Laminar post-stall wakes of tapered swept wings

While tapered swept wings are widely used, the influence of taper on their post-stall wake characteristics remains largely unexplored. To address this issue, we conduct an extensive study using direct numerical simulations to characterize the wing taper and sweep effects on laminar separated wakes. We analyze flows behind NACA 0015 cross-sectional profile wings at post-stall angles of attack $\alpha=14^\circ$--$22^\circ$ with taper ratios $\lambda=0.27$--$1$, leading edge sweep angles $0^\circ$--$50^\circ$, and semi aspect ratios $sAR =1$ and $2$ at a mean-chord-based Reynolds number of $600$. Tapered wings have smaller tip chord length, which generates a weaker tip vortex, and attenuates inboard downwash. This results in the development of unsteadiness over a large portion of the wingspan at high angles of attack. For tapered wings with backward-swept leading edges unsteadiness emerges near the wing tip. On the other hand, wings with forward-swept trailing edges are shown to concentrate wake shedding structures near the wing root. For highly swept untapered wings, the wake is steady, while unsteady shedding vortices appear near the tip for tapered wings with high leading edge sweep angles. For such wings, larger wake oscillations emerge near the root as the taper ratio decreases. While the combination of taper and sweep increases flow unsteadiness, we find that tapered swept wings have more enhanced aerodynamic performance than untapered and unswept wings, exhibiting higher time-averaged lift and lift-to-drag ratio. The current findings shed light on the fundamental aspects of flow separation over tapered wings in the absence of turbulent flow effects

Linear modal instabilities around post-stall swept finite-aspect ratio wings at low Reynolds numbers

Linear modal instabilities of flow over finite-span untapered wings have been investigated numerically at Reynolds number 400, at a range of angles of attack and sweep on two wings having aspect ratios 4 and 8. Base flows have been generated by direct numerical simulation, marching the unsteady incompressible three-dimensional Navier-Stokes equations to a steady state, or using selective frequency damping to obtain stationary linearly unstable flows. Unstable three-dimensional linear global modes of swept wings have been identified for the first time using spectral-element time-stepping solvers. The effect of the wing geometry and flow parameters on these modes has been examined in detail. An increase of the angle of attack was found to destabilize the flow, while an increase of the sweep angle had the opposite effect. On unswept wings, TriGlobal analysis revealed that the most unstable global mode peaks in the midspan region of the wake; the peak of the mode structure moves towards the tip as sweep is increased. Data-driven analysis was then employed to study the effects of wing geometry and flow conditions on the nonlinear wake. On unswept wings, the dominant mode at low angles of attack is a Kelvin-Helmholtz-like instability, qualitatively analogous with global modes of infinite-span wings under same conditions. At higher angles of attack and moderate sweep angles, the dominant mode is a structure denominated the interaction mode. At high sweep angles, this mode evolves into elongated streamwise vortices on higher aspect ratio wings, while on shorter wings it becomes indistinguishable from tip-vortex instability.Comment: 41 pages, 27 figure

On the formation of three-dimensional flows over finite-aspect-ratio wings under tip effects

We perform DNS of flow over finite-aspect-ratio NACA 0015 wings to characterize the tip effects on the wake dynamics. This study focuses on the development of three-dimensional separated flow over the wing, and discuss flow structures formed on the wing surface as well as in the far field wake. Vorticity is introduced into the flow in a predominantly two-dimensional manner. The vortex sheet from the wing tip rolls up around the free end to form the tip vortex. At its inception, the tip vortex is weak and its effect is spatially confined. As the flow around the tip separates, the tip effects extend farther in the spanwise direction, generating noticeable three dimensionality in the wake. For low-aspect-ratio wings, the wake remains stable due to the strong downwash over the entire span. Increasing the aspect ratio allows unsteady vortical flow to emerge away from the tip at sufficiently high angles of attack. These unsteady vortices shed and form closed vortical loops. For higher-aspect-ratio wings, the tip effects retard the near-tip shedding process, which desynchronizes from the two-dimensional shedding over the mid-span region, yielding vortex dislocation. At high angles of attack, the tip vortex exhibits noticeable undulations due to the strong interaction with the unsteady shedding vortices. The spanwise distribution of force coefficients is related to the three-dimensional wake dynamics and the tip effects. Vortical elements in the wake that are responsible for the generation of lift and drag forces are identified through the force element analysis. We note that at high angles of attack, a stationary vortical structure forms at the leading edge near the tip, giving rise to locally high lift and drag forces. The analysis performed here reveals how the vortical flow around the tip influences the separation physics, the global wake dynamics, and the spanwise force distributions

