Targeted treatment for chronic lymphocytic leukemia

The treatment of chronic lymphocytic leukemia (CLL) has evolved over the last few decades. Recognition has increased of several key components of CLL biology currently manipulated for therapeutics. A milestone in the treatment of CLL was reached with the incorporation of immunotherapy with conventional chemotherapy. The fludarabine/cyclophosphamide/rituximab combination has demonstrated survival advantage for the first time in the treatment of CLL. Several other biological compounds are being explored with the hope of improving responses, impacting survival, and ultimately curing CLL. Important agents being tested are targeted on CLL surface molecules and their ligands, signal transduction protein and oncogenes. This review provides a brief summary of the recent advances made in preclinical and clinical investigation of selected promising therapeutic agents, which lead the target-directed therapeutic approach

Knockdown of the Drosophila Fused in Sarcoma (FUS) Homologue Causes Deficient Locomotive Behavior and Shortening of Motoneuron Terminal Branches

Mutations in the fused in sarcoma/translated in liposarcoma gene (FUS/TLS, FUS) have been identified in sporadic and familial forms of amyotrophic lateral sclerosis (ALS). FUS is an RNA-binding protein that is normally localized in the nucleus, but is mislocalized to the cytoplasm in ALS, and comprises cytoplasmic inclusions in ALS-affected areas. However, it is still unknown whether the neurodegeneration that occurs in ALS is caused by the loss of FUS nuclear function, or by the gain of toxic function due to cytoplasmic FUS aggregation. Cabeza (Caz) is a Drosophila orthologue of human FUS. Here, we generated Drosophila models with Caz knockdown, and investigated their phenotypes. In wild-type Drosophila, Caz was strongly expressed in the central nervous system of larvae and adults. Caz did not colocalize with a presynaptic marker, suggesting that Caz physiologically functions in neuronal cell bodies and/or their axons. Fly models with neuron-specific Caz knockdown exhibited reduced climbing ability in adulthood and anatomical defects in presynaptic terminals of motoneurons in third instar larvae. Our results demonstrated that decreased expression of Drosophila Caz is sufficient to cause degeneration of motoneurons and locomotive disability in the absence of abnormal cytoplasmic Caz aggregates, suggesting that the pathogenic mechanism underlying FUS-related ALS should be ascribed more to the loss of physiological FUS functions in the nucleus than to the toxicity of cytoplasmic FUS aggregates. Since the Caz-knockdown Drosophila model we presented recapitulates key features of human ALS, it would be a suitable animal model for the screening of genes and chemicals that might modify the pathogenic processes that lead to the degeneration of motoneurons in ALS

Molecular Determinants and Genetic Modifiers of Aggregation and Toxicity for the ALS Disease Protein FUS/TLS

A combination of yeast genetics and protein biochemistry define how the fused in sarcoma (FUS) protein might contribute to Lou Gehrig's disease

