The next-generation Open Targets Platform: reimagined, redesigned, rebuilt.

The Open Targets Platform (https://platform.opentargets.org/) is an open source resource to systematically assist drug target identification and prioritisation using publicly available data. Since our last update, we have reimagined, redesigned, and rebuilt the Platform in order to streamline data integration and harmonisation, expand the ways in which users can explore the data, and improve the user experience. The gene-disease causal evidence has been enhanced and expanded to better capture disease causality across rare, common, and somatic diseases. For target and drug annotations, we have incorporated new features that help assess target safety and tractability, including genetic constraint, PROTACtability assessments, and AlphaFold structure predictions. We have also introduced new machine learning applications for knowledge extraction from the published literature, clinical trial information, and drug labels. The new technologies and frameworks introduced since the last update will ease the introduction of new features and the creation of separate instances of the Platform adapted to user requirements. Our new Community forum, expanded training materials, and outreach programme support our users in a range of use cases.

Assessment of TLL1 variant and risk of hepatocellular carcinoma in Latin Americans and Europeans.

INTRODUCTION AND OBJECTIVES: Tolloid like protein 1 (TLL1) rs17047200 has been reported to be associated with HCC development and liver fibrosis. However, to our knowledge, no studies have been performed on Latin Americans and comparative differences between TLL1 rs17047200 in HCC patients from Latin America and Europe are undefined. MATERIALS AND METHODS: Cross-sectional analysis was performed on Latin American and European individuals. We analyzed TLL1 rs17047200 on DNA from 1194 individuals, including 420 patients with HCC (86.0 % cirrhotics) and 774 without HCC (65.9 % cirrhotics). RESULTS: TLL1 rs17047200 genotype AT/TT was not associated with HCC development in Latin Americans (OR: 0.699, 95 %CI 0.456-1.072, p = 0.101) or Europeans (OR: 0.736, 95 %CI 0.447-1.211, p = 0.228). TLL1 AT/TT was not correlated with fibrosis stages among metabolic dysfunction-associated steatotic liver disease (MASLD) patients from Latin America (OR: 0.975, 95 %CI 0.496-1.918, p = 0.941). Among Europeans, alcohol-related HCC had lower TLL1 AT/TT frequencies than cirrhosis (18.3 % versus 42.3 %, OR: 0.273, 95 %CI 0.096-0.773, p = 0.015). CONCLUSIONS: We found no evidence that the TLL1 rs17047200 AT/TT genotype is a risk factor for HCC development in Latin Americans or Europeans. A larger study integrating ethnic and etiology backgrounds is needed to determine the importance of the TLL1 SNP in HCC development.

Management of refractory hepatic hydrothorax: a report of two cases and review of the literature.

Hepatic hydrothorax is a transudative pleural effusion in patients with cirrhosis. A 56-year-old cirrhotic patient presented with dyspnea and desaturation; his chest images showed a right pleural effusion. Another 66-year-old woman with cirrhosis, developed during her hospitalization acute respiratory failure, and her chest X- ray showed left pleural effusion. Initially, both patients were prescribed a dietary sodium restriction and diuretics. Nevertheless, they didn't have a good response so a chest tube was placed, and an octreotide infusion partially reduced the volume of the pleural drainage allowing a pleurodesis. We report two cases of refractory hepatic hydrothorax with multiple treatments including octreotide and pleurodesis.

MBOAT7 rs641738 Variant Is Not Associated with an Increased Risk of Hepatocellular Carcinoma in a Latin American Cohort.

