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Purpose: Pluronic block copolymers are potent sensitizers of multidrug resistant cancers. SP1049C, a Pluronic-based micellar formulation of doxorubicin (Dox) has completed Phase II clinical trial and demonstrated safety and efficacy in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction. This study elucidates the ability of SP1049C to deplete cancer stem cells (CSC) and decrease tumorigenicity of cancer cells in vivo. Experimental Design: P388 murine leukemia ascitic tumor was grown in BDF1 mice. The animals were treated with: (a) saline, (b) Pluronics alone, (c) Dox or (d) SP1049C. The ascitic cancer cells were isolated at different passages and examined for 1) in vitro colony formation potential, 2) in vivo tumorigenicity and aggressiveness, 3) development of drug resistance and Wnt signaling activation 4) global DNA methylation profiles, and 5) expression of CSC markers. Results: SP1049C treatment reduced tumor aggressiveness, in vivo tumor formation frequency and in vitro clonogenic potential of the ascitic cells compared to drug, saline and polymer controls. SP1049C also prevented overexpression of BCRP and activation of Wnt-β-catenin signaling observed with Dox alone. Moreover, SP1049C significantly altered the DNA methylation profiles of the cells. Finally, SP1049C decreased CD133+ P388 cells populations, which displayed CSC-like properties and were more tumorigenic compared to CD133− cells. Conclusions: SP1049C therapy effectively suppresses the tumorigenicity and aggressiveness of P388 cells in a mouse model. This may be due to enhanced activity of SP1049C against CSC and/or altered epigenetic regulation restricting appearance of malignant cancer cell phenotype. [ABSTRACT FROM AUTHOR]

MiRNAs and proteins play important roles in different stages of breast tumor development and serve as biomarkers for the early diagnosis of breast cancer. A new algorithm that combines machine learning algorithms and multilayer complex network analysis is hereby proposed to explore the potential diagnostic values of miRNAs and proteins. XGBoost and random forest algorithms were employed to screen the most important miRNAs and proteins. Maximal information coefficient was applied to assess intralayer and interlayer connection. A multilayer complex network was constructed to identify miRNAs and proteins that could serve as biomarkers for breast cancer. Proteins and miRNAs that are nodes in the network were subsequently categorized into two network layers considering their distinct functions. The betweenness centrality was used as the first measurement of the importance of the nodes within each single layer. The degree of the nodes was chosen as the second measurement to map their signalling pathways. By combining these two measurements into one score and comparing the difference of the same candidate between normal tissue and cancer tissue, this novel multilayer network analysis could be applied to successfully identify molecules associated with breast cancer. [ABSTRACT FROM AUTHOR]

Disparities in hepatocellular carcinoma (HCC) incidence and survival have been observed between ethnic groups including African-Americans (AA) and European-Americans (EA). The evaluation of the changes in the levels of metabolites in samples stratified by race could provide a snapshot of ethnically diverse disease related pathways and identify reliable biomarkers. In this study, we considered AA and EA to investigate metabolites that may be associated with HCC in a race-specific manner. The levels of 46 metabolites in plasma samples, collected from patients recruited at MedStar Georgetown University Hospital, were analyzed by Agilent GC-qMS in selected ion monitoring (SIM) mode. A least absolute shrinkage and selection operator (LASSO) regression model was applied to select metabolites with significant changes in HCC vs. cirrhosis in three groups: (1) AA and EA combined; (2) AA separately; and (3) EA separately. In addition, metabolites that distinguish HCC cases from cirrhosis in these three groups were selected by excluding those without HCV infection. The performances of the metabolites selected by LASSO in each group were evaluated through a leave-one-out cross-validation. We identified race-specific metabolites that differentiated HCC cases from cirrhotic controls, yielding better area under the receiver operating characteristics (ROC) curve (AUC) compared to alpha-fetoprotein (AFP), the serological marker widely used for the diagnosis of HCC. This study sheds light on metabolites that could potentially be used as biomarkers for HCC by monitoring their levels in high-risk population of cirrhotic patients in a race-specific manner. [ABSTRACT FROM AUTHOR]

Background: Radiofrequency ablation (RFA) is one of the curative therapies for hepatocellular carcinoma (HCC), however, accelerated progression of residual HCC after incomplete RFA has been reported more frequently. The underlying molecular mechanism of this phenomenon remains to be elucidated. In this study, we used an incomplete RFA orthotopic HCC nude mouse model to study the invasive and metastatic potential of residual cancer as well as the correlated mechanism. Methods: The incomplete RFA orthotopic nude mouse models were established using high metastatic potential HCC cell line HCCLM3 and low metastatic potential HCC cell line HepG2, respectively. The changes in cellular morphology, motility, metastasis and epithelial–mesenchymal transition (EMT), and HCC cell molecular markers after in vitro and in vivo incomplete RFA intervention were observed. Results: Pulmonary and intraperitoneal metastasis were observed in an in vivo study. The underlying pro-invasive mechanism of incomplete RFA appeared to be associated with promoting EMT, including down-regulation of E-cadherin and up-regulation of N-cadherin and vimentin. These results were in accordance with the in vitro response of HCC cells to heat intervention. Further studies demonstrated that β-catenin was a pivotal factor during this course and blocking β-catenin reduced metastasis and EMT phenotype changes in heat-treated HCCLM3 cells in vitro. Conclusion: Incomplete RFA enhanced the invasive and metastatic potential of residual cancer, accompanying with EMT-like phenotype changes by activating β-catenin signaling in HCCLM3 cells. [ABSTRACT FROM AUTHOR]

