A Brief Digital Cognitive Assessment for Detection of Cognitive Impairment in Cuban Older Adults. Rodríguez-Salgado AM, Llibre-Guerra JJ, Tsoy E, Peñalver-Guía, Erlhoff SJ. J Alzheimers Dis. 2020 Nov 18. DOI: 10.3233/JAD-200985. Online ahead of print.
Background Rapid technological advances offer a possibility to develop cost-effective digital cognitive assessment tools. However, it is unclear whether these measures are suitable for application in populations from Low and middle-income countries (LMIC). Objective To examine the accuracy and validity of the Brain Health Assessment (BHA) in detecting cognitive impairment in a Cuban population. Methods In this cross-sectional study, 146 participants (cognitively healthy = 53, mild cognitive impairment (MCI) = 46, dementia = 47) were recruited at primary care and tertiary clinics. The main outcomes included: accuracy of the BHA and the Montreal Cognitive Assessment (MoCA) in discriminating between controls and cognitively impaired groups (MCI and dementia) and correlations between the BHA subtests of memory, executive functions, and visuospatial skills and criterion-standard paper-and-pencil tests in the same domains. Results The BHA had an AUC of 0.95 (95% CI: 0.91-0.98) in discriminating between controls and cognitively impaired groups (MCI and dementia, combined) with 0.91 sensitivity at 0.85 specificity. In discriminating between control and MCI groups only, the BHA tests had an AUC of 0.94 (95% CI: 0.90-0.99) with 0.71 sensitivity at 0.85 specificity. Performance was superior to the MoCA across all diagnostic groups. Concurrent and discriminant validity analyses showed moderate to strong correlations between the BHA tests and standard paper-and-pencil measures in the same domain and weak correlations with standard measures in unrelated domains. Conclusion The BHA has excellent performance characteristics in detecting cognitive impairment including dementia and MCI in a Hispanic population in Cuba and outperformed the MoCA. These results support potential application of digital cognitive assessment for older adults in LMIC.
A Simplest Method to Enhance the Benefits of Internal Thoracic Artery Distal Occlusion. López-de la Cruz Y, Quintero Fleites YF, Abi Rezk MN. Braz J Cardiovasc Surg. 2020 Dec 23. DOI: 10.21470/1678-9741-2020-0308. Online ahead of print.
A common element of internal thoracic artery harvesting techniques is a distal vascular clamp placement at the end of the procedure, not only to avoid bleeding, but also to increase the internal hydrostatic pressure, diameter and flow. The logic indicates that the placement of this clamp at the beginning of the dissection will allow the artery to benefit earlier from these advantages.
After more than five years of experience, we present a modification in the classical technique of skeletonized harvesting of the internal thoracic artery, consisting of artery distal occlusion at the beginning of the procedure. Some of its advantages are discussed.
Clinical profile and predictors of in-hospital mortality among older patients admitted for COVID-19. Becerra-Muñoz VM, Núñez-Gil IJ, Maroun Eid C, García Aguado M, Romero R, Huang J, et al. Age Ageing. 2020 Nov 17;afaa258. DOI: 10.1093/ageing/afaa258. Online ahead of print.
Background The coronavirus disease 2019 (COVID-19) is characterized by poor outcomes and mortality, particularly in older patients. Methods Post-hoc analysis of the international, multicentre, “real-world” HOPE COVID-19 registry. All patients aged ≥65 years hospitalised for COVID-19 were selected. Epidemiological, clinical, analytical and outcome data were obtained. A comparative study between two age subgroups, 65-74 and ≥75 years, was performed. The primary endpoint was all cause in-hospital mortality. Results 1,520 patients aged ≥65 years (60.3% male, median age of 76 [IQR 71-83] years) were included. Comorbidities such as hypertension (69.2%), dyslipidemia (48.6%), cardiovascular diseases (any chronic heart disease in 38.4% and cerebrovascular disease in 12.5%), and chronic lung disease (25.3%) were prevalent, and 49.6% were on ACEI/ARBs. Patients aged 75 years and older suffered more in-hospital complications (respiratory failure, heart failure, renal failure, sepsis) and a significantly higher mortality (18.4 vs. 48.2%, P < 0.001), but fewer admissions to intensive care units (11.2 vs. 4.8%). In the overall cohort, multivariable analysis demonstrated age ≥75 (OR 3.54), chronic kidney disease (OR 3.36), dementia (OR 8,06), peripheral oxygen saturation at admission <92% (OR 5.85), severe lymphopenia (<500/mm3) (OR 3.36) and qSOFA (Quick Sequential Organ Failure Assessment Score) >1 (OR 8.31) to be independent predictors of mortality. Conclusion Patients aged ≥65 years hospitalised for COVID-19 had high rates of in-hospital complications and mortality, especially among patients 75 years or older. Age ≥75 years, dementia, peripheral oxygen saturation <92%, severe lymphopenia and qSOFA scale >1 were independent predictors of mortality in this population.
