A Cerberus-Inspired Anti-Infective Multicomponent Gatekeeper Hydrogel against Infections with the Emerging “Superbug” Yeast Candida auris. Kubiczek D, Flaig C, Raber H, Dietz S, Kissmann AK, Heerde T, et al. Macromol Biosci. 2020 Apr;20(4):e2000005.
The pathogenic yeast Candida auris has received increasing attention due to its ability to cause fatal infections, its resistance toward important fungicides, and its ability to persist on surfaces including medical devices in hospitals. To brace health care systems for this considerable risk, alternative therapeutic approaches such as antifungal peptides are urgently needed. In clinical wound care, a significant focus has been directed toward novel surgical (wound) dressings as first defense lines against C. auris. Inspired by Cerberus the Greek mythological “hound of Hades” that prevents the living from entering and the dead from leaving hell, the preparation of a gatekeeper hybrid hydrogel is reported featuring lectin-mediated high-affinity immobilization of C. auris cells from a collagen gel as a model substratum in combination with a release of an antifungal peptide drug to kill the trapped cells. The vision is an efficient and safe two-layer medical composite hydrogel for the treatment of severe wound infections that typically occur in hospitals. Providing this new armament to the repertoire of possibilities for wound care in critical (intensive care) units may open new routes to shield and defend patients from infections and clinical facilities from spreading and invasion of C. auris and probably other fungal pathogens.
Acute cocaine treatment enhances the antagonistic allosteric adenosine A2A-dopamine D2 receptor-receptor interactions in rat dorsal striatum without increasing significantly extracellular dopamine levels. Romero-Fernández W, Zhou Z, Beggiato S, Wydra K, Filip M, Tanganelli S, et al. Pharmacol Rep. 2020 Apr;72(2):332–9.
Background Antagonistic adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) receptor-receptor interactions have previously been demonstrated in A2AR-D2R heteroreceptor complexes in the rat dorsal striatum. They mainly involve a reduction of affinity in the high-affinity component of the D2R agonist binding site upon activation in vivo of the A2AR by an A2AR agonist. Upon cocaine self-administration, this antagonistic A2AR-D2R interaction disappeared in the dorsal striatum. Methods In the current experiments, it was tested whether such modifications in the antagonistic A2AR-D2R receptor-receptor interactions can develop also after an acute systemic injection of a low cocaine dose (1 mg/kg; sc). Results Microdialysis experiments indicated that acute cocaine did not significantly alter the extracellular dopamine levels in the dorsal striatum of the awake Wistar rats. Competition dopamine receptor binding experiments demonstrated that in the acute cocaine group, the A2AR agonist CGS-21680 produced significantly larger increases in the D2R Ki, High values (reduction of high-affinity) versus the saline-injected (i.e. control) group. Furthermore, in the dorsal striatum membrane preparation from acute cocaine-injected rats, CGS-21680 also produced significant increases in the D2R Ki, Low values (reduction of low-affinity) and in the proportion of D2Rs in the high-affinity state (RH). Such significant effects were not observed with CGS-21680 in the control group. Conclusions The molecular mechanism involved in the acute cocaine-induced increase in the antagonistic allosteric A2AR-D2R receptor-receptor interactions may be an increased formation of higher-order complexes A2AR-D2R-sigma1R in which cocaine by binding to the sigma1R protomer also allosterically enhances the inhibitory A2AR-D2R interaction in this receptor complex.
Bone plate repositioned over the antrostomy after sinus floor elevation: an experimental study in sheep. Perini A, Ferrante G, Sivolella S, Velez JU, Bengazi F, Botticelli D. Int J Implant Dent. 2020 Mar 18;6(1):11. DOI: 10.1186/s40729-020-0207-1.
