Anti-Claudin-2 Antibody-Drug Conjugates for the Treatment of Colorectal Cancer Liver Metastasis.

We have demonstrated that Claudin-2 is required for colorectal cancer (CRC) liver metastasis. Expression of Claudin-2 in primary CRC is associated with poor survival and is highly expressed in liver metastases. Claudin-2 also promotes breast cancer liver metastasis by enabling seeding and cancer cell survival. These observations support Claudin-2 as a potential therapeutic target for managing patients with liver metastases. Antibody-drug conjugates (ADCs) are promising anti-tumor therapeutics that combine the specific targeting ability of monoclonal antibodies with the potent cell killing activity of cytotoxic drugs. Here we report the generation of twenty-eight anti-Claudin-2 antibodies for which the binding specificities, the cross-reactivity with Claudin family members and the cross-species reactivity were assessed by flow cytometry analysis. Multiple drug conjugates were tested and PNU was selected for conjugation with anti-Claudin-2 antibodies binding either extracellular loop 1 or extracellular loop 2. Anti-Claudin-2 ADCs were efficiently internalized and effective at killing Claudin-2-expressing CRC cancer cells in vitro. Importantly, PNU-conjugated-anti-Claudin-2 ADCs impaired the development of replacement type CRC liver metastases in vivo, using established CRC cell lines and patient-derived xenograft (PDX) models of CRC liver metastases. Our results suggest that the development of ADCs targeting Claudin-2 is a promising therapeutic strategy for managing CRC liver-metastatic patients that present with replacement type liver metastases.

Clinical Findings and Genetic Analysis of Nine Mexican Families with Bartter Syndrome.

BACKGROUND: Bartter's syndrome (BS) is a group of salt-wasting tubulopathies characterized by hypokalemia, metabolic alkalosis, hypercalciuria, secondary hyperaldosteronism, and low or normal blood pressure. Loss-of-function variants in genes encoding for five proteins expressed in the thick ascending limb of Henle in the nephron, produced different genetic types of BS. AIM: Clinical and genetic analysis of families with Antenatal Bartter syndrome (ABS) and with Classic Bartter syndrome (CBS). METHODS: Nine patients from unrelated non-consanguineous Mexican families were studied. Massive parallel sequencing of a gene panel or whole-exome sequencing was used to identify the causative gene. RESULTS: Proband 1 was homozygous for the pathogenic variant p.Arg302Gln in the SLC12A1 gene encoding for the sodium-potassium-chloride NKCC2 cotransporter. Proband 3 was homozygous for the nonsense variant p.Cys308* in the KCNJ1 gene encoding for the ROMK potassium channel. Probands 7, 8, and 9 showed variants in the CLCKNB gene encoding the chloride channel ClC-Kb: proband 7 was compound heterozygous for the deletion of the entire gene and the missense change p.Arg438Cys; proband 8 presented a homozygous deletion of the whole gene and proband 9 was homozygous for the nonsense mutation p.Arg595*. A heterozygous variant of unknown significance was detected in the SLC12A1 gene in proband 2, and no variants were found in SLC12A1, KCNJ1, BSND, CLCNKA, CLCNKB, and MAGED2 genes in probands 4, 5, and 6. CONCLUSIONS: Genetic analysis identified loss-of-function variants in the SLC12A1, KCNJ1, and CLCNKB genes in four patients with ABS and in the CLCNKB gene in two patients with CBS.

Diagnostic Performance of Airway Ultrasound for the Assessment of Difficult Laryngoscopy: A Systematic Review and Meta-Analysis.

OBJECTIVE: This study aimed to review and appraise the evidence regarding airway ultrasound assessment in predicting difficult laryngoscopy in adult patients. DESIGN: A systematic review of the literature was conducted according to the Cochrane collaboration guidelines and the recommendations for the systematic review and meta-analysis of diagnostic studies. Observational studies that evaluated the diagnostic performance of airway ultrasound for the prediction of difficult laryngoscopy were included for consideration. SETTING: Literature searches were performed in 4 databases (PubMed [Medline], Embase, Clinical Trials, and Google Scholar) to identify all observational studies using any ultrasound technique to assess difficult laryngoscopy. The search terms included "sonography," "ultrasound," "airway," "difficult airway," "difficult laryngoscopy," "Cormack," "risk factors," "ultrasound at the point of care," "difficult ventilation," "difficult intubation" and others, combined with sensitive filters. The search was done for studies performed in the last 20 years in English or Spanish. PARTICIPANTS: Adult patients older than 18 years old under general anesthesia for an elective procedure. Evident anatomic airway abnormalities, obstetric populations, those using an alternative imaging method besides ultrasound, and animal studies were excluded. INTERVENTIONS: Preoperative bedside ultrasound measuring distances and ratios from the skin to different reference points, such as the ratio of the hyomental distance in a neutral position (HMDN) and hyomental distance in extension (HMDR), HMDN, and the skin-to-epiglottis distance (SED), the preepiglottic area, and tongue thickness, among others. MEASUREMENTS AND MAIN RESULTS: A total of 24 studies evaluated the prediction of a difficult laryngoscopy using airway ultrasound. The diagnostic performance and the number of ultrasound parameters reported in the studies were variable. Meta-analysis was performed for 3 measurements consistently included in most studies. The SED and the HMDR ratio presented a sensitivity of 75% and 61%, respectively, and a specificity of 86% and 88%, respectively. The ratio of the preepiglottic distance to the epiglottic distance at the midpoint of the vocal cords (pre-E/E-VC) presented the best performance for predicting a difficult laryngoscopy (sensitivity: 82%, specificity: 83%, diagnostic odds ratio: 22.2). CONCLUSION: With the currently available evidence, the 3 commonly used point-of-care ultrasound measures used to identify difficult laryngoscopy, (SED, HMDR, and pre-E/E-VC), showed better sensitivity and similar specificity to clinical measures. Future studies and more data may change the authors' confidence in these conclusions, given the wide variability of measurements noted in studies.

