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// Min He 1, * , Jia-Xin Zhang 1, * , Yi-Zhou Jiang 1 , Ying-Le Chen 1 , Hai-Yuan Yang 1 , Li-Chen Tang 1 , Zhi-Ming Shao 1 and Gen-Hong Di 1 1 Department of Breast Surgery, Key Laboratory of Breast Cancer, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China * These authors have contributed equally to this work Correspondence to: Gen-Hong Di, email: genhongdi@163.com Keywords: lymph node ratio, triple-negative breast cancer, prognosis Received: December 21, 2016 Accepted: March 29, 2017 Published: April 25, 2017 ABSTRACT Background: We aimed to evaluate the prognostic value of the lymph node ratio (LNR) in patients with axillary lymph node-positive triple-negative breast cancer (TNBC). Methods: The prognostic efficacy was investigated in the first cohort from the Surveillance, Epidemiology, and End Results (SEER) dataset (n=4114) and was further validated in an independent cohort from Fudan University Shanghai Cancer Center (n=417). Patients were classified into low-, medium- and high-risk LNR groups. Results: Multivariate analysis revealed that the LNR was an independent predictor of overall survival (hazard ratio (HR) for high-risk LNR: 3.24; 95% confidence interval (CI): 2.56 to 4.09) and breast cancer-specific survival (HR for high-risk LNR: 3.57; 95% CI: 2.76 to 4.62) in the SEER population and also for disease-free survival (HR for high-risk LNR: 4.29; 95% CI: 2.24-8.21) in the validation population. Subgroup analysis revealed that patient classification according to the LNR could discriminate among groups of patients with different survival rates based on pathological nodal (pN) staging. Conclusion: The LNR shows potential for use as an additional prognostic factor for TNBC patients with positive lymph node involvement. Considering the heterogeneity of TNBC, use of the LNR might allow for optimization of the pN staging system and should be considered when making treatment decisions.

// Xin-Xing Zhu 1, 2, * , Ya-Wei Yan 1, 2, * , Chun-Zhi Ai 1 , Shan Jiang 1 , Shan-Shan Xu 1 , Min Niu 3 , Xiang-Zhen Wang 4 , Gen-Shen Zhong 5 , Xi-Feng Lu 6 , Yu Xue 7 , Shaoqi Tian 8 , Guangyao Li 9 , Shaojun Tang 10 , Yi-Zhou Jiang 1 1 Institute for Advanced Study, Shenzhen University, Shenzhen, Guangdong, China 2 Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, Guangdong, China 3 Department of Statics, University of Wisconsin-Madison, Madison, WI, USA 4 Maternal and Child Health Hospital of Nanshan District, Shenzhen, Guangdong, China 5 The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China 6 Department of Physiology, Center for Diabetes, Obesity and Metabolism, Shenzhen University, Shenzhen, Guangdong, China 7 Minnan Normal University, Zhangzhou, Fujian, China 8 The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China 9 Department of Health Outcomes and Policy, College of Medicine, University of Florida, Gainesville, FL, USA 10 Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington, DC, USA * These authors contributed equally to this work Correspondence to: Yi-Zhou Jiang, email: jiangyz@szu.edu.cn Keywords: Jarid2, bladder tumors, tumor-initiating cells, p16, histone modification Received: November 24, 2016 Accepted: February 07, 2017 Published: February 20, 2017 ABSTRACT Bladder cancer is the most common urologic malignancy in China, with an increase of the incidence and mortality rates over past decades. Recent studies suggest that bladder tumors are maintained by a rare fraction of cells with stem cell proprieties. Targeting these bladder tumor initiating cell (TICs) population can overcome the drug-resistance of bladder cancer. However, the molecular and genetic mechanisms regulating TICs in bladder cancer remain poorly defined. Jarid2 is implicated in signaling pathways regulating cancer cell epithelial-mesenchymal transition, and stem cell maintenance. The goal of our study was to examine whether Jarid2 plays a role in the regulation of TICs in bladder cancer. We found that knockdown of Jarid2 was able to inhibit the invasive ability and sphere-forming capacity in bladder cancer cells. Moreover, knockdown of Jarid2 reduced the proportion of TICs and impaired the tumorigenicity of bladder cancer TICs in vivo . Conversely, ectopic overexpression of Jarid2 promoted the invasive ability and sphere-forming capacity in bladder cancer cells. Mechanistically, reduced Jarid2 expression led to the upregulation of p16 and H3K27me3 level at p16 promoter region. Collectively, we provided evidence that Jarid2 via modulation of p16 is a putative novel therapeutic target for treating malignant bladder cancer.

Intra-tumor heterogeneity (ITH) plays a pivotal role in driving breast cancer progression and therapeutic resistance. We used a mutant-allele tumor heterogeneity (MATH) algorithm to measure ITH and explored its correlation with clinical parameters and multi-omics data.We assessed 916 female breast cancer patients from The Cancer Genome Atlas. We calculated the MATH values from whole-exome sequencing data and further investigated their correlation with clinical characteristics, somatic mutations, somatic copy number alterations (SCNAs), and gene enrichment.The patients were divided into low, intermediate, and high MATH groups. High T stage, African American race, and triple-negative or basal-like subtype were associated with a higher MATH level (all P 0.001). In hormone receptor-positive and human epidermal growth factor receptor-negative patients, the high MATH group showed a tendency toward a worse overall survival (P = 0.052); Furthermore, the TP53 mutation rate increased as MATH was elevated (P 0.001), whereas CDH1 mutations were correlated with a lower level of MATH (P = 0.002). Several focal and arm-level SCNA events were more common in the high MATH group (P 0.05), including Chr8q24 with only the MYC gene in the "peak" region. Similarly, high MATH was associated with gene set enrichment related to the MYC pathway and proliferation.Our integrative analysis reveals the clinical and genetic relevance of ITH in breast cancer. These results also suggest the origin and natural history of clonal evolution and intra-tumor genetic heterogeneity, which warrant further investigation.

Despite substantial evidence for the central role of hemodynamic shear stress in the functional integrity of vascular endothelial cells, hemodynamic and molecular regulation of the endocardial endothelium lining the heart chambers remains understudied. We propose that regional differences in intracardiac hemodynamics influence differential endocardial gene expression leading to phenotypic heterogeneity of this cell layer. Measurement of intracardiac hemodynamics was performed using 4-dimensional flow MRI in healthy humans (n=8) and pigs (n=5). Local wall shear stress (WSS) and oscillatory shear indices (OSI) were calculated in three distinct regions of the LV – base, mid-ventricle (midV), and apex. In both the humans and pigs, WSS values were significantly lower in the apex and midV relative to the base. Additionally, both the apex and midV had greater oscillatory shear indices (OSI) than the base. To investigate regional phenotype, endocardial endothelial cells (EEC) were isolated from an additional 8 pigs and RNA sequencing was performed. A false discovery rate of 0.10 identified 1051 differentially expressed genes between the base and apex, and 321 between base and midV. Pathway analyses revealed apical upregulation of genes associated with translation initiation. Furthermore, tissue factor pathway inhibitor (TFPI; mean 50-fold) and prostacyclin synthase (PTGIS; 5-fold), genes prominently associated with antithrombotic protection, were consistently upregulated in LV apex. These spatio-temporal WSS values in defined regions of the left ventricle link local hemodynamics to regional heterogeneity in endocardial gene expression.

Epigenetics is the regulation of gene expression (transcription) in response to changes in the cell environment through genomic modifications that largely involve the non-coding fraction of the human genome and that cannot be attributed to modification of the primary DNA sequence. Epigenetics is dominant in establishing cell fate and positioning during programmed embryonic development. However the same pathways are used by mature postnatal and adult mammalian cells during normal physiology and are implicated in disease mechanisms. Recent research demonstrates that blood flow and pressure are cell environments that can influence transcription via epigenetic pathways. The principal epigenetic pathways are chemical modification of cytosine residues of DNA (DNA methylation) and of the amino tails of histone proteins associated with DNA in nucleosomes. They also encompass the post-transcriptional degradation of mRNA transcripts by non-coding RNAs (ncRNA). In vascular endothelium, epigenetic pathways respond to temporal and spatial variations of flow and pressure, particularly hemodynamic disturbed blood flow, with important consequences for gene expression. The biofluid environment is linked by mechanotransduction and solute transport to cardiovascular cell phenotypes via signaling pathways and epigenetic regulation for which there is an adequate interdisciplinary infrastructure with robust tools and methods available. Epigenetic mechanisms may be less familiar than acute genomic signaling to Investigators at the interface of biofluids, biomechanics and cardiovascular biology. Here we introduce a biofluids / cellular biomechanics readership to the principal epigenetic pathways and provide a contextual overview of endothelial epigenetic plasticity in the regulation of flow-responsive transcription.

