Design of diversity and focused combinatorial libraries in drug discovery.

Using well-characterized chemical reactions and readily available monomers, chemists are able to create sets of compounds, termed libraries, which are useful in drug discovery processes. The design of combinatorial chemical libraries can be complex and there has been much information recently published offering suggestions on how the design process can be carried out. This review focuses on literature with the goal of organizing current thinking.

Comparing gene discovery from Affymetrix GeneChip microarrays and Clontech PCR-select cDNA subtraction: a case study.

Background: Several high throughput technologies have been employed to identify differentially regulated genes that may be molecular targets for drug discovery. Here we compared the sets of differentially regulated genes discovered using two experimental approaches: a subtracted suppressive hybridization (SSH) cDNA library methodology and Affymetrix GeneChip technology. In this "case study" we explored the transcriptional pattern changes during the in vitro differentiation of human monocytes to myeloid dendritic cells (DC), and evaluated the potential for novel gene discovery using the SSH methodology.

[Effect of postoperative transcatheter arterial chemoembolization on hepatocellular carcinoma patients with residual tumor].

Objective: To evaluate the effect of postoperative adjuvant transcatheter arterial chemoembolization (TACE) on hepatocellular carcinoma (HCC) patients with residual tumor.

Methods: The patients were classified into intervention group (with adjuvant TACE) and control group (without adjuvant TACE) who were further stratified to those with high risk (patients with single tumor > 5 cm in diameter, or with multiple tumors, invasion to blood vessels), and low risk factors. Univariate analysis and Cox model were used to analyse prognostic factors.

Prevention of hepatocellular carcinoma in mice by IL-2 and B7-1 genes co-transfected liver cancer cell vaccines.

Aim: To study the immunoprotective effect of liver cancer vaccine with co-transfected IL-2 and B7-1 genes on hepatocarcinogenesis in mice.

Methods: The murine liver cancer cell line Hepal-6 was transfected with IL-2 and/or B7-1 gene via recombinant adenoviral vectors and the liver cancer vaccines were prepared. C57BL/6 mice were immunized with these vaccines and challenged with the parental Hepal-6 cells afterwards.

[Smoking and alcohol consumption as risk factors of pulmonary tuberculosis in Chengdu: a matched case-control study].

Objective: The aim of this study was to assess the relationship between personal behaviors (smoking and alcohol consumption) and contracting pulmonary tuberculosis.

Methods: 346 persons (173 cases and 173 controls) were selected from 12 communities of Chengdu area, all the cases were active TB patients (by WHO criteria) from March 1996 to March 1997. Controls were matched for age, sex and living district.

[Immunoprotective effect of IL-2 and B7-1 gene co-transfected liver cancer vaccines on hepatocarcinogenesis in mice].

Objective: To study the immunoprotective effect of IL-2 and B7-1 gene co-transfected liver cancer vaccine on hepatocarcinogenesis in mice.

Methods: The murine liver cancer cell strain Hepal-6 was transfected with IL-2 and/or B7-1 gene via recombinant adenovirus vectors and the liver cancer vaccines were prepared. C57BL/6 mice were immunized with the vaccines and challenged with the parental Hepal-6 cells afterwards.

Immunofluorescent labeling of cancer marker Her2 and other cellular targets with semiconductor quantum dots.

Semiconductor quantum dots (QDs) are among the most promising emerging fluorescent labels for cellular imaging. However, it is unclear whether QDs, which are nanoparticles rather than small molecules, can specifically and effectively label molecular targets at a subcellular level. Here we have used QDs linked to immunoglobulin G (IgG) and streptavidin to label the breast cancer marker Her2 on the surface of fixed and live cancer cells, to stain actin and microtubule fibers in the cytoplasm, and to detect nuclear antigens inside the nucleus.

[Social economical status, behaviors and environment as the risk factors of tuberculosis in Chengdu China].

Objective: To study the risk factors of pulmonary tuberculosis in Chengdu, Southwest China.

Methods: A population-based case-control study was used which included 174 cases selected from 12 communities in Chengdu and 174 controls selected from registered population with normal chest radiograph. Cases were active TB patients which were matched for age, sex with controls, then interviewed by trained interviewers using a standardized questionnaire.

Two-dimensional IR spectroscopy can be designed to eliminate the diagonal peaks and expose only the crosspeaks needed for structure determination.

The power of two-dimensional (2D) IR spectroscopy as a structural method with unprecedented time resolution is greatly improved by the introduction of IR polarization conditions that completely eliminate diagonal peaks from the spectra and leave only the crosspeaks needed for structure determination. This approach represents a key step forward in the applications of 2D IR to proteins, peptides, and other complex molecules where crosspeaks are often obscured by diagonal peaks. The technique is verified on the model compound 1,3-cyclohexanedione and subsequently used to clarify the distribution of structures that the acetylproline-NH(2) dipeptide adopts in chloroform.

Molecular regulation of genes encoding xenobiotic-metabolizing enzymes: mechanisms involving endogenous factors.

It is widely recognized that xenobiotic-metabolizing enzymes play a fundamental role in the basic processes of carcinogenesis and toxicity on one hand, and chemoprevention and drug efficacy on the other. Realization that different factors can profoundly affect the expression of these enzymes at the genome level has resulted in an enhanced appreciation of the importance these genes play in our modern industrialized age. There continues to be rapid proliferation of studies addressing the molecular regulation of these genes.

Interferon-gamma activates outwardly rectifying chloride channels in the human bronchial epithelial cell line BEAS-2B.