Development of a 3D functional assay and identification of biomarkers, predictive for response of high-grade serous ovarian cancer (HGSOC) patients to poly-ADP ribose polymerase inhibitors (PARPis): targeted therapy. Sheta R, Bachvarova M, Plante M, Rnaud MC, Sebastianelli A, Gregoire J, et al. J Transl Med. 2020 Nov 19;18(1):439. DOI 10.1186/s12967-020-02613-4.
Background Poly(ADP-ribose) polymerase inhibitors (PARPis) specifically target homologous recombination deficiency (HRD) cells and display good therapeutic effect in women with advanced-stage BRCA1/2-mutated breast and epithelial ovarian cancer (EOC). However, about 50% of high grade serous ovarian cancers (HGSOC) present with HRD due to epigenetic BRCA1 inactivation, as well as genetic/epigenetic inactivation(s) of other HR genes, a feature known as “BRCAness”. Therefore, there is a potential for extending the use of PARPis to these patients if HR status can be identified. Methods We have developed a 3D (spheroid) functional assay to assess the sensitivity of two PARPis (niraparib and olaparib) in ascites-derived primary cell cultures (AsPCs) from HGSOC patients. A method for AsPCs preparation was established based on a matrix (agarose), allowing for easy isolation and successive propagation of monolayer and 3D AsPCs. Based on this method, we performed cytotoxicity assays on 42 AsPCs grown both as monolayers and spheroids. Results The response to PARPis treatment in monolayer AsPCs, was significantly higher, compared to 3D AsPCs, as 88% and 52% of the monolayer AsPCs displayed sensitivity to niraparib and olaparib respectively, while 66% of the 3D AsPCs were sensitive to niraparib and 38% to olaparib, the latter being more consistent with previous estimates of HRD (40%-60%) in EOC. Moreover, niraparib displayed a significantly stronger cytotoxic effect in both in 3D and monolayer AsPCs, which was confirmed by consecutive analyses of the HR pathway activity (γH2AX foci formation) in PARPis-sensitive and resistant AsPCs. Global gene expression comparison of 6 PARPi-resistant and 6 PARPi-sensitive 3D AsPCs was indicative for the predominant downregulation of numerous genes and networks with previously demonstrated roles in EOC chemoresistance, suggesting that the PARPis-sensitive AsPCs could display enhanced sensitivity to other chemotherapeutic drugs, commonly applied in cancer management. Microarray data validation identified 24 potential gene biomarkers associated with PARPis sensitivity. The differential expression of 7 selected biomarkers was consecutively confirmed by immunohistochemistry in matched EOC tumor samples. Conclusion The application of this assay and the potential biomarkers with possible predictive significance to PARPis therapy of EOC patients now need testing in the setting of a clinical trial.
Diagnosis of intestinal protozoan infections in patients in Cuba by microscopy and molecular methods: advantages and disadvantages. Jerez Puebla LE, Núñez-Fernández FA, Fraga Nodarse J, Atencio Millán, Cruz Rodríguez I, Martínez Silva I, et al. J Microbiol Methods. 2020 Nov 12;179:106102. DOI: 10.1016/j.mimet.2020.106102. Online ahead of print.
Microscopy is the gold standard for diagnosis of intestinal parasitic diseases in many countries, including Cuba, although molecular approaches often have higher sensitivity as well as other advantages. Fecal samples from 133 patients were analyzed by light microscopy and also real-time multiplex qPCR targeting Giardia duodenalis, Cryptosporidium spp., and Entamoeba histolytica, and, separately, Dientamoeba fragilis. Microscopy revealed G. duodenalis occurred most commonly (17 patients), followed by Blastocystis spp. (12 patients). In a few patients, Entamoeba histolytica/E. dispar, Cryptosporidium spp., and Cyclospora cayetanensis were identified. Molecular analysis identified 4 more G. duodenalis infections and 2 more Cryptosporidium spp. infections; concordance between microscopy and PCR showed almost perfect agreement for G. duodenalis (κ = 0.88) and substantial agreement for Cryptosporidium (κ = 0.74). PCR indicated that E. dispar, rather than E. histolytica, had been identified by microscopy. Additionally, 16 D. fragilis infections were detected using molecular methods. Although both microscopy and molecular techniques have a place in parasitology diagnostics, for parasites such as D. fragilis, where microscopy can underestimate occurrence, molecular techniques may be preferable, and also essential for distinguishing between morphologically similar microorganisms such as E. histolytica and E. dispar. Although in resource-constrained countries such as Cuba, microscopy is extremely important as a diagnostic tool for intestinal parasites, inclusion of molecular techniques could be invaluable for selected protozoa.
