The p53 tumor-suppressor plays a critical role in the prevention of human cancer. In the absence of cellular stress, the p53 protein is maintained at low steady-state levels and exerts very little, ...if any, effect on cell fate. However, in response to various types of stress, p53 becomes activated; this is reflected in elevated protein levels, as well as augmented biochemical capabilities. As a consequence of p53 activation, cells can undergo marked phenotypic changes, ranging from increased DNA repair to senescence and apoptosis. This review deals with the mechanisms that underlie the apoptotic activities of p53, as well as the complex interactions between p53 and central regulatory signaling networks. In p53-mediated apoptosis, the major role is played by the ability of p53 to transactivate specific target genes. The choice of particular subsets of target genes, dictated by covalent p53 modifications and protein-protein interactions, can make the difference between life and apoptotic death of a cell. In addition, transcriptional repression of antiapoptotic genes, as well as transcription-independent activities of p53, can also contribute to the apoptotic effects of p53. Regarding the crosstalk between p53 and signaling networks, this review focuses on the interplay between p53 and two pivotal regulatory proteins: beta-catenin and Akt/PKB. Both proteins can regulate p53 as well as be regulated by it. In addition, p53 interacts with the GSK-3beta kinase, which serves as a link between Akt and beta-catenin. This review discusses how the functional balance between these different interactions might dictate the likelihood of a given cell to become cancerous or be eliminated from the replicative pool, resulting in suppression of cancer.
Mutant p53 gain-of-function in cancer Oren, Moshe; Rotter, Varda
Cold Spring Harbor perspectives in biology,
02/2010, Letnik:
2, Številka:
2
Journal Article
Recenzirano
Odprti dostop
In its wild-type form, p53 is a major tumor suppressor whose function is critical for protection against cancer. Many human tumors carry missense mutations in the TP53 gene, encoding p53. Typically, ...the affected tumor cells accumulate excessive amounts of the mutant p53 protein. Various lines of evidence indicate that, in addition to abrogating the tumor suppressor functions of wild-type p53, the common types of cancer-associated p53 mutations also endow the mutant protein with new activities that can contribute actively to various stages of tumor progression and to increased resistance to anticancer treatments. Collectively, these activities are referred to as mutant p53 gain-of-function. This article addresses the biological manifestations of mutant p53 gain-of-function, the underlying molecular mechanisms, and their possible clinical implications.
BACKGROUND:The iPhone X (Apple, Inc., Cupertino, Calif.) is the first smartphone to be released with a high-fidelity three-dimensional scanner. At present, half of all U.S. smartphone users use an ...iPhone. Recent data suggest that the majority of these 230 million individuals will upgrade to the iPhone X within 2 years. This represents a profound expansion in access to three-dimensional scanning technology, not only for plastic surgeons but for their patients as well. The purpose of this study was to compare the iPhone X scanner against a popular, portable three-dimensional camera used in plastic surgery (Canfield Vectra H1; Canfield Scientific, Inc., Parsippany, N.J.).
METHODS:Sixteen human subjects underwent three-dimensional facial capture with the iPhone X and Canfield Vectra H1. Results were compared using color map analysis and surface distances between key anatomical landmarks. To assess repeatability and precision of the iPhone X three-dimensional scanner, six facial scans of a single participant were obtained and compared using color map analysis. In addition, three-dimensionally–printed facial masks (n = 3) were captured with each device and compared.
RESULTS:For the experiments, average root mean square was 0.44 mm following color map analysis and 0.46 mm for surface distance between anatomical landmarks. For repeatability and precision testing, average root mean square difference following color map analysis was 0.35 mm. For the three-dimensionally–printed facial mask comparison, average root mean square difference was 0.28 mm.
CONCLUSIONS:The iPhone X offers three-dimensional scanning that is accurate and precise to within 0.5 mm when compared to a commonly used, validated, and expensive three-dimensional camera. This represents a significant reduction in the barrier to access to three-dimensional scanning technology for both patients and surgeons.
Objective
To assess the reliability and validity of Turkish version of SARC-F in regard to screening with current definitions of sarcopenia, muscle mass and functional measures.
Design
...Cross-sectional study.
Participants
Community-dwelling older adults aged >=65 years admitting to a geriatric outpatient clinic.
Measurements
Muscle mass (bioimpedance analysis), handgrip strength, usual gait speed, chair sit-to-stand test, functional reach test, short physical performance battery, SARC-F questionnaire, FRAIL questionnaire Sarcopenia was evaluated with 4 current different definitions: European Working Group on Sarcopenia in Older People’s (EWGSOP); Foundation for the National Institutes of Health (FNIH), International Working Group on Sarcopenia (IWGS) and Society on Sarcopenia, Cachexia and Wasting Disorders (SCWD).
