Loss of tumor suppressor TMEM127 drives RET-mediated transformation through disrupted membrane dynamics.

Internalization from the cell membrane and endosomal trafficking of receptor tyrosine kinases (RTKs) are important regulators of signaling in normal cells that can frequently be disrupted in cancer. The adrenal tumor pheochromocytoma (PCC) can be caused by activating mutations of the rearranged during transfection (RET) receptor tyrosine kinase, or inactivation of TMEM127, a transmembrane tumor suppressor implicated in trafficking of endosomal cargos. However, the role of aberrant receptor trafficking in PCC is not well understood. Here, we show that loss of TMEM127 causes wildtype RET protein accumulation on the cell surface, where increased receptor density facilitates constitutive ligand-independent activity and downstream signaling, driving cell proliferation. Loss of TMEM127 altered normal cell membrane organization and recruitment and stabilization of membrane protein complexes, impaired assembly, and maturation of clathrin-coated pits, and reduced internalization and degradation of cell surface RET. In addition to RTKs, TMEM127 depletion also promoted surface accumulation of several other transmembrane proteins, suggesting it may cause global defects in surface protein activity and function. Together, our data identify TMEM127 as an important determinant of membrane organization including membrane protein diffusability and protein complex assembly and provide a novel paradigm for oncogenesis in PCC where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation.

Loss of Tumour Suppressor TMEM127 Drives RET-mediated Transformation Through Disrupted Membrane Dynamics.

Internalization from the cell membrane and endosomal trafficking of receptor tyrosine kinases (RTK) are important regulators of signaling in normal cells that can frequently be disrupted in cancer. The adrenal tumour pheochromocytoma (PCC) can be caused by activating mutations of the RET receptor tyrosine kinase, or inactivation of TMEM127, a transmembrane tumour suppressor implicated in trafficking of endosomal cargos. However, the role of aberrant receptor trafficking in PCC is not well understood. Here, we show that loss of TMEM127 causes wildtype RET protein accumulation on the cell surface, where increased receptor density facilitates constitutive ligand-independent activity and downstream signaling, driving cell proliferation. Loss of TMEM127 altered normal cell membrane organization and recruitment and stabilization of membrane protein complexes, impaired assembly, and maturation of clathrin coated pits, and reduced internalization and degradation of cell surface RET. In addition to RTKs, TMEM127 depletion also promoted surface accumulation of several other transmembrane proteins, suggesting it may cause global defects in surface protein activity and function. Together, our data identify TMEM127 as an important determinant of membrane organization including membrane protein diffusability, and protein complex assembly and provide a novel paradigm for oncogenesis in PCC where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation.

Galectin-3 in biliary atresia and other pediatric cholestatic liver diseases.

AIMS: Biliary atresia (BA) is characterized by intrahepatic inflammation and rapid progression of liver fibrosis. Galectin-3, a beta-galactoside binding protein, is a key regulator of inflammation and fibrosis. The aim of this study was to characterize circulating and hepatic Galectin-3 levels in children with BA. METHODS: Plasma and liver samples were obtained from children with early BA at time of Kasai hepatoportoenterostomy, late BA at time of transplant, early and late other cholestatic liver diseases (CLD), and controls. Plasma Galectin-3 was measured using standard enzyme-linked immunoassay. Liver tissue was analyzed with multiplex immunohistochemistry and quantified using whole slide analysis. Statistical comparisons were made using nonparametric testing. RESULTS: Plasma Galectin-3 in late BA was significantly higher than in early BA (20.82 [12.45-30.46] vs. 11.30 [8.74-16.83] ng/mL, p = 0.0096). Galectin-3 levels correlated with markers of disease severity and interleukin-6. There were significantly more Galectin-3+ M2 macrophages in late BA in comparison to late other CLD (162 [157-233] vs. 49 [33-59] cells/mm2, p = 0.03). The number of Galectin-3+ M2 macrophages correlated with the number of activated hepatic stellate cells and bile duct proliferation. CONCLUSIONS: Plasma Galectin-3 is higher in late BA at time of transplant in comparison to early BA at time of Kasai. The number of Galectin-3 expressing M2 macrophages in late BA is elevated relative to late other CLD and was associated with other prognostic histological findings. Galectin-3 targeted therapy may be beneficial in slowing disease progression to cirrhosis in children with BA.

