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Biomedical subjects

Michael A Simon

Publications and source records attributed to Michael A Simon.

At least 19 recordsLinked to original sources
PubMed2007

Argon beam coagulation as an adjuvant for local control of giant cell tumor.

The argon beam coagulator is gaining popularity as an adjuvant therapy for treatment of giant cell tumors of bone. However, the effectiveness and functional implications of this treatment have not been assessed. To determine whether the argon beam coagulator could be a viable adjuvant treatment option, we examined the recurrence rate and functional outcome of patients with giant cell tumors who were treated with the argon beam coagulator, as an adjuvant to curettage and cementation. Thirty-seven patients who received argon beam coagulation as an adjuvant treatment for giant cell tumors diagnosed between 1993 and 2000 were identified. The median age of the patients was 32 years (range, 16-64 years). The mean followup was 73.7 months (range, 0.5-108 months). Three patients had osseous recurrences (8.3%) and one had a soft tissue recurrence. The 5-year Kaplan-Meier disease-free survival estimate was 87.2% (95% confidence interval, range, 76.3-99.8). No patient had radiographic evidence of arthritis. The average Musculoskeletal Tumor Society score was 28. Short form-36 evaluation showed no change in functional or mental perception in these patients compared with US norms. These data suggest argon beam coagulation as an adjuvant therapy is associated with in a low rate of local recurrence and is a reasonable adjuvant treatment option.

Adolescent↗
PubMed2006

Csk differentially regulates Src64 during distinct morphological events in Drosophila germ cells.

The Src family protein tyrosine kinases (SFKs) are crucial regulators of cellular morphology. In Drosophila, Src64 controls complex morphological events that occur during oogenesis. Recent studies have identified key Src64-dependent mechanisms that regulate actin cytoskeletal dynamics during the growth of actin-rich ring canals, which act as intercellular bridges between germ cells. By contrast, the molecular mechanisms that regulate Src64 activity levels and potential roles for Src64 in additional morphological events in the ovary have not been defined. In this report, we demonstrate that regulation of Src64 by Drosophila C-terminal-Src Kinase (Csk) contributes to the packaging of germline cysts by overlying somatic follicle cells during egg chamber formation. These results uncover novel roles for both Csk and Src64 in a dynamic event that involves adhesion, communication between cell types and control of cell motility. Strikingly, Src64 and Csk function in the germline to control packaging, not in migrating follicle cells, suggesting novel functions for this signaling cassette in regulating dynamic adhesion. In contrast to the role played by Csk in the regulation of Src64 activity during packaging, Csk is dispensable for ring canal growth control, indicating that distinct mechanisms control Src64 activity during different morphological events.

Animals↗
PubMed2006

Sprouty proteins are in vivo targets of Corkscrew/SHP-2 tyrosine phosphatases.

Drosophila Corkscrew protein and its vertebrate ortholog SHP-2 (now known as Ptpn11) positively modulate receptor tyrosine kinase (RTK) signaling during development, but how these tyrosine phosphatases promote tyrosine kinase signaling is not well understood. Sprouty proteins are tyrosine-phosphorylated RTK feedback inhibitors, but their regulation and mechanism of action are also poorly understood. Here, we show that Corkscrew/SHP-2 proteins control Sprouty phosphorylation and function. Genetic experiments demonstrate that Corkscrew/SHP-2 and Sprouty proteins have opposite effects on RTK-mediated developmental events in Drosophila and an RTK signaling process in cultured mammalian cells, and the genes display dose-sensitive genetic interactions. In cultured cells, inactivation of SHP-2 increases phosphorylation on the critical tyrosine of Sprouty 1. SHP-2 associates in a complex with Sprouty 1 in cultured cells and in vitro, and a purified SHP-2 protein dephosphorylates the critical tyrosine of Sprouty 1. Substrate-trapping forms of Corkscrew bind Sprouty in cultured Drosophila cells and the developing eye. These results identify Sprouty proteins as in vivo targets of Corkscrew/SHP-2 tyrosine phosphatases and show how Corkscrew/SHP-2 proteins can promote RTK signaling by inactivating a feedback inhibitor. We propose that this double-negative feedback circuit shapes the output profile of RTK signaling events.