The objective of this study was to compare the healing of the augmented sinus at which the antrostomy was covered with a membrane or the repositioned bone plate. Eight sheep underwent bilateral maxillary sinus floor augmentation. The control site was covered with a resorbable membrane, while at the experimental site the bone plate was repositioned, and both were secured with cyanoacrylate. Animals were euthanised after 4 months and histomorphometric analysis was performed. A large amount of the graft appeared to be partially interpenetrated by the newly formed bone. Statistical analysis demonstrated different percentages of the new bone and bone interpenetrated to the graft between test and control site in the close-to-window area respectively 22.1 ± 12.6 vs 7.5 ± 4.5 (P = 0.028) and 66.1 ± 14.7 vs 44.2 ± 15.1 (P = 0.046). Other areas showed no difference in the bone and graft amount. More bone was found at the edges of the antrostomy in the experimental site, without statistical significance. In the centre of the antrostomy, the replaced bony window appeared bonded to the newly formed bone. No remnants and no biological response to cyanoacrylate were observed. The repositioning of the bony window after sinus floor elevation in sheep led to a larger amount of newly formed bone in the close-to-window zone of the grafted area. The bony window appeared partially bonded to the new bone. Newly formed bone was found interpenetrating the graft granules.
Characterization of aged male BALB/ccenp mice as a model of dementia. Esquivel N, García Y, Lores B, Gutiérrez M, Rodríguez C. Lab Anim Res. 2020 Mar 5;36:7. DOI: 10.1186/s42826-020-00038-0. eCollection 2020.
Dementia is defined as cognitive impairment in more than one cognitive area and leads to an abnormal degree of impairment in the ability to remember past events. Among mice models of dementia the most used strains are SAMP8 and C57BL/6. There is no reference to characterizing a model of dementia in naturally aged mice of the BALB/c strain, or to the minimum age at which these animals can be used. The aim of this study was the characterization of aged male BALB/ccenp mice as a model of dementia from the evaluation of behavioural, pathological and biochemical markers. One hundred and twenty mice were used and 10 of these were analysed from 8 to 9 months of age, and every 4 months, in a comparative way to young control animals from 4 to 5 months. At the age of 12-13 months there was cognitive impairment in the animals from the Y-maze and object recognition tests and this impairment was maintained at 16-17 months of age. An increase in oxidative damage to proteins in the brains of aged animals was also found in relation to young animals; as well as a decrease in the concentration of triglycerides. At the age of 16-17 months, a significant decrease in the size of the thymus and brain was obtained. We consider that it’s a very useful option to use animals 12-13 months of age where there are symptoms of cognitive deficiency, histopathological and biochemical elements characteristic of dementia.
Could myocardial viability be related to left ventricular dyssynchrony? Simultaneous evaluation by gated SPECT-MPI. Padrón K, Peix A, Cabrera L, Garcia J, Rodríguez L, Carrillo R, et al. J Nucl Cardiol. 2020 Apr 3. DOI: 10.1007/s12350-020-02047-x. [Epub ahead of print]
Background Left ventricular contraction dyssynchrony (LVCD) has been related to induced ischemia and transmural scar but the interplay of myocardial viability and dyssynchrony is unknown. The aim of the present study was to establish the role of dyssynchrony in the context of a viability study performed with nitrate augmentation gated single photon emission computed tomography (GSPECT) myocardial perfusion imaging (MPI). Methods Fifty-four consecutive patients with ischemic dilated cardiomyopathy (IDC) and depressed left ventricular ejection fraction (LVEF) were included. They underwent a two-day rest/nitroglycerine (NTG) study GSPECT MPI to determine the myocardial viability. Patients with a nitrate-induced uptake increase of > 10% vs baseline, in at least, two consecutive dysfunctional segments were considered viable as well as those who showed no improvement in the uptake but the uptake was > 50% on post NTG study. Patients with no nitrate-induced uptake increase of > 10% and the uptake of < 50% were considered non-viable. Perfusion, function and LVCD were compared in 25 viable patients vs 29 non-viable patients at baseline and after NTG administration. Results After NTG administration, in the viable group, the LVEF increased (36.44 ± 6.64% vs 39.84 ± 6.39%) and the end-systolic volume decreased significantly (119.28 ± 31.77 mL vs 109.08 ± 33.17 mL) (P < 0.01). These patients also experienced a significant reduction in the LVCD variables: phase standard deviation was reduced in the post NTG study (57.77° ± 19.47° vs 52.02° ± 17.09°) as well as the phase histogram bandwidth (190.20° ± 78.83° vs 178.0° ± 76.14°) (P < 0.05). Functional and LVCD variables remained similar in the non-viable patients (P > 0.05). Conclusion In patients with IDC and depressed LVEF, the myocardial viability detected by rest/ NTG GSPECT MPI, might determine LVCD improvement.
