Meningioma Genomics: Diagnostic, Prognostic, and Therapeutic Applications

There has been a recent revolution in our understanding of the genetic factors that drive meningioma, punctuating an equilibrium that has existed since Cushing’s germinal studies nearly a century ago. A growing appreciation that meningiomas share similar biologic features with other malignancies has allowed extrapolation of management strategies and lessons from intra-axial central nervous system neoplasms and systemic cancers to meningiomas. These features include a natural proclivity for invasion, frequent intratumoral heterogeneity, and correlation between biologic profile and clinical behavior. Next-generation sequencing has characterized recurrent somatic mutations in NF2, TRAF7, KLF4, AKT1, SMO, and PIK3CA, which are collectively present in ~80% of sporadic meningiomas. Genomic features of meningioma further associate with tumor location, histologic subtype, and possibly clinical behavior. Such genomic decryption, along with advances in targeted pharmacotherapy, provides a maturing integrated view of meningiomas. We review recent advances in meningioma genomics and probe their potential applications in diagnostic, therapeutic, and prognostic frontiers

Framework for a Protein Ontology

Biomedical ontologies are emerging as critical tools in genomic and proteomic research, where complex data in disparate resources need to be integrated. A number of ontologies describe properties that can be attributed to proteins. For example, protein functions are described by the Gene Ontology (GO) and human diseases by SNOMED CT or ICD10. There is, however, a gap in the current set of ontologies – one that describes the protein entities themselves and their relationships. We have designed the PRotein Ontology (PRO) to facilitate protein annotation and to guide new experiments. The components of PRO extend from the classification of proteins on the basis of evolutionary relationships to the representation of the multiple protein forms of a gene (products generated by genetic variation, alternative splicing, proteolytic cleavage, and other post-translational modifications). PRO will allow the specification of relationships between PRO, GO and other ontologies in the OBO Foundry. Here we describe the initial development of PRO, illustrated using human and mouse proteins involved in the transforming growth factor-beta and bone morphogenetic protein signaling pathways

Evaluating the Impact of Resident Participation and the July Effect on Outcomes in Autologous Breast Reconstruction

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Management of intracranial melanomas in the era of precision medicine

Melanoma is the most lethal of skin cancers, in part because of its proclivity for rapid and distant metastasis. It is also potentially the most neurotropic cancer in terms of probability of CNS metastasis from the primary lesion. Despite surgical resection and radiotherapy, prognosis remains guarded for patients with brain metastases. Over the past five years, a new domain of personalized therapy has emerged for advanced melanoma patients with the introduction of BRAF and other MAP kinase pathway inhibitors, immunotherapy, and combinatory therapeutic strategies. By targeting critical cellular signaling pathways and unleashing the adaptive immune response against tumor antigens, a subset of melanoma patients have demonstrated remarkable responses to these treatments. Over time, acquired resistance to these modalities inexorably develops, providing new challenges to overcome. We review the rapidly evolving terrain for intracranial melanoma treatment, address likely and potential mechanisms of resistance, as well as evaluate promising future therapeutic approaches currently under clinical investigation

Thoracic endovascular aortic repair of metachronous thoracic aortic aneurysms following prior infrarenal abdominal aortic aneurysm repair

Objective: Thoracic endovascular aortic repair (TEVAR) of metachronous thoracic aortic aneurysms (M-TAAs) following previous infrarenal abdominal aortic aneurysm (AAA) repair has been associated with higher spinal cord ischemia (SCI) risk compared with TEVAR of primary thoracic aortic aneurysms (TAAs). However, data on the impact of the type of prior infrarenal aortic repair on outcomes are scarce. In this study, we examined perioperative outcomes and long-term mortality following TEVAR M-TAA compared with primary TEVAR of TAA. Methods: We identified all Vascular Quality Initiative (VQI) patients who underwent TEVAR of TAA in the descending thoracic aorta from 2013 to 2022. Only patients undergoing primary TEVAR or TEVAR following infrarenal open (OAR) or endovascular (EVAR) repair were included. We performed univariate analyses to identify differences in baseline and procedural characteristics, and multivariable analyses for perioperative outcomes and 5-year mortality using logistic and Cox regression, respectively. Results: We included 1493 patients who underwent primary TEVAR (81%) or TEVAR following prior OAR (9.0%) or prior EVAR (9.7%). Compared with primary TEVAR, patients undergoing TEVAR M-TAA were older, more commonly male, white, and had higher rates of hypertension, smoking, and renal dysfunction. Patients with M-TAA were more likely to be asymptomatic and have larger diameters at presentation but were exposed to greater contrast volume and procedural times relative to primary TEVAR patients. Following risk-adjustment, compared with primary TEVAR, TEVAR after prior EVAR was associated with higher perioperative mortality (9.7% vs 3.9%; odds ratio [OR], 5.3; 95% confidence interval [CI], 2.3-12; P &lt; .001) and 5-year mortality (40% vs 24%; hazard ratio [HR], 2.1; 95% CI, 1.4-3.1; P = .001). Specifically, among octogenarians (n = 375; 25%), the perioperative and 5-year mortality differences were even more pronounced (perioperative mortality: 17% vs 8.4%; OR, 6.7; 95% CI, 2.2-21; P = .001; 5-year mortality: 50% vs 27%; HR, 3.0; 95% CI, 1.5-5.7; P = .010). However, in-hospital complications, including SCI (2.6% vs 2.8%; OR, 1.2; 95% CI, 0.33-3.3; P = .77), were not notably different. In contrast, TEVAR after previous OAR was associated with comparable perioperative mortality (4.4% vs 3.9%; OR, 1.2; 95% CI, 0.32-3.8; P = .73), 5-year mortality (28% vs 24%; HR, 1.3; 95% CI, 0.80-2.1; P = .54), and in-hospital complications, including SCI (2.6% vs 0.7%; OR, 0.21; 95% CI, 0.01-1.1; P = .16). Conclusions: Patients undergoing TEVAR of M-TAAs after prior EVAR, particularly octogenarians, have higher perioperative and 5-year mortality and therefore, represent a high-risk group. Future efforts should strive to discern the underlying factors leading to these poorer outcomes; meanwhile, these findings emphasize the need for careful patient selection and appropriate preoperative counseling in these high-risk individuals.</p

