Prognostic value of the Lung Immune Prognostic Index for HER-2-negative metastatic gastric cancer.

Background: The aim of this study was to explore whether the Lung Immune Prognostic Index (LIPI) is associated with clinical outcomes in patients with metastatic gastric cancer (MGC) treated with anti-PD-1 and chemotherapy. Methods: Patients with MGC treated with an anti-PD-1 therapy or chemotherapy were enrolled. This study was composed of two cohorts including 266 patients in the anti-PD-1-treated group and 139 patients in the chemotherapy-treated group. Results: Patients treated with anti-PD-1 therapy that also showed a good LIPI showed a longer median progression-free survival and median overall survival in patients with an intermediate or poor LIPI. These outcomes were not observed in the chemotherapy cohort. Conclusion: Good LIPI correlated with better outcomes for patients with MGC in the anti-PD-1-treated group but not in the chemotherapy-treated group.

Partial response to RC-48 as palliative treatment in a patient with locallocally advanced carcinoma ex pleomorphic adenoma harboring a HER2 mutation: a case report.

BACKGROUND: Carcinoma ex pleomorphic adenoma (CXPA) is a neoplasm of the salivary gland that causes 3.6% of salivary gland tumors and 12% of salivary gland malignancies. Its prognosis is determined by the histological progression beyond the adenoma capsule. CXPA is thought to be a malignant transformation of a primary or recurrent pleomorphic adenoma and is associated with both benign and malignant lesions. Salivary gland cancers represent a rare heterogeneous group of neoplasms with complex clinicopathological characteristics and distinct biological behavior. CASE DESCRIPTION: This case report summarizes the treatment of a 57-year-old male patient with CXPA of the left parotid gland, harboring HER2 amplification with poor prognosis. The overall survival of the patient has been > 3.5 years. The application and outcome of an immune checkpoint inhibitor and targeted therapy combination regimens in the treatment of CXPA carcinoma are discussed. CONCLUSION: Targeted therapy combined with immunotherapy has long-term clinical benefits and targeted therapy which has a high clinical response rate (immunotherapy + dual-targeting three-drug regimens) may present an ideal choice for the treatment of patients with rare and/or refractory tumors without compromising patient safety.

Clinicopathologic Analysis of Micropapillary Urothelial Carcinoma of the Upper Urinary Tract: Implications for HER2-Targeted Therapy.

Introduction/Background To determine the clinical significance of micropapillary urothelial carcinoma (MPUC) of the upper urinary tract (UTUC) and a potential therapeutic strategy. Patients and Methods A retrospective cohort study was conducted to examine the incidence of micropapillary UTUC from 2010 to 2018 and its clinicopathological characteristics. Clinical outcomes and cancer-specific survival (CSS) were compared between MPUC and conventional UTUC matched by stage within a 6-month variation of receiving surgery. Results A total of 24 MPUC cases were identified out of 901 cases (2.7%) of urothelial carcinoma (UC) of the renal pelvis and ureter. MPUC was significantly smaller (<3 cm) and associated with nodal metastasis compared with conventional UTUC (P = .017 & 0.021, respectively); however, no significant difference was observed for lymphovascular invasion, distant metastasis, or CSS (P > 0.50, respectively) compared with match controls. Six MPUC patients (25%) developed metastasis to the liver, lymph nodes, and lung during follow-up. Patients with HER2-positive MPUC (3 of 4) had a significantly higher risk of metastasis compared with HER2-negative MPUC (3 of 20; P = 0.035). Conclusions MPUC is an aggressive variant of UTUC and usually presents as a small locally advanced disease. HER2 immunohistochemistry may identify the subset of patients with micropapillary UTUC that are candidates for targeted therapy.

Phase 1 study of oral selective estrogen receptor degrader (SERD) amcenestrant (SAR439859), in Japanese women with ER-positive and HER2-negative advanced breast cancer (AMEERA-2).

