TRANSLATIONAL IMPACT
Ontology highlight
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PROVIDER: S-EPMC3014346 | biostudies-literature | 2011 Jan
REPOSITORIES: biostudies-literature
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Project description:The value of biomedical research-a $1.7 trillion annual investment-is ultimately determined by its downstream, real-world impact, whose predictability from simple citation metrics remains unquantified. Here we sought to determine the comparative predictability of future real-world translation-as indexed by inclusion in patents, guidelines, or policy documents-from complex models of title/abstract-level content versus citations and metadata alone. We quantify predictive performance out of sample, ahead of time, across major domains, using the entire corpus of biomedical research captured by Microsoft Academic Graph from 1990-2019, encompassing 43.3 million papers. We show that citations are only moderately predictive of translational impact. In contrast, high-dimensional models of titles, abstracts, and metadata exhibit high fidelity (area under the receiver operating curve [AUROC] > 0.9), generalize across time and domain, and transfer to recognizing papers of Nobel laureates. We argue that content-based impact models are superior to conventional, citation-based measures and sustain a stronger evidence-based claim to the objective measurement of translational potential.
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Project description:Far too much biomedical research is wasted and ends in the so called "Valley of Death": the gap that exists between biomedical research and its clinical application. While the translational process requires collaboration between many disciplines, current translational medicine focuses on single disciplines. Therefore, educational pathways that integrate clinical and research skills in interdisciplinary and interprofessional contexts are needed. The Eureka institute (http://www.eurekainstitute.org/) was founded to address these issues. The institute organizes an annual 1-week international certificate course to educate professionals in the domains of translational medicine. Study design: This study set out to investigate the impact of the Eureka certificate course on the alumni, focusing on their ability to engage in translational activities and thus become more proficient translational professionals. An explanatory, mixed-methods study was executed. Data collection: A questionnaire was distributed to collect quantitative data on the number of alumni who were able to apply what they learned during the Eureka course and engage in translational activities. Questionnaire data were also used to inform the semi-structured interviews that were conducted subsequently. Results: Fifty-one percent of the alumni reported that participating in the Eureka course played a role in their decision to change to a different job or in the way they were accomplishing their everyday work. Ten conditions for change that either hampered or supported the Eureka alumni's engagement in translational research activities were identified. Further, the learning outcomes of the Eureka course that impacted the alumni's professional activities were explored using Personal Professional Theory (PPT). The insight that alumni gained in the full translational spectrum and stakeholders involved stimulated reflection on their own role within that pathway. Further, according to the alumni, the course provided them with the skills and confidence to pursue a career as translational professional. These learning outcomes, in combination with conditions that supported alumni's engagement in translational activities, such as supportive professional partners, opportunities to network or collaborate, and a translational work environment, contributed to the large number of alumni that were able to engage in translational activities.
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Project description:Intratumoral genetic heterogeneity (ITH) poses a significant challenge to utilizing sequencing for decision making in the management of cancer. Although sequencing of multiple tumor regions can address the pitfalls of ITH, it does so at a significant increase in cost and resource utilization. We propose a pooled multiregional sequencing strategy, whereby DNA aliquots from multiple tumor regions are mixed prior to sequencing, as a cost-effective strategy to boost translational value by addressing ITH while preserving valuable residual tissue for secondary analysis. Focusing on kidney cancer, we demonstrate that DNA pooling from as few as two regions significantly increases mutation detection while reducing clonality misattribution. This leads to an increased fraction of patients identified with therapeutically actionable mutations, improved patient risk stratification, and improved inference of evolutionary trajectories with an accuracy comparable to bona fide multiregional sequencing. The same approach applied to non-small-cell lung cancer data substantially improves tumor mutational burden (TMB) detection. Our findings demonstrate that pooled DNA sequencing strategies are a cost-effective alternative to address intrinsic genetic heterogeneity in clinical settings.
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Project description:The National Institutes of Health (NIH) has long supported using nonhuman primate (NHP) models for research on kidney, pancreatic islet, heart, and lung transplantation. The primary purpose of this research has been to develop new treatments for down-modulating or preventing deleterious immune responses after transplantation in human patients. Here, we discuss NIH-funded NHP studies of immune cell depletion, costimulation blockade, regulatory cell therapy, desensitization, and mixed hematopoietic chimerism that either preceded clinical trials or prevented the human application of therapies that were toxic or ineffective.
