Toxicity Testing of Restorative Dental Materials Using Brine Shrimp Larvae (Artemia salina)

This study investigated the effect of extracts of different composites, glass ionomer cement (GIC)s and compomers on the viability of brine shrimp larvae. Ethanolic extracts of four dental composites (Z-100; Solitaire 2; Filtek P60 and Synergy), a conventional GIC (Ketac-Fil), a resin-modified glass ionomer cement (Vitremer), two compomers (F2000; Dyract AP), and a flowable compomer (Dyract Flow) were prepared from each material. Following evaporation of the ethanol, the extracts were resuspended in distilled water, which was then used to test the effects on the viability of brine shrimp larvae. For the composites, the extract of Synergy was the least toxic (88% viability) followed by the extracts of Solitaire 2, Z100 and P60 (75%, 67.5% and 50% viability, respectively). One-way ANOVA revealed highly significant differences between the resin composite materials (

Neural network-based diagnostic tool for detecting stator inter-turn faults in line start permanent magnet synchronous motors

Three-phase line-start permanent magnet synchronous motors are considered among the most promising types of motors in industrial applications. However, these motors experience several faults, which may cause significant financial losses. This paper proposed a feed-forward neural network-based diagnostic tool for accurate and fast detection of the location and severity of stator inter-turn faults. The input to the neural network is a group of representative statistical and frequency-based features extracted from the steady-state three-phase stator current signals. The current signals with different numbers of shorted turns and loading conditions are captured using the developed finite element JMAG ™ model for interior mount LSPMSM. In addition, an experimental set-up was built to validate the finite element model and the proposed diagnostics tool. The simulation and experimental test results showed an overall accuracy of 93.125% in detecting the location and the size of inter-turn, whereas, the accuracy in detecting the location of the fault is 100%

Denosumab Use in a Patient with Bisphosphonate-Resistant Humoral Hypercalcemia of Malignancy

ABSTRACT Objective: To describe the use of denosumab as an option for treating bisphosphonate-resistant humoral hypercalcemia of malignancy. Methods: We present the clinical history and laboratory findings of a patient with a review of related literature. Results: A 62 year-old male with stage IV laryngeal squamous cell carcinoma and lung metastases had multiple hospital admissions for asymptomatic hypercalcemia. The patient had no known bone metastases. His laboratory data showed a high calcium level, a low level of intact PTH and a high level of PTHrP, which confirmed the diagnosis of humoral hypercalcemia of malignancy. There was atypically an elevated level of 1,25(OH)2D. The patient was treated with fluids, prednisone, calcitonin, and bisphosphonates. Hypercalcemia was refractory to bisphosphonate treatment as well as other modalities. Denosumab treatment was then added. Denosumab along with bisphosphonate produced an added effect on lowering calcium levels. Conclusion: Denosumab provides potentially a new treatment option for bisphosphonate refractory humoral hypercalcemia of malignancy, especially in the presence of high PTHrP and 1,25(OH)2D. Abbreviations: PTH: Parathyroid Hormone, PTHrP: Parathyroid Hormone Related Peptide, HHM: Humoral Hypercalcemia of Malignancy. 1,25(OH)2D: 1,25-dihydroxyvitamin D. TSH: Thyroid stimulating hormone. RANKL: Receptor activator of nuclear factor kappa-B ligand. Key words: hypercalcemia, squamous cell carcinoma, malignancy, denosumab, bisphosphonate,1,25-dihydroxyvitamin D. This material presented in part at the American Association of Clinical Endocrinologists, 23rd Annual Scientific and Clinical Congress, No. 633, 2014

Denosumab Use in a Patient with Bisphosphonate-Resistant Humoral Hypercalcemia of Malignancy

Objective: To describe the use of denosumab as an option for treating bisphosphonate-resistant humoral hypercalcemia of malignancy. Methods: We present the clinical history and laboratory findings of a patient with a review of related literature. Results: A 62 year-old male with stage IV laryngeal squamous cell carcinoma and lung metastases had multiple hospital admissions for asymptomatic hypercalcemia. The patient had no known bone metastases. His laboratory data showed a high calcium level, a low level of intact PTH and a high level of PTHrP, which confirmed the diagnosis of humoral hypercalcemia of malignancy. There was atypically an elevated level of 1,25(OH)2D. The patient was treated with fluids, prednisone, calcitonin, and bisphosphonates. Hypercalcemia was refractory to bisphosphonate treatment as well as other modalities. Denosumab treatment was then added. Denosumab along with bisphosphonate produced an added effect on lowering calcium levels. Conclusion: Denosumab provides potentially a new treatment option for bisphosphonate refractory humoral hypercalcemia of malignancy, especially in the presence of high PTHrP and 1,25(OH)2D. Abbreviations: PTH: Parathyroid Hormone, PTHrP: Parathyroid Hormone Related Peptide, HHM: Humoral Hypercalcemia of Malignancy. 1,25(OH)2D: 1,25-dihydroxyvitamin D. TSH: Thyroid stimulating hormone. RANKL: Receptor activator of nuclear factor kappa-B ligand. Key words: hypercalcemia, squamous cell carcinoma, malignancy, denosumab, bisphosphonate,1,25-dihydroxyvitamin D. This material presented in part at the American Association of Clinical Endocrinologists, 23rd Annual Scientific and Clinical Congress, No. 633, 2014

Endoplasmic Reticulum Quality Control Is Involved in the Mechanism of Endoglin-Mediated Hereditary Haemorrhagic Telangiectasia

