SYNTHESIS OF NOVEL CYCLOHEXANONE DERIVATIVES AS BCR-ABL T1351 INHIBITORS

Objective: Several 3(rd) generation inhibitors are being developed for the treatment of patients with Chronic myelogenous leukemia (CML). The present work mainly aims to discover novel small molecular inhibitors against important molecular target T3151 ABL mutant involved in leukemia.Methods: Docking study was carried out and the binding affinity of the proteins with the phenothiazine compounds 3a-h and 7a-c was measured. The docking scores of the N-acylated compounds 7a-c are higher than 3a-h. The drug likeliness of these compounds was tested by the Lipinski's rule of five. The phenothiazine compounds with good docking scores and 7a-c were synthesized and screened by in-vitro methods for inducing antiproliferative effect by trypan blue and MTT assay and induction of apoptosis in K562 cells.Results: All the N-acylated compounds and, in particular, 7c with a chloro substituent in the para position of the phenyl ring appeared to be most potent molecule with an IC50 value of 32.44 and 24.01(µg/ml) by trypan blue and MTT assay respectively. Further, a dose-dependent increase in LDH release was observed, confirming the antiproliferative potential of the compounds.Conclusion: The compounds 7a-c was tested for antiproliferative effect against K562 cell lines by MTT assay LDH assay and Trypan blue assay. All the compounds 7a-h behaves as 3(rd) generation inhibitors for the treatment of patients with Chronic myelogenous leukemia (CML). These can act as a template for the further development and optimization studies.Â

Novel compound heterozygous <i>ASXL3</i> mutation causing Bainbridge-ropers like syndrome and primary IGF1 deficiency.

BackgroundDe novo truncating and splicing mutations in the additional sex combs-like 3 (ASXL3) gene have been implicated in the development of Bainbridge-Ropers syndrome (BRPS) characterised by severe developmental delay, feeding problems, short stature and characteristic facial features.Case presentationWe describe, for the first time, a patient with severe short stature, learning difficulties, feeding difficulties and dysmorphic features with a novel compound heterozygous mutation in ASXL3.Additionally the patient also has primary insulin like growth factor-1 (IGF1) deficiency. The mutations occur in exon 11 and proximal part of exon 12 and are strongly conserved at the protein level across various species. In-silico analyses using PolyPhen-2 and SIFT predict the amino acid substitutions to be potentially deleterious to the protein function. Detailed bioinformatics analysis show that the molecular defects caused by the two compound heterozygous mutations synergistically impact on two points of the molecular interaction network of ASXL3.ConclusionWe hypothesise that ASXL3 potentially has a role in transcriptional activation of IGF1 involved in signalling pathways that regulate cell proliferation and growth, which could be contributing to short stature encountered in these patients

Pancreatic endocrine and exocrine function in children following near-total pancreatectomy for diffuse congenital hyperinsulinism.

Published onlineJournal ArticleCONTEXT: Congenital hyperinsulinism (CHI), the commonest cause of persistent hypoglycaemia, has two main histological subtypes: diffuse and focal. Diffuse CHI, if medically unresponsive, is managed with near-total pancreatectomy. Post-pancreatectomy, in addition to persistent hypoglycaemia, there is a very high risk of diabetes mellitus and pancreatic exocrine insufficiency. SETTING: International referral centre for the management of CHI. PATIENTS: Medically unresponsive diffuse CHI patients managed with near-total pancreatectomy between 1994 and 2012. INTERVENTION: Near-total pancreatectomy. MAIN OUTCOME MEASURES: Persistent hypoglycaemia post near-total pancreatectomy, insulin-dependent diabetes mellitus, clinical and biochemical (faecal elastase 1) pancreatic exocrine insufficiency. RESULTS: Of more than 300 patients with CHI managed during this time period, 45 children had medically unresponsive diffuse disease and were managed with near-total pancreatectomy. After near-total pancreatectomy, 60% of children had persistent hypoglycaemia requiring medical interventions. The incidence of insulin dependent diabetes mellitus was 96% at 11 years after surgery. Thirty-two patients (72%) had biochemical evidence of severe pancreatic exocrine insufficiency (Faecal elastase 1<100 µg/g). Clinical exocrine insufficiency was observed in 22 (49%) patients. No statistically significant difference in weight and height standard deviation score (SDS) was found between untreated subclinical pancreatic exocrine insufficiency patients and treated clinical pancreatic exocrine insufficiency patients. CONCLUSIONS: The outcome of diffuse CHI patients after near-total pancreatectomy is very unsatisfactory. The incidence of persistent hypoglycaemia and insulin-dependent diabetes mellitus is very high. The presence of clinical rather than biochemical pancreatic exocrine insufficiency should inform decisions about pancreatic enzyme supplementation

