In silico methods for immunogenicity risk assessment and human homology screening for therapeutic antibodies.

In silico immunogenicity risk assessment has been an important step in the development path for many biologic therapeutics, including monoclonal antibodies. Even if the source of a given biologic is 'fully human', T cell epitopes that are contained in the sequences of the biologic may activate the immune system, enabling the development of anti-drug antibodies that can reduce drug efficacy and may contribute to adverse events. Computational tools that identify T cell epitopes from primary amino acid sequences have been used to assess the immunogenic potential of therapeutic candidates for several decades. To facilitate larger scale analyses and accelerate preclinical immunogenicity risk assessment, our group developed an integrated web-based platform called ISPRI, (Immunogenicity Screening and Protein Re-engineering Interface) that provides hands-on access through a secure web-based interface for scientists working in large and mid-sized biotech companies in the US, Europe, and Japan. This toolkit has evolved and now contains an array of algorithms that can be used individually and/or consecutively for immunogenicity assessment and protein engineering. Most analyses start with the advanced epitope mapping tool (EpiMatrix), then proceed to identify epitope clusters using ClustiMer, and then use a tool called JanusMatrix to define whether any of the T cell epitope clusters may generate a regulatory T cell response which may diminish or eliminate anti-drug antibody formation. Candidates can be compared to similar products on a normalized immunogenicity scale. Should modifications to the biologic sequence be an option, a tool for moderating putative immunogenicity by editing T cell epitopes out of the sequence is available (OptiMatrix). Although this perspective discusses the in-silico immunogenicity risk assessment for monoclonal antibodies, bi-specifics, multi-specifics, and antibody-drug conjugates, the analysis of additional therapeutic modalities such as enzyme replacement proteins, blood factor proteins, CAR-T, gene therapy products, and peptide drugs is also made available on the ISPRI platform.

ISPRI (Interactive Screening and Protein Reengineering Interface): Integrated, cloud-based, comprehensive toolkit for Immunogenicity Risk Assessment.EpiMatrix Immunogenicity Score: Combined T effector and Treg Epitope Content per unit protein.Tregitopes: Treg Epitopes found in IgG Framework that have been shown to modulate antigen-specific effector T cell responses.ClustiMer: Tool for identifying epitope rich polypeptides from within a given protein sequence.JanusMatrix: Tool for Predicting Tolerance, Putative Treg Epitopes, and Anti-self-immune responses.OptiMatrix: Tool for modifying T cell epitope sequences to reduce (or enhance) MHC binding.

A SARS-CoV-2 NSP7 homolog of a Treg epitope suppresses CD4+ and CD8+ T cell memory responses.

Pathogens escape host defenses by T-cell epitope mutation or deletion (immune escape) and by simulating the appearance of human T cell epitopes (immune camouflage). We identified a highly conserved, human-like T cell epitope in non-structural protein 7 (NSP7) of SARS-CoV-2, RNA-dependent RNA polymerase (RdRp) hetero-tetramer complex. Remarkably, this T cell epitope has significant homology to a T regulatory cell epitope (Tregitope) previously identified in the Fc region of human immunoglobulin G (IgG) (Tregitope 289). We hypothesized that the SARS-CoV-2 NSP7 epitope (NSP7-289) may induce suppressive responses by engaging and activating pre-existing regulatory T cells. We therefore compared NSP7-289 and IgG Tregitopes (289 and 289z, a shorter version of 289 that isolates the shared NSP7 epitope) in vitro. Tregitope peptides 289, 289z and NSP7-289 bound to multiple HLA-DRB1 alleles in vitro and suppressed CD4+ and CD8+ T cell memory responses. Identification and in vitro validation of SARS-CoV-2 NSP7-289 provides further evidence of immune camouflage and suggests that pathogens can use human-like epitopes to evade immune response and potentially enhance host tolerance. Further exploration of the role of cross-conserved Tregs in human immune responses to pathogens such as SARS-CoV-2 is warranted.

Visualizing Monocarboxylates and Other Relevant Metabolites in the Ex Vivo Drosophila Larval Brain Using Genetically Encoded Sensors.

