Activation of peroxymonosulfate with ZIF-67-derived Co/N-doped porous carbon nanocubes for the degradation of Congo red dye.

In this study, porous carbon nanocubes encapsulated magnetic metallic Co nanoparticles (denoted as Co@N-PCNC) was prepared via pyrolyzing ZIF-67 nanocubes precursor at 600 °C and characterized by various technologies. It was used to activate peroxymonosulfate (PMS) to degrade Congo red (CR) dye efficiently. Over 98.45% of 50 mg L-1 CR was degraded using 0.033 mM PMS activated by 75 mg L-1 Co@N-PCNC within 12 min. The free radical quenching experiments were performed to reveal the nature of the reactive oxygen species radicals generated throughout the catalytic oxidation of CR. The effects of common inorganic anions and the water matrix on CR removal were studied. Moreover, the results of the kinetic study revealed the suitability of the pseudo-first-order and Langmuir-Hinshelwood kinetic models for illustrating CR degradation using the Co@N-PCNC/PMS system. Ultimately, the Co@N-PCNC displayed good operational stability, and after five cycles, the CR removal rate can still maintain over 90% after 12 min.

The Magic Triangle in Oral Potentially Malignant Disorders: Vitamin D, Vitamin D Receptor, and Malignancy.

OPMDs (oral potentially malignant disorders) are a group of disorders affecting the oral mucosa that are characterized by aberrant cell proliferation and a higher risk of malignant transformation. Vitamin D (VitD) and its receptor (VDR) have been extensively studied for their potential contributions to the prevention and therapeutic management of various diseases and neoplastic conditions, including oral cancer. Observational studies suggest correlations between VitD deficiency and higher cancer risk, worse prognosis, and increased mortality rates. Interestingly, emerging data also suggest a link between VitD insufficiency and the onset or progression of OPMDs. Understanding the role of the VitD-VDR axis not only in established oral tumors but also in OPMDs might thus enable early detection and prevention of malignant transformation. With this article, we want to provide an overview of current knowledge about OPMDs and VitD and investigate their potential association and ramifications for clinical management of OPMDs.

Exploiting Vitamin D Receptor and Its Ligands to Target Squamous Cell Carcinomas of the Head and Neck.

Vitamin D (VitD) and its receptor (VDR) have been intensively investigated in many cancers. As knowledge for head and neck cancer (HNC) is limited, we investigated the (pre)clinical and therapeutic relevance of the VDR/VitD-axis. We found that VDR was differentially expressed in HNC tumors, correlating to the patients' clinical parameters. Poorly differentiated tumors showed high VDR and Ki67 expression, whereas the VDR and Ki67 levels decreased from moderate to well-differentiated tumors. The VitD serum levels were lowest in patients with poorly differentiated cancers (4.1 ± 0.5 ng/mL), increasing from moderate (7.3 ± 4.3 ng/mL) to well-differentiated (13.2 ± 3.4 ng/mL) tumors. Notably, females showed higher VitD insufficiency compared to males, correlating with poor differentiation of the tumor. To mechanistically uncover VDR/VitD's pathophysiological relevance, we demonstrated that VitD induced VDR nuclear-translocation (VitD < 100 nM) in HNC cells. RNA sequencing and heat map analysis showed that various nuclear receptors were differentially expressed in cisplatin-resistant versus sensitive HNC cells including VDR and the VDR interaction partner retinoic acid receptor (RXR). However, RXR expression was not significantly correlated with the clinical parameters, and cotreatment with its ligand, retinoic acid, did not enhance the killing by cisplatin. Moreover, the Chou-Talalay algorithm uncovered that VitD/cisplatin combinations synergistically killed tumor cells (VitD < 100 nM) and also inhibited the PI3K/Akt/mTOR pathway. Importantly, these findings were confirmed in 3D-tumor-spheroid models mimicking the patients' tumor microarchitecture. Here, VitD already affected the 3D-tumor-spheroid formation, which was not seen in the 2D-cultures. We conclude that novel VDR/VitD-targeted drug combinations and nuclear receptors should also be intensely explored for HNC. Gender-specific VDR/VitD-effects may be correlated to socioeconomic differences and need to be considered during VitD (supplementation)-therapies.

The Vitamin D Receptor-BIM Axis Overcomes Cisplatin Resistance in Head and Neck Cancer.

