Activation of Anthracene Endoperoxides in Leishmania and Impairment of Mitochondrial Functions. Geroldinger G, Tonner M, Fudickar W, De Sarkar S, Dighal A, Monzote L, et al. Molecules. 2018 Jul 10;23(7). pii: E1680. DOI: 10.3390/molecules23071680.
Leishmaniasis is a vector-borne disease caused by protozoal Leishmania. Because of resistance development against current drugs, new antileishmanial compounds are urgently needed. Endoperoxides (EPs) are successfully used in malaria therapy, and experimental evidence of their potential against leishmaniasis exists. Anthracene endoperoxides (AcEPs) have so far been only technically used and not explored for their leishmanicidal potential. This study verified the in vitro efficiency and mechanism of AcEPs against both Leishmania promastigotes and axenic amastigotes (L. tarentolae and L. donovani) as well as their toxicity in J774 macrophages. Additionally, the kinetics and radical products of AcEPs’ reaction with iron, the formation of radicals by AcEPs in Leishmania, as well as the resulting impairment of parasite mitochondrial functions were studied. Using electron paramagnetic resonance combined with spin trapping, photometry, and fluorescence-based oximetry, AcEPs were demonstrated to (i) show antileishmanial activity in vitro at IC50 values in a low micromolar range, (ii) exhibit host cell toxicity in J774 macrophages, (iii) react rapidly with iron (II) resulting in the formation of oxygen- and carbon-centered radicals, (iv) produce carbon-centered radicals which could secondarily trigger superoxide radical formation in Leishmania, and (v) impair mitochondrial functions in Leishmania during parasite killing. Overall, the data of different AcEPs demonstrate that their structures besides the peroxo bridge strongly influence their activity and mechanism of their antileishmanial action.
Back and forth between cancer treatment and cancer control programs: Insights from the Cuban experience.Lage A, Romero T. Semin Oncol. 2018 Jan; 45(1–2):12–7
Cancer control is a wider concept than oncology, and includes comprehensive actions for prevention, early diagnosis, treatment, services organization, and education, aiming to modify hard indicators such as incidence, mortality rates, and survival at a population scale. Based on these concepts, organized national cancer programs appeared in several countries in the second half of the 20th century. But at the same time, scientific efforts began to modify the landscape of cancer control. Evidence of mortality reductions began to appear, cancer-driving mutations became measurable, many novel drugs were registered, the methodology of clinical trials spread through health systems, targeted drugs and immunotherapy entered into the mainstream of therapeutics, and treatment goals started to shift from cure to chronic control. The implementation and impact of organized interventions for cancer control show variations according to the context of diverse countries, and scientists and health decision makers can learn from studying these diverse experiences. Among the salient features of cancer control in Cuba are the simultaneous development of a primary care network with abundant human resources and a national biotechnology industry with capacity to provide both generic and innovating drugs and diagnostic systems. The program intentionally assumes the goal of accelerating the transformation of advanced cancer into a chronic disease susceptible of long-term control. The implications of this strategy for population interventions and for scientific research are discussed.
CIMAvax-EGF: Toward long-term survival of advanced NSCLC. Saavedra D, Neninger E, Rodríguez C, Viada C, Mazorra Z, Lage A, et al. Semin Oncol. 2018 Jan;45(1–2):34–40.
Lung cancer remains one of the leading causes of cancer-related deaths. Non-small cell lung cancer (NSCLC) is the most common histologic type of lung cancer. Medical and scientific progress has led to longer survival in an increasing number of patients suffering from cancer. Concerning patients with advanced NSCLC, there is a subgroup with long-term survival. The human epidermal growth factor receptor (EGFR) family plays a key role in tumor development. This cluster of genes is associated with augmented angiogenesis and enhanced proliferation, survival, and migration of tumor cells. The CIMAvax-EGF vaccine consists of a chemical conjugate of the EGF with the P64 protein derived from the Meningitis B bacteria and the Montanide ISA 51, as adjuvant. The vaccine induces antibodies against EGF that results in EGF withdrawal. CIMAvax-EGF has been demonstrated to be safe and immunogenic in advanced NSCLC patients. Here we summarize the current knowledge of the mechanism of action of CIMAvax-EGF, highlighting the impact of this anti-EGF-based vaccine on the long-term survival of advanced NSCLC patients.