BACKGROUND: The rs641738 C > T single-nucleotide polymorphism of MBOAT7 has been associated with hepatocellular carcinoma (HCC) and nonalcoholic fatty liver disease (NAFLD). Latin Americans have high rates of HCC and NAFLD, but no assessment between MBOAT7 and HCC has been performed in this population. AIMS: We provide the first assessment of the impact of MBOAT7 on HCC risk in Latin Americans. METHODS: Patients were prospectively recruited into the ESCALON network, designed to collect samples from Latin American patients with HCC in 6 South American countries (Argentina, Ecuador, Brazil, Chile, Peru, and Colombia). A European cohort and the general Hispanic population of gnomAD database were included for comparison. Associations between HCC and MBOAT7 were evaluated using logistic regression. RESULTS: In total, 310 cases of HCC and 493 cases of cirrhosis without HCC were assessed. The MBOAT7 TT genotype was not predictive of HCC in Latin Americans (TT vs CC OR adjusted = 1.15, 95% CI 0.66-2.01, p = 0.610) or Europeans (TT vs CC OR adjusted = 1.20, 95% CI 0.59-2.43, p = 0.621). No significant association was noted on subgroup analysis for NAFLD, viral hepatitis, or alcohol-related liver disease. The TT genotype was increased in the NAFLD-cirrhosis cohort of Latin Americans compared to a non-cirrhotic NAFLD cohort (TT vs CC + CT OR = 2.75, 95% CI 1.10-6.87, p = 0.031). CONCLUSION: The rs631738 C > T allele of MBOAT7 was not associated with increased risk of HCC in Latin Americans or Europeans. An increase in the risk of cirrhosis was noted with the TT genotype in Latin Americans with NAFLD.

Changing epidemiology of hepatocellular carcinoma in South America: A report from the South American liver research network.

INTRODUCTION AND OBJECTIVES: Most epidemiological data on hepatocellular carcinoma (HCC) originate from resource-rich countries. We have previously described the epidemiology of HCC in South America through the South American Liver Research Network. Here, we provide an update on the changing epidemiology of HCC in the continent seven years since that report. MATERIALS AND METHODS: We evaluated all cases of HCC diagnosed between 2019 to 2021 in centers from six countries in South America. A templated, retrospective chart review of patient characteristics at the time of HCC diagnosis, including basic demographic, clinical and laboratory data, was completed. Diagnosis of HCC was made radiologically or histologically for all cases via institutional standards. RESULTS: Centers contributed to a total of 339 HCC cases. Peru accounted for 37% (n=125) of patients; Brazil 16% (n=57); Chile 15% (n=51); Colombia 14% (n=48); Argentina 9% (n=29); and Ecuador 9% (n=29). The median age at HCC diagnosis was 67 years (IQR 59-73) and 61% were male. The most common risk factor was nonalcoholic fatty liver disease (NAFLD, 37%), followed by hepatitis C (17%), alcohol use disorder (11%) and hepatitis B (12%). The majority of HCCs occurred in the setting of cirrhosis (80%). HBV-related HCC occurred at a younger age compared to other causes, with a median age of 46 years (IQR 36-64). CONCLUSIONS: We report dramatic changes in the epidemiology of HCC in South America over the last decade, with a substantial increase in NAFLD-related HCC. HBV-related HCC still occurs at a much younger age when compared to other causes.

Open Targets Platform: supporting systematic drug-target identification and prioritisation.

The Open Targets Platform (https://www.targetvalidation.org/) provides users with a queryable knowledgebase and user interface to aid systematic target identification and prioritisation for drug discovery based upon underlying evidence. It is publicly available and the underlying code is open source. Since our last update two years ago, we have had 10 releases to maintain and continuously improve evidence for target-disease relationships from 20 different data sources. In addition, we have integrated new evidence from key datasets, including prioritised targets identified from genome-wide CRISPR knockout screens in 300 cancer models (Project Score), and GWAS/UK BioBank statistical genetic analysis evidence from the Open Targets Genetics Portal. We have evolved our evidence scoring framework to improve target identification. To aid the prioritisation of targets and inform on the potential impact of modulating a given target, we have added evaluation of post-marketing adverse drug reactions and new curated information on target tractability and safety. We have also developed the user interface and backend technologies to improve performance and usability. In this article, we describe the latest enhancements to the Platform, to address the fundamental challenge that developing effective and safe drugs is difficult and expensive.

Open Targets Genetics: systematic identification of trait-associated genes using large-scale genetics and functional genomics.