Evaluation of factors leading to poor outcomes for pediatric acute lymphoblastic leukemia in Mexico: a multi-institutional report of 2,116 patients.

Background and aims: Pediatric acute lymphoblastic leukemia (ALL) survival rates in low- and middle-income countries are lower due to deficiencies in multilevel factors, including access to timely diagnosis, risk-stratified therapy, and comprehensive supportive care. This retrospective study aimed to analyze outcomes for pediatric ALL at 16 centers in Mexico. Methods: Patients <18 years of age with newly diagnosed B- and T-cell ALL treated between January 2011 and December 2019 were included. Clinical and biological characteristics and their association with outcomes were examined. Results: Overall, 2,116 patients with a median age of 6.3 years were included. B-cell immunophenotype was identified in 1,889 (89.3%) patients. The median white blood cells at diagnosis were 11.2.5 × 103/mm3. CNS-1 status was reported in 1,810 (85.5%), CNS-2 in 67 (3.2%), and CNS-3 in 61 (2.9%). A total of 1,488 patients (70.4%) were classified as high-risk at diagnosis. However, in 52.5% (991/1,889) of patients with B-cell ALL, the reported risk group did not match the calculated risk group allocation based on National Cancer Institute (NCI) criteria. Fluorescence in situ hybridization (FISH) and PCR tests were performed for 407 (19.2%) and 736 (34.8%) patients, respectively. Minimal residual disease (MRD) during induction was performed in 1,158 patients (54.7%). The median follow-up was 3.7 years. During induction, 191 patients died (9.1%), and 45 patients (2.1%) experienced induction failure. A total of 365 deaths (17.3%) occurred, including 174 deaths after remission. Six percent (176) of patients abandoned treatment. The 5-year event-free survival (EFS) was 58.9% ± 1.7% for B-cell ALL and 47.4% ± 5.9% for T-cell ALL, while the 5-year overall survival (OS) was 67.5% ± 1.6% for B-cell ALL and 54.3% ± 0.6% for T-cell ALL. The 5-year cumulative incidence of central nervous system (CNS) relapse was 5.5% ± 0.6%. For the whole cohort, significantly higher outcomes were seen for patients aged 1-10 years, with DNA index >0.9, with hyperdiploid ALL, and without substantial treatment modifications. In multivariable analyses, age and Day 15 MRD continued to have a significant effect on EFS. Conclusion: Outcomes in this multi-institutional cohort describe poor outcomes, influenced by incomplete and inconsistent risk stratification, early toxic death, high on-treatment mortality, and high CNS relapse rate. Adopting comprehensive risk-stratification strategies, evidence-informed de-intensification for favorable-risk patients and optimized supportive care could improve outcomes.

Eficacia del nimotuzumab según índices inflamatorios en pacientes con cáncer de pulmón no microcítico avanzado

Introducción: La respuesta a las terapias en el cáncer de pulmón avanzado pudiera estar relacionada con determinados factores pronósticos como los índices inflamatorios. Objetivo: Evaluar la eficacia del anticuerpo monoclonal humanizado nimotuzumab en pacientes portadores de cáncer de pulmón no microcítico avanzado según índices inflamatorios. Método: Se realizó un estudio de evaluación longitudinal retrospectivo, en un universo de 498 pacientes mayores de 18 años, con diagnóstico citohistológico de cáncer de pulmón de células no pequeñas, en estadios avanzados, después de la primera línea de terapia oncológica, incluidos en ensayos clínicos multicéntricos promovidos por el Centro de Inmunología Molecular desde 2002 a 2018. Se aplicó la estadística descriptiva, se utilizó el software x-tile 3.6.1 para el test de Kaplan Meier; se consideraron diferencias significativas cuando p< 0,05. Resultados: En los pacientes analizados el nimotuzumab mostró beneficio terapéutico en el grupo de pacientes no progresores a la primera línea de tratamiento con quimioterapia o quimiorradioterapia, cuando tenían menor índice de neutrófilos/linfocitos (p= 0,017 y p= 0,027) y menor índice de plaquetas/linfocitos (p= 0,030 y p= 0,009). Conclusión: La selección de un paciente con menor índice inflamatorio beneficia la eficacia del tratamiento con el AcM humanizado nimotuzumab en el cáncer de pulmón avanzado no microcítico, la que se convierte en una herramienta predictiva de la respuesta al tratamiento.