In the present study, we explored the expression and correlation of survivin with HIF-1α, TGF-β1 and TFE3 in adenoid cystic carcinoma (AdCC). The expression of survivin, HIF-1α, TGF-β1 and TFE3 was assessed by immunohistochemical staining of a tissue microarray containing tissue samples of normal salivary gland (NSG), pleomorphic adenoma (PA) and AdCC. Correlation analysis of these proteins revealed that increased survivin expression was associated with the overexpression of HIF-1α (P<0.001, r = 0.5599), TGF-β1 (P<0.001, r = 0.6616) and TFE3 (P<0.001, r = 0.7747). The expression of survivin, HIF-1α, TGF-β1 and TFE3 was not correlated with the pathological type of human AdCC (P>0.05). Selective inhibition of survivin by YM155 and siRNA significantly reduced human SACC-83 cell proliferation, with the corresponding decrease in expression of HIF-1α, TGF-β1 and TFE3. The data indicate that the overexpression of survivin in AdCC is related to HIF-1α, TGF-β1 and TFE3. We hypothesize from these findings that the inhibition of survivin may be a novel strategy for neoadjuvant chemotherapeutic and radiosensitive treatment of AdCC. [ABSTRACT FROM AUTHOR]

Objective: The purpose of study was to prospectively evaluate the diagnostic performance of dynamic contrast-enhanced MR imaging in the differentiation of malignant lesions from benign ones in patients with BI-RADS 3–4 microcalcifications detected by mammography. Materials and Methods: 93 women with 100 microcalcifications had undergone breast MRI from June 2010 to July 2013. Subsequently, 91 received open biopsy and 2 received stereotactic vacuum-assisted biopsy. All results were compared with histological findings. The PPV, NPV and area under curve (AUC) of the mammography and breast MRI were calculated. Results: There were 31 (31.0%) BI-RADS 3 microcalcifications and 69 (69.0%) BI-RADS 4. The PPV and NPV of mammography is 65.2% (45/69) and 90.3% (28/31). The PPV and NPV of breast MRI was 90.2% (46/51) and 95.9% (47/49). Among 31 BI-RADS 3 microcalcifications, the PPV and NPV of breast MRI was 100% (3/3) and 100% (28/28). Among 69 BI-RADS 4 microcalcifications, the PPV and NPV of breast MRI was 89.6% (43/48) and 90.5% (19/21). The AUC of mammography and breast MRI assessment were 0.738 (95% CI, 0.639–0.837) and 0.931 (95% CI, 0.874–0.988) (p<0.05). Conclusion: Dynamic contrast-enhanced MR imaging of breast is able to be applied to predict the risk of malignance before follow-up for BI-RADS 3 microcalcifications and biopsy for BI-RADS 4 microcalcifications. [ABSTRACT FROM AUTHOR]

Introduction: Bortezomib has significantly improved multiple myeloma (MM) response rates, but strategies for choosing bortezomib-based regimens for initial MM therapy are not standardized. Here, we describe four bortezomib-based therapies in Chinese MM patients to determine the optimal chemotherapeutic approach. Methods: Newly diagnosed symptomatic MM patients at three hematological centers between February 1, 2006 and May 31, 2013 were treated with therapies including bortezomib plus dexamethasone (PD) or combinations of PD with either adriamycin (PAD), cyclophosphamide (PCD) or thalidomide (PTD) for every 28 days. Results: The overall response rate of all the 215 eligible patients was 90.2%. The ORR for PCD, PAD, PTD and PD were 97.4%, 93.2%, 85.3% and 77.8% while the effects with VGPR or better were 63.7%, 62.7%, 44.2% and 37.8%, respectively. The effect of ORR, VGPR and CR/nCR for the PCD regimen was better than the PD protocol. Median PFS for all patients was 29.0 months with significant differences observed among treatment groups. Median OS of all the patients was not reached, but three-drug combinations were superior to PD alone. Frequently observed toxicities were neutropenia, thrombocytopenia, fatigue, infection, herpes zoster, and peripheral neuropathy. The incidence of peripheral neuropathy (PN) in PTD group was significantly higher than other three groups, especially grade 2–3 PN. Treatment with anti-viral agent acyclovir significantly reduced the incidence of herpes zoster. Conclusions: Our experience indicated that bortezomib-based regimens were effective and well-tolerated in the Chinese population studied; three-drug combinations PCD, PAD were superior to PD, especially with respect to PCD. [ABSTRACT FROM AUTHOR]