Open Targets Genetics (https://genetics.opentargets.org) is an open-access integrative resource that aggregates human GWAS and functional genomics data including gene expression, protein abundance, chromatin interaction and conformation data from a wide range of cell types and tissues to make robust connections between GWAS-associated loci, variants and likely causal genes. This enables systematic identification and prioritisation of likely causal variants and genes across all published trait-associated loci. In this paper, we describe the public resources we aggregate, the technology and analyses we use, and the functionality that the portal offers. Open Targets Genetics can be searched by variant, gene or study/phenotype. It offers tools that enable users to prioritise causal variants and genes at disease-associated loci and access systematic cross-disease and disease-molecular trait colocalization analysis across 92 cell types and tissues including the eQTL Catalogue. Data visualizations such as Manhattan-like plots, regional plots, credible sets overlap between studies and PheWAS plots enable users to explore GWAS signals in depth. The integrated data is made available through the web portal, for bulk download and via a GraphQL API, and the software is open source. Applications of this integrated data include identification of novel targets for drug discovery and drug repurposing.

Hybridization of Evolutionary Operators with Elitist Iterated Racing for the Simulation Optimization of Traffic Lights Programs.

In the traffic light scheduling problem, the evaluation of candidate solutions requires the simulation of a process under various (traffic) scenarios. Thus, good solutions should not only achieve good objective function values, but they must be robust (low variance) across all different scenarios. Previous work has shown that combining IRACE with evolutionary operators is effective for this task due to the power of evolutionary operators in numerical optimization. In this article, we further explore the hybridization of evolutionary operators and the elitist iterated racing of IRACE for the simulation-optimization of traffic light programs. We review previous works from the literature to find the evolutionary operators performing the best when facing this problem to propose new hybrid algorithms. We evaluate our approach over a realistic case study derived from the traffic network of Málaga (Spain) with 275 traffic lights that should be scheduled optimally. The experimental analysis reveals that the hybrid algorithm comprising IRACE plus differential evolution offers statistically better results than the other algorithms when the budget of simulations is low. In contrast, IRACE performs better than the hybrids for a high simulations budget, although the optimization time is much longer.

Bottom-Up Synthesized MoS2 Interfacing Polymer Carbon Nanodots with Electrocatalytic Activity for Hydrogen Evolution.

The preparation of an MoS2 -polymer carbon nanodot (MoS2 -PCND) hybrid material was accomplished by employing an easy and fast bottom-up synthetic approach. Specifically, MoS2 -PCND was realized by the thermal decomposition of ammonium tetrathiomolybdate and the in situ complexation of Mo with carboxylic acid units present on the surface of PCNDs. The newly prepared hybrid material was comprehensively characterized by spectroscopy, thermal means, and electron microscopy. The electrocatalytic activity of MoS2 -PCND was examined in the hydrogen evolution reaction (HER) and compared with that of the corresponding hybrid material prepared by a top-down approach, namely MoS2 -PCND(exf-fun), in which MoS2 was firstly exfoliated and then covalently functionalized with PCNDs. The MoS2 -PCND hybrid material showed superior electrocatalytic activity toward the HER with low Tafel slope, excellent electrocatalytic stability, and an onset potential of -0.16 V versus RHE. The superior catalytic performance of MoS2 -PCND was rationalized by considering the catalytically active sites of MoS2 , the effective charge/energy-transfer phenomena from PCNDs to MoS2 , and the synergetic effect between MoS2 and PCNDs in the hybrid material.

Sorafenib for Treatment of Hepatocellular Carcinoma: A Survival Analysis From the South American Liver Research Network.

