Colorectal cancer after bariatric surgery (Cric-Abs 2020): Sicob (Italian society of obesity surgery) endorsed national survey

Background The published colorectal cancer (CRC) outcomes after bariatric surgery (BS) are conflicting, with some anecdotal studies reporting increased risks. The present nationwide survey CRIC-ABS 2020 (Colo-Rectal Cancer Incidence-After Bariatric Surgery-2020), endorsed by the Italian Society of Obesity Surgery (SICOB), aims to report its incidence in Italy after BS, comparing the two commonest laparoscopic procedures-Sleeve Gastrectomy (SG) and Roux-en-Y gastric bypass (GBP). Methods Two online questionnaires-first having 11 questions on SG/GBP frequency with a follow-up of 5-10 years, and the second containing 15 questions on CRC incidence and management, were administered to 53 referral bariatric, high volume centers. A standardized incidence ratio (SIR-a ratio of the observed number of cases to the expected number) with 95% confidence intervals (CI) was calculated along with CRC incidence risk computation for baseline characteristics. Results Data for 20,571 patients from 34 (63%) centers between 2010 and 2015 were collected, of which 14,431 had SG (70%) and 6140 GBP (30%). 22 patients (0.10%, mean age = 53 +/- 12 years, 13 males), SG: 12 and GBP: 10, developed CRC after 4.3 +/- 2.3 years. Overall incidence was higher among males for both groups (SG: 0.15% vs 0.05%; GBP: 0.35% vs 0.09%) and the GBP cohort having slightly older patients. The right colon was most affected (n = 13) and SIR categorized/sex had fewer values < 1, except for GBP males (SIR = 1.07). Conclusion Low CRC incidence after BS at 10 years (0.10%), and no difference between procedures was seen, suggesting that BS does not trigger the neoplasm development

Which Lynch syndrome screening programs could be implemented in the "real world"? A systematic review of economic evaluations

Purpose: Lynch syndrome (LS) screening can significantly reduce cancer morbidity and mortality in mutation carriers. Our aim was to identify cost-effective LS screening programs that can be implemented in the "real world."Methods: We performed a systematic review of full economic evaluations of genetic screening for LS in different target populations; health outcomes were estimated in life-years gained or quality-adjusted life-years.Results: Overall, 20 studies were included in the systematic review. Based on the study populations, we identified six categories of LS screening program: colorectal cancer (CRC)-based, endometrial cancer-based, general population-based, LS family registry-based, cascade testing-based, and genetics clinic-based screening programs. We performed an in-depth analysis of CRC-based LS programs, classifying them into three additional subcategories: universal, age-targeted, and selective. In five studies, universal programs based on immunohistochemistry, either alone or in combination with the BRAF test, were cost-effective compared with no screening, while in two studies age-targeted programs with a cutoff of 70 years were cost-effective when compared with age-targeted programs with lower age thresholds. Conclusion: Universal or <70 years-age-targeted CRC-based LS screening programs are cost-effective and should be implemented in the "real world

Relationship Between Particle And Biological Properties Of Emulsion-Templated, Freeze-Dried Lopinavir Nanoparticle Dispersions

Background Nanomedicine has the potential to enhance bioavailability and delivery of low-solubility compounds to sanctuary sites. Lopinavir (LPV) is a protease inhibitor (PI) with low bioavailability (<2%) that requires boosting with ritonavir. We assessed relationships between size (z-average), surface charge (zeta potential), and polydispersity with cytotoxicity, cellular accumulation ratio (CAR), and transcellular permeability of a LPV nanodispersion library. Methods Seventy-four dispersions containing 0.1 micro Ci 3H-LPV were generated. Cellular accumulation in lymphocytes (CEM), monocytes (THP1), monocyte-derived macrophages (ATHP1), hepatic (HepG2), and intestinal (Caco-2) cells as well as apical to basolateral (A>B) permeability across Caco-2 monolayers was determined. Data were log transformed and models to describe relationships between particle properties and biological characteristics were constructed using multiple linear regression. Results Median (range) z-average, polydispersity, and zeta potential were 436 (184 to 3145) nm, 0.3 (0.1 to 0.9), and –3.7 (–56.7 to 39.7) mV, respectively. Dispersions exhibiting higher and lower values than aqueous solutions were observed for all biological characteristics. Cytotoxicity of dispersions was lower in all cells compared to aqueous LPV and predictable from models containing z-average and zeta potential (e.g., r = 0.47; p = 0.001 for CEM). A number of dispersions exhibited higher CAR than for aqueous LPV. E.g., median (range) CAR was 17.0 (2.8 to 105.1) in CEM compared to 13.1 for aqueous LPV. In HepG2 (r = –0.38), Caco-2 (r = –0.39), THP1 (r = –0.14), and CEM (r = –0.09) inverse correlations with polydispersity were observed but in phagocytic ATHP1 cells a direct relationship was evident (r = 0.28). In all cells, CAR was predictable from models containing z-average and polydispersity (e.g., r = 0.41; p = 0.006 for Caco-2). The rate of A>B permeation across Caco-2 cells was 6.3 (1.8 to 20.7)%/h compared to 2.5%/h for aqueous LPV but no relationship with particle properties was seen. Conclusions Understanding relationships between particle and biological properties will facilitate generation of effective nanomedicines. We have generated some LPV nanodispersions with greatly enhanced cellular accumulation and transcellular permeability but reduced cytotoxicity. Following careful safety evaluation, the ability to nano-enhance PI could increase bioavailability and thereby alter the requirement for boosting