Purpose: Cancers with short interval between diagnosis and metastasis are associated with aggressive clinical course. Specifically, metastatic relapse of triple-negative breast cancer (TNBC) within 2 years of initial primary diagnosis is associated with marked chemoresistance, rapid progression, and poor prognosis. We hypothesized that rapid relapse TNBCs (rrTNBC; distant metastatic relapse or death 2 years) or no relapse (nrTNBC; no distant relapse or death with at least 5 years follow-up). Patients and Methods: We identified 453 primary TNBCs from three publicly-available datasets and characterized each as rrTNBC, lrTNBC, or nrTNBC. We compiled primary tumor clinical and multi-omic data, including transcriptome (n=453), copy number alterations (CNAs; n=317), and mutations in 171 cancer-related genes (n=317), then calculated expression and immune signatures. Results: Patients with rrTNBC were higher stage at diagnosis (Chi-square p Citation Format: Yiqing Zhang, William Nock, Meghan Wyse, Zachary Weber, Elizabeth J Adams, Asad Sarah, Sinclair Stockard, David Tallman, Jasneet Singh, Junu Bae, Eric P Winer, Nancy U Lin, Yi-Zhou Jiang, Ding Ma, Peng Wang, Leming Shi, Wei Huang, Zhi-Ming Shao, Claire Verschraegen, Mathew Cherian, Maryam B Lustberg, Bhuvana Ramaswamy, Sagar Sardesai, Jeffrey VanDeusen, Nicole Williams, Wesolowski Robert, Daniel G Stover. Machine learning predicts rapid relapse in triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-05-02.

Breast tumor initiating cells (BTICs) with ALDH+CD24−CD44+ phenotype are the most tumorigenic and invasive cell population in breast cancer. However, the molecular mechanisms are still unclear. Here, it is found that a negative immune regulator interleukin‐1 receptor type 2 (IL1R2) is upregulated in breast cancer (BC) tissues and especially in BTICs. BC patients with high IL1R2 expression have a poorer overall survival and relapse‐free survival. High IL1R2 promotes BTIC self‐renewal and BC cell proliferation and invasion. Mechanistically, IL1R2 is activated by IL1β, as demonstrated by the fact that IL1β induces the release of IL1R2 intracellular domain (icd‐IL1R2) and icd‐IL1R2 then interacts with the deubiquitinase USP15 at the UBL2 domain and promotes its activity, which finally induces BMI1 deubiquitination at lysine 81 and stabilizes BMI1 protein. In addition, IL1R2 neutralizing antibody can suppress the protein expression of both IL1R2 and BMI1, and significantly abrogates the promoting effect of IL1R2 on BTIC self‐renewal and BC cell growth both in vitro and in vivo. The current results indicate that blocking IL1R2 with neutralizing antibody provides a therapeutic approach to inhibit BC progression by targeting BTICs., Interleukin‐1 receptor type 2 (IL1R2) increases BMI1 deubiquitination and stability via binding and enhancing the activity of ubiquitin‐specific protease 15 (USP15) in cell nuclei, intrinsically promoting the self‐renewal of breast tumor initiating cells (BTICs) as well as breast cancer cell proliferation and invasion. Targeting IL1R2 with its neutralizing antibody inhibits the self‐renewal of BTICs, breast tumorigenesis, and cancer resistance to docetaxel.

Background Age at the time of breast cancer diagnosis not only predicts clinical outcome but also indicates distinct molecular characteristics that provide the rationale for appropriate treatment strategies. However, to the authors' knowledge, little is known regarding the molecular profile and biological basis of triple-negative breast cancers (TNBCs) occurring in young and elderly patients. Methods Using the study institution's largest, single-center, multiomics TNBC data set, the authors analyzed the clinical and genomic features of young (aged ≤39 years) and elderly (aged ≥65 years) patients with TNBC. Results In the current study, a total of 50 patients, 354 patients, and 69 patients, respectively, were grouped as young, intermediate, and elderly patients with TNBC. Young patients with TNBC had worse short-term survival, upregulation of DNA repair, cell cycle and RNA metabolism gene sets, frequent pathogenic germline variants, and predominant homologous recombination deficiency-related mutational signatures. Several copy number alterations also were found to be enriched in young patients with TNBC. Nearly one-half of the TNBC cases in elderly patients were of the luminal androgen receptor subtype. TNBC in elderly patients was identified as being associated with severe fibrosis; a lower Ki-67 index; and somatic mutations in PIK3CA, KMT2D, ERBB2, ERBB3, and their corresponding pathways. Elderly patients with TNBC also were more likely to harbor targetable mutations. Conclusions The findings of the current study indicated that young patients with TNBC had an enhanced cell cycle, which may have helped to explain their inferior short-term survival, whereas the homologous recombination deficiency and enriched pathogenic germline variants observed among young patients with TNBC suggested the need for genetic counseling and testing, as well as the potential use of DNA damage agents and poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors. Molecular characteristics of elderly patients with TNBC, although suggesting less response to chemotherapy, provided a rationale for the routine detection of actionable somatic mutations.

Purpose: The tumor microenvironment has a profound impact on prognosis and immunotherapy. However, the landscape of the triple-negative breast cancer (TNBC) microenvironment has not been fully understood. Experimental Design: Using the largest original multi-omics dataset of TNBC (n = 386), we conducted an extensive immunogenomic analysis to explore the heterogeneity and prognostic significance of the TNBC microenvironment. We further analyzed the potential immune escape mechanisms of TNBC. Results: The TNBC microenvironment phenotypes were classified into three heterogeneous clusters: cluster 1, the “immune-desert” cluster, with low microenvironment cell infiltration; cluster 2, the “innate immune-inactivated” cluster, with resting innate immune cells and nonimmune stromal cells infiltration; and cluster 3, the “immune-inflamed” cluster, with abundant adaptive and innate immune cells infiltration. The clustering result was validated internally with pathologic sections and externally with The Cancer Genome Atlas and METABRIC cohorts. The microenvironment clusters had significant prognostic efficacy. In terms of potential immune escape mechanisms, cluster 1 was characterized by an incapability to attract immune cells, and MYC amplification was correlated with low immune infiltration. In cluster 2, chemotaxis but inactivation of innate immunity and low tumor antigen burden might contribute to immune escape, and mutations in the PI3K-AKT pathway might be correlated with this effect. Cluster 3 featured high expression of immune checkpoint molecules. Conclusions: Our study represents a step toward personalized immunotherapy for patients with TNBC. Immune checkpoint inhibitors might be effective for “immune-inflamed” cluster, and the transformation of “cold tumors” into “hot tumors” should be considered for “immune-desert” and “innate immune-inactivated” clusters.

The research area of the wearable electrochemical sensors is increasingly growing which are valuable for healthcare and fitness applications owing to their simplicity of operation, low-cost, and compact size. In this work, optimizing of programmable analog front-end for fully integrated wearable sweat sensor is proposed. The proposed system can detect glucose, lactate, sodium, potassium at the same time with low-power consumption which is suitable for continuous real-time sweat sensing system. The average power consumption of analog front-end in the proposed system is less than 2 mW at 3.3 V supply voltage.

Acquired therapy resistance is a major problem for anticancer treatment, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model, we show that endocrine resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Consistently, similar gene expression changes are found in clinical breast tumours and patient-derived xenograft samples that are resistant to endocrine therapies. Mechanistically, the differential interactions between oestrogen receptor α and other oncogenic transcription factors, exemplified by GATA3 and AP1, drive global enhancer gain/loss reprogramming, profoundly altering breast cancer transcriptional programs. Our functional studies in multiple culture and xenograft models reveal a coordinated role of GATA3 and AP1 in re-organizing enhancer landscapes and regulating cancer phenotypes. Collectively, our study suggests that differential high-order assemblies of transcription factors on enhancers trigger genome-wide enhancer reprogramming, resulting in transcriptional transitions that promote tumour phenotypic plasticity and therapy resistance.

