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Gene therapy is a technique where a gene is inserted into a person’s cells to prevent or treat a serious disease. The added gene may be a healthy version of the gene that is mutated in the patient, or it could be a different gene that inactivates or compensates for the patient’s disease-causing gene. For example, in patients with severe combined immunodeficiency (SCID) due to a mutation in the gene for the enzyme adenosine deaminase, a functioning version of the gene can be...
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Integration by parts is a fundamental technique in calculus for evaluating integrals involving the product of two functions. It is particularly useful when direct integration is not feasible. The method is based on the product rule for differentiation, which states that the derivative of a product equals the derivative of the first function times the second, plus the first function times the derivative of the second. By integrating this identity and rearranging terms, the integration by parts...
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Definite integrals involving the product of two functions over a fixed interval can be evaluated using integration by parts. This method rewrites the integral as the difference of a product evaluated at the endpoints and a remaining definite integral that is often simpler to compute.A representative example is the definite integral of the inverse tangent function. Since there is no direct integration formula for arctan ⁡x, the integrand is rewritten as a product of arctan⁡ x and the...
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Integrative Bayesian Analysis Identifies Rhabdomyosarcoma Disease Genes.

Lin Xu1, Yanbin Zheng2, Jing Liu2

  • 1Department of Pediatrics, Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX; Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX.

Cell Reports
|July 5, 2018
PubMed
Summary

Researchers identified 29 cancer-driving genes in rhabdomyosarcoma using a new computational tool, iExCN. These genes, linked to cell cycle and DNA binding, offer potential therapeutic targets and impact patient survival.

Keywords:
Bayesian algorithmCRISPR/Cas9childhood cancerintegrative genomic analysisoncogenerhabdomyosarcomatumor suppressor gene

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Area of Science:

  • Oncology
  • Genomics
  • Computational Biology

Background:

  • Identifying oncogenic drivers and tumor suppressors is crucial for cancer treatment.
  • Rhabdomyosarcoma (RMS) presents challenges in pinpointing key genetic alterations.
  • DNA copy-number variants significantly influence gene expression in cancer.

Purpose of the Study:

  • To develop a computational and experimental strategy for genome-scale identification and validation of cancer driver genes.
  • To identify novel oncogenic drivers and tumor suppressors in rhabdomyosarcoma.
  • To assess the functional impact of identified genes on RMS biology and patient survival.

Main Methods:

  • Developed iExCN, a Bayesian algorithm for predicting gene expression changes from DNA copy-number variants.
  • Employed CRISPR/Cas9 "mini-pool" screens for high-throughput functional validation of candidate genes.
  • Integrated computational predictions with experimental validation in rhabdomyosarcoma models.
  • Analyzed two independent patient cohorts to correlate gene alterations with survival outcomes.

Main Results:

  • The iExCN algorithm identified 29 potential rhabdomyosarcoma drivers and suppressors.
  • Identified genes were enriched for cell-cycle and nucleic-acid-binding functions.
  • Functional studies confirmed many iExCN genes as RMS-specific or shared vulnerabilities.
  • Coordinated repression of iExCN genes during skeletal muscle differentiation was observed.
  • Copy-number alterations in iExCN genes correlated significantly with patient survival.

Conclusions:

  • Multiple drivers contribute to rhabdomyosarcoma pathogenesis.
  • The iExCN strategy is effective for discovering disease-associated genes in cancer.
  • Identified rhabdomyosarcoma drivers represent potential therapeutic targets.
  • The number of copy-number altered iExCN genes is a prognostic biomarker for RMS survival.