New efficient synthesis of resorcinylic macrolides via ynolides: establishment of cycloproparadicicol as synthetically feasible preclinical anticancer agent based on Hsp90 as the target.

A program currently ongoing in our laboratory envisions natural macrolide radicicol-based inhibitors targeting the molecular chaperone Hsp90. Such inhibitors can be potential anticancer agents due to their ability to induce the breakdown of a variety of oncogenic proteins. In this account, we first concern ourselves with a vastly important total synthesis of such an inhibitor.

Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors.

The development of therapeutic inhibitors of key signaling pathways has been hampered by the inability to assess the effect of a drug on its target in the patient. 17-allylaminogeldanamycin (17-AAG) is the first Hsp90 inhibitor to be tested in a clinical trial. It causes the degradation of HER2 and other Hsp90 targets, and has antitumor activity in preclinical models.

General method for the synthesis of 8-arylsulfanyl adenine derivatives.

We report a general method for the synthesis of 8-arylsulfanyl adenine derivatives using a mild protocol of coupling 8-mercaptoadenine with a variety of aryl iodides.

Eyelid splitting and extirpation of hair follicles using a radiosurgical technique for treatment of trichiasis.

Background And Objective: To describe a new, simple, and rapid surgical modification for the treatment of trichiasis.

Patients And Methods: In this noncomparative, prospective, interventional case series, 12 eyelids of 8 consecutive patients suffering from acquired trichiasis were treated by splitting the eyelid margin using a radiosurgical technique and then extirpating the hair follicles. The main outcome measure was successful resolution of trichiasis without recurrence during a follow-up period of at least 1 year.

Surgical management and outcome of osteosarcoma patients with unilateral pulmonary metastases.

Purpose: The surgical management of osteosarcoma patients with unilateral pulmonary nodules is controversial. The authors reviewed their institutional experience to evaluate the incidence of occult contralateral metastases.

Methods: Data were obtained retrospectively on all consecutive osteosarcoma patients from 1980 to 2002.

The impact of gross total resection on local control and survival in high-risk neuroblastoma.

Background/purpose: Gross total resection of the primary tumor in treatment of high-risk neuroblastoma remains controversial. Furthermore, there are few reports of the effect of primary tumor resection on local control as opposed to overall survival. The authors reviewed their institutional experience to assess the effect of primary tumor resection on local control and overall survival.

GeneAnnot: comprehensive two-way linking between oligonucleotide array probesets and GeneCards genes.

Motivation: High density oligonucleotide arrays are usually annotated in a one-to-one fashion, with each probeset assigned to one gene. However, in reality, subsets of oligonucleotides in a probeset may match sequences within more than one gene, potentially leading to misinterpretations. Moreover, a gene is often represented by more than one probeset, and analyzing probe matches at the mRNA level can help one deduce whether these probesets are derived from the same or different splice variants.

GeneAnnot: interfacing GeneCards with high-throughput gene expression compendia.

The interpretation of microarray expression results often includes extensive efforts to identify and annotate the gene representatives immobilised on the arrays. In this paper we describe the usage of our automatic GeneAnnot system, which links between Affymetrix arrays and the rich human gene annotations available in GeneCards. We explain GeneCards search options and results display; elaborate on the presentation of expression information in GeneCards, including both our whole-genome GeneNote project and external expression resources; describe the various parameters and displays used by GeneAnnot to assess the annotation quality and probeset specificity; and show how to search GeneAnnot and GeneNote websites directly.

Combination treatment with 17-N-allylamino-17-demethoxy geldanamycin and acute irradiation produces supra-additive growth suppression in human prostate carcinoma spheroids.

Failure to control localized prostate cancer can result not only in localized disease progression but also distant metastatic spread. Whereas significant advances in both surgical technique and radiation therapy have improved local control rates with decreased morbidity, consistent long-term control remains elusive. This study investigates the potential of 17-N-allylamino-17-demethoxy geldanamycin (17AAG), a geldanamycin derivative, to sensitize tumor cells to ionizing radiation, permitting a significant improvement to targeted radiotherapies of prostate carcinoma.

The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells.

AKT, a serine/threonine kinase that promotes cell survival, can be activated by overexpression of the receptor tyrosine kinase ErbB2. Conversely, down-regulation of ErbB2 inhibits AKT activation. Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells, and we show that ErbB2 inhibits PP1-dependent dephosphorylation of AKT.

Successful treatment with mitomycin C eye drops for conjunctival diffuse intraepithelial neoplasia with sebaceous features.

Conjunctival biopsy specimens from the right eye of a 66-year-old woman who had a 10-year history of an irritated and swollen right upper eyelid were diagnosed as diffuse intraepithelial neoplasia with sebaceous features. The treatment consisted of two courses, 2 weeks apart, of 0.02% mitomycin C eye drops.

Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing.

For many years, lactate has been known to accelerate collagen deposition in cultured fibroblasts and, without detailed explanation, has been presumed to stimulate angiogenesis. Similarly, hypoxia has been linked to angiogenic effects and collagen deposition from cultured cells. Paradoxically, however, wound angiogenesis and collagen deposition are increased by breathing oxygen and decreased by hypoxia.

Synthesis of novel fluorescent probes for the molecular chaperone Hsp90.