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Project description:High-grade osteosarcoma (HGOS) is a very aggressive bone tumor which primarily affects adolescents and young adults. Although not advanced as is the case for other cancers, pharmacogenetic and pharmacogenomic studies applied to HGOS have been providing hope for an improved understanding of the biology and the identification of genetic biomarkers, which may impact on clinical care management. Recent developments of pharmacogenetics and pharmacogenomics in HGOS are expected to: i) highlight genetic events that trigger oncogenesis or which may act as drivers of disease; ii) validate research models that best predict clinical behavior; and iii) indicate genetic biomarkers associated with clinical outcome (in terms of treatment response, survival probability and susceptibility to chemotherapy-related toxicities). The generated body of information may be translated to clinical settings, in order to improve both effectiveness and safety of conventional chemotherapy trials as well as to indicate new tailored treatment strategies. Here, we review and summarize the current scientific evidence for each of the aforementioned issues in view of possible clinical applications.
| S-EPMC7369799 | biostudies-literature
Project description:TFIIH is a complex essential for transcription of protein-coding genes by RNA polymerase II, DNA repair of UV-lesions and transcription of rRNA by RNA polymerase I. Mutations in TFIIH cause the cancer prone DNA-repair disorder xeroderma pigmentosum (XP) and the developmental and premature aging disorders trichothiodystrophy (TTD) and Cockayne syndrome. A total of 50% of the TTD cases are caused by TFIIH mutations. Using TFIIH mutant patient cells from TTD and XP subjects we can show that the stress-sensitivity of the proteome is reduced in TTD, but not in XP. Using three different methods to investigate the accuracy of protein synthesis by the ribosome, we demonstrate that translational fidelity of the ribosomes of TTD, but not XP cells, is decreased. The process of ribosomal synthesis and maturation is affected in TTD cells and can lead to instable ribosomes. Isolated ribosomes from TTD patients show an elevated error rate when challenged with oxidized mRNA, explaining the oxidative hypersensitivity of TTD cells. Treatment of TTD cells with N-acetyl cysteine normalized the increased translational error-rate and restored translational fidelity. Here we describe a pathomechanism that might be relevant for our understanding of impaired development and aging-associated neurodegeneration.
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Project description:The ribosomal GTPase associated center constitutes the ribosomal area, which is the landing platform for translational GTPases and stimulates their hydrolytic activity. The ribosomal stalk represents a landmark structure in this center, and in eukaryotes is composed of uL11, uL10 and P1/P2 proteins. The modus operandi of the uL11 protein has not been exhaustively studied in vivo neither in prokaryotic nor in eukaryotic cells. Using a yeast model, we have brought functional insight into the translational apparatus deprived of uL11, filling the gap between structural and biochemical studies. We show that the uL11 is an important element in various aspects of 'ribosomal life'. uL11 is involved in 'birth' (biogenesis and initiation), by taking part in Tif6 release and contributing to ribosomal subunit-joining at the initiation step of translation. uL11 is particularly engaged in the 'active life' of the ribosome, in elongation, being responsible for the interplay with eEF1A and fidelity of translation and contributing to a lesser extent to eEF2-dependent translocation. Our results define the uL11 protein as a critical GAC element universally involved in trGTPase 'productive state' stabilization, being primarily a part of the ribosomal element allosterically contributing to the fidelity of the decoding event.
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Project description:Colorectal cancer (CRC) develops through a multi-step process characterized by the acquisition of multiple somatic mutations in oncogenes and tumor-suppressor genes, epigenetic alterations and genomic instability. These events lead to the progression from precancerous lesions to advanced carcinomas. This process requires several years in a sporadic setting, while occurring at an early age and or faster in patients affected by hereditary CRC-predisposing syndromes. Since advanced CRC is largely untreatable or unresponsive to standard or targeted therapies, the endoscopic treatment of colonic lesions remains the most efficient CRC-preventive strategy. In this review, we discuss recent studies that have assessed the genetic alterations in early colorectal lesions in both hereditary and sporadic settings. Establishing the genetic profile of early colorectal lesions is a critical goal in the development of risk-based preventive strategies.
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Project description:This work examines translational science in cancer based on theories of innovation that posit a relationship between the maturation of technologies and their capacity to generate successful products. We examined the growth of technologies associated with 138 anticancer drugs using an analytical model that identifies the point of initiation of exponential growth and the point at which growth slows as the technology becomes established. Approval of targeted and biological products corresponded with technological maturation, with first approval averaging 14 years after the established point and 44 years after initiation of associated technologies. The lag in cancer drug approvals after the increases in cancer funding and dramatic scientific advances of the 1970s thus reflects predictable timelines of technology maturation. Analytical models of technological maturation may be used for technological forecasting to guide more efficient translation of scientific discoveries into cures.
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Project description:Human processed pseudogenes are copies of cellular RNAs reverse transcribed and inserted into the nuclear genome by the enzymatic machinery of L1 (LINE1) non-LTR retrotransposons. Although it is generally accepted that germline expression is crucial for the heritable retroposition of cellular mRNAs, little is known about the influences of RNA stability, mRNA quality control and compartmentalization of translation on the retroposition of processed pseudogenes. We found that frequently retroposed human mRNAs are derived from stable transcripts with translation-competent functional reading frames that are resistant to nonsense-mediated RNA decay. They are preferentially translated on free cytoplasmic ribosomes and encode soluble proteins. Our results indicate that interactions between mRNAs and L1 proteins seem to occur at free cytoplasmic ribosomes.
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