A novel chromosomal abnormality t (9;14)(p24;q13) in B-acute lymphoblastic leukemia

Acute lymphoblastic leukemia is a malignant disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow. We describe the clinical, morphologic, immunophenotypic and cytogenetic findings in the case of a 26-year-old man with B-lymphoblastic leukemia. Surface marker analysis revealed that they are positive for CD markers CD10, CD19, CD13, CD34, CD45 and HLA-DR, but negative for CD20, CD33, CD117 and CD11C markers. Cytogenetic analysis established a novel translocation, t (9;14)(p24;q13). Apart from this, spectral karyotyping revealed an additional translocation, t (6p; 14q). This is the first documented case of B-lymphoblastic leukemia with concurrent occurrence of both abnormalities. Further studies are needed to understand the role of this abnormality in carcinogenesis.     

Pharmacophore and Virtual Screening of JAK3 inhibitors

Janus kinase 3 (JAK3) is a non-receptor tyrosine kinases family of protein which is comprised of JAK1, JAK2, JAK3 and TYK2. It plays an important role in immune function and lymphoid development and it only resides in the hematopoietic system. Therefore, selective targeting JAK3 is a rational approach in developing new therapeutic molecule. In this study, about 116 JAK3 inhibitors were collected from the literature and were used to build four-point pharmacophore model using Phase (Schrodinger module). The statistically significant pharmacophore hypothesis of AAHR.92 with r2 value of 0.942 was used as 3D query to search against 3D database namely Zincpharmer. A total of 2, 27,483 compounds obtained as hit were subjected to high throughput virtual screening (HTVS module of Schrodinger). Among the hits, ten compounds with good G-score ranging from -12.96 to -11.18 with good binding energy to JAK3 were identified.     

Associations between brain microstructures,metabolites, and cognitive deficits during chronic HIV-1 infection of humanized mice

Background

Host-species specificity of the human immunodeficiency virus (HIV) limits pathobiologic, diagnostic and therapeutic research investigations to humans and non-human primates. The emergence of humanized mice as a model for viral infection of the nervous system has overcome such restrictions enabling research for HIV-associated end organ disease including behavioral, cognitive and neuropathologic deficits reflective of neuroAIDS. Chronic HIV-1 infection of NOD/scid-IL-2Rg_c ^null mice transplanted with human CD34⁺ hematopoietic stem cells (CD34-NSG) leads to persistent viremia, profound CD4⁺ T lymphocyte loss and infection of human monocyte-macrophages in the meninges and perivascular spaces. Murine cells are not infected with virus.

Methods

Changes in mouse behavior were measured, starting at 8 weeks after viral infection. These were recorded coordinate with magnetic resonance spectroscopy metabolites including N-acetylaspartate (NAA), creatine and choline. Diffusion tensor magnetic resonance imaging (DTI) was recorded against multispectral immunohistochemical staining for neuronal markers that included microtubule associated protein-2 (MAP2), neurofilament (NF) and synaptophysin (SYN); for astrocyte glial fibrillary acidic protein (GFAP); and for microglial ionized calcium binding adaptor molecule 1 (Iba-1). Oligodendrocyte numbers and integrity were measured for myelin associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (MOG) antigens.

Results

Behavioral abnormalities were readily observed in HIV-1 infected mice. Longitudinal open field activity tests demonstrated lack of habituation indicating potential for memory loss and persistent anxiety in HIV-1 infected mice compared to uninfected controls. End-point NAA and creatine in the cerebral cortex increased with decreased MAG. NAA and glutamate decreased with decreased SYN and MAG. Robust inflammation reflected GFAP and Iba-1 staining intensities. DTI metrics were coordinate with deregulation of NF, Iba-1, MOG and MAG levels in the whisker barrel and MAP2, NF, MAG, MOG and SYN in the corpus callosum.

Conclusions

The findings are consistent with some of the clinical, biochemical and pathobiologic features of human HIV-1 nervous system infections. This model will prove useful towards investigating the mechanisms of HIV-1 induced neuropathology and in developing novel biomarkers and therapeutic strategies for disease.