Heat shock protein 90 (Hsp90) is a molecular chaperone necessary for maintaining oncogenic transformation. There is substantial interest in developing novel agents that bind to the N-terminal of the chaperone. Here we report the synthesis and characterization of two fluorescent Hsp90 inhibitors and probe their use in an Hsp90 fluorescent polarization assay.

Minimally invasive surgical techniques for the reconstruction of calcaneal fractures.

The soft tissues play a crucial part in both the stabilization of the multiple joint surfaces of the calcaneus and in allowing propulsion as needed. Therefore, minimally invasive functional stabilization of heel bone fracture is a promising technique, which may bypass all published controversies. Experience has shown that ligamentotaxis, which means the use of mechanical forces applied to the soft-tissue envelope of fractures without the surgical disruption of the latter, contributes to fracture healing and reconstruction.

Hsp90 as a therapeutic target in prostate cancer.

Prostate cancers are hormone-dependent malignancies that respond to drugs that reduce circulating testosterone levels or prevent binding of this ligand to the androgen receptor (AR). While effective, these approaches are not curative and, in almost all cases, progression to a castration-resistant state is eventually observed. The mechanisms underlying the development of hormone resistance are poorly defined but several molecular changes are commonly associated with this process.

Development of purine-scaffold small molecule inhibitors of Hsp90.

The Hsp90 chaperones play a key role in regulating the physiology of cells exposed to environmental stress and in maintaining the malignant phenotype in tumor cells. Agents that interfere with the function of the chaperone may thus be beneficial in the treatment of cancers. The ansamycins (geldanamycin and herbimycin) and the unrelated natural product radicicol were found to bind to the N-terminal pocket of Hsp90 and inhibit its function.

Computed tomography and radiation risks: what pediatric health care providers should know.

Computed tomography (CT) is an extremely valuable diagnostic tool. Recent advances, particularly multidetector technology, have provided increased and more diverse applications. However, there is also the potential for inappropriate use and unnecessary radiation dose.

High-level expression of cancer/testis antigen NY-ESO-1 and human granulocyte-macrophage colony-stimulating factor in dendritic cells with a bicistronic retroviral vector.

Tumor-specific genes delivered to dendritic cells (DCs) have been used for the generation of cytotoxic T cells (CTLs), but their application has been limited on the one hand by low viral titers resulting in low transduction efficiency and poor protein production, and on the other hand by immunogenicity of the selectable marker and poor viability of the DCs. We addressed these limitations by creating a multipurpose master vector (pMV) and cloning the tumor gene NY-ESO-1, which is highly expressed in more than 50% of advanced myeloma patients. pMV was constructed from a Moloney murine leukemia virus (Mo-MuLV)-based retroviral backbone with the following features: (1) an extended packaging signal to achieve high viral titers, (2) a splice acceptor region to facilitate protein production, (3) a nonimmunogenic selectable marker, dihydrofolate reductase-L22Y (DHFR(L22Y)), to exclude the generation of CTLs against the selectable marker, (4) an internal ribosomal entry site between the tumor-specific gene (NY-ESO-1) and the selectable marker DHFR(L22Y) for coexpression of two heterologous gene products from a single bicistronic mRNA, minimizing the possibility of differential expression of these two genes, and (5) human granulocyte-macrophage colony-stimulating factor (hGM-CSF) cDNA driven by the human T-lymphotropic virus promoter to enhance DC function and viability.

Microtiter cell-based assay for detection of agents that alter cellular levels of Her2 and EGFR.

Overexpression of the transmembrane tyrosine kinases Her2 and EGFR is associated with aggressive malignancies, and several therapeutic strategies targeting the two receptors are now in various stages of clinical development. Most of the known agents block the activation or inhibit the activity of the kinases; however, a more significant therapeutic outcome may result from degrading these oncoproteins. Here, we report the development of a microtiter cell-based assay that sensitively detects cellular levels of Her2 and EGFR.

GeneLoc: exon-based integration of human genome maps.

Motivation: Despite the numerous available whole-genome mapping resources, no comprehensive, integrated map of the human genome yet exists.

Results: GeneLoc, software adjunct to GeneCards and UDB, integrates gene lists by comparing genomic coordinates at the exon level and assigns unique and meaningful identifiers to each gene.

[Thyroid orbitopathy].

Thyroid Orbitopathy (T.O) is the most common orbital disease caused by a systemic illness. The clinical manifestations of T.

Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors.

We have examined the possible mechanisms of resistance to the epidermal growth factor receptor (EGFR) inhibitors in tumor cells with variable levels of EGFR. ZD1839 (Iressa) is a small-molecular-weight, ATP-mimetic that specifically inhibits the EGFR tyrosine kinase. A431 cell growth was markedly inhibited by ZD1839 (IC(50)< or =0.

Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol.

The phosphatidylinositol 3'-kinase/Akt pathway is activated frequently in human cancer, and has been implicated in tumor proliferation, cell survival, and resistance to apoptotic stimuli. Akt forms a complex with heat shock protein (Hsp) 90 and Cdc37, and inhibitors of Hsp90 cause Akt degradation. 17-allylamino-17-demethoxygeldanamycin (17-AGG) is an Hsp90 inhibitor currently in Phase I clinical trial.