We report that highly crystallized iron oxide nanoparticles (HCIONPs) made by thermal decomposition and further coating with a polysiloxane-containing copolymer can be used as effective mediators for photothermal therapy. Irradiation of a HCIONP solution containing 0.5 mg mL À1 Fe, for instance, with an 885 nm diode laser at a power of 2.5 W cm À2 , induces a temperature increase of 33 C from room temperature, while water produced only a $3 C increase as the control. In vivo studies are further evaluated for effective photothermal therapy using the as-prepared HCIONPs. Benefiting from the great antibiofouling property of the polymer coating and minimized hydrodynamic size (whole particle size: 24 nm), the nanoparticles intravenously administered to SUM-159 tumor-bearing mice can effectively accumulate within the tumor tissue (5.3% of injection dose) through the enhanced permeability and retention effect. After applying the same laser conditions to irradiate the tumors, complete tumor regression is observed within three weeks without disease relapse over the course of three months. Conversely, control mice exhibit continuous tumor growth leading to animal mortality within four weeks.To better understand the photothermal effect of HCIONPs and potentially improve their photothermal efficiency, we compare their photothermal effect and crystal structures with commercially available magnetic nanoparticles. Our data show that after applying the same laser to commercially available magnetic nanoparticles from FeREX at the same iron concentration, the temperature is only increased by 7.4 C. We further use synchrotron-XRD and high-resolution TEM to compare the crystal structures of both magnetic nanoparticles. The data show that both magnetic nanoparticles are Fe 3 O 4 but asprepared HCIONPs are highly crystalline and have preferred lattice plane orientations, which may be the cause of their enhanced photothermal efficiency. Taken together, these data suggest that HCIONPs, with unique lattice orientations and small size as well as antifouling coating, can be used as promising mediators for photothermal cancer therapy.

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Although trastuzumab is an effective treatment in early stage HER2+ breast cancer the majority of advanced HER2+ breast cancers develop trastuzumab resistance, especially in the 40% of breast cancers with loss of PTEN. However, HER2+ breast cancer patients continue to receive trastuzumab regardless PTEN status and the consequence of therapy in these patients is unknown. We demonstrate that continued use of trastuzumab in HER2+ cells with loss of PTEN induces the epithelial-mesenchymal transition (EMT) and transform HER2+ to a triple negative breast cancer. These transformed cells exhibited mesenchymal morphology and gene expression markers, while parent HER2+ cells showed epithelial morphology and markers. The transformed cells exhibited loss of dependence on ERBB family signaling (such as HER2, HER3, HER4, BTC, HRG, EGF) and reduced estrogen and progesterone receptors. Continued use of trastuzumab in HER2+ PTEN− cells increased the frequency of cancer stem cells (CSCs) and metastasis potential. Strikingly, parental HER2+ cells and transformed resistant cells respond to treatment differently. Transformed resistant cells were sensitive to chemical probe (sulforaphane) through inhibition of IL-6/STAT3/NF-κB positive feedback loop whereas parental HER2+ cells did not respond. This data suggests that trastuzumab resistance in HER2+ PTEN− breast cancer induces EMT and subtype switching, which requires unique treatment options.

Background. Carboxypeptidase A4 (CPA4) belongs to a member of the metallocarboxypeptidase family, and its expression in lung cancer samples and clinical significance are still not investigated until now. In this study, we aimed to evaluate the level of CPA4 in non-small-cell lung cancer (NSCLC) samples and correlate its level with clinical outcome.Methods. CPA4 gene expression in lung cancer tissues were analyzed by using the Oncomine database (www.oncomine.org). The expression of CPA4, Survivin and VEGF in lung cancer and adjacent normal tissues were evaluated by IHC using the corresponding primary antibodies on two different commercial tissue arrays (Shanghai Biochip Co., Ltd., Shanghai, China). Their levels in serum were determined by using commercial human enzyme-linked immunosorbent assay kits. We also examined their relations to clinicopathologic parameters, and explored the diagnostic and prognostic value in NSCLC.Results. We identified an elevation of CPA4 in mRNA level and gene amplification in lung cancer tissues in comparison to normal lung tissues. High CPA4 expression was observed in 120/165 (72.7%) NSCLC samples, and significantly correlated with Tumor size, Depth of invasion, Lymph Node Metastasis, Stage, VEGF level and Survivin level. High CPA4 expression is associated with poor prognosis of NSCLC patients. Multivariable Cox regression analysis demonstrated that CPA4 expression was an independent prognostic factor. Furthermore, serum CPA4 level was also significantly higher in NSCLC patients than in healthy controls. Logistic regression analysis revealed that serum CPA4 and CYFRA21-1 level were the significant parameters for detecting NSCLC. Receiver operating characteristic curves (ROC) in NSCLC patients versus normal people yielded the optimal cut-off value was 2.70 ng/ml for CPA4 and 19 ng/ml for CYFRA21-1, respectively. The area under ROC curve (AUC) was 0.830 for the combination of the two tumor markers.Conclusion. Our results demonstrated that overexpression of CPA4 in NSCLC is associated with an unfavorable prognosis, and serum CPA4 level combining with serum CYFRA21-1 level could be used to aid early detection of NSCLC.

Continued use of trastuzumab in PTEN-deficient HER2+ breast cancer induces the epithelial-to-mesenchymal transition (EMT), transforms HER2+ to triple negative breast cancer, and expands breast cancer stem cells (BCSCs). Using cancer cell lines with two distinct states, epithelial and mesenchymal, we identified novel targets during EMT in PTEN-deficient trastuzumab-resistant breast cancer. Differential gene expression and distinct responses to a small molecule in BT474 (HER2+ trastuzumab-sensitive) and the PTEN-deficient trastuzumab-resistant derivative (BT474-PTEN-LTT) provided the selection tools to identify targets during EMT. siRNA knockdown and small molecule inhibition confirmed MEOX1 as one of the critical molecular targets to regulate both BCSCs and mesenchymal-like cell proliferation. MEOX1 was associated with poor survival, lymph node metastasis, and stage of breast cancer patients. These findings suggest that MEOX1 is a clinically relevant novel target in BCSCs and mesenchymal-like cancer cells in PTEN-deficient trastuzumab resistant breast cancer and may serve as target for future drug development.