Clinical and Electrophysiological Differences between Subjects with Dysphonetic Dyslexia and Non-Specific Reading Delay. Bosch-Bayard J, Peluso V, Galán L, Valdés Sosa P, Chiarenza GA. Brain Sci. 2018 Sep 10;8(9). pii: E172. DOI: 10.3390/brainsci8090172.
Reading is essentially a two-channel function, requiring the integration of intact visual and auditory processes both peripheral and central. It is essential for normal reading that these component processes go forward automatically. Based on this model, Boder described three main subtypes of dyslexia: dysphonetic dyslexia (DD), dyseidetic, mixed and besides a fourth group defined non-specific reading delay (NSRD). The subtypes are identified by an algorithm that considers the reading quotient and the % of errors in the spelling test. Chiarenza and Bindelli have developed the Direct Test of Reading and Spelling (DTRS), a computerized, modified and validated version to the Italian language of the Boder test. The sample consisted of 169 subjects with DD and 36 children with NSRD. The diagnosis of dyslexia was made according to the DSM-V criteria. The DTRS was used to identify the dyslexia subtypes and the NSRD group. 2⁻5 min of artefact-free EEG (electroencephalogram), recorded at rest with eyes closed, according to 10⁻20 system were analyzed. Stability based Biomarkers identification methodology was applied to the DTRS and the quantitative EEG (QEEG). The reading quotients and the errors of the reading and spelling test were significantly different in the two groups. The DD group had significantly higher activity in delta and theta bands compared to NSRD group in the frontal, central and parietal areas bilaterally. The classification equation for the QEEG, both at the scalp and the sources levels, obtained an area under the robust Receiver Operating Curve (ROC) of 0.73. However, we obtained a discrimination equation for the DTRS items which did not participate in the Boder classification algorithm, with a specificity and sensitivity of 0.94 to discriminate DD from NSRD. These results demonstrate for the first time the existence of different neuropsychological and neurophysiological patterns between children with DD and children with NSRD. They may also provide clinicians and therapists warning signals deriving from the anamnesis and the results of the DTRS that should lead to an earlier diagnosis of reading delay, which is usually very late diagnosed and therefore, untreated until the secondary school level.
Combining computational and experimental biology to develop therapeutically valuable IL2 muteins. León K, García-Martínez K, Carmenate T, Rojas G. Semin Oncol. 2018 Jan;45(1–2):95–104.
High-dose IL2, first approved in 1992, has been used in the treatment of advanced renal cell carcinoma and melanoma. In these indications, IL2 induces long lasting objective responses in 5% to 20% of patients. However, toxicity and the unexpected expansion of regulatory T cells (Tregs) have limited its practical use and therapeutic impact, respectively. At the Center of Molecular Immunology in Havana, Cuba, a project was launched in 2005 to rationally design IL2 muteins that could be deployed in the therapy of cancer. The basic goal was to uncouple the pleiotropic effect of IL2 on different immune T cells, to obtain a mutein with a therapeutic index that was better than that achieved with wild type (wt) IL2. Using a combination of computational and experimental biology approaches, we predicted and developed two novel IL2 muteins with therapeutic potential. The first, designated no-alpha mutein, is an agonist of IL2R signaling with a reduced ability to expand Treg in vivo. In mice, the no-alpha mutein IL2 has higher antitumor activity and lower toxicity than wt IL2. It represents a potential best-in-class drug that has begun phase I/II clinical trials in solid tumors. The second, designated no-gamma mutein, is an antagonist of IL2R signaling, with some preferential affinity for Tregs. This mutein has antitumor activity in mice that likely derives from its ability to reduce Treg accumulation in vivo. It represents a first-in-class drug that offers a novel strategy to inhibit Treg activity in vivo.
Crystal structure of an L chain optimised 14F7 anti-ganglioside Fv suggests a unique tumour-specificity through an unusual H-chain CDR3 architecture. Bjerregaard-Andersen K, Johannesen H, Abdel-Rahman N, Heggelund JE, Hoås HM, Abraha F, et al. Sci Rep. 2018 Jul 18;8(1):10836. DOI: 10.1038/s41598-018-28918-5.
