Indocyanine green loaded hyaluronan-derived nanoparticles for fluorescence-enhanced surgical imaging of pancreatic cancer

Pancreatic ductal adenocarcinoma is highly lethal and surgical resection is the only potential curative treatment for the disease. In this study, hyaluronic acid derived nanoparticles with physico-chemically entrapped indocyanine green, termed NanoICG, were utilized for intraoperative near infrared fluorescence detection of pancreatic cancer. NanoICG was not cytotoxic to healthy pancreatic epithelial cells and did not induce chemotaxis or phagocytosis, it accumulated significantly within the pancreas in an orthotopic pancreatic ductal adenocarcinoma model, and demonstrated contrast-enhancement for pancreatic lesions relative to non-diseased portions of the pancreas. Fluorescence microscopy showed higher fluorescence intensity in pancreatic lesions and splenic metastases due to NanoICG compared to ICG alone. The in vivo safety profile of NanoICG, including, biochemical, hematological, and pathological analysis of NanoICG-treated healthy mice, indicates negligible toxicity. These results suggest that NanoICG is a promising contrast agent for intraoperative detection of pancreatic tumors.     

Antibody persistence and safety and immunogenicity of a second booster dose nine years after a first booster vaccination with a reduced antigen diphtheria-tetanus-acellular pertussis vaccine (Tdap) in adults

BackgroundOver the last decades, pertussis showed periodic increases in its incidence among adults, despite being a vaccine-preventable disease.MethodsThis phase III, multicenter, extension study (NCT00489970) was conducted in adults from the United States, followed at Year (Y) 5 and Y9 post-vaccination with a dose of reduced-antigen-content tetanus-diphtheria-acellular pertussis vaccine containing either 3 (Tdap-B group) or 5 pertussis components (Tdap-A group). Willing participants in Tdap groups and newly-recruited participants (Control group) received one Tdap-B dose at Y9. Antibody persistence (at Y5 and Y9) and safety of Tdap-B at Y9 were assessed. Non-inferiority of immune response elicited by 2 Tdap doses was evaluated at Y9: (i) versus one Tdap-B dose for diphtheria and tetanus in terms of seroprotection rates; (ii) for all antigens in terms of booster response rates (Tdap-B and Tdap-A groups versus Control group); and (iii) for pertussis antigens in terms of geometric mean concentrations (GMCs) versus a 3-dose series of a combined diphtheria-tetanus-acellular pertussis vaccine (DTPa) administered during infancy.Results1257 participants were enrolled at Y5 and 809 participants were vaccinated at Y9. Seroprotection rates in both Tdap groups were ≥98.4% and ≥98.0% (Y5) and ≥98.3% and ≥98.1% (Y9) for diphtheria and tetanus, respectively. For pertussis antigens, antibody concentrations above assay cut-offs were observed for ≥76.6% (Y5) and ≥84.9% (Y9) of participants in Tdap groups. At Y9, one month post-Tdap vaccination, comparable seroprotection/seropositivity rates and antibody GMCs were observed among groups. Non-inferiority of immune responses in both Tdap groups was demonstrated when compared to the Control group for diphtheria and tetanus and to a 3-dose DTPa series for pertussis antigens. Non-inferiority criteria in terms of booster response were not met for all antigens. No safety concerns were raised.ConclusionA second dose of Tdap-B administered in adults, 9 years after initial Tdap vaccination, is immunogenic and well-tolerated.     

