Screening and evaluation of ethanolic extract from Casuarina equisetifolia inflorescence on isolated chick rectum, frog rectum and frog rectus abdominus muscle for identification of muscarinic and nicotinic receptor’s action

The present experiments were undertaken to justify the use of an ethanolic extract from inflorescence of Casuarina equisetifolia, Family: Casuarinaceae, influencing the nicotine responses on isolated chick rectum and frog rectum (Smooth Muscles) and frog rectus abdominus muscle (Skeletal Muscle). The isolated tissues were mounted in organ bath filled with physiological solution and was suitably aerated. After equilibration, responses were taken to different doses of nicotine (log doses) till a ceiling response was obtained. A sub-maximal dose of nicotine was selected and responses to this dose was taken and ensured that there is reproducibility of response. The drum was allowed to move for 1min., different concentrations of extracts into the organ baths were added and allowed to act for 1min without flushing the baths, then the sub-maximal dose of nicotine was added and allowed to act for 1min. this procedure was repeated (without extract) till the original response was obtained. The inference drawn from these experiments, the ethanolic extract of inflorescence of Casuarina equisetifolia antagonised the action of nicotine on isolated chick rectum, relaxed the effect of nicotine on frog rectum and it potentiated the effect of nicotine on frog rectus abdominus muscle. The nicotine receptors of rectus abdominus is activated, perhaps by the prevention of hydrolysis of acetylcholine by the extract. Based on the results obtained from the isolated chick rectum the ethanolic extract is having antinicotinic activity and it may act on the nicotinic acetylcholine receptors (nAChRs) as well as muscarinic acetylcholine receptors (mAChRs) on other isolated tissues. The extract might contain ganglionic blocking activity or non-specific activity or membrane stabilising activity also. Keywords: Nicotine, Ethanolic extract, Inflorescence of Casuarina equisetifolia, Isolated Chick Rectum, Isolated Frog Rectum and Isolated Frog Rectus Abdominus Muscle

Single dose oral toxicity study of ethanolic extract from inflorescence of Casuarina equisetifolia in Wistar rats

The purpose of the study was to evaluate the single dose oral toxicity of the ethanolic extract from inflorescence of Casuarina equisetifolia, Family: Casuarinaceae in female Wistar Rats. The acute toxicity study was carried out based on Organization for Economic Co-operation and Development (OECD) Test Guideline 423. However, this plant safety evaluation data was not available so, selected the starting dose from 300 mg/kg body weight. The animals were orally administered a single dose of 300 mg/kg body weight and followed by 2000 mg/kg body weight in next step. Signs of toxicity and mortality were observed after 30 min, 1, 2, 4 and 24h of administration of the extract and once daily for 14 days. There was no mortality in the tested animals and no abnormal clinical signs were observed related to test item. No abnormalities were detected in gross pathology observations in all the rats at both the dose levels. Based on observations of the present study, it can be concluded that the LD50 of ethanolic extract from inflorescence of Casuarina equisetifolia is greater than 2000mg/kg body weight and can be classified as Category 5; however, further studies are needed to confirm long term toxicities. Keywords: Acute oral toxicity, ethanolic extract from inflorescence of Casuarina equisetifolia, LD50, OECD Test Guideline, Wistar Rat

Numerical investigation of MHD free convection flow of a non-Newtonian fluid past an impulsively started vertical plate in the presence of thermal diffusion and radiation absorption

AbstractA numerical investigation is carried out on an unsteady MHD free convection flow of a well-known non-Newtonian visco elastic second order Rivlin-Erickson fluid past an impulsively started semi-infinite vertical plate in the presence of homogeneous chemical reaction, thermal radiation, thermal diffusion, radiation absorption and heat absorption with constant mass flux. The presence of viscous dissipation is also considered at the plate under the influence of uniform transverse magnetic field. The flow is governed by a coupled nonlinear system of partial differential equations which are solved numerically by using finite difference method. The effects of various physical parameters on the flow quantities viz. velocity, temperature, concentration, Skin friction, Nusselt number and Sherwood number are studied numerically. The results are discussed with the help of graphs. We observed that the velocity decreases with an increase in magnetic field parameter, Schmidt number, and Prandtl number while it increases with an increase in Grashof number, modified Grashof number, visco-elastic parameter and Soret number. Temperature increases with an increase in radiation absorption parameter, Eckert number and visco-elastic parameter while it decreases with increasing values of radiation parameter, Prandtl number and heat absorption parameter. Concentration increases with increase in Soret number while it decreases with an increase in Schmidt number and chemical reaction parameter

Molecular and Clinical Activity of CDX-3379, an Anti-ErbB3 Monoclonal Antibody, in Head and Neck Squamous Cell Carcinoma Patients.

