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To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.

Each year in the United States, many factors are considered in the National Football League's draft process, including scouting reports, interviews, medical tests, and measures of players' strength, speed, anthropometry, and personality. Recently, an increased emphasis has been placed on players' psychometrically measured cognitive abilities. Historically, offensive linemen have been excluded from NFL research, since they do not have individual performance statistics. In this study, we attempted to fill that research gap by investigating correlates of offensive linemen's measured vigilance/impulsivity. We obtained archival player data from 85 offensive linemen in the years from 2014–2021 prior to each of these players' NFL draft. We then used false start penalties per game (FSPG) as an index of their vigilance/impulsivity (and general success) on the field, and we related those values to Reaction Time tests through hierarchical multiple regression analyses. After controlling for draft placement, these players' higher accuracy on a Choice Reaction Time task accounted for a statistically significant percentage of the variance associated with their FSPG statistics. We discuss the practical utility for player development of these and other cognitive assessments now used in the NFL. [ABSTRACT FROM AUTHOR]

Background: The current study presents the effort of a global collaborative group to review the management and outcomes of malignant tumors of the skull base worldwide. Patients and methods: A total of 28 institutions contributed data on 3061 patients. Analysis evaluated clinical variables, survival outcomes, and multivariable factors associated with outcomes. Results: The median age was 56 years (IQR 44–67). The open surgical approach was used in 55% (n = 1680) of cases, endoscopic resection was performed in 36% (n = 1087), and the combined approach in 9.6% (n = 294). With a median follow‐up of 7.1 years, the 5‐year OS DSS and RFS were 65%, 71.7% and 53%, respectively. On multivariable analysis, older age, comorbidities, histology, dural/intracranial involvement, positive margins, advanced stage, and primary site were independent prognostic factors for OS, DSS, and RFS. Adjuvant RT was a protective prognostic factor. Conclusion: The progress across various disciplines may have contributed to improved OS and DSS in this study compared to previous reports. [ABSTRACT FROM AUTHOR]

Background: There are no large studies reporting oncological or survival outcomes for patients diagnosed with perineural spread (PNS) of cutaneous squamous cell carcinoma (cSCC) via the ophthalmic nerve (V1). Where orbital exenteration may be necessary for curative treatment, it is critical to have survival data with which the morbidity associated with surgical treatment can be justified. Furthermore, with the emerging treatment option of immunotherapy, current standard of care outcomes are needed to help guide future trial design and eventually changed management guidelines. Objective: To determine the oncological and survival outcomes observed in patients with PNS of cSCC via V1. Materials and methods: Retrospective analysis of prospectively maintained cohort of patients with PNS of cSCC via V1 treated in a tertiary Australian head and neck oncology/skull base referral center. Consecutive sample of 53 patients managed between March 1, 1999 and April 30, 2020. Follow‐up closure date was September 1, 2021. Curative‐intent surgery, curative‐intent radiotherapy, or palliative care was undertaken. Endpoints included five‐year overall, disease‐specific, and disease‐free survival from the date of treatment. Results: Five‐year Kaplan–Meier overall survival was 61.9% (95% CI 46.2%–74.3%), with disease‐specific survival of 74.6% (95% CI 58.8%–85.3%), and disease‐free survival 62.1% (95% CI 46.5%–74.3%). Survival was superior in patients treated via surgery and adjuvant radiotherapy than in those receiving surgery alone or definitive radiotherapy. Survival was superior among patients with less advanced disease as assessed by the Williams zonal staging system; patients with Zone 1 disease had disease‐specific survival of 94.1% at 5 years with 82.5% disease‐free survival. Discussion: Five‐year oncological and survival outcomes in this cohort were favorable. Superior survival was observed in patients treated with curative‐intent surgery and adjuvant radiotherapy. Less extensive disease as delineated by the Williams zonal staging system was associated with improved survival. Conclusion: Surgical resection with adjuvant radiotherapy confers favourable oncological and survival outcome in patients with V1 PNS, particularly with early disease limited to Zone 1. [ABSTRACT FROM AUTHOR]

Understanding how proteins evolve under selective pressure is a longstanding challenge. The immensity of the search space has limited efforts to systematically evaluate the impact of multiple simultaneous mutations, so mutations have typically been assessed individually. However, epistasis, or the way in which mutations interact, prevents accurate prediction of combinatorial mutations based on measurements of individual mutations. Here, we use artificial intelligence to define the entire functional sequence landscape of a protein binding site in silico, and we call this approach Complete Combinatorial Mutational Enumeration (CCME). By leveraging CCME, we are able to construct a comprehensive map of the evolutionary connectivity within this functional sequence landscape. As a proof of concept, we applied CCME to the ACE2 binding site of the SARS‐CoV‐2 spike protein receptor binding domain. We selected representative variants from across the functional sequence landscape for testing in the laboratory. We identified variants that retained functionality to bind ACE2 despite changing over 40% of evaluated residue positions, and the variants now escape binding and neutralization by monoclonal antibodies. This work represents a crucial initial stride toward achieving precise predictions of pathogen evolution, opening avenues for proactive mitigation. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Advanced skull base malignancies are a heterogenous subset of head and neck cancers, and management is often complex. In recent times, there has been a paradigm shift in surgical technique and the advent of novel systemic options. Our goal was to analyse the long‐term outcomes of a single quaternary head and neck and skull base service.A retrospective review of 127 patients with advanced anterior skull base malignancies that were treated at our institution between 1999 and 2015 was performed. Multiple variables were investigated to assess their significance on 5 and 10‐year outcomes.The mean age was 60.9 (± 12.6 SD). Sixty‐four percent were males and 36% were females. Ninety percent of patients had T4 disease. Median survival time was 133 months. The 5‐year overall survival (OS) was 66.2%, disease‐specific survival (DSS) was 74.7%, and recurrence‐free survival (RFS) was 65.0%. The 10‐year OS was 55.1%, DSS was 72.1%, and RFS was 53.4%. Histological type and margin status significantly affected OS & DSS.Surgical management of advanced skull base tumours has evolved over the last few decades at our institution with acceptable survival outcomes and complication rates. Histological diagnosis and margin status are the main predictors of survival. The addition of neoadjuvant systemic agents in current trials may improve outcomes. [ABSTRACT FROM AUTHOR]