A review on machine learning approaches and trends in drug discovery

Abstract: Drug discovery aims at finding new compounds with specific chemical properties for the treatment of diseases. In the last years, the approach used in this search presents an important component in computer science with the skyrocketing of machine learning techniques due to its democratization. With the objectives set by the Precision Medicine initiative and the new challenges generated, it is necessary to establish robust, standard and reproducible computational methodologies to achieve the objectives set. Currently, predictive models based on Machine Learning have gained great importance in the step prior to preclinical studies. This stage manages to drastically reduce costs and research times in the discovery of new drugs. This review article focuses on how these new methodologies are being used in recent years of research. Analyzing the state of the art in this field will give us an idea of where cheminformatics will be developed in the short term, the limitations it presents and the positive results it has achieved. This review will focus mainly on the methods used to model the molecular data, as well as the biological problems addressed and the Machine Learning algorithms used for drug discovery in recent years.Instituto de Salud Carlos III; PI17/01826Instituto de Salud Carlos III; PI17/01561Xunta de Galicia; Ref. ED431D 2017/16Xunta de Galicia; Ref. ED431D 2017/23Xunta de Galicia; Ref. ED431C 2018/4

Evaluation of transparent 20l polypropylene buckets for household solar water disinfection (SoDis) of drinking water in resource poor environments

Solar water disinfection (SODIS) is an appropriate technology for treating drinking water in developing communities, as it is e¬ective, low- or zero-cost, easy to use. The WHO recognises SODIS as an appropriate intervention to provide drinking water after manmade or natural disasters. Nevertheless, uptake is low due partially to the burden of using small volume polyethylene terephthalate (PET) bottles (1.5-2 L). A major challenge is to develop a low cost transparent container for disinfecting larger volumes of water. This study examines the capability of transparent polypropylene (PP) buckets of 5 and 20 litres volume, as SODIS containers using three waterborne pathogen indicator organisms: E. coli, MS2-phage and Cryptosporidium parvum oocysts

Efficacy and safety of FOLFIRI/Aflibercept (FA) in an elderly population with metastatic colorectal cancer (mCRC) after the failure of an oxaliplatin-based regimen

Introduction: Aflibercept (ziv-aflibercept) significantly improves progression-free (PFS) and overall survival (OS) when added to FOLFIRI, compared with FOLFIRI alone, in the overall population of patients pretreated with oxaliplatin-based therapy. A subset analysis of elderly patients included in the registration VELOUR trial suggested that elderly (> 65 years) patients have a consistent, albeit small benefit in OS in PFS and a higher percentage of grade 3-4 toxicity. Our hypothesis was that selected patients with good PS could benefit from FOLFIRI-aflibercept (FA), provided they underwent careful monitoring of toxicity, and rapid intervention. Methods: We conducted a retrospective, multicentre, observational study of elderly patients (> 70 years) with mCRC treated with FOLFIRI-aflibercept after progression on an oxaliplatin-based regimen as part of routine clinical practice at seven hospitals from the Galician Research Group on Digestive Tumours (GITuD). Results: Of 315 patients treated with FA between June 2013 to November 2018, 71 elderly patients were recorded in this study. Median age was 72.7 years (range 70-84 years) and 33.4% were over 75 years (compared with only 14% in the VELOUR study subanalysis), 66.2 % were male, 83.1 % ECOG PS0-1, 43.7 % left-sided location, 76.1 % low grade, 63.4% RASmt and 2.8% BRAFmt, 66.2 % synchronous presentation and 77.5 % primary tumor resection. Prior therapy included bevacizumab (57.7%) and anti-EGFR agents (22.5%). Median of FA cycles was 9 (range 1-35 cycles). Overall Response Rate (ORR) and disease control rate (DCR) were 31.0 % and 63.4 %, respectively. With a median follow up of 27.1 months, median PFS was 6.6 months (95% CI, 5.0-8.3 months) and median OS was 15.1 months (95% CI, 12.1-18.1 months). The most common grade 3-4 toxicities were asthenia (18.3%), neutropenia (15.5%), diarrhoea (11.3%) and mucositis (9.9%). Aflibercept most common grade 3-4 related toxicities were hypertension (5.6%), dysphonia (5.6%), proteinuria (2.8%). Two patients experienced grade 5 toxicity (1 cerebrovascular event and 1 bowel perforation). This toxicity was managed with dose reduction of aflibercept in 39.4 % of cases, dose reduction of FOLFIRI on 57.7% and led to the discontinuation of aflibercept in 39.4%. Conclusion: Older patients with mCRC are underrepresented in clinical trials. The VELOUR study included only 6.4% patients over 65 years of age and only 14% of those over 65 were 75 years or older. Elderly patients treated with FA in the VELOUR trial experienced a higher rate of G3-4 adverse events (89.3% versus 80.5%) but this increase in toxicity was even more evident in the control arm (67.4% versus 59.4%). Our series confirms that with careful dose adjustment based on toxicity, including dose interruption if necessary elderly patients can be treated with FA with a 49.3% of grade 3-4 toxicity a PFS of 6.6 months and OS of 15.1 months, results that are comparable to those of younger patients