GOALS: We aim to describe the efficacy, safety profile, and variables associated with survival in patients with hepatocellular carcinoma (HCC) treated with sorafenib in South America. BACKGROUND: Sorafenib has been shown to improve survival in patients with advanced HCC. There are few data on sorafenib use for HCC in South America. STUDY: We performed a retrospective analysis of HCC cases treated with sorafenib from 8 medical centers in 5 South American countries, between January 2010 and June 2017. The primary endpoint was overall survival (OS), which was defined as time from sorafenib initiation to death or last follow-up. Risk factors for decreased OS were assessed using Cox proportional hazard regression and log-rank tests. RESULTS: Of 1336 evaluated patients, 127 were treated with sorafenib and were included in the study. The median age of individuals was 65 years (interquartile range, 55 to 71) and 70% were male individuals. Median OS in all patients was 8 months (interquartile range, 2 to 17). Variables associated with survival on multivariate analysis were platelets >/<250,000 mm (2 vs. 8 mo, P=0.01) and Barcelona Clinic Liver Cancer (BCLC) stage (A/B, 13 vs. C/D, 6 mo; P=0.04). In a subanalysis of patients with BCLC stage C, platelets >/<250,000 mm were also independently associated with survival (2 vs. 5.5 mo, P=0.03). Patients lived longer if they experienced any side effects from sorafenib use (11 vs. 2 mo, P=0.009). Patients who stopped sorafenib because of side effects had shorter survival compared with patients who were able to tolerate side effects and continue treatment (7.5 vs. 13 mo, P=0.01). CONCLUSIONS: Pretreatment elevation of platelets and advanced BCLC stage were independently associated with poor survival on sorafenib in a South American cohort.

A tool box to ascertain the nature of doping and photoresponse in single-walled carbon nanotubes.

The effect of doping on the electronic properties in bulk single-walled carbon nanotube (SWCNT) samples is studied for the first time using a new in situ Raman spectroelectrochemical method, and further verified by DFT calculations and photoresponse. We use p-/n-doped SWCNTs prepared by diazonium reactions as a versatile chemical strategy to control the SWCNT behavior. The measured and calculated data testify an acceptor effect of 4-aminobenzenesulfonic acid (p-doping), and a donor effect (n-doping) in the case of benzyl alcohol. In addition, pristine and covalently functionalized SWCNTs were used for the preparation of photoactive film electrodes. The photocathodic current in the photoelectrochemical cell is consistently modulated by the doping group. These results validate the in situ Raman spectroelectrochemistry as a unique tool box for predicting the electronic properties of functionalized SWCNTs in the form of thin films and their operational functionality in thin film devices for future optoelectronic applications.

Hepatocellular carcinoma in South America: Evaluation of risk factors, demographics and therapy.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Most studies addressing the epidemiology of HCC originate from developed countries. This study reports the preliminary findings of a multinational approach to characterize HCC in South America. METHODS: We evaluated 1336 HCC patients seen at 14 centres in six South American countries using a retrospective study design with participating centres completing a template chart of patient characteristics. The diagnosis of HCC was made radiographically or histologically for all cases according to institutional standards. Methodology of surveillance for each centre was following AASLD or EASL recommendations. RESULTS: Sixty-eight percent of individuals were male with a median age of 64 years at time of diagnosis. The most common risk factor for HCC was hepatitis C infection (HCV, 48%), followed by alcoholic cirrhosis (22%), Hepatitis B infection (HBV, 14%) and NAFLD (9%). We found that among individuals with HBV-related HCC, 38% were diagnosed before age 50. The most commonly provided therapy was transarterial chemoembolization (35% of HCCs) with few individuals being considered for liver transplant (<20%). Only 47% of HCCs were diagnosed during surveillance, and there was no difference in age of diagnosis between those diagnosed incidentally vs by surveillance. Nonetheless, being diagnosed during surveillance was associated with improved overall survival (P = .01). CONCLUSIONS: Our study represents the largest cohort to date reporting characteristics and outcomes of HCC across South America. We found an important number of HCCs diagnosed outside of surveillance programmes, with associated increased mortality in those patients.

HAP score as prognostic factor of hepatocellular carcinoma treated with transarterial chemoembolization in a Latin American center.