Electronic Equalization of High-Speed Multi-mode Fiber Links

The objective of this research is to investigate low-complexity, efficient electronic equalizers to increase the data rate and possibly extend the reach of multi-mode fiber (MMF) links. Specifically, we begin by baselining the performance limits of conventional receivers. A robust, in-house mode solver was developed as part of this research and is currently being used by one of the largest fiber manufacturers in their internal R &D work. A detailed performance assessment of the impact of decision feedback equalizers has been conducted using an extensive model of the installed fiber base. The finite-length DFE results were instrumental in influencing the IEEE 802.3aq standardization effort. In particular, we were able to achieve a reach of 220m but the original goal of 300m was unattainable on 99% of the installed fiber base using DFEs of moderate complexity. A low-cost equalizer that has excellent performance, the bi-directional DFE, was applied to the MMF channel for the first time. The performance of the infinite-length BiDFE was characterized without any constraints on the signal-to-noise ratio and on the receiver front-end, as has been previously done in the literature. A new joint optimization technique that helps the finite-length BiDFE perform significantly better than the infinite-length DFE was developed. It was shown that given a finite number of filter coefficients, the BiDFE utilizes them better than the conventional DFE. Furthermore, a reach of 350-400m at a data rate of 10 Gbps was shown to be feasible with equalizers of complexity similar to that currently available. A multiple-input, multiple-output (MIMO) characterization of the MMF channel was developed through the simultaneous use of both center and offset launch together with the two-segment photo-detector. The potential benefit of MIMO processing for MMF links was demonstrated by computing Shannon capacity bounds. It was established that the 2x2 MIMO channel performs about 1.4 dBo better than the conventional 1x1 link at 10 Gbps with practical joint launch. The MIMO scheme still has a performance improvement of 1dBo at 20 Gbps thereby indicating that 20 Gbps transmission is feasible. Performance evaluation of multi-km MMF links was conducted using a comprehensive model that accounts for mode coupling effects. It was determined that ignoring mode coupling can result in under-estimation of the optimum DFE penalty by as much as 1~dBo for 1km links.Ph.D.Committee Chair: Ralph, Stephen; Committee Member: Barry, John; Committee Member: Lingle Jr., Robert; Committee Member: McLaughlin, Steven; Committee Member: Verriest, Eri

Induction of the plasminogen activator inhibitor-2 in cells expressing the ZNF198/FGFR1 fusion kinase that is involved in atypical myeloproliferative disease

The ZNF198/FGFR1 fusion kinase associated with an atypical myeloproliferative disease is constitutively activated and regulates several STAT transcription factors. We used oligonucleotide microarrays to compare the gene-expression profiles between HEK-293 cells that stably express either the ZNF198/FGFR1 chimeric protein or the wild-type ZNF198 gene. Expression of the plasminogen activator inhibitor-2 (PAI-2/SERPINB2) was highly increased in cells expressing the fusion gene. Western blot analysis demonstrated that HEK-293 cells do not express PAI-2 endogenously, but in ZNF198/FGFR1-expressing cells 2 molecular forms of PAI-2, which were 47 kDa and 32 kDa, were expressed intracellularly, and a 60-kDa form was secreted. Similarly, expression of ZNF198/FGFR1 in BaF/3 mouse hematopoietic cells also induced the expression of the PAI-2 protein. Immunoprecipitation analysis revealed that both intracellular forms of PAI-2 bind to the ZNF198/FGFR1 kinase. Treatment of HEK-293 and BaF/3 cells with TNF-α in the presence of cycloheximide, induced apoptosis in both cases. In contrast, HEK-293 and BaF/3 cells expressing ZNF198/FGFR1 were resistant to TNF-α-induced apoptosis. These observations suggest that expression of the ZNF198/FGFR1 fusion gene is associated with specific PAI-2-mediated resistance to apoptosis which may contribute to the highly malignant nature of leukemic cells carrying this fusion kinase gene

A Study of Early Age Shear Properties of 3D Printable Cementitious Mixes with Fiber Reinforcements

The use of Fiber Reinforcement in digitally manufactured concrete is not only one of the viable techniques in the otherwise difficult reinforcement strategy but also a segue to the use of highly durable Ultra High Performance Concretes in 3D printing. For this, the characterization of early age mechanical properties such as tensile, shear and compressive strength of printable Fiber Reinforced Concrete is very important in the design process. The printability of fresh concrete which is defined as combination of pumpability, extrudability and buildability can be characterized using the tensile strength of filament, the shear strength and the compressive strength of the freshly printed element. This study aims on defining the shear strength of 3D printable cementitious mortars at early ages focusing on the “printability window” highlighting the phase transitions in printed concrete. Highly cohesive mortar with high Sulfo-Aluminate cement content is cast with Basalt fibers in specially designed molds to understand these said properties at various times from casting namely, 30, 45, 60 and 90 min. Repeatability of the methodology has been established using 3 iterations of each experiment and crack - failure patterns have been studied closely. Further study on developing the Kupfer’s failure envelopes is underway by including the compressive strength study obtained through penetration tests and tensile strength study