A phase 1 open-label, sequential dose-escalation study investigating the safety, tolerability, and pharmacokinetics of intravenous TLC388 administered to patients with advanced solid tumors.

PURPOSE: The first-in-human phase 1 trial examined the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetic profile, and antitumor activity of TLC388, a novel camptothecin with a unique lactone ring modification, in patients with advanced solid tumors. EXPERIMENTAL DESIGN: TLC388 was administered intravenously to patients with metastatic chemotherapy refractory solid tumors on days 1, 8, and 15 of a 28-day cycle. Patients underwent tumor assessments every other cycle. Pharmacokinetic samples were drawn on days 1, 8, and 15 of cycles 1 and 2. RESULTS: Fifty-four patients were enrolled at doses ranging from 1.5 to 60.0 mg/m(2) over 12 cohorts. Treatment was generally well-tolerated and no cumulative toxicity observed. Two of six patients treated at 60.0 mg/m(2) developed DLTs of grade 3 neutropenia causing dose delay and grade 3 febrile neutropenia. The next lower dose, 50.0 mg/m(2), was declared as MTD. Treatment-related grade 3-4 hematologic toxicities included neutropenia (19 %), leukopenia (15 %), anemia (9 %), and thrombocytopenia (7 %). Grade 3-4 nonhematologic toxicities included diarrhea (2 %) and hyponatremia (4 %). Pharmacokinetics of both diastereomers (S,R and S,S) of TLC388, a mixture of two diastereomers, was dose independent; mean (SD) values for the volume of distribution at steady-state and clearance were 857 (1122) L/m(2) for S,R and 996 (1333) L/m(2) for S,S, and 2174 (2526) L/h-m(2) for S,R and 2670 (2988) L/h-m(2) for S,S, respectively. The half-life values averaged 0.67 (1.15) hours for S,R and 0.64 (1.11) hours for S,S. The best overall response was stable disease in 21 (39 %) patients. Prolonged (≥ 6 months) stable disease was noted in eight patients. CONCLUSIONS: TLC388 at 50 mg/m(2) on the current treatment schedule is generally safe and well tolerated.

Fabrication and Characteristics of SnAgCu Alloy Nanowires for Electrical Connection Application.

As electronic products become more functional, the devices are required to provide better performances and meet ever smaller form factor requirements. To achieve a higher I/O density within the smallest form factor package, applying nanotechniques to electronic packaging can be regarded as a possible approach in microelectronic technology. Sn-3.0 wt% Ag-0.5 wt% Cu (SAC305) is a common solder material of electrical connections in microelectronic devices. In this study, SAC305 alloy nanowire was fabricated in a porous alumina membrane with a pore diameter of 50 nm by the pressure casting method. The crystal structure and composition analyses of SAC305 nanowires show that the main structure of the nanowire is ß-Sn, and the intermetallic compound, Ag3Sn, locates randomly but always appears on the top of the nanowire. Furthermore, differential scanning calorimetry (DSC) results indicate the melting point of SAC305 alloy nanowire is around 227.7 °C. The melting point of SAC305 alloy nanowire is significantly higher than that of SAC305 bulk alloy (219.4 °C). It is supposed that the non-uniform phase distribution and composite difference between the nanowires causes the change of melting temperature.

Structural and functional characterization of the upstream regulatory region of the human gene encoding prostate apoptosis response factor-4.

Prostate apoptosis response factor-4 (Par-4) is critical to cell growth and apoptosis. Induction of Par-4 expression has been shown to be required for apoptosis in a diversity of cellular systems, including neurons. Neuronal populations in individuals with degenerative disorders show elevated levels of Par-4 protein in advance of cellular and functional loss. To understand the regulation of par-4 expression, we isolated and characterized 5.7 kb of the human par-4 promoter. We demonstrated that the isolated promoter was functional. Similar to the endogenous par-4 gene, par-4 expression could be induced upon apoptotic insult with thapsigargin following introduction of the promoter DNA into human A375 cells. Also, increased levels of the atypical protein kinase C, zetaPKC, was shown to negatively regulate expression from the ectopic par-4 promoter. A 550 bp sequence immediately upstream to the 5'-untranslated region of the gene was found to be responsible for par-4 promoter induction to apoptosis by thapsigargin.

LEF1-mediated regulation of Delta-like1 links Wnt and Notch signaling in somitogenesis.

Wnt signaling, which is mediated by LEF1/TCF transcription factors, has been placed upstream of the Notch pathway in vertebrate somitogenesis. Here, we examine the molecular basis for this presumed hierarchy and show that a targeted mutation of Lef1, which abrogates LEF1 function and impairs the activity of coexpressed TCF factors, affects the patterning of somites and the expression of components of the Notch pathway. LEF1 was found to bind multiple sites in the Dll1 promoter in vitro and in vivo. Moreover, mutations of LEF1-binding sites in the Dll1 promoter impair expression of a Dll1-LacZ transgene in the presomitic mesoderm. Finally, the induced expression of LEF1-beta-catenin activates the expression of endogenous Dll1 in fibroblastic cells. Thus, Wnt signaling can affect the Notch pathway by a LEF1-mediated regulation of Dll1.