Targeted cancer immunotherapy offers increased efficacy concomitantly with reduced side effects. One antibody with promising clinical potential is 14F7, which specifically recognises the NeuGc GM3 ganglioside. This antigen is found in the plasma membrane of a range of tumours, but is essentially absent from healthy human cells. 14F7 can discriminate NeuGc GM3 from the very similar NeuAc GM3, a common component of cell membranes. The molecular basis for this unique specificity is poorly understood. Here we designed and expressed 14F7-derived single-chain Fvs (scFvs), which retained the specificity of the parent antibody. Detailed expression and purification protocols are described as well as the synthesis of the NeuGc GM3 trisaccharide. The most successful scFv construct, which comprises an alternative variable light chain (VLA), allowed structure determination to 2.2 Å resolution. The structure gives insights into the conformation of the important CDR H3 loop and the suspected antigen binding site. Furthermore, the presence of VLA instead of the original VL elucidates how this subdomain indirectly stabilises the CDR H3 loop. The current work may serve as a guideline for the efficient production of scFvs for structure determination.
Deliberations of the Strategic Advisory Group of Experts on Immunization on the use of CYD-TDV dengue vaccine. Wilder-Smith A, Hombach J, Ferguson N, Selgelid M, O’Brien K, Vannice K, et al. Lancet Infect Dis. 2018 Sep 5. pii: S1473-3099(18)30494-8. DOI: 10.1016/S1473-3099(18)30494-8. [Epub ahead of print]
The Strategic Advisory Group of Experts (SAGE) on Immunization advises WHO on global policies for vaccines. In April, 2016, SAGE issued recommendations on the use of the first licenced dengue vaccine, CYD-TDV. In November, 2017, a retrospective analysis of clinical trial data, stratifying participants according to their dengue serostatus before the first vaccine dose, showed that although in high seroprevalence settings the vaccine provides overall population benefit, there was an excess risk of severe dengue in seronegative vaccinees. SAGE’s working group on dengue vaccines met to discuss the new data and mainly considered two vaccination strategies: vaccination of populations with dengue seroprevalence rates above 80% or screening of individuals before vaccination, and vaccinating only seropositive individuals. We report on the deliberations that informed the recommendation of the pre-vaccination screening strategy, in April, 2018. Important research and implementation questions remain for CYD-TDV, including the development of a highly sensitive and specific rapid diagnostic test to determine serostatus, simplified immunisation schedules, and assessment of the need for booster doses.
Differential effects of two therapeutic cancer vaccines on short- and long-term survival populations among patients with advanced lung cancer. Semin Oncol. 2018 Jan;45(1–2):52–7. Sánchez L, Muchene L, Lorenzo-Luaces P, Viada C, Rodríguez PC, Alfonso S, et al.
Background Progress in immunotherapy has revolutionized the treatment landscape for advanced lung cancer, with emerging evidence of patients experiencing long-term survivals. The goal of this study was to explore the existence of short- and long-term survival populations and to assess the effect of immunotherapy on them. Methods Data from two randomized, multicenter, controlled clinical trials was used to evaluate the effect of two therapeutic vaccines (anti-idiotypic vaccine VAXIRA and anti-EGF vaccine CIMAVAX) on survival curves in advanced non-small cell lung cancer patients. Data were fitted to Kaplan-Meier, standard Weibull survival, and two-component Weibull mixture models. Bayesian Information Criterion was used for model selection. Results VAXIRA did not modify, neither the fraction of patients with long-term survivals (0.18 in the control group v 0.19 with VAXIRA, P = .88), nor the median overall survival of the patients in the short-term survival subpopulation (6.8 v 7.8 months, P = .24). However, this vaccine showed great benefit for the patients belonging to the subpopulation of patients with long-term survival (33.8 v 76.6 months, P <.0001). CIMAVAX showed impact in the overall survival of both short- and long-term populations (6.8 v 8.8 months, P = .005 and 33.8 v 61.8 months, P = .007). It also increased the proportion of patients with long-term survival (from 0.18 to 0.28, P = .02). Conclusions This study shows that therapeutic vaccines produce differential effects on short- and long-term survival populations and illustrates the application of advanced statistical methods to deal with the long-term evolution of patients with advanced lung cancer in the era of immunotherapy.
