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Abstract Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response.

Abstract Osimertinib sensitive and resistant NSCLC NCI-H1975 clones are used to model osimertinib acquired resistance in humanized and non-humanized mice and delineate potential resistance mechanisms. No new EGFR mutations or loss of the EGFR T790M mutation are found in resistant clones. Resistant tumors grown under continuous osimertinib pressure both in humanized and non-humanized mice show aggressive tumor regrowth which is significantly less sensitive to osimertinib as compared with parental tumors. 3-phosphoinositide-dependent kinase 1 (PDK1) is identified as a potential driver of osimertinib acquired resistance, and its selective inhibition by BX795 and CRISPR gene knock out, sensitizes resistant clones. In-vivo inhibition of PDK1 enhances the osimertinib sensitivity against osimertinib resistant xenograft and a patient derived xenograft (PDX) tumors. PDK1 knock-out dysregulates PI3K/Akt/mTOR signaling, promotes cell cycle arrest at the G1 phase. Yes-associated protein (YAP) and active-YAP are upregulated in resistant tumors, and PDK1 knock-out inhibits nuclear translocation of YAP. Higher expression of PDK1 and an association between PDK1 and YAP are found in patients with progressive disease following osimertinib treatment. PDK1 is a central upstream regulator of two critical drug resistance pathways: PI3K/AKT/mTOR and YAP.

IntroductionMultisystem inflammatory syndrome in children associated with coronavirus disease 2019 (MIS-C), a novel hyperinflammatory condition secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is associated with severe outcomes such as coronary artery aneurysm and death.MethodsThis multicenter, retrospective, observational cohort study including eight centers in Mexico, aimed to describe the clinical characteristics and outcomes of patients with MIS-C. Patient data were evaluated using latent class analysis (LCA) to categorize patients into three phenotypes: toxic shock syndrome-like (TSSL)-MIS-C, Kawasaki disease-like (KDL)-MIS-C, and nonspecific MIS-C (NS-MIS-C). Risk factors for adverse outcomes were estimated using multilevel mixed-effects logistic regression.ResultsThe study included 239 patients with MIS-C, including 61 (26%), 70 (29%), and 108 (45%) patients in the TSSL-MIS-C, KDL-MIS-C, and NS-MIS-C groups, respectively. Fifty-four percent of the patients were admitted to the intensive care unit, and 42%, 78%, and 41% received intravenous immunoglobulin, systemic glucocorticoids, and anticoagulants, respectively. Coronary artery dilatation and aneurysms were found in 5.7% and 13.2% of the patients in whom coronary artery diameter was measured, respectively. Any cause in-hospital mortality was 5.4%. Hospitalization after ten days of symptoms was associated with coronary artery abnormalities (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.2–2.0). Age ≥10 years (OR: 5.6, 95% CI: 1.4–2.04), severe underlying condition (OR: 9.3, 95% CI: 2.8–31.0), platelet count 1.2 (OR: 3.8, 95% CI: 1.05–13.9), and serum ferritin concentration >1,500 mg/dl at admission (OR: 52, 95% CI: 5.9–463) were risk factors for death.DiscussionMortality in patients with MIS-C was higher than reported in other series, probably because of a high rate of cases with serious underlying diseases.

IntroductionIn children, the manifestations of coronavirus disease 2019 (COVID-19) in the acute phase are considered mild compared with those in adults; however, some children experience a severe disease that requires hospitalization. This study was designed to present the operation and follow-up results of the Post-COVID-19 Detection and Monitoring Sequels Clinic of Hospital Infantil de Mexico Federico Gómez in managing children with a history of SARS-CoV-2 infection.MethodsThis was a prospective study conducted from July 2020 to December 2021, which included 215 children aged 0–18 years who tested positive for SARS-CoV-2 on polymerase chain reaction and/or immunoglobulin G test. The follow-up was conducted in the pulmonology medical consultation; ambulatory and hospitalized patients were assessed at 2, 4, 6, and 12 months.ResultsThe median age of the patients was 9.02 years, and neurological, endocrinological, pulmonary, oncological, and cardiological comorbidities were the most commonly observed among the patients. Moreover, 32.6% of the children had persistent symptoms at 2 months, 9.3% at 4 months, and 2.3% at 6 months, including dyspnea, dry cough, fatigue, and runny nose; the main acute complications were severe pneumonia, coagulopathy, nosocomial infections, acute renal injury, cardiac dysfunction, and pulmonary fibrosis. The more representative sequelae were alopecia, radiculopathy, perniosis, psoriasis, anxiety, and depression.ConclusionsThis study showed that children experience persistent symptoms, such as dyspnea, dry cough, fatigue, and runny nose, although to a lesser extent than adults, with significant clinical improvement 6 months after the acute infection. These results indicate the importance of monitoring children with COVID-19 through face-to-face consultations or telemedicine, with the objective of offering multidisciplinary and individualized care to preserve the health and quality of life of these children.

