Retinoic Acid Signaling and Development of the Respiratory System.

Retinoic acid (RA), the bioactive metabolite of vitamin A (VA), has long been recognized as a critical regulator of the development of the respiratory system. During embryogenesis, RA signaling is involved in the development of the trachea, airways, lung, and diaphragm. During postnatal life, RA continues to impact respiratory health. Disruption of RA activity during embryonic development produces dramatic phenotypes in animal models and human diseases, including tracheoesophageal fistula, tracheomalacia, congenital diaphragmatic hernia (CDH), and lung agenesis or hypoplasia. Several experimental methods have been used to target RA pathways during the formation of the embryonic lung. These have been performed in different animal models using gain- and loss-of-function strategies and dietary, pharmacologic, and genetic approaches that deplete retinoid stores or disrupt retinoid signaling. Experiments utilizing these methods have led to a deeper understanding of RA's role as an important signaling molecule that influences all stages of lung development. Current research is uncovering RA cross talk interactions with other embryonic signaling factors, such as fibroblast growth factors, WNT, and transforming growth factor-beta.

Directed differentiation of mouse pluripotent stem cells into functional lung-specific mesenchyme.

While the generation of many lineages from pluripotent stem cells has resulted in basic discoveries and clinical trials, the derivation of tissue-specific mesenchyme via directed differentiation has markedly lagged. The derivation of lung-specific mesenchyme is particularly important since this tissue plays crucial roles in lung development and disease. Here we generate a mouse induced pluripotent stem cell (iPSC) line carrying a lung-specific mesenchymal reporter/lineage tracer. We identify the pathways (RA and Shh) necessary to specify lung mesenchyme and find that mouse iPSC-derived lung mesenchyme (iLM) expresses key molecular and functional features of primary developing lung mesenchyme. iLM recombined with engineered lung epithelial progenitors self-organizes into 3D organoids with juxtaposed layers of epithelium and mesenchyme. Co-culture increases yield of lung epithelial progenitors and impacts epithelial and mesenchymal differentiation programs, suggesting functional crosstalk. Our iPSC-derived population thus provides an inexhaustible source of cells for studying lung development, modeling diseases, and developing therapeutics.

Heart Rate from Progressive Volitional Cycling Test Is Associated with Endothelial Dysfunction Outcomes in Hypertensive Chilean Adults.

BACKGROUND: A progressive volitional cycling test is useful in determining exercise prescription in populations with cardiovascular and metabolic diseases. However, little is known about the association between heart rate during this test and endothelial dysfunction (EDys) parameters in hypertensive (HTN) patients. OBJECTIVE: To investigate the association between EDys markers (flow-mediated dilation [FMD], pulse wave velocity of the brachial artery [PWVba], and carotid-intima media thickness [cIMT]) and heart rate during a cycling test in HTN adults. A secondary aim was to characterize cardiovascular, anthropometric, and body composition outcomes in this population. METHODS: This was a descriptive clinical study in which adults (men and women) were assigned to one of three groups: HTN, elevated blood pressure (Ele), or a normotensive control group (CG), and completed a progressive cycling test. The primary outcomes were FMD, PWVba, cIMT, and heart rate (HR) at 25-50 watts (HR25-50), 50-100 watts (HR50-100), and 75-150 watts (HR75-150) of the Astrand test. Secondary outcomes included body mass index (BMI), waist circumference, body fat percentage (BF%), skeletal muscle mass (SMM), resting metabolic rate (RMR), and estimated body age, as measured by a bio-impedance digital scale. RESULTS: Analyses of the associations between FMD, PWV, and HR25-50, HR50-100, and HR75-150 watts revealed no significant association in the HTN, Ele, and CG groups. However, a significant association was found between cIMT and HR75-150 watts in the HTN group (R2 47.1, ß -0.650, p = 0.038). There was also a significant trend (p = 0.047) towards increasing PWVba in the CG, Ele, and HTN groups. CONCLUSION: Heart rate during a progressive cycling test is associated with the EDys parameters cIMT in HTN patients, with particularly strong predictive capacity for vascular parameters in the second and third stages of the Astrand exercise test compared to normotensive control.

Lung adenocarcinoma and pulmonary actinomycosis: a cautionary tale.

BACKGROUND: Pulmonary actinomycosis is a rare and slowly progressive bacterial infection that is often mistaken for lung cancer. Multiple case reports caution against premature diagnosis of malignancy without proper consideration of potential Actinomyces infection. However, no cases in the English literature have been reported that demonstrate the possible coexistence of Actinomyces and lung cancer. CASE DESCRIPTION: We present two cases of patients with culture-positive Actinomyces who were later found to have concomitant biopsy-proven lung adenocarcinoma. CONCLUSIONS: In the workup of a newly identified lung mass, positive culture for Actinomyces does not rule out an underlying malignancy.

LI-RADS treatment response algorithm after first-line DEB-TACE: reproducibility and prognostic value at initial post-treatment CT/MRI.