Emerging pathways of communication between the heart and non-cardiac organs.
Hardy-Rando E, Fernández-Patrón C. J Biomed Res. 2018 Jul 2. DOI: 10.7555/JBR.32.20170137. [Epub ahead of print]
The breakthrough discovery of cardiac natriuretic peptides provided the first direct demonstration of the connection between the heart and the kidneys for the maintenance of sodium and volume homeostasis in health and disease. Yet, little is still known about how the heart and other organs cross-talk. Here, we review three physiological mechanisms of communication linking the heart to other organs through: i) cardiac natriuretic peptides, ii) the microRNA-208a/mediator complex subunit-13 axis and iii) the matrix metalloproteinase-2 (MMP-2)/C-C motif chemokine ligand-7/cardiac secreted phospholipase A2 (sPLA2) axis – a pathway which likely applies to the many cytokines, which are cleaved and regulated by MMP-2. We also suggest experimental strategies to answer still open questions on the latter pathway. In short, we review evidence showing how the cardiac secretome influences the metabolic and inflammatory status of non-cardiac organs as well as the heart.
Generation of monoclonal antibodies against 17α-hydroxyprogesterone for newborn screening of congenital adrenal hyperplasia. Morejón García G, García de la Rosa I, González Reyes EC, Rubio Torres A, Quintana Guerra JM, Hernández Marín M, et al. Clin Chim Acta. 2018 Jul 10;485:311–5.
Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder caused by the deficiency of one of the five enzymes involved in the biosynthesis of corticosteroids. The most common form of the disease is the lack of 21-hydroxylase which provokes an accumulation of high levels of 17α-hydroxyprogesterone (17-OHP), the main biochemical marker for illness detection. Given the significance of neonatal diagnosis for ensuring a timely treatment to patients suffering from CAH, newborn screening is worldwide performed for the determination of 17-OHP from dried blood spots on filter paper. The non-specificity of antisera employed in immunoassays and the cross-reaction with fetal adrenal hormones produce an overestimation in the 17-OHP quantification. Immunization of mice with 17-OHP-3-(O-carboxymethyl) oxime-bovine serum albumin led to the generation of 15 anti-17-OHP IgG1-and-IgG2b-secreting hybridomas. The 6E2G9 monoclonal antibody presents cross-reactivity values similar to those achieved by rabbit antibodies employed in the solid phase of UMELISA® 17-OH Progesterona Neonatal, assay for the newborn screening of CAH in Cuba. Additionally, the use of 6E2G9 in the evaluation of dried blood spots samples from newborns on filter paper showed a decrease in the mean 17-OHP levels, thus demonstrating it can replace the conventional rabbit antisera
Global Unmet Needs in Cardiac Surgery. Zilla P, Yacoub M, Zühlke L, Beyersdorf F, Sliwa K, Khubulava G, et al. Glob Heart. 2018 Sep 20. pii: S2211-8160(18)30094-2. DOI: 10.1016/j.gheart.2018.08.002. [Epub ahead of print]
More than 6 billion people live outside industrialized countries and have insufficient access to cardiac surgery. Given the recently confirmed high prevailing mortality for rheumatic heart disease in many of these countries together with increasing numbers of patients needing interventions for lifestyle diseases due to an accelerating epidemiological transition, a significant need for cardiac surgery could be assumed. Yet, need estimates were largely based on extrapolated screening studies while true service levels remained unknown. A multi-author effort representing 16 high-, middle-, and low-income countries was undertaken to narrow the need assessment for cardiac surgery including rheumatic and lifestyle cardiac diseases as well as congenital heart disease on the basis of existing data deduction. Actual levels of cardiac surgery were determined in each of these countries on the basis of questionnaires, national databases, or annual reports of national societies. Need estimates range from 200 operations per million in low-income countries that are nonendemic for rheumatic heart disease to >1,000 operations per million in high-income countries representing the end of the epidemiological transition. Actually provided levels of cardiac surgery range from 0.5 per million in the assessed low- and lower-middle income countries (average 107 ± 113 per million; representing a population of 1.6 billion) to 500 in the upper-middle-income countries (average 270 ± 163 per million representing a population of 1.9 billion). By combining need estimates with the assessment of de facto provided levels of cardiac surgery, it emerged that a significant degree of underdelivery of often lifesaving open heart surgery does not only prevail in low-income countries but is also disturbingly high in middle-income countries.
