The MHC Associated Peptide Proteomics assay is a useful tool for the non-clinical assessment of immunogenicity.

The propensity of therapeutic proteins to elicit an immune response, poses a significant challenge in clinical development and safety of the patients. Assessment of immunogenicity is crucial to predict potential adverse events and design safer biologics. In this study, we employed MHC Associated Peptide Proteomics (MAPPS) to comprehensively evaluate the immunogenic potential of re-engineered variants of immunogenic FVIIa analog (Vatreptacog Alfa). Our finding revealed the correlation between the protein sequence affinity for MHCII and the number of peptides identified in a MAPPS assay and this further correlates with the reduced T-cell responses. Moreover, MAPPS enable the identification of "relevant" T cell epitopes and may contribute to the development of biologics with lower immunogenic potential.

Robotic construction analysis: simulation with virtual reality.

Advances in robotic construction are evident and increasing every year, bringing present and potential improvements. However, the economic and social impacts are hard to assess and quantify without physical in situ testing, which is expensive and time-consuming. This paper presents a methodology for the simulation of robotic construction technologies, namely drones, using a virtual reality environment. Our hypothesis is that a virtual reality simulation of a robotic construction (H1) has the potential of increasing the precision of predicting the construction duration and cost and (H2) allows for the detection of construction problems. The study begins with a review of the literature on drones, robotic arms, and hybrid automatic construction solutions, as well as virtual reality construction simulations, summarising the robotic technologies currently being used, mainly in academic research, to assemble construction elements. It then proposes a construction simulation methodology applied to three architectonic elements to analyse different approaches and different scenarios for robotic construction simulation methodology. A construction simulation is tested, and the data is analysed and compared with traditional construction methods, focussing on construction time and costs.

Incorporation of Hydrophilic Macrocycles Into Drug-Linker Reagents Produces Antibody-Drug Conjugates With Enhanced in vivo Performance.

Antibody-drug conjugates (ADCs) have begun to fulfil their promise as targeted cancer therapeutics with ten clinical approvals to date. As the field matures, much attention has focused upon the key factors required to produce safe and efficacious ADCs. Recently the role that linker-payload reagent design has on the properties of ADCs has been highlighted as an important consideration for developers. We have investigated the effect of incorporating hydrophilic macrocycles into reagent structures on the in vitro and in vivo behavior of ADCs. Bis-sulfone based disulfide rebridging reagents bearing Val-Cit-PABC-MMAE linker-payloads were synthesized with a panel of cyclodextrins and crown ethers integrated into their structures via a glutamic acid branching point. Brentuximab was selected as a model antibody and ten ADCs with a drug-to-antibody ratio (DAR) of 4 were prepared for biological evaluation. In vitro, the ADCs prepared showed broadly similar potency (range: 16-34 pM) and were comparable to Adcetris® (16 pM). In vivo, the cyclodextrin containing ADCs showed greater efficacy than Adcetris® and the most efficacious variant (incorporating a 3'-amino-α-cyclodextrin component) matched a 24-unit poly(ethylene glycol) (PEG) containing comparator. The ADCs bearing crown ethers also displayed enhanced in vivo efficacy compared to Adcetris®, the most active variant (containing a 1-aza-42-crown-14 macrocycle) was superior to an analogous ADC with a larger 24-unit PEG chain. In summary, we have demonstrated that hydrophilic macrocycles can be effectively incorporated into ADC reagent design and offer the potential for enhanced alternatives to established drug-linker architectures.

Prognostic factors for ESD of early gastric cancers: a systematic review and meta-analysis.

