Engagement of the Mannose Receptor by Tumoral Mucins Activates an Immune Suppressive Phenotype in Human Tumor-Associated Macrophages

Tumor-Associated Macrophages (TAMs) are abundantly present in the stroma of solid tumors and modulate several important biological processes, such as neoangiogenesis, cancer cell proliferation and invasion, and suppression of adaptive immune responses. Myeloid C-type lectin receptors (CLRs) constitute a large family of transmembrane carbohydrate-binding receptors that recognize pathogens as well as endogenous glycoproteins. Several lines of evidence demonstrate that some CLRs can inhibit the immune response. In this study we investigated TAM-associated molecules potentially involved in their immune suppressive activity. We found that TAMs isolated from human ovarian carcinoma samples predominantly express the CLRs Dectin-1, MDL-1, MGL, DCIR, and most abundantly the Mannose Receptor (MR). Components of carcinomatous ascites and purified tumoral mucins (CA125 and TAG-72) bound the MR and induced its internalization. MR engagement by tumoral mucins and by an agonist anti-MR antibody modulated cytokine production by TAM toward an immune-suppressive profile: increase of IL-10, absence of IL-12, and decrease of the Th1-attracting chemokine CCL3. This study highlights that tumoral mucin-mediated ligation of the MR on infiltrating TAM may contribute to their immune suppressive phenotype

Impact of pulsed-wave-Doppler velocity-envelope tracing techniques on classification of complete fetal cardiac cycles

Fetal echocardiography is an operator-dependent examination technique requiring a high level of expertise. Pulsed-wave Doppler (PWD) is often used as a reference for the mechanical activity of the heart, from which several quantitative parameters can be extracted. These aspects suggest the development of software tools that can reliably identify complete and clinically meaningful fetal cardiac cycles that can enable their automatic measurement. Several scientific works have addressed the tracing of the PWD velocity envelope. In this work, we assess the different steps involved in the signal processing chains that enable PWD envelope tracing. We apply a supervised classifier trained on envelopes traced by different signal processing chains for distinguishing complete and measurable PWD heartbeats from incomplete or malformed ones, which makes it possible to determine the impact of each of the different processing steps on the detection accuracy. In this study, we collected 43 images and labeled 174,319 PWD segments from 25 pregnant women volunteers. By considering seven envelope tracing techniques and the 23 different processing steps involved in their implementation, the results of our study reveal that, compared to the steps investigated in most other works, those that achieve binarisation and envelope extraction are significantly more important (p < 0.05). The best approaches among those studied enabled greater than 98% accuracy on our large manually annotated dataset

Brownian refrigeration by hybrid tunnel junctions

Voltage fluctuations generated in a hot resistor can cause extraction of heat from a colder normal metal electrode of a hybrid tunnel junction between a normal metal and a superconductor. We extend the analysis presented in [Phys. Rev. Lett. 98, 210604 (2007)] of this heat rectifying system, bearing resemblance to a Maxwell's demon. Explicit analytic calculations show that the entropy of the total system is always increasing. We then consider a single electron transistor configuration with two hybrid junctions in series, and show how the cooling is influenced by charging effects. We analyze also the cooling effect from nonequilibrium fluctuations instead of thermal noise, focusing on the shot noise generated in another tunnel junction. We conclude by discussing limitations for an experimental observation of the effect.Comment: 16 pages, 16 figure

Tumor-associated macrophages as incessant builders and destroyers of the cancer stroma

