. All rights reserved.

Myasthenia gravis (MG) is a rare debilitating autoimmune neuromuscular disorder. Many studies have focused on the mechanism and treatment strategies of MG. However, the exact pathogenesis of MG and effective treatment strategies remain unclear. Recent studies have indicated that microRNAs (miRNAs or miRs) can regulate the pathological pathways of MG, suggesting their potential role in novel treatments. In the present study, we created a comprehensive catalog of experimentally confirmed MG risk genes and miRNAs by manually mining published literature and public databases. Based on these genes and miRNAs, we identified 41 MG risk pathways and 105 approved drugs that can affect these pathways. Some important MG-related pathways, such as hsa04060 (cytokine-cytokine receptor interaction) and hsa05200 (pathway in cancer), were found to be regulated by MG risk miRNAs and drugs. Furthermore, we constructed an miRNA-regulated drug-pathway network and identified miRNAs and drugs that synergistically regulate key MG pathways and biological processes. We developed a drug repurposing strategy to identify 25 drug repurposing candidates for MG; several of these drugs, such as rituximab, adalimumab, sunitinib, and muromonab, have the potential to be novel MG treatment drugs. This study provides novel insight into the pathogenesis of MG and potential drug candidates for MG were identified.

Microbial infection is one of the most common diseases in the world, which gives rise to morbidity and mortality. At present, the main treatment is using antibiotic drugs. However, the side effects range from fever and nausea to major allergic reactions cannot be ignored. Moreover, the increasing drug resistance also necessitates a new safe alternative therapeutic approach against the microbial infections. As non-antibiotic methods, photodynamic therapies (PDT) and anti-microbial blue light (ABL) therapies have been investigated in this field. However, one challenge of the PDT is the introduction of photosensitizers to the specific pathogens rather than the host cells. In contrast, ABL therapies inactivate the microbes without the involvement of exogenous photosensitizers. The general mechanism of ABL therapies is that ABL can excite the endogenous photosensitizers, and trigger the accumulation of cytotoxic reactive oxygen species (ROS), which in turn leads to cell damage. In this study, we investigated the inhibitive capability of the 405nm LED light source on Candida albicans (C. albicans). C. albicans is the most common pathogen of fungal infections. The intracellular ROS level of C. albicans was detected after the ABL irradiation. The results obtained from this study demonstrated that irradiation of 405nm LED significantly inactivated the C. albicans. The viability of C. albicans was reduced to 1% after 25 minutes of ABL exposure of 50mW/cm2. On the other hand, the intracellular ROS was increased by the ABL irradiation. This study demonstrates the effectiveness of applying 405nm LED to threat the infection caused by C. albicans, as the result of the stimulated accumulation of the intracellular cytotoxic ROS by this light.

To estimate the cumulative risk of contralateral breast cancer (CBC) in BRCA1/2 carriers in a large cohort of unselected Chinese breast cancer patients. Our study comprised 9,401 unselected Chinese breast cancer patients and BRCA1/2 germline mutations were determined in all patients. After a median follow-up of 5.7 years, 181 patients developed CBC in this cohort. Compared to noncarriers, BRCA1 and BRCA2 carriers had a 4.52-fold (95% CI, 2.63-7.76) and 5.54-fold (95% CI, 3.51-8.74) increased risk of CBC, respectively. The 10-year cumulative risk of CBC was 15.5% (95% CI, 9.9-24.2) for BRCA1 carriers, 17.5% (95% CI, 10.9-28.0) for BRCA2 carriers and 3.2% (95% CI, 2.5-4.1) for noncarriers. Younger age at first breast cancer diagnosis was significantly associated with an increased 10-year risk of CBC for BRCA1 carriers (≤40 years vs. >40 years: 21.5% vs. 11.9%, unadjusted hazard ratio [HR] = 2.51, 95% CI, 1.03-6.15, p = 0.044), but not for BRCA2 carriers and noncarriers. The 10-year cumulative CBC risk was significantly higher in both BRCA1 and BRCA2 carriers who had a family history of breast cancer than in those who did not (BRCA1: 27.5% vs. 9.4%, adjusted HR = 2.64, 95% CI, 1.01-6.97, p = 0.049; BRCA2: 27.1% vs. 12.8%, adjusted HR = 2.29, 95% CI, 1.04-5.06, p = 0.040). In conclusion, the risk of CBC was a substantial high in BRCA1/2 carriers in unselected Chinese breast cancer patients, and CBC risk is much more remarkable in both BRCA1 and BRCA2 carriers who had a family history of breast cancer. Younger age at first breast cancer diagnosis also enhanced CBC risk in BRCA1 carriers.

