MV-MS-FETE: Multi-view multi-scale feature extractor and transformer encoder for stenosis recognition in echocardiograms

Background: aortic stenosis is a common heart valve disease that mainly affects older people in developed countries. Its early detection is crucial to prevent the irreversible disease progression and, eventually, death. A typical screening technique to detect stenosis uses echocardiograms; however, variations introduced by other tissues, camera movements, and uneven lighting can hamper the visual inspection, leading to misdiagnosis. To address these issues, effective solutions involve employing deep learning algorithms to assist clinicians in detecting and classifying stenosis by developing models that can predict this pathology from single heart views. Although promising, the visual information conveyed by a single image may not be sufficient for an accurate diagnosis, especially when using an automatic system; thus, this indicates that different solutions should be explored. Methodology: following this rationale, this paper proposes a novel deep learning architecture, composed of a multi-view, multi-scale feature extractor, and a transformer encoder (MV-MS-FETE) to predict stenosis from parasternal long and short-axis views. In particular, starting from the latter, the designed model extracts relevant features at multiple scales along its feature extractor component and takes advantage of a transformer encoder to perform the final classification. Results: experiments were performed on the recently released Tufts medical echocardiogram public dataset, which comprises 27,788 images split into training, validation, and test sets. Due to the recent release of this collection, tests were also conducted on several state-of-the-art models to create multi-view and single-view benchmarks. For all models, standard classification metrics were computed (e.g., precision, F1-score). The obtained results show that the proposed approach outperforms other multi-view methods in terms of accuracy and F1-score and has more stable performance throughout the training procedure. Furthermore, the experiments also highlight that multi-view methods generally perform better than their single-view counterparts. Conclusion: this paper introduces a novel multi-view and multi-scale model for aortic stenosis recognition, as well as three benchmarks to evaluate it, effectively providing multi-view and single-view comparisons that fully highlight the model's effectiveness in aiding clinicians in performing diagnoses while also producing several baselines for the aortic stenosis recognition task

Physiological responses of Arundo donax ecotypes to drought: a common garden study

Genetic analyses have suggested that the clonal reproduction of Arundo donax has resulted in low genetic diversity. However, an earlier common garden phenotyping experiment identified specimens of A. donax with contrasting biomass yields (ecotypes 6 and 20). We utilized the same well-established stands to investigate the photosynthetic and stress physiology of the A. donax ecotypes under irrigated and drought conditions. Ecotype 6 produced the largest yields in both treatments. The A. donax ecotypes exhibited identical high leaf-level rates of photosynthesis (PN) and stomatal conductance (Gs) in the well-watered treatment. Soil drying induced reductions in PN and Gs, decreased use of light energy for photochemistry, impaired function of photosystem II and increased heat dissipation similarly in the two ecotypes. Levels of biologically active free-abscisic acid (ABA) and fixed glycosylated-ABA increased earlier in response to the onset of water deficit in ecotype 6; however, as drought progressed, the ecotypes showed similar increases in both forms of ABA. This may suggest that because of the low genetic variability in A. donax the genes responding to drought might have been activated similarly in the two ecotypes, resulting in identical physiological responses to water deficit. Despite the lack of physiological ecotypic differences that could be associated with yield, A. donax retained a high degree of PN and biomass gain under water deficit stress conditions. This may enable utilization of A. donax as a fast growing biomass crop in rain-fed marginal lands in hot drought prone climates

Intratumoral heterogeneity and clonal evolution in liver cancer

Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCR-seq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves single-biopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how the different components of the HCC ecosystem interact during cancer evolution

Guideline Application in Real world: multi-Institutional Based survey of Adjuvant and first-Line pancreatic Ductal adenocarcinoma treatment in Italy. Primary analysis of the GARIBALDI survey

Background: Information about the adherence to scientific societies guidelines in the ‘real-world’ therapeutic management of oncological patients are lacking. This multicenter, prospective survey was aimed to improve the knowledge relative to 2017-2018 recommendations of the Italian Association of Medical Oncology (AIOM). Patients and methods: Treatment-naive adult patients with pancreatic adenocarcinoma were enrolled. Group A received adjuvant therapy, group B received primary chemotherapy, and group C had metastatic disease. The results on patients accrued until 31 October 2019 with a mature follow-up were presented. Results: Since July 2017, 833 eligible patients of 923 (90%) were enrolled in 44 Italian centers. The median age was 69 years (range 36-89 years; 24% >75 years); 48% were female; 93% had Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1; group A: 16%, group B: 30%; group C: 54%; 72% Nord, 13% Center, 15% South. In group A, guidelines adherence was 68% [95% confidence interval (CI) 59% to 76%]; 53% of patients received gemcitabine and 15% gemcitabine + capecitabine; median CA19.9 was 29 (range 0-7300; not reported 15%); median survival was 36.4 months (95% CI 27.5-47.3 months). In group B, guidelines adherence was 96% (95% CI 92% to 98%); 55% of patients received nab-paclitaxel + gemcitabine, 27% FOLFIRINOX, 12% gemcitabine, and 3% clinical trial; median CA19.9 was 337 (range 0-20220; not reported 9%); median survival was 18.1 months (95% CI 15.6-19.9 months). In group C, guidelines adherence was 96% (95% CI 94% to 98%); 71% of patients received nab-paclitaxel + gemcitabine, 16% gemcitabine, 8% FOLFIRINOX, and 4% clinical trial; liver and lung metastases were reported in 76% and 23% of patients, respectively; median CA19.9 value was 760 (range 0-1374500; not reported 9%); median survival was 10.0 months (95% CI 9.1-11.1 months). Conclusions: The GARIBALDI survey shows a very high rate of adherence to guidelines and survival outcome in line with the literature. CA19.9 testing should be enhanced; nutritional and psychological counseling represent an unmet need. Enrollment to assess adherence to updated AIOM guidelines is ongoing

Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains

Genetics of disease, diagnosis and treatmen

Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants.

To assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants. We analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants. The number of rare likely deleterious variants in functionally intolerant genes ("other hits") correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in autism probands carrying gene-disruptive variants (n=184, p=0.03) compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes. Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified

Rural World, Migration, and Agriculture in Mediterranean EU: An Introduction

AbstractThis book investigates the dynamics that are reshaping human and natural landscapes in the European agrarian world, with a specific focus on Mediterranean Europe. We focus here on more marginal rural settings, where the potential for agricultural intensification is structurally limited. These areas in particular have suffered from the geographical and socio-economic polarization of development patterns and have paid a relevant burden to the recent crisis

Differentiation of human adipose-derived stem cells into neuron/motoneuron-like cells for cell replacement therapy of spinal cord injury

Human adipose-derived stem cells (hADSCs) are increasingly presumed to be a prospective stem cell source for cell replacement therapy in various degenerative and/or traumatic diseases. The potential of trans-differentiating hADSCs into motor neuron cells indisputably provides an alternative way for spinal cord injury (SCI) treatment. In the present study, a stepwise and efficient hADSC trans-differentiation protocol with retinoic acid (RA), sonic hedgehog (SHH), and neurotrophic factors were developed. With this protocol hADSCs could be converted into electrophysiologically active motoneuron-like cells (hADSC-MNs), which expressed both a cohort of pan neuronal markers and motor neuron specific markers. Moreover, after being primed for neuronal differentiation with RA/SHH, hADSCs were transplanted into SCI mouse model and they survived, migrated, and integrated into injured site and led to partial functional recovery of SCI mice. When ablating the transplanted hADSC-MNs harboring HSV-TK-mCherry overexpression system with antivirial Ganciclovir (GCV), functional relapse was detected by motor-evoked potential (MEP) and BMS assays, implying that transplanted hADSC-MNs participated in rebuilding the neural circuits, which was further confirmed by retrograde neuronal tracing system (WGA). GFP-labeled hADSC-MNs were subjected to whole-cell patch-clamp recording in acute spinal cord slice preparation and both action potentials and synaptic activities were recorded, which further confirmed that those pre-conditioned hADSCs indeed became functionally active neurons in vivo. As well, transplanted hADSC-MNs largely prevented the formation of injury-induced cavities and exerted obvious immune-suppression effect as revealed by preventing astrocyte reactivation and favoring the secretion of a spectrum of anti-inflammatory cytokines and chemokines. Our work suggests that hADSCs can be readily transformed into MNs in vitro, and stay viable in spinal cord of the SCI mouse and exert multi-therapeutic effects by rebuilding the broken circuitry and optimizing the microenvironment through immunosuppression

Pholiotic acid promotes apoptosis in human metastatic melanoma cells

Mushrooms produce a great variety of secondary metabolites that can be successful in both prevention and treatment of various cancers. In particular, higher Basidiomycete mushrooms contain various types of biologically active low-molecular compounds in fruiting bodies with suggested anticarcinogenic effects. The polyamine analogue {(2R)-2-[(S)-3-hydroxy-3-methylglutaryloxy] putrescine dicinnamamide} indicated with the name pholiotic acid, isolated for the first time by us from the fruiting bodies of the Basidiomycete Pholiota spumosa (Fr.) Sing. (Strophariaceae), inhibited the viability of human prostate cancer cells, such as other polyamine synthetic analogues that have shown antitumor activity in several types of cancer, including melanoma. Melanoma is an aggressive skin cancer that can metastasize to other organs and presents a high resistance to conventional therapies. In light of these considerations, the present study was therefore designed to assess whether this putrescine derivative could inhibit the growth of human metastatic melanoma cell lines, M14 and A2058. The results obtained demonstrate that this natural compound, at 12.5–50 μM concentration, was able to reduce cell viability of both cancer cells inducing cell death by intrinsic apoptotic pathway that probably involves PTEN activity, inhibition of Hsp70 expression and reactive oxygen species production. On the other hand, the increased expression of enzymes involved in polyamine catabolism trigger apoptotic cell death leading to polyamine depletion and generation of reactive oxygen species as by-products. In conclusion, these findings, starting point for further investigation, implement available our data to support pholiotic acid as an attractive potential chemopreventive agent, and provide a basis for further research into the use of this polyamine derivative as potential anticancer agent for melanoma in combination with existing therapies to improve treatment efficacy and overcome the obstacle of drug resistance