Tumor-Associated Macrophages (TAM) are key components of the reactive stroma of tumors. In most, although not all cancers, their presence is associated with poor patient prognosis. In addition to releasing cytokines and growth factors for tumor and endothelial cells, a distinguished feature of TAM is their high-rate degradation of the extra-cellular matrix. This incessant stroma remodelling favours the release of matrix-bound growth factors and promotes tumor cell motility and invasion. In addition, TAM produce matrix proteins, some of which are typical of the neoplastic tissues. The gene expression profile of TAM isolated from human tumors reveals a matrix-related signature with the up-regulation of genes coding for different matrix proteins, as well as several proteolytic enzymes. Among ECM components are: osteopontin, osteoactivin, collagens and fibronectin, including also a truncated isoform of fibronectin termed migration stimulation factor. In addition to serve as structural proteins, these matrix components have key functions in the regulation of the vessel network, in the inductionof tumor cell motility and degradation of cellular debris. Among proteolytic enzymes are: matrix metalloproteases, cathepsins, lysosomal and ADAM proteases, and the urokinase-type plasminogen activator. The degrading activity of TAM, coupled to the production of bio-active ECM proteins, co-operate to the build-up and maintenance of an inflammatory micro-environment which eventually promotes tumor progression

Innovation and development after the earthquake in Emilia

The 2012 earthquake in Emilia-Romagna (Italy) has shaken up the collective understanding on the socioeconomic importance of a vast territory that generates almost 2% of Italian GDP. The area affected by the earthquake is characterized by the presence of important industrial and agricultural districts, and by good practices of local governance that are internationally renowned. Private and public buildings, factories, offices and retail shops, historical and cultural heritage sites have been severely damaged. Not only, but it set in motion transformations in the socio-economic system that might have unexpected consequences and that undermine the quick recovery of the local system: different agents, at different levels, taking individual and collective decisions, generate a cascade of changes that interact with its evolution path. Indeed, earthquakes pose challenges, but provide unprecedented opportunities: strategic decisions by economic and political agents, newly available financial resources, coordination or lack of coordination among main stakeholders, and so on. The following paper provides an overview of the first results of Energie Sisma Emilia research project: it aims at collecting and disseminating relevant knowledge and evidence in order to design policies. In particular, it identifies the agents propelling innovation processes, and analyses their strategies in ever-changing environment. The paper starts with a socio-economic analysis of the area struck by the earthquake, followed by the results of three of the focus groups conducted. Eventually, it illustrates a specific innovation: the introduction and implementation of the digital infrastructure “Mude”

Functional magnetic resonance imaging in the evaluation of the elastic properties of ascending aortic aneurysm

Objective: To evaluate the aortic wall elasticity using the maximal rate of systolic distension (MRSD) and maximal rate of diastolic recoil (MRDR) and their correlation with the aortic size index (ASI). Methods: Forty-eight patients with thoracic aortic aneurysm were enrolled in this study. A standard magnetic resonance imaging (MRI) protocol was used to calculate MRSD and MRDR. Both MRSD and MRDR were expressed as percentile of maximal area/10-3 sec. ASI (maximal aortic diameter/body surface area) was calculated. A correlation between MRSD, MRDR, ASI, and the patient’s age was performed using regression plot. Results: A significant correlation between MRSD (t=-4,36; r2=0.29; P≤0.0001), MRDR (t=3.92; r2=0.25; P=0.0003), and ASI (25±4.33 mm/m2; range 15,48-35,14 mm/m2) is observed. As ASI increases, aortic MRSD and MRDR decrease. Such inverse correlation between MRSD, MRDR, and ASI indicates increased stiffness of the ascending aorta. A significant correlation between the patient’s age and the decrease in MRSD and MRDR is observed. Conclusion: MRSD and MRDR are significantly correlated with ASI and the patient’s age. They seem to describe properly the increasing stiffness of aortas. These two new indexes provide a promising, accessible, and reproducible approach to evaluate the

Sutureless Valve in Repeated Aortic Valve Replacement: Results from an International Prospective Registry

