Purpose
To develop and validate an interpretable deep learning model to predict overall and disease-specific survival (OS/DSS) in clear cell renal cell carcinoma (ccRCC).
Methods
Digitised ...haematoxylin and eosin-stained slides from The Cancer Genome Atlas were used as a training set for a vision transformer (ViT) to extract image features with a self-supervised model called DINO (self-distillation with no labels). Extracted features were used in Cox regression models to prognosticate OS and DSS. Kaplan–Meier for univariable evaluation and Cox regression analyses for multivariable evaluation of the DINO-ViT risk groups were performed for prediction of OS and DSS. For validation, a cohort from a tertiary care centre was used.
Results
A significant risk stratification was achieved in univariable analysis for OS and DSS in the training (
n
= 443, log rank test,
p
< 0.01) and validation set (
n
= 266,
p
< 0.01). In multivariable analysis, including age, metastatic status, tumour size and grading, the DINO-ViT risk stratification was a significant predictor for OS (hazard ratio HR 3.03; 95%-confidence interval 95%-CI 2.11–4.35;
p
< 0.01) and DSS (HR 4.90; 95%-CI 2.78–8.64;
p
< 0.01) in the training set but only for DSS in the validation set (HR 2.31; 95%-CI 1.15–4.65;
p
= 0.02). DINO-ViT visualisation showed that features were mainly extracted from nuclei, cytoplasm, and peritumoural stroma, demonstrating good interpretability.
Conclusion
The DINO-ViT can identify high-risk patients using histological images of ccRCC. This model might improve individual risk-adapted renal cancer therapy in the future.
The SC3p hydrophobin of Schizophyllum commune is a small hydrophobic protein (100-101 amino acids with eight cysteine residues) that self-assembles at a water/air interface and coats aerial hyphae ...with an SDS-insoluble protein membrane, at the outer side highly hydrophobic and with a typical rodlet pattern. SC3p monomers in water also self-assemble at the interfaces between water and oils or hydrophobic solids. These materials are then coated with a 10 nm thick SDS-insoluble assemblage of SC3p making their surfaces hydrophilic. Hyphae of S. commune growing on a Teflon surface became firmly attached and SC3p was shown to be present between the fungal cell wall and the Teflon. Decreased attachment of hyphae to Teflon was observed in strains not expressing SC3, i.e. a strain containing a targeted mutation in this gene and a regulatory mutant thn. These findings indicate that hydrophobins, in addition to forming hydrophobic wall coatings, play a role in adherence of fungal hyphae to hydrophobic surfaces.
Aims The progression of human heart failure is associated with increased protein phosphatase 1 (PP1) activity, which leads to a higher dephosphorylation of cardiac regulatory proteins such as ...phospholamban. In this study, we tested the hypothesis whether the inhibitor-2 (I-2) of PP1 can mediate cardiac protection by inhibition of PP1 activity. Methods and results We induced pressure overload by transverse aortic constriction (TAC) for 28 days in transgenic (TG) mice with heart-directed overexpression of a constitutively active form of I-2 (TGTAC) and wild-type littermates (WTTAC). Both groups were compared with sham-operated mice. TAC treatment resulted in comparable ventricular hypertrophy in both groups. However, TGTAC exhibited a higher atrial mass and an enhanced ventricular mRNA expression of β-myosin heavy chain. The increased afterload was associated with the development of focal fibrosis in TG. Consistent with signs of overt heart failure, fractional shortening and diastolic function were impaired in TGTAC as revealed by Doppler echocardiography. The contractility was reduced in catheterized banded TG mice, which is in line with a depressed shortening of isolated myocytes. This is due to profoundly abnormal cytosolic Ca2+ transients and a reduced stimulation of phosphorylation of phospholamban (PLB)Ser16 after TAC in TG mice. Moreover, administration of isoproterenol was followed by a blunted contractile response in isolated myocytes of TGTAC mice. Conclusion These results suggest that cardiac-specific overexpression of a constitutively active form of I-2 is deleterious for cardiac function under conditions of pressure overload. Thus, the long-term inhibition of PP1 by I-2 is not a therapeutic option in the treatment of heart failure.