Dominantly inherited Alzheimer’s disease in Latin America: Genetic heterogeneity and clinical phenotypes. Llibre-Guerra JJ, Li Y, Allergri, Chrem Mendez P, Surace EI, Llibre-Rodríguez JJ, et al. Alzheimers Dement. 2020 nov 23. DOI: 10.1002/alz.12227. Online ahead of print.
Introduction A growing number of dominantly inherited Alzheimer’s disease (DIAD) cases have become known in Latin American (LatAm) in recent years. However, questions regarding mutation distribution and frequency by country remain open. Methods A literature review was completed aimed to provide estimates for DIAD pathogenic variants in the LatAm population. The search strategies were established using a combination of standardized terms for DIAD and LatAm. Results Twenty-four DIAD pathogenic variants have been reported in LatAm countries. Our combined dataset included 3583 individuals at risk; countries with highest DIAD frequencies were Colombia (n = 1905), Puerto Rico (n = 672), and Mexico (n = 463), usually attributable to founder effects. We found relatively few reports with extensive documentation on biomarker profiles and disease progression. Discussion Future DIAD studies will be required in LatAm, albeit with a more systematic approach to include fluid biomarker and imaging studies. Regional efforts are under way to extend the DIAD observational studies and clinical trials to Latin America.
Implants placed into alveoli with periapical lesions: an experimental study in dogs. Real M, Bengazi F, Urbizo Velez J, Federico De Rossi E, Mainetti T, Botticelli D. Oral. Maxillofac Surg. 2020 Nov 21. DOI: 10.1007/s10006-020-00926-8. Online ahead of print.
Objective To histologically analyze the effect of a curettage of the granulation tissue on healing at implants installed immediately after the extraction of teeth presenting periapical lesions. Material and methods In seven dogs, the dental pulp was removed from the pulp chamber and from the root canals of the right and left third and the fourth mandibular premolars and of the left second premolar. The chambers were left opened and, after 3 months, apical lesions were present, and the premolars were extracted. One alveolus each premolar was selected and, before implant installation, the apical lesions of two alveoli were curetted (curettage group) while the other three were not treated (no-treatment group). The second right premolar was also extracted (Negative control group). Six implants each dog were installed, and a fully submerged healing was allowed. Four months after, biopsies were collected, and histological analyses were performed. Results The proportions of new bone at the entire body of the implant was 70.2 ± 10.7% at the no-treatment group, 72.1 ± 14.8% at the curettage group, and 69.6 ± 3.7% at the negative control group. The respective new bone proportion at the apical aspect of the implants was 68.4 ± 17.5%, 61.5 ± 27.3%, and 78.1 ± 5.7%. None of the differences among the various groups were statistically significant. No inflammatory infiltrates were seen in the apical region. Conclusions In this experimental study, it is concluded that the removal of the granulation tissue seems not to be necessary to obtain a proper osseointegration of implants installed immediately after the extraction of teeth presenting a periapical lesion.
Insulin Resistance at the Crossroad of Alzheimer Disease Pathology: A Review. Berlanga-Acosta J, Guillén-Nieto G, Rodríguez-Rodríguez N, Bringas-Vega, ML, García-Del-Barco-Herrera D, Berlanga-Sáez JO, et al. Front Endocrinol (Lausanne). 2020 Nov 5;11:560375. DOI: 0.3389/fendo.2020.560375.