High relaxivity contrast agents for magnetic resonance imaging (MRI)

The development of Gd(III)-based contrast agents for MRI applications has intensified in recent years due to the paramagnetic ion’s long electron spin relaxation time and large effective magnetic moment, µeff. Secondly, the exploitation of the long lived luminescent properties of the Ln(III) ions has lead to the development of luminescent lanthanide probes for sensing, time resolved immunoassay and imaging applications. Herein a series of novel Ln-DO3A based complexes are reported. Modulation of relaxivity, r1, (Gd) and emission intensity (Eu, Tb, Sm and Dy) has been achieved in three ways: Firstly, mono- and bis-methyl Ln-dpp-DO3A based complexes have been prepared, where dpp is a pendant diphenylphosphinamide moiety. These show pH responsive relaxivity (Gd) and luminescence (Eu) with calculated pKa values of 8.65 (± 0.09) and 8.59 (± 0.14). Sensitised emission of Eu(III), Tb(III), Dy(III) and Sm(III) has been observed following excitation of the dpp antenna at λex ~ 270 nm. Relaxivities have been measured as r1 = 7.9 mMˉ¹sˉ¹and r1 = 8.2 mMˉ¹sˉ¹ in acidic media, q = 2 and r1 = 5.4 mMˉ¹sˉ¹ and r1 = 4.4 mMˉ¹sˉ¹ in basic media, q = 1 for the mono- and bis-methyl Gd-dpp-DO3A complexes respectively. The pH responsive behaviour has been attributed to the reversible ligation of the dpp moiety. Secondly, non-covalent attachment of the mono- and bis-methyl Gd-dpp-DO3A-based complexes to Human Serum Albumin (HSA) at pH 7.4 resulted in a 64% (r1 = 11.7 mMˉ¹sˉ ¹) and a 146% (r1 = 16.0 mMˉ¹sˉ¹) enhancement in relaxivity, with binding affinities, K, determined from luminescence studies as K = 22,268 ± 12% Mˉ¹and K = 20,059 ± 14% Mˉ¹ for the mono- and bis-methyl dpp Eu-dpp-DO3A complexes respectively. The negatively charged [Gd-dpp-aDO3A]3ˉ complex was developed in order to improve the observed relaxivity of the HSA bound species: r1 = 16.0 mMˉ¹sˉ¹, K = 17,915 (± 14%) Mˉ¹. Competitive binding studies with the fluorescent probes dansylsarcosine and warfarin showed each of the dpp complex analogues to bind preferentially to HSA site II, only the S-enantiomer of the mono-methyl Gd-dpp-DO3A showed an affinity for site I. Finally, an accumulation and activation strategy following enzyme activity has been demonstrated. Neutral q = 2 Gd(III) ethyl and acetoxymethyl ester Ln-DO3MA based complexes have shown decreased relaxivity in the presence of carbonate due to the inner sphere water molecule displacement by bidentate anion binding. The binding is suppressed by the introduction of negative charge to the complex following enzymatic hydrolysis of the ester groups, resulting in ~ 84% relaxivity enhancement (Gd) as well as Eu luminescence quenching. The high observed relaxivity of the ethyl ester model: r1 = 10.2 mMˉ¹sˉ¹ is attributed to the extremely short observed water exchange lifetime, τm = 7.9 ns

High relaxivity contrast agents for magnetic resonance imaging (MRI)