Effect of an ecosystem-centered community participation programme on the incidence of dengue. A field randomized, controlled trial. Newton-Sánchez OA, de la Cruz Ruiz M, Torres-Rojo Y, Ochoa-Díaz-López H, Delgado-Enciso I, Hernández-Suárez CM, et al. Int J Public Health. 2020 Mar 17. DOI: 10.1007/s00038-020-01345-y. [Epub ahead of print]
Objectives The purpose of this study is to analyse the effect of a community participation programme based on the ecosystem model on the incidence of dengue in urban communities. Methods A randomized controlled field trial was conducted in the state of Colima, Mexico. The intervention consisted of a community participation programme focused on the ecosystem; simultaneously, the control groups were communities that only received the usual official prevention programs. The incidence of dengue was estimated in people of both groups due to the appearance of de novo IgM antibodies during the follow-up period. Results The incidence of dengue in the intervened group was 2.58%/month (n = 818) and in control group 2.26%/month (n = 994), with a risk ratio of 1.14 (95% CI 0.89-1.45) and a PAF of 0.06 (95% CI - 0.056 to 0.16). The A. aegypti larval density (Breteau Index) was reduced in the treated group. Conclusions The implementation of a community participation programme in the cities of Colima, Mexico, showed a slightly counterproductive effect on the incidence of dengue. This happened even with a reduction in the A. aegypti index.
Effect of Type and Concentration of Nanoclay on the Mechanical and Physicochemical Properties of Bis-GMA/TTEGDMA Dental Resins. Encalada-Alayola JJ, Veranes-Pantoja Y, Uribe-Calderón JA, Cauich-Rodríguez JV, Cervantes-Uc JM. Polymers (Basel). 2020 Mar 6;12(3). pii: E601. DOI: 10.3390/polym12030601.
Bis-GMA/TTEGDMA-based resin composites were prepared with two different types of nanoclays: an organically modified laminar clay (Cloisite® 30B, montmorillonite, MMT) and microfibrous clay (palygorskite, PLG). Their physicochemical and mechanical properties were then determined. Both MMT and PLG nanoclays were added into monomer mixture (1:1 ratio) at different loading levels (0, 2, 4, 6, 8 and 10 wt.%), and the resulting composites were characterized by scanning electron microscopy (SEM), thermogravimetric analysis (TGA), dynamic mechanical analysis (DMA) and mechanical testing (bending and compressive properties). Thermal properties, depth of cure and water absorption were not greatly affected by the type of nanoclay, while the mechanical properties of dental resin composites depended on both the variety and concentration of nanoclay. In this regard, composites containing MMT displayed higher mechanical strength (both flexural and compression) than those resins prepared with PLG due to a poor nanoclay dispersion as revealed by SEM. Solubility of the composites was dependent not only on nanoclay-type but also the mineral concentration. Dental composites fulfilled the minimum depth cure and solubility criteria set by the ISO 4049 standard. In contrast, the minimum bending strength (50 MPa) established by the international standard was only satisfied by the dental resins containing MMT. Based on these results, composites containing either MMT or PLG (at low filler contents) are potentially suitable for use in dental restorative resins, although those prepared with MMT displayed better results.