Insulin plays a major neuroprotective and trophic function for cerebral cell population, thus countering apoptosis, beta-amyloid toxicity, and oxidative stress; favoring neuronal survival; and enhancing memory and learning processes. Insulin resistance and impaired cerebral glucose metabolism are invariantly reported in Alzheimer’s disease (AD) and other neurodegenerative processes. AD is a fatal neurodegenerative disorder in which progressive glucose hypometabolism parallels to cognitive impairment. Although AD may appear and progress in virtue of multifactorial nosogenic ingredients, multiple interperpetuative and interconnected vicious circles appear to drive disease pathophysiology. The disease is primarily a metabolic/energetic disorder in which amyloid accumulation may appear as a by-product of more proximal events, especially in the late-onset form. As a bridge between AD and type 2 diabetes, activation of c-Jun N-terminal kinase (JNK) pathway with the ensued serine phosphorylation of the insulin response substrate (IRS)-1/2 may be at the crossroads of insulin resistance and its subsequent dysmetabolic consequences. Central insulin axis bankruptcy translates in neuronal vulnerability and demise. As a link in the chain of pathogenic vicious circles, mitochondrial dysfunction, oxidative stress, and peripheral/central immune-inflammation are increasingly advocated as major pathology drivers. Pharmacological interventions addressed to preserve insulin axis physiology, mitochondrial biogenesis-integral functionality, and mitophagy of diseased organelles may attenuate the adjacent spillover of free radicals that further perpetuate mitochondrial damages and catalyze inflammation. Central and/or peripheral inflammation may account for a local flood of proinflammatory cytokines that along with astrogliosis amplify insulin resistance, mitochondrial dysfunction, and oxidative stress. All these elements are endogenous stressor, pro-senescent factors that contribute to JNK activation. Taken together, these evidences incite to identify novel multi-mechanistic approaches to succeed in ameliorating this pandemic affliction.
JM-20 protects against 6-hydroxydopamine-induced neurotoxicity in models of Parkinson’s disease: mitochondrial protection and antioxidant properties. Fonseca-Fonseca LA, Amaral da Silva VD, Wong-Guerra M, Ramírez-Sánchez J, Padrón Yaquis AS,Ochoa-Rodríguez E, et al. Neurotoxicology. 2020 Nov 21;82:89–98.
We have previously shown that JM-20, a new chemical entity consisting of 1,5-benzodiazepine fused to a dihydropyridine moiety, protects against rotenone-induced neurotoxicity in an experimental model of Parkinson’s disease (PD). The aim of this study was to investigate the effect of a novel hybrid molecule, named JM-20, in in vitro and in vivo models of PD induced by 6-hydroxydopamine (6-OHDA). PC-12 cells were exposed to 6-OHDA and treated with JM-20. Protection against mitochondrial damage induced by 6-OHDA was also investigated using isolated rat brain mitochondria. We found that JM-20 protected PC-12 cells against cytotoxicity induced by 6-OHDA and inhibited hydrogen peroxide generation, mitochondrial swelling and membrane potential dissipation. For in vivo experiments, adult male Wistar rats were lesioned in the substantia nigra pars compacta (SNpc) by 6-OHDA administration. JM-20 was orally administered (10, 20 or 40 mg/kg), intragastric via gavage, 24 h after surgery and daily for seven days. Treatment with JM-20 significantly reduced the percentage of motor asymmetry and increased vertical exploration. It improved the redox state of the SNpc and the striatal tissue of these animals. Also, JM-20 reduced glial fibrillary acidic protein overexpression and increased tyrosine hydroxylase-positive cell number, both in SNpc. Altogether, these results demonstrate that JM-20 is a potential neuroprotective agent against 6-OHDA-induced damage in both in vitro and in vivo models. The mechanism underlying JM-20 neuroprotection against 6-OHDA appears to be associated with the control of oxidative injury and mitochondrial impairment.
Multi-Institution Research and Education Collaboration Identifies New Antimicrobial Compounds. Fuller AA, Dounay AB, Schirch D, Rivera DG, Handsford KA, Elliot AG, et al. ACS Chem Biol. 2020 Dec 18;15(12):3187–96.
New antibiotics are urgently needed to address increasing rates of multidrug resistant infections. Seventy-six diversely functionalized compounds, comprising five structural scaffolds, were synthesized and tested for their ability to inhibit microbial growth. Twenty-six compounds showed activity in the primary phenotypic screen at the Community for Open Antimicrobial Drug Discovery (CO-ADD). Follow-up testing of active molecules confirmed that two unnatural dipeptides inhibit the growth of Cryptococcus neoformans with a minimum inhibitory concentration (MIC) ≤ 8 μg/mL. Syntheses were carried out by undergraduate students at five schools implementing Distributed Drug Discovery (D3) programs. This report showcases that a collaborative research and educational process is a powerful approach to discover new molecules inhibiting microbial growth. Educational gains for students engaged in this project are highlighted in parallel to the research advances. Aspects of D3 that contribute to its success, including an emphasis on reproducibility of procedures, are discussed to underscore the power of this approach to solve important research problems and to inform other coupled chemical biology research and teaching endeavors.