Animals↗
PubMed2006

Radical cystectomy after bacillus Calmette-Guérin for high-risk Ta, T1, and carcinoma in situ: defining the risk of initial bladder preservation.

OBJECTIVES: To critically evaluate the survival of patients with high-grade Ta or T1 urothelial cancer (UC) or carcinoma in situ of the bladder who have received bacillus Calmette-Guérin (BCG) and who have undergone radical cystectomy. METHODS: We retrospectively reviewed our single-surgeon database of those patients who underwent cystectomy and previously received BCG. We evaluated the baseline characteristics, pathologic outcomes, and survival data. RESULTS: Of 313 patients who underwent cystectomy between January 1992 and March 2004, 90 (29%) received BCG before bladder removal. The mean time from the first BCG course to the date of cystectomy was 27.9 months. The mean duration of follow-up from cystectomy was 32.1 months. The risk of progression to muscle invasion for those who underwent cystectomy less than or more than 1 year from the time of their first BCG dose was 59% and 36%, respectively (P = 0.05). The disease-specific survival rate was 81% versus 80% for those who underwent early versus delayed cystectomy (P = 0.9). CONCLUSIONS: Patients with high-grade UC are at risk of dying from this cancer, even if they ultimately undergo cystectomy. Patients who receive BCG should be appropriately counseled that they remain at risk for disease progression and death from UC. It is difficult to ascertain the proper time to proceed with cystectomy if an initial bladder conservation approach is used.

Adjuvants, Immunologic↗
PubMed2006

Prostate specific antigen recurrence rates are low after radical retropubic prostatectomy and positive margins.

PURPOSE: Treatment in patients with a positive surgical margin after radical retropubic prostatectomy is controversial. Options are observation, radiation therapy and early hormone therapy. Making the appropriate choice should be based on an understanding of the risk of recurrence without treatment. MATERIALS AND METHODS: We reviewed the records of 1,383 patients after radical retropubic prostatectomy was performed by a single surgeon. All specimens were analyzed by a single pathologist. Of the patients 936 met criteria for analysis. RESULTS: Mean followup in these 936 patients was 45.8 months (minimum 12). The overall PSA biochemical recurrence rate was 11.5% (108 of 936 cases). Of the 936 patients 350 (37%) had tumor at an inked margin. These patients had a recurrence rate of 19% (67 of 350), while patients with negative margins had a recurrence rate of 7% (41 of 586). This difference was statistically significant (p <0.01). Multivariate HR analysis revealed that significant risk factors for recurrence in the 936 patients were PSA greater than 20 ng/ml, clinical stage T2 or greater, Gleason 7 or greater, seminal vesicle involvement, extraprostatic extension, a visual estimate of prostate cancer volume of greater than 9.1% and positive surgical margins. Statistically significant risk factors for recurrence in patients with a positive margin on multivariate HR analysis were PSA greater than 20 ng/ml, Gleason score 7 or greater and seminal vesicle involvement. CONCLUSIONS: Although the positive margin rate in this series was 37%, the recurrence rate in these patients was only 19%. It is important to consider other factors, such as PSA, Gleason score, seminal vesicle involvement and extraprostatic extension, when making treatment decisions.

Humans↗
PubMed2006

Complications of intravesical therapy for urothelial cancer of the bladder.

PURPOSE: Intravesical therapy is an integral part of treatment in patients with superficial urothelial carcinoma of the bladder. The American Urological Association and European Association of Urology guidelines on bladder cancer incorporate it for the treatment of superficial bladder cancer. Given the extensive use of intravesical immunotherapy and chemotherapy, it is essential for the practicing urologist to be aware of the local and systemic side effects of these therapies. MATERIALS AND METHODS: We reviewed the literature on intravesical immunotherapy and chemotherapy with particular emphasis on side effects, complications and their management. A Medline search of the English language literature for the last 25 years was done on Entrez PubMed and all relevant articles were studied in full. All side effects and complications were studied and their management was reviewed. RESULTS: Intravesical therapy for transitional cell carcinoma of the bladder is generally safe. There is a high incidence of local, usually self-limiting, relatively minor side effects and infrequent, potentially severe local and systemic side effects. Most side effects are avoidable. CONCLUSIONS: Although intravesical therapy is generally safe, local and systemic side effects occur and it is important to be aware of them. Identifying complications early, preventing them when possible and managing them efficiently are critical. Most complications are preventable. Knowing the risks and benefits of chemotherapeutic and immunotherapeutic agents may decrease the short-term and long-term toxicity of these agents. Adherence to guidelines may prevent inappropriate use, which can lead to unnecessary complications, resulting in bladder dysfunction and even cystectomy.