Treatment success of head and neck squamous cell carcinoma (HNSCC) is often hindered by cisplatin resistance. As inherent and acquired therapy resistance counteracts improvement in long-term survival, novel multi-targeting strategies triggering cancer cell apoptosis are urgently required. Here, we identify the vitamin D receptor (VDR) as being significantly overexpressed in tumors of HNSCC patients (n = 604; p = 0.0059), correlating with tumor differentiation (p = 0.0002), HPV status (p = 0.00026), and perineural invasion (p = 0.0087). The VDR, a member of the nuclear receptor superfamily, is activated by its ligand vitamin D (VitD) and analogs, triggering multiple cellular responses. As we found that the VDR was also upregulated in our cisplatin-resistant HNSCC models, we investigated its effect on overcoming cisplatin resistance. We discovered that VitD/cisplatin combinations synergistically killed even cisplatin-resistant cells at clinically achievable levels. Similar results were obtained for the clinically used VitD analog Maxacalcitol. Moreover, VitD/cisplatin combinations inhibited tumor cell migration by E-cadherin upregulation. Signaling pathway analyses revealed that VitD co-treatments triggered cancer cell death by increasing the expression of the pro-apoptotic BCL-2 family protein BIM. BIM's pro-apoptotic activity in HNSCC cells was confirmed by ectopic overexpression studies. Importantly, BIM expression is positively associated with HNSCC patients' (n = 539) prognosis, as high expression correlated with improved survival (p = 0.0111), improved therapy response (p = 0.0026), and remission (p = 0.004). Collectively, by identifying, for the first time, the VDR/BIM axis, we here provide a molecular rationale for the reported anti-cancer activity of VitD/analogs in combination therapies. Our data also suggest its exploitation as a potential strategy to overcome cisplatin resistance in HNSCC and other malignancies by inducing additional pro-apoptotic pathways.

Impact of Secretion-Active Osteoblast-Specific Factor 2 in Promoting Progression and Metastasis of Head and Neck Cancer.

Treatment success of head and neck cancer (HNC) is still hampered by tumor relapse due to metastases. Our study aimed to identify biomarkers by exploiting transcriptomics profiles of patient-matched metastases, primary tumors, and normal tissue mucosa as well as the TCGA HNC cohort data sets. Analyses identified osteoblast-specific factor 2 (OSF-2) as significantly overexpressed in lymph node metastases and primary tumors compared to normal tissue. High OSF-2 levels correlate with metastatic disease and reduced overall survival of predominantly HPV-negative HNC patients. No significant correlation was observed with tumor localization or therapy response. These findings were supported by the fact that OSF-2 expression was not elevated in cisplatin-resistant HNC cell lines. OSF-2 was strongly expressed in tumor-associated fibroblasts, suggesting a tumor microenvironment-promoting function. Molecular cloning and expression studies of OSF-2 variants from patients identified an evolutionary conserved bona fide protein secretion signal (1MIPFLPMFSLLLLLIVNPINA21). OSF-2 enhanced cell migration and cellular survival under stress conditions, which could be mimicked by the extracellular administration of recombinant protein. Here, OSF-2 executes its functions via ß1 integrin, resulting in the phosphorylation of PI3K and activation of the Akt/PKB signaling pathway. Collectively, we suggest OSF-2 as a potential prognostic biomarker and drug target, promoting metastases by supporting the tumor microenvironment and lymph node metastases survival rather than by enhancing primary tumor proliferation or therapy resistance.

Identification of cytokeratin24 as a tumor suppressor for the management of head and neck cancer.

To improve management of head and neck squamous cell carcinoma patients, we need to increase our understanding of carcinogenesis, to identify biomarkers, and drug targets. This study aimed to identify novel biomarkers by providing transcriptomics profiles of matched primary tumors, lymph node metastasis, and non-malignant tissue of 20 HNSCC patients as well as by bioinformatic analyses of a TCGA HNSCC cohort, comprising 554 patients. We provide cancer cell signaling networks differentially expressed in tumors versus metastases, such as mesenchymal-epithelial transition, and structural integrity networks. As a proof of principle study, we exploited the data sets and performed functional analyses of a novel cytokeratin, cytokeratin24 (cKRT24), which had not been described as biomarker for tumors before. Survival analysis revealed that low cKRT24 expression correlated with poor overall survival in HNSCC. Experimentally, downregulation of cKRT24 in primary tumors, metastases, and HNSCC cell lines was verified on mRNA and protein level. Cloning and ectopic overexpression of cKRT24 not only affected viability and growth of HNSSC cell lines, but also inhibited tumor growth in murine xenograft studies. We conclude that cKRT24 functions as a tumor suppressor in HNSCC, and may serve as an additional prognostic biomarker and novel target to support current HNSCC treatments.

Profiling Cisplatin Resistance in Head and Neck Cancer: A Critical Role of the VRAC Ion Channel for Chemoresistance.

Treatment success of head and neck cancers (HNSCC) is often hindered by tumor relapses due to therapy resistances. This study aimed at profiling cisplatin resistance mechanisms and identifying biomarkers potentially suitable as drug targets and for patient stratification. Bioinformatic analyses of suggested resistance factors in a cohort of 565 HNSCC patients identified the VRAC ion channel as a clinically relevant indicator for recurrent diseases following radiochemotherapy (p = 0.042). Other drug import/export transporters, such as CTR1, OCT1, or MRP1, were found to be less relevant. To experimentally verify VRAC's critical role for cisplatin resistance, we used CRISPR/Cas9 knockout resulting in cisplatin-resistant HNSCC cells, which could be resensitized by VRAC expression. Next-generation sequencing further underlined VRAC's importance and identified VRAC-regulated signaling networks, potentially also contributing to cisplatin resistance. CTR1, OCT1, or MRP1 did not contribute to increased cisplatin resistance. In addition to two-dimensional HNSCC models, three-dimensional tumor spheroid cultures confirmed VRAC's unique role for cisplatin sensitivity. Here, resistance correlated with DNA damage and downstream apoptosis. The cisplatin specificity of the identified VRAC pathway was verified by testing paclitaxel and doxorubicin. Our results were independently confirmed in naturally occurring, cisplatin-resistant HNSCC cancer cell models. Collectively, we here demonstrate VRAC's role for cisplatin resistance in HNSCC and its relevance as a potential drug target and/or prognostic biomarker for chemotherapy resistance.