Background: Estrogen receptor-positive, progesterone receptor-positive, and HER2-positive breast cancers (triple-positive breast cancers, TPBCs) account for 5% to 10% of all breast cancers. The clinical and molecular features of TPBCs remain elusive. In this study, we aim to analyze the multiomics landscape and responsiveness of TPBCs to trastuzumab. Methods: We employed five cohorts. The first cohort was from the Surveillance, Epidemiology, and End Results database (n=32,056) and was used to determine the clinical characteristics of TPBC. The second, third and fourth cohorts were from The Cancer Genome Atlas (n=162), GSE2603 (n=37) and GSE2109 (n=30) datasets, respectively, and were used to examine the genomic features and molecular classification of TPBC. The fifth cohort comprised TPBC patients treated at Fudan University Shanghai Cancer Center (FUSCC, n=171) and was used to investigate an immunohistochemistry-defined luminal A-like subgroup of TPBC. Results: Patients with TPBC had a significantly better prognosis than those with ER-PR-HER2+ breast cancer. Genomic analysis revealed that TPBCs showed a lower TP53 mutation rate (30% vs. 69%, P < 0.001) and lower levels of HER2 mRNA and protein expression than ER-PR-HER2+ breast cancers. More than 40% of TPBCs were classified as the luminal A intrinsic subtype, with an even lower HER2 expression level. Based on the immunohistochemical detection of CDCA8, BCL2 and STC2, we identified a luminal A-like subgroup of TPBCs in the FUSCC cohort (CDCA8-negative, BCL2- and/or STC2-positive). Patients with luminal A-like TPBC had a better prognosis and benefited less from trastuzumab than those with TPBC of other subtypes. Conclusions: TPBCs consist of clinically and genomically heterogeneous subgroups that may require different therapeutic strategies. The luminal A-like subgroup of TPBCs is associated with a better prognosis and reduced benefit from trastuzumab.

The long noncoding RNA HOXA-AS3 has recently been reported to act as a critical regulator in inflammation-linked lung adenocarcinoma. However, the roles of HOXA-AS3 in endothelium inflammation and related vascular disorders remain poorly defined. In the current study, we identified HOXA-AS3 to be a critical activator to promote NF-κB-mediated endothelium inflammation. HOXA-AS3, a chromatin-associated regulator which colocalizes with NF-κB at specific gene promoters, was found to interact with NF-κB and positively regulate its activity through control of the expression of the NF-κB inhibitor protein IκBα and the acetylation status at the K310 site of p65. More importantly, clinicopathological analysis showed that HOXA-AS3 expression has a significant positive correlation with atherosclerosis. Thus, we conclude that HOXA-AS3 may serve as a crucial biomarker for the clinical diagnosis of atherosclerosis, as well as a promising therapeutic target for the treatment of multiple inflammatory vascular diseases. In addition, this study suggests the functional importance of HOXA-AS3 in the regulation of inflammatory disorders.

HERV loci transcribed lncRNA TROJAN promotes TNBC progression through ZMYND8 degradation by the ubiquitin-proteasome pathway., Human endogenous retroviruses (HERVs) play pivotal roles in the development of breast cancer. However, the detailed mechanisms of noncoding HERVs remain elusive. Here, our genome-wide transcriptome analysis of HERVs revealed that a primate long noncoding RNA, which we dubbed TROJAN, was highly expressed in human triple-negative breast cancer (TNBC). TROJAN promoted TNBC proliferation and invasion and indicated poor patient outcomes. We further confirmed that TROJAN could bind to ZMYND8, a metastasis-repressing factor, and increase its degradation through the ubiquitin-proteasome pathway by repelling ZNF592. TROJAN also epigenetically up-regulated metastasis-related genes in multiple cell lines. Correlations between TROJAN and ZMYND8 were subsequently confirmed in clinical samples. Furthermore, our study verified that antisense oligonucleotide therapy targeting TROJAN substantially suppressed TNBC progression in vivo. In conclusion, the long noncoding RNA TROJAN promotes TNBC progression and serves as a potential therapeutic target.

Background Whether primary tumor surgery should be performed in breast cancer patients with metastatic disease at diagnosis has been debated for decades. This study aims to evaluate the value of primary tumor surgery with respect to the mortality of patients with de novo stage IV breast cancer and to define the heterogeneity of this population. Methods De novo stage IV patients from the Surveillance, Epidemiology and End Results database (SEER) from 2010 to 2015 were included in our study. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to achieve balanced baseline characteristics. The effect of surgery was assessed by Kaplan-Meier curves and Cox regression models. Results Of the 11,684 patients eligible for analysis, 3,730 (31.92%) received primary tumor surgery. Multivariate Cox regression in the PSM cohort revealed that surgery was associated with better outcomes than those in the nonsurgery group in terms of overall survival (OS) [hazard ratio (HR): 0.51; 95% CI: 0.48–0.55; P2 metastatic sites) did not benefit from surgery (HR: 0.78; 95% CI: 0.31–1.97, P=0.596 and 0.78, 95% CI: 0.31–1.97, P=0.596 for OS and BCSS, respectively). Conclusions Primary tumor surgery significantly prolonged the survival of patients with de novo stage IV breast cancer. However, triple-negative breast cancer patients with more than two metastatic sites may not benefit from surgery.

Nowadays, cardiovascular disease is still one of the primary diseases that limit life expectation of humans. To address this challenge, this work reports an Internet of Medical Things (IoMT)-based cardiovascular healthcare system with cross-layer optimization from sensing patch to cloud platform. A wearable ECG patch with a custom System-on-Chip (SoC) features a miniaturized footprint, low power consumption, and embedded signal processing capability. The patch also integrates wireless connectivity with mobile devices and cloud platform for optimizing the complete system. On the big picture, a “wearable patch-mobile-cloud” hybrid computing framework is proposed with cross-layer optimization for performance-power trade-off in embedded-computing. The measurement results demonstrate that the on-patch compression ratio of the raw ECG signal can reach 12.07 yielding a percentage root mean square variation of 2.29%. In the test with the MIT-BIH database, the average improvement of signal to noise ratio and mean square error are 12.63 dB and 94.47%, respectively. The average accuracy of disease prediction operation executed in cloud platform is 97%.

In present study we aimed to explore the possible structural feature of Cytochrome P450 (CYP) 17A1 that contributes to the metabolic specificity. The predicable 3D-QSAR (Quantitative Structure-Activity Relationships) models were first developed with CoMFA (Comparative Molecular Field Analysis) and CoMSIA (Comparative Molecular Similarity Indices Analysis) methods based on a training set of 76 non-steroid inhibitors, then verified by a test set of 20 inhibitors. Our data demonstrates a cross-validation correlation coefficient q2s of 0.534 and 0.545, as well as a non-cross-validation correlation coefficient r2s of 0.904 and 0.889, respectively. The contours were generated to indicate the specific inhibitor feature. Further, molecular docking was used to probe the interacting feature between CYP17A1 and its non-steroid inhibitors or its natural substrates. We found the crucial binding features for the non-steroid inhibitor selection can be described as the suitable molecular length and the ability to fulfill the active pocket of CYP17A1, the hydrophobic parent body and the H-bond formed with special residues. Whereas, the distances between reaction site and the oxidative or the per-oxidative center played an important role in the substrate metabolism of 17α-hydroxylase and 17,20-lyase. This study helps to design and screen potential candidates for therapy of prostate cancer and other androgen-dependent diseases. Keywords: CYP17A1, Metabolic specificity, Inhibitors and substrates, 3D-QSAR, Docking

With the improvement in the survival of breast cancer, developing second primary malignancy becomes a serious health issue. The aim of this study was to explore the survival of breast cancer patients with second primary malignancy, and to evaluate the impact of chemotherapy on the risk of different cancer sites. Obtaining data from the Surveillance, Epidemiology, and End Results database, we calculated the standardized incidence ratio (SIR) for second primary malignancy in breast cancer survivors between 2000 and 2014. Overall survival and cancer-specific survival were analyzed with Kaplan–Meier method. Then, we further conducted stratified sub-analyses according to chemotherapy. The overall risk of second primary cancer for all sites was significantly elevated in breast cancer patients (SIR = 1.15, 95% CI 1.14–1.16). Overall survival and cancer-specific survival of the patients with breast cancer only were significantly better than the patients with multiple primary cancers (both P

