Molecular subtypes predict the prognosis of male breast cancer: a retrospective cohort study.

Background: Male breast cancer is rare, and something different from female breast cancer. The characteristics of molecular subtype in male breast cancer is unclear and lack of large-sample study. Methods: A retrospective study was conducted to investigate the characteristics and prognosis of patients with male breast cancer using the data recorded in the Surveillance, Epidemiology, and End Results (SEER) database from 2010-2014. A total of 1,597 cases were enrolled with median age of 66 years. The study endpoint was considered as patient death. The molecular subtype was defined by estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, hormone receptor (HR) positive was defined as ER positive with or without PR positive, including 1,373 cases of HR+/HER2- tumor (86%), 182 cases of HR+/HER2+ tumor (11.4%), 13 cases of HR-/HER2+ tumor (0.8%) and 29 cases with triple negative (TN) tumor (1.8%), respectively. Results: There were significant differences in distributions of age, race, grade, tumor size and American Joint Committee on Cancer (AJCC) stage between different molecular subtypes. Patients of different molecular subtypes differed significantly in 5 years overall survival and cause-specific survival (CSS). Five-year CSS (5y-CSS) rates of different molecular subtypes was 89.2% (HER2-/HR+), 78.4% (HER2+/HR+), 72.6% (HER2+/HR-) and 43.2% (TN), respectively. According to Cox regression, age ≥65 years [P=0.001, hazard ratio (HR) =2.136 (1.372, 3.324)], ER negative [P=0.02, HR =2.481 (1.159, 5.319)], PR negative [P=0.007, HR =2.294 (1.256, 4.184)], TN subtype [P<0.001, HR =10.676 (4.441, 25.665)], AJCC stage IV [P<0.001, HR =21.222 (10.377, 43.4)], tumor size >5 cm or T4 [P<0.001, HR =2.577 (0.978, 6.792)], Stage M1 [P=0.001, HR =4.519 (1.929, 10.587)] and Black race [P=0.002, HR =2.322 (1.442, 3.74)] were independent prognostic factors for poorer CSS. Conclusions: Just like female, molecular subtypes also varied in male breast cancer. It could be a predictor for survival and improve the strategy making in clinical practice.

YEATS4 is associated with poor prognosis and promotes epithelial-to-mesenchymal transition and metastasis by regulating ZEB1 expression in breast cancer.

YEATS domain-containing protein 4 (YEATS4) is implicated in several oncogenic signaling pathways, and its expression is involved in various types of cancer; regardless, the pathophysiologic effects of YEATS4 on breast cancer remain unclear. This study finds that YEATS4 is increasingly expressed with breast cancer progression, and its expression is related to poor outcome and distant metastasis. YEATS4 overexpression in breast cancer cells strengthens their malignant characteristics in vitro and in vivo, particularly inducing epithelial-to-mesenchymal transition (EMT) and consequently, metastatic capability in breast cancer cells. By contrast, deleting YEATS4 in breast cancer cells with high-grade malignancy reduced these characteristics. With regard to the molecular mechanism, YEATS4 mediates histone H3K27ac at specific sites of the ZEB1 promoter to regulate its expression at the transcription level. Depleting ZEB1 blocks YEATS4-induced EMT, migration, invasion, and metastasis. YEATS4 expression is also positively correlated with ZEB1 expression in patients with breast cancer. Co-expression of YEATS4 and ZEB1 correlates with the shortest distant metastasis-free period. Taken together, our data reveal the critical role of YEATS4 in the progression and metastasis of breast cancer, as well as support YEATS4 as a potential therapeutic target and prognostic biomarker for breast cancer.

OSR1 phosphorylates the Smad2/3 linker region and induces TGF-ß1 autocrine to promote EMT and metastasis in breast cancer.

Oxidative stress-responsive kinase 1 (OSR1) plays a critical role in multiple carcinogenic signal pathways, and its overexpression has been found in various types of cancer; however, the pathophysiological role of OSR1 in breast cancer has not been evaluated. This study aims to elaborate on the role of OSR1 in breast cancer metastasis and the specific regulatory mechanism. Our results showed that OSR1 mRNA and protein were upregulated in both human breast cancer samples and cell lines. Moreover, phosphorylated OSR1 (p-OSR1) was an independent poor prognostic indicator in patients with breast cancer. OSR1 upregulation induced epithelial-to-mesenchymal transition (EMT) in normal and malignant mammary epithelial cells with the increasing metastatic capacity. In contrast, deleting OSR1 in aggressive breast cancer cells inhibited these phenotypes. OSR1 is the critical activator for transcription factors of EMT. Mechanistically, we found that OSR1 can directly interact and phosphorylate the linker region of Smad2 at Thr220 and Smad3 at Thr179. Phosphorylated Smad2/3 translocated into the nucleus to enhance transforming growth factor-ß1 (TGF-ß1) autocrine signalling and increase the transcription of EMT regulators. Importantly, interruption of the OSR1-Smad2/3-TGF-ß1 signalling axis elicited a robust anti-EMT and anti-metastatic effect in vitro and in vivo. Taken together, we conclude that OSR1-mediated Smad2/3-TGF-ß1 signalling promotes EMT and metastasis representing a promising therapeutic target in breast cancer treatment.