The development of Gd(III)-based contrast agents for MRI applications has intensified in recent years due to the paramagnetic ion’s long electron spin relaxation time and large effective magnetic moment, µeff. Secondly, the exploitation of the long lived luminescent properties of the Ln(III) ions has lead to the development of luminescent lanthanide probes for sensing, time resolved immunoassay and imaging applications. Herein a series of novel Ln-DO3A based complexes are reported. Modulation of relaxivity, r1, (Gd) and emission intensity (Eu, Tb, Sm and Dy) has been achieved in three ways: Firstly, mono- and bis-methyl Ln-dpp-DO3A based complexes have been prepared, where dpp is a pendant diphenylphosphinamide moiety. These show pH responsive relaxivity (Gd) and luminescence (Eu) with calculated pKa values of 8.65 (± 0.09) and 8.59 (± 0.14). Sensitised emission of Eu(III), Tb(III), Dy(III) and Sm(III) has been observed following excitation of the dpp antenna at λex ~ 270 nm. Relaxivities have been measured as r1 = 7.9 mMˉ¹sˉ¹and r1 = 8.2 mMˉ¹sˉ¹ in acidic media, q = 2 and r1 = 5.4 mMˉ¹sˉ¹ and r1 = 4.4 mMˉ¹sˉ¹ in basic media, q = 1 for the mono- and bis-methyl Gd-dpp-DO3A complexes respectively. The pH responsive behaviour has been attributed to the reversible ligation of the dpp moiety. Secondly, non-covalent attachment of the mono- and bis-methyl Gd-dpp-DO3A-based complexes to Human Serum Albumin (HSA) at pH 7.4 resulted in a 64% (r1 = 11.7 mMˉ¹sˉ ¹) and a 146% (r1 = 16.0 mMˉ¹sˉ¹) enhancement in relaxivity, with binding affinities, K, determined from luminescence studies as K = 22,268 ± 12% Mˉ¹and K = 20,059 ± 14% Mˉ¹ for the mono- and bis-methyl dpp Eu-dpp-DO3A complexes respectively. The negatively charged [Gd-dpp-aDO3A]3ˉ complex was developed in order to improve the observed relaxivity of the HSA bound species: r1 = 16.0 mMˉ¹sˉ¹, K = 17,915 (± 14%) Mˉ¹. Competitive binding studies with the fluorescent probes dansylsarcosine and warfarin showed each of the dpp complex analogues to bind preferentially to HSA site II, only the S-enantiomer of the mono-methyl Gd-dpp-DO3A showed an affinity for site I. Finally, an accumulation and activation strategy following enzyme activity has been demonstrated. Neutral q = 2 Gd(III) ethyl and acetoxymethyl ester Ln-DO3MA based complexes have shown decreased relaxivity in the presence of carbonate due to the inner sphere water molecule displacement by bidentate anion binding. The binding is suppressed by the introduction of negative charge to the complex following enzymatic hydrolysis of the ester groups, resulting in ~ 84% relaxivity enhancement (Gd) as well as Eu luminescence quenching. The high observed relaxivity of the ethyl ester model: r1 = 10.2 mMˉ¹sˉ¹ is attributed to the extremely short observed water exchange lifetime, τm = 7.9 ns.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Research Spotlight:Nanomedicines for HIV therapy

Heterogeneity in response to HIV treatments has been attributed to several causes including variability in pharmacokinetic exposure. Nanomedicine applications have a variety of advantages compared with traditional formulations, such as the potential to increase bioavailability and specifically target the site of action. Our group is focusing on the development of nanoformulations using a closed-loop design process in which nanoparticle optimization (disposition, activity and safety) is a continuous process based on experimental pharmacological data from in vitro and in vivo models. Solid drug nanoparticles, polymer-based drug-delivery carriers as well as nanoemulsions are nanomedicine options with potential application to improve antiretroviral deployment

Augmented Inhibition of CYP3A4 in Human Primary Hepatocytes by Ritonavir Solid Drug Nanoparticles

Ritonavir is a protease inhibitor utilized primarily as a pharmaco-enhancer with concomitantly administered antiviral drugs including other protease inhibitors. However, poor tolerance, serious side effects, and toxicities associated with drug–drug interactions are common during exposure to ritonavir. The aim of this work was to investigate the impact of nanoformulation on ritonavir pharmacological properties. Emulsion-templated freeze-drying techniques were used to generate ritonavir (10 wt %) solid drug nanoparticle formulations. A total of 68 ritonavir formulations containing various mixtures of excipients were assessed for inhibition of CYP3A4 in baculosomes and primary human hepatocytes. Accumulation and cytotoxicity were assessed in HepG2 (hepatocytes), Caco-2 (intestinal), THP-1 (monocytes), A-THP-1 (macrophage), and CEM (lymphocytes). Transcellular permeation across Caco-2 cells was also assessed. From 68 solid drug nanoparticle formulations tested, 50 (73.5%) for baculosome and 44 (64.7%) for human primary hepatocytes exhibited enhanced CYP3A4 inhibition relative to an aqueous ritonavir solution. Sixty-one (89.7%) and 49 (72%) solid drug nanoformulations had higher apical to basal permeation across Caco-2 cells than aqueous solution of ritonavir after 60 and 120 min, respectively. No significant difference in cellular accumulation was observed for any solid drug nanoparticle for any cell type compared to aqueous ritonavir. However, incubation with the vast majority of solid drug nanoparticle formulations resulted in lower cytotoxicity of ritonavir than detected with an aqueous solution. These data provide in vitro proof of concept for improved inhibition of CYP3A4 by ritonavir through formation of solid drug nanoparticles. Nanodispersions also showed enhanced permeability across Caco-2 cells lower cytotoxicity across hepatic, intestinal, and immune cell types compared to an aqueous solution of ritonavir