Immunohistochemical Analysis of CYP11B2, CYP11B1 and ß-catenin Helps Subtyping and Relates With Clinical Characteristics of Unilateral Primary Aldosteronism.

Background: Primary aldosteronism is caused by aldosterone overproduction. While conventional hematoxylin-eosin staining can demonstrate morphological abnormality, it cannot provide any functional histopathological information. We aimed to identify the diagnostic, functional and prognostic value of CYP11B2, CYP11B1, and ß-catenin immunostaining in unilateral hyperaldosteronism. Method: A total of 134 patients with unilateral hyperaldosteronism were recruited in our study. The expression of CYP11B2, CYP11B1, and ß-catenin was evaluated semiquantitatively on 134 patients' sections using immunohistochemistry technology and the relationship with clinical data was assessed. Results: Patients were classified into four subtypes based on CYP11B2 staining as below: (1)118 patients with unilateral single aldosterone-producing adenoma (APA), (2)11 with unilateral multiple APA, (3)four with aldosterone-producing cell cluster (APCC), and (4)one with an undefined source. Adjusted CYP11B2 H-score was correlated with serum aldosterone, aldosterone to renin ratio (ARR), and serum potassium. In the abnormal ß-catenin staining group, hypertension duration, aldosterone, ARR, cortisol, tumor diameter, tumor area, and CYP11B2 H-score were significantly higher than those of the wild-type group. Serum potassium level was significantly lower in the abnormal ß-catenin staining group. Age, gender, BMI, family history of hypertension, adjusted CYP11B2 and CYP11B1 H-scores differed significantly between complete clinical success and incomplete clinical success groups. Age, gender and family history of hypertension were independently associated with complete clinical success based on multivariate logistic regression analysis. Conclusion: CYP11B2 immunostaining could improve the differential diagnosis of unilateral hyperaldosteronism. Adjusted CYP11B2 H-score could be used as a histopathological marker to reflect the severity of unilateral APA. Dysregulation of Wnt/ß-catenin signaling and impaired ß-catenin degradation may provoke the proliferation and enhance the steroidogenic ability of APA tumor cells, indicating that the Wnt pathway might be a potential, actionable, therapeutic target in the treatment of hyperaldosteronism. Age, sex and family history of hypertension were independent predictors of clinical outcome after adrenalectomy for unilateral hyperaldosteronism.

Influence of Body Mass Index on Survival and Prognosis in Squamous Cell Carcinoma of Head and Neck.

OBJECTIVE: Differences in body mass index (BMI) were used to analyze the survival and prognosis of SCCHN patients. PATIENTS AND METHODS: A retrospective cohort study was conducted to select 323 patients who underwent surgical treatment for SCCHN from June 2013 to June 2016. The patients were divided into a healthy BMI group (BMI<24kg/m2), an overweight group (24kg/m2≤BMI<28kg/m2) and an obese group (BMI≥28 kg/m2). Various statistical methods were used to summarize and analyze clinical data, complications, disease specific survival (DSS), the overall survival (OS), and recurrence-free survival (RFS) within the last 3 y. RESULTS: At 3 y, OS (54.40%) and DSS (51.94%) were slightly lower in the obese group compared with the overweight (64.62%, 61.92%) and healthy BMI groups (64.66%, 65.02%), but no statistical significance was found in DSS (P=0.178), OS (P=0.123) and RFS (P=0.362). The difference in operation duration (P=0.008) and bleeding volume (P=0.001) in obese patients was consistent with those in diabetes mellitus (P=0.002) and coronary heart disease (P=0.000). A high incidence of pharyngeal fistula was observed in obese (P=0.014) and overweight patients (P=0.025), but mouth floor fistula (P=0.038), lung infection (P=0.047), fat liquefaction (P=0.003) and lower extremities deep venous thrombosis (P=0.020) were only found in the obese group. Cox univariatable and multivariatable analysis showed that clinical stage, T stage, and N stage were independent prognostic factors for patients with SCCHN, which was not related to BMI. CONCLUSION: BMI was associated with a higher probability of complications. However, BMI had no significant correlation with 3-year OS, RFS and DSS, and was not a prognostic indicator for patients with SCCHN.

Self-Assembled and Self-Monitored Sorafenib/Indocyanine Green Nanodrug with Synergistic Antitumor Activity Mediated by Hyperthermia and Reactive Oxygen Species-Induced Apoptosis.