Introduction: The response to therapies in advanced lung cancer could be related to certain prognostic factors such as inflammatory indices. Objective: To evaluate the efficacy of the humanized monoclonal antibody nimotuzumab in patients with advanced non-small cell lung cancer according to inflammatory indices. Method: A retrospective longitudinal evaluation study was carried out in a universe of 498 patients older than 18 years, with a cytohistological diagnosis of non-small cell lung cancer, in advanced stages, after the first line of oncological therapy, including in multicenter clinical trials promoted by the Center for Molecular Immunology from 2002 to 2018. Descriptive statistics were applied, the x-tile 3.6.1 software was used for the Kaplan Meier test, significant differences were considered when p< 0,05. Results: In the patients analyzed, nimotuzumab showed therapeutic benefit in the group of patients who did not progress to the first line of treatment with chemotherapy or chemoradiotherapy, when they had a lower neutrophil-lymphocyte index (p= 0,017 and p= 0,027) and a lower platelet-lymphocyte index (p= 0,030 and p= 0,009). Conclusion: Selecting a patient with a lower inflammatory index benefits the efficacy of treatment with the humanized mAb nimotuzumab in advanced non-small cell lung cancer, which becomes a predictive tool for response to treatment.

Aportes de la Educación 4.0 y la caja de herramientas tecnológicas a exigencias educativas actuales / Contributions of Education 4.0 and the Technological Toolbox according to Current Educational Demands

Los cambios tecnológicos de la cuarta revolución industrial reflejan transformaciones en todos los ámbitos: laboral, educativo, político, etcétera, lo que cambia de manera radical la forma de estudiar, trabajar, comprar y socializar. El objetivo de este trabajo fue identificar elementos de la educación 4.0 y la caja de herramientas tecnológicas que aporten a las exigencias educativas actuales. El nuevo paradigma supone, por parte de las instituciones, una serie de acciones encaminadas a incrementar la flexibilidad de tiempo y espacio para toda la comunidad participante, tomar en cuenta las necesidades de aprendizaje de los alumnos, aplicar el aprendizaje semipresencial y el autoaprendizaje con base en las TIC, y mejorar las estrategias de aprendizaje colaborativo. Para el diseño de nuevos proyectos de innovación educativa se deben considerar los cuatro componentes centrales de la Educación 4.0: las competencias, los métodos de aprendizaje, las tecnologías de la información y la comunicación, y la infraestructura. La caja de herramientas del docente continúa siendo un elemento necesario para la estructuración metodológica de los contenidos y el apoyo tecnológico al proceso educativo en general, pues resulta un fenómeno complejo que forma parte del ecosistema de aprendizaje. Los requerimientos actuales, orientados a la adopción de la tecnología como una necesidad para hacer frente a la dinámica moderna de las economías y el conocimiento, demandan la modernización de la educación en sus diferentes niveles, en especial la educación superior con una visión regenerativa de la educación, los cuales incluyen elementos de la caja de herramientas y la Educación 4.0(AU)

The technological changes of the fourth industrial revolution show transformations in all areas (labor, education, politics, among others), which produces a radical change in the way to study, work, shop and socialize. The objective of this work was to identify elements of Education 4.0 and the technological toolbox that contribute to satisfy the current educational demands. The new paradigm implies that institutions take a series of actions aimed at increasing the flexibility of time and space for the whole participating community, considering the learning needs of students, applying blended learning and ICT-based self-learning, as well as improving collaborative learning strategies. In view of designing new educational innovation projects, consideration must be given to the four central components of Education 4.0: competences, learning methods, information and communication technologies, as well as infrastructure. Any professor's toolbox continues to be a necessary element for structuring contents methodologically and supporting the general educational process technologically, since this is a complex phenomenon belonging to the learning ecosystem. Current requirements, oriented to implementing technology as a necessity to face the modern dynamics of economies and knowledge, demand that education be modernized at different levels, especially higher education, with a regenerative vision of education, including elements from the toolbox and Education 4.0(AU)

Multi-target withaferin-A analogues as promising anti-kinetoplastid agents through the programmed cell death.

