ABIDE: an accurate predictive model of liver decompensation in patients with non-alcoholic fatty liver-related cirrhosis. Calzadilla-Bertot L, Vilar-Gómez E, Wai-Sun Wong V, Romero-Gómez M, Aller-de la Fuente R, Lai-Hung Wong G, et al. Hepatology. 2020 Sep 25. DOI: 10.1002/hep.31576. Online ahead of print.

Non-alcoholic fatty liver disease (NAFLD) is an increasingly important cause of liver cirrhosis and subsequent complications. We retrospectively developed and validated a model to predict hepatic decompensation in NAFLD patients with cirrhosis and compared this with currently available models. Baseline variables from an international cohort of 299 biopsy-proven NAFLD patients with compensated cirrhosis were examined to construct a model using competing risk multivariate regression and Akaike/Bayesian information criteria. Validation was performed in 244 biopsy-proven NAFLD cirrhosis patients from the United States. Prognostic accuracy was compared with the NAFLD Fibrosis score (NFS), FIB-4, MELD , Child-Turcotte-Pugh (CTP) and ALBI-FIB-4 score using time-dependent area under the curve (tAUC) analysis. During a median follow-up of 5.6 years (range 2.4-14.1) and 5.4 years (range 1.5-13.8), hepatic decompensation occurred in 81 and 132 patients in the derivation and validation cohorts respectively. In the derivation cohort, independent predictors of hepatic decompensation (AST/ALT ratio, Bilirubin, International normalized ratio, type 2 Diabetes and OEsophageal varices) were combined into the ABIDE model. Subjects with a score ≥4.1 compared to those with a score <4.1, had a higher risk of decompensation (sHR 6.7, 95% CI 4.0-11.2, p<0.001), a greater five-year cumulative incidence (37% versus 6%, p<0.001) and shorter mean duration to decompensation (3.8 vs 6.7 years, p<0.001). The accuracy of the ABIDE model at 5 years was good in the derivation (tAUC 0.80, 95% CI 0.73-0.84) and validation cohorts (0.78, 95% CI 0.74-0.81) and was significantly more accurate than the NFS (0.72), FIB-4 (0.74), MELD (0.69), CTP (0.72) and ALBI-FIB-4 (0.73) (all p<0.001). CONCLUSIONS: In NAFLD patients with compensated cirrhosis, ABIDE, a predictive model of routine clinical measures predicts future hepatic decompensation.

Alcohol drinking and head and neck cancer risk: the joint effect of intensity and duration. Gioia Di Credico, Jerry Polesel, Luigino Dal Maso, Francesco Pauli, Nicola Torelli, Daniele Luce, et al. Br J Cancer. 2020 Aug 24. DOI: 10.1038/s41416-020-01031-z. Online ahead of print.

Background Alcohol is a well-established risk factor for head and neck cancer (HNC). This study aims to explore the effect of alcohol intensity and duration, as joint continuous exposures, on HNC risk. Methods Data from 26 case-control studies in the INHANCE Consortium were used, including never and current drinkers who drunk ≤10 drinks/day for ≤54 years (24234 controls, 4085 oral cavity, 3359 oropharyngeal, 983 hypopharyngeal and 3340 laryngeal cancers). The dose-response relationship between the risk and the joint exposure to drinking intensity and duration was investigated through bivariate regression spline models, adjusting for potential confounders, including tobacco smoking. Results For all subsites, cancer risk steeply increased with increasing drinks/day, with no appreciable threshold effect at lower intensities. For each intensity level, the risk of oral cavity, hypopharyngeal and laryngeal cancers did not vary according to years of drinking, suggesting no effect of duration. For oropharyngeal cancer, the risk increased with durations up to 28 years, flattening thereafter. The risk peaked at the higher levels of intensity and duration for all subsites (odds ratio = 7.95 for oral cavity, 12.86 for oropharynx, 24.96 for hypopharynx and 6.60 for larynx). Conclusions Present results further encourage the reduction of alcohol intensity to mitigate HNC risk.