Mobile application for the evaluation and planning of nursing workload in the intensive care unit. da Silva R, Baptista A, Serra RL, Magalhães DSF. Int J Med Inform. 2020 Mar 9;137:104120. DOI: 10.1016/j.ijmedinf.2020.104120. [Epub ahead of print]
Objective In this study, we present an application type software which employs the Nursing Activities Score (NAS), a management tool for measuring nursing workload prospectively. Method The system was developed in two modules: WEB (controlled from an Internet browser) for data administration using Java Script; and APP (operated from a smartphone or tablet device) for data acquisition using Hypertext Preprocessor (PHP). White and black box tests were performed in the software. Results A software was developed with an interface that allows the calculation of the scale score by the same professional who provided assistance, generating reports to help nursing management. The functional test was successfully performed using the Android operational system. Conclusion The efficiency of the software was demonstrated by the functional test and the main innovations brought herein are the prospective use and the generation of management reports, which can contribute positively by improving nursing quality and safety in the intensive care unit.
New Aspects of VEGF, GABA, and Glutamate Signaling in the Neocortex of Human Temporal Lobe Pharmacoresistant Epilepsy Revealed by RT-qPCR Arrays. Castro-Torres RD, Ureña-Guerrero ME, Morales-Chacón LM, Lorigados-Pedre L, Estupiñán-Díaz B, Rocha L, et al. J Mol Neurosci. 2020 Mar 6. DOI: 10.1007/s12031-020-01519-6. [Epub ahead of print]
In the epilepsy spectrum, temporal lobe epilepsy (TLE) is the most common and devastating focal and symptomatic epilepsy form in adults, where more than 30% of patients develop pharmacoresistance. It is not fully understood how the gene expression contributes to establishing an epileptic phenotype. Cerebrovascular remodeling directed by VEGF (vascular endothelial growth factor) signaling might modulate the synaptic neurotransmission in the epileptic brain. To address this question, the gene expression was profiled in biopsies of the temporal cortex from diagnosed patients with pharmacoresistant TLE that underwent surgical resection to seizure control. One hundred sixty-eight genes related to VEGF signaling and GABA and glutamate neurotransmissions were evaluated. Genes related to downstream signaling -phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinases (MAPK), and Janus-activated kinase/signal transducer and activator of transcription (JAK/STAT) pathways- and neurotransmitters metabolism were evaluated too. Thirty-nine genes were upregulated. The genes encoding for G protein q polypeptide, serine racemase, gephyrin, and glutamate/cystine antiporter system xCT appeared as novel upregulated genes in the pharmacoresistant TLE. ClueGO, a Cytoscape plugin, was used to build a gene network associated using Gene Ontology (GO) terminology. Enrichment analysis by ClueGO retrieves that positive regulation of endothelial cell proliferation, nerve development, and neuronal apoptosis were over-represented categories. In conclusion, VEGF signaling is confirmed as a relevant mediator in the pharmacoresistant TLE. In addition, the enrichment analysis applied to differentially expressed genes suggests new pharmacological targets to be assessed in the treatment of pharmacoresistant TLE. Results make up an approximation to better understand the epileptic brain and complement the available data.
Prediction of dementia risk in low-income and middle-income countries (the 10/66 Study): an independent external validation of existing models. Stephan BCM, Pakpahan E, Siervo M, Licher S, Muniz-Terrera G, Mohan D, et al. Lancet Glob Health. 2020 Apr;8(4):e524–e35.
