Targeting leiomyomas with all-trans-retinoic acid at phosphoinositide 3-kinase pathway suppression: Effective roles of β-catenin and of signaling interactions.

Aim: Leiomyomas, monoclonal tumors developed by the transformation of myometrium somatic stem cells, are a major health concern that can severely impair quality of life. Pathological alterations of signaling pathways have been recognized as a key feature in a variety of human diseases. Our objective was to analyze treatment with all-trans-retinoic acid (ATRA) by suppression of the phosphoinositide 3-kinase (PI3K) pathway on growth, signaling pattern and interactions among PI3K/B-cell lymphoma 2 (Bcl2)/retinol leiomyoma proteins.

Survival-apoptosis associated signaling in GNE myopathy-cultured myoblasts.

GNE Myopathy (GNEM) is a neuromuscular disorder caused by mutations in the GNE gene. It is a slowly progressive distal and proximal muscle weakness sparing the quadriceps. In this study, we applied our model of mutated M743T GNE enzyme skeletal muscle-cultured myoblasts and paired healthy controls to depict the pattern of signaling proteins controlling survival and/or apoptosis of the PI3K/AKT, BCL2, ARTS/XIAP pathways, examined the effects of metabolic changes/stimuli on their expression and activation, and their potential role in GNEM.

All-trans-retinoic acid mediates changes in PI3K and retinoic acid signaling proteins of leiomyomas.

Objective: To detect changes induced by all-trans-retinoic acid (ATRA) on the expression and activation of target proteins of the retinoic acid (RA) and PI3K/Akt pathways involved in leiomyoma growth.

Design: A study on human tissue cultures.

Setting: Hadassah University Hospital.

The proteomic profile of hereditary inclusion body myopathy.

Hereditary inclusion body myopathy (HIBM) is an adult onset, slowly progressive distal and proximal myopathy. Although the causing gene, GNE, encodes for a key enzyme in the biosynthesis of sialic acid, its primary function in HIBM remains unknown. The goal of this study was to unravel new clues on the biological pathways leading to HIBM by proteomic comparison.

Comparison of topical iodine and silver sulfadiazine as therapies against sulfur mustard burns in a pig model.

Sulfur mustard (SM) is a powerful vesicant used as an agent of chemical warfare. The severity of lesions incurred after exposure to SM reiterated the need for an efficient and rapid neutralizing agent against SM. Previous studies have shown that postexposure treatment with iodine is effective against SM lesions in rodents.

Optimization of energy-consuming pathways towards rapid growth in HPV-transformed cells.

Cancer is a complex, multi-step process characterized by misregulated signal transduction and altered metabolism. Cancer cells divide faster than normal cells and their growth rates have been reported to correlate with increased metabolic flux during cell transformation. Here we report on progressive changes in essential elements of the biochemical network, in an in vitro model of transformation, consisting of primary human keratinocytes, human keratinocytes immortalized by human papillomavirus 16 (HPV16) and passaged repeatedly in vitro, and the extensively-passaged cells subsequently treated with the carcinogen benzo[a]pyrene.

Inhibition of leiomyoma cell proliferation in vitro by genistein and the protein tyrosine kinase inhibitor TKS050.

Objective: To determine the potency of TKS050, a new epidermal growth factor receptor (EGFR) inhibitor and genistein, a naturally occurring protein tyrosine kinase inhibitor, to inhibit leiomyoma cell proliferation in vitro.

Design: Establishment of paired cultures of leiomyoma and normal myometrial samples.

Setting: University clinical research laboratory.

Activation of dsRNA dependent protein kinase PKR in Karpas299 does not lead to cell death.

Activated double-stranded RNA (dsRNA)-dependent protein kinase PKR is a potent growth inhibitory protein that is primarily activated in virally infected cells, inducing them to die. We have recently shown that PKR can be selectively activated in cancer cells, by in situ generation of dsRNA following introduction of antisense RNA complementary to an RNA expressed specifically in the cancer cell. The feasibility of this approach was demonstrated using a glioblastoma line that overexpresses a truncated form of the EGFR.

A cellular screening assay to test the ability of PKR to induce cell death in mammalian cells.

Long double-stranded RNA (>30 bp), usually expressed in cells infected with RNA viruses, triggers antiviral responses that induce apoptosis of the infected cells. PKR can be selectively activated in glioblastoma cells by in situ generation of dsRNA following introduction of antisense RNA complementary to an RNA expressed specifically in these cells. Harnessing PKR for the selective killing of cancer cells is potentially a powerful strategy for treating cancer, but we were unable to induce apoptosis by this approach in a T cell lymphoma.

Performance and safety of skin allografts.

Skin preservation for transplantation began almost 200 years ago with the pioneering work of Baronio (cited by in Ref. ). Since that time, hundreds of papers have been published on the preservation of skin for later application in wound treatment.

No overall hyposialylation in hereditary inclusion body myopathy myoblasts carrying the homozygous M712T GNE mutation.

Hereditary inclusion body myopathy (HIBM) is a unique group of neuromuscular disorders characterized by adult-onset, slowly progressive distal and proximal muscle weakness, which is caused by mutations in UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), the key enzyme in the biosynthetic pathway of sialic acid. In order to investigate the consequences of the mutated GNE enzyme in muscle cells, we have established cell cultures from muscle biopsies carrying either kinase or epimerase mutations. While all myoblasts carrying a mutated GNE gene show a reduction in their epimerase activity, only the cells derived from the patient carrying a homozygous epimerase mutation present also a significant reduction in the overall membrane bound sialic acid.

The AG1478 tyrosine kinase inhibitor is an effective suppressor of leiomyoma cell growth.

Background: Uterine leiomyomas are the most common benign smooth muscle cell tumours in women. Formation of leiomyomas, still not completely understood, is viewed as a multistep process, with involvement of ovarian steroid hormones, cytokines and growth factors. Our study aimed to identify tyrosine kinase inhibitors as potential 'signal transduction therapeutics' for leiomyomas, underlying the effect of ovarian steroidal hormones.

Flame burn protection: assessment of a new, air-cooled fireproof garment.

A new, air-cooled fireproof garment for tank crewmen was assessed regarding its efficacy for burn protection. A pig model was developed with a flame infliction instrument specially designed for this experiment. This pneumatic tool can initiate eight simultaneous flame injuries where the distance of skin from burn source and exposure time are adjustable.

Inhibitors that target protein kinases for the treatment of ovarian carcinoma.

Objective: Ovarian cancer is the leading cause of death from gynecologic malignancies in the United States. In an attempt to develop drugs that suppress ovarian cancer cells, we examined the effect of selective inhibitors of protein tyrosine kinases-tyrphostins, which are likely to play a role in ovarian cancer cells.

Study Design: We examined the cellular and biochemical effects of tyrphostins AG1478, PP2, AGL2592, and AG490 from four different families on the ovarian carcinoma cell line OV1063.

Tyrosine kinase inhibitors suppress the growth of non-hodgkin B lymphomas.

Non-Hodgkin lymphomas usually become resistant to chemotherapy and relapse due to the their intense antiapoptotic robustness. Furthermore, the slow growth of these malignancies limits the effectiveness of drugs aimed mainly at the proliferative pathways. Because protein tyrosine kinases (PTKs) play a key role in both proliferative and antiapoptotic pathways we screened our library of PTK inhibitors for agents that induce growth arrest and apoptosis in non-Hodgkin B cell lymphoma cell lines.