Bienestar psicológico y consumo de sustancias psicoactivas en adultos jóvenes del Quindío / Psychological well-being and consumption of psychoactive substances in young adults from Quindío

El consumo de Sustancias Psicoactivas (SPA) es una problemática que por años ha generado afectaciones en los ámbitos individual y colectivo, contribuyendo al aumento en las cifras de problemáticas psicosociales y de salud. El objetivo del estudio fue establecer la relación entre el bienestar psicológico y el consumo de SPA en 97 personas de 18 a 25 años del departamento del Quindío. Para ello, se implementó un diseño transversal con alcance correlacional. Los datos se recolectaron mediante la Prueba de Detección de Consumo de Alcohol, Tabaco y otras Sustancias y la Escala del Bienestar Psicológico de Ryff. Se identificó que la mayoría de los participantes se ubicaron en un nivel alto en la mayoría de las dimensiones de la escala de bienestar. El 91,75% de los participantes consumieron alguna sustancia, a lo largo de su vida. Finalmente, se encontró una relación entre la preocupación por otros por el consumo de tabaco y el bajo nivel de autonomía (-0,3144, p < 0,01), y el intento por dejar el consumo alcohol y bajo nivel del dominio del entorno (-0,3275, p < 0,01).

The consumption of psychoactive substances (PAS) generates affectations in the individual and collective spheres, contributing to the increase in the figures of psychosocial and health problems. The objective of the study was to establish the relationship between the consumption of PAS and psychological well-being in 97 people between 18 and 25 years of age in the department of Quindío. For this, a cross-sectional design with correlational scope was implemented. Data were collected using the Alcohol, Tobacco, and Other Substance Use Screening Test and the Ryff Psychological Well-Being Scale. It was identified that the majority of those evaluated were located at a high level in most of the dimensions of the well-being scale. 91,75% of the participants consumed some substance throughout their lives. Finally, a relationship was found between concern for others about tobacco consumption and low level of autonomy (-0,3144, p < 0.01), and the attempt to quit alcohol consumption and low level of mastery of environment (-0,3275, p < 0.01).

El amor como sujeto perenne. Una interpretación sobre las concepciones del amor de pareja en el último quinquenio / Love as a perennial subject. An interpretation of conceptions of couple love in the last five years

El amor es un tema que transversaliza al ser humano en todas sus experiencias vitales; es por ello por lo que constantemente está expuesto a contextos colmados de significados, los cuales, de una u otra manera, forjan una idea sobre término, misma que influye directamente en las relaciones de pareja. El presente artículo surge de una investigación reflexiva acerca de las concepciones del amor de pareja en el último quinquenio del siglo XXI y su relación con las formas de amar, lo cual permitió esclarecer, desde lo documental inicialmente, los modos y maneras de relacionamiento en la actualidad. La reflexión transita desde la idea del amor como problema que interesa, pasando por el camino que conduce al sí mismo del amor, entendiendo que este es el problema perenne; finaliza el artículo con la idea de que absolutizar el amor es negarlo

Love is a theme that transverses and crosses human beings in all their life experiences; that is why it is constantly exposed to contexts full of meanings, which, in one way or another, forge an idea about it, which directly influences couple relationships. This article reflects on the conceptions of couple love in the last five years of the 21st century and its relationship with the ways of loving, which allowed us to clarify, initially at a documentary level, the modes, and ways of relating at present. The reflection moves from the idea of love as a problem of interest, passing through the path that leads to love itself, understanding that this is the perennial problem; the article ends with the idea that to absolutize love is to deny it.

Protection of Mono and Polyunsaturated Fatty Acids from Grapeseed Oil by Spray Drying Using Green Biopolymers as Wall Material.

One of the most common ways to protect oils is microencapsulation, which includes the use of encapsulating agents. Due to the environmental problems facing humanity, this study seeks to combine green biopolymers (microcrystalline cellulose and whey protein isolate) that function as encapsulating agents for grapeseed oil. Grapeseed oil that is obtained from agro-industrial waste has shown health benefits, including cardioprotective, anticancer, antimicrobial, and anti-inflammatory properties. These health benefits have been mainly associated with monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids. In this sense, it has been observed that grapeseed oil can be easily modified by environmental factors such as oxygen, high temperatures, and light, showing the instability and easy degradation of grapeseed oil. In this study, grapeseed oil was encapsulated using the spray-drying technique to conserve its lipidic profile. Powder recovery of the grapeseed oil microcapsules ranged from 65% to 70%. The encapsulation efficiency of the microcapsules varied between 80% and 85%. The FTIR analysis showed chemical interactions that demonstrate chemisorption between the grapeseed oil and the encapsulating material, while the SEM micrographs showed a correct encapsulation in a spherical shape. Gas chromatography showed that the lipid profile of grapeseed oil is preserved thanks to microencapsulation. Release tests showed 80% desorption within the first three hours at pH 5.8. Overall, whey protein and microcrystalline cellulose could be used as a wall material to protect grapeseed oil with the potential application of controlled delivery of fatty acids microcapsules.

