VAD in failing Fontan: simulation of ventricular, cavo-pulmonary and biventricular assistance in systolic/diastolic ventricular dysfunction and in pulmonary vascular resistance increase.

Aim: Due to the lack of donors, VADs could be an alternative to heart transplantation for Failing Fontan patients (PTs). Considering the complex physiopathology and the type of VAD connection, a numerical model (NM) could be useful to support clinical decisions. The aim of this work is to test a NM simulating the VADs effects on failing Fontan for systolic dysfunction (SD), diastolic dysfunction (DD) and pulmonary vascular resistance increase (PRI). Methods: Data of 10 Fontan PTs were used to simulate the PTs baseline using a dedicated NM. Then, for each PTs a SD, a DD and a PRI were simulated. Finally, for each PT and for each pathology, the VADs implantation was simulated. Results: NM can well reproduce PTs baseline. In the case of SD, LVAD increases the cardiac output (CO) (35%) and the arterial systemic pressure (ASP) (25%). With cavo-pulmonary assistance (RVAD) a decrease of inferior vena cava pressure (IVCP) (39%) was observed with 34% increase of CO. With the BIVAD an increase of ASP (29%) and CO (37%) was observed. In the case of DD, the LVAD increases CO (42%), the RVAD decreases the IVCP. In the case of PRI, the highest CO (50%) and ASP (28%) increase is obtained with an RVAD together with the highest decrease of IVCP (53%). Conclusions: The use of NM could be helpful in this innovative field to evaluate the VADs implantation effects on specific PT to support PT and VAD selection

Secreted Gal-3BP is a novel promising target for non-internalizing Antibody–Drug Conjugates

Abstract Galectin-3-binding protein (Gal-3BP) has been identified as a cancer and metastasis-associated, secreted protein that is expressed by the large majority of cancers. The present study describes a special type of non-internalizing antibody-drug-conjugates that specifically target Gal-3BP. Here, we show that the humanized 1959 antibody, which specifically recognizes secreted Gal-3BP, selectively localized around tumor but not normal cells. A site specific disulfide linkage with thiol-maytansinoids to unpaired cysteine residues of 1959, resulting in a drug-antibody ratio of 2, yielded an ADC product, which cured A375m melanoma bearing mice. ADC products based on the non-internalizing 1959 antibody may be useful for the treatment of several human malignancies, as the cognate antigen is abundantly expressed and secreted by several cancers, while being present at low levels in most normal adult tissues

LGALS3BP antibody-drug-conjugate and its use for the treatment of cancer

The present invention relates to a special type of non-internalizing binding moiety- drug-conjugates that specifically target LGALS3BP. From one aspect, the invention relates to an antibody-drug-conjugate comprising an antibody capable of binding to LGALS3BP, said antibody being conjugated to cytotoxic drugs. The invention also comprises methods of the treatment of LGALS3BP-expressing cancer, including administering to a patient the disclosed drug conjugates and pharmaceutical preparations

Studio quantitativo della funzione cardiaca fetale mediante tissue doppler imaging

Background: Il Tissue Doppler Imaging (TDI) è una nuova metodica ultrasonografica in grado di fornire informazioni sulla contrattilità intrinseca e sulle proprietà diastoliche di singoli segmenti miocardici, con parametri scarsamente sensibili alle condizioni di loading cardiaco rispetto alle metodiche Doppler convenzionali. Scopo del nostro studio è stato identificare indici di funzione sisto-diastolica del cuore fetale normale lungo il corso della gravidanza mediante TDI. Materiale e Metodi: Sono stati arruolati 104 feti senza cardiopatia o anomalie extracardiache note di età gestazionale (EG) compresa tra la 23° e la 39. Le immagini sono state acquisite in modalità TDI posizionando il volume campione del doppler pulsato in corrispondenza della parte basale del ventricolo sinistro (VS) e della parte basale del ventricolo destro (VD) nella proiezione apicale 4-camere del cuore fetale. Sono stati misurati i seguenti parametri per entrambi i ventricoli: Velocità di picco sistolica Sw (cm/sec); Velocità di picco diastolica precoce Ew e tardiva Aw (cm/sec); Acceleration Time Ew, Aw, Sw (msec); Deceleration Time Ew, Aw, Sw (msec); Durata Sw, Ew, Aw (msec); Integrale Sw, Ew, Aw (cm2/sec); Rapporto Ew/Aw; Tempo di rilasciamento isovolumetrico (IVRT) (msec). Risultati: I parametri del VS Vel Sw, Vel Ew, Vel Aw, rapporto E/A, IVRT mostrano una correlazione lineare con EG. I parametri Vel Sw e Vel Ew del VD correlano positivamente con EG, ma più debolmente rispetto al VS, mentre Vel Aw del VD mostra una buona correlazione con EG. Come conseguenza il rapporto E/A e IVRT del VD restano stabili durante il corso della gravidanza. Conclusioni: Nel nostro studio abbiamo identificato i valori normali e le variazioni correlate all’EG delle velocità miocardiche di rilasciamento e contrazione del VS e VD in feti normali. Questi dati forniscono informazioni sullo sviluppo della funzione cardiaca fetale normale e ci consentiranno di sviluppare ulteriori ricerche in questo campo.Background: Assessment of cardiac function is difficult in the fetus because of limited accessibility. Tissue Doppler imaging (TDI) is a promising technique with the potential for quantitative assessment of both systolic and diastolic function. The aim of this study was obtain TDI indices of systolic and diastolic functions of the normal fetal heart. Methods: Ventricular myocardial velocities at the left and right ventricular wall were assessed by TDI in 104 fetuses without congenital heart disease or extracardiac anomalies between 23rd and 39th gestational age (GA). Results: Peak Sw, Ew, Aw for both ventricles showed a positive correlation with advancing gestational age, but the correlation between peak Sw and Ew of RV and GA was weakly positive; as a consequence, E/A ratio and IVRT of RV do not change significantly trough gestation Conclusions: This study provides a reference range for fetal systolic and diastolic function in the normal fetal heart of both ventricles. This technique may contribute in future to the study of cardiac function changes associated with pathologic conditions during pregnancy

