Standardization of Fat:SNF ratio of milk and addition of sprouted wheat fada (semolina) for the manufacture of halvasan.

Traditional Indian Dairy Products such as Halvasan are manufactured in India using an age old practice. For manufacture of such products industrially, a standard formulation is required. Halvasan is a region specific, very popular heat desiccated milk product but has not been studied scientifically. Fat and Solids-not-fat (SNF) plays an important role in physico-chemical, sensory, textural characteristics and also the shelf life of any milk sweet. Hence for process standardization of Halvasan manufacture, different levels of Fat:SNF ratios i.e. 0.44, 0.55, 0.66 and 0.77 of milk were studied so that an optimum level yielding best organoleptic characteristics in final product can be selected. The product was made from milk standardized to these ratios of Fat:SNF and the product was manufactured as per the method tentatively employed on the basis of characterization of market samples of the product in laboratory. Based on the sensory results obtained, a Fat:SNF ratio of 0.66 for the milk has been selected. In the similar way, for standardizing the rate of addition of fada (semolina); 30, 40, 50 and 60 g fada (semolina) per kg of milk were added and based on the sensory observations, the level of fada (semolina) addition @50 gm/kg of milk was adjudged the best for Halvasan manufacture and hence selected.

Design and Discovery of N-(3-(2-(2-Hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor Targeting RAS Mutant Cancers: The Path to the Clinic.

Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due to the complex nature of RAF signaling, downstream of activated RAS, and the poor overall kinase selectivity of putative RAF inhibitors. Herein, we describe 15 (LXH254, Aversa, R.; et al. Int. Patent WO2014151616A1, 2014), a selective B/C RAF inhibitor, which was developed by focusing on drug-like properties and selectivity. Our previous tool compound, 3 (RAF709; Nishiguchi, G. A.; et al. J. Med. Chem. 2017, 60, 4969), was potent, selective, efficacious, and well tolerated in preclinical models, but the high human intrinsic clearance precluded further development and prompted further investigation of close analogues. A structure-based approach led to a pyridine series with an alcohol side chain that could interact with the DFG loop and significantly improved cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition led to the discovery of 15. Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials.

Post-radical prostatectomy rectourethral fistula: endosopic management.

Rectal injuries diagnosed during radical prostatectomy are readily treated with primary closure and omental interposition. However, once this fails and a fistula develops, the treatment gets more complex. Various surgeries have been described to manage these fistulae, but these are not done frequently and require a great deal of expertise. We report a patient with post-radical prostatectomy rectourethral fistula, treated with cyanoacrylate glue injected through a colonoscope as the fistulous tract was well visualized per rectum. The patient is voiding well per urethra with no rectal leakage 3 months post-catheter removal. Thus, use of cyanoacrylate glue as a minimally invasive non-surgical technique for management of rectourethral fistula appears to be a good option which can be tried before embarking on major surgery.

Leiomyosarcoma of the inferior vena cava: a case report and review of literature.

Tumors of the inferior vena cava are rare, and most of these are leiomyosarcomas. They are most frequent in the sixth decade of life, with a female predominance. We present a 45-year-old male patient with a tumor involving the entire extent of the inferior vena cava. Computerized tomography revealed a heterogeneously enhancing mass with marked expansion of the inferior vena cava with extraluminal extension. Computerized tomography--guided biopsy of the extraluminal component showed features of a fasciculated spindle cell tumor positive for vimentin, smooth muscle actin, and calponin and negative for S-100 antigen. We discuss the clinical presentation imaging findings and review the literature.

(R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors.

Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization. Structure guided drug design led to the identification of (R)-2-phenylpyrrolidine substituted imidazopyridazines as a series of potent, selective, orally bioavailable pan-TRK inhibitors achieving tumor regression in rats bearing KM12 xenografts. From this work the (R)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of its shape complementarity to the hydrophobic pocket of TRKs.