Influencia de un programa recreativo en la disminución de la ansiedad en estudiantes de bachillerato / Influência de um programa recreativo sobre a redução da ansiedade nos estudantes do ensino secundário / Influence of a recreational program in reducing anxiety in high school students

RESUMEN Las actividades recreativas poseen numerosos efectos positivos en el comportamiento humano, esto puede favorecer a indicadores psicológicos de relevancia como la ansiedad percibida. En tal sentido, se planteó como propósito de la investigación determinar cómo influye un programa recreativo en la disminución de los niveles de ansiedad en estudiantes de bachillerato. La investigación es descriptiva-explicativa, de orden correlacional; se diagnostican intencionalmente a 30 estudiantes de bachillerato a través del test de Beck, antes y después de implementada una propuesta recreativa por ocho semanas. Los porcentajes de ansiedad disminuyeron a medida que se implementa la propuesta de intervención, tanto de forma general como en el análisis por género, al ser significativa la disminución (p=0.003). El presente estudio evidencia que las actividades recreativas pueden contribuir a la disminución de la ansiedad en adolescentes de bachiller, tanto para el género femenino como para el masculino. Se recomienda tres acciones a futuro: ampliar el tiempo de implementación de la propuesta de intervención, realizar estudios por género y direccionar la futura investigación a un nivel cuasiexperimental.

RESUMO As atividades recreativas têm numerosos efeitos positivos no comportamento humano, o que pode favorecer indicadores psicológicos relevantes, tais como a percepção de ansiedade. Neste sentido, o objectivo da investigação era determinar como um programa recreativo influencia a redução dos níveis de ansiedade dos estudantes do ensino secundário. A investigação é descritiva-explicativa, de ordem correlacional; 30 estudantes do ensino secundário foram intencionalmente diagnosticados através do teste Beck, antes e depois da implementação de uma proposta recreativa durante oito semanas. As percentagens de ansiedade diminuíram à medida que a proposta de intervenção foi sendo implementada, tanto em geral como na análise por género, uma vez que a diminuição foi significativa (p=0,003). O presente estudo mostra que as atividades recreativas podem contribuir para a redução da ansiedade nos adolescentes do ensino secundário, tanto para raparigas como para rapazes. Três ações futuras são recomendadas: prolongar o tempo de implementação da proposta de intervenção, realizar estudos por género e orientar a investigação futura para um nível quase experimental.

ABSTRACT Recreational activities have numerous positive effects on human behavior, this can favor relevant psychological indicators such as perceived anxiety. In this sense, the purpose of the research was to determine how a recreational program influences the reduction of anxiety levels in high school students. The research is descriptive-explanatory, correlational; 30 high school students are intentionally diagnosed through the Beck test, before and after implementing a recreational proposal for eight weeks. The percentages of anxiety decreased as the intervention proposal was implemented, both in general and in the analysis by gender, as the decrease was significant (p=0.003). The present study shows that recreational activities can contribute to the reduction of anxiety in high school adolescents, both for the female gender and for the male gender. Three future actions are recommended: extend the implementation time of the intervention proposal, carry out studies by gender and direct future research at a quasi-experimental level.

Estrategia de actividades físico-recreativas para el uso adecuado del tiempo libre en adolescentes / Estratégia de atividades físico-recreativas para o uso adequado do tempo livre nos adolescentes / Strategy of physical recreational activities for the adequate use of the free time in teenagers

RESUMEN En la estrategia con actividades físico-recreativas, en el uso del tiempo libre por adolescentes, se asume una concepción metodológica desde la vinculación de los enfoques cuantitativos y cualitativos, con la articulación de métodos y técnicas que posibilitaron el estudio de los antecedentes y criterios teóricos acerca de los enfoques actuales de ese fenómeno. El objetivo de este trabajo consistió en implementar una estrategia con actividades físico-recreativas que contribuirán al uso adecuado del tiempo libre por los adolescentes de las unidades particulares laicas de Sangolquí. Los resultados avalan la realización de un diagnóstico de necesidades que facilitó la concepción de la estrategia sobre una base científica, en una estructura que se consolidó en etapas y acciones con las vías de control, lo cual permitió una organicidad lógica y coherente en el uso adecuado del tiempo libre por los adolescentes. Este estudio favoreció la modificación del estado inicial del uso del tiempo libre por los adolescentes, al otorgarles un rol protagónico en la búsqueda de sus intereses y la satisfacción de sus necesidades. Esto conduce a arribar al estado deseado y el cumplimiento de los objetivos previstos, al considerar la articulación y la naturaleza cognoscitiva, práctica y axiológica de las actividades. La valoración de los expertos consideró que la estrategia es muy adecuada y ratificaron el valor de la misma, al expresar que puede ser implementada, pues tiene un marco legal y metodológico que avala la pertinencia, la factibilidad y la aplicabilidad de la misma.

