S100A9 promotes glycolytic activity in HER2-positive breast cancer to induce immunosuppression in the tumour microenvironment.

Purpose: The purpose of this study was to investigate the correlation between S100 calcium binding protein A9 (S100A9), tumour glycolysis and tumour infiltrating lymphocytes (TIL) in human epidermal growth factor receptor 2 (HER2) - positive breast cancer (BRCA). Materials and methods: A total of 667 BRCA patients in Xiangya Hospital of Central South University were enrolled in this study. Haematoxylin and eosin (H&E) staining were used to count TIN in tissues. Human breast cancer cell lines (SK-BR-3 cells and BT474 cells) were transfected with S100A9 specific small interfering RNA (siRNA). The expressions of S100A9, glycolytic enzymes and lymphocyte markers were detected by immunohistochemistry (IHC) staining, Western blot and immunofluorescence. Lactate production, glucose consumption and the extracellular acidification rate (ECAR) were detected to assess glycolysis activity. Results: S100A9 was significantly overexpressed in HER2+ cases. The expressions of phosphoglycerol kinase 1 (PGK1), lactate dehydrogenase A (LDHA) and enolase α (ENO1) were significantly up-regulated in S100A9 dominant tissues. The expressions of PGK1, LDHA and ENO1 detected in S100A9 silenced cell lines were significantly down-regulated. Moreover, S100A9 silencing significantly altered lactate production, glucose uptake and ECAR levels in HER2+ cell lines. Co-expression of S100A9 and c-Myc was detected in HER2+ tissues. The absence of S100A9 greatly hindered ß-catenin expression in cell lines, which later induced the phosphorylation of c-Myc.The amount of TILs in cases with abundant S100A9 and LDHA was much greater than in cases with low S100A9 levels and poorer LDHA. TIL deficiency and elevated S100A9 intensity are factors affecting the survival rate of HER2+ BRCA cases. Conclusions: S100A9 overexpression upregulated the glycolysis activity of tumour cells through the c-Myc-related pathway, suppressing lymphocyte infiltration in the tumour stroma, affecting the efficacy of immune regulation and long-term survival of patients.

The prognostic effect of HER2 heterogeneity and YAP1 expression in HER2 positive breast cancer patients: a retrospective study.

Background: This study sought to estimate the prognostic effect of intratumoral heterogeneity (ITH) and Yes-associated protein 1 (YAP1) intensity in human epidermal growth factor receptor 2 (HER2) positive breast cancer patients. We also investigated individualized adjuvant therapy for YAP1-sufficient patients and HER2 heterogeneous patients. Methods: The relationship between prognostic outcomes and clinicopathological variables in 1,650 retrieved breast cancer patients was evaluated. The HER2 intensity and YAP1 expression in HER2-ITH and non-ITH (NITH) patients were also estimated. All patients were followed-up, regardless of whether or not they received intensive treatment, to explore individualized adjuvant therapy for YAP1-sufficient patients and HER2 heterogeneous patients. Results: Over-expression and nuclear localization of YAP1 were significant in HER2-ITH patients. The over-expression of YAP1 and the presence of ITH affected the prognosis of HER2 positive patients. YAP1 intensity and lymph nodes metastases was more obviously affected the survival of HER2-ITH patients, while the prognosis of NITH patients were correlated with clinical Tumor-Node-Metastasis (cTNM) stage and lymph-vascular space invasion (LVSI) status. HER2-NITH patients and YAP1-insufficient patients benefited from a combination of Trastuzumab and Pertuzumab/Lapatinib, while Capecitabine significantly decreased the relapse risk of ITH patients and YAP1-sufficient patients. Conclusions: YAP1 overexpression and nuclear localization was usually observed in HER2-ITH patients. For HER2-NITH patients, an advanced stage of cTNM and LVSI status increased the recurrent risk, and intensified Pertuzumab or Lapatinib treatment (combination with Trastuzumab) improved their survival. For HER2-ITH patients, the overexpression of YAP1 and pathological lymph nodes (pLN) metastases increased recurrent risk, and intensified Capecitabine treatment improved their survival. YAP1 overexpression contributed to a poor prognostic outcome, especially when HER2 signal intensity was insufficient.