1007 Background: Camrelizumab (anti-PD-1 antibody) and nab-paclitaxel (nab-P) have demonstrated promising anti-tumour activity in patients with immunomodulatory (IM) subtype metastatic triple negative breast cancer (TNBC), with 52.6% of ORR observed in heavily pretreated patients in our previous umbrella trial (FUTURE). As antiangiogenic agents were known to enhance the response to immune checkpoint inhibitors, we assessed the efficacy and safety of novel triplet combination of famitinib (tyrosine kinase inhibitor targeting VEGFR-2, PDGFR and c-kit), camrelizumab and nab-paclitaxel in patients with IM subtype advanced TNBC. Methods: In this prospective, single-arm, phase 2 study, eligible patients were 18-70 years and had treatment-naive IM subtype unresectable locally advanced or metastatic TNBC. IM subtype was defined as CD8+ by immunohistochemistry. Eligible patients received camrelizumab (200 mg iv, d1, 15, q4w) with nab-P (100 mg/m2 iv, d1, 8, 15, q4w) and famitinib (20 mg po qd, d1-28, q4w). Treatment was continued until disease progression, patient withdrawal, or unacceptable toxic effects. In the absence of intolerable toxicity, nab-P was to be administered for a minimum of 6 cycles. Primary endpoint was objective response rate according to RECIST v1.1. We explored the predictive biomarkers using targeted sequencing with a 484-gene panel. Results: From Oct 2019 to Oct 2020, 48 patients were enrolled. Confirmed objective responses were achieved in 39 (81.3%; 95% CI 70.2%-92.3%) of 48 patients in the intention-to-treat population and in 39 (84.8%; 95% CI 74.4%-95.2%) of 46 patients in the per-protocol population. Median time to response was 1.8 months (95% CI 1.8-2.0 months). With a median follow-up of 9.0 months, progression-free survival (PFS) and duration of response data were not mature. Thirty patients (62.5%) are still on the study treatment. The 9-month PFS rate was 60.2% (95% CI, 43.2% to 77.3%). Grade 3 or 4 adverse events were neutropenia (33.3%), anaemia (10.4%), febrile neutropenia (10.4%), thrombocytopenia (8.3%), hypertension (4.2%), hypothyroidism (4.2%), proteinuria (2.1%), septicemia (2.1%) and immune related myocarditis (2.1%). Adverse events that led to the discontinuation of any agent occurred in 6.3% of the patients. Two patients had treatment-related serious adverse events. No treatment-related deaths were reported. Biomarker analysis showed that somatic mutations of GSK3A may have the potential to predict immunotherapy response. Conclusions: Addition of famitinib to camrelizumab and nab-paclitaxel showed promising antitumour activity as first-line therapy with manageable toxicity profile for IM subtype advanced TNBC patients. Results from ongoing randomized controlled trial FUTURE-SUPER (NCT 04395989) are eagerly awaited. Clinical trial information: NCT04129996 .

Purpose: Somatic mutations in the tyrosine kinase domain of human epidermal growth factor receptor 2 (HER2) may be an alternative mechanism to HER2 activation and can affect the sensitivity toward HER2-targeted therapies. We aimed to investigate the prevalence, clinicopathologic characteristics, and functional relevance of novel HER2 mutations in breast cancer. Experimental Design: We performed Sanger sequencing of all exons of the HER2 gene in 1,248 primary tumors and 18 paired metastatic samples. Novel HER2 mutations were functionally characterized. Results: The total HER2 somatic mutation rate was 2.24% (28/1,248). Of the seven novel HER2 mutations, L768S and V773L were only detected in HER2-negative tumors, whereas K753E was found in HER2-positive disease. L768S and V773L mutations exhibited a significant increase in tyrosine kinase–specific activity and strongly increased the phosphorylation of signaling proteins in various cell lines. Xenograft experiments showed that NIH3T3 cells bearing the L768S and V773L mutations displayed more rapid growth. MCF10A, BT474, and MDA-MB-231 cells bearing the K753E mutation were resistant to lapatinib, but could be inhibited by neratinib. Finally, comparison of HER2 mutations in 18 pairs of primary and metastatic lesions revealed that the drug-resistant HER2 mutations (K753E and L755S) were enriched in metastatic lesions. Conclusions: HER2-negative breast cancer with activating mutations can benefit from HER2-targeted therapies. Meanwhile, mutations in the HER2 kinase domain might be a key mechanism of resistance to HER2-targeted therapy, and irreversible tyrosine kinase inhibitors such as neratinib may offer alternative treatment options. Clin Cancer Res; 22(19); 4859–69. ©2016 AACR.

// Ke-Da Yu 1, * , Lei Fan 1, * , Li-Xin Qiu 2, * , Hong Ling 1, * , Yi-Zhou Jiang 1 and Zhi-Ming Shao 1 1 Department of Breast Surgery, Shanghai Cancer Center and Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, P.R. China 2 Department of Medical Oncology, Shanghai Cancer Center and Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, P.R. China * These authors have contributed equally to this work Correspondence to: Ke-Da Yu, email: yukeda@163.com , yukeda@fudan.edu.cn Keywords: timing of adjuvant chemotherapy, breast cancer, survival, subtype Received: November 14, 2015 Accepted: May 17, 2016 Published: July 13, 2016 ABSTRACT Purpose: The optimal time from surgery to initiation of adjuvant chemotherapy of breast cancer is still controversial. We investigated the influence of time to adjuvant chemotherapy on survival outcomes according to breast cancer subtype. Results: Longer delay of initiation of adjuvant chemotherapy (≤4 weeks versus >8 weeks)) significantly decreased the DFS (adjusted hazard ratio [HR] of 1.86; 95% confidence interval [CI], 1.19-2.90) and OS (adjusted HR of 2.02; 95% CI, 1.10-3.71). However, a moderate delay (≤4 weeks versus 4-8 weeks) did not significantly influence the survival. We further investigated the effect of time to adjuvant chemotherapy (≤8 versus >8 weeks) on survival according to subtypes. Patients with luminal-A tumors who received delayed chemotherapy had no increased risk of recurrence (HR of 1.15; 95% CI, 0.54-2.43). In contrast, patients with luminal-B, triple-negative, or trastuzumab-untreated HER2-positive tumors would have decreased DFS because of delayed chemotherapy, with HR of 1.93 (95% CI, 1.10-3.34), 2.55 (95% CI, 1.25-5.18), and 2.41 (95% CI, 1.36-4.26), respectively. Methods: Operable women with stage I-IIIa breast cancer between 2003 and 2006 in our institution were included. 1,408 patients were divided into 3 groups according to the time to adjuvant chemotherapy: ≤4 weeks, 4-8 weeks, and >8 weeks. Disease-free survival (DFS) and overall survival (OS) were calculated. Conclusion: Longer delay of adjuvant chemotherapy was associated with worse survival and early initiation of adjuvant chemotherapy should be performed for patients with aggressive tumor subtypes.

Triple-negative breast cancer (TNBC) is an aggressive malignancy with a poor prognosis. Data from the Surveillance, Epidemiology and End Results database (2010–2012) were used to identify 10,771 patients with TNBC, and we assessed the effects of lymph node (LN) status on breast cancer-specific survival (BCSS) and overall survival (OS). In our study, a Kaplan-Meier plot showed that LN-negative patients (N0) had better survival outcomes than LN-positive patients and that patients with ≥10 positive LNs (N3) exhibited the worst survival outcomes regardless of tumor size. A pairwise comparison showed no difference in survival outcomes among each group stratified by tumor size. Further, for LN-positive patients with a tumor size ≤2 cm (T1) or >5 cm (T3), there were similar outcomes between patients with one to three LNs (N1) and those with four to nine LNs (N2), whereas N1 patients experienced significantly better survival outcomes than N3 patients (P

Purpose: By integrating expression profiles of mRNAs and long noncoding RNAs (lncRNA), we tried to develop and validate novel multigene signatures to facilitate individualized treatment of triple-negative breast cancer (TNBC) patients. Experimental Design: We analyzed 165 TNBC samples and 33 paired normal breast tissues using transcriptome microarrays. Tumor-specific mRNAs and lncRNAs were identified and correlated with patients' recurrence-free survival (RFS). Using Cox regression model, we built two multigene signatures incorporating mRNAs and lncRNAs. The prognostic and predictive accuracy of the signatures were tested in a training set of 165 TNBC patients and validated in other 101 TNBC patients. Results: We successfully developed an mRNA and an integrated mRNA–lncRNA signature based on eight mRNAs and two lncRNAs. In the training set, patients in the high-risk group were more likely to suffer from recurrent disease than patients in the low-risk group in both signatures [HR, 10.00; 95% confidence interval (CI), 2.53–39.47, P = 0.001; HR = 4.46, 95% CI, 1.34–14.91, P = 0.015 for integrated signature and mRNA signature, respectively). Results were validated in the validation set (P = 0.019 and 0.030, respectively). In addition, time-dependent receiver operating curve showed that the integrated mRNA–lncRNA signature had a better prognostic value than both the eight-mRNA-only signature and the clinicopathologic risk factors in both sets. We also found through interaction analysis that patients classified into the low-risk group by the integrated mRNA–lncRNA signature had a more favorable response to adjuvant taxane chemotherapy. Conclusions: The multigene signature we developed can accurately predict clinical outcome and benefit of taxane chemotherapy in TNBC patients. Clin Cancer Res; 22(7); 1653–62. ©2016 AACR.