RESUMO Na estratégia com atividades físico-recreativas na utilização do tempo livre pelos adolescentes, assume-se uma concepção metodológica a partir da ligação de abordagens quantitativas e qualitativas, com a articulação de métodos e técnicas que tornaram possível o estudo dos antecedentes e critérios teóricos sobre as atuais abordagens a este fenómeno. O objectivo deste trabalho consistiu em implementar uma estratégia com atividades físico-recreativas que contribuam para a utilização adequada do tempo livre pelos adolescentes nas unidades privadas leigas de Sangolquí. Os resultados apoiam a realização de um diagnóstico de necessidades que facilitou a concepção da estratégia numa base científica, numa estrutura que foi consolidada em fases e ações com os meios de controlo, o que permitiu uma organicidade lógica e coerente na utilização adequada do tempo livre pelos adolescentes. Este estudo favoreceu a modificação do estado inicial de utilização do tempo livre pelos adolescentes, dando-lhes um papel de liderança na prossecução dos seus interesses e na satisfação das suas necessidades. Isto leva a chegar ao estado desejado e ao cumprimento dos objectivos planeados, considerando a articulação e a natureza cognitiva, prática e axiológica das atividades. A avaliação dos peritos considerou a Estratégia Muito Adequada e ratificou o seu valor, expressando que pode ser implementada, uma vez que possui um quadro legal e metodológico que endossa a sua pertinência, viabilidade e aplicabilidade.

ABSTRACT In the strategy with physical-recreational activities, in the use of free time by teenagers, a methodological conception is assumed from the linking of quantitative and qualitative approaches, with the articulation of methods and techniques that made it possible to study the background and theoretical criteria about current approaches to this phenomenon. The objective of this work was to implement a strategy with physical-recreational activities that will contribute to the adequate use of free time by adolescents from the private lay units of Sangolquí. The results support the realization of a diagnosis of needs that facilitated the conception of the strategy on a scientific basis, in a structure that was consolidated in stages and actions with the control channels, which allowed a logical and coherent organization in the appropriate use. Free time for teenagers. This study favored the modification of the initial state of the use of free time by adolescents, by giving them a leading role in the pursuit of their interests and the satisfaction of their needs. This leads to arriving at the desired state and the fulfillment of the planned objectives, when considering the articulation and the cognitive, practical and axiological nature of the activities. The experts' assessment considered that the Strategy is Very Appropriate and ratified its value, expressing that it can be implemented, since it has a legal and methodological framework that supports its relevance, feasibility and applicability.

Incidencia del entrenamiento funcional para potencializar la fuerza en nadadores semilleros del club Varadero / Incidência de treino funcional para potenciar a força dos nadadores do clube Varadero / Incidence of functional training to potentiate strength in beginner swimmers of the Varadero club

RESUMEN El entrenamiento funcional ayuda a potencializar la fuerza en ciertos grupos musculares; de esta manera, el deportista mejora la postura corporal, gana fuerza y resistencia muscular y, por ende, puede incrementar indicadores relacionados con la capacidad física y el rendimiento final. En tal sentido, se planteó como objetivo de la investigación, aplicar un programa de entrenamiento funcional enfocado en el mejoramiento de la fuerza en nadadores semilleros del Club Varadero. La investigación es de tipo descriptiva-explicativa de orden correlacional; se diagnostica una población de 17 nadadores (ambos géneros; 14-16 años) del Club referido. Se aplica un entrenamiento funcional adaptado al nadador sobre la base de cuatro indicadores físicos en dos momentos de aplicado dicho entrenamiento. Se logran diferencias significativas a favor del postest en todas las pruebas físicas, tanto en el test de flexión de codo (p=0.001), como el test de abdominales (p=0.001). Además, se incluyen el salto horizontal (p=0.005) y el salto vertical (p=0.001). Es primordial potencializar el entrenamiento de la capacidad física de la fuerza en nadadores mediante una correcta planificación de entrenamiento funcional, dado el fortalecimiento de los músculos que intervienen en el gesto técnico. Se recomiendan cuatro acciones que influyen en ampliar la muestra de estudio; se hace énfasis en el género femenino; se comparan los resultados de la investigación con otros estudios en otros rangos etarios y se realiza una investigación de tipo cuasiexperimental.