GM3(Neu5Gc) ganglioside: an evolution fixed neoantigen for cancer immunotherapy 7. Labrada M, Dorvignit D, Hevia G, Rodríguez-Zhurbenko N, Hernández AM, Vázquez AM, et al. Semin Oncol. 2018 Jan;45(1–2):41–51.
Numerous molecules have been considered as targets for cancer immunotherapy because of their levels of expression on tumor cells, their putative importance for tumor biology, and relative immunogenicity. In this review we focus on the ganglioside GM3(Neu5Gc), a glycosphingolipid present on the outer side of the plasma membrane of vertebrate cells. The reasons for selecting GM3(Neu5Gc) as a tumor-specific antigen and its use as a target for cancer immunotherapy are discussed, together with the development of antitumor therapies focused on this target by the Center of Molecular Immunology (CIM, Cuba).
HER1-based vaccine: Simultaneous activation of humoral and cellular immune response. Bergado Báez G, Hernández Fernández DR, Mazorra Herrera Z, Sánchez Ramírez B. Semin Oncol. 2018 Jan;45(1–2):75–83.
The human epidermal growth factor receptor 1 (HER1) is a tumor-associated antigen that has been validated as a clinical target for several passive, non-immune therapies currently approved for the treatment of epithelial tumors. HER1 is an oncogene that not only promotes tumor progression and survival, but also immune escape. Its overexpression in some epithelial malignancies has been correlated with a poor prognosis. We developed an approach to target HER1 by specific active immunotherapy, recognizing the extracellular domain of the receptor, using a combination of VSSP and Montanide ISA 51 as adjuvants. We summarize the results obtained with this vaccine in both the preclinical and clinical settings, emphasizing the importance of the induction of both humoral and cellular responses for the success of cancer vaccines as safe therapeutic alternatives for the treatment of cancer.
Histology of atherosclerotic plaque from coronary arteries of deceased patients after coronary artery bypass graft surgery. Pérez Sorí Y, Herrera Moya VA, Puig Reyes, Moreno-Martínez FL, Bermúdez Alemán R, Rodríguez Millares T, et al. Clin Investig Arterioscler. 2018 Sep 24. English, Spanish.
Background and Aim Ischaemic heart disease is an important health problem. The characteristics of atherosclerotic plaques determine patient outcome. The aim of this study was to determine the histological grade of coronary atherosclerotic lesions in deceased patients after coronary artery bypass graft surgery, and to identify the complications of the severe plaques. Method A descriptive, cross-sectional, prospective study was carried out on 21 anatomical pieces of deceased patients over a period of 3 years. The epicardial coronary arteries were sectioned transversally every 1cm, and the odd numbered fragments and the regions of the anastomosis with the grafts were selected. They were embedded in paraffin, stained with haematoxylin-eosin, and the histological slides were studied using an Olympus BHM microscope. Results An age over 50 years (85.7%), male gender (81.0%), and smoking (66.7%) predominated. Peri-operative infarction (38.1%) and cardiogenic shock (33.3%) were the main direct causes of death. The majority of the grafts were of venous origin (64.6%), and 149 lesions were detected, of which 116 (77.8%) were severe plaques, and 47.4% of them were located in the left anterior descending artery. The large majority (81.9%) of the lesions were located in the arterial segments proximal to the graft. A total of 255 histological complications were detected in the severe plaques, with 75.0% showing calcification. Hypertensive patients had more plaques with more complications, but no statistically significant association was found between these variables. Conclusions Severe plaques predominated, mostly located in the proximal segments of the coronary arteries, and the left anterior descending was the most affected artery. Calcification was the most observed complication in the severe plaques.
Identification of (4-(9H-fluoren-9-yl) piperazin-1-yl) methanone derivatives as falcipain 2 inhibitors active against Plasmodium falciparum cultures. Hernádez-González JE, Salas-Sarduy E, Hernández Ramírez LF, Pascual MJ, Álvarez DE, Pabón A, et al. Biochim Biophys Acta Gen Subj. 2018 Sep 22. pii: S0304-4165(18)30303-9. DOI: 10.1016/j.bbagen.2018.09.015.
