Miracle-dz/UniFAR-FTUs huggingface dataset:
Peritumoural Strain Elastography of Newly Diagnosed Breast Tumours: Does Maximum Peritumoural Halo Depth Correlate with Tumour Differentiation and Grade?

To evaluate the diagnostic utility of the maximum ultrasound strain elastography (SE) halo depth in newly diagnosed and histologically confirmed breast lesions, a retrospective study approval was granted by the local Ethical Review Board. Overall, the maximum strain elastography peritumoural halos (SEPHmax)—the maximum distance between the SE stiffening area and the B-mode lesion size—in 428 cases with newly diagnosed breast lesions were retrospectively analysed alongside patient age, affected quadrant, tumour echogenicity, size, acoustic shadowing, and vascularity. Statistical analysis included an ordinary one-way ANOVA to compare the SEPHmax between BI-RADS 2, 3, and 5 groups and between tumour grades 1, 2, and 3. A binary regression analysis was used to determine the correlation between tumour malignancy and the above-mentioned demographic and imaging factors. SEPHmax was significantly higher in BI-RADS 5 tumours (5.5 ± 3.9 mm) compared to BI-RADS 3 (0.9 ± 1.7 mm, p < 0.0001) and 2 (0.6 ± 1.4 mm, p < 0.0001). The receiver operating characteristic area under the curve was 0.933 for the detection of BI-RADS 5 lesions. Furthermore, tumour grades 2 (5.6 ± 3.6 mm, p = 0.001) and 3 (6.8 ± 4.2 mm, p < 0.0001) exhibited significantly higher SEPHmax than grade 1 tumours (4.0 ± 3.9 mm). Similarly, St. Gallen Ki67-stratified low-risk (p = 0.005) and intermediate-risk (p = 0.013) tumours showed smaller SEPHmax than high-risk tumours. Multivariate analysis revealed a significant correlation between malignant differentiation and SEPHmax (standardized regression coefficient 3.17 [95% confidence interval (CI) 2.42–3.92], p < 0.0001), low tumour echogenicity (1.68 [95% CI 0.41–3.00], p = 0.03), and higher patient age (0.89 [95% CI 0.52–1.26], p < 0.0001). High SEPHmax is a strong predictor for tumour malignancy and a higher tumour grade and can be used to improve tumour characterisation before histopathological evaluation. It may also enable radiologists to identify lesions warranting observation rather than immediate biopsy.
Delta/Notch-like Epidermal Growth Factor-Related Receptor (DNER), a Potential Prognostic Marker of Gastric Cancer Regulates Cell Survival and Cell Cycle Progression

Upregulation of the expression of Delta/notch-like epidermal growth factor-related receptor (DNER) and its oncogenic role have been reported in several cancers, including gastric, breast, and prostate cancers. This study aimed to investigate the oncogenic role of DNER and the mechanisms behind its oncogenic role in gastric cancer. Analysis of the RNASeq data of gastric cancer tissues obtained from the TCGA database revealed that the expression of DNER was associated with the pathology of advanced gastric cancer and the prognosis of patients. DNER expression was increased upon stem cell-enriching cancer spheroid culture. Knockdown of DNER expression inhibited cell proliferation and invasion, induced apoptosis, enhanced chemosensitivity, and decreased spheroid formation of SNU-638 gastric cancer cells. DNER silencing elevated the expression of p53, p21cip/waf, and p27, and increased G1 phase cells at the expense of S phase cells. Knockdown of p21cip/waf expression in the DNER-silenced cells partially restored cell viability and S phase progression. DNER silencing also induced the apoptosis of SNU-638 cells. While both cleaved caspases-8 and 9 were detected in adherent cells, only cleaved caspase-8 was found to have increased in spheroid-cultured cells, suggesting a distinct activation pattern of caspase activation depending on the growth condition. Knockdown of p53 expression rescued the DNER-silenced cells from apoptosis and partially restored cell viability. In contrast, overexpression of the Notch intracellular domain (NICD) decreased the expression of p53, p21cip/waf, and cleaved caspase-3 in DNER-silenced cells. Moreover, NICD expression fully reverted the cell viability reduction, arrest in the G1 phase, and elevated apoptosis caused by DNER silencing, thereby suggesting activation of Notch signaling by DNER. Expression of a membrane-unbound mutant of mDNER also decreased cell viability and induced apoptosis. On the other hand, TGF-β signals were found to be involved in DNER expression in both adherent and spheroid-cultured cells. DNER could therefore be a link connecting TGF-β signaling to Notch signaling. Taken together, DNER regulates cell proliferation, survival, and invasive capacity of the gastric cancer cells through the activation of Notch signaling, which may facilitate tumor progression into an advanced stage. This study provides evidences suggesting that DNER could be a potential prognostic marker, a therapeutic target, and a drug candidate in the form of a cell-free mutant.
Effect of Crocetin on Basal Lipolysis in 3T3-L1 Adipocytes