MiR-409-3p regulates angiogenesis, white to brown adipose tissue transition, and insulin resistance through MAP4K3 and ZEB1 signaling pathways.

Endothelial cells (ECs) within the microvasculature of brown adipose tissue (BAT) are important in regulating the plasticity of adipocytes in response to increased metabolic demand by modulating the angiogenic response. However, the mechanism of EC-adipocyte crosstalk during this process is not completely understood. We used RNA sequencing to profile microRNAs derived from BAT ECs of obese mice and identified an anti-angiogenic microRNA, miR-409-3p. MiR-409-3p overexpres- sion inhibited EC angiogenic properties; whereas, its inhibition had the opposite effects. Mechanistic studies revealed that miR-409-3p targets ZEB1 and MAP4K3. Knockdown of ZEB1/MAP4K3 phenocopied the angiogenic effects of miR-409-3p. Adipocytes co-cultured with conditioned media from ECs deficient in miR-409-3p showed increased expression of BAT markers, UCP1 and CIDEA. We identified a pro-angiogenic growth factor, placental growth factor (PLGF), released from ECs in response to miR-409-3p inhibition. Deficiency of ZEB1 or MAP4K3 blocked the release of PLGF from ECs and PLGF stimulation of 3T3-L1 adipocytes increased UCP1 expression in a miR-409-3p dependent manner. MiR-409-3p neutraliza- tion improved BAT angiogenesis, glucose and insulin tolerance, and energy expenditure in mice with diet-induced obesity. These findings establish miR-409-3p as a critical regulator of EC-BAT crosstalk by modulating a ZEB1-MAP4K3-PLGF signaling axis, providing new insights for therapeutic intervention in obesity

Evaluating the Impact of ACGME Resident Duty Hour Restrictions on Patient Outcomes for Bilateral Breast Reductions

Background:. The Accreditation Council for Graduate Medical Education (ACGME) implemented duty-hour restrictions limiting residents to 80 hours per week in 2003 and further extended restrictions in 2011 to improve resident and patient well-being. Numerous studies have examined the effects of these restrictions on patient outcomes with inconclusive results. Few efforts have been made to examine the impact of this reform on the safety of common plastic surgery procedures. This study seeks to assess the influence of ACGME duty-hour restrictions on patient outcomes, using bilateral breast reduction mammoplasty as a marker for resident involvement and operative autonomy. Methods:. Bilateral breast reductions performed in the 3 years before and after each reform were collected from the National Inpatient Sample database: pre-duty hours (2000–2002), duty hours (2006–2008), and extended duty hours (2012–2014). Multivariable logistic regression models were constructed to investigate the association between ACGME duty hour restrictions on medical and surgical complications. Results:. Overall, 19,423 bilateral breast reductions were identified. Medical and surgical complication rates in these patients increased with each successive iteration of duty hour restrictions (P < 0.001). The 2003 duty-hour restriction independently associated with increased surgical (OR = 1.51, P < 0.001) and medical complications (OR = 1.85, P < 0.001). The 2011 extended duty-hour restriction was independently associated with increased surgical complications (OR = 1.39, P < 0.001). Conclusions:. ACGME duty-hour restrictions do not seem associated with better patient outcomes for bilateral breast reduction although there are multiple factors involved. These considerations and consequences should be considered in decisions that affect resident quality of life, education, and patient safety