Background Falcipain 2 (FP-2) is the hemoglobin-degrading cysteine protease of Plasmodium falciparum most extensively targeted to develop novel antimalarials. However, no commercial antimalarial drugs based on FP-2 inhibition are available yet due to the low selectivity of most FP-2 inhibitors against the human cysteine proteases. Methods A structure-based virtual screening (SVBS) using Maybridge HitFinder™ compound database was conducted to identify potential FP-2 inhibitors. In vitro Enzymatic and cell-growth inhibition assays were performed for the top-scoring compounds. Docking, molecular dynamics (MD) simulations and free energy calculations were employed to study the interaction of the best hits with FP-2 and other related enzymes. Results and Conclusions Two hits based on 4-(9H-fluoren-9-yl) piperazin-1-yl) methanone scaffold, HTS07940 and HTS08262, were identified as inhibitors of FP-2 (half-maximal inhibitory concentration (IC50) = 64 μM and 14.7 μM, respectively) without a detectable inhibition against the human off-target cathepsin K (hCatK). HTS07940 and HTS08262 inhibited the growth of the multidrug-resistant P. falciparum strain FCR3 in culture (half-maximal inhibitory concentrations (IC50) = 2.91 μM and 34 μM, respectively) and exhibited only moderate cytotoxicity against HeLa cells (Half-maximal cytotoxic concentration (CC50) = 133 μM and 350 μM, respectively). Free energy calculations reproduced the experimental affinities of the hits for FP-2 and explained the selectivity with respect to hCatK. General Significance To the best of our knowledge, HTS07940 stands among the most selective FP-2 inhibitors identified by SBVS reported so far, displaying moderate antiplasmodial activity and low cytotoxicity against human cells. Hence, this compound constitutes a promising lead for the design of more potent and selective FP-2 inhibitors.
Impairment in exploratory behavior is associated with arc gene overexpression in the dorsolateral striatum of rats with nigral injection of l-buthionine sulfoximine. Díaz-Hung ML, Ruiz-Fuentes JL, Díaz-García A, León-Martínez R, Alberti-Amador E, Pavón-Fuentes N, et al. Neurosci Lett. 2018 Sep 14;687:26–30.
The aims of the present work were to evaluate the exploratory activity in Sprague-Dawley rats, as well as to analyze the nigral and striatal mRNA expression of the plasticity-related genes bdnf and arc after L-buthionine sulfoximine (BSO) injection into substantia nigra compacta. Lesioned rats traveled less distance in open field but did not show a decline in the novel object recognition test. On the other hand, RT-PCR analysis showed overexpression of striatal arc 24 h post-lesion; no significant changes in bdnf expression were observed in nigral or striatal tissue. These results suggest that intranigral BSO injection causes impairment in exploratory behavior in these rats, by affecting locomotion, which is associated with changes in striatal synaptic plasticity.
Inhibition and counter inhibition of Surfacen, a clinical lung surfactant of natural origin. Lugones Y, Blanco O, López-Rodríguez E, Echaide M, Cruz A, Pérez-Gil J. PLoS One. 2018 Sep 20;13(9):e0204050. DOI: 10.1371/journal.pone.0204050. eCollection 2018.
Inactivation of pulmonary surfactant by different components such as serum, cholesterol or meconium contributes to severe respiratory pathologies through destabilization and collapse of airspaces. Recent studies have analyzed in detail how the interfacial properties of natural surfactant purified from animal lungs are altered as a consequence of its exposure to serum proteins or meconium-mobilized cholesterol. It has been also demonstrated that pre-exposure of surfactant to polymers such as hyaluronic acid provides resistance to inactivation by multiple inhibitory agents. In the current work, we have extended these studies to the analysis of Surfacen, a clinical surfactant currently in use to rescue premature babies suffering or at risk of respiratory distress due to congenital lack of surfactant. This surfactant is also strongly inhibited by both meconium and serum when tested in the captive bubble surfactometer (CBS) under conditions mimicking respiratory dynamics. As it occurs with native surfactant, Surfacen is markedly protected from inhibition by pre-exposure to hyaluronic acid, confirming that clinical surfactants can be improved to treat pathologies associated with strongly deactivating contexts, such as those associated with lung injury and inflammation. Remarkably, we found that, under physiologically-mimicking conditions, a cholesterol-free clinical surfactant such as Surfacen is less susceptible to inhibition by cholesterol-mobilizing environments than cholesterol-containing natural surfactant, as a consequence of a markedly reduced susceptibility to incorporation of exogenous cholesterol.