RESUMO O treino funcional ajuda a potenciar a força em certos grupos musculares; desta forma, o atleta melhora a postura corporal, ganha força e resistência muscular e, portanto, pode aumentar os indicadores relacionados com a capacidade física e o desempenho final. Neste sentido, o objectivo da investigação era aplicar um programa de treino funcional centrado na melhoria da força dos nadadores do Clube Varadero. A investigação é do tipo descritivo-explicativo de ordem correlativa; é diagnosticada uma população de 17 nadadores (ambos os sexos; 14-16 anos de idade) do Clube. O treino funcional adaptado ao nadador foi aplicado com base em quatro indicadores físicos em dois momentos após a aplicação do treino. Foram conseguidas diferenças significativas a favor do pós-teste em todos os testes físicos, tanto no teste de flexão do cotovelo (p=0,001) como no teste abdominal (p=0,001). Além disso, o salto horizontal (p=0,005) e o salto vertical (p=0,001) estão incluídos. É essencial melhorar o treino da capacidade física de força dos nadadores através de um planeamento correto do treino funcional, dado o reforço dos músculos envolvidos no gesto técnico. São recomendadas quatro ações que influenciam o alargamento da amostra do estudo; é dada ênfase ao sexo feminino; os resultados da investigação são comparados com outros estudos noutras faixas etárias e é realizado um tipo de investigação quase-experimental.

ABSTRACT Functional training helps to enhance strength in certain muscle groups; in this way, the athlete improves body posture, gains muscle strength and endurance and, therefore, can increase indicators related to physical capacity and final performance. In this sense, the objective of the research was to apply a functional training program focused on the improvement of strength in beginner swimmers of the Varadero Club. The research is of descriptive-explanatory type of correlational order; a population of 17 swimmers (both genders; 14-16 years old) of the referred Club is diagnosed. A functional training adapted to the swimmer is applied on the basis of four physical indicators in two moments of applying said training. Significant differences are achieved in favor of the post- test in all the physical tests, both in the elbow flexion test (p=0.001) and in the abdominal test (p=0.001). In addition, the horizontal jump (p=0.005) and the vertical jump (p=0.001) are included. It is essential to potentiate the training of the physical capacity of strength in swimmers through a correct planning of functional training, given the strengthening of the muscles that intervene in the technical gesture. Four actions are recommended that influence the expansion of the study sample; emphasis is placed on the female gender; The results of the research are compared with other studies in other age ranges and a quasi-experimental type of research is carried out.

Manejo conservador de lesión aerodigestiva: reporte de un caso y revisión de la literatura / Conservative management of aerodigestive injury: A case report andreview of the literature

Introducción. El trauma penetrante de cuello representa un evento desafortunado de baja incidencia y alta complejidad diagnóstica y terapéutica, lo que supone un reto para el cirujano general.Caso clínico. Paciente femenina de 20 años de edad, quien sufrió una herida cervical por proyectil de arma de fuego, desarrollando de forma secundaria una lesión aerodigestiva. Se realizó un tratamiento expectante en un hospital de alta complejidad, con una evolución favorable. Discusión. En la literatura existe un claro debate en cuanto al manejo de las lesiones penetrantes en cuello y la sospecha de lesión orgánica oculta. En nuestro paciente la lesión aerodigestiva fue tratada mediante observación y seguimiento clínico. Conclusiones. El manejo de un paciente con lesión aerodigestiva se puede corroborar mediante las imágenes diagnósticas y se puede tratar de forma expectante con un resultado exitoso, sin agregar morbilidad y con un impacto adecuado en el buen uso de los recursos disponibles

Introduction. Penetrating neck trauma represents an unfortunate event with a low incidence and high diagnostic and therapeutic complexity, which represents a challenge for the general surgeon. Clinical case. A 20-year-old female patient, who suffered a cervical wound from a firearm projectile, secondarily developing an aerodigestive lesion. An expectant treatment was carried out in a high complexity hospital, with a favorable evolution.Discussion. In the literature there is a clear debate regarding the management of penetrating neck injuries and suspected occult organic injury. In our patient, the aerodigestive injury was treated by observation and clinical follow-up.Conclusions. The management of a patient with aerodigestive injury can be corroborated by diagnostic images and can be treated expectantly with a successful result, without adding morbidity and with an adequate impact on the proper use of available resources

Robust Descriptor of Pancreatic Tissue for Automatic Detection of Pancreatic Cancer in Endoscopic Ultrasonography.

Pancreatic cancer (PC) has a reported mortality of 98% and a 5-y survival rate of 6.7%. Experienced gastroenterologists detect 80% of those with early-stage PC by endoscopic ultrasonography (EUS). Here we propose an automatic second reader strategy to detect PC in an entire EUS procedure, rather than focusing on pre-selected frames, as the state-of-the-art methods do. The method unmasks echo tumoral patterns in frames with a high probability of tumor. First, speeded up robust features define a set of interest points with correlated heterogeneities among different filtering scales. Afterward, intensity gradients of each interest point are summarized by 64 features at certain locations and scales. A frame feature vector is built by concatenating statistics of each feature of the 15 groups of scales. Then, binary classification is performed by Support Vector Machine and Adaboost models. Evaluation was performed using a data set comprising 55 participants, 18 of PC class (16,585 frames) and 37 subjects of non-PC class (49,664 frames), randomly splitting 10 times. The proposed method reached an accuracy of 92.1%, sensitivity of 96.3% and specificity of 87.8.3%. The observed results are also stable in noisy experiments while deep learning approaches fail to maintain similar performance.

[Conjunctival mass as the first manifestation of Epstein Barr virus infection]. / Masa conjuntival como primera manifestación de infección por virus del Epstein Barr.