To investigate the prevalence and clinical relevance of PALB2 germline mutations in BRCA1/2-negative breast cancer patients. The exons and intron–exon boundaries of the PALB2 gene were sequenced by multigene panel testing in a cohort of 7657 Chinese BRCA1/2-negative breast cancer patients. Of the 7657 patients, 54 (0.71%) carried pathogenic PALB2 germline mutations, all of which were nonsense or frameshift mutations leading to a truncated protein. The 54 patients carried 42 distinct pathogenic mutations, of which 17 (40.5%) were novel and 8 were recurrent mutations. Compared with non-carriers, PALB2 pathogenic mutation carriers developed breast cancer at a younger age (47.52 years vs. 51.35 years, p = 0.016) and were more likely to have triple-negative (24.1% vs. 13.4%, p = 0.022) or HER2 negative (87.0% vs. 74.2%, p = 0.031) breast cancer and large breast tumors (> 2 cm) at diagnosis (72.2% vs. 57.0%, p = 0.024). PALB2 mutation carriers were also more likely to have family histories of breast and/or ovarian cancer (27.8% vs. 8.4%, p

The spectrum and frequency of BRCA1/2 pathogenic variants may be ethnicity-specific. Whether high-frequency founder mutations are present in Chinese women remains largely unknown. In the current study, germline pathogenic variants in the BRCA1/2 genes were determined in 9,505 unselected Chinese Han breast cancer (BC) patients by next-generation and/ or Sanger sequencing. Four hundred and seventy-one (5.0%) BC patients carried BRCA1/2 pathogenic variants in this cohort. A total of 25 recurrent pathogenic variants (at least found in four unrelated patients) were identified in this cohort (8 BRCA1 and 17 BRCA2 recurrent pathogenic variants), 161 patients carried one of these recurrent pathogenic variants in this cohort of 9,505 patients. All of these 25 recurrent pathogenic variants were further explored whether they had founder effect through haplotype analysis. The most common pathogenic variant, BRCA1 c.5470_5477del, was found in 30 BC patients from 29 unrelated families. Twenty-seven of these 29 unrelated patients who carried this BRCA1 c.5470_5477del mutation shared an identical haplotype, indicating that BRCA1 c.5470_5477del was a founder mutation in the Chinese Han population. Furthermore, BRCA1 c.5470_5477del mutation carriers had a significantly worse survival than noncarriers (disease-free survival, p = 0.049; overall survival, p = 0.029). Taken together, our data suggested that BRCA1 c.5470_5477del is a founder mutation in the Chinese Han population and BRCA1 c.5470_5477del mutation carriers have a poor survival.

BRCA1/2 germline mutations are associated with a high risk of breast cancer, which may preclude mutation carriers from breast-conserving surgery (BCS). This study retrospectively examined whether mutation status influenced the rate of ipsilateral breast tumor recurrence (IBTR) after BCS in Chinese women. Patients who underwent BCS were enrolled in carriers group and non-carriers group according to their BRCA1/2 mutation status in the study. The correlations were analyzed between IBTR incidence and BRCA1/2 mutation. The IBTR cases were further separated into new primary tumor (NP) and true local recurrences (TR). The risk factors of NP were studied in multivariate analysis. 1947 consecutive Chinese women with primary invasive breast cancer were selected. 103 patients were identified as BRCA1/2 mutation carriers and 1844 were non-carriers. BRCA1/2 mutation carriers were younger (P

The prevalence and clinical relevance of TP53 and PIK3CA mutations in pretreatment breast cancer have been previously reported. However, little is known regarding these mutations in residual tumor tissues after neoadjuvant chemotherapy. Here, we investigated the association between TP53 and PIK3CA mutations in residual disease and survival of breast cancers. TP53 and PIK3CA somatic mutations were examined in 353 post-neoadjuvant chemotherapy residual tumor tissues by Sanger sequencing. Survival curves of patients with TP53 and PIK3CA mutations were compared using the Kaplan–Meier method. Fifty-six (15.9%) of the 353 patients carried a TP53 somatic mutation and 79 patients (22.4%) carried a PIK3CA somatic mutation. A total of 18 patients carried co-mutation of TP53 and PIK3CA. Patients with somatic co-mutation were more likely to have high-grade tumors (35.3% vs. 10.6%, P = 0.010), estrogen receptor-negative tumors (55.6% vs. 26.7%, P = 0.009), progesterone receptor-negative tumors (61.1% vs. 30.5%, P = 0.008) and triple-negative tumors (35.3% vs. 13.3%, P = 0.025) compared with non-carriers. More importantly, co-mutation of TP53 and PIK3CA carriers had a significantly worse disease-free survival (DFS) and distant disease-free survival (DDFS) than non-carriers (5-year DFS: 58.0% vs. 83.2%, P