Results
After cross-cultural adaptation, 207 subjects were analysed in the clinical validation study. Mean age was 74.6±6.7 years, 67.6% were women. Against EWGSOP, FNIH, IWGS and SCWD definitions of sarcopenia, sensitivity of SARC-F were %25, 31.6%, 50% and 40%; specificity were 81.4%, 82.4%, 81.8% and 81.7%, respectively. Positive predictive values were between 5.1-15.4% and negative predictive values were 92.3-98.2%. Against parameters of low muscle mass, sensitivity were about 20% and specificity were about 81%. Against parameters of function; for low hand grip strength, sensitivity of SARC-F were 33.7% (for Turkish cut-off); 50% (for FNIH cut-off); specificity were 93.7% (for Turkish cut-off) and 85.8% (for FNIH cut-off). Against low UGS, poor performance in chair sit to stand test, functional reach test, SPPB and presence of positive frailty screening sensitivity were 58.3%, 39.2%, 59.1%, 55.2% and 52.1% while specificity were 97.3%, 97.8%, 88.1%, 99.3% and 91.2%, respectively.
Conclusion
The psychometric performance of Turkish SARC-F was similar to the original SARC-F. It revealed low sensitivity but high specificity with all sarcopenia definitions. Sensitivity and specificity were higher for muscle function tests reflecting its inquiry and input on functional measures. Our findings suggest that SARC-F is an excellent test to exclude muscle function impairment and sarcopenia. SARC-F is relatively a good screening test for functional measures.
Virtual reality and augmented reality devices have recently been described in the surgical literature. The authors have previously explored various iterations of these devices, and although they show ...promise, it has become clear that virtual reality and/or augmented reality devices alone do not adequately meet the demands of surgeons. The solution may lie in a hybrid technology known as mixed reality, which merges many virtual reality and augmented realty features. Microsoft's HoloLens, the first commercially available mixed reality device, provides surgeons intraoperative hands-free access to complex data, the real environment, and bidirectional communication. This report describes the use of HoloLens in the operating room to improve decision-making and surgical workflow. The pace of mixed reality-related technological development will undoubtedly be rapid in the coming years, and plastic surgeons are ideally suited to both lead and benefit from this advance.
Inactivation of the p53 tumor suppressor is a frequent event in tumorigenesis. In most cases, the p53 gene is mutated, giving rise to a stable mutant protein whose accumulation is regarded as a ...hallmark of cancer cells. Mutant p53 proteins not only lose their tumor suppressive activities but often gain additional oncogenic functions that endow cells with growth and survival advantages. Interestingly, mutations in the p53 gene were shown to occur at different phases of the multistep process of malignant transformation, thus contributing differentially to tumor initiation, promotion, aggressiveness, and metastasis. Here, the authors review the different studies on the involvement of p53 inactivation at various stages of tumorigenesis and highlight the specific contribution of p53 mutations at each phase of cancer progression.
Transcatheter aortic valve replacement (TAVR) has emerged as an effective alternative to conventional surgical valve replacement in high-risk patients afflicted by severe aortic stenosis. Despite ...newer-generation devices enhancements, post-procedural complications such as paravalvular leakage (PVL) and related thromboembolic events have been hindering TAVR expansion into lower-risk patients. Computational methods can be used to build and simulate patient-specific deployment of transcatheter aortic valves (TAVs) and help predict the occurrence and degree of PVL. In this study finite element analysis and computational fluid dynamics were used to investigate the influence of procedural parameters on post-deployment hemodynamics on three retrospective clinical cases affected by PVL. Specifically, TAV implantation depth and balloon inflation volume effects on stent anchorage, degree of paravalvular regurgitation and thrombogenic potential were analyzed for cases in which Edwards SAPIEN and Medtronic CoreValve were employed. CFD results were in good agreement with corresponding echocardiography data measured in patients in terms of the PVL jets locations and overall PVL degree. Furthermore, parametric analyses demonstrated that positioning and balloon over-expansion may have a direct impact on the post-deployment TAVR performance, achieving as high as 47% in PVL volume reduction. While the model predicted very well clinical data, further validation on a larger cohort of patients is needed to verify the level of the model’s predictions in various patient-specific conditions. This study demonstrated that rigorous and realistic patient-specific numerical models could potentially serve as a valuable tool to assist physicians in pre-operative TAVR planning and TAV selection to ultimately reduce the risk of clinical complications.
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