Leishmaniasis and Chagas disease, two of the most prevalent neglected tropical diseases, are a world health problem. The harsh reality of these infective diseases is the absence of effective and safe therapies. In this framework, natural products play an important role in overcoming the current need to development new antiparasitic agents. The present study reports the synthesis, antikinetoplastid screening, mechanism study of fourteen withaferin A derivatives (2-15). Nine of them (2-6, 8-10 and 12) showed a potent dose-dependent inhibitory effect on the proliferation of Leishmania amazonensis and L. donovani promastigotes and Trypanosoma cruzi epimastigotes with IC50 values ranging from 0.19 to 24.01 µM. Outstandingly, the fully acetylated derivative 10 (4,27-diacetylwithaferin A) was the most potent compound showing IC50 values of 0.36, 2.82 and 0.19 µM against L. amazonensis, L. donovani and T. cruzi, respectively. Furthermore, analogue 10 exhibited approximately 18 and 36-fold greater antikinetoplastid activity, on L. amazonensis and T. cruzi, than the reference drugs. The activity was accompanied by significantly lower cytotoxicity on the murine macrophage cell line. Moreover, compounds 2, 3, 5-7, 9 and 10 showed more potent activity than the reference drug against the intracellular amastigotes forms of L. amazonensis and T.cruzi, with a good selectivity index on a mammalian cell line. In addition, withaferin A analogues 3, 5-7, 9 and 10 induce programmed cell death through a process of apoptosis-like and autophagy. These results strengthen the anti-parasitic potential of withaferin A-related steroids against neglected tropical diseases caused by Leishmania spp. and T. cruzi parasites.

Withaferin A-silyl ether analogs as potential anti-kinetoplastid agents targeting the programmed cell death.

Current therapies of leishmaniasis and Chagas disease, two of the most widespread neglected tropical diseases, have limited efficacy and toxic side effects. In this regard, natural products play an important role in overcoming the current need for new antiparasitic agents. The present study reports the leishmanicidal and trypanocidal activities of twenty-four known silyl-ether derivatives of withaferin A. Eleven compounds from this series (4, 7, 8, 10, 12, 15, 17, 18, 20, 22 and 25) showed a potent dose-dependent inhibitory effect on the proliferation of Leishmania amazonensis promastigotes and Trypanosoma cruzi epimastigotes respectively, even higher than the references drugs, miltefosine and benznidazole. Among them, the most promising compound, derivative 10, exhibited approximately 34-fold higher leishmanicidal activity and 49-fold higher trypanocidal activity compared to the reference drugs, as well as lower cytotoxicity. Moreover, compounds 4, 7, 10, 12 and 15 were more active than the reference drugs against the amastigote forms of L. amazonensis, presenting a high selectivity index. Assays performed to study the ATP levels, mitochondrial membrane potential, plasma membrane permeability, chromatin condensation, reactive oxygen species and autophagy indicated that these withaferin A-silyl analogs appear to induce events characteristic of apoptosis-like and also autophagy leading to programmed cell death. These findings support the therapeutic potential of withaferin A-related steroids as anti-Leishmania and Trypanosoma agents.

Glaucoma-simulating cupping in a patient with periventricular leukomalacia: a clinical case report / Escavação simulando glaucoma em paciente com leucomalácia periventricular: relato de caso clínico

ABSTRACT Non-glaucomatous papillary cupping constitutes an important differential diagnosis in daily medical practice. There are patients diagnosed and treated as glaucoma, who do not present the disease and are part of the large group of non-glaucomatous optic neuropathies. This case emphasizes directing the diagnostic gaze to these "apparently glaucomatous" optic nerves through a case of periventricular leukomalacia. Patients with a history of prematurity, alterations in the cerebral white matter and presence of optic nerve excavations with normal intraocular pressures.

