Accurate non-invasive biomarkers to diagnose metabolic dysfunction-associated steatotic liver disease (MASLD)-related fibrosis are urgently needed. This study applies a translational approach to ...develop a blood-based biomarker panel for fibrosis detection in MASLD. A molecular gene expression signature identified from a diet-induced MASLD mouse model (LDLr-/-.Leiden) is translated into human blood-based biomarkers based on liver biopsy transcriptomic profiles and protein levels in MASLD patient serum samples. The resulting biomarker panel consists of IGFBP7, SSc5D and Sema4D. LightGBM modeling using this panel demonstrates high accuracy in predicting MASLD fibrosis stage (F0/F1: AUC = 0.82; F2: AUC = 0.89; F3/F4: AUC = 0.87), which is replicated in an independent validation cohort. The overall accuracy of the model outperforms predictions by the existing markers Fib-4, APRI and FibroScan. In conclusion, here we show a disease mechanism-related blood-based biomarker panel with three biomarkers which is able to identify MASLD patients with mild or advanced hepatic fibrosis with high accuracy.
SUMMARY
Nicotinamide adenine dinucleotide (NAD) plays a central role in redox metabolism in all domains of life. Additional roles in regulating posttranslational protein modifications and cell ...signaling implicate NAD as a potential integrator of central metabolism and programs regulating stress responses and development. Here we found that NAD negatively impacts stomatal development in cotyledons of Arabidopsis thaliana. Plants with reduced capacity for NAD+ transport from the cytosol into the mitochondria or the peroxisomes exhibited reduced numbers of stomatal lineage cells and reduced stomatal density. Cotyledons of plants with reduced NAD+ breakdown capacity and NAD+‐treated cotyledons also presented reduced stomatal number. Expression of stomatal lineage‐related genes was repressed in plants with reduced expression of NAD+ transporters as well as in plants treated with NAD+. Impaired NAD+ transport was further associated with an induction of abscisic acid (ABA)‐responsive genes. Inhibition of ABA synthesis rescued the stomatal phenotype in mutants deficient in intracellular NAD+ transport, whereas exogenous NAD+ feeding of aba‐2 and ost1 seedlings, impaired in ABA synthesis and ABA signaling, respectively, did not impact stomatal number, placing NAD upstream of ABA. Additionally, in vivo measurement of ABA dynamics in seedlings of an ABA‐specific optogenetic reporter − ABAleon2.1 − treated with NAD+ showed increases in ABA content suggesting that NAD+ impacts on stomatal development through ABA synthesis and signaling. Our results demonstrate that intracellular NAD+ homeostasis as set by synthesis, breakdown and transport is essential for normal stomatal development, and provide a link between central metabolism, hormone signaling and developmental plasticity.
Significance Statement
NAD+ homeostasis affects ABA metabolism, modulating stomatal development in Arabidopsis cotyledons.
Here we perform whole-exome sequencing of samples from 105 individuals with chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults in Western countries. We found 1,246 somatic ...mutations potentially affecting gene function and identified 78 genes with predicted functional alterations in more than one tumor sample. Among these genes, SF3B1, encoding a subunit of the spliceosomal U2 small nuclear ribonucleoprotein (snRNP), is somatically mutated in 9.7% of affected individuals. Further analysis in 279 individuals with CLL showed that SF3B1 mutations were associated with faster disease progression and poor overall survival. This work provides the first comprehensive catalog of somatic mutations in CLL with relevant clinical correlates and defines a large set of new genes that may drive the development of this common form of leukemia. The results reinforce the idea that targeting several well-known genetic pathways, including mRNA splicing, could be useful in the treatment of CLL and other malignancies.
Background
Cognitive impairment is common in the elderly. Prior studies suggest a link between chronic inflammation and cognitive dysfunction, while aging‐associated epidermal dysfunction has been ...connected to elevations in circulating cytokines.
Objective
We assessed here whether improvements in epidermal function can mitigate the progression of cognitive impairment.
Methods
This randomized, open‐label pilot trial was carried out in two cities in northern China. A total of 200 participants aged ≥65 years were randomly assigned to the emollient‐treated and untreated groups at 1:1 ratio. Participants in the treated group were treated topically with Atopalm cream® twice‐daily from November to the following May each year for three consecutive years, while the untreated subjects served as controls. The Global Deterioration Scale (GDS) was used to assess the severity of cognitive impairment, while epidermal biophysical properties were measured on the forearms and the shins in parallel.
Results
Over the three‐year trial, GDS significantly increased from baseline (P < 0.0001) in the controls, while in the treated group, GDS stabilized. While stratum corneum hydration on the forearms did not change significantly in the controls, transepidermal water loss rates (TEWL), significantly increased by the end of the trial compared to baselines in the controls (P < 0.0001). On the forearms of the treated group, stratum corneum hydration increased (P < 0.0001) while skin surface pH decreased from baseline (P < 0.0001).