Key Points Question Can patients with breast cancer who carry a BRCA1/2 variant safely undergo breast-conserving therapy (BCT)? Findings In this cohort study, 8396 patients with operable primary breast cancer (187 BRCA1 carriers, 304 BRCA2 carriers, and 7905 noncarriers) underwent BCT, mastectomy with radiotherapy, or mastectomy alone. In multivariable analyses, patients with both the BRCA1 and BRCA2 variants who were treated with BCT had a survival rate at least comparable to those treated with mastectomy with radiotherapy or mastectomy alone. Meaning This study suggests that BCT may be an option for patients who carry a BRCA1/2 variant when the tumor is clinically appropriate for this procedure., Importance Whether patients with breast cancer who carry a BRCA1/2 variant can safely undergo breast-conserving therapy (BCT) remains controversial. Objective To compare survival rates after BCT vs mastectomy in BRCA1/2 variant carriers and noncarriers in a large series of unselected patients with breast cancer. Design, Setting, and Participants In this cohort study, a large consecutive series of 8396 unselected patients with primary breast cancer underwent either BCT, mastectomy with radiotherapy, or mastectomy alone from October 1, 2003, to May 31, 2015, at the Breast Center of Peking University Cancer Hospital in China. All patients were assessed for BRCA1/2 germline variant status. Statistical analysis was performed from May 1 to September 30, 2020. Main Outcomes and Measures The primary outcomes were breast cancer–specific survival (BCSS) and overall survival (OS); secondary outcomes included recurrence-free survival, distant recurrence–free survival, and ipsilateral breast tumor recurrence. Results Of these 8396 Chinese patients (8378 women [99.8% women]; mean [SD] age, 50.8 [11.4] years; 187 BRCA1 carriers, 304 BRCA2 carriers, and 7905 noncarriers), 3135 (37.3%) received BCT, 1511 (18.0%) received mastectomy with radiotherapy, and 3750 (44.7%) received mastectomy alone. After a median follow-up of 7.5 years (range, 0.3-16.6 years), both BRCA1 and BRCA2 variant carriers treated with BCT had similar rates of survival compared with those treated with mastectomy with radiotherapy (BCSS: hazard ratio [HR] for BRCA1, 0.58 [95% CI, 0.16-2.10]; P = .41; HR for BRCA2, 0.46 [95% CI, 0.15-1.41]; P = .17; OS: HR for BRCA1, 0.61 [95% CI, 0.18-2.12]; P = .44; HR for BRCA2, 0.72 [95% CI, 0.26-1.96]; P = .52) or mastectomy alone (BCSS: HR for BRCA1, 0.70 [95% CI, 0.22-2.20]; P = .54; HR for BRCA2, 0.59 [95% CI, 0.18-1.93]; P = .39; OS: HR for BRCA1, 0.77 [95% CI, 0.27-2.21]; P = .63; HR for BRCA2, 0.62 [95% CI, 0.22-1.73]; P = .37) after adjusting for clinicopathologic factors and adjuvant therapy. For noncarriers, patients receiving BCT had significantly better survival than those receiving mastectomy with radiotherapy (BCSS: HR, 0.45 [95% CI, 0.36-0.57]; P, This cohort study compares survival rates after breast-conserving therapy vs mastectomy in BRCA1/2 variant carriers and noncarriers in a large series of unselected patients with breast cancer.

We determined the prevalence and characteristics of BRCA1/2 germline mutations in a large cohort of Chinese women with breast cancer. A total of 5931 unselected Chinese women with breast cancer were enrolled in this study and underwent testing for BRCA1/2 mutations. Of these, 543 patients were familial breast cancer, 1033 were early-onset disease (≤40 years) without family history of breast cancer, and 4355 were sporadic breast cancer. In total, 232 patients (3.9 %) carried a BRCA1 or BRCA2 mutation (110 in BRCA1and 122 in BRCA2) in this cohort of 5931 patients. BRCA1/2 mutation rate was 16.9 % (92/543) in familial breast cancers, 5.2 % (54/1033) in early-onset breast cancers (≤40 years), and 2.0 % in sporadic breast cancers (>40 years), respectively. The BRCA1/2 mutation rate was 27.0 % in 111 familial breast cancers diagnosed at and before the age of 40. 41.4 % of mutations in this cohort were specific for Chinese population. Recurrent mutations accounted for 44.8 % of the entire mutations in 2382 cases that BRCA1 and BRCA2 genes were fully sequenced in this study. Both BRCA1 and BRCA2 mutation carriers were significantly more likely to be early-onset and bilateral breast cancers, high-grade cancer, and to have a family history of breast cancer compared with non-carriers. BRCA1 mutation carriers were more likely to be triple-negative cancer than BRCA2 mutation carriers and non-carriers. Our data provide guidelines for Chinese women with breast cancer who should undergo BRCA1/2 genetic testing; additionally, recurrent mutations account for nearly half of the mutations and some of them are specific for Chinese women.