A Quantitative EEG Toolbox for the MNI Neuroinformatics Ecosystem: Normative SPM of EEG Source Spectra. Bosch-Bayard J, Aubert-Vazquez E, Brown ST, Rogers C, Kiar G, Glatard T, et al. Front Neuroinform. 2020 Aug 7;14:33. DOI: 10.3389/fninf.2020.00033.

The Tomographic Quantitative Electroencephalography (qEEGt) toolbox is integrated with the Montreal Neurological Institute (MNI) Neuroinformatics Ecosystem as a docker into the Canadian Brain Imaging Research Platform (CBRAIN). qEEGt produces age-corrected normative Statistical Parametric Maps of EEG log source spectra testing compliance to a normative database. This toolbox was developed at the Cuban Neuroscience Center as part of the first wave of the Cuban Human Brain Mapping Project (CHBMP) and has been validated and used in different health systems for several decades. Incorporation into the MNI ecosystem now provides CBRAIN registered users access to its full functionality and is accompanied by a public release of the source code on GitHub and Zenodo repositories. Among other features are the calculation of EEG scalp spectra and the estimation of their source spectra using the Variable Resolution Electrical Tomography (VARETA) source imaging. Crucially, this is completed by the evaluation of z spectra by means of the built-in age regression equations obtained from the CHBMP database (ages 5-87) to provide normative Statistical Parametric Mapping of EEG log source spectra. Different scalp and source visualization tools are also provided for evaluation of individual subjects prior to further post-processing. Openly releasing this software in the CBRAIN platform will facilitate the use of standardized qEEGt methods in different research and clinical settings. An updated precis of the methods is provided in Appendix I as a reference for the toolbox. qEEGt/CBRAIN is the first installment of instruments developed by the neuroinformatic platform of the Cuba-Canada-China (CCC) project.

Assessment of the clinical utility of pharmacogenetic guidance in a comprehensive medication management service. Rodríguez-Escudero I, Cedeño JA, Rodríguez-Nazario I, Reynaldo-Fernández G, Rodríguez-Vera L, Morales N, et al. J Am Coll Clin Pharm. 2020 Sep;3(6):1028–37. DOI: 10.1002/jac5.1250. Epub 2020 May 2.

Introduction Pharmacists are poised to be the health care professionals best suited to provide medication-reated consults and services based on a patient’s genetics. Despite its potential benefits, the implementation of pharmacogenetic (PGx) testing into primary clinical settings has been slow among medically underserved populations. To our knowledge, this is the first time that PGx-driven recommendations have been incorporated into a Comprehensive Medication Management (CMM) service in a Hispanic population. Objectives The aim of this study is to evaluate the clinical utility of adding PGx guidance into pharmacist-driven CMM. Methods This is a pre- and post-interventional design study. Patients were recruited from a psychologist’s clinic. A total of 24 patients had a face-to-face interview with a pharmacist to complete a CMM, Personal Medication Record, and Medication-Related Action Plan (MAP) blind to PGx findings. Collected buccal DNA samples were genotyped using drug-metabolizing enzymes and transporters (DMET) Plus Array. Results The pharmacist generated new MAPs for each patient based on PGx results. Genetic variants that could potentially affect the safety and effectiveness of at least one drug in the pharmacotherapy were identified in 96% of patients, for whom the pharmacist changed the initial recommendations. Polymorphisms in genes encoding for isoenzymes CYP2D6, CYP2C19, and CYP2C9 were identified in 83%, 52%, and 41% of patients, respectively. Pharmacists performing CMM identified 22 additional medication problems after PGx determinations. Moreover, they agreed with the clinical utility of PGx in the studied sample based on perceived value of adding PGx to traditional CMM and its utility in the decision-making process of pharmacists. Conclusions The study confirmed the critical role to be played by pharmacists in facilitating the clinical usage of relevant genetic information to optimize drug therapy decisions as well as their involvement on many levels of these multidisciplinary implementation efforts, including championing and leading PGx-guided CMM services.

Bestatin and bacitracin inhibit porcine kidney cortex dipeptidyl peptidase IV activity and reduce human melanoma MeWo cell viability. Rivera Méndez L, Arrebola Y, Valdés-Tresanco ME, Díaz-Guevara L, Bergado G, Sánchez B, et al. Int J Biol Macromol. 2020 Aug 23;S0141-8130(20)34249-5.  DOI: 10.1016/j.ijbiomac.2020.08.157. Online ahead of print.