The mechanism of increased chloride currents by inflammatory cytokine, interferon-gamma (IFN-gamma), was investigated in cultured a human bronchial epithelial cell line (BEAS-2B) using cell-attached and inside-out patch configurations. The channel sensitive to chloride ion was activated by forskolin, an activator of adenylate cyclase, or 100 microM dibutyryl 5'-cyclic monophosphate in cell-attached configurations. The conductance of this channel was 40 +/- 4 pS in symmetrical 150 mM chloride solution between membrane potentials of 0 to mV, and this channel was blocked by 500 microM 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), suggesting that this channel was an outwardly rectifying chloride channel (ORCC).

Maximal aryl hydrocarbon receptor activity depends on an interaction with the retinoblastoma protein.

The aryl hydrocarbon receptor (AhR) belongs to the basic helix-loop-helix/periodicity/AhR nuclear translocator/simple-minded (Per-Arnt-Sim) family of transcription factors that regulate critical functions during development and tissue homeostasis. Within this family, the AhR is the only member conditionally activated in response to ligand binding, typified by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We recently demonstrated that the AhR interacts with the retinoblastoma protein (pRb).

Involvement of chemokine receptors in breast cancer metastasis.

Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases.

Insulin-like growth factor I is a dual effector of multiple myeloma cell growth.

Multiple myeloma (MM) is an invariably fatal disease that accounts for approximately 1% to 2% of all human cancers. Surprisingly little is known about the cellular pathways contributing to growth of these tumors. Although the cytokine interleukin-6 has been suggested to be the major stimulus for myeloma cell growth, the role of a second potential growth factor, insulin-like growth factor I (IGF-I), has been less clearly defined.

Expression of PTEN in PTEN-deficient multiple myeloma cells abolishes tumor growth in vivo.

Biochemical abnormalities associated with the development of multiple myeloma have been difficult to define especially in terms of demonstrating an in vivo effect of suspected lesions. Herein, we have identified such a defect associated with lack of expression of PTEN, a cellular phosphatase involved in the regulation of phosphatidylinositol phosphates (PIP's). In myeloma cells, PIP's are required for phosphorylation of Akt, a key event leading to inhibition of apoptosis.

Femtosecond studies of electron dynamics at interfaces.

A delocalized electron at a metal-dielectric interface interacts with the adlayer and spatially localizes or self-traps on the femtosecond time scale into what is termed a small polaron. The dynamics can be studied by two-photon photoemission. Theoretical and experimental analyses reveal the interaction energy and the lattice vibrational mode that mediates electron localization.

Theoretical elucidation of activity differences of five phenolic antioxidants.

Aim: To verify the effectiveness of structure-activity relationship (SAR) and theoretical calculation methods for antioxidants.

Methods: Preliminary elucidation on the differences of activities of 5 antioxidants was performed by SAR. Then semiempirical quantum chemistry method AM1 was employed to calculate the delta HOF value, the difference between the heat of formation of antioxidant and its free radical, which was used as a theoretical parameter to elucidate the differences of activities of the antioxidants thoroughly.

A direct interaction between the aryl hydrocarbon receptor and retinoblastoma protein. Linking dioxin signaling to the cell cycle.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor in eukaryotic cells that alters gene expression in response to the environmental contaminant 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD). In 5L hepatoma cells, TCDD induces a G1 cell cycle arrest through a mechanism that involves the AhR. The retinoblastoma tumor suppressor protein (pRb) controls cell cycle progression through G1 in addition to promoting differentiation.

Development of a non-radioactive DNA probe and in situ hybridization for detection of Anaplasma marginale in ticks and cattle.

A non-radioactive DNA probe was developed for detection of Anaplasma marginale in ticks and cattle. The probe was labeled with digoxigenin 11-dUTP by polymerase chain reaction. The probe was tested on bovine blood and was found to be a sensitive and specific detection method for A.

Summating potential and action potential ratio in Meniere's disease before and after treatment.

Objective: This study aimed to compare the summating potential and action potential ratio (SP:AP) in patients with Meniere's disease before and after various surgical and medical treatments as an indication of change in endolymphatic hydrops to study the progression of Meniere's disease.

Study Design: The study design was a retrospective case review.

Setting: The study was conducted at an otology-neurotology referral center.

Action potential latency shift by rarefaction and condensation clicks in Menière's disease.

Transtympanic electrocochleography using rarefaction and condensation clicks was performed on 122 ears of 112 patients, including 98 ears of 89 patients with Menière's disease (MD) and 24 ears of 23 patients without Menière's disease (NMD). The mean action potential (AP) latency difference between rarefaction and condensation clicks was 0.40 +/- 0.

Step-down trend tests for identifying the minimum effective dose.

Many authors, most recently Tamhane, Hochberg, and Dunnett (18), have studied the problem of determining the minimum effective dose in dose-response studies. Based on past research and on findings from their own extensive simulation study, which covered a wide range of balanced normal homoscedastic situations, Tamhane et al. recommended a procedure they called SD2L, since it exhibited good performance in almost all the situations they studied.

Femtosecond dynamics of electron localization at interfaces.

The dynamics of two-dimensional small-polaron formation at ultrathin alkane layers on a silver(111) surface have been studied with femtosecond time- and angle-resolved two-photon photoemission spectroscopy. Optical excitation creates interfacial electrons in quasi-free states for motion parallel to the interface. These initially delocalized electrons self-trap as small polarons in a localized state within a few hundred femtoseconds.

Femtosecond dynamics of electrons on surfaces and at interfaces.

Two-photon photoemission is a promising new technique that has been developed for the study of electron dynamics at interfaces. A femtosecond laser is used to both create an excited electronic distribution at the surface and eject the distribution for subsequent energy analysis. Time- and momentum-resolved two-photon photoemission spectra as a function of layer thickness fully determine the conduction band dynamics at the interface.