INTRODUCTION: Hepatocellular carcinoma (HCC) in cirrhosis is diagnosed, most of times, when it is not susceptible to curative treatment. Transarterial chemoembolization (TACE) is a palliative therapeutic option with heterogeneous results. The HAP score stratifies patients who will benefit from the first TACE. OBJECTIVE: To evaluate if the HAP score is a prognostic factor of HCC treated with TACE. MATERIALS AND METHODS: Retrospective cohort study in cirrhotic patients with HCC and first TACE at the Edgardo Rebagliati Martins National Hospital, Lima-Peru, from June 2011 to June 20139. The HAP score was applied, mortality and survival were observed with a follow-up of 36 months. RESULTS: We included 54 patients with age of 67.7±9.9 years, 59.3% Child-Pugh A and 40.7% Child-Pugh B, MELD score of 11±2.7; 51.9 and 40.7% were BCLC A and B, respectively; 66.7% had a single tumor and 70.4% had a predominant tumor <5cm. The HAP score classified 8, 14, 26 and 6 patients as HAP A, B, C and D, respectively. The overall survival was 19.5±11.2 months and 32.8±6.5 months for HAP A, 24.9±14.8 months for HAP B, 13.9±5.2 months for HAP C and 14±6.6 months for HAP D. There were no deaths at 12 months in HAP A. At 24 months, mortality for HAP C and D was 100%. At 36 months, the survival rate for HAP A and B was 75 and 42.9%, respectively. CONCLUSIONS: The HAP score is a useful tool to guide the management decisions of cirrhotic patients with HCC requiring TACE due to its value in predicting mortality and survival.

[Perception of the gastroenterologist about the needs of continuing medical education in Peru]. / Percepción del gastroenterólogo sobre las necesidades de educación médica continua en el Perú.

OBJECTIVE: To determine the perception of the gastroenterologist about the needs of continuing medical education (CME) in Peru. MATERIAL AND METHODS: Cross-sectional and descriptive study. The sample was not probabilistic. A survey was applied to the gastroenterologists members of the Society of Gastroenterology of Peru. The questionnaire was developed based on the "Canadian Association of Gastroenterology Educational Needs Assessment Report" with a Likert scale of 5 points (1 = not necessary and 5 = indispensable). The average of the scores obtained in each of the 33 items of the clinical, endoscopic and learning methods areas was determined. RESULTS: There were 75 participants and the average age was 43.40 years (SD ± 10.22 years). The place of work was mainly Lima (68%) and the majority (50.67%) had a service time of less than 5 years. The perception of educational needs in the clinical area was higher for gastric cancer (4.37 ± 0.87) and colon cancer (4.37 ± 0.83); in the endoscopic area were polypectomy (4.15 ± 0.95) and emergency techniques (4.13 ± 0.99). The main learning methods for gastroenterologists were attendance at congresses (4.29 ± 0.83) and endoscopic workshops (4.19 ± 1.06). CONCLUSIONS: The perception of the gastroenterologist surveyed on the needs of CME was mainly on gastric and colon cancer issues. Most of them considered congress attendance as the main learning method.

Early detection of acute transmural myocardial ischemia by the phasic systolic-diastolic changes of local tissue electrical impedance.

Myocardial electrical impedance is influenced by the mechanical activity of the heart. Therefore, the ischemia-induced mechanical dysfunction may cause specific changes in the systolic-diastolic pattern of myocardial impedance, but this is not known. This study aimed to analyze the phasic changes of myocardial resistivity in normal and ischemic conditions. Myocardial resistivity was measured continuously during the cardiac cycle using 26 different simultaneous excitation frequencies (1 kHz-1 MHz) in 7 anesthetized open-chest pigs. Animals were submitted to 30 min regional ischemia by acute left anterior descending coronary artery occlusion. The electrocardiogram, left ventricular (LV) pressure, LV dP/dt, and aortic blood flow were recorded simultaneously. Baseline myocardial resistivity depicted a phasic pattern during the cardiac cycle with higher values at the preejection period (4.19 ± 1.09% increase above the mean, P < 0.001) and lower values during relaxation phase (5.01 ± 0.85% below the mean, P < 0.001). Acute coronary occlusion induced two effects on the phasic resistivity curve: 1) a prompt (5 min ischemia) holosystolic resistivity rise leading to a bell-shaped waveform and to a reduction of the area under the LV pressure-impedance curve (1,427 ± 335 vs. 757 ± 266 Ω·cm·mmHg, P < 0.01, 41 kHz) and 2) a subsequent (5-10 min ischemia) progressive mean resistivity rise (325 ± 23 vs. 438 ± 37 Ω·cm at 30 min, P < 0.01, 1 kHz). The structural and mechanical myocardial dysfunction induced by acute coronary occlusion can be recognized by specific changes in the systolic-diastolic myocardial resistivity curve. Therefore these changes may become a new indicator (surrogate) of evolving acute myocardial ischemia.