The Epstein Barr virus is an infectious disease with a high worldwide prevalence, which can present multiple systemic manifestations. The ophthalmological findings are the least frequent and nonspe cific and, therefore, its diagnosis is complicated and delayed; however, it should always be considered as a diagnostic possibility in the presence of atypical ocular and periocular inflammatory clinical pictures. OBJECTIVE: To describe the clinical case of a patient with the presence of a conjunctival mass as the first finding in Epstein Barr virus infection. CLINICAL CASE: A 4-year-old boy with a 4-day history of left upper eyelid edema and ptosis associated with a large, fast-growing, elevated, painful, and salmon-colored upper bulbar conjunctival mass with extension to the upper fornix associated with bilateral cervical and inguinal lymphadenopathy. Initially, a lymphoproliferative disorder was suspected, with blood count with lymphocytosis and atypical lymphocytes, elevated lactate dehydro genase, peripheral blood smear with an increase in white blood cells and some atypical lymphocytes, bone marrow aspirate with a predominance of granulocytes and predominantly CD8-positive T lym phocytes and an increase in Gamma-Delta T lymphocytes. The orbit CT scan showed thickening of the left upper eyelid with peripheral enhancement and the abdominal CT scan showed splenomegaly. Biopsy confirmed chronic Epstein Barr virus infection with positive IgM and indeterminate IgG anti bodies. Symptomatic management was indicated with satisfactory evolution and complete resolution of the conjunctival lesion and lymphadenopathy. CONCLUSION: Epstein Barr virus infection should be considered as a possible diagnosis in atypical ocular and periocular inflammatory manifestations in the pediatric population.

Isolation and characterization of monoclonal antibodies against human carbonic anhydrase-IX.

The architectural complexity and heterogeneity of the tumor microenvironment (TME) remains a substantial obstacle in the successful treatment of cancer. Hypoxia, caused by insufficient oxygen supply, and acidosis, resulting from the expulsion of acidic metabolites, are prominent features of the TME. To mitigate the consequences of the hostile TME, cancer cells metabolically rewire themselves and express a series of specific transporters and enzymes instrumental to this adaptation. One of these proteins is carbonic anhydrase (CA)IX, a zinc-containing extracellular membrane bound enzyme that has been shown to play a critical role in the maintenance of a neutral intracellular pH (pHi), allowing tumor cells to survive and thrive in these harsh conditions. Although CAIX has been considered a promising cancer target, only two antibody-based therapeutics have been clinically tested so far. To fill this gap, we generated a series of novel monoclonal antibodies (mAbs) that specifically recognize the extracellular domain (ECD) of human CAIX. Here we describe the biophysical and functional properties of a set of antibodies against the CAIX ECD domain and their applicability as: 1) suitable for development as an antibody-drug-conjugate, 2) an inhibitor of CAIX enzyme activity, or 3) an imaging/detection antibody. The results presented here demonstrate the potential of these specific hCAIX mAbs for further development as novel cancer therapeutic and/or diagnostic tools.

Biparatopic single-domain antibodies against Axl achieve ultra-high affinity through intramolecular engagement.

Overexpression of Axl, a TAM-family receptor tyrosine kinase, plays key roles in the formation, growth, and spread of tumors as well as resistance to targeted therapies and chemotherapies. We identified novel llama VHHs against human Axl using multiple complementary phage display selection strategies and characterized a subset of high-affinity VHHs. The VHHs targeted multiple sites in Ig-like domains 1 and 2 of the Axl extracellular domain, including an immunodominant epitope overlapping the site of Gas6 interaction and two additional non-Gas6 competitive epitopes recognized by murine monoclonal antibodies. Only a subset of VHHs cross-reacted with cynomolgus monkey Axl and none recognized mouse Axl. As fusions to human IgG1 Fc, VHH-Fcs bound Axl+ tumor cell lines and mertansine-loaded VHH-Fcs were cytotoxic in vitro against Axl+ cells in proportion to their binding affinities. Engineered biparatopic VHH-VHH heterodimers bound Axl avidly, and a subset of molecules showed dramatically enhanced association rates indicative of intramolecular binding. These VHHs may have applications as modular elements of biologic drugs such as antibody-drug conjugates.

Chronic Unilateral Uveitis as a Manifestation of Leprosy: A Case Report and Literature Review.

Purpose: To describe a case of leprosy presenting chronic anterior uveitis associated with other systemic lesions.Methods: Case report and systematic literature review.Results: We describe the case of a 65-year-old patient presenting clinical features of chronic uveitis and poor response to topical and intravitreal steroid treatment. Upon ocular examination, diffuse iris atrophy and macular edema were observed and laboratory tests for autoimmune and infectious diseases were within normal range. Physical examination revealed the presence of skin lesions on trunk and extremities, which were biopsied and identified as positive for leprosy.Conclusion: The case reported herein presented atypical characteristics of uveitis due to the involvement of the posterior segment of the eye. Leprosy diagnosis could be a challenge, a systematic approach is mandatory to achieve adequate treatment.

Structure-based engineering of pH-dependent antibody binding for selective targeting of solid-tumor microenvironment.