YAP1/MMP7/CXCL16 axis affects efficacy of neoadjuvant chemotherapy via tumor environment immunosuppression in triple-negative breast cancer.

BACKGROUND: To evaluate the association of potential YAP1/MMP7/CXCL16 axis and tumor infiltrating lymphocytes (TILs) related chemo-response in triple-negative breast cancer (TNBC) patients. METHODS: We estimated the messenger RNA (mRNA) expression levels of Yes-associated protein 1 (YAP1), MMP7, and CXCL16 in paired TNBC tumor/para-tumor tissues by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), and performed statistical analysis according to neoadjuvant chemotherapy (NAC) response. Based on The Cancer Genome Atlas (TCGA) data, we noticed outstanding expression of MMP7/CXCL16 in TNBC cases, as well as associations between MMP7/CXCL16 and HIPPO-YAP1-relevant kinases. We also performed gene set enrichment analysis (GSEA) between MMP7/CXCL16 and YAP1-associated pathways. Western blotting assay was employed to evaluate YAP1/MMP7/CXCL16 expression in vitro and their modulation sequence. Logistic model stepwise regression analysis was used to assess YAP1, MMP7, CXCL16, and TILs as therapeutic predictors. Residual cancer burden (RCB) score was calculated and statistically analyzed according to intensity of these variables, and receiver operating characteristic (ROC) curve also showed their predictive value in NAC response. Recruitment efficacy for CD4+/CD8+ TIL cells (TCGA data) as well as quantified TIL cells density were both explored according to YAP1, MMP7, and CXCL16 expression level. RESULTS: Up-regulation of YAP1/MMP7 and down-regulation of CXCL16 were both significant in TNBC cases with poor NAC response. Inhibition of YAP1 induced down-regulation of MMP7 and up-regulation of CXCL16, whereas inhibition of MMP7 also induced up-regulation of CXCL16. It was also shown that MMP7/CXCL16 was enriched in the YAP1-related pathway. Activation of the YAP1/MMP7/CXCL16 axis obviously affected RCB of TNBC cases. The ROC curve also supported the predictive value of YAP1/MMP7/CXCL16 axis and TILs density in NAC response prospect. The density of TILs, meanwhile, demonstrated a strong link with the YAP1/MMP7/CXCL16 axis. Over expression of YAP1/MMP7 significantly suppressed recruitment of CD4+/CD8+ TILs, while CXCL16 over expression had a beneficial impact on anti-tumor immune. CONCLUSIONS: Over expression of causes up-regulation of MMP7 and down-regulation of CXCL16, which suppressed CD4+/CD8+ TILs recruitment and indirectly affected NAC response of TNBC patients.

Optical super-resonance in a customized P T-symmetric system of hybrid interaction.

We investigate the optical resonances in coupled meta-atoms with hybrid interaction pathways. One interaction pathway is the directly near-field coupling between the two meta-atoms. The other interaction pathway is via the continuum in a waveguide functioned as a common bus connecting them. We show that by properly introducing gain or loss into the meta-atoms, the hybrid optical system becomes parity-time (P T) symmetric, in which the effective coupling rate can be customized by manipulating the length of the waveguide. At the exact phase of the customized P T symmetry, the coupled meta-atoms support discrete super-resonant modes that can be observed from the transmission spectra as extremely sharp peaks. At an exception point where the eigenmodes coalesce, albeit the transmission curve is flat, a high-Q factor of the localized field in the meta-atoms can be obtained. Similarities of the super-resonance with the bound states in the continuum (BICs) are discussed. This investigation promotes our understanding about the ways in realizing high-Q optical resonance especially by manipulating the distributions of loss and gain via the concepts of P T and BICs. Many attractive applications are expected.

Kerr-nonlinearity induced bistable-like parity-time phase transition in coupled waveguides.