Bestatin and bacitracin are inhibitors of metallo aminopeptidases and bacterial proteases. However, their effects on other human peptidases, like dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5) are not established. Inhibitors of DPP-IV activity are used for treating type 2 diabetes mellitus, cancers and immune system diseases. Bacitracin and bestatin inhibited porcine membrane-bound DPP-IV (pDPP-IV) activity. Mechanisms were different, i.e. non-competitive with α > 1 (α = 3.93) and K_i value of 75 μM for bestatin, and competitive with K_i value of 630 μM for bacitracin. The binding mode in the tertiary complex enzyme:substrate:bestatin suggested the structural basis of the inhibitory effect and that bestatin is potentially selective for DPP-IV, ineffective vs. S9 family members dipeptidyl peptidase 8/9 and fibroblast activation protein. In the human melanoma MeWo cell line, bestatin and bacitracin inhibited aminopeptidase N (APN) and DPP-IV activities, reduced cell viability and increased DNA fragmentation, suggesting induction of apoptosis. Since bacitracin and bestatin are already marketed drugs, studying in depth the molecular mechanisms underlying their effects on melanoma cells is warranted. Additionally, bestatin emerges as a new lead compound for the development of DPP-IV inhibitors, and a promising dual APN/DPP-IV inhibitor for the treatment of pathologies in which both enzymes are upregulated.

Dengue virus 4: the “black sheep” of the family? Lazo L.  Expert Rev Vaccines. 2020 Aug 27. DOI: 10.1080/14760584.2020.1813578. Online ahead of print.

Introduction The induction of a functional immune response against the four viral serotypes is one of the premises for an effective vaccine against Dengue virus. This is challenging since the immunization with four antigens leads to immunologic phenomena such as antigen interference, immuno-dominance and tolerance. Moreover, the four serotypes have intrinsic features which impact the outcome after the immunization with a tetravalent formulation. Areas covered This work reviews the main studies evidencing the differences between Dengue virus 4 and the rest of the serotypes. We address some peculiarities of this virus and discuss which factors could explain the heterogeneous response achieved after the immune evaluation of tetravalent formulations. Expert Opinion The low immunogenicity associated to serotype 4 could slow down the development of a vaccine against Dengue virus. Achieving similar levels of neutralizing antibodies against the four serotypes has been the goal of many vaccine developers. However, this does not need to be seen as a mandatory dogma. High levels of efficacy against Dengue virus 4 could be reached even if it shows the lowest neutralizing antibody titers among the viral complex. Studies on the efficacy of vaccines, currently in phase III clinical trials, should shed light on this concern in the near future.

Detection of a non-erythropoietic EPO, Neuro-EPO, in blood after intra-nasal administration in rat. Martin L, García Rodríguez JC, Audran M, Ericsson M, Maurice T, Marchand A. Drug Test Anal. 2020 Aug 27. DOI: 10.1002/dta.2924. Online ahead of print.

Non-erythropoietic erythropoietin (EPO) are investigated for their high anti-oxidant properties. A new drug candidate under clinical investigation to treat brain diseases is Neuro-EPO, produced by selecting EPO isoforms with low sialic acid content. Intra-nasal administration allows to bypass the blood-brain barrier to get a fast and concentrated delivery to the brain. The aims of this project were to characterize Neuro-EPO with anti-doping methods used to detect conventional recombinant EPOs (IEF and SDS-PAGE) and to evaluate the window of detection of Neuro-EPO in brain and blood (plasma) after a single intranasal administration in rats. Neuro-EPO drug analyzed by IEF-PAGE presented a very basic profile completely detected only when using a 2-8 o 2-10 pH gradient instead of the conventional 2-6 pH gradient. Its profile consisted in 6 main bands that did not interfere with endogenous EPO profile from human or rat. After SDS-PAGE, a broad band was detected for Neuro-EPO in the same area as endogenous EPO, making Neuro-EPO identification very difficult by this approach. Therefore, IEF was the method for identification chosen after administration in rats. Neuro-EPO was clearly identified in blood 2h and 6h after the delivery. Fainter signals were obtained between 12h and 48 h, but some characteristic very basic bands remained detectable. Surprisingly, brain extracts did not show the presence of Neuro-EPO even 2 hours after administration, indicating a fast degradation or elimination from the brain to the bloodstream. This experiment indicated that detection of Neuro-EPO after intranasal delivery should be possible for a few days.