Studio quantitativo della funzione cardiaca fetale mediante tissue doppler imaging

Background: Il Tissue Doppler Imaging (TDI) è una nuova metodica ultrasonografica in grado di fornire informazioni sulla contrattilità intrinseca e sulle proprietà diastoliche di singoli segmenti miocardici, con parametri scarsamente sensibili alle condizioni di loading cardiaco rispetto alle metodiche Doppler convenzionali. Scopo del nostro studio è stato identificare indici di funzione sisto-diastolica del cuore fetale normale lungo il corso della gravidanza mediante TDI. Materiale e Metodi: Sono stati arruolati 104 feti senza cardiopatia o anomalie extracardiache note di età gestazionale (EG) compresa tra la 23° e la 39. Le immagini sono state acquisite in modalità TDI posizionando il volume campione del doppler pulsato in corrispondenza della parte basale del ventricolo sinistro (VS) e della parte basale del ventricolo destro (VD) nella proiezione apicale 4-camere del cuore fetale. Sono stati misurati i seguenti parametri per entrambi i ventricoli: Velocità di picco sistolica Sw (cm/sec); Velocità di picco diastolica precoce Ew e tardiva Aw (cm/sec); Acceleration Time Ew, Aw, Sw (msec); Deceleration Time Ew, Aw, Sw (msec); Durata Sw, Ew, Aw (msec); Integrale Sw, Ew, Aw (cm2/sec); Rapporto Ew/Aw; Tempo di rilasciamento isovolumetrico (IVRT) (msec). Risultati: I parametri del VS Vel Sw, Vel Ew, Vel Aw, rapporto E/A, IVRT mostrano una correlazione lineare con EG. I parametri Vel Sw e Vel Ew del VD correlano positivamente con EG, ma più debolmente rispetto al VS, mentre Vel Aw del VD mostra una buona correlazione con EG. Come conseguenza il rapporto E/A e IVRT del VD restano stabili durante il corso della gravidanza. Conclusioni: Nel nostro studio abbiamo identificato i valori normali e le variazioni correlate all’EG delle velocità miocardiche di rilasciamento e contrazione del VS e VD in feti normali. Questi dati forniscono informazioni sullo sviluppo della funzione cardiaca fetale normale e ci consentiranno di sviluppare ulteriori ricerche in questo campo.Background: Assessment of cardiac function is difficult in the fetus because of limited accessibility. Tissue Doppler imaging (TDI) is a promising technique with the potential for quantitative assessment of both systolic and diastolic function. The aim of this study was obtain TDI indices of systolic and diastolic functions of the normal fetal heart. Methods: Ventricular myocardial velocities at the left and right ventricular wall were assessed by TDI in 104 fetuses without congenital heart disease or extracardiac anomalies between 23rd and 39th gestational age (GA). Results: Peak Sw, Ew, Aw for both ventricles showed a positive correlation with advancing gestational age, but the correlation between peak Sw and Ew of RV and GA was weakly positive; as a consequence, E/A ratio and IVRT of RV do not change significantly trough gestation Conclusions: This study provides a reference range for fetal systolic and diastolic function in the normal fetal heart of both ventricles. This technique may contribute in future to the study of cardiac function changes associated with pathologic conditions during pregnancy

Galectin-3 binding protein stimulated IL-6 expression is impeded by antibody intervention in SARS-CoV-2 susceptible cell lines

COVID‑19 is the global pandemic that affected our population in the past 2 years. Considerable research has been done to better understand the pathophysiology of this disease and to identify new therapeutic targets, especially for severe cases. Galectin‑3 (Gal‑3) is a receptor present at the surface of different cell types, namely epithelial and inflammatory cells, which has been described as a severity marker in COVID‑19. The activation of Gal‑3 through its binding protein (Gal‑3BP) is directly linked to the production of pro‑inflammatory cytokines that contribute for the cytokine storm (CS) observed in severe COVID‑19 patients. Here, we show that D2, a recombinant fragment of the lectin‑binding region of Gal‑3BP was able to stimulate the expression of IL‑6 in colon and lung epithelial cell lines in β‑galactoside dependent manner. We further show that D2‑induced IL‑6 augmentation was reduced by the anti‑Gal‑3BP monoclonal antibody 1959. Our data confirm and extend prior findings of Gal‑3BP mediated IL‑6 induction, enlightening the potential of its antibody‑mediated s blockage for the prevention and treatment of CS and severe disease in COVID‑19 patients