RESUMO A escavação papilar não glaucomatosa constitui um importante diagnóstico diferencial na prática médica diária. Há pacientes que recebem o diagnóstico de e tratamento para glaucoma, que não apresentam a doença e fazem parte do grande grupo de neuropatias ópticas não glaucomatosas. Este caso enfatiza o direcionamento do olhar diagnóstico para nervos ópticos "aparentemente glaucomatosos" através de um episódio de leucomalácia periventricular. Pacientes com histórico de prematuridade, alterações na substância branca do cérebro e presença de escavações do nervo óptico com pressões intraoculares normais.

Tinea faciei por Trichophyton violaceum: primer caso alóctono reportado en Chile

Trichophyton violaceum es un dermatofito antropofílico endémico en África, Europa, Centroamérica y China. El incremento de los fenómenos de movilidad humana ha contribuido a su aparición en áreas no endémicas. Su principal manifestación clínica es la tinea capitis, seguida por la tinea corporis. En la población pediátrica afecta con mayor frecuencia el cuero cabelludo; y en adultos, la piel glabra. Presentamos el primer caso en Chile de tinea causada por T violaceum. Correspondió a una mujer chilena de 21 años que presentó placas faciales de un mes de evolución después de un viaje a Tanzania, África, sin respuesta a tratamientos médicos previos. Se sospechó una dermatofitosis alóctona y mediante cultivos especiales, se identificó una colonia de crecimiento lento, coloración violeta-negruzca, superficie cerosa y rugosa, con vellosidades aterciopeladas; compatible con T violaceum. Se confirmó mediante secuenciación de ADN ribosomal amplificando la región ITS. Se trató con terbinafina oral con respuesta clínica completa.

Trichophyton violaceum is an anthropophilic dermatophyte endemic in Africa, Europe, Central America and China. The increase in human mobility has recently contributed to the appearance in non-endemic areas. The main clinical manifestation is tinea capitis followed by tinea corporis. We present the first case in Chile of tinea caused by T violaceum. The case was a 21 year-old Chilean woman who presented asymptomatic facial plaques one month after arriving from Tanzania, Africa, with no clinical response to previous medical treatments. An allochthonous dermatophytosis was suspected and with special cultures, a slow-growing colony was identified with a violet-blackish color, waxy and rough surface, and velvety villi; all characteristics of T violaceum. The diagnosis was confirmed by ribosomal DNA sequencing amplifying the ITS region. She was treated with oral terbinafine obtaining a complete clinical response.

Liver transplantation is beneficial regardless of cirrhosis stage or acute-on-chronic liver failure grade: A single-center experience.

BACKGROUND: Liver transplantation for the most critically ill remains controversial; however, it is currently the only curative treatment option. AIM: To assess immediate posttransplant outcomes and compare the short (1 year) and long-term (6 years) posttransplant survival among cirrhotic patients stratified by disease severity. METHODS: We included cirrhotic patients undergoing liver transplantation between 2015 and 2019 and categorized them into compensated cirrhosis (CC), decompensated cirrhosis (DC), and acute-on-chronic liver failure (ACLF). ACLF was further divided into severity grades. Our primary outcomes of interest were total days of intensive care unit (ICU) and hospital stay, development of complications and posttransplant survival at 1 and 6 years. RESULTS: 235 patients underwent liver transplantation (CC = 11, DC = 129 and ACLF = 95). Patients with ACLF had a significantly longer hospital stay [8.0 (6.0-13.0) vs CC, 6.0 (3.0-7.0), and DC 7.0 (4.5-10.0); P = 0.01] and developed more infection-related complications [47 (49.5%), vs CC, 1 (9.1%) and DC, 38 (29.5%); P < 0.01]. Posttransplant survival at 1- and 6-years was similar among groups (P = 0.60 and P = 0.90, respectively). ACLF patients stratified according to ACLF grade [ACLF-1 n = 40 (42.1%), ACLF-2 n = 33 (34.7%) and ACLF-3 n = 22 (23.2%)], had similar ICU and hospital stay length (P = 0.68, P = 0.54), as well as comparable frequencies of overall and infectious post-transplant complications (P = 0.58, P = 0.80). There was no survival difference between ACLF grades at 1 year and 6 years (P = 0.40 and P = 0.15). CONCLUSION: Patients may benefit from liver transplantation regardless of the cirrhosis stage. ACLF patients have a longer hospital stay and frequency of infectious complications; however, excellent, and comparable 1 and 6-year survival rates support their enlisting and transplantation including those with ACLF-3.