Nimotuzumab Site-Specifically Labeled with 89Zr and 225Ac using SpyTag/SpyCatcher for PET imaging and alpha particle radioimmunotherapy of epidermal growth factor receptor positive cancers. Solomon VR, Barreto K, Bernhard W, Alizadeh E, Causey P, Perron R, et al. Cancers (Basel). 2020 Nov 20;12(11):3449.
To develop imaging and therapeutic agents, antibodies are often conjugated randomly to a chelator/radioisotope or drug using a primary amine (NH2) of lysine or sulfhydryl (SH) of cysteine. Random conjugation to NH2 or SH groups can require extreme conditions and may affect target recognition/binding and must therefore be tested. In the present study, nimotuzumab was site-specifically labeled using ∆N-SpyCatcher/SpyTag with different chelators and radiometals. Nimotuzumab is a well-tolerated anti-EGFR antibody with low skin toxicities. First, ΔN-SpyCatcher was reduced using tris(2-carboxyethyl)phosphine (TCEP), which was followed by desferoxamine-maleimide (DFO-mal) conjugation to yield a reactive ΔN-SpyCatcher-DFO. The ΔN-SpyCatcher-DFO was reacted with nimotuzumab-SpyTag to obtain stable nimotuzumab-SpyTag-∆N-SpyCatcher-DFO. Radiolabeling was performed with 89Zr, and the conjugate was used for the in vivo microPET imaging of EGFR-positive MDA-MB-468 xenografts. Similarly, ∆N-SpyCatcher was conjugated to an eighteen-membered macrocyclic chelator macropa-maleimide and used to radiolabel nimotuzumab-SpyTag with actinium-225 (225Ac) for in vivo radiotherapy studies. All constructs were characterized using biolayer interferometry, flow cytometry, radioligand binding assays, HPLC, and bioanalyzer. MicroPET/CT imaging showed a good tumor uptake of 89Zr-nimotuzumab-SpyTag-∆N-SpyCatcher with 6.0 ± 0.6%IA/cc (n= 3) at 48 h post injection. The EC50 of 225Ac-nimotuzumab-SpyTag-∆N-SpyCatcher and 225Ac-control-IgG-SpyTag-∆N-SpyCatcher against an EGFR-positive cell-line (MDA-MB-468) was 3.7 ± 3.3 Bq/mL (0.04 ± 0.03 nM) and 18.5 ± 4.4 Bq/mL (0.2 ± 0.04 nM), respectively. In mice bearing MDA-MB-468 EGFR-positive xenografts, 225Ac-nimotuzumab-SpyTag-∆N-SpyCatcher significantly (p= 0.0017) prolonged the survival of mice (64 days) compared to 225Ac-control IgG (28.5 days), nimotuzumab (28.5 days), or PBS-treated mice (30 days). The results showed that the conjugation and labeling using SpyTag/∆N-SpyCatcher to nimotuzumab did not significantly (p> 0.05) alter the receptor binding of nimotuzumab compared with a non-specific conjugation approach. 225Ac-nimotuzumab-SpyTag-∆N-SpyCatcher was effective in vitro and in an EGFR-positive triple negative breast cancer xenograft model.
Progress, challenges and ways forward supporting cancer surveillance in Latin America. Piñeros M, Abriata MG, de Vries E, Barrios E, Bravo LE, Cueva P, et al. Int J Cancer. 2020 Nov 24.
DOI: 10.1002/ijc.33407.
Population-based cancer registries (PBCRs) are the only means to provide reliable incidence and survival data as a basis for policy-making and resource allocations within cancer care. Yet, less than 3% and 10% of the respective populations of Central America and South America are covered by high-quality cancer registries. The Global Initiative for Cancer Registry Development provides support to improve this situation via the International Agency for Research on Cancer Regional Hub for Latin America. In this paper, we summarize activities (advocacy, technical assistance, training and research) over the last 5 years, their impact and current challenges, including the implementation of new PBCR in four countries in the region. Despite the favorable political support to cancer registration in many countries, the sustainability of cancer registration remains vulnerable. Renewed efforts are needed to improve data quality in Latin America while ensuring maximum visibility of the data collected by disseminating and promoting their use in cancer control.