We analyze the parity-time (PT) symmetric phase in coupled two waveguides with a Kerr-type medium in between. Paying attention to the emitted field from a dipole source inside, we show that when the strength of the dipole increases, the optical Kerr effect can render a phase transition from the exact PT phase to the broken PT phase. Furthermore, a salient phenomenon of bistable-like PT phase is observed, in which the emitted field possesses a paradox between the two kinds of PT phases. We show that the physical mechanism of this bistable-like phenomenon is a globally inhomogeneous PT phase, in which different spatial regions of the whole structure can possess different PT phases (broken or exact). This study highlights the potential to manipulate the PT phase transition by using optical nonlinearity for many interesting applications.

The Hippo Transducer YAP/TAZ as a Biomarker of Therapeutic Response and Prognosis in Trastuzumab-Based Neoadjuvant Therapy Treated HER2-Positive Breast Cancer Patients.

BACKGROUND: We explored the therapeutic and prognostic effect of YAP/TAZ intensityinHER2-positive breast cancer patients. We also investigated the relationship between YAP/TAZ expression and Trastuzumab-resistance. METHODS: We collected clinicopathological information from 397 cases. We evaluated therapeutic and prognostic effect of YAP/TAZ and other variables. We also cultivated Trastuzumab-resistance cell lines and explored relationship between YAP/TAZ and Trastuzumab-resistance. RESULTS: Over-expression of YAP/TAZ was remarkable in Trastuzumab-resistant cells, and so did HER3 and HER2/HER3 heterodimer. Inhibition of YAP/TAZ expression reversed Trastuzumab-resistance.YAP/TAZ deficiency contributed to favorable therapeutic response, and so did hormone receptor insufficiency and chemotherapy dosage inferiority. Deficient YAP/TAZ intensity and abundant hormone receptor intensity contributed to better survival. Over-expression of YAP/TAZ was obvious in recurrent cases in comparison with their matching primary lesions. Prognostic superiority of insufficient YAP/TAZ intensity was more outstanding in hormone receptor negative cases. Over-expression of YAP/TAZ and HER3 was generally synchronous. Absence of HER3 expression in residual lesions might correlate with better breast cancer-free survival. CONCLUSIONS: Over-expression of YAP/TAZ as well as HER-3 and HER2/HER3 heterodimer was synchronously remarkable in Trastuzumab-resistant cell lines. Inhibition of YAP/TAZ expression reversed Trastuzumab resistance. Deficient YAP/TAZ intensity as well as insufficient hormone receptor intensity and high chemotherapy dosage contributed to favorable therapeutic response. Deficient YAP/TAZ intensity and abundant hormone receptor intensity contributed to better survival, and so did absence of HER3expression in residual lesions. Prognostic superiority of YAP/TAZ expression depended on hormone receptor status. Cases with synchronous over-expression of YAP/TAZ and HER3 suffered poor survival, which revealed the potential effect of YAP/TAZ-HER2/HER3 crosstalk in prognosis of HER2-positive patients.

miR­574­5p attenuates proliferation, migration and EMT in triple­negative breast cancer cells by targeting BCL11A and SOX2 to inhibit the SKIL/TAZ/CTGF axis.

Triple­negative breast cancer (TNBC) is a subtype of breast cancer with a high degree of malignancy. TNBC is prone to distant metastasis and has a poor prognosis. A number of TNBC­related microRNAs (miRNAs) have been studied and identified. However, the detailed roles of miR­574­5p in TNBC remain poorly understood. miR­574­5p, SRY (sex determining region Y)­box 2 (SOX2), B­cell lymphoma/leukaemia 11A (BCL11A), SKI like proto­oncogene (SKIL) and epithelial­mesenchymal transition (EMT)­related miRNAs and proteins were measured by reverse transcription­quantitative PCR and western blotting analysis, respectively. A luciferase reporter assay was employed to validate the direct targeting of SOX2 and BCL11A by miR­574­5p. MTT, colony formation and Transwell assays were performed to analyse the biological functions of miR­574­5p in TNBC cells. A nude mouse xenograft model was used to verify the effects of miR­574­5p on the tumorigenesis of TNBC in vivo. The results demonstrated that miR­574­5p levels were decreased in breast cancer tissues and cells. miR­574­5p repressed proliferation, migration and EMT in TNBC cells. Further experiments confirmed that miR­574­5p reduced tumour size and metastasis in vivo. miR­574­5p targeted BCL11A and SOX2 to inhibit the SKIL/transcriptional co­activator with PDZ­binding motif/connective tissue growth factor axis, and the inhibitory effect of miR­574­5p in TNBC cells was at least partly dependent on SOX2 and BCL11A. In addition, the regulation of downstream oncogenes by SOX2 was dependent on BCL11A. To the best of our knowledge, this is the first study to report the association between the miR­574­5p/BCL11A/SOX2 axis and the tumorigenesis of TNBC, which provides a new mechanism for understanding the progression of TNBC.

