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Biomedical subjects

M Strauss

Publications and source records attributed to M Strauss.

At least 91 records · Page 5Linked to original sources
PubMed1997

The vertebrate myosin heavy chain: genetics and assembly properties.

The vertebrate sarcomere is a complex structure composed of numerous proteins arranged in an exquisitely precise manner. Sarcomeric proteins are organized into interdigitating thick or thin filaments and the sliding of these filaments relative to one another constitutes muscle contraction at the sarcomere level. Consequently, an understanding of sarcomeric structure and function requires a thorough knowledge of the individual components of the thick and thin filaments, as well as their associations. Thick filaments are comprised of myosin, which provides the force required to drive muscle contraction and also plays a major structural role in thick filament formation. In addition, a family of thick filament-associated proteins plays a role in organization of the thick filament. We have used both molecular genetic and cell biological approaches to define the diversity of the myosin heavy chain gene family and to analyze the assembly of myosin and it's associated proteins into thick filaments.

Animals↗
PubMed1997

A phase I trial of radiotherapy and simultaneous 24-hour paclitaxel in patients with locally advanced head and neck squamous cell carcinoma.

Preclinical studies have demonstrated that tumor cells exposed to paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) for protracted periods (ie, 24 hours) and then irradiated undergo enhanced radiation-induced cell kill. Importantly, paclitaxel-induced tumor cell mitotic arrest at the time of radiation was associated with the enhanced cell kill. At the Case Western Reserve Cancer Center, we have conducted a phase I trial in 24 patients with either locally advanced or recurrent/metastatic head and neck squamous cell carcinoma to evaluate the clinical and pharmacologic effects of a 24-hour paclitaxel infusion combined with radiotherapy. The maximum tolerated dose was < or =75 mg/m2. Dose-limiting toxicity was febrile granulocytopenia. Mucositis was significant and necessitated the use of enteral feeding tubes in the majority of patients. All patients with locally advanced disease demonstrated either a complete response or major partial response. At a median follow-up of 13.4 months, disease has relapsed in only two of 22 patients with locally advanced disease. Pharmacokinetic studies revealed that a dose of > or =75 mg/m2 achieved near steady-state mean paclitaxel plasma concentrations greatly exceeding the threshold concentrations shown to alter microtubule function and induce tumor cell mitotic arrest in vitro. Pharmacodynamic studies performed at 21 to 26 hours after initiation of infusion demonstrated that a dose of > or =75 mg/m2 uniformly induced tumor cell mitotic arrest and oral epithelial mitotic arrest. The pharmacologic data and outcome results provide a strong rationale for the continued use of a 24-hour paclitaxel infusion and concurrent radiation for the treatment of newly diagnosed, locally advanced head and neck squamous cell carcinoma in an experimental setting.

Adult↗
PubMed1996

Gene transfer into hepatocytes and human liver tissue by baculovirus vectors.

Gene therapy of liver diseases requires the development of efficient vectors for gene transfer in vivo. Retroviral and adenoviral vectors have been shown to deliver genes efficiently into hepatocytes in vitro and in vivo. However, these vectors do not allow for exclusive infection of the liver which would be highly advantageous for in vivo gene therapy strategies. We have recently demonstrated that genetically modified baculoviruses (Autographa californica nuclear polyhedrosis virus) efficiently deliver genes into cultured cells and have a strong preference for hepatocytes of different origin. Baculoviral gene transduction efficiency into human hepatocytes was determined to approach 100% and expression levels are high, provided that gene expression is controlled by mammalian promoters. In this report, we present further properties of baculoviruses regarding their use for hepatocyte gene transfer. Baculovirus-mediated gene expression declines rapidly in the hepatocellular carcinoma cell line Huh7 and more slowly in primary cultures of mouse hepatocytes. Direct application of baculoviruses for gene delivery to the liver in vivo is hampered by serum components, presumably by complement. However, we demonstrate here that baculoviral gene transfer is feasible in ex vivo perfused human liver tissue. This result suggests the development of a strategy using baculoviral vectors for liver-directed gene therapy.

Animals↗
PubMed1996

[Control mechanisms of cell transition from the G1 phase to the S phase--the R point].

The critical moment of regulation when transition of the cell from the G1 to the S phase takes which is decisive for its division is the so-called R-point (restriction point). The disorder of molecular mechanisms controlling the passage of the cell through this site is an associated manifestation of most tumourous processes. A considerable part of this mechanism is the RB protein, binding transcription factors needed for the activation of genes effective in the S phase. Its binding capacity depends on the extent of phosphorylation and on the activity of the appropriate kinases and their inhibitors.