Increased Gal‑3BP plasma levels in hospitalized patients infected with SARS‑CoV‑2

Coronavirus disease 2019 (COVID-19) has quickly turned into a health, fnancial and societal problem globally. The complex pathogenesis of severe acute respiratory syndrome coronavirus centers on the unpredictable clinical progression of the disease, which may evolve abruptly and results in critical and life-threatening clinical complications. Efective laboratory biomarkers that can classify patients according to risk of progression to severe disease are essential for ensuring timely treatment. Gal-3BP is a human secreted protein with innate immune functions, which is upregulated in viral infections, promotes infammation and has been shown to induce IL-6 expression. In this study, Gal-3BP plasma levels were measured retrospectively in a cohort of 84 hospitalized COVID-19 patients. These were classifed as having either “non-severe” or “severe” disease. Compared to healthy controls, Gal-3BP plasma levels were markedly increased in COVID-19 patients (P< 0.0001). Moreover, the levels were higher in severe than in non-severe patients (P < 0.05). As expected, patients with severe disease had plasma levels of IL-6 higher than patients with non-severe disease (P < 0.01). In non-severe disease patients, Gal-3BP levels collected at a late stage (13.3 + 5.7 days after the frst positive PCR result) were signifcantly lower than those collected at an early stage (4.2 + 2.9 days form the frst positive PCR result). Larger prospective analyses are needed to strength our understanding of the prognostic utility of Gal-3BP in COVID-19 patients

Osteogenic properties of a short BMP-2 chimera peptide

Bonemorphogenetic proteins (BMPs) play a key role in bone and cartilage formation. For these properties, BMPs are employed in the field of tissue engineering to induce bone regeneration in damaged tissues. To overcome drawbacks due to the use of entire proteins, synthetic peptides derived from their parent BMPs have come out as promising molecules for biomaterial design. On the structural ground of the experimental BMP-2 receptor complexes reported in the literature, we designed three peptides, reproducing the BMP-2 region responsible for the binding to the type II receptor, ActRIIB. These peptides were characterized by NMR, and the structural features of the peptide–receptor binding interface were highlighted by docking experiments. Peptide– receptor binding affinities were analyzed bymeans of ELISA and surface plasmon resonance techniques. Furthermore, cellular assays were performed to assess their osteoinductive properties. A chimera peptide, obtained by combining the sequence portions 73–92 and 30–34 of BMP-2, shows the best affinity for ActRIIB in the series and represents a good starting point for the design of new compounds able to reproduce osteogenic properties of the parent BMP-2

VAD in failing Fontan: simulations of ventricular, cavo-pulmonary and biventricular assistance in the case of systolic or diastolic ventricular dysfunction and in pulmonary vascular resistance increment.

Considering the lack of donors, ventricular assist devices (VADs) could be an alternative to heart transplantation for failing Fontan patients, in spite of the lack of experience and the complex anatomy and physiopathology of these patients. Considering the high number of variables that play an important role such as type of Fontan failure, type ofVADconnection, and setting (rightVAD[RVAD], left VAD [LVAD], or biventricular VAD [BIVAD]), a numerical model could be useful to support clinical decisions. The aim of this article is to develop and test a lumped parameter model of the cardiovascular system simulating and comparing the VAD effects on failing Fontan. Hemodynamic and echocardiographic data of 10 Fontan patients were used to simulate the baseline patients\u27 condition using a dedicated lumped parameter model. Starting from the simulated baseline and for each patient, a systolic dysfunction, a diastolic dysfunction, and an increment of the pulmonary vascular resistance were simulated. Then, for each patient and for each pathology, the RVAD, LVAD, and BIVAD implantations were simulated. The model can reproduce patients\u27 baseline well. In the case of systolic dysfunction, the LVAD unloads the single ventricle and increases the cardiac output (CO) (35%) and the arterial systemic pressure (Pas) (25%). With RVAD, a decrement of inferior vena cava pressure (Pvci) (39%) was observed with 34% increment of CO, but an increment of the single ventricle external work (SVEW). With the BIVAD, an increment of Pas (29%) and CO (37%) was observed. In the case of diastolic dysfunction, the LVAD increases CO (42%) and the RVAD decreases the Pvci, while both increase the SVEW. In the case of pulmonary vascular resistance increment, the highest CO (50%) and Pas (28%) increment is obtained with an RVAD with the highest decrement of Pvci (53%) and an increment of the SVEW but with the lowest VAD power consumption. The use of numerical models could be helpful in this innovative field to evaluate the effect of VAD implantation on Fontan patients to support patient and VAD type selection personalizing the assistance