High expression of OSR1 as a predictive biomarker for poor prognosis and lymph node metastasis in breast cancer.

PURPOSE: Oxidative stress-responsive kinase 1 (OSR1) plays a crucial role in regulating diverse cellular pathophysiologic functions, including ion homeostasis, development, differentiation, angiogenesis, invasive migration, and metastasis. Regardless, the clinical significance of OSR1 in breast cancer is scarce. The current study was conducted to evaluate the effect of OSR1 on the prognosis of patients with breast cancer with a long-term follow-up. METHODS: OSR1 expression in formalin-fixed and paraffin-embedded tissue specimens was analyzed. These specimens were collected from 551 evaluable breast cancer cases by immunohistochemistry (IHC). OSR1 expression was dichotomized based on the H-score in IHC. The effects of OSR1 levels on the clinicopathological attributes and survival prediction in patients with breast cancer were explored. RESULTS: Among 551 specimens, 183 (33.2%) exhibited high expression of OSR1 in tumor cells. High OSR1 levels were markedly correlated with histologic grade (P = 0.035), ER (P < 0.001) and PgR (P = 0.043) expression, lymph node involvement (P < 0.001), TNM stage (P < 0.001), and axillary surgery procedures (P = 0.003). Univariate analysis results indicate that patients with high OSR1 expression had significantly poor overall survival (P < 0.001), distant disease-free survival (P < 0.001), and breast cancer-specific survival (P < 0.001). Multivariable Cox regression analyses suggest that OSR1 expression was an independent predictive marker of poor prognosis and lymph node metastasis (HR 3.224, 95% CI 1.182-8.702, P = 0.023) in patients with breast cancer. CONCLUSIONS: Our findings indicate that OSR1 is a significantly independent prognosis index for patients with breast cancer with respect to distant disease-free survival, overall survival, and breast cancer-specific survival. High OSR1 expression caused an increase in deaths specifically attributed to breast cancer and was related to increased lymph node metastasis. However, the precise cellular mechanisms for OSR1 in breast cancer require further research.

Meta-analysis of diffusion-weighted imaging in the differential diagnosis of renal lesions.

PURPOSE: To assess the diagnostic value of diffusion-weighted imaging (DWI) in distinguishing between renal malignant and benign lesions. MATERIALS AND METHODS: Electronic databases were systematically searched to identify original studies evaluating DWI findings on renal lesions from January 2000 through January 2018. Pooled weighted estimates of sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were calculated. A summary receiver operator characteristic (sROC) curve was constructed to calculate the area under the sROC curve (AUC). Publication bias was assessed by using Deeks' asymmetry test. RESULTS: A total of 15 studies including 1386 renal lesions were eligible in the meta-analysis. The pooled sensitivity and specificity with a corresponding 95% confidence interval (CI) were 0.83 (95% CI: 0.80-0.86) and 0.74 (95% CI: 0.71-0.78), respectively. The PLR, NLR, and DOR were 3.21 (95% CI: 2.39-4.32), 0.24 (95% CI: 0.18-0.30), and 15.95 (95% CI: 11.19-22.71), respectively. The AUC was 0.87 (95% CI: 0.84-0.90). Significant heterogeneity was observed between the included studies. Reference standard, country, and gradient factor were identified as the most important variable sources. No evidence of notable publication bias was reported. CONCLUSIONS: DWI is an informative MRI modality in discriminating benign and malignant lesions and exhibits moderately high diagnostic accuracy. However, it remains inconclusive and limited in the absence of an optimal b value and ADC cutoff value. High-quality prospective studies regarding DWI have yet to be conducted to explore optimal imaging parameters and diagnostic thresholds.

Histone deacetylase enzyme silencing using shRNAs enhances radiosensitivity of SW579 thyroid cancer cells.