Cyclin-Dependent Kinases↗
PubMed1996

Enhanced protein stability: a novel mechanism of D-type cyclin over-abundance identified in human sarcoma cells.

The mammalian D-type cyclins promote progression through a G1 checkpoint by phosphorylating the retinoblastoma protein (pRB), and can contribute to oncogenesis via their deregulated expression achieved through gene amplification, chromosomal rearrangement, or retroviral integration. We now report a novel mechanism of tumour-associated D-cyclin over-abundance, resulting from enhanced protein stability. In two human cell lines established from a single uterine sarcoma biopsy, pRB-positive SK-UT-1B and pRB-deficient SK-UT-1, aberrant accumulation of functional cyclins D1, and D2 and D3 occurred in the absence of gene amplification and/or elevated mRNA expression. The abundance of D-cyclin proteins remained elevated throughout the cell cycle, and pulse-chase experiments revealed six to 10-fold prolongation of their protein half-lives as compared with either diploid fibroblasts or control U-2-OS sarcoma cells. These results point to a critical regulatory role of D-type cyclin turnover, and contribute to refinement of current views of the role played by the cyclin D-CDK-p16-pRB pathway in cell cycle control and tumorigenesis.

Cyclin D↗
PubMed1996

The retinoblastoma protein modulates expression of genes coding for diverse classes of proteins including components of the extracellular matrix.

The product of the retinoblastoma susceptibility gene, pRb, is a negative regulator of cell growth. It functions by regulating the activity of transcription factors. Rb represses some genes by sequestering or inactivating the positive transcription factor E2F and seems to activate some others by interacting with factors like Sp1 or ATF-2. However, there are only a few examples of genes which are positively regulated by pRb. In order to find out if there are common mechanisms for promoter regulation by pRb, we were interested to identify more genes which are either stimulated or repressed by pRb. Using the method of differential display (DDRT-PCR) in combination with nuclear run-on analyses we were able to detect a number of genes which are upregulated by ectopic expression of the Rb gene in Rb-deficient mammary carcinoma cells. We could demonstrate not only stimulation of the endogenous mutant Rb gene but also positive regulation of genes coding for diverse classes of proteins, including the endothelial growth regulator endothelin-1 and the proteoglycans versican and PG40. As a second approach, we investigated gene expression in cell lines established from Rb deficient heterozygous and homozygous knockout mouse embryos and normal mice. We have identified several genes the expression of which correlates positively or negatively with the presence of Rb. These data provide further evidence for pRb being a master regulator of a complex network of gene activities defining the difference between dividing and resting or differentiated cells.

Animals↗
PubMed1996

[Asymptomatic choledochal cyst].

HISTORY AND FINDINGS: A 45-year-old woman sustained an ankle fracture in an accident. At examination she was found to have marked pallor of skin and mucosae. There was no hint for melaena or haematemesis. INVESTIGATIONS: Biochemical tests showed marked iron deficiency anaemia (haemoglobin 7.5 g/dl) and raised serum bilirubin and C-reactive protein levels (1.94 mg/dl and 85.2 mg/l, respectively). Abdominal sonography revealed a cystic space-occupying mass (8 x 4.5 cm) projecting onto the gallbladder, interpreted as a choledochal cyst of unknown origins without bleeding. After treatment of the ankle fracture an endoscopic retrograde cholangiopancreatography was performed. This showed a large cyst of the choledochal duct into which the cystic and choledochal ducts entered, without evidence of tumour or haematoma. There was also a 1 cm prepapillary common choledochal and Wirsung duct. TREATMENT AND COURSE: With these findings, the diagnosis of a congenital choledochal cyst (type Ia of Todani) could be made. After healing of the ankle fracture the cyst was removed and a Roux Y-anastomosis created. The cystic tissue was benign. At follow-up 6 months later the patient was symptom-free and no longer anaemic. CONCLUSIONS: Congenital choledochal cysts are very rare in Europeans. The symptom-free course with anaemia and no manifestation until adulthood is also very unusual.

Anastomosis, Roux-en-Y↗
PubMed1996

Liver-directed gene transfer and application to therapy.

The liver is an important and attractive target for the development of gene therapy strategies. Many genetic diseases are manifested in the liver, and both infectious and malignant diseases affect this organ. Retroviral and adenoviral vectors have been shown to infect hepatocytes with varying efficiently in vitro and in vivo. The presence of unique receptors at the cellular membrane of hepatocytes has stimulated the development of transfer strategies based on receptor targeting of vectors. The results of a first clinical trial for gene therapy in the liver based on ex vivo gene delivery has shown both the feasibility and the limits of current technology. This review discusses both existing vectors and strategies and prospective developments towards liver-directed gene therapy of genetic and malignant diseases.