Adjuvants, Immunologic↗
PubMed2005

Increased expression of S100A6 is associated with decreased metastasis and inhibition of cell migration and anchorage independent growth in human osteosarcoma.

While most osteosarcoma patients have metastatic or micrometastatic lesions, less than 15% of them have clinically detectable metastatic diseases at presentation. To identify potential markers that may predict osteosarcoma metastasis, we analyzed the expression of S100A6 in 50 osteosarcoma cases and found that 84% of the analyzed specimens stained positive for S100A6. There is a trend towards decreased clinically evident metastasis with increased S100A6 staining. Overexpression of S100A6 in osteosarcoma cells decreases cell motility and anchorage independent growth on collagen gels. Our findings provide evidence that, while S100A6 is commonly overexpressed in human osteosarcoma, loss of its expression correlates with a metastatic phenotype.

Adolescent↗
PubMed2005

An orthotopic model of human osteosarcoma growth and spontaneous pulmonary metastasis.

Osteosarcoma is the most common primary malignancy of bone and patients often develop pulmonary metastases. In order to investigate the pathogenesis of human osteosarcoma, there is a great need to develop a clinically relevant animal model. Here we report the development of an osteosarcoma animal model using three related human osteosarcoma lines, the parental TE-85 and two derivative lines MNNG/HOS and 143B. In vitro characterization demonstrated that the 143B line had the greatest cell migration and the least cell adhesion activities among the three lines. The 143B line also exhibited the greatest ability for anchorage independent growth. When GFP-tagged osteosarcoma cells were injected into the proximal tibia of athymic mice, we found that 143B cells were highly tumorigenic and metastatic, and MNNG/HOS cells were tumorigenic but significantly less metastatic. TE85 cells were neither tumorigenic nor metastatic. The number of pulmonary metastases was found 50-fold higher in 143B injected animals than that in MNNG/HOS injected mice. No pulmonary metastases were detected in TE85 injected animals for up to 8 weeks. Primary tumors formed by MNNG/HOS and 143B cells could be visualized by whole body fluorescence imaging, while the pulmonary metastases were visualized on the necropsied samples. The GFP tagged 143B cells (and to a lesser extent, MNNG/HOS cells) were readily recovered from lung metastases. This clinically relevant model of human osteosarcoma provides varying degrees of tumor growth at the primary site and metastatic potential. Thus, this orthotopic model should be a valuable tool to investigate factors that promote or inhibit osteosarcoma growth and/or metastasis.

Animals↗
PubMed2004

Planar cell polarity in the Drosophila eye is directed by graded Four-jointed and Dachsous expression.

Planar cell polarity (PCP) occurs when the cells of an epithelium are polarized along a common axis lying in the epithelial plane. During the development of PCP, cells respond to long-range directional signals that specify the axis of polarization. In previous work on the Drosophila eye, we proposed that a crucial step in this process is the establishment of graded expression of the cadherin Dachsous (Ds) and the Golgi-associated protein Four-jointed (Fj). These gradients were proposed to specify the direction of polarization by producing an activity gradient of the cadherin Fat within each ommatidium. In this report, I test and confirm the key predictions of this model by altering the patterns of Fj, Ds and Fat expression. It is shown that the gradients of Fj and Ds expression provide partially redundant positional information essential for specifying the polarization axis. I further demonstrate that reversing the Fj and Ds gradients can lead to reversal of the axis of polarization. Finally, it is shown that an ectopic gradient of Fat expression can re-orient PCP in the eye. In contrast to the eye, the endogenous gradients of Fj and Ds expression do not play a major role in directing PCP in the wing. Thus, this study reveals that the two tissues use different strategies to orient their PCP.

Animals↗
PubMed2004

Localization of Tec29 to ring canals is mediated by Src64 and PtdIns(3,4,5)P3-dependent mechanisms.

