SOX11 augments BCR signaling to drive MCL-like tumor development.

Mantle cell lymphoma (MCL) is characterized by increased B-cell receptor (BCR) signaling, and BTK inhibition is an effective therapeutic intervention in MCL patients. The mechanisms leading to increased BCR signaling in MCL are poorly understood, as mutations in upstream regulators of BCR signaling such as CD79A, commonly observed in other lymphomas, are rare in MCL. The transcription factor SOX11 is overexpressed in the majority (78% to 93%) of MCL patients and is considered an MCL-specific oncogene.

Nanocellulose composites with enhanced interfacial compatibility and mechanical properties using a hybrid-toughened epoxy matrix.

Although there is a growing interest in utilizing nanocellulose fibres (NCFs) based composites for achieving a higher sustainability, mechanical performance of these composites is limited due to the poor compatibility between fibre reinforcement and polymer matrices. Here we developed a bio-nanocomposite with an enhanced fibre/resin interface using a hybrid-toughened epoxy. A strong reinforcing effect of NCFs was achieved, demonstrating an increase up to 88% in tensile strength and 298% in tensile modulus as compared to neat petro-based P-epoxy.

From Structure to Properties of Composite Films Derived from Cellulose Nanocrystals.

Many natural materials exhibit a multilayer structure in which adjacent layers rotate in a helicoidal manner. The remarkable optical and mechanical properties of these materials have motivated research and development of man-made materials with similar morphology. Among them, composite materials by cellulose nanocrystals (CNCs) and polymers have attracted great interest; however, the relationship between the cholesteric structure and the material properties is not well understood.

Dual Targeting of CDK4 and ARK5 Using a Novel Kinase Inhibitor ON123300 Exerts Potent Anticancer Activity against Multiple Myeloma.

Multiple myeloma is a fatal plasma cell neoplasm accounting for over 10,000 deaths in the United States each year. Despite new therapies, multiple myeloma remains incurable, and patients ultimately develop drug resistance and succumb to the disease. The response to selective CDK4/6 inhibitors has been modest in multiple myeloma, potentially because of incomplete targeting of other critical myeloma oncogenic kinases.

Harnessing Noxa demethylation to overcome Bortezomib resistance in mantle cell lymphoma.

Bortezomib (BZM) is the first proteasome inhibitor approved for relapsed Mantle Cell Lymphoma (MCL) with durable responses seen in 30%-50% of patients. Given that a large proportion of patients will not respond, BZM resistance is a significant barrier to use this agent in MCL. We hypothesized that a subset of aberrantly methylated genes may be modulating BZM response in MCL patients.

Integrative genomic analysis of temozolomide resistance in diffuse large B-cell lymphoma.

Purpose: Despite advances, there is an urgent need for effective therapeutics for relapsed diffuse large B-cell lymphoma, particularly in elderly patients and primary central nervous system (CNS) lymphoma. Temozolomide (TMZ), an oral DNA-alkylating agent routinely used in the therapy of glioblastoma multiforme, is active in patients with primary CNS lymphoma but the response rates are low. The mechanisms contributing to TMZ resistance are unknown.

Akt inhibitors MK-2206 and nelfinavir overcome mTOR inhibitor resistance in diffuse large B-cell lymphoma.

Purpose: The mTOR pathway is constitutively activated in diffuse large B-cell lymphoma (DLBCL). mTOR inhibitors have activity in DLBCL, although response rates remain low. We evaluated DLBCL cell lines with differential resistance to the mTOR inhibitor rapamycin: (i) to identify gene expression profile(s) (GEP) associated with resistance to rapamycin, (ii) to understand mechanisms of rapamycin resistance, and (iii) to identify compounds likely to synergize with mTOR inhibitor.

Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a mostly incurable malignancy arising from naive B cells (NBCs) in the mantle zone of lymph nodes. We analyzed genomewide methylation in MCL patients with the HELP (HpaII tiny fragment Enrichment by Ligation-mediated PCR) assay and found significant aberrancy in promoter methylation patterns compared with normal NBCs. Using biologic and statistical criteria, we further identified 4 hypermethylated genes CDKN2B, MLF-1, PCDH8, and HOXD8 and 4 hypomethylated genes CD37, HDAC1, NOTCH1, and CDK5 when aberrant methylation was associated with inverse changes in mRNA levels.

Dual fluorescent photochromic colorants bearing pyrano[3,2-c]chromen-5-one moiety.