The high energy requirements of brains due to electrical activity are one of their most distinguishing features. These requirements are met by the production of ATP from glucose and its metabolites, such as the monocarboxylates lactate and pyruvate. It is still unclear how this process is regulated or who the key players are, particularly in Drosophila. Using genetically encoded Förster resonance energy transfer-based sensors, we present a simple method for measuring the transport of monocarboxylates and glucose in glial cells and neurons in an ex-vivo Drosophila larval brain preparation. The protocol describes how to dissect and adhere a larval brain expressing one of the sensors to a glass coverslip. We present the results of an entire experiment in which lactate transport was measured in larval brains by knocking down previously identified monocarboxylate transporters in glial cells. Furthermore, we demonstrate how to rapidly increase neuronal activity and track metabolite changes in the active brain. The described method, which provides all necessary information, can be used to analyze other Drosophila living tissues.

Genomic introgressions from African rice (Oryza glaberrima) in Asian rice (O. sativa) lead to the identification of key QTLs for panicle architecture.

BACKGROUND: Developing high yielding varieties is a major challenge for breeders tackling the challenges of climate change in agriculture. The panicle (inflorescence) architecture of rice is one of the key components of yield potential and displays high inter- and intra-specific variability. The genus Oryza features two different crop species: Asian rice (Oryza sativa L.) and the African rice (O. glaberrima Steud.). One of the main morphological differences between the two independently domesticated species is the structure (or complexity) of the panicle, with O. sativa displaying a highly branched panicle, which in turn produces a larger number of grains than that of O. glaberrima. The gene regulatory network that governs intra- and interspecific panicle diversity is still under-studied. RESULTS: To identify genetic factors linked to panicle architecture diversity in the two species, we used a set of 60 Chromosome Segment Substitution Lines (CSSLs) issued from third generation backcross (BC3DH) and carrying genomic segments from O. glaberrima cv. MG12 in the genetic background of O. sativa Tropical Japonica cv. Caiapó. Phenotypic data were collected for rachis and primary branch length, primary, secondary and tertiary branch number and spikelet number. A total of 15 QTLs were localized on chromosomes 1, 2, 3, 7, 11 and 12, QTLs associated with enhanced secondary and tertiary branch numbers were detected in two CSSLs. Furthermore, BC4F3:5 lines carrying different combinations of substituted segments were produced to decipher the effects of the identified QTL regions on variations in panicle architecture. A detailed analysis of phenotypes versus genotypes was carried out between the two parental genomes within these regions in order to understand how O. glaberrima introgression events may lead to alterations in panicle traits. CONCLUSION: Our analysis led to the detection of genomic variations between O. sativa cv. Caiapó and O. glaberrima cv. MG12 in regions associated with enhanced panicle traits in specific CSSLs. These regions contain a number of key genes that regulate panicle development in O. sativa and their interspecific genomic variations may explain the phenotypic effects observed.

A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models.

Brains are highly metabolically active organs, consuming 20% of a person's energy at resting state. A decline in glucose metabolism is a common feature across a number of neurodegenerative diseases. Another common feature is the progressive accumulation of insoluble protein deposits, it's unclear if the two are linked. Glucose metabolism in the brain is highly coupled between neurons and glia, with glucose taken up by glia and metabolised to lactate, which is then shuttled via transporters to neurons, where it is converted back to pyruvate and fed into the TCA cycle for ATP production. Monocarboxylates are also involved in signalling, and play broad ranging roles in brain homeostasis and metabolic reprogramming. However, the role of monocarboxylates in dementia has not been tested. Here, we find that increasing pyruvate import in Drosophila neurons by over-expression of the transporter bumpel, leads to a rescue of lifespan and behavioural phenotypes in fly models of both frontotemporal dementia and Alzheimer's disease. The rescue is linked to a clearance of late stage autolysosomes, leading to degradation of toxic peptides associated with disease. We propose upregulation of pyruvate import into neurons as potentially a broad-scope therapeutic approach to increase neuronal autophagy, which could be beneficial for multiple dementias.

Identification of immunodominant T cell epitopes induced by natural Zika virus infection.