Healing at implants installed in osteotomies prepared either with a piezoelectric device or drills: an experimental study in dogs. Fujiwara S, Kato S, Bengazi F, Urbizo Velez J, Tumedei M, Kotsu M, et al. Oral Maxillofac Surg. 2020 Aug 15. DOI: 10.1007/s10006-020-00895-y. Online ahead of print.

Objective To compare osseointegration and marginal bone level at implants placed in osteotomies prepared with either conventional drills or a piezoelectric device. Material and methods Three months after the extraction of all mandibular premolars and first molars, two recipient sites were selected. The osteotomies were randomly prepared with either conventional drills (drill sites) or a piezoelectric device (piezoelectric sites). Implants were installed and a submerged healing was allowed. The animals were euthanized in groups of six after 4 and 8 weeks of healing. Biopsies were obtained for histological preparation. Coronal level of osseointegration (bone level) and bone-to-implant contact percentage (BIC%) were evaluated. Results After 4 weeks of healing, the bone level was 0.6 ± 0.9 mm for the piezoelectric sites and 1.6 ± 0.7 mm for the drill sites (p = 0.173). After 8 weeks, the respective measures were 0.9 ± 0.3 mm and 1.0 ± 1.1 mm (p = 0.917). After 4 weeks of healing, a new bone apposed onto the implant surface was found at fractions of 54.9 ± 6.7% and 55.1 ± 16.6% for the piezoelectric and the drill sites, respectively (p = 0.674). The respective total bone fractions, including new and old bone, was 64.0 ± 4.8% and 63.4 ± 20.4% (p = 0.917). After 8 weeks, a new bone increased to 67.4 ± 6.7% and 62.9 ± 12.5% for the piezoelectric and the drill sites, respectively (p = 0.463). The respective total bone fractions were 70.4 ± 5.5% and 67.8 ± 12.1% (p = 0.753). Conclusions The use of a piezoelectric device for implant site preparation is a safe procedure that allows a proper integration since the early periods of healing similar to that observed using conventional drills.

Helicobacter pylori infection in children. Aguilera Matos I, Díaz Oliva SE, Escobedo AA, Villa Jiménez OM, Velazco Villaurrutia YC. BMJ Paediatr Open. 2020 Aug 3;4(1):e000679.
DOI: 10.1136/bmjpo-2020-000679.

Helicobacter pylori infection affects more than half of the world population and it occurs generally in childhood. It is associated with gastroduodenal ulcer, gastric atrophy, intestinal metaplasia, gastric adenocarcinoma and lymphoid tissue-associated lymphoma. It is difficult to eradicate this bacterium due to its high antimicrobial resistance. In children, the infection is asymptomatic in the majority of cases and complications are less common. Probable inverse relationships with allergic diseases and inflammatory bowel diseases are being studied. These reasons mean that the decision to diagnose and treat the infection in children is only considered in specific circumstances in which it provides true benefits. This review focuses on some current considerations regarding epidemiology, diagnosis and treatment of childhood infection, emphasising outcomes and treatment schemes in children.

Identifying predictive biomarkers of CIMAvaxEGF success in non-small cell lung cancer patients. Lorenzo-Luaces P, Sánchez L, Saavedra D, Crombet T, Van der Elst W, Alonso A. BMC Cancer. 2020 Aug 17;20(1):772. DOI: 10.1186/s12885-020-07284-4.