Sensitivity to point-like sources of the ALTO atmospheric particle detector array, designed for 200 GeV\rm 200\,GeV--50 TeV\rm 50\,TeV γ\gamma-ray astronomy

In the context of atmospheric shower arrays designed for $\gamma$-ray astronomy and in the context of the ALTO project, we present: a study of the impact of heavier nuclei in the cosmic-ray background on the estimated $\gamma$-ray detection performance on the basis of dedicated Monte Carlo simulations, a method to calculate the sensitivity to a point-like source, and finally the required observation times to reach a firm detection on a list of known point-like sources.Comment: 16 pages, 7 figures, accepted for publication in JHEAP (Journal of High-Energy Astrophysics

Analysis and design of a novel hybrid topology for power quality improvement using multilevel inverter fed induction motor by reducing vibration for textile wastewater treatment applications

The proposed research involves the design and implementation of a novel hybrid topology for power quality improvement using multilevel inverter fed induction motor by reducing vibration for Textile applications. Various modern applications have started to require higher power gadgets as of late. Staggered inverter is equipped for giving wanted substituting voltage level at output utilizing different low-level DC voltage as an input. In H-connect staggered inverter, the quantity of output level is characterized by the quantity of exchanged capacitor cells. A small amount of voltage can be utilized to produce a supported output voltage by exchanging the capacitor in parallel and in series. Staggered inverter produces less Total Harmonic Distortion (THD), less electromagnetic interference and less voltage inrush on switches. The proposed topology delivers a staircase waveform with higher number of output level utilizing less segments contrasted with a few existing exchanged capacitor multilevel inverter. The task manages cascaded H-connect staggered inverter that can be utilized for both single and three stage change. The structure is created with H-bridge inverter including DC-DC converter. A sine pulse width twist is decided on PWM pulses. The inverter essentially takes care of the issue of capacitor voltage adjusting as every capacitor is charged to the esteem equivalent to one of the information voltages at each cycle. Recreation is finished with the assistance of MATLAB Simulink programming and the exploratory outcomes for current and voltage at various THD esteems are appeared and the equivalent is done for equipment. The prototype structure is conceded and analysed for various parameters of proposed method, which results in reduced switches and proves more efficient than other conventional methods and in addition it is more proficient for pumping process in textile industry for wastewater treatment

Berbris aristata DC: Pharmacognostical Standardization and Phytochemical Studies of its Leaves

Berberis aristata DC. (Fam: Berberidaceae) commonly known as Daruharidra, Indian Barberry or tree turmeric. Leaves of this plant are traditionally used in the treatment of inflammation, wound healing, skin disease, menorrhagia, diarrhea, jaundice and infection of eyes etc. Micromorphology and physicochemical analysis of the leaves of B.aristata were performed as per WHO and Pharmacopoeial methods. Leaves (4.9cm × 1.8cm) are deep green on dorsal and light green on ventral side. Leaves are in tufts of 5 to 8, phyllotaxy verticillate, simple spiny, lanceolate, toothed, leathery, sessile, acuminate apex and reticulate pinnate venation. Microscopic evaluation of leaves showed biconvex midrib and thick lamina. The epidermal layers of the midrib are thick with small, less conspicuous cells and thick cuticle. The vascular system consists of three large vascular bundles; the median one is small than the two lateral bundles; the bundles are collateral and wedge shaped. &nbsp;Lamina is made of epidermal layer on the adaxial side with spindle shaped thick walled cells and papillate cuticle. The abaxial epidermis has squarish or rectangular epidermal cells with prominent spiny cuticular outgrowths. Powder microscopy showed the presence of cuticular papillae, anomocytic stomata and spiny outgrowth. Preliminary phytochemical screening of appropriate solvent extracts showed the presence of alkaloids, sterols, tannins, proteins and amino acids, flavonoids, terpenoids, saponin, carbohydrates and absence of glycosides and volatile and fixed oil. Microscopic analysis and other parameters were informative and provide valuable information in the identification, standardization of B.aristata leaves. Keywords: Berberis aristata, Berberidaceae, leaf, Microscopical evaluation