     

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

Neurodegenerative diseases are distinguished by characteristic protein aggregates initiated by disease‐specific ‘seed’ proteins; however, roles of other co‐aggregated proteins remain largely unexplored. Compact hippocampal aggregates were purified from Alzheimer's and control‐subject pools using magnetic‐bead immunoaffinity pulldowns. Their components were fractionated by electrophoretic mobility and analyzed by high‐resolution proteomics. Although total detergent‐insoluble aggregates from Alzheimer's and controls had similar protein content, within the fractions isolated by tau or Aβ_1–42 pulldown, the protein constituents of Alzheimer‐derived aggregates were more abundant, diverse, and post‐translationally modified than those from controls. Tau‐ and Aβ‐containing aggregates were distinguished by multiple components, and yet shared >90% of their protein constituents, implying similar accretion mechanisms. Alzheimer‐specific protein enrichment in tau‐containing aggregates was corroborated for individuals by three analyses. Five proteins inferred to co‐aggregate with tau were confirmed by precise in situ methods, including proximity ligation amplification that requires co‐localization within 40 nm. Nematode orthologs of 21 proteins, which showed Alzheimer‐specific enrichment in tau‐containing aggregates, were assessed for aggregation‐promoting roles in C. elegans by RNA‐interference ‘knockdown’. Fifteen knockdowns (71%) rescued paralysis of worms expressing muscle Aβ, and 12 (57%) rescued chemotaxis disrupted by neuronal Aβ expression. Proteins identified in compact human aggregates, bound by antibody to total tau, were thus shown to play causal roles in aggregation based on nematode models triggered by Aβ_1–42. These observations imply shared mechanisms driving both types of aggregation, and/or aggregate‐mediated cross‐talk between tau and Aβ. Knowledge of protein components that promote protein accrual in diverse aggregate types implicates common mechanisms and identifies novel targets for drug intervention.     

Effects of administration of Embelin and Curcumin on lipid peroxidation, hepatic glutathione antioxidant defense and hematopoietic system during N-nitrosodiethylamine/Phenobarbital-induced hepatocarcinogenesis in Wistar rats

The effects of administration of Embelin (EMB) and Curcumin (CUR) on lipid peroxidation, hepatic glutathione antioxidant defense and hematopoietic cells were examined during N-nitrosodiethylamine (DENA-200 mg kg⁻¹body wt, single I.P injection) initiated and Phenobarbital (PB-0.05% in drinking water orally for 13 weeks) promoted hepatocarcinogenesis in Wistar strain male albino rats. DENA/PB-induced hepatic damage was manifested by a significant drop in the hepatic glutathione antioxidant defense, increased lipid peroxidation and histological alterations like dysplasia, and atypical cells with abnormal chromatin pattern. Treatment with Curcumin (100 mg kg⁻¹body wt) and Embelin (50 mg kg⁻¹body wt) prevented the drop in hepatic glutathione antioxidant defense, decreased lipid peroxidation, minimized the histological alterations induced by DENA/PB, but showed toxic effects on the hematopoietic cells. Results indicate the beneficial effects of Embelin and Curcumin against oxidative tissue damage during chemically-induced hepatocarinogenesis in rats.     

A short note on oxytocin and stress attenuation

Stress is integral part of life and it initiates appropriate response at times of adversities to promise survival. Stress could be either physiological or psychogenic. Stress is often psychogenic in nature and it induces the release of cortisol from adrenal cortex into circulation by activating Hypo thalamo-pituitary-adrenal axis (HPA). Cortisol thus released mediates the stress response by its catabolic effects to enhance the activity of vital organs during emergency. However, prolonged activation of the HPA axis can lead to physical and mental illness as an outcome of persistent stress. Nature has bestowed the biological system with an array of endogenous mechanisms to buffer stress. Oxytocin, a nano-peptide released by the magno-cellular neurons of hypothalamic paraventricular nucleus (PVN) is an efficient stress buffering neuro-peptide. This hormone mediates many physiological and behavioural functions get released during stress. It attenuates the stress axis initiated by the release of corticotropin releasing hormone (CRH) from the parvocellular neurons of the same hypothalamic nucleus. Oxytocin released by PVN exerts an inhibitory effect on the release of CRH by down-regulating the expression of the gene that transcribes for this hypothalamic hormone. Thus, it inhibits the release of adreno cotico trophic hormone (ACTH) and cortisol, exerting an overall suppressive modulation of the stress axis and attenuates stress.     