Background and study aims Gastric neoplasms are one of the leading types of cancer in the world and early detection is essential to improve prognosis. Endoscopy is the gold-standard diagnostic procedure and allows adequate treatment in selected cases. Endoscopic submucosal dissection (ESD) has been reported to safely address most early gastric cancers (EGCs), with high curability rates. However, data on prognostic factors related to ESDs of EGCs are conflicting. Therefore, we aimed to systematically review the available literature and to perform a meta-analysis to identify the relevant prognostic factors in this context. Methods We performed this study according to PRISMA guidelines. Comparative studies assessing the relationship between curative resection or long-term curability rates and relevant prognostic factors were selected. Prognostic factors were demographic data, lesion features (location, morphology of the lesion, size, and depth of invasion), histological findings, Helycobacter pylori (HP) infection, presence of gastric a atrophy and body mass index (BMI). Finally, we also evaluated risk factors related to metachronous gastric neoplasm. Results The initial search retrieved 2829 records among which 46 studies were included for systematic review and meta-analysis. The total sample comprised 28366 patients and 29282 lesions. Regarding curative resection, pooled data showed no significant influence of sex [odds ratio (OR): 1.15 (0,97, 1.36) P  = 0.10 I 2  = 47 %] , age [OR: 1.00 (0.61, 1.64) P  = 1.00 I 2  = 58 %], posterior vs non-posterior location [OR: 1.35 (0.81, 2.27) P  = 0.25 I 2  = 84 %], depressed vs von-depressed macroscopic type[OR: 1.21 (0.99, 1.49) P  = 0.07 I 2  = 0 %], non-upper vs upper location [OR: 1.41 (0.93, 2.14) P  = 0.10 I 2  = 77 %] and BMI [OR: 0.84 (0.57; 1.26) P  = 0.41 I 2  = 0 %]. Differentiated neoplasms presented greater chance of cure compare to undifferentiated [OR: 0.10 (0.07, 0.15) P  < 0.00001 I 2  = 0 %]. Ulcerated lesions had lower curative rates compared to non-ulcerated [OR: 3.92 (2.81, 5.47) P  < 0.00001 I 2  = 44 %]. Lesions smaller than 20 mm had greater chance of curative resection [OR: 3.94 (3.25, 4.78) P  < 0.00001 I 2  = 38 %]. Bleeding during procedure had lower curative rates compared to non-bleeding [OR: 2.13 (1.56, 2.93) P  < 0.0001 I 2  = 0 %]. Concerning long-term cure, female gender [OR 1.62 (1.33, 1.97) P  < 0.00001 I 2  = 0 %] and the mucosal over SM1 cancers were protective factors [OR: 0.08 (0.02, 0.39) P  = 0.002 I 2  = 86 %]. Gastric atrophy [OR: 0.60 (0.45, 0.81) P  = 0.0006 I 2  = 42 %] and the pepsinogen I/pepsinogen II ratio [OR 2.29 (1.47, 3.57) P  = 0.0002 I 2  = 0 %] were risk factors to metachronous gastric neoplasm. Conclusions Ulcerated lesions, histology, bleeding and size > 20 mm are prognostic factors concerning curative resection. Regarding long-term cure, female gender and mucosal over SM1 cancer are predictive factors. Gastric atrophy and the pepsinogen ratio are risk factors for metachronous gastric neoplasm.

Surveillance in inflammatory bowel disease: is chromoendoscopy the only way to go? A systematic review and meta-analysis of randomized clinical trials.

Background and study aims Ulcerative colitis (UC) and Crohn's disease (CD) have higher risk of colorectal cancer (CRC). Guidelines recommend dysplasia surveillance with dye-spraying chromoendoscopy (DCE). The aim of this systematic review and meta-analysis was to review all randomized clinical trials (RCTs) available and compare the efficacy of different endoscopic methods of surveillance for dysplasia in patients with UC and CD. Methods Databases searched were Medline, EMBASE, Cochrane and SCIELO/LILACS. It was estimated the risk difference (RD) for dichotomous outcomes (number of patients diagnosed with one or more dysplastic lesions, total number of dysplastic lesions diagnosed and number of dysplastic lesions detected by targeted biopsies) and mean difference for continuous outcomes (procedure time). Results This study included 17 RCTs totaling 2,457 patients. There was superiority of DCE when compared to standard-definiton white light endoscopy (SD-WLE). When compared with high-definition (HD) WLE, no difference was observed in all outcomes (number of patients with dysplasia (RD 0.06; 95 % CI [-0.01, 0.13])). Comparing other techniques, no difference was observed between DCE and virtual chromoendoscopy (VCE - including narrow-band imaging [NBI], i-SCAN and flexible spectral imaging color enhancement), in all outcomes except procedure time (mean difference, 6.33 min; 95 % CI, 1.29, 11.33). DCE required a significantly longer procedure time compared with WLE (mean difference, 7.81 min; 95 % CI, 2.76, 12.86). Conclusions We found that dye-spraying chromoendoscopy detected more patients and dysplastic lesions than SD-WLE. Although no difference was observed between DCE and HD-WLE or narrow-band imaging, the main outcomes favored numerically dye-spraying chromoendoscopy, except procedure time. Regarding i-SCAN, FICE and auto-fluorescence imaging, there is still not enough evidence to support or not their recommendation.