Background Immunosenescence biomarkers and peripheral blood parameters are evaluated separately as possible predictive markers of immunotherapy. Here, we illustrate the use of a causal inference model to identify predictive biomarkers of CIMAvaxEGF success in the treatment of Non-Small Cell Lung Cancer Patients. Methods Data from a controlled clinical trial evaluating the effect of CIMAvax-EGF were analyzed retrospectively, following a causal inference approach. Pre-treatment potential predictive biomarkers included basal serum EGF concentration, peripheral blood parameters and immunosenescence biomarkers. The proportion of CD8 + CD28- T cells, CD4+ and CD8+ T cells, CD4/CD8 ratio and CD19+ B cells. The 33 patients with complete information were included. The predictive causal information (PCI) was calculated for all possible models. The model with a minimum number of predictors, but with high prediction accuracy (PCI > 0.7) was selected. Good, rare and poor responder patients were identified using the predictive probability of treatment success. Results The mean of PCI increased from 0.486, when only one predictor is considered, to 0.98 using the multivariate approach with all predictors. The model considering the proportion of CD4+ T cell, basal Epidermal Growth Factor (EGF) concentration, neutrophil to lymphocyte ratio, Monocytes, and Neutrophils as predictors were selected (PCI > 0.74). Patients predicted as good responders according to the pre-treatment biomarkers values treated with CIMAvax-EGF had a significant higher observed survival compared with the control group (p = 0.03). No difference was observed for bad responders. Conclusions Peripheral blood parameters and immunosenescence biomarkers together with basal EGF concentration in serum resulted in good predictors of the CIMAvax-EGF success in advanced NSCLC. Future research should explore molecular and genetic profile as biomarkers for CIMAvax-EGF and it combination with immune-checkpoint inhibitors. The study illustrates the application of a new methodology, based on causal inference, to evaluate multivariate pre-treatment predictors. The multivariate approach allows realistic predictions of the clinical benefit of patients and should be introduced in daily clinical practice.

Issues and recommendations from the OHBM COBIDAS MEEG committee for reproducible EEG and MEG research. Pernet C, Garrido MI, Gramfort A, Maurits N, Michel CM, Pang E, et al. Nat Neurosci. 2020 Sep 21. DOI: 10.1038/s41593-020-00709-0. Online ahead of print.

The Organization for Human Brain Mapping (OHBM) has been active in advocating for the instantiation of best practices in neuroimaging data acquisition, analysis, reporting and sharing of both data and analysis code to deal with issues in science related to reproducibility and replicability. Here we summarize recommendations for such practices in magnetoencephalographic (MEG) and electroencephalographic (EEG) research, recently developed by the OHBM neuroimaging community known by the abbreviated name of COBIDAS MEEG. We discuss the rationale for the guidelines and their general content, which encompass many topics under active discussion in the field. We highlight future opportunities and challenges to maximizing the sharing and exploitation of MEG and EEG data, and we also discuss how this ‘living’ set of guidelines will evolve to continually address new developments in neurophysiological assessment methods and multimodal integration of neurophysiological data with other data types.

Oesophageal eosinophilia and oesophageal diseases in children: are the limits clear? Díaz-Oliva SE, Aguilera-Matos I, Villa Jiménez OM, Escobedo AA. BMJ Paediatr Open. 2020 Aug 4;4(1):e000680. DOI: 10.1136/bmjpo-2020-000680.

Gastro-oesophageal reflux disease, eosinophilic oesophagitis and oesophageal motility disorders are among the most common diseases accompanying oesophageal eosinophilia. They have similarities and their limits are frequently not well defined. This article reviews the main characteristics relating to their similarities and differences, highlighting existing controversies among these diseases, in addition to current knowledge. In the case of a patient with symptoms of oesophageal dysfunction, it is suggested to carry out an integral analysis of the clinical features and diagnostic test results, including histology, while individualising each case before confirming a definitive diagnosis. Future investigation in paediatric patients is necessary to assess eosinophilic infiltration in the various layers of the oesophageal tissue, along with its clinical and pathophysiological implications.

Serum Immunoglobulin Levels, Complement Components 3 and 4, HLA-B27 Allele and Spondyloarthropathy in Patients with Non-Infectious Anterior Uveites. Torres Rives B, Martínez Téllez G, Mataran Valdés M, Collazo Mesa T, Colás González R, Frutos Ambou I. Reumatol Clin. 2020 Sep 2;S1699-258X(20)30191-1. DOI: 10.1016/j.reuma.2020.07.007. Online ahead of print.