Nonreciprocal parity-time phase in magnetized waveguides.

In a single magneto-optical (MO) waveguide, the dispersion of guided bulk wave is reciprocal in the Voigt configuration. Here we show that the parity-time (P T) phase in two coupled MO waveguides can be nonreciprocal if the waveguides are properly biased. The nonreciprocal P T phase is closely related to the asymmetric field profile induced by the MO effect that modifies the coupling strength between adjacent waveguides. We show that it is feasible to switch between broken and conserved P T phases by simply reversing the magnetic bias or the propagating direction of wave. Theoretical analysis and numerical calculation prove our theory. This investigation highlights a flexible method in manipulating the field dynamics of waveguide arrays by using the novel properties of P T phase especially the exceptional points.

Prognostic Factors for Luminal B-like Breast Cancer.

This study aimed to examine the prognostic factors of luminal B-like breast cancer. Clinical data of 695 luminal B-like breast cancer patients who had been treated in our hospital during the period of past 4.5 years were collected and analyzed. Estrogen receptor (ER), progesterone receptor (PgR), antigen identified by monoclonal antibody Ki-67 (Ki67) were immunohistochemically detected. Different cutoffs of ER, PgR, and Ki67 were evaluated. Pearson χ2 test was performed to compare categorical parameters. Univariate and multivariate models were used to evaluate predictors of disease free survival (DFS). The results showed that patients who were younger, and had larger tumors, and more positive lymph nodes were more likely to receive neo-adjuvent chemotherapy (NAC). Patients with ER-positive tumors having <10% positive cells received more anthracycline- and taxane-based chemotherapy and less endocrine therapy than those with ER-positive tumors having ≥10% positive cells (P=0.004 and P=0.007, respectively); however, patients with ER-positive tumors having <10% positive cells experienced more recurrence (P<0.001). PgR expression levels were not associated with therapeutic schedule and DFS. Patients with tumor tissue Ki67 score ≥30% received more anthracycline- and taxane-based chemotherapy and had worse DFS than those with tumor tissue Ki67 score <30%. Univariate and multivariate analysis showed that clinical T stage, lymph nodes, ER, Ki67, and HER2 status were independent prognostic factors. In conclusion, ER-positive rate <10% and Ki67 score ≥30%, similar to higher clinical T stage, more metastatic lymph nodes, and HER2 positive status, may indicate a worse prognosis for luminal B-like breast cancer patients. Multi-center prospective trials with larger sample sizes are necessary for the continued perfection of our work.

Exceptional singular resonance in gain mediated metamaterials.

We study the scattering of optical field by a hybridized metamaterial with properly imprinted gain. We predict that an occasionally real-eigen valued singularity in the interaction matrix of the coupled dark-bright meta-molecule would produce a high-Q resonance. This effect is demonstrated in full-wave three-dimensional finite element optical simulation. Field is efficiently amplified at this resonance. Further investigation shows that the resonance is associated with an exceptional point. The difference of this exceptional singularity from other high-Q resonances such as the spectral singularities in the scattering or transfer matrixes of parity-time symmetric systems and the bound states in the continuum is discussed. The non-Hermitian nature of the exceptional singularity promises some nonlinear applications.

Parity-time symmetry in periodically curved optical waveguides.

