The recently introduced kernelized expectation maximization (KEM) method has shown promise across varied applications. These studies have demonstrated the benefits and drawbacks of the technique when the kernel matrix is estimated from separate anatomical information, for example from magnetic resonance (MR), or from a preliminary PET reconstruction. The contribution of this work is to propose and investigate a list-mode-hybrid KEM (LM-HKEM) reconstruction algorithm with the aim of maintaining the benefits of the anatomically-guided methods and overcome their limitations by incorporating synergistic information iteratively. The HKEM is designed to reduce negative bias associated with low-counts, the problem of PET unique feature suppression reported in the previously mentioned studies using only the MR-based kernel, and to improve contrast of lesions at different count levels. The proposed algorithm is validated using a simulation study, a phantom dataset and two clinical datasets. For each of the real datasets high and low count-levels were investigated. The reconstructed images are assessed and compared with different LM algorithms implemented in STIR. The findings obtained using simulated and real datasets show that anatomically-guided techniques provide reduced partial volume effect and higher contrast compared to standard techniques, and HKEM provides even higher contrast and reduced bias in almost all the cases. This work, therefore argues that using synergistic information, via the kernel method, increases the accuracy of the PET clinical diagnostic examination. The promising quantitative features of the HKEM method give the opportunity to explore many possible clinical applications, such as cancer and inflammation.

Overexpression of SH2-containing-5 0 -inositol phosphatase-2 (SHIP2) correlates with poor survival in breast cancer. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here, we showed that the percentage of SHIP2 1 cells was positively correlated with that of CD24 2 CD44 1 cells in 60 breast cancer specimens. Among 20 estrogen receptor (ER)-negative samples, 17 had greater SHIP2 expression in CD24 2 CD44 1 subpopulation than the remaining subpopulation. Data mining of microarray analysis of 295 breast tumors showed a significant correlation of higher SHIP2 expression with distant metastasis. Examination of patient-derived mouse xenografts revealed that SHIP2 protein and its tyrosine 1135 phosphorylation were significantly higher in BCSCs, identified as CD24 2 CD44 1 or aldehyde dehydrogenase (ALDH 1 ), than non-BCSCs. SHIP2 silencing or inhibitor of SHIP2 phosphatase significantly decreased mammosphere-forming efficiency, ALDH 1 subpopulation in vitro and tumorigenicity of BCSCs in vivo. Overexpression of SHIP2 enhanced the expression of epithelial-mesenchymal transition markers including vimentin (VIM), which was mainly expressed in ER-negative breast cancer cells with higher level in mammospheres than monolayer culture. Ablation of c-Jun N-terminal kinase 1 (JNK1), JNK2, or VIM diminished the increased ALDH 1 population and tumorigenicity, induced by SHIP2 overexpression. BCSCs displayed greater expression of phospho-JNK than nonBCSCs and silencing of JNK suppressed SHIP2-mediated upregulation of VIM. Furthermore, SHIP2 overexpression enhanced Akt activation, but Akt inhibition failed to influence SHIP2-induced phospho-JNK/VIM upregulation. In conclusion, SHIP2 plays a key role in BCSCs of ERnegative breast cancers through activation of Akt and JNK with upregulation of VIM and may serve as a target for therapy directed at BCSCs.

This paper reports on the feasibility of using a quasi-Newton optimization algorithm, limited-memory Broyden-Fletcher-Goldfarb-Shanno with boundary constraints (L-BFGS-B), for penalized image reconstruction problems in emission tomography (ET). For further acceleration, an additional preconditioning technique based on a diagonal approximation of the Hessian was introduced. The convergence rate of L-BFGS-B and the proposed preconditioned algorithm (L-BFGS-B-PC) was evaluated with simulated data with various factors, such as the noise level, penalty type, penalty strength and background level. Data of three F-FDG patient acquisitions were also reconstructed. Results showed that the proposed L-BFGS-B-PC outperforms L-BFGS-B in convergence rate for all simulated conditions and the patient data. Based on these results, L-BFGS-B-PC shows promise for clinical application.