BACKGROUND: This AMEERA-2 study evaluated the pharmacokinetics, efficacy, and safety of the oral selective estrogen receptor degrader amcenestrant as a monotherapy with dose escalation in Japanese postmenopausal women with advanced estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer. METHODS: In this open-label, nonrandomized, phase I study, patients received amcenestrant 400 mg once daily (QD) (n = 7) and 300 mg twice daily (BID) (n = 3). The incidence of dose-limiting toxicities (DLT), recommended dose, maximum tolerated dose (MTD), pharmacokinetics, efficacy, and safety were assessed. RESULTS: No DLTs were observed and MTD was not reached in the 400 mg QD group. One DLT (grade 3 maculopapular rash) was reported in a patient treated with 300 mg BID. After repeated oral administration of either dosing regimen, steady state reached before day 8, without accumulation. Four out of 5 response-evaluable patients from 400 mg QD group achieved clinical benefit and showed tumor shrinkage. No clinical benefit was reported in the 300 mg BID group. Overall, most patients (8/10) experienced a treatment-related adverse event (TRAE), with skin and subcutaneous tissue disorders most commonly reported (4/10 patients). No ≥ grade 3 TRAE in 400 mg QD group and 1 grade 3 TRAE in 300 mg BID group were reported. CONCLUSIONS: Amcenestrant 400 mg QD has a favorable safety profile and has been selected as the recommended Phase II dose for monotherapy for evaluating the safety and efficacy of amcenestrant in a larger, global, randomized clinical trial of patients with metastatic breast cancer. TRIAL REGISTRATION: Clinical trial registration NCT03816839.

Efficacy and safety of pyrotinib in advanced lung adenocarcinoma with HER2 mutations: a multicenter, single-arm, phase II trial.

BACKGROUND: There is currently a lack of effective treatments for non-small cell lung cancer (NSCLC) patients harboring HER2 mutations. We examined the efficacy and safety of, and potential resistance mechanism to, pyrotinib, a pan-HER inhibitor, in advanced NSCLC carrying HER2 mutations. METHODS: In this multicenter, single-arm, phase II trial, stage IIIB-IV NSCLC patients harboring HER2 mutations, as determined using next-generation sequencing, were enrolled and treated with pyrotinib at a dose of 400 mg/day. The primary endpoint was 6-month progression-free survival (PFS) rate, and secondary endpoints were objective response rate (ORR), PFS, overall survival (OS), disease control rate (DCR), and safety. The impact of different HER2 mutation types on sensitivity to pyrotinib and the potential of utilizing mutational profile derived from circulating tumor DNA (ctDNA) to predict disease progression were also explored. RESULTS: Seventy-eight patients were enrolled for efficacy and safety analysis. The 6-month PFS rate was 49.5% (95% confidence interval [CI], 39.2-60.8). Pyrotinib produced an ORR of 19.2% (95% CI, 11.2-30.0), with median PFS of 5.6 months (95% CI, 2.8-8.4), and median OS of 10.5 months (95% CI, 8.7-12.3). The median duration of response was 9.9 months (95% CI, 6.2-13.6). All treatment-related adverse events (TRAEs) were grade 1-3 (all, 91.0%; grade 3, 20.5%), and the most common TRAE was diarrhea (all, 85.9%; grade 3, 16.7%). Patients with exon 20 and non-exon 20 HER2 mutations had ORRs of 17.7% and 25.0%, respectively. Brain metastases at baseline and prior exposure to afatinib were not associated with ORR, PFS, or OS. Loss of HER2 mutations and appearance of amplification in HER2 and EGFR were detected upon disease progression. CONCLUSIONS: Pyrotinib exhibited promising efficacy and acceptable safety in NSCLC patients carrying exon 20 and non-exon 20 HER2 mutations and is worth further investigation. TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR1800020262.

Decitabine potentiates efficacy of doxorubicin in a preclinical trastuzumab-resistant HER2-positive breast cancer models.

