Targeting Epigenetic Regulators for the Treatment of Diffuse Large B-Cell Lymphoma

Small-molecule inhibitors of the histone methyltransferase EZH2 hold great promise for the treatment of Germinal Center B-Cell-like Diffuse Large B-Cell Lymphoma (GCB-DLBCL). Compared to a 60% Objective Response Rate (ORR) in Phase I clinical trials, Phase II trial results for the EZH2 inhibitor EPZ-6438 reported an attenuation of response. Mechanisms contributing to lymphoma cell survival and growth after EZH2 ablation are poorly studied. In EZH2-mutant cells, we found that B-Cell Receptor (BCR) signaling was enhanced after EZH2 inhibitor treatment, and associated with an activated B-cell phenotype. Genetic manipulation of BCR, CD19 and CD79A greatly increased sensitivity to the EZH2 inhibitor EPZ-6438. Combination therapy with SYK, PI3Kdelta and BTK kinase inhibitors was highly synergistic in multiple lymphoma cell lines, regardless of EZH2 mutation status. At the epigenetic level, prolonged treatment with EPZ-6438 increased global levels of Histone H4 Arginine-3 asymmetric di-methylation. In a subset of lymphoma cell lines, combination therapy with EZH2 and Type I PRMT inhibitors showed synergy. Interestingly, Type I PRMT inhibitors were also highly effective as a single-agent, and mediated apoptosis in lymphoma cells by transcriptionally down-regulating the anti-apoptotic protein BCL2. To summarize, we have identified ways to improve EZH2 inhibitor sensitivity in DLBCL cells and revealed a critical role for the arginine methyltransferase PRMT1 in the regulation of lymphoma growth and survival. Therefore, PRMT1 presents a novel and promising target for the treatment of this cancer type

Rheology and microstructure of hydrophilic and hydrophobic fumed silica in nematic liquid crystals

by Goverdhan SinghM.Tech

Interaction between palladium and silicon carbide: A study for Triso nuclear fuel

The unique properties of SiC (wide band gap, high thermal conductivity, high electron mobility, and resistance to radiation effects) permits it to operate reliably at very high temperatures even in harsh environments and as coating layers in TRISO nuclear fuels. To optimize the SiC for use as a coating material in the nuclear reactor fuel design, it is important to elucidate the chemical bonding and interface formation of metal fission products (Pd, Ag, Cs, etc.) with SiC coating layers and to study the diffusion behavior of fission products into TRISO coating materials. It is known in the TRISO community that Pd is able to corrode the SiC layer. However, the detailed nature of this corrosion is still unknown; The objective of this thesis is to study the influence of fission products (Pd) on the chemical and electronic properties of the SiC coating layer in TRISO nuclear fuel particles. For this purpose, three series of interfaces (Pd/SiC) were prepared and studied using X-ray Photoelectron Spectroscopy (XPS) and Ultraviolet Photoelectron Spectroscopy (UPS); The experimental approach comprises the preparation of Pd/SiC interfaces in-situ in our ultra-high vacuum system by electron-beam deposition of Pd onto suitable prepared SiC single crystal surfaces. In order to understand the impact of the SiC surface properties on the interface formation, a variety of surface preparation and modification schemes were employed. The results obtained give detailed information about the Pd/SiC interface formation. Thereby the study shows a diffusion at this interface, which is an important first step in understanding the corrosion of the SiC-layer in the TRISO particles

New approach towards carotane sesquiterpenes: a short synthesis of (-)-daucene

An enantioselective synthesis of sesqui-terpene hydrocarbon (-)-daucene 1 from R-(+)-limonene involving acid catalysed enone- olefln cyclisation (5 ° 6) as the key step is described

Restructuring α -pinene: novel entry into diverse polycarbocyclic frameworks

(-)-α-Pinene 1 has been restructured into a chiral cyclohexenone (+)-6, in which the functionalities were integrated to afford bicyclo[3.3.1]nonan 3,7-diones and a novel tricyclic skeleton 16 related to the sesquiterpene clovene. Intramolecular [2+2] photocycloadditions in (+)-6 and related 5-alkenylcyclohexenones provided an entry into some novel bridged tricyclic systems

Anti-nociceptive and Anti-inflammatory Effects of the Leaf Extract of Vitex trifolia Linn. in Experimental Animals

The effect of Vitex trifolia Linn. (FamilyVerbenaceae) leaf extract was studied for the anti-nociceptive and anti-inflammatory activity in experimental animals. V. trifolia, 25 – 100 mg/kg administered orally for 3 days exhibited graded dose response equivalent to 21.95% - 89.90% protection in the tail flick latent test in rat. The V. trifolia leaf extract (50 and 100 mg/kg, p.o X 3 days) was effective in hot plate reaction time (64.05% and 112.97%, p\u3c 0.01 and p\u3c 0.001), analgesymeter induced mechanical pain (28.17% and 54.42%, p \u3c 0.01 and p \u3c 0.001) and acetic acid- induced writhing (26.68% and 51.79%, p \u3c 0.5 and p \u3c 0.05) in mice. The leaf extract of V. trifolia potentiated the analgesic activity with pentazocine (10 mg/kg, i.p.) and aspirin (25 mg/kg, i.p.). In the carrageenan- induced paw edema V. trifolia leaf extract (50 and 100 mg/kg, p.o X 3 days) decreased paw volume significantly (26.68% and 51.79%) and dose dependent anti-inflammatory activity in 1-3 hour time interval and potentiated with nimesulide (50 mg/kg, p.o.). In summary, this study demonstrates that leaf extract of V. trifolia has significant anti-nociceptive and anti-inflammatory activity

Oxa-bowls: formation of exceptionally stable diozonides with novel, C-H···o hydrogen bond directed, solid state architecture

Several tetraquinane-based diolefins on ozonization furnish unusually stable diozonides of 'bowl-like' topology and their solid state structure reveals interesting architecture woven through a network of unique C-H···O interactions

Total synthesis of the novel tricyclic sesquiterpene sulcatine G

A synthetic approach to the tricyclic sesquiterpene sulcatine G, 2, bearing a novel tricyclo[6.2.0.02,6]decane framework, from commercially available 1,5-cod and leading to the first total synthesis of the natural product is described

Novel tandem ring-opening/ring-closing metathesis reactions of functionalized cyclohexenoids derived from (-)-α-pinene

The cyclohexenone (+)-2, readily obtained from (-)-α -pinene 1 was elaborated to (+)-3 in an attempt to construct the AB rings of taxoids employing the ring-closure metathesis (RCM) reaction as the key step. In the event, a novel ring-opening/ring-closing metathesis reaction was encountered in the relatively strain free cyclohexenyl ring of (+)-3

Baeyer-Villiger oxidation of norbornan-7-ones: long-range substituent effects on regioselectivity

The regioselectivity of the Baeyer-Villiger oxidation of norbornan-7-ones can be steered by the distal 2-endo-substituents present. Hydrolysis of the resulting bicyclic lactones provides a stereospecific route to functionalized cyclohexanes