Integrating theoretical and experimental permeability estimations for provisional biopharmaceutical classification: Application to the WHO essential medicines. Cabrera-Pérez MÁ, Pham-The H, Cervera MF, Hernández-Armengol R, Miranda-Pérez de Alejo C, Brito-Ferrer Y. Biopharm Drug Dispos. 2018 Jul;39(7):354–68.
The accuracy of the provisional estimation of the Biopharmaceutics Classification System (BCS) is heavily influenced by the permeability measurement. In this study, several theoretical and experimental models currently employed for BCS permeability classification have been analysed. The experimental models included the in situ rat intestinal perfusion, the ex vivo rat intestinal tissue in an Ussing chamber, the MDCK and Caco-2 cell monolayers, and the parallel artificial membrane (PAMPA). The theoretical models included the octanol-water partition coefficient and the QSPeR (Quantitative Structure-Permeability Relationship) model recently developed. For model validation, a dataset of 43 compounds has been recompiled and analysed for the suitability for BCS permeability classification in comparison with the use of human intestinal absorption and oral bioavailability values. The application of the final model, based on a majority voting system showed a 95.3% accuracy for predicting human permeability. Finally, the present approach was applied to the 186 orally administered drugs in immediate-release dosage forms of the WHO Model List of Essential Medicines. The percentages of the drugs that were provisionally classified as BCS Class I and Class III was 62.4%, suggesting that in vivo bioequivalence (BE) may potentially be assured with a less expensive and more easily implemented in vitro dissolution test, ensuring the efficiency and quality of pharmaceutical products. The results of the current study improve the accuracy of provisional BCS classification by combining different permeability models.
Nimotuzumab: beyond the EGFR signaling cascade inhibition. Mazorra Z, Chao L, Lavastida A, Sánchez B, Ramos M, Iznaga N, et al. Semin Oncol. 2018 Jan;45(1–2):18–26.
One of the most known oncogenes is the epidermal growth factor receptor (EGFR) family. It activates multiple signaling cascades that promote carcinogenesis and immune evasion. Therefore, these molecules have been extensively targeted in cancer immunotherapy. Beyond EGFR signaling cascade inhibition, some of these agents are able to induce T-cell activation, transforming a passive therapy into a vaccine-like effect. Nimotuzumab is an IgG1 humanized monoclonal antibody directed against the extracellular domain of the EGFR blocking the binding to its ligands. It possesses unique pharmacodynamic properties, which allow treating patients for long-term periods and with very low toxicity. Based on its clinical effect, nimotuzumab has been approved in Cuba and abroad for the treatment of different epithelial tumors. Recently, new potential mechanisms of action of nimotuzumab involving the activation of the innate and adaptive immune response have been reported. This review summarizes the main properties of nimotuzumab in comparison with other EGFR-specific monoclonal antibodies, highlighting its capacity to activate an effective immune response. In addition, differential clinical effects of this antibody and ongoing clinical trials to deeply characterize the biomarkers of clinical benefit are shown.
Potential sexual transmission of Giardia in an endemic region: a case series. Escobedo AA, Acosta-Ballester G, Almirall P, Rodríguez-Morales AJ, Ortíz C, Laffita A, et al. Infez Med. 2018 Jun 1;26(2):171–5.
We present four cases in which probable sexual transmission of Giardia lamblia was suspected. Diagnosing this mode of transmission in endemic areas is often difficult and should be considered only as possible, because exposure to poor sanitation and a potentially contaminated environment are always latent. However, as patients reported, there was no history of drinking tap water, exposure to recreational water, eating contaminated food, or other potential sources of infection but anilingus with an infected partner. We consider that in endemic countries, even when other more frequent modes of transmission could be playing the main role, the possibility of (re)infection due to sexual transmission should not be forgotten. Talking openly with patients, strengthening patient-specific preventive measures and counselling appear to be needed to reduce risks of Giardia infection transmission due to this often neglected route.