Acquired drug resistance and metastasis in breast cancer (BC) are coupled with epigenetic deregulation of gene expression. Epigenetic drugs, aiming to reverse these aberrant transcriptional patterns and sensitize cancer cells to other therapies, provide a new treatment strategy for drug-resistant tumors. Here we investigated the ability of DNA methyltransferase (DNMT) inhibitor decitabine (DAC) to increase the sensitivity of BC cells to anthracycline antibiotic doxorubicin (DOX). Three cell lines representing different molecular BC subtypes, JIMT-1, MDA-MB-231 and T-47D, were used to evaluate the synergy of sequential DAC + DOX treatment in vitro. The cytotoxicity, genotoxicity, apoptosis, and migration capacity were tested in 2D and 3D cultures. Moreover, genome-wide DNA methylation and transcriptomic analyses were employed to understand the differences underlying DAC responsiveness. The ability of DAC to sensitize trastuzumab-resistant HER2-positive JIMT-1 cells to DOX was examined in vivo in an orthotopic xenograft mouse model. DAC and DOX synergistic effect was identified in all tested cell lines, with JIMT-1 cells being most sensitive to DAC. Based on the whole-genome data, we assume that the aggressive behavior of JIMT-1 cells can be related to the enrichment of epithelial-to-mesenchymal transition and stemness-associated pathways in this cell line. The four-week DAC + DOX sequential administration significantly reduced the tumor growth, DNMT1 expression, and global DNA methylation in xenograft tissues. The efficacy of combination therapy was comparable to effect of pegylated liposomal DOX, used exclusively for the treatment of metastatic BC. This work demonstrates the potential of epigenetic drugs to modulate cancer cells' sensitivity to other forms of anticancer therapy.

New Pharmacokinetic Parameters of Imaging Substrates Quantified from Rat Liver Compartments.

Hepatobiliary imaging is increasingly used by pharmacologists to quantify liver concentrations of transporter-dependent drugs. However, liver imaging does not quantify concentrations in extracellular space, hepatocytes, and bile canaliculi. Our study compared the compartmental distribution of two hepatobiliary substrates gadobenate dimeglumine [BOPTA; 0.08 liver extraction ratio (ER)] and mebrofenin (MEB; 0.93 ER) in a model of perfused rat liver. A gamma counter placed over livers measured liver concentrations. Livers were preperfused with gadopentetate dimeglumine to measure extracellular concentrations. Concentrations coming from bile canaliculi and hepatocytes were calculated. Transporter activities were assessed by concentration ratios between compartments and pharmacokinetic parameters that describe the accumulation and decay profiles of hepatocyte concentrations. The high liver concentrations of MEB relied mainly on hepatocyte and bile canaliculi concentrations. In contrast, the three compartments contributed to the low liver concentrations obtained during BOPTA perfusion. Nonlinear regression analysis of substrate accumulation in hepatocytes revealed that cellular efflux is measurable ∼4 minutes after the start of perfusion. The hepatocyte-to-extracellular concentration ratio measured at this time point was much higher during MEB perfusion. BOPTA transport by multidrug resistance associated protein 2 induced an aquaporin-mediated water transport, whereas MEB transport did not. BOPTA clearance from hepatocytes to bile canaliculi was higher than MEB clearance. MEB did not efflux back to sinusoids, whereas BOPTA basolateral efflux contributed to the decrease in hepatocyte concentrations. In conclusion, our ex vivo model quantifies substrate compartmental distribution and transport across hepatocyte membranes and provides an additional understanding of substrate distribution in the liver. SIGNIFICANCE STATEMENT: When transporter-dependent drugs target hepatocytes, cellular concentrations are important to investigate. Low concentrations on cellular targets impair drug therapeutic effects, whereas excessive hepatocyte concentrations may induce cellular toxicity. With a gamma counter placed over rat perfused livers, we measured substrate concentrations in the extracellular space, hepatocytes, and bile canaliculi. Transport across hepatocyte membranes was calculated. The study provides an additional understanding of substrate distribution in the liver.

Comparison of the multigene panel test and OncoScan™ for the determination of HER2 amplification in breast cancer.