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant genetic condition affecting the vascular system and is characterised by epistaxis, arteriovenous malformations and mucocutaneous and gastrointestinal telangiectases. This disorder affects approximately 1 in 8,000 people worldwide. Significant morbidity is associated with this condition in affected individuals, and anaemia can be a consequence of repeated haemorrhages from telangiectasia in the gut and nose. In the majority of the cases reported, the condition is caused by mutations in either ACVRL1 or endoglin genes, which encode components of the TGF-beta signalling pathway. Numerous missense mutations in endoglin have been reported as causative defects for HHT but the exact underlying cellular mechanisms caused by these mutations have not been fully established despite data supporting a role for the endoplasmic reticulum (ER) quality control machinery. For this reason, we examined the subcellular trafficking of twenty-five endoglin disease-causing missense mutations. The mutant proteins were expressed in HeLa and HEK293 cell lines, and their subcellular localizations were established by confocal fluorescence microscopy alongside the analysis of their N-glycosylation profiles. ER quality control was found to be responsible in eight (L32R, V49F, C53R, V125D, A160D, P165L, I271N and A308D) out of eleven mutants located on the orphan extracellular domain in addition to two (C363Y and C382W) out of thirteen mutants in the Zona Pellucida (ZP) domain. In addition, a single intracellular domain missense mutant was examined and found to traffic predominantly to the plasma membrane. These findings support the notion of the involvement of the ER's quality control in the mechanism of a significant number, but not all, missense endoglin mutants found in HHT type 1 patients. Other mechanisms including loss of interactions with signalling partners as well as adverse effects on functional residues are likely to be the cause of the mutant proteins' loss of function

Identification of the Cellular Mechanisms That Modulate Trafficking of Frizzled Family Receptor 4 (FZD4) Missense Mutants Associated With Familial Exudative Vitreoretinopathy

Citation: Milhem RM, Ben-Salem S, AlGazali L, Ali BR. Identification of the cellular mechanisms that modulate trafficking of frizzled family receptor 4 (FZD4) missense mutants associated with familial exudative vitreoretinopathy. Invest Ophthalmol Vis Sci. 2014;55:3423-3431. DOI:10.1167/ iovs.14-13885 PURPOSE. Fifteen missense mutations in the frizzled family receptor 4 (FZD4) reported to cause familial exudative vitreoretinopathy (FEVR) were evaluated to establish the pathological cellular mechanism of disease and to explore novel therapeutic strategies. METHODS. The mutations were generated by site-directed mutagenesis and expressed in HeLa and COS-7 cell lines. Confocal fluorescence microscopy and N-glycosylation profiling were used to observe the subcellular localization of the mutant proteins relative to wild-type (WT). Polyubiquitination studies were used to establish the involvement of the proteasome. Culturing at reduced temperatures and incubation in the presence of chemical compounds were used to enhance mutant protein processing and exit out of the endoplasmic reticulum (ER). RESULTS. Confocal fluorescence microscopy of the mutants showed three distinct subcellular localizations, namely, a plasma membrane pattern, an ER pattern, and a mixed pattern to both compartments. Confocal fluorescence microscopy and N-glycosylation profiling established the predominant ER localization of P33S, G36N, H69Y, M105T, M105V, C181R, C204R, C204Y, and G488D mutants. Coexpression of these mutants with WT FZD4 showed the inability of the mutants to trap WT FZD4. Culturing the expressing cells at reduced temperatures or in the presence of chemical agents directed at ameliorating protein misfolding resulted in partial rescue of trafficking defects observed for M105T and C204Y mutants. CONCLUSIONS. Defective trafficking resulting in haploinsufficiency is a major cellular mechanism for several missense FEVR-causing FZD4 mutants. Our findings indicate that this trafficking defect might be correctable for some mutants, which may offer opportunities for the development of novel therapeutics approaches for this condition

Functional and symptom impact of trametinib versus chemotherapy in BRAF V600E advanced or metastatic melanoma: quality-of-life analyses of the METRIC study

We report the first quality-of-life assessment of a MEK inhibitor in metastatic melanoma from a phase III study. Trametinib prolonged progression-free survival and improved overall survival versus chemotherapy in patients with BRAF V600 mutation-positive melanoma. Less functional impairment, smaller declines in health status, and less exacerbation of symptoms were observed with trametini

Cutaneous head and neck melanoma in OPTiM, a randomized phase 3 trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor for the treatment of unresected stage IIIB/IIIC/IV melanoma.

Background Cutaneous head and neck melanoma has poor outcomes and limited treatment options. In OPTiM, a phase 3 study in patients with unresectable stage IIIB/IIIC/IV melanoma, intralesional administration of the oncolytic virus talimogene laherparepvec improved durable response rate (DRR; continuous response ≥6 months) compared with subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF).Methods Retrospective review of OPTiM identified patients with cutaneous head and neck melanoma given talimogene laherparepvec (n = 61) or GM-CSF (n = 26). Outcomes were compared between talimogene laherparepvec and GM-CSF treated patients with cutaneous head and neck melanoma.Results DRR was higher for talimogene laherparepvec-treated patients than for GM-CSF treated patients (36.1% vs 3.8%; p = .001). A total of 29.5% of patients had a complete response with talimogene laherparepvec versus 0% with GM-CSF. Among talimogene laherparepvec-treated patients with a response, the probability of still being in response after 12 months was 73%. Median overall survival (OS) was 25.2 months for GM-CSF and had not been reached with talimogene laherparepvec.Conclusion Treatment with talimogene laherparepvec was associated with improved response and survival compared with GM-CSF in patients with cutaneous head and neck melanoma. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1752-1758, 2016