Association Between Smoking and Molecular Subtypes of Colorectal Cancer

Background: Smoking is associated with colorectal cancer (CRC) risk. Previous studies suggested this association may be restricted to certain molecular subtypes of CRC, but large-scale comprehensive analysis is lacking. Methods: A total of 9789 CRC cases and 11 231 controls of European ancestry from 11 observational studies were included. We harmonized smoking variables across studies and derived sex study-specific quartiles of pack-years of smoking for analysis. Four somatic colorectal tumor markers were assessed individually and in combination, including BRAF mutation, KRAS mutation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. A multinomial logistic regression analysis was used to assess the association between smoking and risk of CRC subtypes by molecular characteristics, adjusting for age, sex, and study. All statistical tests were 2-sided and adjusted for Bonferroni correction. Results: Heavier smoking was associated with higher risk of CRC overall and stratified by individual markers (P-trend <.001). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and BRAF. Compared with never-smokers, smokers in the fourth quartile of pack-years had a 90% higher risk of CIMP-positive CRC (odds ratio = 1.90, 95% confidence interval = 1.60 to 2.26) but only 35% higher risk for CIMP-negative CRC (odds ratio = 1.35, 95% confidence interval = 1.22 to 1.49; P-difference = 2.1 x 10(-6)). The association was also stronger in tumors that were CIMP positive, MSI high, or KRAS wild type when combined (P-difference <.001). Conclusion: Smoking was associated with differential risk of CRC subtypes defined by molecular characteristics. Heavier smokers had particularly higher risk of CRC subtypes that were CIMP positive and MSI high in combination, suggesting that smoking may be involved in the development of colorectal tumors via the serrated pathway

Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures

Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.87-100%)). All monoallelic MUTYH carriers are classified with the non-MUTYH carriers. The classifier provides evidence for a pathogenic classification for two VUS and a benign classification for five VUS. Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers (p = 2 x 10(-23) and p = 6 x 10(-11), respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers. Germline biallelic pathogenic MUTYH variants predispose patients to colorectal cancer (CRC); however, approaches to identify MUTYH variant carriers are lacking. Here, the authors evaluated mutational signatures that could distinguish MUTYH carriers in large CRC cohorts, and found MUTYH-associated somatic mutations

Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR=0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR=1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features. Large scale sequencing study is of paramount importance to unravel the heterogeneity of colorectal cancer. Here, the authors sequenced 205 cancer genes in more than 2000 tumours and identified additional mutated driver genes, determined that mutational burden and specific mutations in TP53 are associated with survival odds

Clinical-grade Detection of Microsatellite Instability in Colorectal Tumors by Deep Learning

Background and Aims: Microsatellite instability (MSI) and mismatch-repair deficiency (dMMR) in colorectal tumors are used to select treatment for patients. Deep learning can detect MSI and dMMR in tumor samples on routine histology slides faster and cheaper than molecular assays. But clinical application of this technology requires high performance and multisite validation, which have not yet been performed. Methods: We collected hematoxylin and eosin-stained slides, and findings from molecular analyses for MSI and dMMR, from 8836 colorectal tumors (of all stages) included in the MSIDETECT consortium study, from Germany, the Netherlands, the United Kingdom, and the United States. Specimens with dMMR were identified by immunohistochemistry analyses of tissue microarrays for loss of MLH1, MSH2, MSH6, and/or PMS2. Specimens with MSI were identified by genetic analyses. We trained a deep-learning detector to identify samples with MSI from these slides; performance was assessed by cross-validation (n=6406 specimens) and validated in an external cohort (n=771 specimens). Prespecified endpoints were area under the receiver operating characteristic (AUROC) curve and area under the precision-recall curve (AUPRC). Results: The deep-learning detector identified specimens with dMMR or MSI with a mean AUROC curve of 0.92 (lower bound 0.91, upper bound 0.93) and an AUPRC of 0.63 (range, 0.59–0.65), or 67% specificity and 95% sensitivity, in the cross-validation development cohort. In the validation cohort, the classifier identified samples with dMMR with an AUROC curve of 0.95 (range, 0.92–0.96) without image-preprocessing and an AUROC curve of 0.96 (range, 0.93–0.98) after color normalization. Conclusions: We developed a deep-learning system that detects colorectal cancer specimens with dMMR or MSI using hematoxylin and eosin-stained slides; it detected tissues with dMMR with an AUROC of 0.96 in a large, international validation cohort. This system might be used for high-throughput, low-cost evaluation of colorectal tissue specimens

Cutaneous lymphoma international consortium study of outcome in advanced stages of mycosis fungoides and Sézary syndrome: effect of specific prognostic markers on survival and development of a prognostic model

Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers. PATIENTS AND METHODS: Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS). RESULTS: Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%). CONCLUSION: To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients