Intestinal Deletion of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Promotes Expansion of the Resident Stem Cell Compartment.

BACKGROUND: The intestine occupies the critical interface between cholesterol absorption and excretion. Surprisingly little is known about the role of de novo cholesterol synthesis in this organ, and its relationship to whole body cholesterol homeostasis. Here, we investigate the physiological importance of this pathway through genetic deletion of the rate-limiting enzyme. METHODS: Mice lacking 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) in intestinal villus and crypt epithelial cells were generated using a Villin-Cre transgene. Plasma lipids, intestinal morphology, mevalonate pathway metabolites, and gene expression were analyzed. RESULTS: Mice with intestine-specific loss of Hmgcr were markedly smaller at birth, but gain weight at a rate similar to wild-type littermates, and are viable and fertile into adulthood. Intestine lengths and weights were greater relative to body weight in both male and female Hmgcr intestinal knockout mice. Male intestinal knockout had decreased plasma cholesterol levels, whereas fasting triglycerides were lower in both sexes. Lipidomics revealed substantial reductions in numerous nonsterol isoprenoids and sterol intermediates within the epithelial layer, but cholesterol levels were preserved. Hmgcr intestinal knockout mice also showed robust activation of SREBP-2 (sterol-regulatory element binding protein-2) target genes in the epithelium, including the LDLR (low-density lipoprotein receptor). At the cellular level, loss of Hmgcr is compensated for quickly after birth through a dramatic expansion of the stem cell compartment, which persists into adulthood. CONCLUSIONS: Loss of Hmgcr in the intestine is compatible with life through compensatory increases in intestinal absorptive surface area, LDLR expression, and expansion of the resident stem cell compartment.

Cardiac CT and MRI radiomics: systematic review of the literature and radiomics quality score assessment.

OBJECTIVE: To systematically review and evaluate the methodological quality of studies using magnetic resonance imaging (MRI) and computed tomography (CT) radiomics for cardiac applications. METHODS: Multiple medical literature archives (PubMed, Web of Science, and EMBASE) were systematically searched to retrieve original studies focused on cardiac MRI and CT radiomics applications. Two researchers in consensus assessed each investigation using the radiomics quality score (RQS). Subgroup analyses were performed to assess whether the total RQS varied according to study aim, journal quartile, imaging modality, and first author category. RESULTS: From a total of 1961 items, 53 articles were finally included in the analysis. Overall, the studies reached a median total RQS of 7 (IQR, 4-12), corresponding to a percentage score of 19.4% (IQR, 11.1-33.3%). Item scores were particularly low due to lack of prospective design, cost-effectiveness analysis, and open science. Median RQS percentage score was significantly higher in papers where the first author was a medical doctor and in those published on first quartile journals. CONCLUSIONS: The overall methodological quality of radiomics studies in cardiac MRI and CT is still lacking. A higher degree of standardization of the radiomics workflow and higher publication standards for studies are required to allow its translation into clinical practice. KEY POINTS: • RQS has been recently proposed for the overall assessment of the methodological quality of radiomics-based studies. • The 53 included studies on cardiac MRI and CT radiomics applications reached a median total RQS of 7 (IQR, 4-12), corresponding to a percentage of 19.4% (IQR, 11.1-33.3%). • A more standardized methodology in the radiomics workflow is needed, especially in terms of study design, validation, and open science, in order to translate the results to clinical applications.

Cardiovascular magnetic resonance native T1 mapping in Anderson-Fabry disease: a systematic review and meta-analysis.

BACKGROUND: T1 mapping is an established cardiovascular magnetic resonance (CMR) technique that can characterize myocardial tissue. We aimed to determine the weighted mean native T1 values of Anderson-Fabry disease (AFD) patients and the standardized mean differences (SMD) as compared to healthy control subjects. METHODS: A comprehensive literature search of the PubMed, Scopus and Web of Science databases was conducted according to the PRISMA statement to retrieve original studies reporting myocardial native T1 values in AFD patients and healthy controls. A random effects model was used to calculate SMD, and meta-regression analysis was conducted to explore heterogeneity sources. Subgroup analysis was also performed according to scanner field strength and sequence type. RESULTS: From a total of 151 items, 14 articles were included in the final analysis accounting for a total population of 982 subjects. Overall, the weighted mean native T1 values was 984 ± 47 ms in AFD patients and 1016 ± 26 ms in controls (P < 0.0001) with a pooled SMD of - 2.38. In AFD patients there was an inverse correlation between native T1 values and male gender (P = 0.002) and left ventricular hypertrophy (LVH) (P < 0.001). Subgroup analyses confirmed lower T1 values in AFD patients compared to controls with a pooled SMD of -  2.54, -  2.28, -  2.46 for studies performed on 1.5T with modified Look-Locker inversion recovery (MOLLI), shortened MOLLI and saturation-recovery single-shot acquisition, respectively and of -  2.41 for studies conducted on 3T. CONCLUSIONS: Our findings confirm a reduction of native T1 values in AFD patients compared to healthy controls and point out that the degree of T1 shortening in AFD is influenced by gender and LVH. Although T1 mapping is useful in proving cardiac involvement in AFD patients, there is need to standardize shreshold values according to imaging equipment and protocols.

AAV-CRISPR Gene Editing Is Negated by Pre-existing Immunity to Cas9.

Adeno-associated viral (AAV) vectors are a leading candidate for the delivery of CRISPR-Cas9 for therapeutic genome editing in vivo. However, AAV-based delivery involves persistent expression of the Cas9 nuclease, a bacterial protein. Recent studies indicate a high prevalence of neutralizing antibodies and T cells specific to the commonly used Cas9 orthologs from Streptococcus pyogenes (SpCas9) and Staphylococcus aureus (SaCas9) in humans. We tested in a mouse model whether pre-existing immunity to SaCas9 would pose a barrier to liver genome editing with AAV packaging CRISPR-Cas9. Although efficient genome editing occurred in mouse liver with pre-existing SaCas9 immunity, this was accompanied by an increased proportion of CD8+ T cells in the liver. This cytotoxic T cell response was characterized by hepatocyte apoptosis, loss of recombinant AAV genomes, and complete elimination of genome-edited cells, and was followed by compensatory liver regeneration. Our results raise important efficacy and safety concerns for CRISPR-Cas9-based in vivo genome editing in the liver.

Depletion of essential isoprenoids and ER stress induction following acute liver-specific deletion of HMG-CoA reductase.

HMG-CoA reductase (Hmgcr) is the rate-limiting enzyme in the mevalonate pathway and is inhibited by statins. In addition to cholesterol, Hmgcr activity is also required for synthesizing nonsterol isoprenoids, such as dolichol, ubiquinone, and farnesylated and geranylgeranylated proteins. Here, we investigated the effects of Hmgcr inhibition on nonsterol isoprenoids in the liver. We have generated new genetic models to acutely delete genes in the mevalonate pathway in the liver using AAV-mediated delivery of Cre-recombinase (AAV-Cre) or CRISPR/Cas9 (AAV-CRISPR). The genetic deletion of Hmgcr by AAV-Cre resulted in extensive hepatocyte apoptosis and compensatory liver regeneration. At the biochemical level, we observed decreased levels of sterols and depletion of the nonsterol isoprenoids, dolichol and ubiquinone. At the cellular level, Hmgcr-null hepatocytes showed ER stress and impaired N-glycosylation. We further hypothesized that the depletion of dolichol, essential for N-glycosylation, could be responsible for ER stress. Using AAV-CRISPR, we somatically disrupted dehydrodolichyl diphosphate synthase subunit (Dhdds), encoding a branch point enzyme required for dolichol biosynthesis. Dhdds-null livers showed ER stress and impaired N-glycosylation, along with apoptosis and regeneration. Finally, the combined deletion of Hmgcr and Dhdds synergistically exacerbated hepatocyte ER stress. Our data show a critical role for mevalonate-derived dolichol in the liver and suggest that dolichol depletion is at least partially responsible for ER stress and apoptosis upon potent Hmgcr inhibition.

Somatic Editing of Ldlr With Adeno-Associated Viral-CRISPR Is an Efficient Tool for Atherosclerosis Research.

Objective- Atherosclerosis studies in Ldlr knockout mice require breeding to homozygosity and congenic status on C57BL6/J background, a process that is both time and resource intensive. We aimed to develop a new method for generating atherosclerosis through somatic deletion of Ldlr in livers of adult mice. Approach and Results- Overexpression of PCSK9 (proprotein convertase subtilisin/kexin type 9) is currently used to study atherosclerosis, which promotes degradation of LDLR (low-density lipoprotein receptor) in the liver. We sought to determine whether CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats-associated 9) could also be used to generate atherosclerosis through genetic disruption of Ldlr in adult mice. We engineered adeno-associated viral (AAV) vectors expressing Staphylococcus aureus Cas9 and a guide RNA targeting the Ldlr gene (AAV-CRISPR). Both male and female mice received either (1) saline, (2) AAV-CRISPR, or (3) AAV-hPCSK9 (human PCSK9)-D374Y. A fourth group of germline Ldlr-KO mice was included for comparison. Mice were placed on a Western diet and followed for 20 weeks to assess plasma lipids, PCSK9 protein levels, atherosclerosis, and editing efficiency. Disruption of Ldlr with AAV-CRISPR was robust, resulting in severe hypercholesterolemia and atherosclerotic lesions in the aorta. AAV-hPCSK9 also produced hypercholesterolemia and atherosclerosis as expected. Notable sexual dimorphism was observed, wherein AAV-CRISPR was superior for Ldlr removal in male mice, while AAV-hPCSK9 was more effective in female mice. Conclusions- This all-in-one AAV-CRISPR vector targeting Ldlr is an effective and versatile tool to model atherosclerosis with a single injection and provides a useful alternative to the use of germline Ldlr-KO mice.

Assessment of acute myocarditis by cardiac magnetic resonance imaging: Comparison of qualitative and quantitative analysis methods.

BACKGROUND: To compare cardiac magnetic resonance (CMR) qualitative and quantitative analysis methods for the noninvasive assessment of myocardial inflammation in patients with suspected acute myocarditis (AM). METHODS: A total of 61 patients with suspected AM underwent coronary angiography and CMR. Qualitative analysis was performed applying Lake-Louise Criteria (LLC), followed by quantitative analysis based on the evaluation of edema ratio (ER) and global relative enhancement (RE). Diagnostic performance was assessed for each method by measuring the area under the curves (AUC) of the receiver operating characteristic analyses. The final diagnosis of AM was based on symptoms and signs suggestive of cardiac disease, evidence of myocardial injury as defined by electrocardiogram changes, elevated troponin I, exclusion of coronary artery disease by coronary angiography, and clinical and echocardiographic follow-up at 3 months after admission to the chest pain unit. RESULTS: In all patients, coronary angiography did not show significant coronary artery stenosis. Troponin I levels and creatine kinase were higher in patients with AM compared to those without (both P < .001). There were no significant differences among LLC, T2-weighted short inversion time inversion recovery (STIR) sequences, early (EGE), and late (LGE) gadolinium-enhancement sequences for diagnosis of AM. The AUC for qualitative (T2-weighted STIR 0.92, EGE 0.87 and LGE 0.88) and quantitative (ER 0.89 and global RE 0.80) analyses were also similar. CONCLUSIONS: Qualitative and quantitative CMR analysis methods show similar diagnostic accuracy for the diagnosis of AM. These findings suggest that a simplified approach using a shortened CMR protocol including only T2-weighted STIR sequences might be useful to rule out AM in patients with acute coronary syndrome and normal coronary angiography.

Complete deletion of Cd39 is atheroprotective in apolipoprotein E-deficient mice.

Cd39 scavenges extracellular ATP and ADP, ultimately generating adenosine, a nucleoside, which has anti-inflammatory effects in the vasculature. We have evaluated the role of Cd39 in the development of atherosclerosis in hyperlipidemic mice. ApoE KO (Cd39+/+/ApoE-/-) and Cd39/ApoE double KO (DKO) (Cd39-/-/ApoE-/-) mice were maintained on chow or Western diet for up to 20 weeks before evaluation of atherosclerotic lesions. We found that DKO mice exhibited significantly fewer atherosclerotic lesions than ApoE KO mice, irrespective of diet. Analyses of plaque composition revealed diminished foam cells in the fatty streaks and smaller necrotic cores in advanced lesions of DKO mice, when compared with those in ApoE KO mice. This atheroprotective phenotype was associated with impaired platelet reactivity to ADP in vitro and prolonged platelet survival, suggesting decreased platelet activation in vivo. Further studies with either genetic deletion or pharmacological inhibition of Cd39 in macrophages revealed increased cholesterol efflux mediated via ABCA1 to ApoA1. This phenomenon was associated with elevated plasma HDL levels in DKO mice. Our findings indicate that complete deletion of Cd39 paradoxically attenuates development of atherosclerosis in hyperlipidemic mice. We propose that this phenotype occurs, at least in part, from diminished platelet activation, increased plasma HDL levels, and enhanced cholesterol efflux and indicates the complexity of purinergic signaling in atherosclerosis.

Co-expression of functional human Heme Oxygenase 1, Ecto-5'-Nucleotidase and ecto-nucleoside triphosphate diphosphohydrolase-1 by "self-cleaving" 2A peptide system.

We developed an F2A-based multicistronic system to evaluate functional effects of co-expression of three proteins important for xenotransplantation: heme oxygenase 1 (HO1), ecto-5'-nucleotidase (E5NT) and ecto-nucleoside triphosphate diphosphohydrolase-1 (ENTPD1). The tricistronic p2A plasmid that we constructed was able to efficiently drive concurrent expression of HO1, E5NT and ENTPD1 in HEK293T cells. All three overexpressed proteins possessed relevant enzymatic activities, while addition of furin site interfered with protein expression and activity. We conclude that our tricistronic p2A construct is effective and optimal to test the combined protective effects of HO1, E5NT and ENTPD1 against xeno-rejection mechanisms.

Current role of machine learning and radiogenomics in precision neuro-oncology.

In the past few years, artificial intelligence (AI) has been increasingly used to create tools that can enhance workflow in medicine. In particular, neuro-oncology has benefited from the use of AI and especially machine learning (ML) and radiogenomics, which are subfields of AI. ML can be used to develop algorithms that dynamically learn from available medical data in order to automatically do specific tasks. On the other hand, radiogenomics can identify relationships between tumor genetics and imaging features, thus possibly giving new insights into the pathophysiology of tumors. Therefore, ML and radiogenomics could help treatment tailoring, which is crucial in personalized neuro-oncology. The aim of this review is to illustrate current and possible future applications of ML and radiomics in neuro-oncology.

MR image quality in local staging of prostate cancer: Role of PI-QUAL in the detection of extraprostatic extension.

PURPOSE: To assess the impact of prostate MRI image quality by means of the Prostate Imaging Quality (PI-QUAL) score, on the identification of extraprostatic extension of disease (EPE), predicted using the EPE Grade Score, Likert Scale Score (LSS) and a clinical nomogram (MSKCCn). METHODS: We retrospectively included 105 patients with multiparametric prostate MRI prior to prostatectomy. Two radiologists evaluated image quality using PI-QUAL (≥4 was considered high quality) in consensus. All cases were also scored using the EPE Grade, the LSS, and the MSKCCn (dichotomized). Inter-rater reproducibility for each score was also assessed. Accuracy was calculated for the entire population and by image quality, considering two thresholds for EPE Grade (≥2 and = 3) and LSS (≥3 and ≥ 4) and using McNemar's test for comparison. RESULTS: Overall, 66 scans achieved high quality. The accuracy of EPE Grade ranged from 0.695 to 0.743, while LSS achieved values between 0.705 and 0.733. Overall sensitivity for the radiological scores (range = 0.235-0.529) was low irrespective of the PI-QUAL score, while specificity was higher (0.775-0.986). The MSKCCn achieved an AUC of 0.76, outperforming EPE Grade (=3 threshold) in studies with suboptimal image quality (0.821 vs 0.564, p = 0.016). EPE Grade (=3 threshold) accuracy was also better in high image quality studies (0.849 vs 0.564, p = 0.001). Reproducibility was good to excellent overall (95 % Confidence Interval range = 0.782-0.924). CONCLUSION: Assessing image quality by means of PI-QUAL is helpful in the evaluation of EPE, as a scan of low quality makes its performance drop compared to clinical staging tools.

Advanced CMR Techniques in Anderson-Fabry Disease: State of the Art.

Anderson-Fabry disease (AFD) is a rare multisystem X-linked lysosomal storage disorder caused by α-galactosidase A enzyme deficiency. Long-term cardiac involvement in AFD results in left ventricular hypertrophy and myocardial fibrosis, inducing several complications, mainly arrhythmias, valvular dysfunction, and coronary artery disease. Cardiac magnetic resonance (CMR) represents the predominant noninvasive imaging modality for the assessment of cardiac involvement in the AFD, being able to comprehensively assess cardiac regional anatomy, ventricular function as well as to provide tissue characterization. This review aims to explore the role of the most advanced CMR techniques, such as myocardial strain, T1 and T2 mapping, perfusion and hybrid imaging, as diagnostic and prognostic biomarkers.

Adeno-Associated virus 8 delivers an immunomodulatory peptide to mouse liver more efficiently than to rat liver.

Targeting the Kv1.3 potassium channel has proven effective in reducing obesity and the severity of animal models of autoimmune disease. Stichodactyla toxin (ShK), isolated from the sea anemone Stichodactyla helianthus, is a potent blocker of Kv1.3. Several of its analogs are some of the most potent and selective blockers of this channel. However, like most biologics, ShK and its analogs require injections for their delivery, and repeated injections reduce patient compliance during the treatment of chronic diseases. We hypothesized that inducing the expression of an ShK analog by hepatocytes would remove the requirement for frequent injections and lead to a sustained level of Kv1.3 blocker in the circulation. To this goal, we tested the ability of Adeno-Associated Virus (AAV)8 vectors to target hepatocytes for expressing the ShK analog, ShK-235 (AAV-ShK-235) in rodents. We designed AAV8 vectors expressing the target transgene, ShK-235, or Enhanced Green fluorescent protein (EGFP). Transduction of mouse livers led to the production of sufficient levels of functional ShK-235 in the serum from AAV-ShK-235 single-injected mice to block Kv1.3 channels. However, AAV-ShK-235 therapy was not effective in reducing high-fat diet-induced obesity in mice. In addition, injection of even high doses of AAV8-ShK-235 to rats resulted in a very low liver transduction efficiency and failed to reduce inflammation in a well-established rat model of delayed-type hypersensitivity. In conclusion, the AAV8-based delivery of ShK-235 was highly effective in inducing the secretion of functional Kv1.3-blocking peptide in mouse, but not rat, hepatocytes yet did not reduce obesity in mice fed a high-fat diet.

Prediction of 2-[18F]FDG PET-CT SUVmax for Adrenal Mass Characterization: A CT Radiomics Feasibility Study.