When the enamel layer is breached due to external physical and chemical reasons, the underlying dentin is exposed to a wet and bacteria-laden oral environment. Accordingly, some diseases related to exposed dentin, such as dentin hypersensitivity and bacterial invasion, usually occur and affect patients' day-to-day lives. The aim of this study was to evaluate the effectiveness of injectable calcium phosphate cement (CPC) on occluding dentinal tubules and antibacterial properties when loaded with chlorhexidine (CHX) under a simulated oral environment, which was believed to be beneficial for dental biomimetic reconstruction and minimum intervention therapy. The particle size, surface morphology and composition of CPC were characterized using scanning electron microscopy (SEM) and X-ray diffraction (XRD). The apatite formation ability, occluding effects, drug delivery and antibacterial properties of CPC and CHX-loaded CPC were further investigated using non-destructive attenuated total reflection infrared (ATR-IR) spectroscopy, Raman spectroscopy, SEM observation, permeability test, UV analysis and a disk-diffusion method. The results showed that both CPC and CHX-loaded CPC could continually form enamel-like apatite layers on the exposed dentin surface. After facing an acidic environment, the apatite layer still effectively occluded the dentinal tubules. Furthermore, CHX loaded CPC showed a sustained release of CHX over a timeframe of a week and revealed significant antibacterial effect compared to the blank control without CHX. Therefore, the results suggest that due to the unique self-setting ability, injectability, apatite-mineralization capacity and similar composition to a tooth, CPC could be used as a promising biomaterial to reconstruct the breached enamel on exposed dentin through a biomimetic and minimally invasive way. Moreover, due to the excellent drug-delivery property, CPC could easily carry antibiotics to inhibit the bacteria causing further pulp infection.

Objective Early assessment of response to neoadjuvant chemotherapy (NAC) for breast cancer allows therapy to be individualized. The optimal assessment method has not been established. We investigated the accuracy of automated breast ultrasound (ABUS) to predict pathological outcomes after NAC. Methods A total of 290 breast cancer patients were eligible for this study. Tumor response after 2 cycles of chemotherapy was assessed using the product change of two largest perpendicular diameters (PC) or the longest diameter change (LDC). PC and LDC were analyzed on the axial and the coronal planes respectively. Receiver operating characteristic (ROC) curves were used to evaluate overall performance of the prediction methods. Youden's indexes were calculated to select the optimal cut-off value for each method. Sensitivity, specificity, positive and negative predictive values (PPV and NPV) and the area under the ROC curve (AUC) were calculated accordingly. Results ypT0/is was achieved in 42 patients (14.5%) while ypT0 was achieved in 30 patients (10.3%) after NAC. All four prediction methods (PC on axial planes, LDC on axial planes, PC on coronal planes and LDC on coronal planes) displayed high AUCs (all>0.82), with the highest of 0.89 [95% confidence interval (95% CI), 0.83-0.95] when mid-treatment ABUS was used to predict final pathological complete remission (pCR). High sensitivities (85.7%-88.1%) were observed across all four prediction methods while high specificities (81.5%-85.1%) were observed in two methods used PC. The optimal cut-off values defined by our data replicate the WHO and the RECIST criteria. Lower AUCs were observed when mid-treatment ABUS was used to predict poor pathological outcomes. Conclusions ABUS is a useful tool in early evaluation of pCR after NAC while less reliable when predicting poor pathological outcomes.

The prevalence and clinical relevance of TP53 germline mutations in a large unselected breast cancer series are largely unknown. Here, we determined TP53 germline mutations in a large cohort of 10,053 unselected breast cancer patients through multigene panel-based next-generation and/or Sanger sequencing assays. We found that 0.5% of patients (50 cases) carried a pathogenic TP53 germline mutation in this large series of 10,053 unselected breast cancer patients, and the prevalence of TP53 germline mutation was 3.8% in very early onset breast cancer (age ≤30 years) in this large cohort. TP53 mutation carriers were significantly more likely to have early onset cancer (p

The significant roles of microRNAs (miRNAs) in the pathogenesis of myasthenia gravis (MG) have been observed in numerous previous studies. The impact of miRNA clusters on immunity has been demonstrated in previous years; however, the regulation of miRNA clusters in MG remains to be elucidated. In the present study, 245 MG risk genes were collected and 99 MG risk pathways enriched by these genes were identified. A catalog of 126 MG risk miRNAs was then created; the MG risk miRNAs were located on each chromosome and a miRNA cluster was defined as a number of miRNAs with a relative distance of

Knowledge of the pathology of axillary lymph nodes (ALN) in breast cancer patients is critical for determining their treatment. Ultrasound is the best noninvasive evaluation for the ALN status. However, the correlation between negative ultrasound results and the sentinel lymph nodes (SLN) pathology remains unknown. To test the hypothesis that negative ultrasound results of ALN predict the negative pathology results of SLN in breast cancer patients, we assessed the association between ALN ultrasonography‐negative results and the SLN pathology in 3115 patients with breast cancer recruited between October 2010 and April 2016 from a single cancer center, prospective database. Of these patients who met the inclusion criteria, 2317 (74.4%) had no SLN pathological metastasis. In the univariate analysis, other 798 patient with positive SLN tended to be under age 40 and premenopausal, having large tumor sizes (>2 cm), higher histological grade of primary tumor, positive hormone receptors, and negative HER‐2 status (P .05. In conclusion, only a 74.4% consistency between ALN ultrasonography‐negative results and negative pathological SLN results, although menstrual status, tumor size, histologic subtypes of primary tumor and ER status were found to be statistically independent predictors of positive SLN among patients negative for ALN ultrasonography. Therefore, the present study suggests that negative ultrasound results of ALN do not adequately predict the negative pathology results of SLN in breast cancer patients.