Essential Topics About the Imaging Diagnosis and Treatment of Hemorrhagic Stroke: A Comprehensive Review of the 2022 AHA Guidelines.

Intracerebral hemorrhage (ICH) is a severe stroke with a high death rate (40% mortality). The prevalence of hemorrhagic stroke has increased globally, with changes in the underlying cause over time as anticoagulant use and hypertension treatment have improved. The fundamental etiology of ICH and the mechanisms of harm from ICH, particularly the complex interaction between edema, inflammation, and blood product toxicity, have been thoroughly revised by the American Heart Association (AHA) in 2022. Although numerous trials have investigated the best medicinal and surgical management of ICH, there is still no discernible improvement in survival and functional tests. Small vessel diseases, such as cerebral amyloid angiopathy (CAA) or deep perforator arteriopathy (hypertensive arteriopathy), are the most common causes of spontaneous non-traumatic intracerebral hemorrhage (ICH). Even though ICH only causes 10%-15% of all strokes, it contributes significantly to morbidity and mortality, with few acute or preventive treatments proven effective. Current AHA guidelines acknowledge up to 89% sensitivity for unenhanced brain CT and 81% for brain MRI. The imaging findings of both methods are helpful for initial diagnosis and follow-up, sometimes necessary a few hours after admission, especially for detecting hemorrhagic transformation or hematoma expansion. This review summarized the essential topics on hemorrhagic stroke epidemiology, risk factors, physiopathology, mechanisms of injury, current management approaches, findings in neuroimaging, goals and outcomes, recommendations for lifestyle modifications, and future research directions ICH. A list of updated references is included for each topic.

Evaluating Cell Membrane Localization and Intracellular Transport of Proteins by Biotinylation.

Protein translocation to the cell membrane and transport through intracellular compartments are dynamic processes frequently altered in cancer cells. Abnormal protein localization can affect key cell functions, including transduction of extracellular signals and organization of the cytoskeleton, significantly affecting oncogenicity and therapeutic responses. In this chapter, we describe a surface protein biotinylation method that allows the study of membrane localization and endosomal transport of membrane-associated proteins. Surface biotinylation can be used to evaluate baseline protein levels at the membrane, and other processes such as internalization, recycling, and degradation of proteins in response to different treatments or as a consequence of oncogenic mutations. Further, the combination of this technique with other strategies, such as treatments with transport inhibitors, allows investigation of specific steps of protein trafficking through the cell.

Galectin-3 is overexpressed in advanced cirrhosis and predicts post-liver transplant infectious complications.

BACKGROUND & AIMS: Patients with advanced cirrhosis often have immune dysfunction and are more susceptible to infections. Galectin-3 is a ß-galactoside-binding lectin implicated in inflammation, immune regulation and liver fibrosis. We aim to investigate galectin-3 expression in advanced cirrhosis and its ability to predict post-transplant infectious complications. METHODS: We collected sera and liver samples from 129 cirrhotic patients at the time of liver transplantation and from an external cohort of 37 patients with alcoholic liver disease including alcoholic hepatitis (AH) at the time of diagnosis. Galectin-3 was assessed by ELISA, real-time PCR, immunohistochemistry and RNA-seq. Receiver operating characteristic curves and Cox proportional-hazards regression analysis were performed to assess the predictive power of galectin-3 for disease severity and post-transplant infections. RESULTS: Increased galectin-3 levels were found in advanced cirrhosis. Galectin-3 significantly correlated with disease severity parameters and inflammatory markers. Galectin-3 had significant discriminating power for compensated and advanced cirrhosis (AUC = 0.78/0.84, circulating/liver galectin-3; p < .01), and was even higher to discriminate severe AH (AUC = 0.95, p < .0001). Cox Proportional-hazard model showed that galectin-3, MELD-Na and the presence of SIRS predict the development of post-transplant infectious complications. Patients with circulating galectin-3 (>16.58 ng/ml) were at 2.19-fold 95% CI (1.12-4.29) increased risk, but when combined with MELD-Na > 20.0 and SIRS, the risk to develop post-transplant infectious complications, increased to 4.60, 95% CI (2.38-8.90). CONCLUSION: Galectin-3 is a novel biological marker of active inflammation and disease severity that could be clinically useful alone or in combination with other scores to discriminate advanced cirrhosis and predict post-transplant infectious complications.