PurposeErbB3 and its ligand neuregulin-1 (NRG1) are widely expressed in head and neck squamous cell carcinoma (HNSCC) and associated with tumor progression. A "window-of-opportunity" study (NCT02473731) was conducted to evaluate the pharmacodynamic effects of CDX-3379, an anti-ErbB3 mAb, in patients with HNSCC.Patients and methodsTwelve patients with newly diagnosed, operable HNSCC received two infusions of CDX-3379 (1,000 mg) at a 2-week interval prior to tumor resection. The primary study objective was to achieve ≥50% reduction in tumor ErbB3 signaling (phosphorylation of ErbB3; pErbB3) in ≥30% of patients. Other potential tumor biomarkers, pharmacokinetics, safety, and tumor measurements were also assessed.ResultspErbB3 was detectable in all tumors prior to treatment and decreased for 10 of 12 (83%) patients following CDX-3379 dosing, with ≥50% reduction in 7 of 12 (58%; P = 0.04; 95% confidence interval, 27.7%-84.8%). Target trough CDX-3379 serum levels were achieved in all patients. CDX-3379 treatment-related toxicity was grade 1-2 and included diarrhea, fatigue, and acneiform dermatitis. Five of 12 (42%) patients had shrinkage in tumor burden, including a marked clinical response in a patient with human papillomavirus-negative oral cavity HNSCC. All patients with tumor shrinkage had tumors that expressed both NRG1 and ErbB3 and demonstrated reduced pErbB3 with CDX-3379 treatment.ConclusionsThis study demonstrates that CDX-3379 can inhibit tumor ErbB3 phosphorylation in HNSCC. CDX-3379 was well tolerated and associated with measurable tumor regression. A phase II study (NCT03254927) has been initiated to evaluate CDX-3379 in combination with cetuximab for patients with advanced HNSCC

Proteomic Characterization of Head and Neck Cancer Patient-Derived Xenografts.

UnlabelledDespite advances in treatment approaches for head and neck squamous cell carcinoma (HNSCC), survival rates have remained stagnant due to the paucity of preclinical models that accurately reflect the human tumor. Patient-derived xenografts (PDX) are an emerging model system where patient tumors are implanted directly into mice. Increased understanding of the application and limitations of PDXs will facilitate their rational use. Studies to date have not reported protein profiles of PDXs. Therefore, we developed a large cohort of HNSCC PDXs and found that tumor take rate was not influenced by the clinical, pathologic, or processing features. Protein expression profiles, from a subset of the PDXs, were characterized by reverse-phase protein array and the data was compared with The Cancer Genome Atlas HNSCC data. Cluster analysis revealed that HNSCC PDXs were more similar to primary HNSCC than to any other tumor type. Interestingly, while a significant fraction of proteins were expressed similarly in both primary HNSCC and PDXs, a subset of proteins/phosphoproteins were expressed at higher (or lower) levels in PDXs compared with primary HNSCC. These findings indicate that the proteome is generally conserved in PDXs, but mechanisms for both positive and negative model selection and/or differences in the stromal components exist.ImplicationsProteomic characterization of HNSCC PDXs demonstrates potential drivers for model selection and provides a framework for improved utilization of this expanding model system

Human Papillomavirus Regulates HER3 Expression in Head and Neck Cancer: Implications for Targeted HER3 Therapy in HPV+ Patients.

Purpose: Human papillomavirus (HPV) 16 plays an etiologic role in a growing subset of head and neck squamous cell carcinomas (HNSCC), where viral expression of the E6 and E7 oncoproteins is necessary for tumor growth and maintenance. Although patients with HPV+ tumors have a more favorable prognosis, there are currently no HPV-selective therapies. Recent studies identified differential receptor tyrosine kinase (RTK) profiles in HPV+ versus HPV- tumors. One such RTK, HER3, is overexpressed and interacts with phosphoinositide-3-kinase (PI3K) in HPV+ tumors. Therefore, we investigated the role of HPV oncoproteins in regulating HER3-mediated signaling and determined whether HER3 could be a molecular target in HPV+ HNSCC.Experimental Design: HER3 was investigated as a molecular target in HPV+ HNSCC using established cell lines, patient-derived xenografts (PDX), and human tumor specimens. A mechanistic link between HPV and HER3 was examined by augmenting E6 and E7 expression levels in HNSCC cell lines. The dependency of HPV+ and HPV- HNSCC models on HER3 was evaluated with anti-HER3 siRNAs and the clinical stage anti-HER3 monoclonal antibody KTN3379.Results: HER3 was overexpressed in HPV+ HNSCC, where it was associated with worse overall survival in patients with pharyngeal cancer. Further investigation indicated that E6 and E7 regulated HER3 protein expression and downstream PI3K pathway signaling. Targeting HER3 with siRNAs or KTN3379 significantly inhibited the growth of HPV+ cell lines and PDXs.Conclusions: This study uncovers a direct relationship between HPV infection and HER3 in HNSCC and provides a rationale for the clinical evaluation of targeted HER3 therapy for the treatment of HPV+ patients. Clin Cancer Res; 23(12); 3072-83. ©2016 AACR

Phase II trial of CDX-3379 and cetuximab in recurrent/metastatic, HPV-negative, cetuximab-resistant head and neck cancer

In phase I development, CDX-3379, an anti-ErbB3 monoclonal antibody, showed promising molecular and antitumor activity in head and neck squamous cell carcinoma (HNSCC), alone or in combination with cetuximab. Preliminary biomarker data raised the hypothesis of enhanced response in tumors harborin