Objective To identify the relationship between serum immunoglobulin levels, complement components 3 and 4, the presence of the HLA-B27 allele and diagnosis of spondyloarthropathies in patients with non-infectious anterior uveitis. Materials and methods The participants were 197 patients with a non-infectious anterior uveitis. The concentrations of serum immunoglobulins, and C3 and C4 proteins of the complement were determined by turbidimetry. The personal history of suspected immunodeficiency, ophthalmological complications, arthralgia, family history of spondyloarthropathies and the presence of the HLA-B27 allele were collected. Results A family history of spondyloarthropathy, axial arthralgias, and ophthalmological complications were more frequent in HLA-B27 positive patients (P=.0005, P≤.0001, and P≤.0001, respectively) and in patients with spondyloarthropathy diagnoses (P≤.0001, P≤.0001, and P≤.0001, respectively). A personal history of recurrent sepsis, and gastrointestinal abnormalities was associated with the presence of the HLA-B27 allele (P≤.0001, and P=.0240, respectively) and with the diagnosis of spondyloarthropathy (P=.0492, and P=.0017, respectively). IgG decrease was observed (χ2=18.5, OR 5.03, 95% CI 2.32-10.89; P=.0001) and IgM (OR 7.13, 95% CI 1.40-36.4; P=.0128) in patients positive for the HLA-B27 allele and in patients with a diagnosis of spondyloarthropathies (P=.0364 and P=.0028, respectively). The decrease of C3 proteins (OR 4.82; CI 95% 1.35-17.11; P=.0328) and C4 (OR 9.09; CI 95% 2.13-38.88; P=.0074) were associated with a spondyloarthropathies diagnosis. Conclusions Patients with non-infectious anterior uveitis, positive for the HLA-B27 allele and diagnosed with spondyloarthropathies have alterations in serum immunoglobulin levels and complement components 3 and 4, which could contribute to the perpetuation and worse clinical course of this disease.

Study of longitudinal myocardial deformation in patients with ischemic cardiopathy. Pérez-Barreda A, Román-Fernández I, Peix-González A, Rodríguez-Navarro AY, Alfonso-Montero OA, Adrián Naranjo-Domínguez. Arch Cardiol Mex. 2020;90(3):300–8.
DOI: 10.24875/ACM.20000290.

Introduction Cardiovascular diseases are the leading cause of death in Cuba and most of the developed countries. Two-dimensional speckle tracking echocardiography (2D ST) is a recent technique in the evaluation of cardiac function. Objectives To determine the relationship between myocardial deformation measured by 2D ST and coronary circulation in patients with ischemic heart disease, in the CIMEQ, for 1 year. Material and method An analytical, cross-sectional study was carried out with 55 patients with an indication for coronary angiography who underwent 2D echocardiography and 2D ST study with longitudinal strain measurement (LSM). Two groups significant coronary disease (SCD = 32) and not significant (NSCD = 23) were created. SSPS was used to analyze the results. Results The average age was higher in SCD (55.6 ± 9.3 vs. 61.8 ± 8.8, p = 0.014). Men with SCD (47.3%), hypertensive (SCD = 90.6% and NSCD = 65.2%, p = 0.02) and smokers (SCD = 59.4% and NSCD = 17.4%, p = 0.002) predominated. The most frequent diagnosis was chronic stable angina (87%). Three-vessel disease (75%) prevailed in SCD. The LMS was lower in SCD ([−20.0 ± 3.2 vs. −22.1 ± 3.6, p = 0.035]; AUC = 0.458). There were no differences in LSM according to the number of significantly diseased vessels. Conclusions The results found do not justify the use of 2D ST to discriminate SCD.

Sudden intra-hospital death after acute myocardial infarction in Cuba in the last three years. Analysis of institutional records. Rodríguez-Ramos MA, Santos-Medina M. Arch Cardiol Mex. 2020;90(3):341–6. DOI: 10.24875/ACM.20000008.