This study focuses on the development of a piezoelectric device capable of generating feedback vibrations to the user who manipulates it. The objective here is to explore the possibility of developing a haptic system that can replace physical buttons on the tactile screen of in-car systems. The interaction between the user and the developed device allows completing the feedback loop, where the user’s action generates an input signal that is translated and outputted by the device, and then detected and interpreted by the user’s haptic sensors and brain. An FEM (finite element model) via ANSYS multiphysics software was implemented to optimize the haptic performance of the wafer structure consisting of a BaTiO3 multilayered piezocomposite coated on a PET transparent flexible substrate. Several parameters relating to the geometric and mechanical properties of the wafer, together with those of the electrodes, are demonstrated to have significant impact on the actuation ability of the haptic device. To achieve the desired vibration effect on the human skin, the haptic system must be able to drive displacement beyond the detection threshold (~2 µm) at a frequency range of 100–700 Hz. The most optimized actuation ability is obtained when the ratio of the dimension (radius and thickness) between the piezoelectric coating and the substrate layer is equal to ~0.6. Regarding the simulation results, it is revealed that the presence of the conductive electrodes provokes a decrease in the displacement by approximately 25–30%, as the wafer structure becomes stiffer. To ensure the minimum displacement generated by the haptic device above 2 µm, the piezoelectric coating is screen-printed by two stacked layers, electrically connected in parallel. This architecture is expected to boost the displacement amplitude under the same electric field (denoted E) subjected to the single-layered coating. Accordingly, multilayered design seems to be a good alternative to enhance the haptic performance while keeping moderate values of E so as to prevent any undesired electrical breakdown of the coating. Practical characterizations confirmed that E=20 V/μm is sufficient to generate feedback vibrations (under a maximum input load of 5 N) perceived by the fingertip. This result confirms the reliability of the proposed haptic device, despite discrepancies between the predicted theory and the real measurements. Lastly, a demonstrator comprising piezoelectric buttons together with electronic command and conditioning circuits are successfully developed, offering an efficient way to create multiple sensations for the user. On the basis of empirical data acquired from several trials conducted on 20 subjects, statistical analyses together with relevant numerical indicators were implemented to better assess the performance of the developed haptic device.

BackgroundPediatric inflammatory multisystem syndrome (PIMS) is a complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children that resembles Kawasaki syndrome and places them at high risk of cardiorespiratory instability and/or cardiac damage. This study aims to describe the clinical presentation and outcomes of patients with PIMS in Mexico City.MethodsThis was an observational study of children hospitalized for PIMS based on the Centers for Disease Control and Prevention case definition criteria, in a single tertiary care pediatric center in Mexico City between May 1, 2020, and September 30, 2021. Demographic characteristics, epidemiological data, medical history, laboratory tests, cardiologic evaluations, treatment, and clinical outcomes were analyzed.ResultsSeventy-five cases fulfilled the case definition criteria for PIMS [median age: 10.9 years, Interquartile range (IQR): 5.6–15.6]. Fifteen (20%) patients had a severe underlying disease, 48 (64%) were admitted to the intensive care unit, 33 (44%) required invasive mechanical ventilation and 39 (52%) received vasopressor support. The patients were clustered through latent class analysis based on identified symptoms: Cluster 1 had rash or gastrointestinal symptoms (n = 60) and cluster 2 were those with predominantly respiratory manifestations (n = 15). Two patients (2.7%) died, and both had severe underlying conditions. Five patients (6.7%), all from cluster 1, developed coronary aneurysms.ConclusionThere were a high proportion of patients with severe respiratory involvement and positive RT-PCR SARS-CoV-2 and very few cases of coronary aneurysms in our study which suggests that a high proportion of the children had severe acute COVID-19. The clinical manifestations and outcomes are comparable to previously reported international studies.

Background: Child abuse is one of the leading causes of morbidity and mortality worldwide. This study aimed to identify whether the approach to the diagnosis of child abuse was comprehensive in a tertiary care hospital. Methods: We conducted a retrospective study of patients with a final diagnosis of child abuse admitted through the emergency department. Results: A total of 73 confirmed cases were analyzed. We observed a predominance of female patients (65.8%). Physical abuse was the most common type of abuse (80.8%). Complete blood count and a nutritional status analysis were recorded in 100% of the patients and coagulation times in 43%; however, no patient had a thorough bone series study. Conclusions: According to the evidence found in medical records, gaps were detected in the approach to patients with suspected child abuse upon arrival at the emergency department. For this reason, all areas where pediatric medical care is provided should have tools that offer agility and ease of diagnosis.