The diagnostic accuracy of the multigene panel test (MPT) and OncoScan™ in the determination of HER2 amplification in breast tumors remains controversial. In the present study, HER2 copy number was analyzed using both MPT and OncoScan™ in 45 breast tumors and was compared with that in fluorescent in situ hybridization (FISH) analysis. Tumors with low cellularity were examined using tumor cell enrichment and fluorescence­activated cell sorting. Both MPT and OncoScan™ exhibited significant correlations with FISH with respect to the determination of HER2 amplification in breast tumors. However, the correlation coefficient was significantly higher for the comparison of MPT and FISH (r=0.770) compared with that between OncoScan™ and FISH (r=0.564). The accuracy of MPT (93.3%) was slightly higher compared with that in OncoScan™ (84.4%) in determining the HER2 status, which was mostly explained by the higher sensitivity of MPT in tumors with low cellularity (83.3 vs. 33.3%), but not in those with high cellularity (81.8 vs. 72.7%). The specificity was 100% for both tests. The MPT exhibited higher sensitivity in the determination of the amplification of other genes, including MYC, fibroblast growth factor receptor 1 and GATA binding protein 3 in tumors with low cellularity compared with that in tumors with high cellularity. OncoScan™ exhibited low sensitivity without tumor cell enrichment. The results suggested that MPT could be a promising method to determine HER2 status in breast tumors and that it could exhibit improved accuracy compared with that in OncoScan™ in tumors with low cellularity.

Recent advances in aptamer-based sensors for breast cancer diagnosis: special cases for nanomaterial-based VEGF, HER2, and MUC1 aptasensors.

Cancer is one of the most common and important diseases with a high mortality rate. Breast cancer is among the three most common types of cancer in women, and the mortality rate has reached 0.024% in some countries. For early-stage preclinical diagnosis of breast cancer, sensitive and reliable tools are needed. Today, there are many types of biomarkers that have been identified for cancer diagnosis. A wide variety of detection strategies have also been developed for the detection of these biomarkers from serum or other body fluids at physiological concentrations. Aptamers are single-stranded DNA or RNA oligonucleotides and promising in the production of more sensitive and reliable biosensor platforms in combination with a wide range of nanomaterials. Conformational changes triggered by the target analyte have been successfully applied in fluorometric, colorimetric, plasmonic, and electrochemical-based detection strategies. This review article presents aptasensor approaches used in the detection of vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2), and mucin-1 glycoprotein (MUC1) biomarkers, which are frequently studied in the diagnosis of breast cancer. The focus of this review article is on developments of the last decade for detecting these biomarkers using various sensitivity enhancement techniques and nanomaterials.

HER2 in Colorectal Carcinoma: Are We There yet?

HER2 (ERBB2) is a member of the ERBB family of receptor tyrosine kinases and functions to drive signaling in the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways. Overall, approximately 2-3% of CRCs exhibit ERBB2 amplification. Multiple phase II clinical trials have now shown that ERBB2 amplification can be predictive of response to anti-ERBB2 targeted therapy. Consequently, recently released guidelines from the National Comprehensive Cancer Network recommend treatment with anti-ERBB2 targeted therapy for RAS wild-type, ERBB2-amplified metastatic CRC. While circumspection is still needed, ERBB2 amplification has now emerged as the next standard-of-care biomarker for metastatic CRC, expanding targeted therapy options for these patients.

Functional and genomic characterization of three novel cell lines derived from a metastatic gallbladder cancer tumor.

BACKGROUND: Gallbladder cancer (GBC) is the most common tumor of the biliary tract. The incidence of GBC shows a large geographic variability, being particularly frequent in Native American populations. In Chile, GBC represents the second cause of cancer-related death among women. We describe here the establishment of three novel cell lines derived from the ascitic fluid of a Chilean GBC patient, who presented 46% European, 36% Mapuche, 12% Aymara and 6% African ancestry. RESULTS: After immunocytochemical staining of the primary cell culture, we isolated and comprehensively characterized three independent clones (PUC-GBC1, PUC-GBC2 and PUC-GBC3) by short tandem repeat DNA profiling and RNA sequencing as well as karyotype, doubling time, chemosensitivity, in vitro migration capability and in vivo tumorigenicity assay. Primary culture cells showed high expression of CK7, CK19, CA 19-9, MUC1 and MUC16, and negative expression of mesothelial markers. The three isolated clones displayed an epithelial phenotype and an abnormal structure and number of chromosomes. RNA sequencing confirmed the increased expression of cytokeratin and mucin genes, and also of TP53 and ERBB2 with some differences among the three cells lines, and revealed a novel exonic mutation in NF1. The PUC-GBC3 clone was the most aggressive according to histopathological features and the tumorigenic capacity in NSG mice. CONCLUSIONS: The first cell lines established from a Chilean GBC patient represent a new model for studying GBC in patients of Native American descent.