Recent development of monoclonal antibodies as mainstream anticancer agents demands further optimization of their safety for use in humans. Potent targeting and/or effector activities on normal tissues is an obvious toxicity concern. Optimization of specific tumor targeting could be achieved by taking advantage of the extracellular acidity of solid tumors relative to normal tissues. Here, we applied a structure-based computational approach to engineer anti-human epidermal growth factor receptor 2 (Her2) antibodies with selective binding in the acidic tumor microenvironment. We used an affinity maturation platform in which dual-pH histidine-scanning mutagenesis was implemented for pH selectivity optimization. Testing of a small set of designs for binding to the recombinant Her2 ectodomain led to the identification of antigen-binding fragment (Fab) variants with the desired pH-dependent binding behavior. Binding selectivity toward acidic pH was improved by as much as 25-fold relative to the parental bH1-Fab. In vitro experiments on cells expressing intact Her2 confirmed that designed variants formatted as IgG1/k full-size antibodies have high affinity and inhibit the growth of tumor spheroids at a level comparable to that of the benchmark anti-Her2 antibody trastuzumab (Herceptin®) at acidic pH, whereas these effects were significantly reduced at physiological pH. In contrast, both Herceptin and the parental bH1 antibody exhibited strong cell binding and growth inhibition irrespective of pH. This work demonstrates the feasibility of computational optimization of antibodies for selective targeting of the acidic environment such as that found in many solid tumors.

Impact of a Formulation Containing Unusual Polyunsaturated Fatty Acids, Trace Elements, Polyphenols and Plant Sterols on Insulin Resistance and Associated Disturbances.

INTRODUCTION: To evaluate the effect of a lipid-based formulation containing unusual polyunsaturated fatty acids, trace elements, polyphenols and plant sterols on insulin resistance and its associated disturbances among adults at risk of diabetes. METHODS: This was an 8-week, three-arm, open-label randomized clinical trial. We studied individuals aged ≥ 18 years old with diabetes risk given by a body mass index ≥ 25 kg/m2 or a FinnRisc score ≥ 13/20. Participants were randomly assigned to receive: 7 ml sunflower oil (control group), 3.5 ml of the study formulation + 3.5 ml of sunflower oil (low-dose group) or 7 ml of study formulation (high-dose group). RESULTS: We randomized 25 individuals. After one withdrawal in the high-dose group, the study sample comprised nine patients in the control, nine in the low-dose and six in the high-dose groups. The insulin sensitivity increased significantly and in a dose-dependent fashion, up to 10% in the high-dose group. At week 8 the low-dose group exhibited lower glycemic excursions during the oral glucose tolerance test (OGTT), especially 1 h after the glucose challenge (32 mg/dl or 23% lower vs. control group). The incremental area under the glucose curve in the OGTT was 17.1% lower in the low-dose group vs. the control group. Waist circumference increased in the control group, remained constant in the low-dose group and decreased in the high-dose group. C-reactive protein decreased in both formulation groups, up to 50% in the high-dose group. Participants in the formulation groups exhibited increased secretion of GLP-1 and plasma irisin at week 8 vs. the control group. CONCLUSION: The formulation induced favorable changes in insulin sensitivity, glucose tolerance, abdominal obesity and inflammation. These effects and their durability will need to be assessed in larger studies. TRIAL REGISTRATION: NCT03512665. FUNDING: Team Foods Colombia.

Covid-19: herramientas de prevención actual en las unidades de endoscopia / Covid-19: current prevention tools in endoscopy units

A finales de 2019 surgió en Wuhan (China) el SARS-CoV-2, un nuevo coronavirus causante del COVID-19. Al 13 de abril 2020 ha causado en el mundo 1.807.308 infecciones y 119.410 muertes. Por la forma de transmisión del virus y teniendo en cuenta que los servicios de gastroenterología y endoscopia digestiva son una fuente de fácil diseminación, dado a la exposición con aerosoles de manera constante que se emiten durante los procedimientos generando un mayor riesgo tanto para los profesionales de la salud como para los pacientes intervenidos. Es de gran importancia establecer herramientas de prevención dentro de los servicios de gastroenterología y endoscopia digestiva , teniendo en cuenta la evidencia al día de hoy y reconociendo que se está en una búsqueda constante de medidas que disminuyan el riesgo de contagio que permitan generar un ambiente seguro al personal de salud y pacientes. Se realizó una búsqueda en Pubmed con los siguientes términos: ("COVID-19" OR "coronavirus" OR "SARS-Cov-2") y ("gastrointestinal" OR "transmission" OR "intestinal" OR "digestive" OR "endoscopy" OR "esophagogastroduodenoscopy" OR "colonoscopy"). Por lo anterior se debe considerar que todos los pacientes llevados a procedimientos endoscópicos son de alto riesgo y se dará a conocer las herramientas de prevención actuales a nivel mundial.