Molecular docking analysis of selected pyrimidine derivatives with human cyclin-dependent kinase 2

A series of pyrimidine were synthesized, characterized and evaluated for their antioxidant properties using the human cyclin-dependent kinase-2 protein model. Data shows that the pyrimidine derivatives (compound ID 4G) with para fluoro groups substitution at phenyl ring attached to the 4th position (IC50: 98.5µg/ml), compound 4B bearing hydroxy group at para position of phenyl ring (IC50: 117.8 µg/ml) have significant antioxidant activity. Docking data infer that compounds 4c, 4a, 4h and 4b possess binding energy (-7.9, -7.7, -7.5 and -7.4 kcal.mol-1) with 1HCK (PDB ID) receptor.     

Montmorillonite K-10 clay-catalyzed Ferrier rearrangement of 2-C-hydroxymethyl-d-glycals, 3,4,6-tri-O-alkyl-d-glycals, and 3,4-(dihydro-2H-pyran-5-yl)methanol: a few unexpected domino transformations

Montmorillonite K-10 clay-catalyzed substitution reactions of 3,4,6-tri-O-alkyl-2-C-hydroxymethyl-d-glycals, 3,4,6-tri-O-acetyl-d-glycals, 3,4,6-tri-O-alkyl-d-glycals, and 3,4-(dihydro-2H-pyran-5-yl)methanol with a few alcohols and phenols are described. The reactions of 2-C-hydroxymethyl-d-glycals with phenols were similar to those of 2-C-acetoxymethyl-d-glycals and afforded pyrano[2,3-b]benzopyrans. This montmorillonite K-10 clay-catalyzed transformation is facile both under ambient (Method 1) and microwave conditions (Method 2). Ferrier rearrangement of 3,4-(dihydro-2H-pyran-5-yl)methanol with p-cresol, 2,6-xylenol, and ethanol led to totally unexpected transformations. Reaction of 2-C-hydroxymethyl-d-galactal with 2,6-dimethylphenol in the presence of montmorillonite K-10 led to a novel domino transformation affording 4-(5′,6′-dihydro-4H-pyran-3′-ylmethyl)-2,6-dimethylphenol. In contrast, 3,4,6-tri-O-acetyl-d-glucal furnished the Ferrier rearrangement product, 2,6-dimethylphenyl 4,6-di-O-acetyl-2,3-dideoxy-α-d-erythro-hex-2-enopyranoside. Also, isomerization of 3,4,6-tri-O-alkyl-d-glycals to products of allylic rearrangement, 2,3-unsaturated-O-glycosides in good yields is reported.     

In vitro and molecular docking studies of an anti-inflammatory scaffold with human peroxiredoxin 5 and tyrosine kinase receptor

A new series of 4-(3-(2-amino-3,5-dibromophenyl)-1-(4-substitutedbenzoyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (4a-h) compounds were synthesized and evaluated for in-vitro anti-inflammatory activities. The spectral (IR, NMR) and elemental analyses data of the product indicated the formation of new pyrazoles 4a-h. Compound 4e exhibited potent anti-inflammatory property with 85.45 % inhibitions. This value was compared with standard diclofenac sodium. This data is explained using molecular docking analysis of receptor- ligand binding. These results demonstrated that pyrazole derivatives are potential inhibitors of Human Peroxiredoxin 5 and Tyrosine kinase receptor in the treatment of inflammation related illness.