BIM in People2People and Things2People Interactive Process.

In this research work, we present an IoT solution to environment variables using a LoRa transmission technology to give real-time information to users in a Things2People process and achieve savings by promoting behavior changes in a People2People process. These data are stored and later processed to identify patterns and integrate with visualization tools, which allow us to develop an environmental perception while using the system. In this project, we implemented a different approach based on the development of a 3D visualization tool that presents the system collected data, warnings, and other users' perception in an interactive 3D model of the building. This data representation introduces a new People2People interaction approach to achieve savings in shared spaces like public buildings by combining sensor data with the users' individual and collective perception. This approach was validated at the ISCTE-IUL University Campus, where this 3D IoT data representation was presented in mobile devices, and from this, influenced user behavior toward meeting campus sustainability goals.

Adverse events after biliary sphincterotomy: Does the electric current mode make a difference? A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Biliary sphincterotomy is an invasive method that allows access to the bile ducts, however, this procedure is not exempt of complications. Studies in the literature indicate that the mode of electric current used for sphincterotomy may carry different incidences of adverse events such as pancreatitis, hemorrhage, perforation, and cholangitis. AIM: To evaluate the safety of different modes of electrical current during biliary sphincterotomy based on incidence of adverse events. METHODS: We searched articles for this systematic review in Medline, EMBASE, Central Cochrane, Lilacs, and gray literature from inception to September 2019. Data from studies describing different types of electric current were meta-analyzed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The following electric current modalities were evaluated: endocut, blend, pure cut, pure cut followed by blend, monopolar, and bipolar. RESULTS: A total of 1791 patients from 11 randomized clinical trials evaluating the following comparisons: 1. Endocut vs Blend: No statistical difference in the incidence of bleeding (7% vs 13.4%; RD: -0.11 [-0.31, 0.08], P=0.27, I2=86%), pancreatitis (4.4% vs 3.5%; RD: 0.01 [-0.03, 0.04], P=0.62, I2=48%) and perforation (absence of cases in both arms). 2. Endocut vs Pure cut: Higher incidence of mild bleeding (without drop in hemoglobin levels, clinical repercussion or need for endoscopic intervention) in the pure cut group (9.2% vs 28.8%; RD: -0.19 [-0.27, -0.12], P<0.00001, I2=0%). No statistical difference regarding pancreatitis (5.2% vs 0.9%; RD: 0.05 [-0.01, 0.11], P=0.12, I2=57%), perforation (0.4% vs 0%; RD: 0.00 [-0.01, 0.02], P=0.7, I2=0%) or cholangitis (1.8% vs 3.2%; RD: -0.01 [-0.09, 0.06], P=0,7). 3. Pure cut vs blend: higher incidence of mild bleeding in the pure cut group (40.4% vs 16.7%; RD: 0.24 [0.15, 0.33], P<0.00001, I2=0%). No statistical difference concerning incidence of pancreatitis or cholangitis. 4. Pure cut vs Pure cut followed by Blend: No statistical difference regarding incidence of bleeding (22.5% vs 11.7%; RD: -0.10 [-0.24, 0.04], P=0.18, I2=61%) and pancreatitis (8.9% vs 14.8%; RD 0.06 [-0.02, 0.13], P=0.12, I2=0%). 5. Blend vs pure cut followed by blend: no statistical difference regarding incidence of bleeding and pancreatitis (11.3% vs 10.4%; RD -0.01 [-0.11, 0.09], P=0.82, I2=0%). 6. Monopolar vs bipolar: higher incidence of pancreatitis in the monopolar mode group (12% vs 0%; RD 0.12 [0.02, 0.22], P=0.01). CONCLUSION: Pure cut carries higher incidences of mild bleeding compared to endocut and blend. However, this modality might present a lower incidence of pancreatitis. The monopolar mode elicits higher rates of pancreatitis in comparison with the bipolar mode. There is no difference in incidence of cholangitis or perforation between different types of electric current. There is a lack of evidence in the literature to recommend one method over the others, therefore new studies are warranted. As there is no perfect electric current mode, the choice in clinical practice must be based on the patient risk factors.