Liver cancer is a leading cause of cancer morbidity and mortality worldwide, especially in China. Sorafenib (SRF) is currently the most commonly used systemic agent against advanced hepatocellular carcinoma (HCC), which is the most common type of liver cancer. However, HCC patients have only limited benefit and suffer a serious side effect from SRF. Therefore, new approaches are urgently needed to improve the therapeutic effectiveness of SRF and reduce its side effect. In our current study, we developed a self-imaging and self-delivered nanodrug with SRF and indocyanine (ICG) to improve the therapeutic effect of sorafenib against HCC. With the π-π stacking effect between SRF and ICG, a one-step nanoprecipitation method was designed to obtain the SRF/ICG nanoparticles (SINP) via self-assembly. Pluronic F127 was used to shield the SINP to further improve the stability in an aqueous environment. The stability, photothermal effect, cell uptake, ROS production, cytotoxicity, tumor imaging, and tumor-targeting and tumor-killing efficacy of the SINP were evaluated in vitro and in vivo by using an HCC cell line Huh7 and its xenograft tumor model. We found that our designed SINP showed monodisperse stability and efficient photothermal effect both in vitro and in vivo. SINP could rapidly enter Huh7 cells and achieve potent cytotoxicity under near-infrared (NIR) laser irradiation partly by producing a great amount of reactive oxygen species (ROS). SINP had significantly improved stability and blood half-life, and could specifically target tumor via the enhanced permeability and retention (EPR) effect in vivo. In addition, SINP showed improved cytotoxicity in both subcutaneous and orthotopic HCC implantation models in vivo. Overall, this rationally designed sorafenib delivery system with a very high loading capacity (33%) has considerably improved antitumor efficiency in vitro and could completely eliminate subcutaneous tumors without any regrowth in vivo. In conclusion, our self-imaging and self-delivered nanodrug could improve the efficacy of SRF and might be a potential therapy for HCC patients.

Synergistic Cisplatin/Doxorubicin Combination Chemotherapy for Multidrug-Resistant Cancer via Polymeric Nanogels Targeting Delivery.

Combination chemotherapy has been proposed to achieve synergistic effect and minimize drug dose for cancer treatment in clinic application. In this article, the stimuli-responsive polymeric nanogels (<100 nm in size) based on poly(acrylic acid) were designed as codelivery system for doxorubicin and cisplatin to overcome drug resistance. By chelation, electrostatic interaction, and π-π stacking interactions, the nanogels could encapsulate doxorubicin and cisplatin with designed ratio and high capacity. Compared with free drugs, the nanogels could deliver more drugs into MCF-7/ADR cells. Significant accumulation in tumor tissues was observed in the biodistribution experiments. The in vitro antitumor studies demonstrated the superior cell-killing activity of the nanogel drug delivery system with a combination index of 0.84, which indicated the great synergistic effect. All the antitumor experimental data revealed that the combination therapy was effective for the multidrug-resistant MCF-7/ADR tumor with reduced side effects.

Specific On-site Assembly of Multifunctional Magnetic Nanocargos Based on Highly Efficient and Parallelized Bioconjugation: Toward Personalized Cancer Targeting Therapy.

The rational design of particle-based cancer theranostic agents, combining diagnostic and therapeutic features in a single entity, has emerged as an effective approach toward personalized cancer therapy; however, creating a flexible assembly of specific targeting ligands with regard to a broad range of tumor tissues and cells is still challenging. Here, we present a convenient and highly variable on-site assembly strategy for the preparation of multifunctional doxorubicin (DOX)-loaded nanocargos with magnetic supraparticles (MSPs) as a core and redox-degradable poly(methylacrylic acid-co-N,N-bis(acryloyl) cystamine) (P(MAA-co-Cy) as the shell, which could be simultaneously modified with multiple targeting ligands through parallelized bioconjugation on the basis of a streptavidin-biotin (SA-BT) interaction. Under physiological conditions similar to those of the cytoplasm of tumor cells, DOX could be released in a controlled manner from these nanocargos to specific tumor sites, while dual-ligand modified nanocargos showed remarkable proliferation inhibition for the HeLa cells and the SK-OV-3 cells that overexpressed both folate as well as integrin receptors. The experimental results demonstrated that the on-site assembly strategy described herein opens access to highly efficient targeting drug delivery systems toward personalized cancer targeting therapy by incorporating functional diversity, which can be easily achieved through highly efficient and parallelized one-step bioconjugation.

Zinc finger-inspired nanohydrogels with glutathione/pH triggered degradation based on coordination substitution for highly efficient delivery of anti-cancer drugs.

Biodegradable materials used for drug delivery are of great demand due to their ability to degrade into low molecular weight species and further excrete from the body by metabolism. Herein, we report a new kind of zinc(II) crosslinked poly(methacrylic acid) nanohydrogels (ZCLNs) inspired by zinc finger proteins with dual stimuli-triggered degradation (glutathione and pH) for the first time. Compared with the disulfide bond crosslinked nanohydrogels, this new kind of ZCLNs is beneficial to the degradation of a wide range of cells, including normal cells. Ex vivo fluorescence images showed that the DOX-loaded folate-PEG conjugated zinc(II)-crosslinked polymeric nanohydrogels (FPZCLNs-15) preferentially accumulated in tumor tissue and the accumulation in normal tissues was much less compared with DOX-loaded PZCLNs-15 (non-targeted nanohydrogels) and free DOX, the FPZCLNs-15 (targeting system) delivered DOX to the tumor site with approximately 3.6- and 1.6-fold higher than free DOX and PZCLNs-15, respectively. Meanwhile, the PZCLNs-15 and FPZCLNs-15 reduced the concentration of DOX in the heart by 3.2- and 5.0-fold respectively, as compared to the free DOX. Moreover, a superior tumor growth inhibition and negligible damage to normal organs like the heart and kidney, which is reported to be vulnerable to DOX-associated side effects, are further demonstrated.