THE STUDY OF THE EXPRESSION OF CDH1, KI67, P53 AND HER2 IN DIFFUSE GASTRIC CARCINOMA.

Gastric cancer represents the fifth most common malignancy and third most common cause of cancer deaths worldwide. There are two major types of gastric carcinoma: enteric type and diffuse type. Diffuse type gastric cancer is frequently associated with the mutations in E-cadherin coding gene CDH1. In cases of CDH1 mutations complete gastrectomy is indicated. CDH1 mutations are reflected with CDH1 protein loss by immunohistochemistry. The relationship between CDH1 mutations and other markers of tumour aggressiveness, such as tumour proliferation index and the presence of p53 mutations and Her2 amplification is not well studied. Therefore, the aim of our study was to analyse the correlation between CDH1 loss and the expression of Ki67 proliferation marker, mutant oncoprotein p53 and Her2. Standard immunohistochemistry was used to detect the following antigens: CDH1 (MCH-38, Invitrogen), Ki67 (EP5, Bio SB), p53 (DO-7, Leica) and Her2 (EP3, Bio SB). The study results showed that CDH1 mutations, reflected with CDH1 protein loss by immunohistochemistry are detected in 40% of diffuse gastric carcinomas, whilst it is not detected in enteric type gastric carcinomas. Diffuse gastric carcinomas with CDH1 mutations are characterised with more aggressive phenotype, particularly with the presence of higher Ki67 labelling index, p53 mutations and the presence of Her2 positivity. In cases of histological diagnosis of diffuse gastric carcinoma CDH1 testing is recommended.

Her-2 Breast Cancer Outcomes Are Mitigated by Consuming n-3 Polyunsaturated, Saturated, and Monounsaturated Fatty Acids Compared to n-6 Polyunsaturated Fatty Acids.

Lifestyle habits, such as the consumption of a healthy diet, may prevent up to 30-50% of breast cancer (BC) cases. Dietary fats are of specific interest, as research provides strong evidence regarding the association of dietary fats and BC. However, there is limited research on the role of different types of fats including polyunsaturated (PUFA), monounsaturated (MUFA), and saturated fatty acids (SFA). The objective of this study was to determine the effects of lifelong exposure to various dietary fats on mammary tumour development over a 20-week period. Female heterozygous MMTV-neu (ndl) YD5 mouse models were fed five maternal diets containing (1) 10% safflower oil (n-6 PUFA, control), (2) 3% menhaden oil + 7% safflower oil (marine n-3 PUFA, control), (3) 3% flaxseed + 7% safflower oil (plant-based n-3 PUFA), (4) 10% olive oil (MUFA), or (5) 10% lard (SFA). The primary measures, tumour latency, volume, and multiplicity differed by diet treatment in the following general order, n-6 PUFA > plant n-3 PUFA, SFA, MUFA > marine n-3 PUFA. Overall, these findings show that the quality of the diet plays a significant role influencing mammary tumour outcomes.

Correlation between RICTOR overexpression and amplification in advanced solid tumors.