Two tyrosine kinases, Src64 and Tec29, regulate the growth of actin rich-ring canals in the Drosophila ovary. We have shown previously that Src64 directs the localization of Tec29 to ring canals, but the mechanism underlying this process was unknown. Here, we show that Tec29 localizes to ring canals via its Src homology 3 (SH3) and Src homology 2 (SH2) domains. Tec29 activity is required for its own ring canal localization, suggesting that a phosphotyrosine ligand for the SH2 domain is generated by Tec29 itself. Src64 regulates this process by phosphorylating Y677 within the kinase domain of Tec29, an event required for Tec29 activation. We also show that the pleckstrin homology (PH) domain of Tec29 has dual functions in mediating Src64 regulation. In the absence of Src64, the PH domain prevents Tec29 ring canal localization. In the presence of Src64, it enhances membrane targeting of Tec29 by a PI(3,4,5)P(3)-mediated mechanism. In the absence of its PH domain, Tec29 constitutively localizes to ring canals, but still requires Src64 for full activation.

Animals↗
PubMed2004

The incidence and prognosis of osteosarcoma skip metastases.

The poor prognosis for patients with osteosarcoma skip metastases has been established in the literature; however, most of the data in the literature concerning osteosarcoma skip metastases were collected before routine use of magnetic resonance imaging and before the use of modern multiagent chemotherapy regimens. This retrospective multiinstitutional study was done to evaluate the efficacy of magnetic resonance imaging to detect skip metastases and to evaluate the prognosis for these patients when treated with modern multiagent chemotherapy protocols. In a group of 155 patients who were younger than 26 years when diagnosed and treated for high-grade osteosarcoma of the long bones, 10 (6.5%) patients with skip metastases were identified. Eight of the 10 lesions were detected on pretreatment magnetic resonance imaging scans and two were detected only from the surgical pathology specimens. Five patients had concomitant pulmonary metastases at presentation and five patients had no other known site of diseases. All 10 patients died, with an average survival of 32.5 months (range 11-71 months). The five patients with only skip metastases at presentation survived an average of 27.2 months (range 15-44 months). Despite advances in the treatment of patients with osteosarcomas, those with skip metastases continue to have a poor prognosis, and they should be counseled regarding the limitations of current therapies.

Adolescent↗
PubMed2003

Fidelity in planar cell polarity signalling.

The polarity of Drosophila wing hairs displays remarkable fidelity. Each of the approximately 30,000 wing epithelial cells constructs an actin-rich prehair that protrudes from its distal vertex and points distally. The distal location and orientation of the hairs is virtually error free, thus forming a nearly perfect parallel array. This process is controlled by the planar cell polarity signalling pathway. Here we show that interaction between two tiers of the planar cell polarity signalling mechanism results in the observed high fidelity. The first tier, mediated by the cadherin Fat, dictates global orientation by transducing a directional signal to individual cells. The second tier, orchestrated by the 7-pass transmembrane receptor Frizzled, aligns each cell's polarity with that of its neighbours through the action of an intercellular feedback loop, enabling polarity to propagate from cell to cell. We show that all cells need not respond correctly to the presumably subtle signal transmitted by Fat. Subsequent action of the Frizzled feedback loop is sufficient to align all the cells cooperatively. This economical system is therefore highly robust, and produces virtually error-free arrays.

Animals↗
PubMed2003

Current bladder cancer tests: unnecessary or beneficial?

Bladder cancer is currently diagnosed using cystoscopy and cytology in patients with suspicious signs and symptoms. These same tests are used to monitor patients with a history of bladder cancer for recurrence. The recurrence rate for bladder cancer is high, thus necessitating long-term follow-up. Urine cytology requires an experienced cytopathologist and is costly. It has high specificity, but low sensitivity for low-grade bladder tumors. Recently many non-invasive bladder cancer tests, utilizing markers found in the urine, have been developed. The FDA has approved several of these for the use is bladder cancer diagnosis, and many others are undergoing development and investigation. An ideal bladder cancer test would be non-invasive, highly sensitive and specific, inexpensive, easy to perform, and yield highly reproducible results. Many of the tests reviewed meet some, but not all, of these criteria.

Biomarkers, Tumor↗