Use of contrast-enhanced intraoperative ultrasonography during liver surgery for colorectal cancer liver metastases - Its impact on operative outcome. Analysis of a prospective cohort study

Abstract Background Preliminary reports led to discordant conclusions concerning the use of contrast-enhanced intraoperative ultrasonography (CE-IOUS) during surgery for colorectal liver metastases (CLM). The aim of this study was to evaluate the impact of CE-IOUS in patients undergoing surgery for CLM using an advanced preoperative imaging work-up, and well-established reference standards. Materials and methods Forty-seven consecutive patients underwent liver resection using IOUS and CE-IOUS for CLM. All patients underwent preoperative computed tomography (CT) and magnetic resonance imaging (MRI) within 2 weeks prior to surgery. CE-IOUS was performed by injecting intravenously 4.8 ml of sulphur-hexafluoride microbubbles (SonoVue, Bracco, Italy). Reference standards were histology, and 6-month imaging follow-up. Results IOUS discovered 43 additional lesions in 20 patients. CE-IOUS found 10 additional lesions not seen at IOUS in four patients, and confirmed all the IOUS findings. Fourteen CLM in 10 patients appeared within 6 months after surgery. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy were, respectively: 66%, 0%, 98%, 0% and 65% for CT + MRI; 88%, 100%, 100%, 8%, 88% for IOUS and 93%, 100%, 100%, 13%, 93% for IOUS + CE-IOUS. In nine patients CE-IOUS afforded better definition of tumour margins thus helping in resection guidance. Conclusions CE-IOUS improves IOUS findings both for detection and for resection guidance. The combination of IOUS and CE-IOUS should be considered routinely in patients operated for CLM

Synthesis, biophysical characterization and anti-HIV activity of d(TG3AG) Quadruplexes bearing hydrophobic tails at the 5'-end

Novel conjugated G-quadruplex-forming d(TG3AG) oligonucleotides, linked to hydrophobic groups through phosphodiester bonds at 50-end, have been synthesized as potential anti-HIV aptamers, via a fully automated, online phosphoramidite-based solid-phase strategy. Conjugated quadruplexes showed pronounced anti-HIV activity with some preference for HIV-1, with inhibitory activity invariably in the low micromolar range. The CD and DSC monitored thermal denaturation studies on the resulting quadruplexes, indicated the insertion of lipophilic residue at the 50-end, conferring always improved stability to the quadruplex complex (20 < DTm < 40 C). The data suggest no direct functional relationship between the thermal stability and anti-HIV activity of the folded conjugated G-quartets. It would appear that the nature of the residue at 50 end of the d(TG3AG) quadruplexes plays an important role in the thermodynamic stabilization but a minor influence on the anti-HIV activity. Moreover, a detailed CD and DSC analyses indicate a monophasic behaviour for sequences I and V, while for ODNs (II–IV) clearly show that these quadruplex structures deviate from simple two-state melting, supporting the hypothesis that intermediate states along the dissociation pathway may exis

Type III interferons disrupt the lung epithelial barrier upon viral recognition

Viral infections of the lower respiratory tract are a leading cause of mortality. Mounting evidence indicates that most severe cases are characterized by aberrant immune responses and do not depend on viral burden. In this study, we assessed how type III interferons (IFN-λ) contribute to the pathogenesis induced by RNA viruses. We report that IFN-λ is present in the lower, but not upper, airways of patients with coronavirus disease 2019 (COVID-19). In mice, we demonstrate that IFN-λ produced by lung dendritic cells in response to a synthetic viral RNA induces barrier damage, causing susceptibility to lethal bacterial superinfections. These findings provide a strong rationale for rethinking the pathophysiological role of IFN-λ and its possible use in clinical practice against endemic viruses, such as influenza virus as well as the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR &lt; 60 mL/min/1.73 m2) or eGFR reduction &gt; 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR &lt; 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR &gt; 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening

Discovery of novel anti-HIV active G-quadruplex-forming oligonucleotides

A series of d((5')TGGGAG(3')) sequences, 5'-conjugated with a variety of aromatic groups through phosphodiester linkages, were synthesized, showing CD spectra diagnostic of parallel-stranded, tetramolecular G-quadruplex structures. When tested for anti-HIV-1 and HIV-2 activity, potent inhibition of HIV-1 infection in CEM cell cultures was found, associated with high selectivity index values. Surface Plasmon Resonance assays revealed specific binding to HIV-1 gp120 and gp41.status: publishe

Discovery of novel anti-HIV active G-quadruplex-forming oligonucleotides

A series of oligonucleotide sequences conjugated with a variety of aromatic groups through phosphodiester linkages were synthesized showing CD spectra diagnostic of parallel-stranded, tetramolecular G-quadruplex structures

The three dimensional analysis of the Sforzesco brace correction

Scoliosis is a three dimensional deformity, and brace correction should be 3D too. There is a lack of knowledge of the effect of braces, particularly in the sagittal and transverse plane. The aim of this study is to analyse the Sforzesco Brace correction, through all the parameters provided by Eos 3D imaging system

Synthesis, biophysical characterization and anti-HIV activity of glyco-conjugated G-quadruplex forming oligonucleotides

Novel hybrid oligonucleotides carrying the G-quadruplex-forming d(5′TGGGAG3′) sequence, conjugated with mono- or disaccharides at the 3′ or 5′-end through phosphodiester bonds, have been synthesized as potential anti-HIV agents, via a fully automated, online phosphoramidite-based solid-phase strategy. CD-monitored thermal denaturation studies on the resulting quadruplexes indicated the insertion of a single monosaccharide at the 3′- end as the optimal modification, conferring improved stability to the quadruplex complex. In addition, the 3′- conjugation with glucose or mannose converted the anti-HIV inactive unmodified oligomer into active compounds. On the contrary, the 5′-tethering with these monosaccharides, as well as the conjugation, either at the 5′ or 3′- end, with sucrose, were in all cases detrimental to quadruplex stability and did not improve the biological activity. On the basis of the assumption that the kinetically and thermodynamically favored formation of the quadruplex complex is a prerequisite for efficient antiviral activity, a novel bis-conjugated oligonucleotide was designed. This combined a mannose residue at the 3′-phosphate end with bulky aromatic tert-butyldiphenylsilyl (TBDPS) group at the 5′-end, previously shown to markedly favor the formation of quadruplex complexes. The 5′,3′-bisconjugated 6-mer, for which a detailed biophysical characterization has been carried out, resulted in 3-fold greater antiviral activity against HIV-1 than the sole 3′-glyco-conjugated oligonucleotide