In late 2019, SARS-CoV-2, a new coronavirus causing COVID-19, emerged in Wuhan (China). As of April 13 2020 it has caused 1.807.308 infections and 119.410 deaths worldwide. Due to the way this virus is transmitted and considering gastroenterology and digestive endoscopy services are a source of easy dissemination given the constant exposure with aerosols that are emitted during procedures there is an increased risk for both health care professionals and patients undergoing endoscopy. It is of great importance to establish prevention tools within the gastroenterology and digestive endoscopy services, based on the evidence gathered to date and recognizing that we are in a constant search for measures to reduce risk of infection that will provide a safe environment to staff and patients. Pubmed database was searched for the following terms: ("COVID-19" OR "coronavirus" OR "SARS-Cov-2") and "gastrointestinal" OR "transmission" OR "intestinal" OR "digestive" OR "endoscopy" OR "esophagogastroduodenoscopy" OR "colonoscopy"). Therefore, all patients brought in to undergo endoscopic procedures should be considered high-risk and current prevention tools will be made known worldwide.

Un caso de síndrome de embolia grasa: tratamiento y rehabilitación neurológica y cognitiva / A case report off at embolism syndrome: Treatment and neurological and cognitive rehabilitation

Resumen Se reporta el proceso de recuperación y rehabilitación neurológica y cognitiva de una mujer joven que desarrolló un síndrome de embolia grasa con repercusiones neurológicas, después de sufrir un politraumatismo. La paciente era una mujer de 21 años de edad con fractura cerrada de húmero y fémur izquierdos, que presentó un síndrome de embolia grasa, neumotórax izquierdo e hipertensión pulmonar, en las primeras 24 horas después de un accidente. Estuvo hospitalizada un mes y quedó con varios déficits neurológicos centrales, como infartos 'lacunares' y necrosis cortical laminar occipital, así como limitaciones en la bipedestación, la marcha, la visión y las funciones cognitivas. A partir del primer mes después del alta hospitalaria, se comenzó un proceso integral de rehabilitación neurológica y cognitiva en casa, y posteriormente, en una unidad médica de rehabilitación. Durante los primeros dos años después del accidente, la paciente recibió estimulación sensorial, sensoperceptiva y motora, así como rehabilitación motora y visual intensiva. Una vez se recuperó físicamente, se inició un proceso de rehabilitación neuropsicológica. Seis años después del accidente, la paciente terminó sus estudios universitarios y hoy está laboralmente activa. El proceso de rehabilitación neurológica es complejo, individual y difícil, aunque no imposible, y no se puede estandarizar un patrón de recuperación para todos los pacientes. Si bien existe la recuperación espontánea, la cual se da en los primeros seis meses, el caso aquí reportado demuestra que, en la fase crónica, la recuperación se puede lograr, pero requiere de evaluaciones y técnicas coordinadas de rehabilitación neurológica.

Abstract We report the neurological and cognitive recovery and rehabilitation process in a young woman who developed a fat embolism syndrome with neurological repercussions secondary to multiple trauma. The patient was a 21-year-old woman with a closed fracture of the left humerus and femur. She developed fat embolism syndrome, left pneumothorax and pulmonary hypertension in the first 24 hours after the accident. After one month of hospitalization, the patient had several central neurological deficits such as lacunar infarcts and occipital laminar cortical necrosis, as well as limitations in standing, walking, vision, and cognitive functions. An integral process of neurological and cognitive rehabilitation--first at home and later in a medical rehabilitation unit-- was carried out from the first month after being released from the hospital. During the first two years after the accident, the patient received sensory and motor stimulation, motor rehabilitation, and intensive visual rehabilitation. Once recovered physically, a process of neuropsychological rehabilitation began. Six years after the accident, the patient finished her university studies and she is working actively. The neurological rehabilitation process is complex, individual and difficult, but not impossible, and a recovery pattern cannot be standardized for all patients. Although there is spontaneous recovery, which occurs in the first six months, the case here reported shows that in the chronic phase recovery can be achieved but requires evaluations and coordinated techniques of neurological rehabilitation.

Binding and functional profiling of antibody mutants guides selection of optimal candidates as antibody drug conjugates.

An increasingly appreciated conundrum in the discovery of antibody drug conjugates (ADCs) is that an antibody that was selected primarily for strong binding to its cancer target may not serve as an optimal ADC. In this study, we performed mechanistic cell-based experiments to determine the correlation between antibody affinity, avidity, internalization and ADC efficacy. We used structure-guided design to assemble a panel of antibody mutants with predicted Her2 affinities ranging from higher to lower relative to the parent antibody, Herceptin. These antibodies were ranked for binding via SPR and via flow-cytometry on high-Her2 SKOV3 cells and low-Her2 MCF7 cells, the latter acting as a surrogate for low-Her2 normal cells. A subpanel of variants, representative of different Her2-binding affinities (2 strong, 2 moderate and 3 weak), were further screened via high-content imaging for internalization efficacies in high versus low-Her2 cells. Finally, these antibodies were evaluated in ADC cytotoxicity screening assays (using DM1 and MMAE secondary antibodies) and as antibody-drug conjugates (DM1 and PNU159682). Our results identified specific but weak Her2-binding variants as optimal candidates for developing DM1 and PNU ADCs since they exhibited high potencies (low to sub-nM) in high-Her2 SKOV3 cells and low toxicities in low-Her2 cells. The 2 strong-affinity variants were highly potent in SKOV3 cells but also showed significant toxicities in low-Her2 cells and therefore are predicted to be toxic in normal tissues. Our findings show that pharmacological profiling of an antibody library in multiple binding and functional assays allows for selection of optimal ADCs.