Zika virus (ZIKV) is a flavivirus primarily transmitted by Aedes species mosquitoes, first discovered in Africa in 1947, that disseminated through Southeast Asia and the Pacific Islands in the 2000s. The first ZIKV infections in the Americas were identified in 2014, and infections exploded through populations in Brazil and other countries in 2015/16. ZIKV infection during pregnancy can cause severe brain and eye defects in offspring, and infection in adults has been associated with higher risks of Guillain-Barré syndrome. We initiated a study to describe the natural history of Zika (the disease) and the immune response to infection, for which some results have been reported. In this paper, we identify ZIKV-specific CD4+ and CD8+ T cell epitopes that induce responses during infection. Two screening approaches were utilized: an untargeted approach with overlapping peptide arrays spanning the entire viral genome, and a targeted approach utilizing peptides predicted to bind human MHC molecules. Immunoinformatic tools were used to identify conserved MHC class I supertype binders and promiscuous class II binding peptide clusters predicted to bind 9 common class II alleles. T cell responses were evaluated in overnight IFN-γ ELISPOT assays. We found that MHC supertype binding predictions outperformed the bulk overlapping peptide approach. Diverse CD4+ T cell responses were observed in most ZIKV-infected participants, while responses to CD8+ T cell epitopes were more limited. Most individuals developed a robust T cell response against epitopes restricted to a single MHC class I supertype and only a single or few CD8+ T cell epitopes overall, suggesting a strong immunodominance phenomenon. Noteworthy is that many epitopes were commonly immunodominant across persons expressing the same class I supertype. Nearly all of the identified epitopes are unique to ZIKV and are not present in Dengue viruses. Collectively, we identified 31 immunogenic peptides restricted by the 6 major class I supertypes and 27 promiscuous class II epitopes. These sequences are highly relevant for design of T cell-targeted ZIKV vaccines and monitoring T cell responses to Zika virus infection and vaccination.

An updated estimation approach for SEIR models with stochastic perturbations: Application to COVID-19 data in Bogotá.

This paper studies the updated estimation method for estimating the transmission rate changes over time. The models for the population dynamics under SEIR epidemic models with stochastic perturbations are analysed the dynamics of the COVID-19 pandemic in Bogotá, Colombia. We performed computational experiments to interpret COVID-19 dynamics using actual data for the proposed models. We estimate the model parameters and updated their estimates for reported infected and recovered data.

Using machine learning to study the association of sociodemographic indicators, biomarkers, and oral condition in older adults in Colombia.

BACKGROUND: Chronic health conditions and socioeconomic problems that affect the well-being and life expectancy of older adults are common. The objective of this cross-sectional study was to analyze the association between sociodemographic variables, oral conditions, and general health and the biomarkers of older adults using machine learning (ML). METHODS: A total of 15,068 surveys from the national study of Health, Well-Being and Aging (Salud, Bienestar y Envejecimiento) data set were used for this secondary analysis. Of these, 3,128 people provided blood samples for the analysis of blood biomarkers. Sociodemographic, oral health, and general health variables were analyzed using ML and logistic regression. RESULTS: The results of clustering analysis showed that dyslipidemia was associated with poor oral condition, lower socioeconomic status, being female, and low education. The self-perception of oral health in older adults was not associated with the presence of teeth, blood biomarkers, or socioeconomic variables. However, the necessity of replacing a dental prosthesis was associated with the lowest self-perception of oral health. Edentulism was associated with being female, increased age, and smoking. CONCLUSIONS: Socioeconomic and educational disparities, sex, and smoking are important factors for tooth loss and suboptimal blood biomarkers in older adults. ML is a powerful tool for identifying potential variables that may aid in the prevention of systemic and oral diseases in older adults, which would improve geriatric dentistry. PRACTICAL IMPLICATIONS: These findings can help the academic community identify critical sociodemographic and clinical factors that influence the process of healthy aging and serve as a useful guide to enhance health care policies and geriatric oral health care services.

Reassessment of the electrical connection between the pulmonary veins and the left atrium: A study to determine the different contributions of myocardial fibers along the standard ablation circumference.