Objective: To report early and midterm results registry of patients undergoing repeated aortic valve replacement (RAVR) with sutureless prostheses from an international prospective registry (SURE-AVR). Methods: Between March 2011 and June 2019, 69 patients underwent RAVR with self-expandable sutureless aortic bioprostheses at 22 international cardiac centers.Results: Overall mortality was 2.9% with a predicted logistic EuroSCORE 11 of 10.7%. Indications for RAVR were structural valve dysfunction (84.1%) and infective prosthetic endocarditis (15.9%) and were performed in patients with previously implanted bioprostheses (79.7%), mechanical valves (15.9%), and transcatheter valves (4.3%). Minimally invasive approach was performed in 15.9% of patients. Rate of stroke was 1.4% and rate of early valve-related reintervention was 1.4%. Overall survival rate at 1 and 5 years was 97% and 91%, respectively. No major paravalvular leak occurred. Rate of pacemaker implantation was 5.8% and 0.9% per patient-year early and at follow-up, respectively. The mean transvalvular gradient at 1-year and 5-year follow-up was 10.5 mmHg and 11.5 mmHg with a median effective orifice area of 1.8 cm 2 and 1.8 cm 2 , respectively. Conclusions: RAVR with sutureless valves is a safe and effective approach and provides excellent clinical and hemodynamic results up to 5 years

Hormone Receptor-Positive/HER2-Positive Breast Cancer: Hormone Therapy and Anti-HER2 Treatment: An Update on Treatment Strategies

Hormone receptor (HR)-positive/HER2-positive breast cancer represents a distinct subtype expressing estrogen and progesterone receptors with an overexpression of HER2. Approximately 14% of female breast cancer cases are HER2-positive, with the majority being HR-positive. These tumors show a cross-talk between the hormonal and HER2 pathways; the interaction has implications for the treatment options for the disease. In this review, we analyze the biology of HR-positive/HER2-positive breast cancer and summarize the evidence concerning the standard of care options both in neoadjuvant/adjuvant settings and in advanced disease. Additionally, we focus on new trials and drugs for HR-positive/HER2-positive breast cancer and the new entity: HER2-low breast cancer

Clinical outcomes after implantation of a sutureless aortic bioprosthesis with concomitant mitral valve surgery: the SURE-AVR registry

Background: Early treatment of aortic valve stenosis is recommended in eligible symptomatic patients with severe aortic valve stenosis who would otherwise have a poor prognosis. The sutureless aortic valve bioprosthesis offers an alternative to standard aortic valve replacement with a sutured valve, but limited data are available in patients who have undergone multiple valve procedures involving the new, sutureless technology. We sought to investigate outcomes in high operative risk patients with previous or concomitant valve surgery who were implanted with a sutureless valve. Methods: SURE-AVR is an ongoing, prospective, multinational registry of patients undergoing aortic valve replacement. In-hospital and post-discharge outcomes up to 5 years were collected. Results: The study population comprised 78 patients (mean \ub1 SD: age 73.6 \ub1 7.6 years, logistic EuroSCORE 18.0 \ub1 17.5) enrolled at 13 sites who presented for concomitant or previous mitral valve repair (n\ua0= 45) or replacement (n\ua0= 33), with or without additional concomitant procedures, and were implanted with a sutureless valve. Mean \ub1 SD overall aortic cross-clamp time was 109 \ub1 41 min and cardiopulmonary bypass time was 152 \ub1 49 min. Mean \ub1 SD aortic pressure gradients decreased from 37.6 \ub1 17.7 mmHg preoperatively to 13.0 \ub1 5.7 mmHg at hospital discharge, and peak aortic pressure gradient from 61.5 \ub1 28.7 to 23.4 \ub1 10.6 mmHg. Early events included 1 death, 1 transient ischaemic attack, and 1 bleed (all 1.3%); a permanent pacemaker implantation was required in 6 patients (7.7%), and 2 reoperations (not valve related) (2.6%) took place. Over a median follow-up of 55.5 months (Q1 13.4, Q3 68.6), 12 patients died (6 cardiovascular and 6 non-cardiovascular, both 2.1% per patient-year). Five-year survival was 81.3%. Late paravalvular leak occurred in 2 patients (0.7% per patient-year) and permanent pacemaker implantation was required in 3 patients (0.1% per patient-year). There was no apparent rise in mean or peak aortic pressure gradient over the study. Conclusions: These results suggest that the sutureless implant is a technically feasible procedure during mitral surgery and is associated with good clinical outcomes