Background/Aim: Berberine (BBR) is known to be effective at inhibiting cell proliferation and promoting apoptosis in various cancer cells. However, the effects of BBR on triple-negative breast cancer (TNBC) cells remain unclear.The aim of this study was to investigate the cell inhibition effects of BBR on different subtypes of TNBC cells. Methods: Using human TNBC cell lines of different subtypes, namely, MDA-MB-231, MDA-MB-468, MDA-MB-453, and BT-549 as in vitro models, antiproliferative effects of BBR were investigated by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide assay, trypan blue exclusion assay, and clonogenic assay. Furthermore, cell apoptosis and autophagy were analyzed by flow cytometry, immunofluorescent staining, and LC3 Ⅰ/Ⅱ-targeted Western blotting. Various cell growth-related signaling pathways (AKT/ERK/p38) and the expression of proteins present in various cell cycle kinase complexes were analyzed by Western blotting. Results: BBR concentration-dependently suppressed cell proliferation in MDA-MB-468 (0, 3, 6, and 12 μM) and MDA-MB-231 (0, 6.25, 12.5, and 25 μM). The inhibitory effect was not brought about by inducing cell apoptosis, necrosis, or autophagy. Cell cycle analysis disclosed an increased S+G2/M fraction among the BBR-treated MDA-MB-231 and MDA-MB-453 cells; while with the BBRtreated MDA-MB-468 and BT-549 lines, an increased G0/G1 fraction was found. In MDA-MB-231 and MDA-MB-453 cells, by Western blotting, BBR decreased the expression of Cyclin A and CDK1, On the other hand, in BBR-treated MDA-MB-468 and BT-549 cells, there was a decrease in Cyclin D and CDK4 expression. Conclusion: Our results demonstrate that the antiproliferation effects of BBR occur via different mechanisms in different subtypes of TNBC cells,Abbreviations: BBR, berberine; BL1, basal-like1; BL2, basal-like2; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; LAR, luminal androgen receptor; M, mesenchymal; PD-1, programmed death-1; PD-L1, programmed death-1 ligand; PR, progestin receptor; ROS, reactive oxygen species; TNBC, triple-negative breast cancer.

Due to the fact that the treatment of breast cancer depends significantly on the molecular markers present in the cancer, including estrogen receptor (+), progesterone receptor (+) or erbB2 receptor (+), further investigation targeting triple-negative breast cancer (TNBC) subtypes may assist in elucidating the mechanisms of recurrence of TNBC and enable the identification of novel therapeutic strategies for patients with TNBC. The aim of the present study was to compare the gene expression profiles between TNBC samples that were identified as having recurrent and non-recurrent statuses. Between June 2011 and May 2012, a total of 30 patients with TNBC were examined using a follow-up period of at least 5 years. Their clinicopathological information was retrospectively reviewed and they were classified with a status either of recurrence [n=15 stage II (9), IIIA (2), IIIC (4)] or non-recurrence [n=15 stage II (6), IIIA (1), IIIC (8)]. The total RNA from tissue samples obtained from the recurrent and non-recurrent TNBC patients were used to performed oligonucleotide microarray analysis. The dataset was analyzed using GeneSpring software and validated using reverse transcription-quantitative polymerase chain reaction. Principal component analysis demonstrated that there was a marked difference in the gene expression distribution between the stage IIIc recurrent samples and early stage (stages IIa, IIb and IIIa) recurrent samples. In early stage recurrence, the significant pathway-associated upregulated genes were matrix metalloproteinases (MMPs) and genes associated with cancer cell migration (CDH2) and cell adhesion/motility (KRAS, CDC42, RAC1, ICAM and SRGAP2). By contrast, during stage IIIc recurrence, the significant pathway-associated upregulated genes in the recurrent samples were WNT signaling genes, including WNT 4 and WNT 16. It was concluded that there were markedly different distributions and gene expression profiles between stage IIIc recurrent TNBC tumors and early stage (IIa, IIb, IIIa) recurrent TNBC tumors, which provides important information for the development of effective treatment strategies for TNBC.