Medullary breast carcinoma (MBC) is a unique histological subtype of breast cancer. Our study was designed to identify difference in characteristics and outcomes between MBC and invasive ductal carcinoma (IDC), and further confirm the prognostic factors of MBC. Utilizing Surveillance, Epidemiology, and End Results (SEER), we identified 84,764 eligible patients, including 309 MBC and 84,455 IDC. Compared with the IDC group, the MBC group was associated with younger age at diagnosis, higher grade, more advanced stage, larger tumor size, and higher proportion of triple-negative breast cancer (TNBC). Kaplan-Meier analysis and univariate Cox proportional hazard regression model showed that patients with IDC had significantly better breast cancer-specific survival (BCSS) compared to MBC, but they had similar overall survival (OS). However, MBC histology was no longer a surrogate for worse BCSS or OS after 1:1 matching by age, American Joint Committee on Cancer (AJCC) stage, grade and breast subtype. In addition, it was exposed that not married status, high grade, large tumor size, positive nodal status, the subtype of TNBC and no receipt of radiation therapy were significantly associated with poor BCSS and OS. In conclusion, MBC demonstrated more aggressive behavior but similar outcomes compared to IDC, which may be determined by prognostic factors such as breast subtype. These results not only confer deeper insight into MBC but contribute to individualized and tailored therapy, and thereby may improve clinical management and outcomes.

Breast cancer is the most prevalent type of cancer among women. CD59, a membrane complement regulatory protein, has been demonstrated to be overexpressed in most solid tumors, where it facilitates tumor cell escape from complement surveillance. However, the role of CD59 in breast cancer growth and clinical prognosis is not fully revealed. To investigate the role of CD59 in breast cancer growth and prognostic significance, we knocked down CD59 in a breast cancer cell line that is highly metastatic to the lungs, MDA-MB‑231-HM. Cell growth was measured in vitro and in vivo using a xenograft model. In addition, clinical data on a cohort of 120 patients with or without lung metastasis was analyzed based on CD59 expression, which was detected by immunohistochemistry. Knockdown of CD59 significantly inhibited MDA-MB‑231-HM cell growth both in vitro and in vivo. An analysis of clinical data on 120 patients revealed that patients with CD59 overexpression may have a worse prognosis. CD59 may therefore be a prognostic biomarker for poor outcome in breast cancer patients.

Highlight • We find that there are highly homology in HR region of SARS-CoV-2 and SARS-CoV. • We firstly used molecular dynamics method in designing antivirus peptide. • Our antivirus peptide can prevent virus membrane fuse with host cell. • Furthermore, we first calculate the binding energy of HR1 and HR2 in SARS-CoV-2 spike protein., An outbreak caused by 2019 novel coronavirus (2019-nCoV) was first identified in Wuhan City, Hubei Province, China. The new virus was later named SARS-CoV-2. The virus has affected tens of thousands of patients in the world. The infection of SARS-CoV-2 causes severe pneumonia and even death. It is urgently needed to find a therapeutic method to treat patients with SARS-CoV-2 infection. Studies showed that the surface spike (S) protein is essential for the coronavirus binding and entry of host cells. The heptad repeats 1 and 2 (HR1 and HR2) in the S protein play a decisive role in the fusion of the viral membrane with the host cell membrane. We predicted the HR1 and HR2 regions in S protein by sequence alignment. We simulated a computational model of HR1/2 regions and the fusion core. The binding energy of HR1 and HR2 of the fusion core was -33.4kCal/mol. We then designed antivirus peptides by molecular dynamics simulation of the fusion core. The binding energy of HR2-based antiviral peptide to HR1 was -43.0kCal/mol, which was stronger than the natural stage of the fusion core, suggesting that the predicted antiviral peptide can competitively bind with HR1 to prevent forming of the fusion core. The antiviral peptides can prevent SARS-CoV-2 membrane fusion and can potentially be used for the prevention and treatment of infections.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Despite the progress made in precision treatment of cancer patients, targeted treatment is still at its early stage in TNBC, and chemotherapy remains the standard treatment. With the advances in next generation sequencing technology, genomic and transcriptomic analyses have provided deeper insight into the inter-tumoral heterogeneity of TNBC. Much effort has been made to classify TNBCs into different molecular subtypes according to genetic aberrations and expression signatures and to uncover novel treatment targets. In this review, we summarized the current knowledge regarding the molecular classification of TNBC and explore the future paradigm for using molecular classification to guide the development of precision treatment and clinical practice.

A wireless-powered implantable sensor tag for neural recording and brain stimulation (NRS) based on standard Near Field Communication (NFC) protocol is presented. A NRS system is thus established with this dedicated but flexible sensor tag and a Proximity Coupling Device (PCD), which can be replaced with an NFC smart phone. The flexible printed sensor tag consists of a customized NRS System on Chip (SoC) and a customized NFC Proximity Card (PICC) SoC. Neural signals are captured by the sensor tag and transmitted to the PCD wirelessly. The measured signal-to-noise-and-distortion-rate (SNDR) was 35 dB in vitro.

Objectives Patients with T1N0M0 breast cancers are considered to have an excellent prognosis, even in triple-negative breast cancer (TNBC), which is often associated with diminished recurrence-free survival (RFS) and overall survival. Chemotherapy remains the only adjuvant treatment for TNBC, but evidence that adjuvant chemotherapy is beneficial for stage T1N0M0 TNBC patients is limited. In this study, we aimed to evaluate the effect of adjuvant chemotherapy and the benefit of taxanes in T1N0M0 TNBC patients. Material and methods A cohort of 354 consecutive patients with newly diagnosed T1N0M0 TNBC between January 2008 and December 2015 were included from the Fudan University Shanghai Cancer Center. Univariate and multivariate survival analyses were performed to compare patients treated with adjuvant chemotherapy with/without taxane addition. Results Median follow-up was 45 months. Chemotherapy was used in 92.4% of patients. The 5-year estimated RFS rates of patients with and without adjuvant chemotherapy were 94.5% and 83.6%, respectively. In multivariate analysis, adjuvant chemotherapy and a lack of lymphovascular invasion were associated with a significant benefit for RFS. A significant RFS benefit from adjuvant chemotherapy was observed in T1c (hazard ratio, HR = 0.24, 95% CI [0.08–0.76], P = 0.014) but not in T1b (HR = 0.32, 95% CI [0.03–3.18], P = 0.330) subgroups. Addition of taxane to an anthracycline-based regimen was not significantly associated with improved RFS in T1N0M0 TNBC patients. Conclusion Adjuvant chemotherapy improves recurrence-free survival in T1c TNBC patients but not in T1b. Anthracycline-based taxane-free regimens might be sufficient to achieve RFS benefits in T1N0M0 TNBC patients.

We comprehensively analyzed clinical, genomic, and transcriptomic data of a cohort of 465 primary triple-negative breast cancer (TNBC). PIK3CA mutations and copy-number gains of chromosome 22q11 were more frequent in our Chinese cohort than in The Cancer Genome Atlas. We classified TNBCs into four transcriptome-based subtypes: (1) luminal androgen receptor (LAR), (2) immunomodulatory, (3) basal-like immune-suppressed, and (4) mesenchymal-like. Putative therapeutic targets or biomarkers were identified among each subtype. Importantly, the LAR subtype showed more ERBB2 somatic mutations, infrequent mutational signature 3 and frequent CDKN2A loss. The comprehensive profile of TNBCs provided here will serve as a reference to further advance the understanding and precision treatment of TNBC.