Zolmitriptan: A Novel Portal Hypotensive Agent Which Synergizes with Propranolol in Lowering Portal Pressure

Objective: Only a limited proportion of patients needing pharmacological control of portal hypertension are hemodynamic responders to propranolol. Here we analyzed the effects of zolmitriptan on portal pressure and its potential interaction with propranolol. Methods: Zolmitriptan, propranolol or both were tested in two rat models of portal hypertension: common bile duct ligation (CBDL) and CCl4-induced cirrhosis. In these animals we measured different hemodynamic parameters including portal venous pressure, arterial renal flow, portal blood flow and cardiac output. We also studied the changes in superior mesenteric artery perfusion pressure and in arterial wall cAMP levels induced by zolmitriptan, propranolol or both. Moreover, we determined the effect of splanchnic sympathectomy on the response of PVP to zolmitriptan. Results: In both models of portal hypertension zolmitriptan induced a dose-dependent transient descent of portal pressure accompanied by reduction of portal flow with only slight decrease in renal flow. In cirrhotic rats, splanchnic sympathectomy intensified and prolonged zolmitriptan-induced portal pressure descent. Also, propranolol caused more intense and durable portal pressure fall when combined with zolmitriptan. Mesenteric artery perfusion pressure peaked for about 1 min upon zolmitriptan administration but showed no change with propranolol. However propranolol enhanced and prolonged the elevation in mesenteric artery perfusion pressure induced by zolmitriptan. In vitro studies showed that propranolol prevented the inhibitory effects of b2-agonists on zolmitriptan-induced vasoconstriction and the combination of propranolol and zolmitriptan significantly reduced the elevation of cAMP caused by b2-agonists. Conclusion: Zolmitriptan reduces portal hypertension and non-selective beta-blockers can improve this effect. Combinati

The Current Molecular Epidemiological Scenario of Cryptosporidium, Giardia and Blastocystis in Spain. Implication for Public Health

The enteric protozoan parasites Cryptosporidium spp. and Giardia duodenalis are major contributors to the burden of gastrointestinal diseases globally. Both pathogens primarily affect children living in resource-poor settings with limited or no access to clean water and sanitation facilities, but are also significant public health threats in developed countries. Additionally, Cryptosporidium spp. and G. duodenalis are common causes of waterborne and foodborne outbreaks of gastrointestinal disease globally. Besides, the Stramenopile Blastocystis sp. is the most common eukaryotic organism reported in the human gut. Although its pathogenicity is a topic of debate, there is increasing evidence demonstrating that this protist can be associated with gastrointestinal disorders (diarrhoea, irritable bowel syndrome) and extra-intestinal manifestations, including urticaria. Because Cryptosporidium spp., G. duodenalis and Blastocystis sp. share the same transmission (faecal-oral) route, are able to infect a wide range of animal species other than humans with variable host specificities, and their infective forms are environmentally resilient, the study of these pathogens should be ideally approached under the One Health umbrella. In this context, molecular-based methods including PCR and sequencing provide powerful tools to investigate the epidemiology and transmission of these parasites. In Spain, cryptosporidiosis and giardiosis, but not blastocystosis, are notifiable diseases. However, the true incidence of these infections remain largely unknown because underdiagnosing and underreporting. Symptomatic cryptosporidiosis and giardiosis disproportionally affect children under four years of age, but we know now that subclinical infections are also common in apparently healthy individuals of all age groups. However, molecular data regarding the frequency and diversity of these pathogens are limited and spatially and temporally discontinuous. This chapter aims to provide, from a public veterinary health perspective, an updated account on the epidemiology of Cryptosporidium, G. duodenalis and Blastocystis in Spain, with an emphasis on the description of the species/genotypes circulating in symptomatic and asymptomatic human populations. Current knowledge on the presence of these pathogens in production (livestock), companion (dogs and cats) and wildlife animal species is also discussed, including their potential role as natural reservoirs of human infections, and the available evidence of zoonotic (and anthroponotic) transmission events.Research summarized in this chapter and conducted at the Spanish National Centre for Microbiology was funded by the Health Institute Carlos III (ISCIII), Ministry of Economy and Competitiveness (Spain), under projects CP12/03081 and PI16CIII/00024. The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.S