Background To date, dementia prediction models have been exclusively developed and tested in high-income countries (HICs). However, most people with dementia live in low-income and middle-income countries (LMICs), where dementia risk prediction research is almost non-existent and the ability of current models to predict dementia is unknown. This study investigated whether dementia prediction models developed in HICs are applicable to LMICs. Methods Data were from the 10/66 Study. Individuals aged 65 years or older and without dementia at baseline were selected from China, Cuba, the Dominican Republic, Mexico, Peru, Puerto Rico, and Venezuela. Dementia incidence was assessed over 3-5 years, with diagnosis according to the 10/66 Study diagnostic algorithm. Discrimination and calibration were tested for five models: the Cardiovascular Risk Factors, Aging and Dementia risk score (CAIDE); the Study on Aging, Cognition and Dementia (AgeCoDe) model; the Australian National University Alzheimer’s Disease Risk Index (ANU-ADRI); the Brief Dementia Screening Indicator (BDSI); and the Rotterdam Study Basic Dementia Risk Model (BDRM). Models were tested with use of Cox regression. The discriminative accuracy of each model was assessed using Harrell’s concordance (c)-statistic, with a value of 0·70 or higher considered to indicate acceptable discriminative ability. Calibration (model fit) was assessed statistically using the Grønnesby and Borgan test. Findings 11 143 individuals without baseline dementia and with available follow-up data were included in the analysis. During follow-up (mean 3·8 years [SD 1·3]), 1069 people progressed to dementia across all sites (incidence rate 24·9 cases per 1000 person-years). Performance of the models varied. Across countries, the discriminative ability of the CAIDE (0·52≤c≤0·63) and AgeCoDe (0·57≤c≤0·74) models was poor. By contrast, the ANU-ADRI (0·66≤c≤0·78), BDSI (0·62≤c≤0·78), and BDRM (0·66≤c≤0·78) models showed similar levels of discriminative ability to those of the development cohorts. All models showed good calibration, especially at low and intermediate levels of predicted risk. The models validated best in Peru and poorest in the Dominican Republic and China. Interpretation Not all dementia prediction models developed in HICs can be simply extrapolated to LMICs. Further work defining what number and which combination of risk variables works best for predicting risk of dementia in LMICs is needed. However, models that transport well could be used immediately for dementia prevention research and targeted risk reduction in LMICs.
Prevalence and risk factors for wheeze, decreased forced expiratory volume in 1 s and bronchoconstriction in young children living in Havana, Cuba: a population-based cohort study. Suárez-Medina R, Venero-Fernández S, Álvarez-Valdés V, Sardiñas-Baez N, Cristina C, Loinaz-González M, et al. BMJ Open. 2020 Apr 22;10(4):e034192.
Objectives Asthma has not been extensively studied in low-income and middle-income countries, where risk factors and access to treatment may differ from more affluent countries. We aimed to identify the prevalence of asthma and local risk factors in Havana, Cuba. Setting Four municipalities in Havana, Cuba. Participants A population-based cohort study design of young children living in Havana, Cuba. Children were recruited from primary care centres at age 12-15 months. Primary and secondary outcome measures Data on wheeze in the past 12 months, asthma treatment and environmental exposures collected regularly until the age of 6 years, when forced expiratory volume in 1 s (FEV1) and reversibility to aerosolised salbutamol were also measured. Results 1106 children provided data at the age of 6 years old. The prevalence of wheeze in the previous 12 months was 422 (38%), and 294 (33%) of the study population had bronchodilatation of 12% or more in FEV1 after administration of inhaled salbutamol. In the previous 12 months, 182 (16%) of the children had received inhaled corticosteroids, 416 (38%) salbutamol inhalers and 283 (26%) a course of systemic steroids. Wheeze in the first year and a family history of asthma were both positively associated with bronchodilatation to inhaled salbutamol (1.94%; 95% CI 0.81 to 3.08 and 1.85%; CI 0.14 to 3.57, respectively), while paracetamol use in the first year was associated with wheeze at 6 years (OR 1.64, 95% CI 1.14 to 2.35). There were large differences in FEV1, bronchodilatation and risk of wheeze across different geographical areas. Conclusions Asthma is common in young children living in Havana, and the high prevalence of systemic steroids administrated is likely to reflect the underuse of regular inhaled corticosteroids. If replicated in other comparable low-income and middle-income countries, this represents an important global public health issue.