Background: Circumferential ablation around the ipsilateral pulmonary veins (PVs) is the standard strategy for atrial fibrillation ablation. The present study seeks to assess which regions of the standard ablation circumference are the main contributors to the venoatrial electrical connection. Methods: A total of 41 patients were included under a specific atrial fibrillation ablation protocol in which the anterior and posterior segments of the standard circumference, between the equatorial line of the superior and the inferior ipsilateral PVs, were ablated first. If PV isolation was not achieved, ablation was extended superiorly or inferiorly, on the basis of the earliest atrial activation recorded during pacing from inside the PV. Complete PV isolation and the length of the areas not requiring ablation (ANRA) at the time of electrical isolation were evaluated. Results: Ablation of the anterior and posterior segments of the standard circumference led to the isolation of 77% left-PV pairs and 51% right-PV pairs (p = 0,015). A superior extension was required in 23% left-PV pairs and in 46% right-PV pairs, while an inferior extension was required only in 10% left-PV pairs and in 11% right-PV pairs. PV isolation was achieved before completing the standard ablation circumference in 97% left-PV pairs and in 94% right-PV pairs, with a median ANRA of 36.9 (IQR: 30.9-42.1) mm in the left PVs [16.0 (IQR: 12.0-19.0) mm superior and 18.8 (IQR: 16.1-24.9) mm inferior, p < 0.01] and 36.9 (IQR: 30.2-41.0) mm in the right PVs [15.1 (IQR: 10.7-19.1) mm superior and 20.6 (IQR: 16.9-23.3) mm inferior, p < 0.01]. Conclusions: The myocardial fibers along the anterior and posterior regions of the standard ablation circumference are the main contributors to the electrical connection between the pulmonary veins and the left atrium. Ablation of these regions results in PV isolation in the majority of patients.

H1N1 G4 swine influenza T cell epitope analysis in swine and human vaccines and circulating strains uncovers potential risk to swine and humans.

BACKGROUND: Pandemic influenza viruses may emerge from animal reservoirs and spread among humans in the absence of cross-reactive antibodies in the human population. Immune response to highly conserved T cell epitopes in vaccines may still reduce morbidity and limit the spread of the new virus even when cross-protective antibody responses are lacking. METHODS: We used an established epitope content prediction and comparison tool, Epitope Content Comparison (EpiCC), to assess the potential for emergent H1N1 G4 swine influenza A virus (G4) to impact swine and human populations. We identified and computed the total cross-conserved T cell epitope content in HA sequences of human seasonal and experimental influenza vaccines, swine influenza vaccines from Europe and the United States (US) against G4. RESULTS: The overall T cell epitope content of US commercial swine vaccines was poorly conserved with G4, with an average T cell epitope coverage of 35.7%. EpiCC scores for the comparison between current human influenza vaccines and circulating human influenza strains were also very low. In contrast, the T cell epitope coverage of a recent European swine influenza vaccine (HL03) was 65.8% against G4. CONCLUSIONS: Poor T cell epitope cross-conservation between emergent G4 and swine and human influenza vaccines in the US may enable G4 to spread in swine and spillover to human populations in the absence of protective antibody response. One European influenza vaccine, HL03, may protect against emergent G4. This study illustrates the use of the EpiCC tool for prospective assessment of existing vaccine strains against emergent viruses in swine and human populations.

[Acute pancreatitis due to hepatitis B virus. A case report]. / Pancreatitis aguda por virus de la hepatitis B. Reporte de un caso.

Acute pancreatitis is an inflammatory condition that is related to various etiologies. However, an infrequent one is acute infection by hepatotropic viruses. We present the case of a 33-year-old man who consulted the emergency department for abdominal pain and generalized jaundice. Serological studies reported acute infection by Hepatitis B Virus; The patient was managed with clinical and paraclinical monitoring of liver function tests together with supportive therapy with dextrose. The patient persisted with increasing abdominal pain and cholestasis, so they were considered differential. Magnetic resonance imaging of the upper abdomen showed acute non-biliary pancreatitis that was concluded secondary to the infectious process due to hepatitis B after ruling out other causes. The patient did not require changes in management with improvement in liver function tests, so he was discharged from hospital with favorable evolution in outpatient follow-up. Acute pancreatitis secondary to Hepatitis B Virus is a pathology that should be suspected and studied when the patient's clinical picture does not show improvement; Diagnosis is based on measurement of pancreatic enzyme levels.