In this study, the photochromic processes of 8-N,N-dimethylamino-2,2-dimethyl-2H-pyrano[3,2-c]chromen-5-one (1) and its derivatives (2, 3) are investigated with steady-state, temperature-dependent and time-resolved absorption and emission spectroscopy. The differences among compounds 1-3 lie in their various substituents anchored at the pyran moiety that is subject to the photoinduced ring-opening reaction. Compounds 1 and 2 exhibit salient photochromism with a very unique phenomenon, in which fluorescence is observed in 1 for both the ring-closed form (1-CF, lambda(max) approximately 445 nm) and the ring-open form (1-OF, lambda(max) approximately 650 nm in CH2Cl2).

Reactions of 3-benzoyl-7-dimethylamino-4-hydroxycoumarin and their potential applications in solution- and solid-phase synthesis.

3-Benzoyl-7-dimethylamino-4-hydroxycoumarin was synthesized and its UV-vis spectra in various mixtures of MeOH and CH(2)Cl(2) were measured. The diketone lactone exists mainly in the exocyclic-enol form in protic solvents and the endocyclic-enol form in nonpolar solvents. Acetylation, amination and methylation products of the diketone lactone were characterized by X-ray crystallography.

Synthesis and characterization of coumarin-based spiropyran photochromic colorants.

Two coumarin-based spiropyran derivatives were synthesized and characterized in two steps to explore their photochromic properties. Both prepared compounds are sensitive to UV light and change colors upon irradiation. The resulting photogenerated zwitterions revert to the original compounds while being heated.

Design of a coumarin-based triketone as a fluorescent protecting group for primary amines.

A series of 3-acetyl-4-hydroxycoumarin and its derivatives were prepared and evaluated for their potential to function as a fluorescent primary amine protection group. When primary amines or amino acids react with the protecting group 3-acetyl-4-methoxy-7- N, N-dimethylaminocoumarin, the resulting compounds emit blue fluorescence with a quantum yield of 0.25-0.

Novel oxazabicycles as a new class of photochromic colorants.

A new photochromic colorant with an oxazabicyclic moiety has been synthesized by an efficient method. It turns pale red upon UV irradiation and undergoes reverse reaction while being heated. This work may open an exciting new avenue for future development of the photochromic dyes with novel molecular structures.

Design and synthesis of a coumarin-based acidichromic colorant.

This paper describes the fine-tuning of the acidichromic properties of a coumarin-containing colorant 1 by incorporation of electron-donating and electron-withdrawing substituents on the coumarin moiety. Colorant 1 can undergo two distinct and reversible color changes under both strongly acidic and basic conditions, but not in the presence of gaseous ammonia. The results indicated that the bromo-substituted compound 5b changes from red to yellow when exposed to gaseous ammonia, both in solution and on polycarbonate film, suggesting that an electron-withdrawing group at the 7-position of the coumarin moiety made the enolic hydrogen on 5b more susceptible to deprotonation by a base than in the unsubstituted compound 1.

Enzyme inhibition potency enhancement by active site metal chelating and hydrogen bonding induced conformation-restricted cyclopropanecarbonyl derivatives.

Two cyclopropanecarbonyl derivatives were independently found to be 15 and 14 times more potent than the corresponding isopropylcarbonyl analogues as inhibitors of 4-hydroxyphenylpyruvate dioxygenase and dihydroorotate dehydrogenase, respectively. A thorough examination of the co-crystal structures of available enzyme inhibitor complexes and the conformation of X-ray crystal structures of several synthesized cyclopropanecarbonyl derivatives revealed that this enhancement by one order of magnitude of inhibition potency exhibited by cyclopropanecarbonyl derivatives in both enzymes is probably caused by respective metal chelating and hydrogen bonding interactions at the ligand-receptor binding site. These specific interactions subsequently cause the cyclopropyl group of the molecules to adopt a fixed bisected conformation, which is unavailable for isopropylcarbonyl derivatives.

Design and synthesis of novel diphenacoum-derived, conformation-restricted vitamin K 2,3-epoxide reductase inhibitors.

Two novel diphenacoum-derived analogues 5 and 6 are designed, synthesized and tested as potential vitamin K 2,3-epoxide reductase (VKOR) inhibitors. The inhibition studies indicated that 5 is a potent VKOR inhibitor, which confirmed that the replacement of the tetrahydronaphthalene on diphenacoum to a chroman functionality does not have a major impact on inhibition potency. The conformation-restricted compound 6 is a moderate inhibitor which may serve as a lead compound for further study of the mode of action of coumarin-type anticoagulants at the molecular level.