Background. The aim of this study was to investigate the mechanisms by which Timosaponin AIII (TAIII) is able to inhibit HGF-induced invasion activity in the triple negative breast cancer cell line MDA-MB-231. Methods. After pretreatment with different concentrations (10−6~10−8 M) of TAIII, the cells were treated with hepatocyte growth factor (HGF, 15 ng/mL). At different time intervals after coincubation, various parameters, including the expression of c-Met, ERK, COX2, and MMP-9, which were assessed by Western blotting or by real-time PCR, were analyzed. In addition, invasive activity was also monitored. Results. HGF was found to induce c-MET activation and ERK activation, together with increased COX2 protein expression; these changes were followed by a subsequent increase in invasive activity. TAIII was found to suppress HGF-induced invasive activity and COX2 gene expression in a concentration-dependent manner (10−6~10−8 M) in parallel with increases in the phosphoforms of c-Met and ERK after TAIII treatment. The mechanisms by which TAIII suppresses HGF-induced invasive activity were demonstrated to include sustained cytoplasmic and nuclear ERK activation; these led to a suppression of nuclear ATF2 activation, which was followed by downregulation of COX2 and MMP-9 transcription. Conclusion. TAIII suppresses HGF-induced invasive activity in MDA-MB-231 cells via sustained ERK activation.

Background: Accurate assessment of breast volume is an essential component of preoperative planning in one-stage immediate breast reconstruction (IBR) for achieving breast symmetry and a satisfactory cosmetic outcome. In this study, we compared breast volume estimation using three-dimensional (3D) surface imaging with magnetic resonance imaging (MRI) to determine the accuracy of breast volume measurements. Further, a 3D printing mold for facilitating autologous breast reconstruction intraoperatively is described. Methods: Patients scheduled to therapeutic or prophylactic mastectomy with one-stage IBR, either by autologous tissue transfer or direct implant, from 2016 to 2019, were enrolled in this study. 3D surface image and MRI were performed to evaluate breast volume and shape. The results were validated by the water displacement volume of the mastectomy specimen. Finally, a 3D printing mold was designed for breast reconstruction with autologous tissue. Results: Nineteen women who were scheduled to have 20 mastectomies (18 unilateral and one bilateral) were included. There was a strong linear association between breast volume measured using the two different methods and water displacement of mastectomy specimens when a Pearson correlation was used (3D surface image: r = 0.925, p < 0.001; MRI: r = 0.915, p < 0.001). Bland-Altman plots demonstrated no proportional bias between the assessment methods. The coefficient of variation was 52.7% for 3D surface imaging and 59.9% for MRI. The volume of six breasts was evaluated by both measurements and the intraclass correlation coefficient was 0.689 for 3D surface image (p = 0.043) and 0.743 for MRI (p = 0.028). Conclusion: Using 3D surface image to evaluate breast shape and volume is a quick, effective, and convenient method. The accuracy, reproducibility, and reliability of 3D surface imaging were comparable with MRI in our study. In addition, 3D-printed molds can achieve better symmetry and aesthetic outcomes in immediate autologous breast reconstructions.

Background“Precision medicine” is a concept that by utilizing modern molecular diagnostics, an effective therapy is accurately applied for each cancer patient to improve their survival rates. The treatment of triple-negative breast cancer (TNBC) remains a challenging issue. The aim of this study was to compare the molecular subtypes of triple-negative breast cancer (TNBC) between Taiwanese and Non-Asian women.MethodsGEO Datasets for non-Asian (12 groups, n = 1450) and Taiwanese (3 groups, n = 465) breast cancer, including 617 TNBC, were acquired, normalized and cluster analyzed. Then, using TNBC cell lines of different subtypes, namely, MDA-MB-468 (basal-like1, BL1), MDA-MB-231 (mesenchymal stem like, MSL), BT-549 (mesenchymal, M), MDA-MB-453 (luminal androgen receptor, LAR), and DU4475 (immunomodulatory, IM), real-time PCR in triplicate for 47 genes signatures were performed to validate the specificity of these subtypes.ResultsThe results showed that the percentage of TNBC subtypes in non-Asian women, namely, BL1, BL2, IM, M, MSL, and LAR was 13.56, 8.91, 16.80, 20.45, 8.30, and 11.13%, respectively. When data from Taiwanese were normalized and clustered, five TNBC subtypes, namely, BL (8.94%), IM (13.82%), M (22.76%), MSL (30.89%), and LAR (23.58%), were classified. Real-time PCR validated the specificity of these subtypes. Besides, the presence of interaction between IM- and MSL-subtypes suggests the involvement of tumor microenvironment in TNBC subtype classification.ConclusionOur data suggested that there exist different presentations between non-Asian and Taiwanese TNBC subtypes, which provides important information when selection of therapeutic targets or designs for clinical trials for TNBC patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-017-4195-7) contains supplementary material, which is available to authorized users.