Prevalence of and factors associated with Helicobacter pylori infection in preschoolers in Havana, Cuba: A population-based study. Venero-Fernández SJ, Ávila-Ochoa I, Menocal-Herredia L, Caraballo-Sánchez Y, Rosado-García FM, Suárez-Medina R, et al. Rev Gastroenterol Mex. 2020 Mar 20. pii: S0375-0906(20)30015-X. DOI: 10.1016/j.rgmx.2019.03.010.
[Epub ahead of print]
Introduction Helicobacter pylori (H. pylori) infection is usually acquired in childhood. In Cuba, its study in pediatric ages is a little explored field. Aim To identify the prevalence of the infection and its associated risk factors in 3-year-old children in Havana. Materials and methods An analytic, cross-sectional, epidemiologic analysis was conducted on 1,274 children belonging to the cohort of participants in the Natural History of Wheezing in Cuba study (HINASIC for its Spanish acronym) that were 3 years of age and provided a stool sample. H. pylori infection was identified by determining the H. pylori antigen (Ag) in stool, utilizing the commercial Spinreact kit, from Spain. The data were collected through a questionnaire applied by the researchers that included sociodemographic, environmental, and lifestyle variables, as well as infection from other parasites. Prevalence and the prevalence ratio with a 95% confidence interval were calculated and the dichotomous logistic regression analysis was employed. Results The prevalence of positive H. pylori Ag was 5%. Sleeping together was the risk factor found (PR:1.27; 95% CI: 1.03-1.50). Protective factors were drinking water from water delivery trucks (PR: 0.16; 95% CI: 0.04-0.72) and living in a nuclear family unit (PR: 0.94; 95% CI: 0.85-0.99). Conclusions The prevalence of H. pylori infection in early childhood places Havana in an intermediate position at the international level. To control the infection, causal studies should be conducted and opportune interventions implemented.
Robotic therapy for the hemiplegic shoulder pain: a pilot study. Serrezuela RR, Quezada MT, Zayas MH, Pedrón AM, Hermosilla DM, Zamora RS. J Neuroeng Rehabil. 2020 Apr 22;17(1):54.
Backgrounds Exoskeletons development arises with a leading role in neurorehabilitation technologies; however, very few prototypes for upper limbs have been tested, contrasted and duly certified in terms of their effectiveness in clinical environments in order to incorporate into the health system. The purpose of this pilot study was to determine if robotic therapy of Hemiplegic Shoulder Pain (HSP) could lead to functional improvement in terms of diminishing of pain, spasticity, subluxation, the increasing of tone and muscle strength, and the satisfaction degree. Methods An experimental study was conducted in 16 patients with painful shoulder post- ischemic stroke in two experimental groups: conventional and robotic therapy. At different stages of its evolution, the robotic therapy effectiveness applied with anti-gravitational movements was evaluated. Clinical trial was developed at the Physical Medicine and Rehabilitation Department of the Surgical Clinical Hospital “Dr. Juan Bruno Zayas Alfonso” in Santiago de Cuba, from September 2016 – March 2018. Among other variables: the presence of humeral scapular subluxation (HSS), pain, spasticity, mobility, tone and muscle strength, and the satisfaction degree were recorded. Results with 95% reliability were compared between admission and third months of treatment. The Mann-Whitney U-Test, Chi-Square and Fisher’s Exact Tests were used as comparison criteria. Results Robotic therapy positively influenced in the decrease and annulment of pain and the spasticity degree, reaching a range increase of joint movement and the improvement of muscle tone.
Severe dengue categories as research endpoints-Results from a prospective observational study in hospitalised dengue patients. Rosenberger KD, Alexander N, Martinez E, Lum LCS, Dempfle CE, Junghanss T, et al. PLoS Negl Trop Dis. 2020 Mar 4;14(3):e0008076.