Rotating and Neurochemical Activity of Rats Lesioned with Quinolinic Acid and Transplanted with Bone Marrow Mononuclear Cells. Serrano Sánchez T, González Fraguela ME, Blanco Lezcano L, Alberti Amador E, Caballero Fernández B, Robinson Agramonte MLÁ, et al. Behav Sci (Basel). 2018 Sep 20;8(10). pii: E87. DOI: 10.3390/bs8100087.
Huntington’s disease (HD) is an inherited, neurodegenerative disorder that results from the degeneration of striatal neurons, mainly GABAergic neurons. The study of neurochemical activity has provided reliable markers to explain motor disorders. To treat neurodegenerative diseases, stem cell transplants with bone marrow (BM) have been performed for several decades. In this work we determine the effect of mononuclear bone marrow cell (mBMC) transplantation on the rotational behavior and neurochemical activity in a model of Huntington’s disease in rats. Four experimental groups were organized: Group I: Control animals (n = 5); Group II: Lesion with quinolinic acid (QA) in the striatum (n = 5); Group III: Lesion with QA and transplant with mBMC (n = 5); Group IV: Lesion with QA and transplant with culture medium (Dulbecco’s modified Eagle’s medium (DMEM) injection) (n = 5). The rotational activity induced by D-amphetamine was evaluated and the concentration of the neurotransmitter amino acids (glutamate and GABA) was studied. The striatal cell transplantation decreases the rotations induced by D-amphetamine (p < 0.04, Wilcoxon matched pairs test) and improves the changes produced in the levels of neurotransmitters studied. This work suggests that the loss of GABAergic neurons in the brain of rats lesioned with AQ produces behavioral and neurochemical alterations that can be reversed with the use of bone marrow mononuclear cell transplants.
Safety and immunogenicity of the Cuban heptavalent pneumococcal conjugate vaccine in healthy infants. Results from a double-blind randomized control trial Phase I. Martínez CPD, Linares-Pérez N, Toledo-Romaní ME, Delgado YR, Gómez RP, Moreno BP, et al. Vaccine. 2018 Jul 10. pii: S0264-410X(18)30634-0. DOI: 10.1016/j.vaccine.2018.05.027. [Epub ahead of print]
Background Cuba has a new pneumococcal conjugate vaccine candidate (PCV7-TT). This study evaluates the safety and immunogenicity in healthy infants using 2p+1 vaccination schedule. Methods A phase I, controlled, randomized and double blind clinical trial was designed. 30 unvaccinated healthy infants were included. 20 subjects were assigned to study group (PCV7-TT) and 10 to control group (Synflorix®) to receive the vaccines at 7, 8 months of age (primary series) and 11 months (booster dose). Blood samples were collected 30 days after second dose and post booster for antibodies measure analysis by ELISA and OPA. The statistics analysis included the frequency of occurrence for adverse events and the immune response. Non-parametric tests were used to compare the immune response. The clinical trial was published in the Cuban Public Register of Clinical Trials with code RPCEC00000173 available at http://registroclinico.sld.cu. Results Overall, the safety profile of PCV7-TT was similar to Synflorix®. Local reactions were predominant and systemic events were mild in severity. Swelling and redness were frequently associated with PCV7-TT mainly after the first dose (50% and 40% respectively). 15% and 10% of subject reported severe swelling after first dose with PCV7-TT and after second dose with Synflorix®. Mild fever (≥38-≤39), vomiting and sleep disturb were the systemic events reported. 100% of infants achieved pneumococcal IgG antibody concentrations ≥0.35 µg/ml after booster dose for serotypes 1, 14, 18C and 19F in each vaccine group. For serotypes 5, 6B and 23F, more than 80% infants vaccinated with Synflorix® or PCV7-TT achieved protective IgG GMC ≥ 0.35 µg/ml after booster dose. OPA proportion’s responders to the seven common serotypes were 89.5% or more after the primary dose and 100% after booster dose in vaccinated with PCV7-TT. Conclusions The Cuban PCV7-TT is safe, well tolerated and immunogenic in healthy infants.
