HIV Protease Inhibitors Sensitize Human Head and Neck Squamous Carcinoma Cells to Radiation by Activating Endoplasmic Reticulum Stress

Background Human head and neck squamous cell carcinoma (HNSCC) is the sixth most malignant cancer worldwide. Despite significant advances in the delivery of treatment and surgical reconstruction, there is no significant improvement of mortality rates for this disease in the past decades. Radiotherapy is the core component of the clinical combinational therapies for HNSCC. However, the tumor cells have a tendency to develop radiation resistance, which is a major barrier to effective treatment. HIV protease inhibitors (HIV PIs) have been reported with radiosensitizing activities in HNSCC cells, but the underlying cellular/molecular mechanisms remain unclear. Our previous study has shown that HIV PIs induce cell apoptosis via activation of endoplasmic reticulum (ER) stress. The aim of this study was to examine the role of ER stress in HIV PI-induced radiosensitivity in human HNSCC. Methodology and Principal Findings HNSCC cell lines, SQ20B and FaDu, and the most commonly used HIV PIs, lopinavir and ritonavir (L/R), were used in this study. Clonogenic assay was used to assess the radiosensitivity. Cell viability, apoptosis and cell cycle were analyzed using Cellometer Vision CBA. The mRNA and protein levels of ER stress-related genes (eIF2α, CHOP, ATF-4, and XBP-1), as well as cell cycle related protein, cyclin D1, were detected by real time RT-PCR and Western blot analysis, respectively. The results demonstrated that L/R dose-dependently sensitized HNSCC cells to irradiation and inhibited cell growth. L/R-induced activation of ER stress was correlated to down-regulation of cyclin D1 expression and cell cycle arrest under G0/G1 phase. Conclusion and Significance HIV PIs sensitize HNSCC cells to radiotherapy by activation of ER stress and induction of cell cycle arrest. Our results provided evidence that HIV PIs can be potentially used in combination with radiation in the treatment of HNSCC

The Evaluation of Various Restoration Techniques on Internal Adaptation of Composites in Class V Cavities

Aim. The aim of this study was to evaluate the effect of different restoration techniques on the formation of internal microgaps between materials and dentin in class V restorations. Materials and Methods. Twenty-five extracted human premolars were prepared with standardized class V cavity outlines (3 mm × 2 mm × 2 mm). The cavities were randomly divided into 5 groups of 10 cavities each and restored according to manufacturer’s instructions: Group 1: preheating (55°C) conventional composite (Filtek Z250), Group 2: flowable composite (Filtek Flow), Group 3: Filtek Flow + Filtek Z250 light-cured separately, Group 4: Filtek Flow + Filtek Z250 light-cured simultaneously, and Group 5 (control): Filtek Z250 at room temperature (23°C). The specimens were then thermocycled and cross-sectioned through the center of the restoration. Subsequently, impressions were taken, and epoxy resin replicas were made. The internal adaptation of the materials to the axial wall was analyzed under SEM. Results. The preheated Filtek Z250 (Group 1) showed better internal adaptation than the room temperature groups (P<0.05). The combination of Filtek Flow with Filtek Z250 which was light-cured separately (Group 3) exhibited better internal adaptation than control group (P<0.05). Conclusion. Different restoration techniques exhibit different behavior regarding internal adaptation to dentin after photopolymerization

Efficacy and safety of first-line everolimus therapy alone or in combination with octreotide in gastroenteropancreatic neuroendocrine tumors. A hellenic cooperative oncology group (HeCOG) study

The purpose of this study was to explore the efficacy and safety of everolimus administered as a first-line treatment in newly diagnosed patients with metastatic or inoperable gastroenteropancreatic neuroendocrine tumors (GEP NETs). This phase II, multicenter, single-arm study included patients with well-differentiated GEP NETs and a Ki67 &lt; 20%. Everolimus, at 10 mg/day, was administered until disease progression; 18 patients (72%) concomitantly received octreotide long-acting release (LAR), at 30 mg/month. The primary endpoint was the 15-month progression-free survival (PFS) rate. Twenty-five patients (grade 1: 11 patients, grade 2: 14 patients) were enrolled between August 2012 and October 2015. At a median follow-up of 58.1 months, the median PFS was 14.6 months, while the 15-month PFS rate was 48%; median overall survival had not been reached yet. Normal baseline chromogranin A (&lt;4 nmol/l) confirmed a longer PFS (HR = 0.25, 95% CI 0.08–0.77, p = 0.016). Seven patients (28%) achieved an objective response (one complete response and six partial responses) in a median of 2.6 months. Twenty-three grade 3–4 events were recorded (14 patients). No fatal reactions occurred. This prospective phase II study unravels the notable activity of everolimus as a first-line treatment in patients with GEP NETS and contributes valuable information about the high activity of the combination of everolimus and octreotide LAR in this setting. Clinical trial information: NCT01648465. © 2020 by the authors. Licensee MDPI, Basel, Switzerland