Severe dengue was perceived as one clinical disease entity until the WHO 2009 classification stratified it into severe vascular leakage, severe bleeding, and severe organ dysfunction. The objectives of this study were to investigate the potential use of severe dengue categories as endpoints for intervention research. 271 patients with severe dengue among 1734 confirmed dengue patients were followed prospectively in this hospital-based observational study in Latin America and Asia. We compared the distribution of severe dengue categories according to gender and age (below/above 15y), and determined the relative frequency and the overlap of severe dengue categories in the same patients. In a next step, we extended the analysis to candidate moderate severity categories, based on recently suggested definitions which were adapted for our purposes. Severe vascular leakage occurred in 244 (90%), severe bleeding in 39 (14%), and severe organ dysfunction in 28 (10%) of 271 severe dengue patients. A higher frequency of severe leakage was seen in children or adolescents (<15y) compared to adults. More than 80% of the severe leakage cases, and 30-50% of the cases with severe bleeding or severe organ dysfunction, were defined as severe on the basis of that feature alone. In 136 out of 213 patients with severe leakage alone, neither moderate bleeding manifestation nor hepatic involvement was recorded. On the other hand, moderate leakage manifestations were detected in 4 out of 12 cases that were classified as severe based on bleeding alone. A major proportion of severe dengue patients exhibited clinical manifestations of severe vascular leakage only, which may constitute a useful endpoint for intervention research or pathophysiology studies. Severe bleeding and severe organ manifestation were recorded less frequently and exhibited a higher degree of overlap with severe leakage. Severe bleeding without leakage may be associated with individual predisposition or the presence of comorbidities. More detailed assessments are needed to explore this hypothesis. Candidate moderate disease endpoints were investigated and need to be further validated.
Specific humoral response in cancer patients treated with a VEGF-specific active immunotherapy procedure within a compassionate use program. Sánchez Ramírez J, Morera Díaz Y, Bequet-Romero M, Hernández-Bernal F, Martín Bauta Y, Selman-Housein Bernal KH, et al. BMC Immunol. 2020 Mar 14;21(1):12.
Background CIGB-247 is a cancer therapeutic vaccine that uses as antigen a variant of human vascular endothelial growth factor (VEGF) mixed with the bacterially-derived adjuvant VSSP. CIGB-247 has been already evaluated in two phase I clinical trials (CENTAURO and CENTAURO-2), showing to be safe and immunogenic in advanced cancer patients selected under well-defined and controlled clinical conditions. Surviving patients were submitted to monthly re-immunizations and some of them showed objective clinical benefits. Based on these results, a compassionate use program (CUP) with CIGB-247 was initiated for patients that did not meet the strict entry criteria applied for the CENTAURO and CENTAURO-2 clinical trials, but could potentially benefit from the application of this cancer therapeutic vaccine. Results Polyclonal IgM, IgA and IgG antibodies specific for VEGF were detected by ELISA in serum samples from patients vaccinated with 400 μg of antigen combined with 200 μg of VSSP. Polyclonal antibody response showed no cross reactivity for other VEGF family member molecules like VEGF-C and VEGF-D. Serum from immunized individuals was able to block the binding of VEGF to its receptors VEGFR2 and VEGFR1. IgG fraction purified from immune sera shared the aforementioned characteristics and also inhibited the interaction between VEGF and the therapeutic recombinant antibody bevacizumab, an anti-angiogenic drug approved for the treatment of different tumors. No serious adverse events attributable to CIGB-247 have been documented yet in participants of the CIGB-247 CUP. The present paper is a first report of our findings concerning the humoral response and safety characteristics in treated CIGB-247 CUP cancer patients. The study has provided the unique opportunity of not only testing CIGB-247 in a broader clinical spectrum sample of Cuban cancer patients, but also within the context of the day-to-day clinical practice and treatment settings for these diseases in Cuban medical institutions. Conclusions The CIGB-247 CUP has demonstrated that immunization and follow-up of a variety of cancer patients, under day-to-day clinical practice conditions in several Cuban medical institutions, replicate our previous findings in clinical trials: CIGB-247 is safe and immunogenic.