Ultraviolet Pretreatment of Titanium Dioxide and Tin-Doped Indium Oxide Surfaces as a Promoter of the Adsorption of Organic Molecules in Dry Deposition Processes: Light Patterning of Organic Nanowires.

In this article we present the preactivation of TiO2 and ITO by UV irradiation under ambient conditions as a tool to enhance the incorporation of organic molecules on these oxides by evaporation at low pressures. The deposition of π-stacked molecules on TiO2 and ITO at controlled substrate temperature and in the presence of Ar is thoroughly followed by SEM, UV-vis, XRD, RBS, and photoluminescence spectroscopy, and the effect is exploited for the patterning formation of small-molecule organic nanowires (ONWs). X-ray photoelectron spectroscopy (XPS) in situ experiments and molecular dynamics simulations add critical information to fully elucidate the mechanism behind the increase in the number of adsorption centers for the organic molecules. Finally, the formation of hybrid organic/inorganic semiconductors is also explored as a result of the controlled vacuum sublimation of organic molecules on the open thin film microstructure of mesoporous TiO2.

A new spiral microelectrode assembly for electroporation and impedance measurements of adherent cell monolayers.

In this study, a new microelectrode assembly based on spiral geometry applicable to in situ electroporation of adherent cell monolayers on standard multiwell plates is presented. Furthermore, the structure is specially conceived to perform electrical impedance spectroscopy (EIS) measurements during electroporation. Its performance for cell membrane permeabilization is tested with a fluorescent probe. Gene electrotransfer is also assayed using a plasmid DNA encoding GFP in four different cell lines (CHO, HEK293, 3T3-L1 and FTO2B). Additionally, siRNA α-GFP electrotransfection is tested in GFP gene-expressing CHO cells. Our data show considerable differences between permeabilization and gene transfer results and cell line dependence on gene expression rates. Successful siRNA electro-mediated delivery is also achieved. We demonstrate the applicability of our device for electroporation-mediated gene transfer of adherent cells in standard laboratory conditions. Finally, electrical impedance measurements during electroporation of CHO and 3T3-L1 cells are also given.

[Addition of bismuth subsalicylate to triple eradication therapy for Helicobacter pylori infection: efficiency and adverse events]. / Adición de subsalicilato de Bismuto a la terapia triple erradicadora de la infección por Helicobacter pylori: efectividad y efectos adversos.

OBJECTIVES: To establish the efficiency and adverse effects of the addition of bismuth subsalicylate to triple eradication therapy for Helicobacter pylori infection. MATERIAL AND METHODS: Double blind controlled experimental trial. The study population consisted of 54 patients with Helicobacter pylori infection: 29 were allocated to the experimental group, who received the usual triple plus bismuth subsalicylate therapy, and 24 received the triple therapy plus placebo. RESULTS: The average age was 47+-14.9 years, 66.7% of the patients were women. Both groups underwent the breath test: it was negative in 89.7% of the patients from the experimental group and 80% of the patients from the placebo group (p=0.319). The adverse events of both groups were: diarrhea (10.3% in the experimental group vs 16% in the placebo group; p=0.537), dark feces (37.9% in the experimental group vs 0% in the placebo group; p=0.001), abdominal pain (20.7% in the experimental group vs 52% in the placebo group; p=0.016). Nausea only were present in 3% of the patients of placebo group p=0.055). CONCLUSIONS: The association of bismuth subsalicylate to the triple therapy scheme for the eradication of Helicobacter pylori was effective in 89.7% of patients, whereas 80% of efficiency in the experimental group.