A gasolina é uma mistura complexa de substâncias, dentre elas estão hidrocarbonetos como o benzeno, tolueno, etilbenzeno e xilenos (BTEX), sendo esses compostos emitidos para a atmosfera, com destaque ao benzeno, por ser comprovadamente carcinogênico. Objetivamos avaliar as concentrações de BTEX no ar de postos de revenda de combustíveis no Município do Rio de Janeiro, Brasil, e calcular o risco de câncer associado a estas exposições. Foram realizados dois tipos de amostragem (fixa e móvel) adaptadas da metodologia nº 1.501 do Instituto Nacional de Segurança e Saúde Ocupacional (Estados Unidos), em seis postos de revenda de combustíveis na Zona Oeste da cidade. A amostragem fixa foi feita próxima às bombas de combustível, enquanto a móvel foi realizada através da coleta do ar na zona respiratória dos trabalhadores (frentistas), conforme estes se deslocavam pelo posto. As amostras foram analisadas por cromatografia gasosa com detecção por ionização em chama. Com os resultados das amostragens foram feitos os cálculos de risco à saúde, usando os indicadores Quociente de perigo (HQ) e Risco de câncer (CR), para avaliar os possíveis efeitos não-carcinogênicos e carcinogênicos, respectivamente, nos trabalhadores dos postos de revenda de combustíveis. As concentrações ambientais para a maioria dos compostos BTEX foram abaixo dos limites preconizados, menos para o benzeno, um composto carcinogênico, que apresentou concentrações muito acima dos limites, levando a altos valores de risco de câncer. Os resultados demonstraram que há riscos à saúde dos trabalhadores de postos de revenda de combustíveis, principalmente o risco de desenvolver câncer, devido à exposição excessiva ao benzeno.

The pandemic caused by SARS CoV-2 (COVID-19) has affected millions of people since 2020. There are clinical differences and in mortality between the adult and paediatric population. Recently, the immune response through the development of antibodies has gained relevance due to the risk of reinfection and vaccines' development.Objective: Was to compare the association of clinical history and the clinical presentation of the disease with the development of IgG antibodies against SARS-CoV-2 in paediatric and adult patients with a history of positive reverse transcriptase-polymerase chain reaction (RT-PCR) results.Methods: Cross-sectional observational study carried out in a Paediatric Hospital in Mexico City included patients under 18 years of age and health personnel with positive RT-PCR for COVID-19 comparing antibody expression. The development of specific IgG antibodies was measured, the presence of comorbidities, duration, and severity of symptoms was determined.Results: Sixty-one subjects (20 < 18 years and 41 > 18 years) were analysed. The median sample collection was 3 weeks. There were no differences in the expression of specific antibodies; no differences were shown according to the symptoms' severity. A positive correlation (r = 0.77) was demonstrated between the duration of symptoms and antibody levels.Conclusions: In conclusion, there is a clear association between the duration of the symptoms associated with SARS-CoV-2 infection and the IgG units generated in paediatric and adult patients convalescing from COVID-19.

Introduction: Respiratory viruses are among the leading causes of disease and death among children. Co-circulation of influenza and SARS-CoV2 can lead to diagnostic and management difficulties given the similarities in the clinical picture.Methods: This is a cohort of all children hospitalized with SARS-CoV2 infection from March to September 3rd 2020, and all children admitted with influenza throughout five flu-seasons (2013–2018) at a pediatric referral hospital. Patients with influenza were identified from the clinical laboratory database. All hospitalized patients with confirmed SARS-CoV2 infection were followed-up prospectively.Results: A total of 295 patients with influenza and 133 with SARS-CoV2 infection were included. The median age was 3.7 years for influenza and 5.3 years for SARS-CoV2. Comorbidities were frequent in both groups, but they were more common in patients with influenza (96.6 vs. 82.7%, p < 0.001). Fever and cough were the most common clinical manifestations in both groups. Rhinorrhea was present in more than half of children with influenza but was infrequent in those with COVID-19 (53.6 vs. 5.8%, p < 0.001). Overall, 6.4% percent of patients with influenza and 7.5% percent of patients with SARS-CoV2 infection died. In-hospital mortality and the need for mechanical ventilation among symptomatic patients were similar between groups in the multivariate analysis.Conclusions: Influenza and COVID-19 have a similar picture in pediatric patients, which makes diagnostic testing necessary for adequate diagnosis and management. Even though most cases of COVID-19 in children are asymptomatic or mild, the risk of death among hospitalized patients with comorbidities may be substantial, especially among infants.