肺部超声评分在急性呼吸窘迫综合征患者预后及病情严重程度中的评估价值

[目的]探讨肺部超声(LUS)评分在急性呼吸窘迫综合征(ARDS)患者预后及病情严重程度中的评估价值.[方法]选取2018年1月至2019年1月在本院呼吸内科诊治的ARDS患者103例,根据柏林2012年ARDS病情标准分为轻度组11例,中度组43例,重度组49例;再根据预后分为存活组72例,死亡组31例.所有患者均于入院当天行LUS检查和动脉血气分析,并采用急性生理学与慢性健康状况评分系统Ⅱ(APACHEⅡ)评分评价预后并比较.采用逐步线性回归分析LUS评分与预后及病情严重程度的相关性.[结果]存活组患者LUS评分、APACHEⅡ评分分别为(15.71±2.31)分、(13.69±2.06)分,均显著低于死亡组的(23.77±4.82)分、(24.73±3.94)分,其差异均有统计学意义(t=11.726,P<0.001;t=10.861,P<0.001).轻、中、重度组LUS评分、呼气末正压通气(PEEP)依次升高;氧合指数(PaO2/FiO2)依次降低,组间比较差异均有统计学意义(P<0.05).逐步线性回归分析显示:LUS评分与预后及病情严重程度呈正相关.[结论]LUS评分与ARDS患者预后及病情严重程度呈正相关,可作为评估ARDS患者病情和预后的重要辅助指标.     

Diagnosis of gallbladder diseases by contrast-enhanced phase-inversion harmonic ultrasonography

We evaluated the usefulness of contrast-enhanced ultrasonography(US) for detecting and differentiating gallbladder lesions. Contrast-enhanced coded phase-inversion harmonic US was performed on 90 patients with gallbladder abnormalities. After administering Levovist, we observed the gallbladders in real time. Contrast-enhanced coded phase-inversion harmonic ultrasonography was compared with B-mode US and contrast-enhanced computer tomography (CT) with regard to the sensitivity and specificity in depicting the elevated gallbladder lesions. Furthermore, we assessed how the vascular patterns of the elevated gallbladder lesions depicted by contrast-enhanced US correlated with the diagnosis. Contrast-enhanced US efficiently discriminated true lesions from biliary sludge, unlike B-mode US. Consequently, contrast-enhanced US was more specific (100%) than B-mode US (81%), although their sensitivities were similar (98% and 96%, respectively). Contrast-enhanced US was also more sensitive that contrast-enhanced CT (98% versus 79%), although the two methods were equally sensitive (100% versus 95%). We classified the vascular patterns of the abnormalities depicted by contrast-enhanced US in the 90 cases into types 1 to 4, which represent branch-like, heterogeneous, homogeneous, and avascular patterns, respectively. All type 1 and 2 lesions were over 10 mm in size while most (88%) type 3 lesions were 10 mm or less in size. While the majority of carcinomas (86%) were type 1 or 2, three benign lesions also showed these patterns. Thus, the vascular pattern may simply reflect the size of the lesion and therefore its usefulness in diagnosing gallbladder lesions may be limited. Nevertheless, contrast-enhanced US is clearly superior to the other techniques in discriminating biliary sludge from other lesions.     

Current status of magnetic resonance imaging (MRI) and ultrasonography fusion software platforms for guidance of prostate biopsies

Prostate MRI is currently the best diagnostic imaging method for detecting PCa. Magnetic resonance imaging (MRI)/ultrasonography (US) fusion allows the sensitivity and specificity of MRI to be combined with the real‐time capabilities of transrectal ultrasonography (TRUS). Multiple approaches and techniques exist for MRI/US fusion and include direct ‘in bore’ MRI biopsies, cognitive fusion, and MRI/US fusion via software‐based image coregistration platforms.     

Gating function of isoleucine-116 in TM-3 (position III:16/3.40) for the activity state of the CC-chemokine receptor 5 (CCR5)

Background and Purpose

A conserved amino acid within a protein family indicates a significance of the residue. In the centre of transmembrane helix (TM)-5, position V:13/5.47, an aromatic amino acid is conserved among class A 7TM receptors. However, in 37% of chemokine receptors – a subgroup of 7TM receptors – it is a leucine indicating an altered function. Here, we describe the significance of this position and its possible interaction with TM-3 for CCR5 activity.

Experimental Approach

The effects of [L203F]-CCR5 in TM-5 (position V:13/5.47), [I116A]-CCR5 in TM-3 (III:16/3.40) and [L203F;G286F]-CCR5 (V:13/5.47;VII:09/7.42) were determined in G-protein-and β-arrestin-coupled signalling. Computational modelling monitored changes in amino acid conformation.