Objective To analyze possible predisposing causes of in hospital sudden cardiac death (SCD) after an acute myocardial infarction (IMA) in Cuban registries. Material and methods A search of clinical records of patients with IMA in Cuba was performed in the databases of national journals, Scientific Library On-line and Medline. Those articles published since 2016 were prioritized for inclusion. Sudden death is defined as that secondary to malignant ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation) as well as patients with cardiac rupture with pulseless electrical activity or asystole as a form of presentation. Subsequently, the relationship of this parameter with the occurrence of sudden death was evaluated in 710 patients from the Registry of Acute Coronary Syndromes (RESCUE). Results In the out-of-hospital setting, more than half of SCD are secondary to an IMA. Once in the hospital, mortality in Cuba from IMA is homogeneous. Only centers with coronary interventionism escape this phenomenon. Although not totally lethal, the presence of malignant ventricular arrhythmias is associated with a worse prognosis and its prevalence is not homogeneous in the reviewed records. Conclusions Sudden death after IMA will continue to be one of the main causes of death of patients in the acute phase in Cuba.

Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase Inhibitor. Romaniello D, Marrocco I, Belugali Nataraj N, Ferrer I, Drago-García D, Vaknin I, et al. Cancers (Basel). 2020 Aug 24;12(9):E2394. DOI: 10.3390/cancers12092394.

Although two growth factor receptors, EGFR and HER2, are amongst the best targets for cancer treatment, no agents targeting HER3, their kinase-defective family member, have so far been approved. Because emergence of resistance of lung tumors to EGFR kinase inhibitors (EGFRi) associates with compensatory up-regulation of HER3 and several secreted forms, we anticipated that blocking HER3 would prevent resistance. As demonstrated herein, a neutralizing anti-HER3 antibody we generated can clear HER3 from the cell surface, as well as reduce HER3 cleavage by ADAM10, a surface metalloproteinase. When combined with a kinase inhibitor and an anti-EGFR antibody, the antibody completely blocked patient-derived xenograft models that acquired resistance to EGFRi. We found that the underlying mechanism involves posttranslational down regulation of HER3, suppression of MET and AXL up regulation, as well as concomitant inhibition of AKT signaling and up regulation of BIM, which mediates apoptosis. Thus, although HER3 is nearly devoid of kinase activity, it can still serve as an effective drug target in the context of acquired resistance. Because this study simulated in animals the situation of patients who develop resistance to EGFRi and remain with no obvious treatment options, the observations presented herein may warrant clinical testing.

Therapeutic Effectiveness of Interferon-α2b Against COVID-19: The Cuban Experience. Pereda R, González D, Blas Rivero H, Rivero JC, Pérez A, López LR, et al. J Interferon Cytokine Res. 2020 Sep;40(9):438–42. DOI: 10.1089/jir.2020.0124.

A prospective observational study was conducted for assessing the therapeutic efficacy of interferon (IFN)-α2b in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the first month after the coronavirus disease 2019 (COVID-19) outbreak began in Cuba. From March 11th to April 14th, 814 patients were confirmed SARS-CoV-2 positive in Cuba. Seven hundred sixty-one (93.4%) were treated with a combination of oral antivirals (lopinavir/ritonavir and chloroquine) with intramuscular administration of IFN-α2b (Heberon^® Alpha R, Center for Genetic Engineering and Biotechnology, Havana, Cuba), 3 times per week, for 2 weeks. Fifty-three patients received the approved COVID protocol without IFN treatment. The proportion of patients discharged from hospital (without clinical and radiological symptoms and nondetectable virus by real-time polymerase chain reaction) was higher in the IFN-treated compared with the non-IFN treated group (95.4% vs. 26.1%, P < 0.01). The case fatality rate (CFR) for all patients was 2.95%, and for those patients who received IFN-α2b the CFR was reduced to 0.92. Intensive care was required for 82 patients (10.1%), 42 (5.5%) had been treated with IFN. This report provides preliminary evidence for the therapeutic effectiveness of IFN-α2b for COVID-19 and suggests that the use of Heberon Alpha R may contribute to complete recovery of patients.