Oldhamianoside II is a novel triterpenoidsaponin that can be isolated from the roots of Gypsophila oldhamiana. In vitro and in vivo experiments have revealed that it inhibits tumor growth and metastasis in various types of tumor; however, the exact mechanism remains to be fully elucidated. In the present study, oldhamianoside II treatment in prostate cancer cells exerted substantial anticancer activity, including decreased cell proliferation and invasion. Mechanistically, oldhamianoside II was found to reverse the epithelial-mesenchymal transition (EMT), as demonstrated by its induction of E-cadherin and suppression of vimentin and N-cadherin at the mRNA and protein levels. Furthermore, oldhamianoside II treatment upregulated Wnt antagonist expression and promoted the proteasome-mediated degradation of β-catenin to inhibit the activity of β-catenin signaling. In summary, the present study revealed that oldhamianoside II exerts its antitumor effects via the regulation of EMT and β-catenin function, and further supports its potential for use in clinical treatment.

Background RECQL is a number of the RecQ DNA helicase family and plays an important role in maintaining genome stability. Although several studies have reported that RECQL mutations were correlated with the susceptibility to breast cancer, the effect on prognosis in breast cancer was not yet clarified. Here, we explored the association between RECQL expression level and survival in patients with breast cancer. Methods In the first cohort, the RECQL mRNA expression level was evaluated in 774 primary breast cancer patients using a quantitative real-time PCR assay. Then, in the second independent cohort, the level of RECQL protein expression was detected in 322 patients with breast cancer using immunohistochemistry assay. Survival curves of patients with RECQL expression were compared using the Kaplan-Meier method with log-rank test. Results In the first cohort of 774 breast cancer patients, the low expression level of RECQL mRNA was significantly correlated with aggressive clinicopathological characteristics, including the positive lymph node status (P = 0.026), HER2 overexpression (P

Breast cancer is believed to result from the interplay of genetic and non-genetic risk factors, and individual genetic variation may influence the efficacy of chemotherapy. Here we conducted a genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with response to anthracycline- and taxane-based neoadjuvant chemotherapy in breast cancer patients. In the discovery stage, we divided 92 patients who received anthracycline-based neoadjuvant chemotherapy into 2 groups according to pathologic response and performed a genome-wide study using Affymetrix SNP6.0 genechip. Of 389,795 SNPs associated with pathologic complete response (pCR), we identified 2 SNPs, rs6044100 and rs1799937, that were significantly associated with pCR after neoadjuvant chemotherapy. In the validation stage, genotype analysis of samples from an independent cohort of 401 patients who received anthracycline-based neoadjuvant regimens and 467 patients who received taxane-based regimens was performed using sequencing analysis. We found that only SNP rs1799937, located in the WT1 gene, was associated with pCR after anthracycline-based neoadjuvant therapy (AA vs GG; odds ratio [OR], 2.81; 95% confidence interval [CI], 1.13–6.98; P < 0.05) but not after taxane-based neoadjuvant therapy (AA vs GG; OR, 0.85; 95% CI, 0.36–2.04; P = 0.72). These results suggest that WT1 may be a potential target of anthracycline-based neoadjuvant therapy for breast cancer.

The role of TP53 mutations in predicting response to neoadjuvant chemotherapy in breast cancer remains controversial. The aims of this study were to investigate whether TP53 mutations were associated with response and survival in breast cancer patients who received neoadjuvant chemotherapy. Therefore, we identified TP53 mutations in the core-needle biopsy tumor samples obtained before the neoadjuvant chemotherapy from 351 operable primary breast cancer patients who either received anthracycline/cyclophosphamide-based (n = 252) or paclitaxel (n = 99) neoadjuvant chemotherapy. We found that 41.0% (144 of 351) of patients harbored TP53 mutations, and 14.8% of patients achieved a pCR (pathologic complete response) after neoadjuvant chemotherapy. Among patients treated with anthracycline/cyclophosphamide (n = 252), patients with TP53 mutations had a significantly higher pCR rate than those with wild-type (28.6 vs.7.1%; p < 0.001), and TP53 mutation was an independent favorable predictor of pCR [odds ratio (OR) = 3.41; 95% confidence interval (CI) 1.50-7.77; p = 0.003] in this group; moreover, patients with TP53 mutation had a better distant recurrence-free survival (DRFS) than those with wild-type [unadjusted hazard ratio (HR) = 0.43; 95% CI 0.20-0.94; p = 0.030] in this group. Among patients treated with paclitaxel (n = 99), no significant difference in pCR rates was observed between patients with or without TP53 mutations (15.2 vs. 11.3%; p = 0.57). Our results suggested that patients with TP53 mutations are more likely to respond to anthracycline/ cyclophosphamide-based neoadjuvant chemotherapy and have a favorable survival.