BACKGROUND: Indeterminate adrenal masses (AM) pose a diagnostic challenge, and 2-[18F]FDG PET-CT serves as a problem-solving tool. Aim of this study was to investigate whether CT radiomics features could be used to predict the 2-[18F]FDG SUVmax of AM. METHODS: Patients with AM on 2-[18F]FDG PET-CT scan were grouped based on iodine contrast injection as CT contrast-enhanced (CE) or CT unenhanced (NCE). Two-dimensional segmentations of AM were manually obtained by multiple operators on CT images. Image resampling and discretization (bin number = 16) were performed. 919 features were calculated using PyRadiomics. After scaling, unstable, redundant, and low variance features were discarded. Using linear regression and the Uniform Manifold Approximation and Projection technique, a CT radiomics synthetic value (RadSV) was obtained. The correlation between CT RadSV and 2-[18F]FDG SUVmax was assessed with Pearson test. RESULTS: A total of 725 patients underwent PET-CT from April 2020 to April 2021. In 150 (21%) patients, a total of 179 AM (29 bilateral) were detected. Group CE consisted of 84 patients with 108 AM (size = 18.1 ± 4.9 mm) and Group NCE of 66 patients with 71 AM (size = 18.5 ± 3.8 mm). In both groups, 39 features were selected. No statisticallyf significant correlation between CT RadSV and 2-[18F]FDG SUVmax was found (Group CE, r = 0.18 and p = 0.058; Group NCE, r = 0.13 and p = 0.27). CONCLUSIONS: It might not be feasible to predict 2-[18F]FDG SUVmax of AM using CT RadSV. Its role as a problem-solving tool for indeterminate AM remains fundamental.

MRI Liver Imaging Integrated with Texture Analysis in Native Liver Survivor Patients with Biliary Atresia after Kasai Portoenterostomy: Correlation with Medical Outcome after Surgical Treatment.

Kasai portoenterostomy (KP) plays a crucial role in the treatment of biliary atresia (BA). The aim is to correlate MRI quantitative findings of native liver survivor BA patients after KP with a medical outcome. Thirty patients were classified as having ideal medical outcomes (Group 1; n = 11) if laboratory parameter values were in the normal range and there was no evidence of chronic liver disease complications; otherwise, they were classified as having nonideal medical outcomes (Group 2; n = 19). Liver and spleen volumes, portal vein diameter, liver mean, and maximum and minimum ADC values were measured; similarly, ADC and T2-weighted textural parameters were obtained using ROI analysis. The liver volume was significantly (p = 0.007) lower in Group 2 than in Group 1 (954.88 ± 218.31 cm3 vs. 1140.94 ± 134.62 cm3); conversely, the spleen volume was significantly (p < 0.001) higher (555.49 ± 263.92 cm3 vs. 231.83 ± 70.97 cm3). No differences were found in the portal vein diameter, liver ADC values, or ADC and T2-weighted textural parameters. In conclusion, significant quantitative morpho-volumetric liver and spleen abnormalities occurred in BA patients with nonideal medical outcomes after KP, but no significant microstructural liver abnormalities detectable by ADC values and ADC and T2-weighted textural parameters were found between the groups.

In vivo expansion of gene-targeted hepatocytes through transient inhibition of an essential gene.

Homology Directed Repair (HDR)-based genome editing is an approach that could permanently correct a broad range of genetic diseases. However, its utility is limited by inefficient and imprecise DNA repair mechanisms in terminally differentiated tissues. Here, we tested "Repair Drive", a novel method for improving targeted gene insertion in the liver by selectively expanding correctly repaired hepatocytes in vivo. Our system consists of transient conditioning of the liver by knocking down an essential gene, and delivery of an untargetable version of the essential gene in cis with a therapeutic transgene. We show that Repair Drive dramatically increases the percentage of correctly targeted hepatocytes, up to 25%. This resulted in a five-fold increased expression of a therapeutic transgene. Repair Drive was well-tolerated and did not induce toxicity or tumorigenesis in long term follow up. This approach will broaden the range of liver diseases that can be treated with somatic genome editing.

In Vivo Gene Editing in Lipid and Atherosclerosis Research.

The low-density lipoprotein receptor (Ldlr) and apolipoprotein E (Apoe) germline knockout (KO) models have provided fundamental insights in lipid and atherosclerosis research for decades. However, testing new candidate genes in these models requires extensive breeding, which is highly time and resource consuming. In this chapter, we provide methods for rapidly modeling hypercholesterolemia and atherosclerosis as well as testing new genes in adult mice through somatic gene editing. Adeno-associated viral (AAV) vectors are exploited to deliver the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 genome editing system (AAV-CRISPR) to the liver. This tool enables rapid and efficient editing of lipid- and atherosclerosis-related genes in the liver.

