The PAX3 gene encodes a member of the PAX family of transcription factors that is characterized by a highly conserved paired box motif. The PAX3 protein is a transcription factor consisting of an N-terminal DNA binding domain (containing a paired box and homeodomain) and a C-terminal transcriptional activation domain. This protein is expressed during development of skeletal muscle, central nervous system and neural crest derivatives, and regulates expression of target genes that impact on proliferation, survival, differentiation and motility in these lineages. Germline mutations of the murine Pax3 and human PAX3 genes cause deficiencies in these developmental lineages and result in the Splotch phenotype and Waardenburg syndrome, respectively. Somatic genetic rearrangements that juxtapose the PAX3 DNA binding domain to the transcriptional activation domain of other transcription factors deregulate PAX3 function and contribute to the pathogenesis of the soft tissue cancers alveolar rhabdomyosarcoma and biphenotypic sinonasal sarcoma. The wild-type PAX3 protein is also expressed in other cancers related to developmental lineages that normally express this protein and exerts phenotypic effects related to its normal developmental role.
Evidence of cancer immunosurveillance and immunoediting processes has been primarily demonstrated in mouse models of chemically induced oncogenesis. Although these models are very tractable, they are characterized by high mutational loads that represent a minority of human cancers. In this study, we sought to determine whether cancer immunosurveillance and immunoediting could be demonstrated in a more clinically relevant oncogene-induced model of carcinogenesis, the MMTV-PyMT (PyMT) mammary carcinoma model. This model system in the FVB/NJ strain background was previously used to demonstrate that adaptive immunity had no role in limiting primary cancer formation and in fact promoted metastasis, thus calling into question whether cancer immunosurveillance operated in preventing the development of breast cancer. Our current study in the C57BL/6 strain backgrounds provides a different conclusion, as we report here the existence of an adaptive immunosurveillance of PyMT mammary carcinomas using two independent models of immune deficiency. PyMT mice bred onto a Rag1 ¡/¡ background or immune suppressed by chronic tacrolimus therapy both demonstrated accelerated development of mammary carcinomas. By generating a bank of cell lines from these animals, we further show that a subset of PyMT cell lines had delayed growth after transplantation into wild-type (WT) syngeneic, but not immune-deficient hosts. This reduced growth rate in immunocompetent animals was characterized by an increase in immune cell infiltration and tissue differentiation. Furthermore, loss of the immune cell infiltration that characterized immunoediting of slow growing cell lines, changed them into fast growing variants capable of progressing in the immunocompetent model. In conclusion, our study provides evidence that immunosurveillance and immunoediting of PyMT-derived cell lines modulate tumor progression in this oncogene-induced model of cancer.
We describe the development of automated workflows that support computed-aided drug discovery (CADD) and molecular dynamics (MD) simulations and are included as part of the National Biomedical Computational Resource (NBCR). The main workflow components include: file-management tasks, ligand force field parameterization, receptor-ligand molecular dynamics (MD) simulations, job submission and monitoring on relevant high-performance computing (HPC) resources, receptor structural clustering, virtual screening (VS), and statistical analyses of the VS results. The workflows aim to standardize simulation and analysis and promote best practices within the molecular simulation and CADD communities. Each component is developed as a stand-alone workflow, which allows easy integration into larger frameworks built to suit user needs, while remaining intuitive and easy to extend.
The 12q13-q14 chromosomal region is recurrently amplified in 25% of fusion-positive (FP) rhabdomyosarcoma (RMS) cases and is associated with a poor prognosis. To identify amplified oncogenes in FP RMS, we compared the size, gene composition and expression of 12q13-q14 amplicons in FP RMS with other cancer categories (glioblastoma multiforme, lung adenocarcinoma and liposarcoma) in which 12q13-q14 amplification frequently occurs. We uncovered a 0.2 Mb region that is commonly amplified across these cancers and includes CDK4 and six other genes that are overexpressed in amplicon-positive samples. Additionally, we identified a 0.5 Mb segment that is only recurrently amplified in FP RMS and includes four genes that are overexpressed in amplicon-positive RMS. Among these genes, only SHMT2 was overexpressed at the protein level in an amplicon-positive RMS cell line. SHMT2 knockdown in ampliconpositive RMS cells suppressed growth, transformation and tumorigenesis, whereas overexpression in amplicon-negative RMS cells promoted these phenotypes. High SHMT2 expression reduced sensitivity of FP RMS cells to SHIN1, a direct SHMT2 inhibitor, but sensitized cells to pemetrexed, an inhibitor of the folate cycle. In conclusion, our study demonstrated that SHMT2 contributes to tumorigenesis in FP RMS and that SHMT2 amplification predicts differential response to drugs targeting this metabolic pathway.
Purpose In response to the COVID-19 pandemic, new policy waivers permitted reimbursement of telehealth services in urban settings. The aim of this study was to assess patient satisfaction with telehealth services during the COVID-19 pandemic in an outpatient urban nephrology practice. Methods Patients who had virtual encounters were asked to complete an online survey regarding their experiences with telehealth services. Results Twenty-one percent of eligible patients completed the survey. Patients (83.6%) reported overall positive experiences with telehealth and want to see a hybrid healthcare model in the future (80.1%). Additionally, most patients found telehealth appointments convenient to make and telehealth encounters convenient to conduct. Ethnicity, age, gender, and insurance type did not have a statistically significant impact on satisfaction ratings. Technical issues were not encountered by 79.5% of patients and patients were willing to use the video feature. However, if they had technical issues, patient satisfaction ratings were negatively impacted. Conclusion Telehealth services are beneficial to patients with regards to convenience, decreased transportation costs and time, increased accessibility to healthcare, and decreased overall opportunity costs. However, challenges still remain with the deployment of telehealth and will be dependent on patients’ digital health literacy, access to broadband internet and devices, and legislation and/or regulations. Limitations of the study, including small sample size and surveying patients from a nephrology practice, may prevent it from being generalizable. Additional studies with a larger sample size and multiple specialties may be needed to generalize patients’ satisfaction with telehealth services. Supplementary Information The online version contains supplementary material available at 10.1007/s11255-023-03627-9.
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