This study investigated the dewaterability and extracellular polymeric substances (EPS) characteristics of food waste digestates collected from different sources and after different anaerobic digestion times. The specific resistance to filtration, normalized capillary suction time and bound water indicated that the dewaterability of the digestates from restaurant food waste was inferior to those of household kitchen waste. However, the anaerobic digestion course was more vital to digestate dewaterability than the digested materials. The dewaterability significantly deteriorated and high amounts of EPS were extracted in the fast hydrolysis period, suggesting that the accumulated hydrolysates contributed to the low dewaterability. A long digestion time of over 30 days also led to low dewaterability. Correlation analysis and partial least square analysis indicated that EPS characteristics have an important influence on the dehydration of anaerobic digestates, with bound water being more influenced by polysaccharides and the other dewaterability indexes more affected by proteins.

The Pro1170Ala polymorphism is one of the most common polymorphisms of human epidermal growth factor receptor 2 (HER2) and may affect the clinical outcome in breast cancer. Therefore, in the present study, the incidence of the HER2 Pro1170Ala polymorphism was determined in 3,305 female patients with operable primary breast cancer using a DNA-sequencing assay, and the potential association with survival was investigated. Of these 3,305 patients, 29% (955/3,305) were homozygous for the Pro/Pro genotype, 51% (1,679/3,305) were heterozygous for the Pro/Ala genotype and 20% (671/3,305) were homozygous for the Ala/Ala genotype. The frequency of this polymorphism conformed to the Hardy-Weinberg equilibrium (P=0.175). No significant association between the HER2 Pro1170Ala polymorphism and recurrence-free survival (RFS) or distant recurrence-free survival (DRFS) was identified in the entire cohort of 3,305 patients. HER2 status was available for 3,170/3,305 patients; no significant association between the HER2 Pro1170Ala polymorphism and survival was identified in HER2-positive patients (n=728). However, among the HER2-negative patients (n=2,442), those with the Pro/Ala or Ala/Ala genotype had a significantly decreased RFS [unadjusted hazard ratio (HR), 1.45; 95% confidence interval (CI), 1.03-2.04; P=0.033] and DRFS (unadjusted HR, 1.65; 95% CI, 1.11-2.44; P=0.012) compared with those with the Pro/Pro genotype. Multivariate analysis revealed that the Pro/Ala or Ala/Ala genotype was an independent unfavorable factor for DRFS (adjusted HR, 1.63; 95% CI, 1.05-2.53; P=0.029) in the subgroup of HER2-negative patients. The results of the present study suggest that patients with HER2-negative breast cancer with the HER2 Pro1170Ala polymorphism variant exhibit a decreased survival outcome.

It has been demonstrated that single nucleotide polymorphisms (SNPs) of SIPA1 (signal-induced proliferation associated gene 1) are associated with metastatic efficiency in both human and rodents. The purpose of this study was to determine whether SIPA1 545 C > T polymorphism was associated with overall survival in patients with metastatic breast cancer. In this study, SIPA1 545 C > T polymorphism was detected in 185 metastatic breast cancer patients using polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP). Survival curves for patients with SIPA1 545 C > T polymorphism was compared using the Kaplan-Meier method with log-rank tests. We found that SIPA1 545 C > T polymorphism was significantly associated with survival in 185 patients with metastatic breast cancer. Patients with SIPA1 545 T/T genotype had a significantly worse overall survival (OS) than did patients with C/T or C/C genotype (50.0% vs. 62.9%, P = 0.042). Moreover, in multivariate analysis, as compared with the C/C or C/T genotype, the T/T genotype remained an independent unfavorable prognostic marker of OS in this cohort (hazard ratio [HR] = 2.16; 95% CI = 1.12–4.15; P = 0.022). Our findings indicate that metastatic breast cancer patients with SIPA1 545 T/T genotype have a poorer survival compared to patients with C/C or C/T genotype.

In this study, we identified 74 differentially expressed autophagy-related genes in glioma patients. Analysis using a Cox proportional hazard regression model showed that MAPK8IP1 and SH3GLB1, two autophagy-related genes, were associated with the prognostic signature for glioma. Glioma patients from the CGGA batches 1 and 2, GSE4412 and TCGA datasets could be divided into high- and low-risk groups with different survival times based on levels of MAPK8IP1 and SH3GLB1 expression. The autophagy-related signature was an independent predictor of survival outcomes in glioma patients. MAPK8IP1 overexpression and SH3GLB1 knockdown inhibited glioma cell proliferation, migration and invasion, and improved Temozolomide sensitivity. These findings suggest autophagy-related genes like MAPK8IP1 and SH3GLB1 could be potential therapeutic targets in glioma.