Crocetin (CCT) is a natural saffron-derived apocarotenoid that possesses healthy properties such as anti-adipogenic, anti-inflammatory, and antioxidant activities. Lipolysis is enhanced in obesity and correlates with a pro-inflammatory, pro-oxidant state. In this context, we aimed to investigate whether CCT affects lipolysis. To evaluate CCT’s possible lipolytic effect, 3T3-L1 adipocytes were treated with CCT10μM at day 5 post-differentiation. Glycerol content and antioxidant activity were assessed using colorimetric assays. Gene expression was measured using qRT-PCR to evaluate the effect of CCT on key lipolytic enzymes and on nitric oxide synthase (NOS) expression. Total lipid accumulation was assessed using Oil Red O staining. CCT10μM decreased glycerol release from 3T3-L1 adipocytes and downregulated adipose tissue triglyceride lipase (ATGL) and perilipin-1, but not hormone-sensitive lipase (HSL), suggesting an anti-lipolytic effect. CCT increased catalase (CAT) and superoxide dismutase (SOD) activity, thus showing an antioxidant effect. In addition, CCT exhibited an anti-inflammatory profile, i.e., diminished inducible NOS (NOS2) and resistin expression, while enhanced the expression of adiponectin. CCT10μM also decreased intracellular fat and C/EBPα expression (a transcription factor involved in adipogenesis), thus revealing an anti-adipogenic effect. These findings point to CCT as a promising biocompound for improving lipid mobilisation in obesity.
New Insights into Immunopathology Associated to Bothrops lanceolatus Snake Envenomation: Focus on PLA2 Toxin

The systemic increase in inflammatory mediator levels can induce diverse pathological disorders, including potentially thrombus formation, which may be lethal. Among the clinical conditions in which the formation of thrombi dictates the patient’s prognosis, envenomation by Bothrops lanceolatus should be emphasized, as it can evolve to stroke, myocardial infarction and pulmonary embolism. Despite their life-threatening potential, the immunopathological events and toxins involved in these reactions remain poorly explored. Therefore, in the present study, we examined the immunopathological events triggered by a PLA2 purified from B. lanceolatus venom, using an ex vivo human blood model of inflammation. Our results showed that the purified PLA2 from the venom of B. lanceolatus damages human erythrocytes in a dose dependent way. The cell injury was associated with a decrease in the levels of CD55 and CD59 complement regulators on the cell surface. Moreover, the generation of anaphylatoxins (C3a and C5a) and the soluble terminal complement complex (sTCC) indicates that human blood exposure to the toxin activates the complement system. Increased production of TNF-α, CXCL8, CCL2 and CCL5 followed complement activation. The venom PLA2 also triggered the generation of lipid mediators, as evidenced by the detected high levels of LTB4, PGE2 and TXB2. The scenario here observed of red blood cell damage, dysfunctions of the complement regulatory proteins, accompanied by an inflammatory mediator storm, suggests that B. lanceolatus venom PLA2 contributes to the thrombotic disorders present in the envenomed individuals.
An International Non-Inferiority Study for the Benchmarking of AI for Routine Radiology Cases: Chest X-ray, Fluorography and Mammography

An international reader study was conducted to gauge an average diagnostic accuracy of radiologists interpreting chest X-ray images, including those from fluorography and mammography, and establish requirements for stand-alone radiological artificial intelligence (AI) models. The retrospective studies in the datasets were labelled as containing or not containing target pathological findings based on a consensus of two experienced radiologists, and the results of a laboratory test and follow-up examination, where applicable. A total of 204 radiologists from 11 countries with various experience performed an assessment of the dataset with a 5-point Likert scale via a web platform. Eight commercial radiological AI models analyzed the same dataset. The AI AUROC was 0.87 (95% CI:0.83–0.9) versus 0.96 (95% CI 0.94–0.97) for radiologists. The sensitivity and specificity of AI versus radiologists were 0.71 (95% CI 0.64–0.78) versus 0.91 (95% CI 0.86–0.95) and 0.93 (95% CI 0.89–0.96) versus 0.9 (95% CI 0.85–0.94) for AI. The overall diagnostic accuracy of radiologists was superior to AI for chest X-ray and mammography. However, the accuracy of AI was noninferior to the least experienced radiologists for mammography and fluorography, and to all radiologists for chest X-ray. Therefore, an AI-based first reading could be recommended to reduce the workload burden of radiologists for the most common radiological studies such as chest X-ray and mammography.
Mentally Demanding Work and Strain: Effects of Study Duration on Fatigue, Vigor, and Distress in Undergraduate Medical Students