Beacons and BIM Models for Indoor Guidance and Location.

This research work uses a simplified approach to combine location information from a beacon's propagation signal interaction with a mobile device sensor (accelerometer and gyroscope) with local building information to give real-time location and guidance to a user inside a building. This is an interactive process with visualisation information that can help user's orientation inside unknown buildings and the data stored from different users can provide useful information about users' movements inside a public building. Beacons installed on the building at specific pre-defined positions emit signals that give a geographic position with an associated imprecision, related with Bluetooth's range. This uncertainty is handled by building layout and users' movement in a developed system that maps users' position, gives guidance, and stores user movements. This system is based on an App (Find Me!) for Android OS (Operating System) which captures the Bluetooth Low Energy (BLE) signal coming from the beacon(s) and shows, through a map, the location of the user's smartphone and guide him to the desired destination. Also, the beacons can deliver relevant context information. The application was tested by a panel of new and habitual campus users against traditional wayfinding alternatives yielding navigation times about 30% smaller, respectively.

The synthesis and kinetic evaluation of aryl α-aminophosphonates as novel inhibitors of T. cruzi trans-sialidase.

The trans-sialidase protein expressed by Trypanosoma cruzi is an important enzyme in the life cycle of this human pathogenic parasite and is considered a promising target for the development of new drug treatments against Chagas' disease. Here we describe α-amino phosphonates as a novel class of inhibitor of T. cruzi trans-sialidase. Molecular modelling studies were initially used to predict the active-site binding affinities for a series of amino phosphonates, which were subsequently synthesised and their IC50s determined in vitro. The measured inhibitory activities show some correlation with the predictions from molecular modelling, with 1-napthyl derivatives found to be the most potent inhibitors having IC50s in the low micromolar range. Interestingly, kinetic analysis of the mode of inhibition demonstrated that the α-aminophosphonates tested here operate in a non-competitive manner.

Modulation of drug-linker design to enhance in vivo potency of homogeneous antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are a promising class of anticancer agents which have undergone substantial development over the past decade and are now achieving clinical success. The development of novel site-specific conjugation technologies enables the systematic study of architectural features within the antibody conjugated drug linker that may affect overall therapeutic indices. Here we describe the results of a systematic study investigating the impact of drug-linker design on the in vivo properties of a series of homogeneous ADCs with a conserved site of conjugation, a monodisperse drug loading, a lysosomal release functionality and monomethyl auristatin E as a cytotoxic payload. The ADCs, which differed only in the relative position of certain drug-linker elements within the reagent, were first evaluated in vitro using anti-proliferation assays and in vivo using mouse pharmacokinetics (PK). Regardless of the position of a discrete polymer unit, the ADCs showed comparable in vitro potencies, but the in vivo PK properties varied widely. The best performing drug-linker design was further used to prepare ADCs with different drug loadings of 4, 6 and 8 drugs per antibody and compared to Adcetris® in a Karpas-299 mouse xenograft model. The most efficacious ADC showed complete tumor regression and 10/10 tumor free survivors at a single 0.5mg/kg dose. This study revealed drug-linker design as a critical parameter in ADC development, with the potential to enhance ADC in vivo potency for producing more efficacious ADCs.

Comparative analysis of tropaeolin adsorption onto raw and acid-treated kaolinite: optimization by Response Surface Methodology.