This study evaluated the effects of sodium hypochlorite (NaOCl) with different concentrations and exposure time on the structural, compositional and mechanical properties of human dentin in vitro. Sixty dentin slabs were obtained from freshly extracted premolars, randomly distributed into four groups (n=15), and treated with 1%, 5%, 10% NaOCl and distilled water (control group), respectively, for a total of 60 min. Attenuated total reflection infrared (ATR-IR) spectroscopy, Raman spectroscopy and X-ray diffraction (XRD) were carried out before, 10 min and 60 min after the treatment. Scanning electron microscopy (SEM) and flexural strength test were conducted as well. The results showed that dentins experienced morphological alterations in the NaOCl groups, but not in the control group. Two-way repeated-measures analysis of variance revealed that the carbonate:mineral ratio (C:M), Raman relative intensity (RRI), a-axis, c-axis length and full width at half maximum (FWHM) with the increase of time and concentration in the NaOCl groups were not significantly different from those in the control group (P0.05). Nevertheless, the mineral:matrix ratio (M:M) increased and the flexural strength declined with the increase of concentration and the extension of time in the NaOCl groups (P0.05). Additionally, it was found that the M:M and the flexural strength remained unchanged after 1% NaOCl treatment (P0.05), and the morphology changes were unnoticeable within 10 min in 1% NaOCl group. These results indicated that NaOCl has no significant effects on the inorganic mineral of human dentin; but it undermines and eliminates the organic content concentration- and time-dependently, which in turn influences the flexural strength and toughness of dentins. In addition, an irrigation of 1% NaOCl within 10 min can minimize the effects of NaOCl on the structural and mechanical properties of dentin during root canal treatment.

BRCA1/2 mutations represent approximately 5 % of unselected Chinese women with breast cancer. However, the breast cancer risk of Chinese women with BRCA1/2 mutations is unknown. Therefore, the aim of this study was to estimate the age-specific cumulative risk of breast cancer in Chinese women who carry a BRCA1 or BRCA2 mutation. Our study included 1816 unselected Chinese women with breast cancer and 5549 female first-degree relatives of these probands. All probands were screened for BRCA1/2 mutation. The age-specific cumulative risks of BRCA1/2 carriers were estimated using the kin-cohort study by comparing the history of breast cancer in first-degree female relatives of BRCA1/2 carriers and non-carriers. Among the 1816 probands, 125 BRCA1/2 pathogenic mutations were identified (70 in the BRCA1 gene and 55 in the BRCA2 gene). The incidence of breast cancer in the first-degree female relatives of BRCA1/2 mutation carriers was significantly higher (3.7-fold and 4.4-fold for BRCA1 and BRCA2 mutation carriers, respectively) than in non-carriers. The estimated cumulative risks of breast cancer by age 70 years were 37.9 % [95 % confidence interval (CI) 24.1-54.4 %] for BRCA1 mutation carriers and 36.5 % (95 % CI 26.7-51.8 %) for BRCA2 mutation carriers, respectively. Our study suggests that the breast cancer risk of Chinese women with BRCA1/2 mutations appears to be relatively high by the age of 70. Therefore, genetic counseling, enhanced surveillance, and individual preventive strategies should be provided for Chinese women who carry a BRCA1/2 mutation.

Recent studies suggested that breast cancer patients who carry a BRCA1 germline mutation benefit from poly (ADP-ribose) polymerase (PARP) inhibitors; therefore, it would be of great interest to detect BRCA1 somatic mutations in sporadic breast cancers. In this study, we detected BRCA1 somatic mutations in tumor cDNA from 144 Chinese women with sporadic breast cancer by using polymerase chain reaction (PCR)-direct sequencing assay. In total, eight BRCA1 alterations (three nonsense mutations and five missense mutations) were identified in this cohort of 144 sporadic breast cancers. We further confirmed that 5 out of 144(3.5%) sporadic breast cancer cases carried a BRCA1 somatic mutation, including two novel nonsense mutations (c.191_212del22 and c.2963C>G) resulting in a truncated protein and three missense mutations (c.114G>T, c.925A>C, and c.824G>A). The two cases with BRCA1 somatic truncating mutations also contained a TP53 somatic mutation in the tumors. Our study suggested that a small subset of sporadic breast cancers do harbor BRCA1 somatic mutations; these patients who carry a BRCA1 somatic mutation may be potential candidates for treatment with PARP inhibitors.

The association between the CHEK2 and breast cancer risk in Chinese women is unknown. Here, we screened the full CHEK2 coding sequence in 118 Chinese familial breast cancer cases who are negative for mutations in BRCA1 and BRCA2, one recurrent mutation, CHEK2 c.1111C>T (p.H371Y), was identified in five index cases in this cohort. Functional analysis suggested that CHEK2 p.H371Y was a pathogenic mutation that resulted in decreased kinase activity. We further screened the CHEK2 p.H371Y mutation in 909 unselected breast cancer cases and 1,228 healthy individuals. The frequencies of the CHEK2 p.H371Y in familial and unselected breast cancer cases and controls were 4.24% (5/118), 1.76% (16/909), and 0.73% (9/1228), respectively. The p.H371Y mutation was significantly associated with increased breast cancer risk in unselected breast cancer (odds ratio [OR] 2.43, 95% confidence interval [CI] 1.07–5.52, P = 0.034). Our results indicate that the recurrent mutation, p.H371Y, confers a moderate risk of breast cancer in Chinese women. Hum Mutat 32:1–4, 2011. © 2011 Wiley-Liss, Inc.