The aim of the present study was to screen the enzymes that are associated with the radiosensitivity of SW579 thyroid cancer cells, and investigate whether radiation, combined with specific RNA interference on the screened enzymes, enhances radiosensitivity of SW579 thyroid cancer cells. Quantitative polymerase chain reaction (qPCR) was used to analyze epigenetic enzyme expression changes before and after radiotherapy, and four enzymes, histone deacetylase 1 (HDAC1), HDAC2, HDAC4 and HDAC6 were screened. Western blot analysis was performed to analyze the change in HDAC1, HDAC2, HDAC4 and HDAC6 protein expression following radiotherapy. Short hairpin RNA (ShRNA)­HDAC1, shRNA­HDAC2, shRNA­HDAC4 and shRNA­HDAC6 plasmids were constructed and SW579 cells were transfected with corresponding shRNA­HDACs. Reverse transcription­qPCR was used to detect whether downregulation of HDAC mRNAs had been effective. In addition, shRNA and shRNA negative control (NC) pools were established and transfected into the SW579 cells. The samples were divided into four groups; control, trichostatin A, shRNA pool and shRNA NC pool, to analyze the effective enhancement of specific shRNA on radiosensitivity in thyroid cancer cells. The morphological changes were observed in the SW579 cells, and the number of tumor cells decreased markedly in the shRNA pool group compared with that of the other three groups. Therefore, it was concluded that HDACs present a potential target for increasing the sensitivity of thyroid cancer cells to radiotherapy, and shRNA­HDAC interference combined with radiotherapy promotes the radiosensitivity of tumors.

Lentivirus-mediated knockdown of CEP55 suppresses cell proliferation of breast cancer cells.

Centrosomal protein 55 (CEP55), as a microtubule-bundling protein, plays an important role in cell cycle regulation. CEP55 has been recognized recently in several human cancers. In this study, we first observed that the mRNA level of CEP55 is commonly up-regulated in breast cancer compared with their normal counterparts as demonstrated by data derived from Oncomine database. To further evaluate the functional role of CEP55 in breast cancer cells. Expression of CEP55 was efficiently knocked down using lentivirus-mediated RNA interference in human breast cancer cell line ZR-75-30, as evidenced by quantitative real-time PCR (qRT-PCR) and Western blot analysis. Further investigations revealed that CEP55 knockdown significantly inhibited cell proliferation and colony formation. Moreover, flow cytometer analysis indicated knockdown of CEP55 induced cell cycle arrested at G0/G1 phase and cell apoptosis. These findings suggest that CEP55 plays a crucial role in promoting breast cancer cell proliferation and it might be a potential therapeutic target in breast cancer.

Could Tumor Size Be A Predictor for Papillary Thyroid Microcarcinoma: a Retrospective Cohort Study.

BACKGROUND: Central lymph node metastasis(CLNM) is common in papillary thyroid microcarcinoma (PTMC). The aim of this study was to define the pathohistologic risk grading based on surgical outcomes. MATERIALS AND METHODS: Statistical analysis was performed to figure out the optimal cut-off values of size in preoperative ultrasound images for defining the risk of CLNM in papillary thyroid microcarcinoma. Receiver operating characteristic curves (ROC) studies were carried out to determine the cutoff value(s) for the predictor(s). All the patients were divided into two groups according to the above size and the clinic-pathological and immunohistochemical parameters were compared to determine the significance of findings. RESULTS: The optimal cut-off value of tumor size to predict the risk of CLNM in papillary thyroid microcarcinoma was 0.575 cm (area under the curve 0.721) according to the ROC curves. Significant differences were observed on the multifocality, extrathyroidal extension and central lymph node metastasis between two groups which were divided according to the tumor size by the cutoff values. Patients in two groups showed different positive rate and intensity of Ki67. CONCLUSIONS: The size of PTMC in ultrasound images are helpful to predict the aggressiveness of the tumors, it could be an easy predictor for PTMC prognosis and assist us to choose treatment.

[Portal venous and enteric drainage in simultaneous pancreas kidney transplantation].

OBJECTIVE: To summarize the initial experience of simultaneous pancreas kidney transplantation (SPK) with portal venous and enteric drainage. METHODS: Between Jane 2001 and Jane 2003, SPK were performed in 5 patients. Systemic venous-enteric drainage (SED) was used in the first 2 patients and portal venous-enteric drainage (PED) in the last 3 cases. All patient were immunosuppressed with quadruple therapy, which included anti-CD25 mAb (Zenapax/Simulect) induction therapy, FK506, mycophenolate mofetil (MMF), and prednisone baseline therapy. The complications were analyzed. RESULTS: Serum glucose and renal function of the 5 cases were normal and no further insulin was needed within 7 days post-operation. No technique complications such as duodenal fistula and thrombosis were observed, One episode of acute rejection of kidney allograft occurred in one patient with SED, and resolved with a bolus corticosteroids. One case with SED and one with PED were died of sepsis and FK506 toxicity 4 weeks after transplantation. The death occurred with functioning pancreas graft. No latter complications were observed in the 3 survived patients with excellent graft functions. CONCLUSIONS: Both methods of SED and PED can be performed successfully and with no latter complications. But with its potential physiologic and immunologic advantages, PED might be a standard procedure for SPK.