Estrogen receptor-positive, progesterone receptor-negative, and human epidermal growth factor receptor 2 (HER2)-negative (ER+PR-HER2-) breast cancer comprise a special type of breast cancer that constitutes ~10% of all breast cancer patients. ER+PR-HER2- tumor benefits less from endocrine therapy, while its genomic features remain elusive. In this study, we systematically assessed the multiomic landscape and endocrine responsiveness of ER+PR-HER2- breast cancer. Methods: This study incorporated five cohorts. The first and second cohorts were from the Surveillance, Epidemiology, and End Results database (n=130,856) and Molecular Taxonomy of Breast Cancer International Consortium (n=1,055) for analyzing survival outcomes and endocrine responsiveness. The third cohort was from The Cancer Genome Atlas (n=630) for multiomic analysis and endocrine-resistant subgroup exploration. The fourth cohort, from the MD Anderson database (n=92), was employed to assist gene selection. The fifth cohort was a prospective observational cohort from Fudan University Shanghai Cancer Center (n=245) that was utilized to validate the gene-defined subgroup by immunohistochemistry (IHC). Results: Clinically, ER+PR-HER2- tumors showed lower endocrine responsiveness than did ER+PR+HER2- tumors. Genomically, copy number loss or promoter methylation of PR genes occurred in 75% of ER+PR-HER2- tumors, collectively explaining PR loss. ER+PR-HER2- tumors had higher TP53 (30.3% vs. 17.0%) and lower PIK3CA mutation rates (25.8% vs. 42.7%) and exhibited more ZNF703 (21.5% vs. 13.6%) and RPS6KB1 (18.5% vs. 7.8%) amplification events than ER+PR+HER2- tumors. Among ER+PR-HER2- tumors, nearly 20% were of the PAM50-defined non-luminal-like subgroup and manifested lower endocrine sensitivity scores and enriched biosynthesis, metabolism and DNA replication pathways. We further identified the non-luminal-like subgroup using three IHC markers, GATA3, CK5, and EGFR. These IHC-defined non-luminal-like (GATA3-negative, CK5-positive and/or EGFR-positive) tumors received limited benefit from adjuvant endocrine therapy. Conclusion: ER+PR-HER2- breast cancer consists of clinically and genomically distinct groups that may require different treatment strategies. The non-luminal-like subgroup was associated with reduced benefit from endocrine therapy.

Luminal breast cancer (BC) has a sustained risk of late disease recurrence and death. Considerable numbers of patients suffer from antiendocrine therapy resistance. Here, we identified a novel lncRNA whose expression is high in breast cancer and especially higher in luminal breast cancer, dubbed LOL (lncRNA of luminal), that acts as a natural sponge for let-7 microRNAs to regulate tumor growth and tamoxifen resistance. LOL overexpression in parental MCF-7 cells exhibited a proliferative advantage in the addition of tamoxifen than negative control. Knocking down LOL in TamR MCF-7 cells, recovered the sensitivity of cells to tamoxifen. Strikingly, we demonstrated that LOL is transcribed from a genomic locus of an enhancer to maintain its high expression in luminal BC and that it is extremely sensitive to enhancer-regulating factors, such as ZMYND8 and BRD4. Estrogen deprivation or ERα signaling pathway blockage can further stimulate LOL expression, which can promote tumor progression. Clinical analysis of 374 luminal breast cancer samples indicated that LOL is an independent prognostic factor for poor survival in luminal BC. In conclusion, targeting LOL using preclinical/clinical drugs, such as BRD4 inhibitors, may represent a promising approach to inhibit luminal breast cancer progression and tamoxifen resistance.

Background Renal cell carcinoma (RCC) is the most common kidney cancer, accounting for approximately 80–90% of all primary kidney cancer. Treatment for patients with advanced RCC remains unsatisfactory. Rare cancer stem cells (CSCs) are proposed to be responsible for failure of current treatment. Methods OncoLnc was used as a tool for interactively exploring survival correlations. Gene manipulation and expression analysis were carried out using siRNA, RT-PCR and Western blotting. Wound healing and invasion assays were used for phenotypical characterization. Aldefluor assay and FACS sorting Sphere culture were used to determine the “stemness” of CSCs. Co-Immunoprecipitation (Co-IP) was used to examine the interaction between OCT4 and CBFA2T2. Student’s t-test and Chi square test was used to analyze statistical significance. Results CBFA2T2 expression can significantly predict the survival of RCC patients. Knocking-down of CBFA2T2 can inhibit cell migration and invasion in RCC cells in vitro, and reduce ALDHhigh CSCs populations. CBFA2T2 expression is necessary for sphere-forming ability and cancer stem cells marker expression in RCC cell lines. Conclusions Our data suggest that CBFA2T2 expression correlates with aggressive characteristics of RCC and CBFA2T2 is required for maintenance of “stemness” through regulation of stem cells factors, thereby highlighting CBFA2T2 as a potential therapeutic target for RCC treatment. Electronic supplementary material The online version of this article (10.1186/s12935-017-0473-z) contains supplementary material, which is available to authorized users.

Rationale: An elevated level of plasma LDL (low-density lipoprotein) is an established risk factor for cardiovascular disease. Recently, we reported that the (pro)renin receptor ([P]RR) regulates LDL metabolism in vitro via the LDLR (LDL receptor) and SORT1 (sortilin-1), independently of the renin–angiotensin system. Objectives: To investigate the physiological role of (P)RR in lipid metabolism in vivo. Methods and Results: We used N-acetylgalactosamine modified antisense oligonucleotides to specifically inhibit hepatic (P)RR expression in C57BL/6 mice and studied the consequences this has on lipid metabolism. In line with our earlier report, hepatic (P)RR silencing increased plasma LDL-C (LDL cholesterol). Unexpectedly, this also resulted in markedly reduced plasma triglycerides in a SORT1-independent manner in C57BL/6 mice fed a normal- or high-fat diet. In LDLR-deficient mice, hepatic (P)RR inhibition reduced both plasma cholesterol and triglycerides, in a diet-independent manner. Mechanistically, we found that (P)RR inhibition decreased protein abundance of ACC (acetyl-CoA carboxylase) and PDH (pyruvate dehydrogenase). This alteration reprograms hepatic metabolism, leading to reduced lipid synthesis and increased fatty acid oxidation. As a result, hepatic (P)RR inhibition attenuated diet-induced obesity and hepatosteatosis. Conclusions: Collectively, our study suggests that (P)RR plays a key role in energy homeostasis and regulation of plasma lipids by integrating hepatic glucose and lipid metabolism.

// Alimujiang Wushou 1,2 , Yi-Zhou Jiang 1,2 , Yi-Rong Liu 1,2 and Zhi-Ming Shao 1,2 1 Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China Correspondence to: Zhi-Ming Shao, email: // Keywords : Solitary fibrous tumor and SEER analysis Received : August 09, 2015 Accepted : October 06, 2015 Published : October 19, 2015 Abstract Background: Solitary fibrous tumor’s (SFT) demographic features, clinicopathologic characteristics, treatment outcome and disease-specific prognostic factors were unexplored comprehensively. Methods: SEER program was used to identify patients diagnosed with SFT from 1973 to 2012. Overall collected data were analyzed by using the SPSS 18.0. Results: In total, 804 cases were found including 613 cases with SFT-specific mortality and 801 patients were analyzed for overall survival (OS). The 3-year disease specific survival (DSS), 5-year DSS and 10-year DSS were 73.3%, 65.7% and 53.3%. The 3-year OS, 5-year OS and 10-year OS were 71.9%, 63.3% and 47.3%. In the multivariate survival analysis, the age > 51 years (hazard ratio [HR] = 1.851 for DSS, P = 0.024 and HR = 1.652 for OS, P = 0.033; Reference [Ref] ≤ 51 years for DSS and ≤ 53 years for OS), SEER stage metastasized tumor (HR = 4.269 for DSS, P = 0.000 and HR = 2.905 for OS, P = 0.028, Ref - localized + regional tumor), pathologic grade III + IV (HR = 2.734 for DSS, P = 0.001 and HR = 2.585 for OS, P = 0.000, Ref - grade I + II) were adversely associated with DSS and OS. In addition, surgery was favorably associated with DSS (HR = 0.217, P = 0.045, Ref - surgery + radiotherapy). Conclusions: The surgery was an independent prognostic factor for DSS. The patient’s age, SEER stage and pathologic grade were SFT-specific independent prognostic indicators for DSS and OS.

Arterial endothelial phenotype is regulated by local hemodynamic forces that are linked to regional susceptibility to atherogenesis. A complex hierarchy of transcriptional, translational, and post-translational mechanisms is greatly influenced by the characteristics of local arterial shear stress environments. We discuss the emerging role of localized disturbed blood flow on epigenetic mechanisms of endothelial responses to biomechanical stress, including transcriptional regulation by proximal promoter DNA methylation, and post-transcriptional and translational regulation of gene and protein expression by chromatin remodeling and noncoding RNA-based mechanisms. Dynamic responses to flow characteristics in vivo and in vitro include site-specific differentially methylated regions of swine and mouse endothelial methylomes, histone marks regulating chromatin conformation, microRNAs, and long noncoding RNAs. Flow-mediated epigenomic responses intersect with cis and trans factor regulation to maintain endothelial function in a shear-stressed environment and may contribute to localized endothelial dysfunctions that promote atherosusceptibility.