Rapamycin-insensitive companion of mTOR (RICTOR) is a key component of mammalian target of rapamycin (mTOR) complex 2 (mTORC2), and promotes cellular proliferation and survival through the activation of downstream AGC kinase family members. The amplification of RICTOR has been proposed as a therapeutically relevant genomic alteration. However, other than next-generation sequencing, precise diagnostic methods to detect RICTOR amplification in advanced solid cancers have not been fully explored. We performed immunohistochemistry (IHC) analysis on solid tumor tissues from 435 cancer patients. Overexpression of RICTOR was found in 213 cases (49.0 %: 1+, 29.4 %; 2+, 15.2 %; 3+, 4.4 %) consisting of 111 colorectal cancers, 42 gastric cancers, 16 renal cell carcinomas, 8 soft tissue sarcomas, 6 hepatocellular carcinomas, 6 cholangiocarcinomas, 4 lung cancers, and 37 other tumors. RICTOR overexpression was heterogeneous (stained < 50 % of the tumor volume) in 32.4 % (12/37) of IHC-positive cases. We performed fluorescence in situ hybridization (FISH) in 37 RICTOR-overexpressed IHC-positive cases (1+, 12; 2+, 11; 3+, 14) and 13 IHC-negative solid tumors. FISH enabled us to detect RICTOR amplification in 7/12 (58.3 %) IHC 1+, 10/11 (90.9 %) IHC 2+, and 11/14 (78.6 %) IHC 3+ cases. In total, there was amplification in 75.7 % (n = 28) of the RICTOR-overexpressed cases, according to FISH. There was RICTOR amplification in only 7.7 % of the RICTOR IHC-negative cases. RICTOR amplification was significantly more common in IHC-positive cases than in IHC-negative cases (p < 0.0001). The IHC results correlated well with those of FISH (r = 0.60). RICTOR overexpression is more common in solid tumors than previously reported in cases detected by next-generation sequencing. This discrepancy may be caused by intratumoral heterogeneity. In conclusion, heterogeneous RICTOR overexpression is common in solid tumors and RICTOR IHC can be used as a screening tool to detect RICTOR amplification.

Functional and genomic characterization of three novel cell lines derived from a metastatic gallbladder cancer tumor

BACKGROUND: Gallbladder cancer (GBC) is the most common tumor of the biliary tract. The incidence of GBC shows a large geographic variability, being particularly frequent in Native American populations. In Chile, GBC represents the second cause of cancer-related death among women. We describe here the establishment of three novel cell lines derived from the ascitic fluid of a Chilean GBC patient, who presented 46% European, 36% Mapuche, 12% Aymara and 6% African ancestry. RESULTS: After immunocytochemical staining of the primary cell culture, we isolated and comprehensively characterized three independent clones (PUC-GBC1, PUC-GBC2 and PUC-GBC3) by short tandem repeat DNA profiling and RNA sequencing as well as karyotype, doubling time, chemosensitivity, in vitro migration capability and in vivo tumorigenicity assay. Primary culture cells showed high expression of CK7, CK19, CA 19-9, MUC1 and MUC16, and negative expression of mesothelial markers. The three isolated clones displayed an epithelial phenotype and an abnormal structure and number of chromosomes. RNA sequencing confirmed the increased expression of cytokeratin and mucin genes, and also of TP53 and ERBB2 with some differences among the three cells lines, and revealed a novel exonic mutation in NF1. The PUC-GBC3 clone was the most aggressive according to histopathological features and the tumorigenic capacity in NSG mice. CONCLUSIONS: The first cell lines established from a Chilean GBC patient represent a new model for studying GBC in patients of Native American descent.

Metabolic modulation regulates cardiac wall morphogenesis in zebrafish.

During cardiac development, cardiomyocytes form complex inner wall structures called trabeculae. Despite significant investigation into this process, the potential role of metabolism has not been addressed. Using single cell resolution imaging in zebrafish, we find that cardiomyocytes seeding the trabecular layer actively change their shape while compact layer cardiomyocytes remain static. We show that Erbb2 signaling, which is required for trabeculation, activates glycolysis to support changes in cardiomyocyte shape and behavior. Pharmacological inhibition of glycolysis impairs cardiac trabeculation, and cardiomyocyte-specific loss- and gain-of-function manipulations of glycolysis decrease and increase trabeculation, respectively. In addition, loss of the glycolytic enzyme pyruvate kinase M2 impairs trabeculation. Experiments with rat neonatal cardiomyocytes in culture further support these observations. Our findings reveal new roles for glycolysis in regulating cardiomyocyte behavior during cardiac wall morphogenesis.

Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart.

While the heart regenerates poorly in mammals, efficient heart regeneration occurs in zebrafish. Studies in zebrafish have resulted in a model in which preexisting cardiomyocytes dedifferentiate and reinitiate proliferation to replace the lost myocardium. To identify which processes occur in proliferating cardiomyocytes we have used a single-cell RNA-sequencing approach. We uncovered that proliferating border zone cardiomyocytes have very distinct transcriptomes compared to the nonproliferating remote cardiomyocytes and that they resemble embryonic cardiomyocytes. Moreover, these cells have reduced expression of mitochondrial genes and reduced mitochondrial activity, while glycolysis gene expression and glucose uptake are increased, indicative for metabolic reprogramming. Furthermore, we find that the metabolic reprogramming of border zone cardiomyocytes is induced by Nrg1/ErbB2 signaling and is important for their proliferation. This mechanism is conserved in murine hearts in which cardiomyocyte proliferation is induced by activating ErbB2 signaling. Together these results demonstrate that glycolysis regulates cardiomyocyte proliferation during heart regeneration.

Evaluating the HER-2 status of breast cancer using mammography radiomics features.

PURPOSE: The aim of our study was to evaluate the HER-2 status in breast cancer patients using mammography (MG) radiomics features. METHODS: A total of 306 Chinese female patients with invasive ductal carcinoma of no special type (IDC-NST) enrolled from January 2013 to July 2018 were divided into a training set (n = 244) and a testing set (n = 62). One hundred and eighty-six radiomics features were extracted from digital MG images based on the training set. The least absolute shrinkage and selection operator (LASSO) method was used to select the optimal predictive features for HER-2 status from the training set. Both support vector machine (SVM) and logistic regression models were employed based on the selected features. The area under the receiver operating characteristic (ROC) curves (AUCs) of the training set and testing set were used to evaluate the predictive performance of the models. RESULTS: Compared with the SVM model, the performance of the logistic regression model using a combination of cranial caudal (CC) and mediolateral oblique (MLO) MG views was optimal. In the training set, the sensitivity, specificity, accuracy and area under the curve (AUC) values of the logistic regression model for evaluating HER-2 status based on quantitative radiomics features were 87.29%, 58.73%, 80.00% and 0.846 (95% confidence interval (CI), 0.800-0.887), respectively, and in the testing set, the values were 73.91%, 68.75%, 77.00% and 0.787 (95% CI, 0.673-0.885), respectively. CONCLUSIONS: Radiomics features could be an efficient tool for the preoperative evaluation of HER-2 status in patients with breast cancer.

Dysregulated expression of repetitive DNA in ER+/HER2- breast cancer.

Limited studies on breast cancer indicated pathogenic changes in the expressions of some repeat elements. A global analysis was much needed within this context to distinguish the most significant repeats from more than a thousand repeat motifs. Utilising a previously presented RNA-seq dataset, we studied expression changes of all repeats in ER+/HER2- human breast tumour samples obtained from 22 patients in comparison to matched normal tissues. Fifty six (56) repeat subtypes including satellites and transposons were found to be differentially expressed and most of them were novel for breast cancer. HERVKC4-int and HERV1_LTRc, whose expressions correlated well with that of the estrogen receptor gene ESR1, were upregulated at the highest level. REP522 and D20S16 satellites were also significantly upregulated along with insignificant increases in the expressions of other satellites including HSATI and BSR/beta. Interestingly, expressions of REP522 and D20S16 correlated with many key breast cancer pathway (e.g. BRCA1, BRCA2, AKT1, MTOR, KRAS) and survival genes; possibly highlighting their importance in the carcinogenesis of breast. Additional differentially expressed elements such as L1P and various MER transposons also exhibited a similar pattern. Finally, our repeat enrichment analysis on the promoters of differentially expressed genes revealed further links between additional repeats and nearby genes.