Key Results

[L203F]-CCR5 increased the basal level of G-protein coupling (20–70% of E_max) and β-arrestin recruitment (50% of E_max) with a threefold increase in agonist potency. In silico, [I116A]-CCR5 switched χ1-angle in [L203F]-CCR5. Furthermore, [I116A]-CCR5 was constitutively active to a similar degree as [L203F]-CCR5. Tyr²⁴⁴ in TM-6 (VI:09/6.44) moved towards TM-5 in silico, consistent with its previously shown function for CCR5 activation. On [L203F;G286F]-CCR5 the antagonist aplaviroc was converted to a superagonist.

Conclusions and Implications

The results imply that an aromatic amino acid in the centre of TM-5 controls the level of receptor activity. Furthermore, Ile¹¹⁶ acts as a gate for the movement of Tyr²⁴⁴ towards TM-5 in the active state, a mechanism proposed previously for the β₂-adrenoceptor. The results provide an understanding of chemokine receptor function and thereby information for the development of biased and non-biased antagonists and inverse agonists.     

Approaches and considerations for the assessment of immunotoxicity for environmental chemicals: A workshop summary

As experience is gained with toxicology testing and as new assays and technologies are developed, it is critical for stakeholders to discuss opportunities to advance our overall testing strategies. To facilitate these discussions, a workshop on practices for assessing immunotoxicity for environmental chemicals was held with the goal of sharing perspectives on immunotoxicity testing strategies and experiences, developmental immunotoxicity (DIT), and integrated and alternative approaches to immunotoxicity testing. Experiences across the chemical and pharmaceutical industries suggested that standard toxicity studies, combined with triggered-based testing approaches, represent an effective and efficient approach to evaluate immunotoxic potential. Additionally, discussions on study design, critical windows, and new guideline approaches and experiences identified important factors to consider before initiating DIT evaluations including assay choice and timing and the impact of existing adult data. Participants agreed that integrating endpoints into standard repeat-dose studies should be considered for fulfilling any immunotoxicity testing requirements, while also maximizing information and reducing animal use. Participants also acknowledged that in vitro evaluation of immunosuppression is complex and may require the use of multiple assays that are still being developed. These workshop discussions should contribute to developing an effective but more resource and animal efficient approach for evaluating chemical immunotoxicity.     

The epidemiology of non-alcoholic steatohepatitis (NASH) in the United States between 2010-2020: a population-based study

Introduction and objectivesNon-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD) that can progress to liver cirrhosis, liver failure and hepatocellular carcinoma. It is the second leading cause of liver transplant in the US. We aim to investigate the prevalence, demographics and risk factors NASH patients in the US.Patients and methodsWe used a large database (Explorys IBM) that aggregates electronic health records from 26 nationwide healthcare systems. We identified adults with NASH between 2010-2020. Demographics including age, gender and race were collected. NASH risk factors including Diabetes Millets (DM), Hyperlipidemia (HLD), Hypertension (HTN) and Obesity were also collected. Cochran-Armitage test was used to assess the statistical significance of year-by-year trend. Univariable and multivariable logistic regression were used to estimate the odds ratio (OR) of risk factors.ResultsNASH annual prevalence rate increased from 1.51% in 2010 to 2.79% in 2020 (p < 0.0001). The proportion of patients with NASH by gender was 54.1% female vs 45.9% male (OR 1.04 [0.91-1.11]). Caucasian had higher odds of NASH than non-Caucasian (OR 1.42 [1.31-1.54]). NASH is strongly associated with DM and obesity (OR 18.61 [17.35-19.94]) and (OR 20.97 [17.87-23.21]), respectively. Other components of metabolic syndrome were associated with NASH to a lesser degree; HTN (OR 3.24 [3.20-3.28]) and HLD (OR 4.93 [4.85-4.01]).ConclusionThe prevalence of NASH has significantly increased in the US in the last decade. This is likely related to the increased prevalence of risk factors as well as increased awareness of the disease.