The coupling strength between two parity-time (PT) symmetric resonators determines whether the PT phase is broken or not. Here we investigate the scenario that two optical waveguides are spatially curved so that they switch periodically between unbroken and broken PT phases. We show that the existence of locally broken PT phase does not necessarily render a broken phase to waves propagating inside. Criteria are proposed to characterize the collective dynamics of wave near the Brillouin zone (BZ) edge, toward the cases of a totally broken phase, a partially broken phase, or a totally unbroken phase. We also discuss the characteristics of two special kinds of exceptional points (EPs) at the BZ edge, and show that their field patterns are displaced by half a period with each other. Full-wave numerical simulation proves our analysis. Potential applications especially these associated with EPs are discussed. This study helps us to understand how the locally PT-symmetric related eigenstate influences the globally collective dynamics of wave in spatially periodic configuration.

Switchable generation of rectangular noise-like pulse and dissipative soliton resonance in a fiber laser.

We report on the switchable generation of a rectangular noise-like pulse (NLP) and a dissipative soliton resonance (DSR) in a fiber laser with highly nonlinear effect at very low pump power. The NLP centered at 1530.5 nm demonstrates a new characteristic that its profile evolves gradually from rectangular shape to Gaussian-like shape with the increasing pump power. By appropriately manipulating the polarization controller (PC), the laser switches emit a DSR pulse centered at 1551.3 nm. The duration of the DSR could broaden from 17.4 ns to the cavity round trip time with increasing the pump power, while keeping the pulse profile and the intensity unaltered. This type of fiber laser may not only facilitate further investigations of the characteristics of NLP and DSR but also serve as a multi-functional optical source for potential applications.

Relative dose intensity and therapy efficacy in different breast cancer molecular subtypes: a retrospective study of early stage breast cancer patients treated with neoadjuvant chemotherapy.

To investigate the relationship between chemotherapy dose intensity and therapy efficacy of different molecular subtypes. Clinical and pathological features of the patients with breast cancer were retreived from the hospital records. 315 patients were analyzed (251 showed clinical response, 38 acquired pCR). Patients with positive ER status, negative PR status, higher Ki67 level and higher RTDI had better therapy response. 13.5 and 84.5 % were identified the benchmark of Ki67 and RTDI, respectively. As the result of interior-subgroup comparison, luminal subgroups acquired better response rate when RTDI ≥ 84.5 %. In patients of luminal breast cancer, tumor size change arose from increasing of dose intensity and finally showed reached a plateau after RTDI ≥ 95 % (r (2) = 0.303, p < 0.001). As the result of intersubgroup comparison, TNBC patients were more likely to acquired better clinical and pathology response when RDTI < 84.5 %. Ki67 change arose sharply from increasing of dose intensity when RDTI < 84.5 % (r (2) = 0.656, p < 0.001), whereas the regression curve showed a terminal plateau in patients of RDTI ≥ 84.5 % (r (2) = 0.427, p < 0.001). Given lower RTDI, luminal patients are less likely to achieve response, and TNBC patients are associated with higher response rate. Dissimilar of therapy efficacy between luminal subtype and TNBC becomes inconspicuous as RTDI rises. Chemosensitivity may associate with dose intensity, especially in luminal subtypes, and tailored therapeutic strategies should be considered.

[Metabolic complications and quality of life in prostate cancer patients after receiving endocrine treatment].