A Rare Case of an Intracranial Dermoid Cyst with Atypical Appearance on Computed Tomography and Magnetic Resonance Imaging.

BACKGROUND Dermoid cysts are rare benign intracranial tumors that usually present classic computed tomography (CT) and magnetic resonance imaging (MRI) characteristics, allowing for relatively simple diagnostic confirmation. Atypical imaging features can occur due to their diverse ectodermal-derived content, which can result in a diagnostic dilemma. Making an accurate diagnosis is essential for adequate management. CASE REPORT We present a case of a 39-year-old woman with past medical history of increased blood pressure, presenting with worsening headaches non-refractory to medication. Imaging revealed an extra-axial lesion within the midline posterior fossa with an occipital transdiploic linear channel. The lesion was T2 profoundly hypointense on brain MRI, and prominently hyperdense on non-contrast CT scan. Catheter angiography excluded vascular etiology. After complete lesion resection, results of the histopathologic examination were consistent with a dermoid cyst. Dermoid cysts that are hyperdense on CT and hypointense on T2-WI are extremely rare. CONCLUSIONS Complete surgical resection is the treatment of choice for most dermoid cysts. Atypical radiologic features, in an already rare intracranial tumor, can delay correct diagnosis and management. Recognition of these findings is therefore important for adequate imaging analysis of these lesions.

Time-Dependent Changes of Laboratory Parameters as Independent Predictors of All-Cause Mortality in COVID-19 Patients.

Independent predictors of mortality for COVID-19 patients have been identified upon hospital admission; however, how they behave after hospitalization remains unknown. The aim of this study is to identify clinical and laboratory parameters from admission to discharge or death that distinguish survivors and non-survivors of COVID-19, including those with independent ability to predict mortality. In a cohort of 266 adult patients, clinical and laboratory data were analyzed from admission and throughout hospital stay until discharge or death. Upon admission, non-survivors had significantly increased C reactive protein (CRP), neutrophil count, neutrophil to lymphocyte ratio (NLR) (p < 0.0001, each), ferritin (p < 0.001), and AST (aspartate transaminase) (p = 0.009) compared to survivors. During the hospital stay, deceased patients maintained elevated CRP (21.7 mg/dL [admission] vs. 19.3 [hospitalization], p = 0.060), ferritin, neutrophil count and NLR. Conversely, survivors showed significant reductions in CRP (15.8 mg/dL [admission] vs. 9.3 [hospitalization], p < 0.0001], ferritin, neutrophil count and NLR during hospital stay. Upon admission, elevated CRP, ferritin, and diabetes were independent predictors of mortality, as were persistently high CRP, neutrophilia, and the requirement of invasive mechanical ventilation during hospital stay. Inflammatory and clinical parameters distinguishing survivors from non-survivors upon admission changed significantly during hospital stay. These markers warrant close evaluation to monitor and predict patients' outcome once hospitalized.

Como Predecir el Cambio del Tejido Blando Facial Luego de Cirugía Ortognática. Una Revisión de la Literatura

RESUMEN: Habitualmente los pacientes buscan estética en un tratamiento de ortodoncia, y al tener que someterse a una cirugía ortognática, lo que más les preocupa es cómo se verán luego de ésta. Hoy en día existe variados softwares para mostrar una imagen virtual del resultado del tejido esquelético y blando luego de una cirugía, pero no se ha llegado a consenso de que tan fiables son, ya que cada ortodoncista puede utilizar distintos métodos de medición. En este estudio queremos realizar una revisión bibliográfica para evaluar el efecto de la cirugía Lefort I y sagital bilateral de rama sobre el tejido blando del tercio medio e inferior en pacientes que han tenido tratamiento ortodóncico. Para así, en un futuro, poder predecir el comportamiento del tejido blando a través del tratamiento quirúrgico.