Animals↗
PubMed1996

Relationship between sleepiness and general health status.

One commonly used instrument for evaluating general health and functional status is the medical outcomes survey short form 36 (MOS). Scores obtained from this instrument are known to vary with chronic diseases and depression. However, the degree to which these health dimensions may be influenced by sleep quality or sleepiness is not well understood. A cross-sectional study was performed on the association between general health status, as determined by the MOS, with sleepiness, assessed using a standardized questionnaire [the Epworth sleepiness scale (ESS)] and the multiple sleep latency test (MSLT). One hundred twenty-nine subjects (68 women), aged 25-65 years, without severe chronic medical or psychiatric illnesses, underwent an overnight sleep study, followed by an MSLT (consisting of a series of four attempts at napping at 2-hour intervals), and completed the MOS and the ESS. The mean MSLT score was 11 +/- 2 minutes, (range 2-20) and the mean ESS score was 10 +/- 5 (range 0-24). Scores for the MOS dimensions "general health perceptions", "energy/fatigue", and "role limitations due to emotional problems" were correlated significantly with ESS scores (r = -0.30, -0.41, and -0.30, respectively; p values were all < 0.001). The MSLT was also significantly correlated with "energy/fatigue" (r = -0.19; p < 0.05). After considering the effects of chronic illness and/or body mass index in a multiple hierarchical regression analysis, sleepiness, as assessed by the ESS score, explained 8% of the variance in general health perceptions, 17% of the variance in energy/fatigue, 6% of the variance in the summary measure of well-being, and 3% of the variance in the summary measure of functional status. The variation of MOS scores with sleepiness, unrelated to age or chronic disease, suggests that measures of general health status may be broadly influenced by sleepiness and sleep quality. These data suggest that 1) sleepiness has an important impact on general health and functional status, specifically influencing self-perceptions regarding energy/fatigue; 2) a more specific assessment of sleepiness in general health evaluations may help explain some of the observed variability in these measures across subjects; and 3) general health measures may be useful in the evaluations of patients with sleep disorders.

Adult↗
PubMed1996

Ultrastructural study of peripheral nerve injury induced by monopolar and bipolar diathermy.

The effect of unipolar and bipolar electrocoagulation on human and albino rat peripheral nerves was examined by transmission electron microscopy. The greater auricular nerve obtained from operated patients and the femoral nerve of an albino rat were chosen for this study. The nerves were divided into three groups: controls, segments of nerves spot-coagulated with unipolar instruments, and segments of nerves spot-coagulated with bipolar instruments. Significant cell injury, expressed by marked damage of the Schwann cells, was induced by unipolar coagulation in both myelinated and unmyelinated nerves, in humans as well as in the albino rat. However, in bipolar-treated nerves, the Schwann cell architecture remained well preserved in both types of nerves. The results are in favor of bipolar electrocoagulation when applied in areas rich in neurovascular supplies.

Animals↗
PubMed1996

Evaluation of HBV promoters for use in hepatic gene therapy.

Strategies for in vivo hepatic gene therapy will require regulatory elements which allow for long-term expression of therapeutic genes and restriction of expression to hepatocytes. This study investigates the suitability of promoters derived from hepatitis B virus (HBV) for liver-specific gene expression in vectors for hepatic gene therapy. We provide three hepatocyte-specific promoters, the HBV core promoter, the HBV core promoter linked directly to the HBV enhancer I, and a hybrid promoter containing the HBV enhancer II and a basic CMV promoter, which are hepatocyte-specific and allow for increasing levels of reporter gene expression. Moreover, in long-term expression studies using our promoter constructs in the context of an EBV based expression system we found that expression from these promoters remained nearly unchanged over a period of at least two months in hepatocyte-derived cell lines.

3T3 Cells↗
PubMed1996

Gene therapy: prospects for treatment of liver disease.

Gene therapy in the liver for treatment of metabolic diseases is a great challenge. The development of vectors for gene transfer to hepatocytes in vitro and to the liver in vivo has advanced very rapidly within the last few years. However, none of the existing vectors would allow for expression of therapeutic levels of a gene product for a longer period of time. Our laboratory is developing alternative strategies for gene transfer to the liver in vivo which are based on composite vectors consisting of envelopes and promoters derived from hepatitis B virus, an EBV-derived replicon, and the chromosomal protein HMG1. Hepatocyte specificity of both, binding of the particles and expression of foreign genes, was demonstrated.

Arteriosclerosis↗