Conclusions
These results suggest that improvements in epidermal function with topical emollient can mitigate the progression of cognitive impairment. However, the sample size was relatively small, and trials in a larger cohort are needed to validate the present results.
Breast cancer imaging phenotype is diverse and may relate to molecular alterations driving cancer behavior. We systematically reviewed and meta-analyzed relations between breast cancer imaging ...features and human epidermal growth factor receptor type 2 (HER2) overexpression as a marker of breast cancer aggressiveness. MEDLINE and EMBASE were searched for mammography, breast ultrasound, magnetic resonance imaging (MRI), and/or (18)Ffluorodeoxyglucose positron emission tomography studies through February 2013. Of 68 imaging features that could be pooled (85 articles, 23,255 cancers; random-effects meta-analysis), 11 significantly related to HER2 overexpression. Results based on five or more studies and robustness in subgroup analyses were as follows: the presence of microcalcifications on mammography pooled odds ratio (pOR), 3.14; 95% confidence interval (CI), 2.46-4.00 or ultrasound (mass-associated pOR, 2.95; 95% CI, 2.34-3.71), branching or fine linear microcalcifications (pOR, 2.11; 95% CI, 1.07-4.14) or extremely dense breasts on mammography (pOR, 1.37; 95% CI, 1.07-1.76), and washout (pOR, 1.57; 95% CI, 1.11-2.21) or fast initial kinetics (pOR, 2.60; 95% CI, 1.43-4.73) on MRI all increased the chance of HER2 overexpression. Maximum (18)Ffluorodeoxyglucose standardized uptake value (SUVmax) was higher upon HER2 overexpression (pooled mean difference, +0.76; 95% CI, 0.10-1.42). These results show that several imaging features relate to HER2 overexpression, lending credibility to the hypothesis that imaging phenotype reflects cancer behavior. This implies prognostic relevance, which is especially relevant as imaging is readily available during diagnostic work-up.
Obesity remains a public health problem worldwide. The high prevalence of this condition in the population raises further concerns, considering that comorbidities are often associated with obesity. ...Among the comorbidities closely associated with obesity, metabolic syndrome (MS) is particularly important, which potentially increases the risk of manifestation of other disorders, such as the prothrombotic and systemic pro-inflammatory states.
A randomized, controlled clinical trial was performed involving female patients (n = 32) aged between 18 and 65 years, with a clinical diagnosis of MS, with severe obesity undergoing Roux-en-Y gastric bypass (RYGB). The study design followed the Consolidated Standards of Reporting Trials statement (CONSORT). Lipid profile, blood glucose and adipokines (adiponectin, leptin, and resistin) and (cytokines IL-1β, IL-6, IL-17, IL-23, and TNF-α) in blood plasma samples were evaluated before and six months after RYGB.
Patients undergoing RYGB (BSG) showed a significant improvement from preoperative grade III obesity to postoperative grade I obesity. The results showed that while HDL levels increased, the other parameters showed a significant reduction in their postoperative values when compared not only to the values observed before surgery in the BSG group, but also to the values obtained in the control group (CG). As for systemic inflammatory markers adiponectin, leptin, resistin, IL-1β, IL-6, IL-17, IL-23 and TNF- α it was observed that the levels of resistin and IL-17 in the second evaluation increased significantly when compared to the levels observed in the first evaluation in the CG. In the BSG group, while the levels of adiponectin increased, the levels of the other markers showed significant reductions in the postoperative period, in relation to the respective preoperative levels. The analysis of Spearman's correlation coefficient showed a significant positive correlation between IL-17 and IL-23 in the preoperative period, significant positive correlations between TNF-α and IL-6, TNF-α and IL-17, IL-6 and IL-17, and IL-17 and IL-23 were observed postoperatively.
According to our results, the reduction of anthropometric measurements induced by RYGB, significantly improves not only the plasma biochemical parameters (lipid profile and glycemia), but also the systemic inflammatory status of severely obese patients with MS. Trials registration NCT02409160.
Checkpoint inhibition has radically improved the perspective for patients with metastatic cancer, but predicting who will not respond with high certainty remains difficult. Imaging-derived biomarkers ...may be able to provide additional insights into the heterogeneity in tumour response between patients. In this systematic review, we aimed to summarise and qualitatively assess the current evidence on imaging biomarkers that predict response and survival in patients treated with checkpoint inhibitors in all cancer types.
PubMed and Embase were searched from database inception to 29th November 2021. Articles eligible for inclusion described baseline imaging predictive factors, radiomics and/or imaging machine learning models for predicting response and survival in patients with any kind of malignancy treated with checkpoint inhibitors. Risk of bias was assessed using the QUIPS and PROBAST tools and data was extracted.