Síndrome nefrótico por enfermedad de cambios mínimos asociado a enfermedad de Graves y uso de metimazol

Introduction: Graves' disease causes kidney injury through a series of multiple mechanisms, including the treatment for this condition. Nephrotic syndrome due to minimal change disease (MCD) is an unusual form of such kidney injury; the association between methimazole use and MCD is also rare. Case presentation: A 36-year-old woman with a history of Graves' disease in use of methimazole for several months, who presents edematous syndrome due to nephrotic syndrome associated with a KDIGO stage 3 acute kidney injury. Thionamide-induced hypothyroidism and the need of thyroid hormone replacement therapy was evidenced at the time of consultation. Based on a renal biopsy, the patient was diagnosed with MCD, her condition worsened as she experienced oliguria and hypervolemia, therefore, renal replacement therapy with hemodialysis was temporarily required. Methimazole administration was suspended, and treatment consisting of prednisolone administration and levothyroxine supplementation was started, achieving hemodialysis suspension, gradual improvement of proteinuria until remission and a full-maintained recovery of renal clearance. Radioiodine therapy was implemented as definitive treatment for Graves' disease, obtaining a successful outcome. Conclusions: Graves' disease and methimazole use are possible causes of minimal change disease; systemic corticosteroid therapy is a possible management. However, further basic, clinical and epidemiological research on this subject is required.

Introducción: La enfermedad de Graves genera daño renal por múltiples mecanismos, incluyendo sus tratamientos. El síndrome nefrótico por enfermedad de cambios mínimos, es una forma inusual de dicho daño renal en la enfermedad de Graves; la asociación de esta condición renal con el metimazol también es anómalo. Presentación del caso: Una mujer de 36 años con antecedente de enfermedad de Graves en uso de metimazol hacía meses, quien debutó con síndrome edematoso por síndrome nefrótico asociado a una lesión renal aguda KDIGO etapa 3. Se evidenció hipotiroidismo inducido por la tionamida con necesidad de suplencia al momento de la consulta. Asimismo, se realizó biopsia renal que concluyó en enfermedad de cambios mínimos. La paciente progresó a oliguria con hipervolemia sin respuesta a diurético del asa por lo que requirió terapia de reemplazo renal con hemodiálisis de forma transitoria. Se retiró el metimazol, se dio manejo con prednisolona y con suplencia tiroidea, lográndose el retiro de la hemodiálisis con mejoría gradual de la proteinuria hasta la remisión y recuperación de la depuración renal de forma plena y mantenida. Se dio manejo definitivo a la enfermedad de Graves con yodo radioactivo con éxito terapéutico. Discusión y conclusiones: La enfermedad de Graves y el metimazol son causas posibles de enfermedad de cambios mínimos; el tratamiento con corticoide sistémico se postula como una posible estrategia de manejo. Se requiere más investigación básica, clínica y epidemiológica en el tema.

Effects of Domestication on Plant-Microbiome Interactions.

Through the process of domestication, selection is targeted on a limited number of plant traits that are typically associated with yield. As an unintended consequence, domesticated plants often perform poorly compared to their wild progenitors for a multitude of traits that were not under selection during domestication, including abiotic and biotic stress tolerance. Over the past decade, advances in sequencing technology have allowed for the rigorous characterization of host-associated microbial communities, termed the microbiome. It is now clear that nearly every conceivable plant interaction with the environment is mediated by interactions with the microbiome. For this reason, plant-microbiome interactions are an area of great promise for plant breeding and crop improvement. Here, we review the literature to assess the potential impact that domestication has had on plant-microbiome interactions and the current understanding of the genetic basis of microbiome variation to inform plant breeding efforts. Overall, we find limited evidence that domestication impacts the diversity of microbiomes, but domestication is often associated with shifts in the abundance and composition of microbial communities, including taxa of known functional significance. Moreover, genome-wide association studies and mutant analysis have not revealed a consistent set of core candidate genes or genetic pathways that confer variation in microbiomes across systems. However, such studies do implicate a consistent role for plant immunity, root traits, root and leaf exudates and cell wall integrity as key traits that control microbiome colonization and assembly. Therefore, selection on these key traits may pose the most immediate promise for enhancing plant-microbiome interactions through breeding.

ADXS31142 Immunotherapy ± Pembrolizumab Treatment for Metastatic Castration-Resistant Prostate Cancer: Open-Label Phase I/II KEYNOTE-046 Study.