OBJECTIVE: To compare the incidences of anemia, osteoporosis, and irritable bowel syndrome (IBS) after the application of different endocrine therapies in patients with prostate cancer. METHODS: Totally 125 patients aged 58 to 84 years with biopsy-confirmed local prostate cancer were recruited between September 2008 and September 2010. Of them 52 treated with orchiectomy (castration group) and 73 with luteinizing hormone-releasing hormone analogue (goserelin acetate 3.6mg/month) combined with androgen antagonist (bicalutamide 50mg/d) for at least 12 months (hormone group), but without blood transfusion or erythropoietin. Changes in total testosterone (TT), free testosterone (FT), prostate specific antigen (PSA), hemoglobin (Hb), red blood cell (RBC), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red blood cell distribution width (RDW), bone mineral density (BMD) and gastrointestinal symptom rating scales (GSRS) were recorded and analyzed before treatment and 12 months after the initiation of treatment. RESULTS: In the castration group, after 12 months, TT (P=0.0007), FT (P=0.0003), PSA (P=0.0006), Hb (P=0.0001), RBC (P=0.020), Hct (P=0.016), Z-score of lumbar spine (P=0.008), and femoral neck (P=0.004) decreased significantly, and GSRS (P=0.029) increased significantly. In hormone group, after 12 months, TT (P=0.0008), FT (P=0.0006), PSA (P=0.0006), Hb (P=0.0003), RBC (P=0.0001), Hct (P=0.0002), Z-score of lumbar spine (P=0.002), femoral neck (P=0.0002), and RDW (P=0.045) decreased significantly, and GSRS (P=0.010) increased significantly. After 12 months, TT (P=0.004), FT (P=0.012), PSA (P=0.007), Hb (P=0.016), Z-score of lumbar spine (P=0.033), and femoral neck (P=0.015) in hormone group were significantly lower than in the castration group, while GSRS (P=0.027) in hormone group was significantly higher than in the castration group. The incidences of anemia (P=0.006), osteoporosis (P=0.009), and IBS (P=0.022) were significantly different between these two groups. The serum level of testosterone was positively correlated with Hb, RBC, Hct, and BMD in both groups (P=0.039). Negative linear correlations could be seen between serum level of testosterone and GSRS in both groups (P=0.021), and between serum level of testosterone and RDW in medical group only (P=0.044). CONCLUSION: The endocrine therapies, particularly maximal androgen blockage, in patients with prostate cancer can be associated with anemia, osteoporosis, and IBS.

Metabolic syndrome and androgen deprivation therapy in metabolic complications of prostate cancer patients.

BACKGROUND: Incidence of prostate cancer in Chinese males grows significantly in the past decades. Androgen deprivation therapy has been generally employed in the treatment of locally advanced and metastatic prostate cancer for many years, yet only little data was known about the metabolic syndrome in patients receiving hormonal therapy. This study described the prevalence and the changing trends of hormone-related metabolic complications, and analyzed their correlation with different therapies. METHODS: In 125 patients treated with castration or maximal androgen blockage for at least 12 months, metabolic indicators were analyzed. RESULTS: Totally, 13.5% patients in castration group and 30.1% patients in maximal androgen blockage group were diagnosed metabolic syndrome 12 months after the beginning of treatments (χ(2) = 4.739, P = 0.029). In castration group, increased triglyceride and decreased high-density lipoprotein-cholesterol were significant at the month 12, increased fasting plasma glucose and blood pressure were significant at the month 4. In maximal androgen blockage group, increased triglyceride and decreased high-density lipoprotein-cholesterol were significant at the month 4, increased fasting plasma glucose and blood pressure were significant at the month 8. Total testosterone and free testosterone in maximal androgen blockage group were significantly lower than castration group at all visits, which were proved to show positive or negative correlations with metabolic indications. Severity of metabolic complications in maximal androgen blockage group was generally more serious than people received castration, with significantly statistical difference or not. Trends of high-density lipoprotein-cholesterol and fasting plasma glucose were significant different between two kinds of therapy (P = 0.005, P = 0.019, respectively). CONCLUSIONS: Prostate cancer patients receiving androgen deprivation therapy were at high risk of suffering metabolic syndrome. Severity of metabolic complications under different hormonal therapies were not completely consistent, suggested that androgen deprivation therapy may be individualized.

[Metabolic disorder after androgen deprivation therapy in patients with prostate cancer].

The prevalence of prostate cancer, a common malignancy of urinary system in elderly males, has increased rapidly in China in recent years. Currently most prostate cancer patients are treated with androgen deprivation therapy (ADT). However, ADT-induced metabolic disorders such as metabolic syndrome has remarkably impaired the quality of life and decreased the survival rate.