Despite an increase in the number of molecular epidemiological studies conducted in recent years to evaluate the association between human papillomavirus (HPV) and the risk of breast carcinoma, these studies remain inconclusive. Here we aim to detect HPV DNA in various tissues from patients with breast carcinoma using the method of HPV capture combined with massive paralleled sequencing (MPS). To validate the confidence of our methods, 15 cervical cancer samples were tested by PCR and the new method. Results showed that there was 100% consistence between the two methods.DNA from peripheral blood, tumor tissue, adjacent lymph nodes and adjacent normal tissue were collected from seven malignant breast cancer patients, and HPV type 16(HPV16) was detected in 1/7, 1/7, 1/7and 1/7 of patients respectively. Peripheral blood, tumor tissue and adjacent normal tissue were also collected from two patients with benign breast tumor, and 1/2, 2/2 and 2/2 was detected to have HPV16 DNA respectively. MPS metrics including mapping ratio, coverage, depth and SNVs were provided to characterize HPV in samples. The average coverage was 69% and 61.2% for malignant and benign samples respectively. 126 SNVs were identified in all 9 samples. The maximum number of SNVs was located in the gene of E2 and E4 among all samples. Our study not only provided an efficient method to capture HPV DNA, but detected the SNVS, coverage, SNV type and depth. The finding has provided further clue of association between HPV16 and breast cancer. [ABSTRACT FROM AUTHOR]

The breast cancer stem cells (BCSC) play important roles in breast cancer occurrence, recurrence and metastasis. However, the role of estrogen signaling, a signaling pathway important in development and progression of breast cancer, in regulation of BCSC has not been well established. Previously, we identified and cloned a variant of estrogen receptor α, ER-α36, with a molecular weight of 36 kDa. ER-α36 lacks both transactivation domains AF-1 and AF-2 of the 66 kDa full-length ER-α (ER-α66) and mediates rapid estrogen signaling to promote proliferation of breast cancer cells. In this study, we aim to investigate the function and the underlying mechanism of ER-α36-mediated rapid estrogen signaling in growth regulation of the ER-positive breast cancer stem/progenitor cells. ER-positive breast cancer cells MCF7 and T47D as well as the variants with different levels of ER-α36 expression were used. The effects of estrogen on BCSC's abilities of growth, self-renewal, differentiation and tumor-seeding were examined using tumorsphere formation, flow cytometry, indirect immunofluorence staining and in vivo xenograft assays. The underlying mechanisms were also studied with Western-blot analysis. We found that 17-β-estradiol (E2β) treatment increased the population of ER-positive breast cancer stem/progenitor cells while failed to do so in the cells with knocked-down levels of ER-α36 expression. Cells with forced expression of recombinant ER-α36, however, responded strongly to E2β treatment by increasing growth in vitro and tumor-seeding efficiency in vivo. The rapid estrogen signaling via the AKT/GSK3β pathway is involved in estrogen-stimulated growth of ER-positive breast cancer stem/progenitor cells. We concluded that ER-α36-mediated rapid estrogen signaling plays an important role in regulation and maintenance of ER-positive breast cancer stem/progenitor cells. [ABSTRACT FROM AUTHOR]

Oxidative stress has been reported to play an important role in progression and prognostication in various kinds of cancers. However, the role and clinical significance of oxidative stress markers Keap1 and Nrf2 in oral squamous cell carcinoma (OSCC) has not been elucidated. This study aimed to investigate the correlation of oxidative stress markers Keap1 and Nrf2 expression and pathological features in OSCC by using tissue microarray. Tissue microarrays containing 17 normal oral mucosa, 7 oral epithelial dysplasia and 43 OSCC specimens were studied by immunohistochemistry. The association among these proteins and pathological features were analyzed. Expression of oxidative stress markers Keap1, Nrf2, and antioxidants PPIA, Prdx6, as well as CD147 was found to increase consecutively from normal oral mucosa to OSCC, and the Keap1, Nrf2, PPIA, Prdx6, CD147 expression in OSCC were significantly higher when compared to normal oral mucosa. Expression of Keap1, Nrf2 in tumors was not found to be significantly associated with T category, lymph node metastases, and pathological grade. Furthermore, we checked the relationship among these oxidative stress markers and found that Keap1 was significantly correlated with Nrf2, Prdx6 and CD147. Significant relationship between Nrf2 and Prdx6 was also detected. Finally, we found patients with overexpression of Keap1 and Nrf2 had not significantly worse overall survival by Kaplan–Meier analysis. These findings suggest that ROS markers are associated with carcinogenesis and progression of OSCC, which may have prognostic value and could be regarded as potential therapeutic targets in OSCC. [ABSTRACT FROM AUTHOR]