BACKGROUND: ADXS31-142 is an attenuated Listeria monocytogenes-based immunotherapy targeting prostate-specific antigen (PSA), being evaluated as monotherapy and combined with pembrolizumab for metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: The 2-part phase I/II KEYNOTE-046 study enrolled men with mCRPC who have progressed after 2 or fewer prior systemic treatment regimens in the metastatic setting. In Part A, intravenous ADXS31-142 monotherapy was given every 3 weeks (q3w) to 3 dose-escalation cohorts. In Part B, ADXS31-142 (1 × 109 colony-forming units) plus pembrolizumab (200 mg) was administered intravenously q3w for 3 doses with a fourth pembrolizumab dose 3 weeks later (12-week cycles) for up to 24 months or until progression/toxicity. Endpoints included safety, overall response rate, progression-free survival (PFS), overall survival (OS), and immunogenicity. RESULTS: Fifty patients received ADXS31-142 alone (n = 13) or with pembrolizumab (n = 37). Among the 37 RECIST-evaluable patients (n = 8 Part A; n = 29 Part B), there were no objective responses. Median PFS was 2.2 months (95% CI: 0.8-7.4) with monotherapy and 5.4 months (95% CI: 2.3-7.9) with the combination; median OS was 7.8 months (95% CI: 4.4-18.5) and 33.7 months (95% CI: 15.4-not evaluable), respectively. Promising OS benefit was observed in combination-treated patients who had received prior docetaxel (16.0 months, 95% CI: 6.4-34.6; n = 20) and those with visceral metastasis (16.4 months, 95% CI 4.0-not evaluable; n = 11). All patients had ≥1 treatment-related adverse event, mostly grade 1/2 manageable events. No additive toxicity was observed with combination treatment. CONCLUSIONS: Combining ADXS31-142 with pembrolizumab was safe and well tolerated. The observed OS in mCRPC warrants further testing of this combination. CLINICAL TRIAL REGISTRATION: NCT02325557.

Pancreatitis aguda por virus de la hepatitis B. Reporte de un caso

La pancreatitis aguda es una condición inflamatoria que está relacionada con diversas etiologías. Sin embargo, una infrecuente es la infección aguda por virus hepatotropos. Se presenta el caso de un hombre de 33 años quien consultó al servicio de urgencias por dolor abdominal e ictericia generalizada. Los estudios serológicos reportaron infección aguda por Virus de la Hepatitis B; el paciente fue manejado con vigilancia clínica y paraclínica de pruebas de función hepática junto con terapia de soporte con dextrosa. El paciente persistió con dolor abdominal y colestasis en aumento por lo que se consideraron diferenciales. La imagen por resonancia magnética de hemiabdomen superior demostró pancreatitis aguda no biliar que se concluyó secundaria al proceso infeccioso por hepatitis B al descartar otras causas. El paciente no requirió cambios en el manejo con mejoría en pruebas de función hepática por lo que se dio egreso hospitalario con evolución favorable en el seguimiento ambulatorio. La pancreatitis aguda secundaria al Virus de la Hepatitis B es una patología que se debe sospechar y estudiar cuando el cuadro clínico del paciente no demuestra mejoría; el diagnóstico se fundamenta en la medición de los niveles de las enzimas pancreáticas.

Acute pancreatitis is an inflammatory condition that is related to various etiologies. However, an infrequent one is acute infection by hepatotropic viruses. We present the case of a 33-year-old man who consulted the emergency department for abdominal pain and generalized jaundice. Serological studies reported acute infection by Hepatitis B Virus; The patient was managed with clinical and paraclinical monitoring of liver function tests together with supportive therapy with dextrose. The patient persisted with increasing abdominal pain and cholestasis, so they were considered differential. Magnetic resonance imaging of the upper abdomen showed acute non-biliary pancreatitis that was concluded secondary to the infectious process due to hepatitis B after ruling out other causes. The patient did not require changes in management with improvement in liver function tests, so he was discharged from hospital with favorable evolution in outpatient follow-up. Acute pancreatitis secondary to Hepatitis B Virus is a pathology that should be suspected and studied when the patient's clinical picture does not show improvement; Diagnosis is based on measurement of pancreatic enzyme levels.

Stochastic modeling, analysis, and simulation of the COVID-19 pandemic with explicit behavioral changes in Bogotá: A case study.

