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Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 ([BCL-X.sub.L]), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by [BCL-X.sub.L] inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers., Apoptosis, or programmed cell death, is a conserved and regulated process that is the primary mechanism for the removal of aged, damaged and unnecessary cells. The ability to block apoptotic [...]

In this paper, we propose a new method for constructing a bilinear pairing over (hyper)elliptic curves, which we call the R-ate pairing. This pairing is a generalization of the Ate and [Ate.sub.i] pairing, and can be computed more efficiently. Using the R-ate pairing, the loop length in Miller's algorithm can be as small as log([r.sup.1/[phi](k)]) for some pairing-friendly elliptic curves which have not reached this lower bound. Therefore, we obtain savings of between 29% and 69% in overall costs compared to the [Ate.sub.i] pairing. On supersingular hyperelliptic curves of genus 2, we show that this approach makes the loop length in Miller's algorithm shorter than that of the Ate pairing. Index Terms--Ate pairing, elliptic curves, hyperelliptic curves, pairing based cryptography, Tate pairing.

The effect of source/drain device parameters on series resistance contribution is analyzed by employing a physical model. This model well characterizes nanoscale complementary metal-oxide-semiconductor (CMOS) structure and resistance characteristics.

The fabrication of a new, in-situ lateral field emitter array is described.

Photoresist reflow is used in making a novel offset gated poly-Si thin-film transistor (TFT) with subgate. The novel TFT has an innovative gate pattern and its hydrogenation effect does not conform with previous results. It has been observed that hydrogenation improves when the space between the maingate and subgate is wider for the same offset length. The leakage current is two orders of magnitude lower than those for nonoffset gated devices. Its ON current is almost identical with the latter on the frequency range 10 to 100 KHz.

The bryostatins are a unique family of emerging cancer chemotherapeutic candidates isolated from marine bryozoa. Although the biochemical basis for their therapeutic activity is not known, these macrolactones exhibit high affinities for protein kinase C (PKC) isozymes, compete for the phorbol ester binding site on PKC, and stimulate kinase activity in vitro and in vivo. Unlike the phorbol esters, they are not first-stage tumor promoters. The design, computer modeling, NMR solution structure, PKC binding, and functional assays of a unique class of synthetic bryostatin analogs are described. These analogs (7b, 7c, and 8) retain the putative recognition domain of the bryostatins but are simplified through deletions and modifications in the C4-C14 spacer domain. Computer modeling of an analog prototype (7a) indicates that it exists preferentially in two distinct conformational classes, one in close agreement with the crystal structure of bryostatin 1. The solution structure of synthetic analog 7c was determined by NMR spectroscopy and found to be very similar to the previously reported structures of bryostatins 1 and 10. Analogs 7b, 7c, and 8 bound strongly to PKC isozymes with [K.sub.i] = 297, 3.4, and 8.3 nM, respectively. Control 7d, like the corresponding bryostatin derivative, exhibited weak PKC affinity, as did the derivative, 9, lacking the spacer domain. Like bryostatin, acetal 7c exhibited significant levels of in vitro growth inhibitory activity (1.8-170 ng/ml) against several human cancer cell lines, providing an important step toward the development of simplified, synthetically accessible analogs of the bryostatins.

The basicity of an amine has a great impact on physico-chemical properties and pharmacokinetics. To attenuate the basicity of morpholine, a bicyclic amine was designed and synthesized with the introduction of an additional beta-oxygen and a transannular cyclization and reduction of bridgehead alpha-chloro amine functionality produces the topographically unusual amine in good yield.

A new oxidation method has been established to fabricate polycrystalline silicon thin film transistor with a smooth surface roughness at the gate oxide/poly-Si layer interface. The technique dramatically improves subthreshold swing and threshold voltage. Evidence suggests that the device's improved performance is directly related to its surface roughness.

The synthesis of a class of synthetic bryostatin analogues with potent growth inhibitory activity against several human cancer cell lines and exhibiting a high affinity for protein kinase C (PKC) is described. The assembly of a modified bryostatin ring system from readily prepared subunits was accomplished by using an esterification-macrotranscetalization method. Of the units tested, acetal 24a showed great growth inhibitory activity and affinity for PKC.

Dactomelynes can be successfully synthesized from beta-alkoxyacrylates through two independent radical cyclization reactions. A general synthetic method for stereoselective halides does not exist but the beta-alkoxyacrylates are stereoselective when used as radical acceptors without extraneous steric influence. The beta-alkoxyacrylates are prepared from (-)-diethyl D-tartrate.