Aims: The impact of the extent of mentally demanding work on the next-day’s strain is largely unknown, as existing studies generally investigate consequences of extended versus normal workdays. The present study sought to fill this gap by investigating how short work periods of mentally demanding academic work impact strain reactions in medical students preparing for an exam, using days of no work as reference category. Method: The observational design involved students repeatedly self-reporting fatigue, vigor, distress, and the preceding day’s study duration. Hours of nocturnal sleep, attending paid work and compulsory classes, gender, and proximity to the exam were controls in the linear model (generalized estimating equations). Forty-nine students provided 411 self-reports (M = 8.6, SD = 7.0 self-reports/student). Results: Engaging in mentally demanding work was associated with increased distress and work periods > 4 h with increased fatigue. Distress, vigor loss, and fatigue increased in proximity to the exam. Conclusion: Despite students’ high control of their schedule, even short periods of mentally highly demanding work may impair next-day’s well-being when task motivation is high. Freelancers and students might require health-promoting scheduling of work and leisure to avoid an accumulation of strain.
Pharmacokinetic Analysis of Zonarol, a Marine Algal Hydroquinone, in Mice Using HPLC with Fluorescence Detection

Zonarol, which was discovered in the brown algae Dictyopteris undulata, has antibiotic, antioxidative, anti-inflammatory, and neuroprotective hydroquinone properties. Additionally, a daily treatment of zonarol taken orally has been proven to prevent ulcerative colitis and nonalcoholic fatty liver disease in experimentally induced mice models. In this study, to elucidate the physiological behavior of zonarol in vivo, the establishment of quantitative methods for the determination of zonarol in biological samples and basic pharmacokinetics parameters after oral or intravenous administration with purified zonarol to mice were investigated. The zonarol (20–600 ng/mL) in this study was dose-dependently detected using an HPLC-FI system as a single peak on the ODS column with 80% aqueous methanol at 332 nm with an excitation of 293 nm. The pharmacokinetic parameters were derived from a non-compartment analysis of the plasma concentration of zonarol following oral or intravenous treatment in mice. The absolute bioavailability of zonarol was calculated as 25.0%. Interestingly, the maximal distribution of zonarol in the brain (2.525 ± 1.334 µg/g tissue) at 30 min was observed to be higher and slower than that in the liver and kidney at 15 min after bolus intravenous administrations to the mice (10 mg/kg BW). Based on these results, zonarol might be a candidate for a potential drug, an effective tool for drug delivery, or enhancing the treatment of cerebral disease.
Language Network Connectivity of Euthymic Bipolar Patients Is Altered at Rest and during a Verbal Fluency Task

Abnormalities of the Language Network (LN) have been found in different psychiatric conditions (e.g., schizophrenia and bipolar disorder), supporting the hypothesis that language plays a central role in a high-level integration/connectivity of second-level cognitive processes and the underlying cortical regions. This view implies a continuum of shared neural alterations along the psychotic disorder spectrum. In particular, bipolar disorder (BD) patients were recently documented to have an altered LN asymmetry during resting state. The extent to which the LN architecture is altered and stable also during a language task has yet to be investigated. To address this question, we analyzed fMRI data recorded during an open-eyes resting state session and a silent verbal fluency task in 16 euthymic BD patients and 16 matched healthy controls (HC). Functional connectivity in the LN of both groups was computed using spatial independent component analysis, and group comparisons were carried out to assess the network organization during both rest and active linguistic task conditions. The LN of BD patients involved left and right brain areas during both resting state and linguistic task. Compared to the left-lateralized network found in HC, the BD group was characterized by two anterior clusters (in left frontal and right temporo-insular regions) and the disengagement of the posterior language areas, especially during the verbal fluency task. Our findings support the hypothesis that reduced language lateralization may represent a biological marker across different psychotic disorders and that the altered language network connectivity found at rest in bipolar patients is stable and pervasive as it is also impaired during a verbal fluency task.
Social Return on Investment of Social Prescribing via a Diabetes Technician for Preventing Type 2 Diabetes Progression