Although there are some studies to investigate germline mutations in BRCA1/2 genes in Chinese women with familial breast cancer, many of them suffer relatively small sample size. In this study, we screened germline mutations in BRCA1/2 genes in a cohort of 409 Chinese women with familial breast cancer from north China by using a PCR-sequencing assay. A total of 43 deleterious mutations in BRCA1/2 genes were identified in this cohort, including 17 novel mutations and 6 recurrent mutations. The frequencies of BRCA1 and BRCA2 mutations were 3.9% (16/409) and 6.6% (27/409), respectively; the mutation rate of BRCA2 was 1.7-fold higher than that of BRCA1. The entire mutation rate of BRCA1/2 was 10.5% in this cohort; however, the mutation rate of BRCA1/2 genes was 23.0% in 78 familial breast cancer patients whose tumors were diagnosed at or before the age of 40. The mean age at diagnosis of breast cancer in BRCA1 carriers (42.8 years) and BRCA2 carriers (45.1 years) was younger than non-carriers (51.0 years) in this cohort (P = 0.005; P = 0.01, respectively). In addition, both BRCA1 carriers and BRCA2 carriers were more likely to exhibit triple-negative breast cancer (ER-, PgR-, and HER2-) than non-carriers (BRCA1 carriers vs. non-carriers, 69.2 vs. 23.0%, P = 0.001; BRCA2 carriers vs. non-carriers, 45.8 vs. 23.0%, P = 0.01). Our study suggested that the spectrum and characteristics of BRCA1/2 mutations in Chinese familial breast cancer exhibit some unique features, and Chinese women with familial breast cancer whose tumors are diagnosed at or before the age of 40 are good candidates for BRCA1/2 testing.

Background The prevalence of BRCA1 somatic mutations status in triple-negative breast cancer (TNBC) has not been well documented. The aims of this study were to determine the frequency of BRCA1 somatic mutations and to investigate the association between BRCA1 deleterious somatic mutation status and response to neoadjuvant chemotherapy in women with TNBC. Methods Two hundred and five TNBC patients without BRCA1 germline mutations were enrolled in this study. Fresh tumor tissues were available for this cohort of 205 patients, including 112 patients with fresh core needle biopsy tumor tissues before treatment and 93 patients with fresh tumor tissues procured after surgery. BRCA1 somatic mutations were determined in the tumor samples using PCR-direct sequencing assay. Among the 112 patients with core needle biopsy samples, 97 patients received neoadjuvant chemotherapy. Results Eight patients (3.9%) carried a BRCA1 pathogenic somatic mutation in this cohort of 205 TNBC patients. These eight BRCA1 deleterious somatic mutations included five frameshift or nonsense mutations (c.191_212del22, c.1664delA, c.4674_4675 + 17del, c.3671_3672insTTCC, c.1162A > T), one splicing site mutation (c.134 + 2T > G) and two missense mutations (c.5511G > C and c.286G > A). No significant differences in tumor characteristics between BRCA1 deleterious somatic mutation carriers and non-carriers were observed. The pCR (pathologic complete response) rate was 32.0% in the 97 patients who received neoadjuvant chemotherapy. BRCA1 deleterious somatic mutation carriers (n = 5) had a higher pCR rate than did non-carriers (n = 92) (BRCA1 carriers vs non-carriers, 60.0% vs 30.4%, P = 0.32), although it did not reach a significance due to a small sample size. Conclusions A small subset of TNBC patients carried a BRCA1 deleterious somatic mutation; BRCA1 somatic mutation carriers are likely to respond to neoadjuvant chemotherapy.

Email: njyou@263.net p73 gene shares structural and functional similarities to p53, and plays an important role in modulating cell-cycle arrest and apoptosis. A common non-coding polymorphism of exon 2 of the p73 gene (designated as GC/AT) may affect gene expression, thus, it may lead to functional significance. The correlation of this polymorphism with breast cancer survival has not been investigated. In this study, by using genomic DNA p73 GC/AT polymorphism was detected by PCR-SSCP in 526 breast cancer patients with a median follow-up of 7.3 years. Among the 526 breast cancer patients, 4% of the patients were homozygous for the AT/AT genotype, 39% were heterozygous GC/AT and 57% were homozygous for the GC/GC genotype. We found that patients with the GC/GC genotype had a significantly worse clinical outcome than did patients with the AT Variants (AT/AT or GC/AT genotype) (5-year disease-free survival, 74.2 versus 95.0 or 84.1%, P = 0.02; 5-year overall survival, 78.9 versus 95.0 or 87.5%, P = 0.01, respectively). As compared with the GC/AT and AT/AT genotypes, the GC/GC genotype remained an independent prognostic indicator of disease-free survival (HR 1.82, P = 0.003) and overall survival (HR 1.99, P = 0.004) in multivariate analysis. Our results suggest that the GC/GC genotype is significantly associated with poor prognosis in breast cancer and raise the possibility that analysis of p73 polymorphism may provide useful prognostic information for breast cancer patients. Additional independent studies are needed to confirm these findings.