Poor adherence to depression treatment is common. Understanding determinants of poor adherence to therapy is crucial to ensure optimal clinical outcomes. The aim of this study was to describe ...characteristics of dosing history in participants with depression receiving once daily escitalopram. Participants were randomly assigned to interpersonal psychotherapy (IPT) or pharmacotherapy. Participants assigned to IPT who did not evidence a response or remission had escitalopram added to their treatment. Adherence to pharmacotherapy was assessed using an electronically monitored pill cap (MEMS). Fifty-four participants on escitalopram alone and 32 on escitalopram+IPT were monitored. After 200 days, 71.7% of the participants in the escitalopram group and 54.8% of those in the escitalopram+IPT group were still engaged with the dosing regimen. Of those engaged in the dosing regimen, 17.9% (average over 210 days) of the participants did not take their medication (nonexecution). In 69% of the days participants took the correct dosage required. On average, participants had three drug holidays and the mean length of a holiday was 7 days per patient. No difference in adherence patterns was observed between patients receiving escitalopram alone vs. IPT+escitalopram. Early discontinuation of treatment and suboptimal daily execution of the prescribed regimen are the most common facets of poor adherence in this study population.
Proepicardial cells give rise to epicardium, coronary vasculature and cardiac fibroblasts. The proepicardium is derived from the mesodermal lining of the prospective pericardial cavity that ...simultaneously contributes myocardium to the venous pole of the elongating primitive heart tube. Using proepicardial explant cultures, we show that proepicardial cells have the potential to differentiate into cardiac muscle cells, reflecting the multipotency of this pericardial mesoderm. The differentiation into the myocardial or epicardial lineage is mediated by the cooperative action of BMP and FGF signaling. BMP2 is expressed in the distal IFT myocardium and stimulates cardiomyocyte formation. FGF2 is expressed in the proepicardium and stimulates differentiation into the epicardial lineage. In the base of the proepicardium, coexpression of BMP2 and FGF2 inhibits both myocardial and epicardial differentiation. We conclude that the epicardial/myocardial lineage decisions are mediated by an extrinsic, inductive mechanism, which is determined by the position of the cells in the pericardial mesoderm.
The inundated area of the Okavango Delta changes annually and interannually. The variability relates to regional precipitation over the catchment area in the Angolan highlands, and to local rainfall. ...The patterns of the wetland were captured using more than 3000 satellite images for the period 1972 to 2000, near daily NOAA AVHRR data for 1985–2000, and less frequent images of the Landsat sensors from 1972 onwards. One AVHRR image for every 10-day period was classified into land and water using an unsupervised classification method. Evaluation against Landsat TM and ERS2-ATSR data indicate an agreement of 89% for the size of estimated inundation area. Results show that the wetland area has varied between approximately 2450 km2 and 11 400 km2 during the last 30 years.
The SC3 hydrophobin gene of Schizophyllum commune was disrupted by homologous integration of an SC3 genomic fragment interrupted by a phleomycin resistance cassette. The phenotype of the mutant was ...particularly clear in sealed plates in which formation of aerial hyphae was blocked. In non-sealed plates aerial hyphae did form but these were hydrophilic and not hydrophobic as in wild-type strains. Complementation with a genomic SC3 clone restored formation of hydrophobic aerial hyphae in sealed plates. In a dikaryon homozygous for the SC3 mutation normal sporulating fruiting bodies were produced but aerial hyphae were hydrophilic.
The primary objective of the prospective, randomized, multicenter, phase 3 biomarker MATADOR trial (ISRCTN61893718) is to generate a gene expression profile that can predict benefit from either ...docetaxel, doxorubicin, and cyclophosphamide (TAC) or dose-dense scheduled doxorubicin and cyclophosphamide (ddAC). Patients with a pT1-3, pN0-3 tumor were randomized 1:1 between ddAC and TAC. The primary endpoint was a gene profile-treatment interaction for recurrence-free survival (RFS). We observed 117 RFS events in 664 patients with a median follow-up of 7 years. Hallmark gene set analyses showed significant association between enrichment in immune-related gene expression and favorable outcome after TAC in hormone receptor-negative, human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) (triple-negative breast cancer TNBC). We validated this association in TNBC patients treated with TAC on H&E slides; stromal tumor-infiltrating lymphocytes (sTILs) ≥20% was associated with longer RFS (hazard ratio 0.18, p = 0.01), while in patients treated with ddAC no difference in RFS was seen (hazard ratio 0.92, p = 0.86, pinteraction = 0.02).
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•This proof-of-concept randomized biomarker trial design demonstrates scientific utility•High sTILs can guide chemotherapy choice in high-risk triple-negative breast cancer•Gene expression analyses identify biological processes informative for taxane benefit•Immune processes interact differentially with outcome after TAC vs. ddAC chemotherapy
Cancer; Clinical genetics; Oncology
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