Objective: To (1) identify types of technology that promote motor ability in children younger than 5 years of age, (2) report on the type of support these devices provide, and (3) evaluate their potential for use in the community (outside of the laboratory or clinic). Data Sources: A literature search of PubMed was conducted in February 2019 using specific terms, including child, rehabilitation, movement, and instrumentation. Study Selection: The search yielded 451 peer-reviewed articles, which were screened by multiple reviewers. Articles that described the use of devices for the purpose of motor rehabilitation and/or assistance (regardless of device type or body part targeted) in the age range of 0-5 years were eligible for inclusion. Data Extraction: In conformity with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, final stage data extraction consisted of full text readings where each article was reviewed twice by 3 independent reviewers. Data Synthesis: About half of the devices available (46%) for children younger than 5 years of age are orthotics and corrective casting devices. There are more facilitative (ie, power mobility devices) than inhibitive (ie, casting) technologies being used. Approximately 60% of the devices are designed for use by a single body part. Walking is the most common motor skill addressed. Although most of the devices were used to some degree outside of the laboratory or clinic, most of the devices available are considered investigative and are not available for commercial purchase. Conclusions: Many types of pediatric devices to assist movement exist, but the current scope of employed devices is limited. There is a need for developing technology that allows for, if not supports, high-dosage, early, and variable motor practice that can take place in community settings.

INTRODUCTION:In Pediatrics, adverse drug reactions (ADRs) affect morbidity and mortality. In Mexico, the characteristics of ADRs and suspect drugs have not been described in hospitalized children. OBJECTIVE:To estimate the frequency of ADRs and describe them, as well as suspect drugs, in a tertiary care pediatric hospital in Mexico. METHODS:A total of 1,649 Hospital Infantil de Mexico Federico Gómez ADR reports were analyzed. Completeness of the information was assessed, and ADRs severity and seriousness were assigned based on NOM-220-SSA1-2012, with causality being established according to the Naranjo algorithm. ADRs were classified with WHO Adverse Drug Reaction Terminology (WHO-ART). The drugs involved in ADRs were categorized according to the Anatomical Therapeutic Chemical (ATC) classification. Descriptive analysis was performed using the SPSS 20 statistical package. RESULTS:Of all the reports, 5.8% lacked sufficient information for the analysis (grade 0). ADRs frequency ranged from 2.12% to 8.07%. ADRs occurred most commonly in children (56.9%), in the female gender (52%), in subjects with normal BMI Z-score (46.6%) and malnutrition (35.3%), diagnosed with neoplasms (72.2%) and in the Emergency Department (70.0%). ADRs were severe in 14.4% of cases, in 81.0% they were serious and 2.1% were classified as definite. Most common serious ADR was febrile neutropenia (44.5%). The 0.7% of patients recovering with sequelae; 1.1% died (with the medication being associated) and 70.3% were admitted to the hospital as a result of an ADR. Antineoplastic and immunomodulating agents were more commonly associated with serious ADRs. CONCLUSION:ADRs affected morbidity and mortality, which is why strengthening pharmacovigilance programs in Mexican pediatric hospitals is necessary.

Summary: Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor and bi-functional lipid and protein phosphatase. We report that the metabolic regulator pyruvate dehydrogenase kinase1 (PDHK1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The PTEN protein phosphatase dephosphorylates nuclear factor κB (NF-κB)-activating protein (NKAP) and limits NFκB activation to suppress expression of PDHK1, a NF-κB target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to induce aerobic glycolysis and PDHK1 cellular dependence. PTEN-deficient human tumors harbor increased PDHK1, a biomarker of decreased patient survival. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers. : The tumor suppressor PTEN is widely inactivated in cancers and tumor syndromes. Currently, there is no effective therapeutic strategy in the clinic for PTEN-deficient cancers. Chatterjee et al. found that PTEN-deficient cells and cancers are uniquely sensitive to PDHK1 inhibition and propose PDHK1 as a potential therapeutic target in PTEN-deficient cancers. Keywords: PTEN, protein phosphatase, PDHK1, NKAP, NF-κB, synthetic lethality, metabolism, signaling, cancer

Although oncogene-targeted therapy often elicits profound initial tumor responses in patients, responses are generally incomplete because some tumor cells survive initial therapy as residual disease that enables eventual acquired resistance. The mechanisms underlying tumor cell adaptation and survival during initial therapy are incompletely understood. Here, through the study of EGFR mutant lung adenocarcinoma, we show that NF-κB signaling is rapidly engaged upon initial EGFR inhibitor treatment to promote tumor cell survival and residual disease. EGFR oncogene inhibition induced an EGFR-TRAF2-RIP1-IKK complex that stimulated an NF-κB-mediated transcriptional survival program. The direct NF-κB inhibitor PBS-1086 suppressed this adaptive survival program and increased the magnitude and duration of initial EGFR inhibitor response in multiple NSCLC models, including a patient-derived xenograft. These findings unveil NF-κB activation as a critical adaptive survival mechanism engaged by EGFR oncogene inhibition and provide rationale for EGFR and NF-κB co-inhibition to eliminate residual disease and enhance patient responses.

Introducción: La notificación espontánea depende de la capacidad de los médicos de detectar las reacciones adversas a medicamentos (RAM) y del hábito de reportarlas. En 2008 y 2009, la frecuencia de reportes de RAM al Programa Electrónico de Farmacovigilancia (SISFAR) del total de egresos del Hospital Infantil de México Federico Gómez fueron bajas (0.44 y 0.20%, respectivamente). Por esta razón, en el 2010 se decidió evaluar la capacidad de los médicos de identificar las RAM utilizando como estrategia la revisión de los expedientes clínicos. Métodos: Se llevó a cabo un estudio observacional, descriptivo, transversal y retrospectivo en el Departamento de Urgencias (DU), del 1 de marzo al 31 de agosto del 2010. Se clasificaron y cuantificaron como RAM identificadas por los médicos cuando existió evidencia por escrito en el expediente clínico de que ellos habían asociado una manifestación clínica con una RAM, incluyendo además la evaluación del número de reportes al SISFAR. Se realizó el análisis descriptivo con SPSS versión 18. Resultados: La frecuencia de RAM de los pacientes que ingresaron al DU fue del 21.8%. El 86% de ellas fueron identificadas por los médicos en el expediente clínico y el 14% por el farmacéutico. Se reportó solamente el 6.1% al SISFAR. Conclusiones: Aunque fue elevada la identificación de las RAM en el expediente clínico, es posible que existan algunas que no se hayan detectado. Por otra parte, se confirmó el elevado grado de subreporte al SISFAR, por lo que se requieren acciones para fomentar el hábito del reporte.

Introducción: La infección del tracto urinario en los niños es reconocida como una causa de morbilidad y de condiciones médicas crónicas, por lo que resulta indispensable conocer con claridad la patogénesis de esta enfermedad. Sin embargo, la resistencia creciente complica su tratamiento ya que aumenta la morbilidad, los costos, la estancia hospitalaria y el uso de fármacos de mayor espectro antimicrobiano. El propósito de este estudio fue determinar la susceptibilidad antimicrobiana de los uropatógenos aislados en niños. Métodos: Se incluyeron en el estudio 457 niños que asistieron a la consulta externa y a urgencias del Hospital Infantil de México Federico Gómez, con síntomas de infección del tracto urinario baja no complicada. La orina fue tomada a la mitad del chorro o por cateterismo, y se realizó la identificación y la susceptibilidad antimicrobiana. Resultados: Los patógenos aislados con mayor frecuencia fueron: Escherichia coli (E. coli) (312, 68.3%), Enterococcus spp. (42, 11%), Klebsiella pneumoniae (K. pneumoniae) (40, 8.7%), Pseudomonas aeruginosa (P. aeruginosa) (34, 7.5%), Proteus mirabilis (P. mirabilis) (21, 4.5%), Enterobacter cloacae (8, 1.7%). La resistencia para trimetoprima/sulfametoxazol fue del 73.7, 62.2, 100, 52, 50%,respectivamente, para E. coli, K. pneumoniae, P. aeruginosa, P. mirabilis y Enterobacter spp., del 92.5% para Enterococcus faecalis (E. faecalis) y del 49.9% para Enterococcus faecium (E. faecium). Para ampicilina fue del 86.3, 45, 100, 47.9 y 66.6% para las mismas bacterias, respectivamente. Para ciprofloxacina del 33.8, 9, 18.8, 0 y 0%; para nitrofurantoína del 4.4, 13, 97.7, 70, 0% para enterobacterias, del 0% para E. faecalis y del 16.7% para E. faecium. Conclusiones: Los antimicrobianos frecuentemente prescritos para el tratamiento empírico de la infección del tracto urinario no complicada demuestran resistencia importante o baja susceptibilidad cuando se les probó frente a las cepas aisladas.