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Biomedical subjects

Kristy Weber

Publications and source records attributed to Kristy Weber.

6 recordsLinked to original sources
PubMed2024

Oncogene-induced matrix reorganization controls CD8+ T cell function in the soft-tissue sarcoma microenvironment.

CD8+ T cell dysfunction impedes antitumor immunity in solid cancers, but the underlying mechanisms are diverse and poorly understood. Extracellular matrix (ECM) composition has been linked to impaired T cell migration and enhanced tumor progression; however, impacts of individual ECM molecules on T cell function in the tumor microenvironment (TME) are only beginning to be elucidated. Upstream regulators of aberrant ECM deposition and organization in solid tumors are equally ill-defined. Therefore, we investigated how ECM composition modulates CD8+ T cell function in undifferentiated pleomorphic sarcoma (UPS), an immunologically active desmoplastic tumor. Using an autochthonous murine model of UPS and data from multiple human patient cohorts, we discovered a multifaceted mechanism wherein the transcriptional coactivator YAP1 promotes collagen VI (COLVI) deposition in the UPS TME. In turn, COLVI induces CD8+ T cell dysfunction and immune evasion by remodeling fibrillar collagen and inhibiting T cell autophagic flux. Unexpectedly, collagen I (COLI) opposed COLVI in this setting, promoting CD8+ T cell function and acting as a tumor suppressor. Thus, CD8+ T cell responses in sarcoma depend on oncogene-mediated ECM composition and remodeling.

CD8-Positive T-Lymphocytes↗
PubMed2005

Tumoral calcinosis in infants: a report of three cases and review of the literature.

Tumoral calcinosis is the deposition of calcium crystals and salts in the periarticular soft tissues. It commonly is seen as a complication of renal dialysis or in patients with a hereditary disposition. Occasionally, it is seen as an isolated condition with no known cause. Tumoral calcinosis usually affects adults and rarely, children. This disorder is extremely uncommon in infants. Only 13 cases have been reported. In this study three additional infants with tumoral calcinosis are reported, bringing the total to 16 cases. These 16 cases provide the opportunity to compare tumoral calcinosis in infants (younger than 18 months) with the disease in older patients. Although histologic and radiologic features in infants and adults are identical, some clinical features differ. In almost all infants, the disease develops without any predisposing factors, such as a family history. Surgical removal of lesions in infants is curative. By contrast, lesions in adults tend to recur after surgery.

Bone Neoplasms↗
PubMed2005

Unicameral bone cysts of the pelvis: a study of 16 cases.

Unicameral bone cysts of the pelvis are extremely rare. This study summarizes the clinical, radiologic and pathologic features of 16 cases. Patients ranged in age from nine to 69. Most lesions were in the anterior portion of the iliac wing; many appeared to be related to an open iliac crest apophysis. This suggests that the pathogenesis of unicameral bone cysts in this portion of the ilium is similar to that seen in the proximal humerus and the proximal femur. The correct diagnosis was made preoperatively in only five cases. This indicates that, although they are well documented, unicameral bone cysts of the pelvis remain a diagnostic problem. Patients received a spectrum of treatments from curettage to observation. There appeared to be no difference in the outcome after any form of treatment. Therefore, unicameral bone cysts of the pelvis can be managed conservatively. The choice to manage patients conservatively depends on making the correct diagnosis based on clinical history and imaging. The most effective imaging is a combination of plain radiographs, computed tomography (CT) and magnetic resonance imaging (MRI).

Adolescent↗
PubMed2003

A fully human antimelanoma cellular adhesion molecule/MUC18 antibody inhibits spontaneous pulmonary metastasis of osteosarcoma cells in vivo.

PURPOSE: The melanoma cellular adhesion molecule, also known as MUC18, is highly expressed on several tumors, including bone sarcomas. The level of MUC18 expression has been found to correlate directly with tumor progression and metastatic potential. These observations have established MUC18 as a candidate mediator of tumor growth and metastasis, and suggest that blockade of MUC18 might be a potential target for immunotherapy against several MUC18-expressing tumors, including human bone sarcomas. EXPERIMENTAL DESIGN: To investigate whether blockade of MUC18 might be a potential target for immunotherapy against osteosarcoma, we have recently developed a fully human anti-MUC18 antibody, ABX-MA1. We studied the effect of ABX-MA1 on growth, adhesion, invasion, and metastasis of human osteosaroma cells both in vitro and in vivo. RESULTS: MUC18 was widely expressed on both osteosarcoma and Ewing's sarcoma cells. ABX-MA1 had no effect on the proliferation of osteosarcoma cells in vitro, nor did it significantly inhibit the growth of KRIB human osteosarcoma cells when they were orthotopically implanted into the tibias of nude mice. However, after 6 weeks, significantly fewer ABX-MA1-treated mice developed spontaneous pulmonary metastases than did IgG-treated control mice. Additionally, ABX-MA1 decreased the invasion of osteosarcoma cells through Matrigel-coated filters and disrupted homotypic adhesion between osteosarcoma cells and their heterotypic interaction with human vascular endothelial cells. CONCLUSIONS: Our findings demonstrate that MUC18 plays a central role in the metastasis of osteosarcoma and suggest that targeted inhibition of this antigen by ABX-MA1 may be a novel immunotherapeutic approach in the management of this tumor.

Animals↗
PubMed2002

Inhibition of platelet-derived growth factor-mediated proliferation of osteosarcoma cells by the novel tyrosine kinase inhibitor STI571.

PURPOSE: Osteosarcoma is an aggressive primary bone cancer characterized by expression of platelet-derived growth factor (PDGF) and its cognate receptor. Coexpression of the growth factor and receptor suggests their role in autocrine or paracrine growth mechanisms. It has been reported previously that STI571 has specific activity in inhibiting select tyrosine kinase receptors, including PDGF and c-Kit. Osteosarcomas express low levels of c-Kit but abundant levels of PDGF receptor (PDGFR). EXPERIMENTAL DESIGN: To investigate the potential of STI571 as therapy for osteosarcoma, we studied its effects on PDGF-mediated cell growth in vitro and in an in vivo mouse model. RESULTS: PDGF acted as a potent mitogen in a dose-dependent manner in two osteosarcoma cell lines. STI571 (1.0 micro M) inhibited both PDGFR-alpha and PDGFR-beta phosphorylation and the downstream phosphorylation targets extracellular signal-regulated kinase and Akt. STI571 also inhibited PDGF-mediated growth and induced apoptosis in vitro as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and terminal deoxynucleotidyl transferase-mediated nick end labeling staining. To study the effect of STI571 alone or in combination with Taxol in an in vivo model, an osteosarcoma cell line (KRIB) was transplanted into the tibia of athymic nude mice. Mice were treated with STI571 (50 mg/kg p.o. q M-F), Taxol (8 mg/kg i.p. weekly), or STI571 plus Taxol for 6 weeks. There was no significant difference in tumor size between treatment and control mice. Aberrant signaling pathways downstream of the PDGFR in the v-Ki-ras oncogene-transformed KRIB cell line may in part explain this finding. CONCLUSIONS: Our data demonstrate that STI571 inhibits PDGF-mediated growth and leads to apoptosis of osteosarcoma cells in vitro by selective inhibition of the PDGFR tyrosine kinase. The effectiveness of STI571 in our studies suggests targeting of PDGFRs as a novel treatment for osteosarcoma.

Animals↗