Pharmacognostical Standardization and Phytochemical Studies on the leaves of Solanum torvum Sw

A genus of plant belongs to the family Solanaceae well distributed in India more than 26 species which are found naturalised in India. Solanum torvum Sw. is a medium sized flowering plant in the Solanaceae family that is found in India, Malaysia. Transverse section of lamina showed the adaxial part has thick, short hump; the midrib and the adaxial hump have thin, angular epidermal cells. The upper part of adaxial hump has a few layers sclerenchyma cells. The inner layer of the adaxial midrib also has few layers of thick walled cells. The ground tissue consists of wide circular thin walled parenchyma cells with narrow inter cellular spaces. The vascular system of the midrib showed bi-collateral structure. Non glandular, profusely branched, thick walled, lignified epidermal trichome occurs as both on the veins and lamina. Physico-chemical standards such as Foreign Matter, Total Ash, Water Soluble Ash, Sulphated Ash, Loss on Drying, Water Soluble Extractive, Alcohol Soluble Extractive and Crude Fiber Content in percentage were estimated. Preliminary phytochemical screening of appropriate solvent extracts showed the presence of Alkaloids, Amino Acids, Carbohydrates, Cellulose, Lignin, Fats &amp; Fixed Oils, Flavonoids, Glycosides, Tannins, Proteins, Starch, Steroids and Triterpenoids and absence of Volatile Oil, Mucilage and Pectin. Microscopic analysis and other parameters were informative and provide valuable information in the identification, standardization of Solanum torvum leaves. Keywords: Solanum torvum, Solanaceae, leaf, Microscopical evaluation

Young people with Type 1 diabetes of non-white ethnicity and lower socio-economic status have poorer glycaemic control in England and Wales

Background The impact of ethnicity and socio-economic status (SES) on glycaemic control during childhood Type 1 diabetes is poorly understood in England and Wales. Methods We studied 18 478 children with Type 1 diabetes

Variation in Glycemic Outcomes in Focal Forms of Congenital Hyperinsulinism - The UK Perspective

Context: In focal congenital hyperinsulinism (CHI), localized clonal expansion of pancreatic β-cells causes excess insulin secretion and severe hypoglycemia. Surgery is curative, but not all lesions are amenable to surgery. Objective: We describe surgical and nonsurgical outcomes of focal CHI in a national cohort. Methods: Patients with focal CHI were retrospectively reviewed at 2 specialist centers, 2003-2018. Results: Of 59 patients with focal CHI, 57 had heterozygous mutations in ABCC8/KCNJ11 (51 paternally inherited, 6 de novo). Fluorine-18 L-3,4 dihydroxyphenylalanine positron emission tomography computed tomography scan identified focal lesions in 51 patients. In 5 patients, imaging was inconclusive; the diagnosis was established by frozen section histopathology in 3 patients, a lesion was not identified in 1 patient, and 1 declined surgery. Most patients (n = 56) were unresponsive to diazoxide, of whom 33 were unresponsive or partially responsive to somatostatin receptor analog (SSRA) therapy. Fifty-five patients underwent surgery: 40 had immediate resolution of CHI, 10 had persistent hypoglycemia and a focus was not identified on biopsy in 5. In the 10 patients with persistent hypoglycemia, 7 underwent further surgery with resolution in 4 and ongoing hypoglycemia requiring SSRA in 3. Nine (15% of cohort) patients (1 complex surgical access; 4 biopsy negative; 4 declined surgery) were managed conservatively; medication was discontinued in 8 children at a median (range) age 2.4 (1.5-7.7) years and 1 remains on SSRA at 16 years with improved fasting tolerance and reduction in SSRA dose. Conclusion: Despite a unifying genetic basis of disease, we report inherent heterogeneity in focal CHI patients impacting outcomes of both surgical and medical management