Purpose Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is primarily treated with trastuzumab and other HER2-targeted therapies. However, approximately 30% of HER2-positive tumors exhibit de novo resistance, whereas 40% acquire resistance to these therapies. The mechanisms underlying drug resistance are unclear, and a better understanding of acquired resistance to HER2-targeted therapy is essential for the development of more effective therapeutics. Methods We enrolled 11 patients with HER2-positive breast cancer, all of whom had been treated with trastuzumab for one year and developed lung metastasis in the follow-up. We conducted exome sequencing of the primary and paired metastatic tumors from four patients. We identified somatic mutations in HER2 (K753E and L755S) affecting the kinase domain only in the metastatic lesions of two cases. Sanger sequencing was performed to analyze all exons of the HER2 gene in the paired primary and metastatic tumors of the remaining seven cases. Furthermore, we enrolled 48 patients with HER2-positive disease who underwent trastuzumab-based neoadjuvant therapy. We performed Sanger sequencing of the HER2 gene in paired tumor DNA before and after neoadjuvant therapy. To determine the phenotype of these mutations, we functionally characterized the HER2 mutations using protein structure analysis, in vitro kinase assays, cell culture, and xenograft experiments. Results We identified somatic mutations in HER2 affecting the kinase domain in four of 11 metastatic tumors (one case with K753E and three cases with L755S). None of the primary tumors harbored HER2 mutations. Furthermore, Sanger sequencing in the neoadjuvant setting revealed two of 48 cases harboring HER2 mutations (K753E and L755S) in the post-treatment samples, none of whom had any HER2 mutation in the paired pre-treatment tumor. Protein structure visualization hinted that the HER2 L753 and L755 side chains were in close proximity to the binding site for small-molecule inhibitors, indicating mutations at this residue might produce drug resistance. In vitro kinase assays revealed that HER2 K753E had greater tyrosine kinase-specific activity than wild-type. HER2 autophosphorylation, phosphorylation of HER2’s dimerization partners (EGFR or HER3) and downstream signaling proteins were significantly upregulated in MCF10A and MCF7 cells overexpressing HER2 K753E or L755S. Trastuzumab or lapatinib treatment did not decrease the number of colonies formed in MCF10A cells transduced with K753E or L755S. MCF7 cells bearing K753E or L755S mutant could reverse the inhibition of lapatinib in xenografts. The MCF10A-HER2 K753E and L755S cells were resistant to trastuzumab (IC50>1000μg/mL) and lapatinib (IC50>10μmol/L) but could be readily inhibited by neratinib (IC50 of 15 nmol/L), an irreversible kinase inhibitor of HER2. Conclusion These data implicate that mutations in HER2 kinase domain are a key mechanism in resistance to HER2-targeted therapy. The selection of functional HER2 mutations might act as potential drivers of trastuzumab resistance during the progression of HER2-positive disease. Furthermore, more potent HER2 inhibitors such as neratinib might be of therapeutic benefit for trastuzumab-resistant breast cancer. Citation Format: Yizhou Jiang, Ke-Da Yu, Wen-Jia Zuo, Yu-Jie Wang, Zhi-Ming Shao. Exome sequencing identified emergence of HER2 kinase domain mutations in trastuzumab-resistant breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-04-02.

Neoadjuvant chemotherapy (NAC) is the standard of care for locally advanced breast cancer (LABC). However, the lack of efficient method to predict the treatment response and prognosis limits the clinical evaluation of the patient eligibility. Elevated lymphocyte-to-monocyte ratio (LMR) has been reported to be associated with favorable prognosis in some hematology malignancies and nasopharyngeal carcinoma, but has not been studied in breast cancer. The purpose of this study is to evaluate whether the LMR is a predictor of the curative impact of LABC patients after NAC and short/long-term mortality. A retrospective cohort of 542 LABC patients who received NAC was recruited between May 2002 and August 2011. The counts for peripheral absolute lymphocyte and monocyte before NAC were retrieved, and the LMR was calculated. Receiver operating characteristic curve analysis, univariate and multivariate Cox proportional hazards analyses were applied to evaluate the associations of LMR with overall survival (OS) and disease-free survival (DFS) respectively. Univariate analysis revealed that higher LMR level (≥4.25) was significantly related to better overall response rate (P = 0.005). Univariate analysis revealed that higher LMR level (≥4.25) was significantly associated with superior OS (P = 0.014), DFS (P = 0.009). The higher lymphocyte count (≥1.5×109/L) was significantly associated with better OS (P = 0.035), while the lower monocyte count ( Citation Format: Lei Wang, Xiao-Jian Ni, Guo-Wei Qian, Qian-Wen Ou-Yang, Xiao-Lan Zhang, Yi-Zhou Jiang, Sheng Chen, Xin Hu, Zhi-Ming Shao. Elevated peripheral blood lymphocyte-to-monocyte ratio predicts favorable response and prognosis in locally advanced breast cancer after neoadjuvant chemotherapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-11-09.

// Xi Jin 1, * , Yi-Zhou Jiang 1, * , Sheng Chen 1, * , Ke-Da Yu 1 , Zhi-Ming Shao 1 , Gen-Hong Di 1 1 Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China * These authors have contributed equally to this work Correspondence to: Gen-Hong Di, e-mail: didy@medmail.com.cn Yi-Zhou Jiang, e-mail: yizhoujiang@fudan.edu.cn Keywords: breast cancer, neoadjuvant chemotherapy, receptor conversion, prognosis Received: January 12, 2015 Accepted: February 05, 2015 Published: March 16, 2015 ABSTRACT The hormone receptor (HR) status and human epidermal growth hormone receptor 2 (HER2) status of patients with breast cancer may change following neoadjuvant chemotherapy (NCT). This prospective observational study aimed to evaluate the prognostic impact of receptor conversion in breast cancer patients treated with NCT.Of the 423 consecutive patients who had residual disease in the breast after NCT, 55 (13.0%) changed from HR (+) to HR (−), 23 (5.4%) changed from HR (−) to HR (+), 27 (6.4%) changed from HER2 (+) to HER2 (−), and 13 (3.1%) changed from HER2 (−) to HER2 (+). A total of 54 (12.8%) changed to the triple-negative (TN) tumor phenotype. The loss of HR positivity was an independent prognostic factor for worse disease-free survival (DFS) and worse overall survival (OS) in multivariate survival analysis. Furthermore, the switch to the TN phenotype after NCT was another independent prognostic factor for worse survival for both DFS and OS. In conclusion, patients with breast cancer may experience changes in HR status, HER2 status and tumor phenotype after NCT. The loss of HR positivity and the switch to the TN phenotype after NCT were associated with a worse patient outcome.

This paper presents a potential methodology regarding the safety evaluation of front-line builders that based on whose psychological factors. The methodology is extended by the impact of front-lines builders’ psychological factors on the safety of construction, by researching on the SAS, SDS and self-restraint related factors to investigate the physiology and psychological condition of bridge and tunnel builders in Anhui, China, from which we aim to create a safety model of relatively related factors via the statistics of investigation.

Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor is involved in regulation of many essential biological processes including vascular development and angiogenesis. 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is an AhR ligand, which regulates immune responses and cancer cell growth. However, the roles of the ITE/AhR pathway in mediating placental angiogenesis remains elusive. Here, we determined if ITE affected placental angiogenic responses via AhR in human umbilical vein (HUVECs) and artery endothelial (HUAECs) cells in vitro. We observed that ITE dose- and time-dependently inhibited proliferation and viability of HUAECs and HUVECs, whereas it inhibited migration of HUAECs, but not HUVECs. While AhR siRNA significantly suppressed AhR protein expression in HUVECs and HUAECs, it attenuated the ITE-inhibited angiogenic responses of HUAECs, but not HUVECs. Collectively, ITE suppressed angiogenic responses of HUAECs and HUVECs, dependent and independent of AhR, respectively. These data suggest that ITE may regulate placental angiogenesis.

AFF1 and AFF4 belong to the AFF (AF4/FMR2) family of proteins, which function as scaffolding proteins linking two different transcription elongation factors, positive elongation factor b (P-TEFb) and ELL1/2, in super elongation complexes (SECs). Both AFF1 and AFF4 regulate gene transcription through elongation and chromatin remodeling. However, their function in the osteogenic differentiation of mesenchymal stem cells (MSCs) is unknown. In this study, we show that small interfering RNA (siRNA)-mediated depletion of AFF1 in human MSCs leads to increased alkaline phosphatase (ALP) activity, enhanced mineralization and upregulated expression of osteogenic-related genes. On the contrary, depletion of AFF4 significantly inhibits the osteogenic potential of MSCs. In addition, we confirm that overexpression of AFF1 and AFF4 differentially affects osteogenic differentiation in vitro and MSC-mediated bone formation in vivo. Mechanistically, we find that AFF1 regulates the expression of DKK1 via binding to its promoter region. Depletion of DKK1 in HA-AFF1-overexpressing MSCs abrogates the impairment of osteogenic differentiation. Moreover, we detect that AFF4 is enriched in the promoter region of ID1. AFF4 knockdown blunts the BRE luciferase activity, SP7 expression and ALP activity induced by BMP2 treatment. In conclusion, our data indicate that AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs.