The comparative adsorption of Tropaeolin (TP) onto raw kaolinite (RK) and kaolinite submitted to acid treatment (AK) was studied. RK and AK were characterized by zeta potential and energy dispersive X-ray spectroscopy (EDS). The adsorption was investigated using Composite Central Design (CCD) and the parameters evaluated were initial TP solution concentration, quantity of adsorbent and the pH of the solution. The optimized parameters were: initial TP solution concentration of 75 mg L(-1), pH 4 and 0.12 g adsorbent. Kinetic data were evaluated by pseudo-first order, pseudo-second order and Avrami models. The equilibrium adsorption was analyzed by Langmuir, Freundlich and Sips isotherms. The kinetic data were best fitted to the pseudo-second order model. The Sips isotherm model gives the better correlation to predict the adsorption equilibrium. The maximum adsorption capacities were 18.3 mg g(-1) and 23.2 mg g(-1) for RK and AK, respectively. The calculated thermodynamic parameters showed that the process was spontaneous, endothermic and involving the disorganization of the adsorption system for both adsorbents. The desorption step showed that the AK sample was more suitable as an adsorbent.

Optimization by Response Surface Methodology of the adsorption of Coomassie Blue dye on natural and acid-treated clays.

The effect of acid treatment on natural agalmatolite (AN) and natural kaolinite (KN) was investigated, together with the influence of those modifications on the removal of Coomassie Blue (CB) dye. The process was optimized using the Response Surface Methodology (RSM) developed by the application of the quadratic model associated with the Central Composite Design. Adsorption was promoted by initial CB concentration of 25 mg L(-1), pH 2 and adsorbent mass of 0.1 g. The adsorption kinetics study carried out in optimized conditions established that the equilibrium times were 1 h for AN and AA (treated agalmatolite), 4 h for KN and 2 h for KA (treated kaolinite). The kinetics data for AN, KN and KA were best fitted to the pseudo second order model, whilst for AA, the result pointed to the pseudo first order model. In the isotherm of adsorption the maximum quantities were obtained with reference to 11.29 mg g(-1), 9.84 mg g(-1), 22.89 mg g(-1) and 30.08 mg g(-1) for the samples AN, AA, KN and KA respectively. The data fitting showed that the Sips model was the most satisfactory for all the adsorbents. The calculated thermodynamic parameters showed that the process was spontaneous in all the adsorbents, endothermic for the KN and KA samples, exothermic for AN and AA, involved the disorganization of the adsorption system for the KN and KA and its organization for the AN and AA samples. The results showed that the KN and KA samples were more appropriate for use as adsorbents.

Mechanism-based covalent neuraminidase inhibitors with broad-spectrum influenza antiviral activity.

Influenza antiviral agents play important roles in modulating disease severity and in controlling pandemics while vaccines are prepared, but the development of resistance to agents like the commonly used neuraminidase inhibitor oseltamivir may limit their future utility. We report here on a new class of specific, mechanism-based anti-influenza drugs that function through the formation of a stabilized covalent intermediate in the influenza neuraminidase enzyme, and we confirm this mode of action with structural and mechanistic studies. These compounds function in cell-based assays and in animal models, with efficacies comparable to that of the neuraminidase inhibitor zanamivir and with broad-spectrum activity against drug-resistant strains in vitro. The similarity of their structure to that of the natural substrate and their mechanism-based design make these attractive antiviral candidates.

Sugar bislactones by one-step oxidative dimerisation with pyridinium chlorochromate versus regioselective oxidation of vicinal diols.

Synthesis of 10-membered bislactones by PCC oxidation of methyl 2,6-di-O-pivaloyl-alpha-D-glucopyranoside and methyl 4,6-O-benzylidene-alpha-D-glucopyranoside is described, with emphasis on their structure elucidation using the information gained by combination of NMR spectroscopic techniques with X-ray diffraction data. In alternative, the use of PCC and PCC adsorbed on silica gel or alumina for the regioselective oxidation of vicinal diols in sugars is also reported. Both bislactones showed antifungal activity against Candida albicans, and were slightly active against the bacteria Bacillus subtilis. The bislactone presenting pivaloyl protecting groups also promoted some growth inhibition of Staphylococcus aureus.

Metástase única de adenocarcinoma no talo, com sítio primário desconhecido: relato de caso com revisäo da literatura / Adenocarcinoma single metastasis of the talus, with unknown primary origin: case report and literature review

Relata-se caso de adenocarcinoma matastático do talo, com localizaçäo única e sítio primário desconhecido, em paciente do sexo masculino de 65 anos de idade. Trata-se do primeiro caso a ser relatado no Brasil. Os autores chamam a atentpo para os cuidados a serem tomados na investigaçäo diagnóstica, devendo-se para isso obedecer a um protocolo.