In this paper, a stochastic epidemiological model is presented as an extension of a compartmental SEIR model with random perturbations to analyze the dynamics of the COVID-19 pandemic in the city of Bogotá D.C., Colombia. This model incorporates the spread of COVID-19 impacted by social behaviors in the population and allows for projecting the number of infected, recovered, and deceased individuals considering the mitigation measures, namely confinement and partial relaxed restrictions. Also, the role of randomness using the concept of Brownian motion is emphasized to explain the behavior of the population. Computational experiments for the stochastic model with random perturbations were performed, and the model is validated through numerical simulations for actual data from Bogotá D.C.

In silico Immunogenicity Assessment for Sequences Containing Unnatural Amino Acids: A Method Using Existing in silico Algorithm Infrastructure and a Vision for Future Enhancements.

The in silico prediction of T cell epitopes within any peptide or biologic drug candidate serves as an important first step for assessing immunogenicity. T cell epitopes bind human leukocyte antigen (HLA) by a well-characterized interaction of amino acid side chains and pockets in the HLA molecule binding groove. Immunoinformatics tools, such as the EpiMatrix algorithm, have been developed to screen natural amino acid sequences for peptides that will bind HLA. In addition to commonly occurring in synthetic peptide impurities, unnatural amino acids (UAA) are also often incorporated into novel peptide therapeutics to improve properties of the drug product. To date, the HLA binding properties of peptides containing UAA are not accurately estimated by most algorithms. Both scenarios warrant the need for enhanced predictive tools. The authors developed an in silico method for modeling the impact of a given UAA on a peptide's likelihood of binding to HLA and, by extension, its immunogenic potential. In silico assessment of immunogenic potential allows for risk-based selection of best candidate peptides in further confirmatory in vitro, ex vivo and in vivo assays, thereby reducing the overall cost of immunogenicity evaluation. Examples demonstrating in silico immunogenicity prediction for product impurities that are commonly found in formulations of the generic peptides teriparatide and semaglutide are provided. Next, this article discusses how HLA binding studies can be used to estimate the binding potentials of commonly encountered UAA and "correct" in silico estimates of binding based on their naturally occurring counterparts. As demonstrated here, these in vitro binding studies are usually performed with known ligands which have been modified to contain UAA in HLA anchor positions. An example using D-amino acids in relative binding position 1 (P1) of the PADRE peptide is presented. As more HLA binding data become available, new predictive models allowing for the direct estimation of HLA binding for peptides containing UAA can be established.

Tumor renal con extensión al atrio derecho a través de la vena cava inferior: reporte de caso / Renal tumor with extension to the right atrium through the inferior vena cava: case report

Resumen El presente articulo describe un caso clínico de una paciente con un ''trombo tumoral''. Estos son tumores que se extienden desde el órgano afectado hasta el atrio derecho, por la vena cava inferior. Hasta el 10 % de los tumores descritos pueden alcanzar la vena cava inferior y el 1 % de estos llegan a atrio derecho. El carcinoma de células renales es el más frecuente en producir este cuadro. El objetivo del articulo es mostrar que es fundamental realizar un adecuado diagnóstico diferencial, ya que existen diferentes procesos tumorales que pueden causar un ''trombo tumoral'' y diferentes causas de masas en el atrio derecho. La clínica de los pacientes con este cuadro será por obstrucción de la vena cava. El diagnóstico se realiza con estudios de imágenes, ultrasonido (US), ecocardiograma, tomografía axial computarizada (TAC) y resonancia magnética. El manejo debe de ser quirúrgico, sin embargo, presenta pronóstico desfavorable, en algunos casos se puede resecar el tumor primario y extraer la masa que ha invadido la vena cava inferior.

Abstract: This article describes a clinical case of a patient with a 'tumoral thrombus''. These are tumors that extend from the affected organ to the right atrium, through the inferior vena cava. Up to 10% of the tumors described can reach the inferior vena cava and 1% of these reach the right atrium. Renal cell carcinoma is the most common to produce this condition. The objective of the article is to show that it is essential to carry out an adequate differential diagnosis since there are different tumor processes that can cause a ''tumoral thrombus'' and different causes of masses in the right atrium. The symptoms of patients with this condition will be caused by the obstruction of the vena cava. The diagnosis is made with imaging studies, ultrasound (US), echocardiography, computerized axial tomography (CT) and magnetic resonance imaging. The management must be surgical, however it has an unfavorable prognosis, in some cases the primary tumor can be resected and the mass that has invaded the inferior vena cava removed.