COVID-19 chest CT and laboratory features of B.1.617.2 (Delta variant) vs B.1.1.7 (Alpha variant) surge: a single center case-control study.

Purpose: To assess clinical, laboratory and radiological differences between Delta and Alpha SARS-CoV-2 variants. Materials and Methods: Twenty SARS-CoV-2 patients admitted from 30th of August to 30th of October 2021 (period with estimated highest prevalence of Delta variant circulation in Italy) were enrolled. Patients were matched in a 1:1 ratio with same gender and same age +/- 2 years controls admitted from 1st of September 2020 to 30th of January 2021 (predominant circulation of Alpha variant). Chest computed tomography (CT) were retrospectively evaluated. Main clinical parameters, radiological and laboratory findings were compared between two groups. Results: Patients with probable Delta variant had significantly higher CT severity scores, lower PaO2/FiO2 ratio and higher C-reactive protein and lactate dehydrogenase levels at admission. On multivariate analysis, probable Delta variant infection was associated with higher CT severity score. Ground glass opacities and crazy paving patterns were more frequently noticed than consolidation, with the latter being more frequent in Delta cohort, even though not significantly. According to prevalent imaging pattern, the consolidation one was significantly associated with pregnancy (p=0.008). Conclusions: Patients admitted during predominance of Delta variant circulation had a more severe lung involvement compared to patients in infected when Alpha variant was predominant. Despite imaging pattern seems to be not influenced by viral variant and other clinical variables, the consolidative pattern was observed more frequently in pregnancy.

Co-targeting triple-negative breast cancer cells and endothelial cells by metronomic chemotherapy inhibits cell regrowth and migration via downregulation of the FAK/VEGFR2/VEGF axis and autophagy/apoptosis activation.

High-dose standard-of-care chemotherapy is the only option for triple-negative breast cancer (TNBC) patients, which eventually die due to metastatic tumors. Recently, metronomic chemotherapy (mCHT) showed advantages in treating TNBCs leading us to investigate the anti-metastatic and anti-angiogenic potential of metronomic 5-Fluorouracil plus Vinorelbine (5-FU+VNR) on endothelial cells (ECs) and TNBCs in comparison to standard treatment (STD). We found that 10-fold lower doses of 5-FU+VNR given mCHT vs. STD inhibits cell proliferation and survival of ECs and TNBC cells. Both schedules strongly affect ECs migration and invasion, but in TNBC cells mCHT is significantly more effective than STD in impairing cell migration and invasion. The two treatments disrupt FAK/VEGFR/VEGF signaling in both ECs and TNBC cells. mCHT, and to a much lesser extent STD treatment, induces apoptosis in ECs, whereas it switches the route of cell death from apoptosis (as induced by STD) to autophagy in TNBC cells. mCHT-treated TNBCs-derived conditioned medium also strongly affects ECs' migration, modulates different angiogenesis-associated proteins, and hampers angiogenesis in matrix sponge in vivo. In conclusion, mCHT administration of 5-FU+VNR is more effective than STD schedule in controlling cell proliferation/survival and migration/invasion of both ECs and TNBC cells and has a strong anti-angiogenic effect. Our data suggest that the stabilization of tumor growth observed in TNBC patients treated with mCHT therapy schedule is likely due not only to direct cytotoxic effects but also to anti-metastatic and anti-angiogenic effects.

Dual-Energy CT of the Heart: A Review.

Dual-energy computed tomography (DECT) represents an emerging imaging technique which consists of the acquisition of two separate datasets utilizing two different X-ray spectra energies. Several cardiac DECT applications have been assessed, such as virtual monoenergetic images, virtual non-contrast reconstructions, and iodine myocardial perfusion maps, which are demonstrated to improve diagnostic accuracy and image quality while reducing both radiation and contrast media administration. This review will summarize the technical basis of DECT and review the principal cardiac applications currently adopted in clinical practice, exploring possible future applications.