In total, 119 studies including 15,580 patients were selected. Of these studies, 73 investigated simple imaging factors. 45 studies investigated radiomic features or deep learning models. Predictors of worse survival were (i) higher tumour burden, (ii) presence of liver metastases, (iii) less subcutaneous adipose tissue, (iv) less dense muscle and (v) presence of symptomatic brain metastases. Hazard rate ratios did not exceed 2.00 for any predictor in the larger and higher quality studies. The added value of baseline fluorodeoxyglucose positron emission tomography parameters in predicting response to treatment was limited. Pilot studies of radioactive drug tracer imaging showed promising results. Reports on radiomics were almost unanimously positive, but numerous methodological concerns exist.
There is well-supported evidence for several imaging biomarkers that can be used in clinical decision making. Further research, however, is needed into biomarkers that can more accurately identify which patients who will not benefit from checkpoint inhibition. Radiomics and radioactive drug labelling appear to be promising approaches for this purpose.
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•Higher tumour burden and the presence of liver metastasis indicate worse survival.•presence of symptomatic brain metastases predicts worse survival in patients with melanoma.•More subcutaneous fat and skeletal muscle may be predictive of better survival.•Radioactive drug labelling techniques show promising results in pilot studies.•Radiomics appear promising in published literature but require further validation.
Summary Background Radiation dermatitis is a common side‐effect of radiation therapy, but there is no current consensus about its appropriate therapy.
Objectives To compare treatment with topical ...0·1% methylprednisolone vs. 0·5% dexpanthenol in a cohort of patients undergoing fractionated radiation therapy for breast cancer.
Methods In a randomized, double‐blind design, treatment was initiated at the beginning of radiation therapy and continued for 2 weeks after termination of radiation. Outcomes were compared by three different measures: clinical (symptom score), functional (transepidermal water loss, TEWL) and subjective (quality of life, QOL).
Results In a preliminary cohort of untreated patients undergoing radiation therapy, clinical signs and TEWL levels increased progressively during radiation therapy, reaching highest values at 5 and 4 weeks, respectively. Although neither topical treatment reduced the incidence of radiation dermatitis, both delayed the emergence of greatest clinical and TEWL scores until approximately 6 and 5 weeks, respectively. With topical corticosteroids, clinical symptoms and TEWL were less pronounced than with dexpanthenol. Whereas general QOL improved after completion of radiation therapy, skin‐related QOL declined. However, the skin‐related QOL decline could be at least in part reversed by use of topical corticosteroid vs. dexpanthenol‐containing emollient.
Conclusions We provide evidence that prophylactic and ongoing use of topical therapy with either topical corticosteroid or a dexpanthenol‐containing emollient ameliorates, but does not prevent radiation dermatitis. Our data suggest, but do not prove, a benefit of a topical corticosteroid vs. a dexpanthenol‐containing emollient. Further controlled studies with larger cohorts will be needed to determine optimal forms of topical therapy for radiation dermatitis.
The dental prosthesis market is rapidly evolving to meet patient and clinical demands. These new materials must have good flexural strength, toughness, aesthetic properties, and reliability in ...performance for structural applications. The present work aimed to compare the bending strength of 4 types of chairside lithium disilicate (Li2Si2O5) glass-ceramics used for dental prosthesis and to analyze the influence of heat treatment on the transformation of lithium metasilicate (Li2SiO3) into lithium disilicate. The three-ball test for the biaxial flexion test (B3B) was used. Weibull statistical analysis was used, and it showed that samples with a higher percentage of zirconia have a greater tendency to fail. The flexion tests showed that the addition of more than 10% of zirconia reduced the flexural strength. The heat treatment process improves and provides greater mechanical strength. The XRD results indicated that the samples with the lowest percentage of zirconia exhibited greater crystallinity and corroborated the microstructural analysis. SEM analyses showed a greater amount and elongated crystals of lithium disilicate when comparing samples with a higher percentage of zirconia. Therefore, samples with lower zirconia showed greater flexural strength than samples with higher additions of zirconia.
Past studies show beneficial as well as detrimental effects of subthalamic nucleus deep-brain stimulation on impulsive behaviour. We address this paradox by investigating individuals with Parkinson’s ...disease treated with subthalamic nucleus stimulation (n = 17) and healthy controls without Parkinson’s disease (n = 17) on performance in a Simon task. In this reaction time task, conflict between premature response impulses and goal-directed action selection is manipulated. We applied distributional analytic methods to separate the strength of the initial response impulse from the proficiency of inhibitory control engaged subsequently to suppress the impulse. Patients with Parkinson’s disease were tested when stimulation was either turned on or off. Mean conflict interference effects did not differ between controls and patients, or within patients when stimulation was on versus off. In contrast, distributional analyses revealed two dissociable effects of subthalamic nucleus stimulation. Fast response errors indicated that stimulation increased impulsive, premature responding in high conflict situations. Later in the reaction process, however, stimulation improved the proficiency with which inhibitory control was engaged to suppress these impulses selectively, thereby facilitating selection of the correct action. This temporal dissociation supports a conceptual framework for resolving past paradoxical findings and further highlights that dynamic aspects of impulse and inhibitory control underlying goal-directed behaviour rely in part on neural circuitry inclusive of the subthalamic nucleus.
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