ABSTRACT: Usually patients seek aesthetics in orthodontic treatment, and having to undergo orthognathic surgery, what they are most concerned about is how they will look after it. Nowadays there are various softwares to show a virtual image of the result of skeletal and soft tissue after surgery, but no consensus has been reached on how reliable they are, since each orthodontist can use different measurement methods. In this study, we want to carry out a bibliographic review to evaluate the effect of Lefort I and bilateral sagittal branch surgery on the soft tissue of the middle and lower third in patients who have undergone orthodontic treatment. Thus, in the future, to be able to predict the behavior of soft tissue through surgical treatment.

Galectin-3 as a potential prognostic biomarker of severe COVID-19 in SARS-CoV-2 infected patients.

Severe COVID-19 is associated with a systemic hyperinflammatory response leading to acute respiratory distress syndrome (ARDS), multi-organ failure, and death. Galectin-3 is a ß-galactoside binding lectin known to drive neutrophil infiltration and the release of pro-inflammatory cytokines contributing to airway inflammation. Thus, we aimed to investigate the potential of galectin-3 as a biomarker of severe COVID-19 outcomes. We prospectively included 156 patients with RT-PCR confirmed COVID-19. A severe outcome was defined as the requirement of invasive mechanical ventilation (IMV) and/or in-hospital death. A non-severe outcome was defined as discharge without IMV requirement. We used receiver operating characteristic (ROC) and multivariable logistic regression analysis to determine the prognostic ability of serum galectin-3 for a severe outcome. Galectin-3 levels discriminated well between severe and non-severe outcomes and correlated with markers of COVID-19 severity, (CRP, NLR, D-dimer, and neutrophil count). Using a forward-stepwise logistic regression analysis we identified galectin-3 [odds ratio (OR) 3.68 (95% CI 1.47-9.20), p < 0.01] to be an independent predictor of severe outcome. Furthermore, galectin-3 in combination with CRP, albumin and CT pulmonary affection > 50%, had significantly improved ability to predict severe outcomes [AUC 0.85 (95% CI 0.79-0.91, p < 0.0001)]. Based on the evidence presented here, we recommend clinicians measure galectin-3 levels upon admission to facilitate allocation of appropriate resources in a timely manner to COVID-19 patients at highest risk of severe outcome.

Genome-driven medicine for patients with recurrent glioma enrolled in early phase trials.

BACKGROUND: Recent studies showed that patients with glioma can safely participate in early phase clinical trials; however, clinical benefits in this population were limited. We aimed to evaluate the benefit of molecular profiling to guide enrolment in early phase trials for patients with recurrent glioma. METHODS: Records of patients enrolled in early phase trials of cytotoxic therapies, small molecule inhibitors or monoclonal antibodies from 2008 to 2018 were reviewed for clinico-pathological characteristics, toxicity, response, progression-free survival and overall survival (OS). The primary objective was to evaluate response rates in molecularly-oriented versus non-molecularly-oriented patients. RESULTS: Eighty-eight patients were enrolled, of whom 45 (51.1%) patients were molecularly-oriented. Targets included IDH1/2 (n = 15), BRAF (n = 11), and FGFR1 (n = 3) mutations, FGFR2-3 fusions (n = 9), and mismatch repair deficiency (n = 7). Among patients with high-grade glioma (n = 74), the rate of stable disease ≥6 months and partial or complete response was 25.7% in molecularly-oriented versus 5.1% in non-molecularly-oriented patients (p = 0.02). Upon multivariable adjustment, baseline steroid use ≥20 mg prednisone equivalent per day was associated with shorter OS (OR 3.15 [95% CI 1.62-6.13], p = 0.0008), while molecular enrichment strategy was associated with longer OS (OR 0.40 [95% CI 0.22-0.73], p = 0.003). Nine (10.2%) patients experienced grade 3-4 toxicity and no dose limiting toxicity (DLT) occurred in both cohorts. CONCLUSION: The use of molecular profiling to guide enrolment in early phase trials is feasible and might provide benefits to selected patients with glioma. Further studies are warranted to confirm these results in larger randomised settings and identify the patients most likely to benefit from this approach.