In order to investigate clinicopathological characteristics and prognosis of mixed invasive ductal and lobular carcinoma (IDC-L), 209,109 primary breast cancer patients diagnosed with invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC) or IDC-L were included. It was found that IDC-L patients had lower tumor grade and higher hormone receptor positive proportions than IDC patients. Moreover, IDC-L patients were younger and had a similar hormone receptor status compared with ILC patients. Kaplan-Meier plots showed that the breast cancer-specific survival (BCSS) of IDC-L patients was significantly better than IDC patients (P

To examine the clinicopathologic characteristics and survival outcomes of different histologic types of triple-negative breast cancer (TNBC).We used the SEER database to identify patients with TNBC diagnosed between 2010 and 2014. Our analysis focused on the seven most prevalent histologic types. Differences were compared between invasive carcinoma of no special type (NST) and the other six types.Significant differences were observed in age at diagnosis, tumor grade, size, nodal status and treatment. As tumor size increased, the number of positive lymph nodes increased markedly in invasive lobular carcinoma (ILC) and mixed NST and lobular carcinoma (NST-ILC), while in metaplastic carcinoma the number only increased slightly. In multivariate survival analyses, compared with patients with invasive carcinoma NST, breast cancer-specific survival (BCSS) and overall survival (OS) were worse for those with NST-ILC (BCSS: hazard ratio [HR] 1.81, P .001; OS: HR 1.56, P = .005) or metaplastic carcinoma (BCSS: HR 1.95, P .001; OS: HR 1.73, P .001). By contrast, patients with medullary (HR 0.40, P = .010) or apocrine carcinoma (HR 0.27, P = .008) showed better BCSS. Time-dependent receiver operating characteristic (ROC) analyses indicated that T category in ILC and N category in metaplastic carcinoma were of less prognostic value.According to the histologic classification of TNBC, this heterogeneous disease can be divided into several entities with different clinicopathologic features and prognoses. In the era of molecular subtyping of breast cancer, the histologic classification of TNBC is still of considerable clinical significance.

Rehabilitation of stroke survivors has been increasing in importance in recent years with increase in the occurrence of stroke. However, current clinical classification assessment is time-consuming while the result is not accurate and varies across physicians. This paper introduces an IoT-based upper limb rehabilitation assessment system for stroke survivors based on wireless sensing sub-system, data cloud, computing cloud and software based on Android platform. The system can automatically perform objective assessment. It is designed for home rehabilitation as well as for the concept of graded rehabilitation therapy.

Osteosarcoma is the most common primary bone sarcoma that mostly occurs in young adults. The causes of osteosarcoma are heterogeneous and still not fully understood. Identification of novel, important oncogenic factors in osteosarcoma and development of better, effective therapeutic approaches are in urgent need for better treatment of osteosarcoma patients. In this study, we uncovered that the oncogene MYC is significantly upregulated in metastastic osteosarcoma samples. In addition, high MYC expression is associated with poor survival of osteosarcoma patients. Analysis of MYC targets in osteosarcoma revealed that most of the osteosarcoma super enhancer genes are bound by MYC. Treatment of osteosarcoma cells with super enhancer inhibitors THZ1 and JQ1 effectively suppresses the proliferation, migration, and invasion of osteosarcoma cells. Mechanistically, THZ1 treatment suppresses a large group of super enhancer containing MYC target genes including CDK6 and TGFB2. These findings revealed that the MYC-driven super enhancer signaling is crucial for the osteosarcoma tumorigenesis and targeting the MYC/super enhancer axis represents as a promising therapeutic strategy for treatment of osteosarcoma patients., Bone cancer: Disease-promoting DNA regions revealed as therapeutic targets Insight into a molecular pathway involved in an aggressive bone cancer has suggested a new approach to its treatment. Osteosarcoma usually develops in growing bone tissue, but often spreads to other organs, consequently reducing survival. The molecular mechanisms behind osteosarcoma are not fully understood. A team led by Shuibin Lin from Sun Yat-sen University investigated the role of MYC, a gene that is important in other cancers. They found that increased expression of MYC is associated with the spread of osteosarcoma and a poor prognosis because the protein product of MYC activates many super-enhancers, regions of DNA that increase the expression of cancer-related genes. Inhibition of the super-enhancers suppressed growth and spreading of osteosarcoma in cultured cells and a mouse model, suggesting a novel therapeutic approach to osteosarcoma.

EGFR inhibitors, even with therapeutics superiorities in anticancer, can cause idiosyncratic pulmonary and hepatic toxicities that are associated with the reactive electrophile bioactivated by Cytochrome P450s (P450s). Until now, neither has the electrophilic intermediate been caught experimentally, nor has the subtle mechanism been declared. Herein, the underlying mechanism of bioactivation mediated by P450s was explored by DFT calculations for a case of EGFR inhibitor, Erlotinib. Based on the calculation and analysis, we suggest that with other metabolites, reactive electrophiles of Erlotinib: epoxide and quinine-imine, can be generated by several steps along the oxidative reaction pathway. The generation of epoxide needs two steps: (1) the addition of Erlotinib to Compound I (Cpd I) and (2) the rearrangement of protons. Whereas, quinine-imine needs a further oxidation step (3) via which quinone is generated and ultimately turns into quinine-imine. Although both reactive electrophiles can be produced for either face-on or side-on pose of Erlotinib, the analysis of energy barriers indicates that the side-on path is preferred in solvent environment. In the rate-determining step, e.g. the addition of Erlotinib to the porphyrin, the reaction barrier for side-on conformation is decreased in aqueous and protein environment compared with gas phase, whereas, the barrier for face-on pose is increased in solvent environment. The simulated mechanism is in good agreement with the speculation in previous experiment. The understanding of the subtle mechanism of bioactivation of Erlotinib will provide theoretical support for toxicological mechanism of EGFR inhibitors.

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, mediates a broad spectrum of biological processes, including ovarian growth and ovulation. Recently, we found that an endogenous AhR ligand (ITE) can inhibit ovarian cancer proliferation and migration via the AhR. Here, we tested whether 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, an exogenous AhR ligand) may exert similar anti-ovarian cancer activities using human ovarian cancer and non-cancerous human ovarian surface epithelial cells. Two human ovarian cancer cell lines (SKOV-3 and OVCAR-3) and one human ovarian surface epithelial cell line (IOSE-385) were used. Cell proliferation and migration activities were determined using crystal violet and FluoroBlok insert system assays, respectively. AhR protein expression was assessed by Western blotting. Expression of cytochrome P450, family 1, member A1 (CYP1A1) and member B1 (CYP1B1) mRNA was assessed by qPCR. Small interfering RNAs (siRNAs) were used to knock down AhR expression. We found that TCDD dose-dependently suppressed OVCAR-3 cell proliferation, with a maximum effect (~70 % reduction) at 100 nM. However, TCDD did not affect SKOV-3 and IOSE-385 cell proliferation and migration. The estimated IC50 of TCDD for inhibiting OVCAR-3 cell proliferation was 4.6 nM. At 10 nM, TCDD time-dependently decreased AhR protein levels, while it significantly increased CYP1A1 and CYP1B1 mRNA levels in SKOV-3, OVCAR-3 and IOSE-385 cells, indicating activation of AhR signaling. siRNA-mediated AhR knockdown readily blocked TCDD-mediated suppression of OVCAR-3 cell proliferation. Our data indicate that TCDD can suppress human ovarian cancer cell proliferation via the AhR signaling pathway and that TCDD exhibits an anti-proliferative activity in at least a subset of human ovarian cancer cells.

Atherosclerosis is a multi-focal disease; it is associated with arterial curvatures, asymmetries and branches/bifurcations where non-uniform arterial geometry generates patterns of blood flow that are considerably more complex than elsewhere, and are collectively referred to as disturbed flow. Such regions are predisposed to atherosclerosis and are the sites of ‘athero-susceptible’ endothelial cells that express regionally different cell phenotypes than endothelium in nearby athero-protected locations. The regulatory hierarchy of endothelial function includes control at the epigenetic level. MicroRNAs and histone modifications are established epigenetic regulators that respond to disturbed flow. However, very recent reports have linked transcriptional regulation by DNA methylation to endothelial gene expression in disturbed flow in vivo and in vitro. We outline these in the context of site-specific atherosusceptibility mediated by local hemodynamics.