In Wales, the prevalence of Type 2 Diabetes Mellitus (T2DM) has increased from 7.3% in 2016 to 8% in 2020, creating a major concern for the National Health Service (NHS). Social prescribing (SP) has been found to decrease T2DM prevalence and improve wellbeing. The MY LIFE programme, a scheme evaluated between June 2021 and February 2022 in the Conwy West Primary Care Cluster, aimed to prevent T2DM by referring prediabetic patients with a BMI of ≥30 to a diabetes technician (DT), who then signposted patients to community-based SP programmes, such as the National Exercise Referral Scheme (NERS), KindEating, and Slimming World. Although some patients engaged with SP, others chose to connect only with the DT. A Social Return on Investment (SROI) analysis was conducted to evaluate those patients who engaged with the DT plus SP, and those who connected solely with the DT. Relevant participant outcomes included ‘mental wellbeing’ and ‘good overall health’, which were measured at baseline (n = 54) and at the eight-week follow-up (n = 24). The estimated social value for every GBP 1 invested for participants who engaged with the ‘DT only’ ranged from GBP 4.67 to 4.70. The social value for participants who engaged with the ‘DT plus SP programme’ ranged from GBP 4.23 to 5.07. The results indicated that most of the social value generated was associated with connecting with the DT.
Long-Term Pioglitazone Treatment Has No Significant Impact on Microglial Activation and Tau Pathology in P301S Mice

Neuroinflammation is one disease hallmark on the road to neurodegeneration in primary tauopathies. Thus, immunomodulation might be a suitable treatment strategy to delay or even prevent the occurrence of symptoms and thus relieve the burden for patients and caregivers. In recent years, the peroxisome proliferator-activated receptor γ (PPARγ) has received increasing attention as it is immediately involved in the regulation of the immune system and can be targeted by the anti-diabetic drug pioglitazone. Previous studies have shown significant immunomodulation in amyloid-β (Aβ) mouse models by pioglitazone. In this study, we performed long-term treatment over six months in P301S mice as a tauopathy model with either pioglitazone or placebo. We performed serial 18 kDa translocator protein positron-emission-tomography (TSPO-PET) imaging and terminal immunohistochemistry to assess microglial activation during treatment. Tau pathology was quantified via immunohistochemistry at the end of the study. Long-term pioglitazone treatment had no significant effect on TSPO-PET, immunohistochemistry read-outs of microglial activation, or tau pathology levels in P301S mice. Thus, we conclude that pioglitazone modifies the time course of Aβ-dependent microglial activation, but does not significantly modulate microglial activation in response to tau pathology.
The Lack of Synergy between Carvedilol and the Preventive Effect of Dexrazoxane in the Model of Chronic Anthracycline-Induced Cardiomyopathy

The anticancer efficacy of doxorubicin (DOX) is dose-limited because of cardiomyopathy, the most significant adverse effect. Initially, cardiotoxicity develops clinically silently, but it eventually appears as dilated cardiomyopathy with a very poor prognosis. Dexrazoxane (DEX) is the only FDA-approved drug to prevent the development of anthracycline cardiomyopathy, but its efficacy is insufficient. Carvedilol (CVD) is another product being tested in clinical trials for the same indication. This study’s objective was to evaluate anthracycline cardiotoxicity in rats treated with CVD in combination with DEX. The studies were conducted using male Wistar rats receiving DOX (1.6 mg/kg b.w. i.p., cumulative dose: 16 mg/kg b.w.), DOX and DEX (25 mg/kg b.w. i.p.), DOX and CVD (1 mg/kg b.w. i.p.), or a combination (DOX + DEX + CVD) for 10 weeks. Afterward, in the 11th and 21st weeks of the study, echocardiography (ECHO) was performed, and the tissues were collected. The addition of CVD to DEX as a cardioprotective factor against DOX had no favorable advantages in terms of functional (ECHO), morphological (microscopic evaluation), and biochemical alterations (cardiac troponin I and brain natriuretic peptide levels), as well as systemic toxicity (mortality and presence of ascites). Moreover, alterations caused by DOX were abolished at the tissue level by DEX; however, when CVD was added, the persistence of DOX-induced unfavorable alterations was observed. The addition of CVD normalized the aberrant expression of the vast majority of indicated genes in the DOX + DEX group. Overall, the results indicate that there is no justification to use a simultaneous treatment of DEX and CVD in DOX-induced cardiotoxicity.
Leukocyte Imbalances in Mucopolysaccharidoses Patients