Subcutaneous allergen immunotherapy for asthma: A randomized, double-blind, placebo-controlled study with a standardized Blomia tropicalis vaccine. Castro-Almarales RL, Ronquillo-Díaz M, Álvarez-Castelló M, Rodríguez-Canosa J, González-León M, Enríquez-Domínguez I, et al. World Allergy Organ J. 2020 Apr 10;13(4):100098.
Background Sensitization to Blomia tropicalis (Bt) is very frequent in the tropics, and particularly in Cuba, being a significant cause of allergic asthma. Allergen immunotherapy (AIT) with Bt can be a therapeutic option, however, placebo-controlled clinical trials have not been reported. Objective To assess the therapeutic effect and safety of AIT for asthma using a standardized allergen vaccine of B. tropicalis by subcutaneous route, in allergic asthmatic patients exposed and sensitized to this mite species. Methods A double-blind, placebo-controlled Phase II trial was conducted in 35 adults (18 with treatment and 17 with placebo), with mild to moderate asthma, predominantly sensitized to Bt. AIT was administered subcutaneously in increasing doses from 4 to 6000 Biological Units using a locally manufactured standardized extract (BIOCEN, Cuba). Patient assessment was performed using symptom-medication score (SMS), peak expiratory flow and skin reactivity relative to Histamine as measured by skin prick test (SPT). Results The 12-month treatment achieved a significant (p < 0.001) decrease of SMS. Symptom score showed only 41% (CI: 26-61) of placebo values, whereas medication was 34.5% (22.4%-63.3%). Treatment was regarded clinically effective in 67% of patients (OR 32; 95%CI: 17 to 102). The effect size on symptoms and medication was higher than has been reported with equivalent allergen dosages of D. pteronyssinus and D. siboney in Cuban asthmatic patients. Skin reactivity to Bt was also significantly reduced (p = 0.0001), increasing 148-fold the allergen threshold to elicit a positive skin test. This desensitization effect was specific to Bt and did not modify the reactivity to Dermatophagoides. The change of specific skin reactivity was significantly (p < 0.05) correlated to clinical improvement. All adverse events were local with a frequency of 2.4% of injections. Conclusions Subcutaneous AIT with Blomia tropicalis was effective and safe in asthmatic adults exposed and sensitized to this mite species in a tropical environment.
Thermosensitive hydrogels as sustained drug delivery system for CTLA-4 checkpoint blocking antibodies. Chung CK, Fransen MF, van der Maaden K, Campos Y, García-Couce J, Kralisch D, et al. J Control Release. 2020 Apr 2;323:1–11.
Thermosensitive poloxamer 407 (P407) hydrogels were evaluated as slow release system for optimizing CTLA-4 therapy. Slow release reduces systemic antibody levels and potentially mitigates the side effects of CTLA-4 therapy. The 25% P407 hydrogel is injectable at room temperature and depots are established quickly after subcutaneous injection. Scanning electron microscopy revealed the porous structure of the hydrogel, average pore surface was 1335 μm2. Release studies were optimized using the human IgG antibody. IgG was easily incorporated in the hydrogel by simple mixing and no antibodies were lost during preparation. In vitro, hydrogels showed low burst release within the first 24 h. Total IgG load was gradually released within 120 h. In vitro cytotoxicity assays showed that P407 is not cytotoxic and induces no immune activation by itself. In vivo, P407 hydrogels significantly reduced serum IgG levels, were biocompatible and were broken down 1 week after injection. Finally, local hydrogel delivery of anti-CTLA-4 antibodies near established tumors effectively slowed down tumor growth, whilst significantly reduced serum anti-CTLA-4 levels. Altogether, P407 hydrogels represent promising delivery systems for the optimization of CTLA-4 blocking therapy.