Nano Meets Micro-Translational Nanotechnology in Medicine: Nano-Based Applications for Early Tumor Detection and Therapy.

Nanomaterials have great potential for the prevention and treatment of cancer. Circulating tumor cells (CTCs) are cancer cells of solid tumor origin entering the peripheral blood after detachment from a primary tumor. The occurrence and circulation of CTCs are accepted as a prerequisite for the formation of metastases, which is the major cause of cancer-associated deaths. Due to their clinical significance CTCs are intensively discussed to be used as liquid biopsy for early diagnosis and prognosis of cancer. However, there are substantial challenges for the clinical use of CTCs based on their extreme rarity and heterogeneous biology. Therefore, methods for effective isolation and detection of CTCs are urgently needed. With the rapid development of nanotechnology and its wide applications in the biomedical field, researchers have designed various nano-sized systems with the capability of CTCs detection, isolation, and CTCs-targeted cancer therapy. In the present review, we summarize the underlying mechanisms of CTC-associated tumor metastasis, and give detailed information about the unique properties of CTCs that can be harnessed for their effective analytical detection and enrichment. Furthermore, we want to give an overview of representative nano-systems for CTC isolation, and highlight recent achievements in microfluidics and lab-on-a-chip technologies. We also emphasize the recent advances in nano-based CTCs-targeted cancer therapy. We conclude by critically discussing recent CTC-based nano-systems with high therapeutic and diagnostic potential as well as their biocompatibility as a practical example of applied nanotechnology.

Clinical Management Protocol for Dental Implants Inserted in Patients with Active Lichen Planus. Part II 4-Year Follow-Up.

PURPOSE: To evaluate marginal bone loss (MBL) of dental implants inserted in active lichen planus patients. MATERIALS AND METHODS: The study included 59 subjects divided into 3 groups depending on their lichen planus diagnosis and administration of a low dose of corticosteroids: 17 healthy individuals, 20 controlled lichen planus patients controlled using low doses of systemic corticosteroids, and 22 noncontrolled lichen planus patients. During 4-year follow-up sessions MBL was evaluated, and biopsies were collected from lichen planus patients and examined. Two-way ANOVA was used to analyze the data (α = 0.05). RESULTS: There was no statistically significant difference in MBL between healthy and controlled patients; however, noncontrolled patients exhibited increased MBL (F = 1309, p < 0.001) which reached 2.53 mm after 4 years. There were significant interactions between state of the disease (F = 1309, p < 0.001), evaluation time (F = 317, p < 0.001), and interaction between state of the disease and observation time (F = 159, p < 0.001). Histopathologic examination of collected biopsies revealed healthy tissue architecture of the controlled patients, while inflammatory cellular infiltration and signs of classical destructive tissue were observed for noncontrolled patients. CONCLUSIONS: Lichen planus patients receiving dental implants should be controlled on a low-dose of corticosteroids to prevent accelerated MBL and to reduce remission of clinical manifestations.

The influence of local delivery of bisphosphonate on osseointegration of dental implants.

Data sourcesThe databases searched were the Cochrane Library, PubMed/Medline, Embase, ISI Web of Knowledge, Scopus and SIGLE OpenGrey. Databases were searched with no restriction on year of publication or language.Study selectionRandomised controlled clinical trials (RCTs), prospective and retrospective studies, case-control studies and case series studies in humans were included. The test group received implants with the local delivery of bisphosphonates, controls received implants only. Studies involving patients with metabolic bone diseases or undergoing systemic medications for bone bio-modulation or immunosuppression or with relevant pathologies were excluded.Data extraction and synthesisThree authors independently selected studies with disagreements being resolved by discussion. Study quality was assessed by two reviewers using the Newcastle-Ottawa scale (NOS).ResultsThree articles published between 2010 and 2013 met the selection criteria. Sample size ranged from five to 39. Mean age was 52.6 to 66. Efficacy was assessed using radiographic analysis, implant stability quotient (ISQ) and histological assessment. Despite methodological differences, all articles reported positive results for osseointegration when a local bisphosphonate was used, either on the implant surface or direct application of a pharmacologically active compound at the surgical site or in the form of a gel directly at the surgical site. Greater implant stability, better implant survival rates and reduced peri-implant bone loss were recorded in the test groups compared with controls. As well as formation of lamellar bone trabeculae in intimate contact with the implants.ConclusionsThe local use of a bisphosphonate appears to favour the osseointegration of titanium implants in humans.