Mucopolysaccharidoses (MPSs) are rare inherited lysosomal storage diseases (LSDs) caused by deficient activity in one of the enzymes responsible for glycosaminoglycans lysosomal degradation. MPS II is caused by pathogenic mutations in the IDS gene, leading to deficient activity of the enzyme iduronate-2-sulfatase, which causes dermatan and heparan sulfate storage in the lysosomes. In MPS VI, there is dermatan sulfate lysosomal accumulation due to pathogenic mutations in the ARSB gene, leading to arylsulfatase B deficiency. Alterations in the immune system of MPS mouse models have already been described, but data concerning MPSs patients is still scarce. Herein, we study different leukocyte populations in MPS II and VI disease patients. MPS VI, but not MPS II patients, have a decrease percentage of natural killer (NK) cells and monocytes when compared with controls. No alterations were identified in the percentage of T, invariant NKT, and B cells in both groups of MPS disease patients. However, we discovered alterations in the naïve versus memory status of both helper and cytotoxic T cells in MPS VI disease patients compared to control group. Indeed, MPS VI disease patients have a higher frequency of naïve T cells and, consequently, lower memory T cell frequency than control subjects. Altogether, these results reveal MPS VI disease-specific alterations in some leukocyte populations, suggesting that the type of substrate accumulated and/or enzyme deficiency in the lysosome may have a particular effect on the normal cellular composition of the immune system.
Positronium formation via excitonlike states on Si and Ge surfaces

Recent experiments combining lifetime and laser spectroscopy of positronium (Ps) show that these atoms are emitted from p-Si(100) at a rate that depends on the sample temperature, suggesting a thermal activation process, but with an energy that does not, precluding direct thermal activation as the emission mechanism. Moreover, the amount of Ps emitted is substantially increased if the target is irradiated with 532 nm laser light just prior to the implantation of the positrons. Our interpretation of these data was that the Ps was emitted via an excitonlike positron-electron surface state, not dissimilar to an electronic surface exciton observed on Si in two-photon photoemission measurements. The hypothesis that this state may be populated by electrons from one of the occupied electronic surface states, either thermally or by laser excitation, is consistent with our observations and suggests that one should expect a high Ps yield at room temperature from an n-doped Si(100) sample, since in this case the same surface states will already be occupied. Here we present data obtained with an n-Si(100) target that supports our model, and also reveals the unexpected result that the kinetic energy of Ps emitted from this material actually decreases when it is heated, an effect we attribute to shifts in the surface energy levels due to the presence of a high density of thermally generated electrons. We show data obtained with a Ge(100) sample that corroborate the idea that the effects we observe are related to surface electron states, and hence should occur for any indirect-band-gap semiconductor with dangling-bond states. Our model is further confirmed by the observation that the Ps yield from p-Si depends linearly on the surface density of the implanted positrons due to the effects of electron-hole pairs created as the positrons slow down. © 2011 American Physical Society.
The ST2/IL-33 Pathway in Adult and Paediatric Heart Disease and Transplantation

ST2 is a member of interleukin 1 receptor family with soluble sST2 and transmembrane ST2L isoforms. The ligand of ST2 is IL-33, which determines the activation of numerous intracytoplasmic mediators following the binding with ST2L and IL-1RAcP, leading to nuclear signal and cardiovascular effect. Differently, sST2 is released in the blood and works as a decoy receptor, binding IL-33 and blocking IL-33/ST2L interaction. sST2 is mainly involved in maintaining homeostasis and/or alterations of different tissues, as counterbalance/activation of IL-33/ST2L axis is typically involved in the development of fibrosis, tissue damage, inflammation and remodeling. sST2 has been described in different clinical reports as a fundamental prognostic marker in patients with cardiovascular disease, as well as marker for the treatment monitoring of patients with heart failure; however, further studies are needed to better elucidate its role. In this review we reported the current knowledge about its role in coronary artery disease, heart failure, heart transplantation, heart valve disease, pulmonary arterial hypertension, and cardiovascular interventions.