PURPOSE: To evaluate the inter-reader reproducibility and prognostic accuracy of the Liver Imaging Reporting and Data System (LI-RADS) treatment response algorithm (LR-TR) at the time of initial post-treatment evaluation following drug-eluting beads transarterial chemoembolization (DEB-TACE) for hepatocellular carcinoma (HCC). METHODS: This retrospective study included patients with HCC who underwent first-line DEB-TACE between January 2011 and December 2015. Six readers (three fellowship-trained radiologists and three radiology trainees) independently assessed lesion-level response in up to two treated lesions per LR-TR and modified Response Evaluation Criteria in Solid Tumors (mRECIST)-target criteria, as well as patient-level response per mRECIST-overall criteria, on the initial post-treatment CT/MRI. Inter-reader agreement was calculated by Fleiss' multi-reader κ. We tested whether LR-TR, mRECIST-target, and mRECIST-overall response were associated with overall survival using Kaplan-Meier and Cox proportional hazard model analyses. RESULTS: A total of 82 patients with 113 treated target lesions were included. Inter-reader agreement was moderate for LR-TR and mRECIST-overall (κ range 0.42-0.57), and substantial for mRECIST-target (κ range 0.62-0.66), among all three reader-groups: all readers, experienced readers, and less-experienced readers. LR-TR and mRECIST-target response were not significantly associated with overall survival regardless of reader experience (P > 0.05). In contrast, mRECIST-overall response was significantly associated with overall survival when assessed by all readers (P = 0.02) and experienced readers (P = 0.03), but not by the less-experienced readers (P = 0.35). CONCLUSION: Although LR-TR algorithm has moderate inter-reader reproducibility, it alone may not predict overall survival on the initial post-treatment CT/MRI after first-line DEB-TACE for HCC.

CT and MRI findings in leptomeningeal melanocytosis.

Leptomeningeal melanocytosis is a rare cause of seizure in the pediatric population. Shown here is a case of this disease in a 9-year-old male who presented with seizures and minor trauma. Imaging showed progression of leptomeningeal enhancement in the setting of increased seizure activity, and biopsy confirmed the diagnosis. The patient received immunotherapy but eventually succumbed to the disease. This case serves as an educational tool to improve awareness of melanocytic proliferation as a differential consideration for leptomeningeal enhancement.

Increased PEA3/E1AF and decreased Net/Elk-3, both ETS proteins, characterize human NSCLC progression and regulate caveolin-1 transcription in Calu-1 and NCI-H23 NSCLC cell lines.

Caveolin-1 protein has been called a 'conditional tumor suppressor' because it can either suppress or enhance tumor progression depending on cellular context. Caveolin-1 levels are dynamic in non-small-cell lung cancer, with increased levels in metastatic tumor cells. We have shown previously that transactivation of an erythroblastosis virus-transforming sequence (ETS) cis-element enhances caveolin-1 expression in a murine lung epithelial cell line. Based on high sequence homology between the murine and human caveolin-1 promoters, we proposed that ETS proteins might regulate caveolin-1 expression in human lung tumorigenesis. We confirm that caveolin-1 is not detected in well-differentiated primary lung tumors. Polyoma virus enhancer activator 3 (PEA3), a pro-metastatic ETS protein in breast cancer, is expressed at low levels in well-differentiated tumors and high levels in poorly differentiated tumors. Conversely, Net, a known ETS repressor, is expressed at high levels in the nucleus of well-differentiated primary tumor cells. In tumor cells in metastatic lymph node sites, caveolin-1 and PEA3 are highly expressed, whereas Net is now expressed in the cytoplasm. We studied transcriptional regulation of caveolin-1 in two human lung cancer cell lines, Calu-1 (high caveolin-1 expressing) and NCI-H23 (low caveolin-1 expressing). Chromatin immunoprecipitation-binding assays and small interfering RNA experiments show that PEA3 is a transcriptional activator in Calu-1 cells and that Net is a transcriptional repressor in NCI-H23 cells. These results suggest that Net may suppress caveolin-1 transcription in primary lung tumors and that PEA3 may activate caveolin-1 transcription in metastatic lymph nodes.

Generation of a Purified iPSC-Derived Smooth Muscle-like Population for Cell Sheet Engineering.

Induced pluripotent stem cells (iPSCs) provide a potential source for the derivation of smooth muscle cells (SMCs); however, current approaches are limited by the production of heterogeneous cell types and a paucity of tools or markers for tracking and purifying candidate SMCs. Here, we develop murine and human iPSC lines carrying fluorochrome reporters (Acta2hrGFP and ACTA2eGFP, respectively) that identify Acta2+/ACTA2+ cells as they emerge in vitro in real time during iPSC-directed differentiation. We find that Acta2hrGFP+ and ACTA2eGFP+ cells can be sorted to purity and are enriched in markers characteristic of an immature or synthetic SMC. We characterize the resulting GFP+ populations through global transcriptomic profiling and functional studies, including the capacity to form engineered cell sheets. We conclude that these reporter lines allow for generation of sortable, live iPSC-derived Acta2+/ACTA2+ cells highly enriched in smooth muscle lineages for basic developmental studies, tissue engineering, or future clinical regenerative applications.

Usefulness of nuclear whole-body bone scanning for diagnosis of leprosy.

Leprosy, or Hansen's disease, is rare in the United States. Given its rarity, as well as the pathognomonic dermatologic findings, there are few cases in which nuclear medicine imaging plays a role in the diagnostic workup. We present a 39-year-old man who presented with chronic abdominal pain, skin ulcers, and hypercalcemia who underwent computed tomography of the chest and a whole-body bone scan to evaluate for possible underlying neoplasm due to his profound hypercalcemia. Although the diagnosis of leprosy had been established by lower-extremity skin biopsy upon admission, workup for other potential concurrent etiologies of hypercalcemia was performed before initiating therapy. We present the computed tomography scans, nuclear medicine images, and corresponding skin findings of this case.

[Anthropometric characteristics and functional fitness of Chilean community-dwelling older adults]. / Características antropométricas y condición física funcional de adultos mayores chilenos insertos en la comunidad.

INTRODUCTION: Anthropometry and functional fitness (FF) are fundamental aspects for functional independence conservation of older adults (OA). However, little has been investigated in chilean OA. OBJECTIVE: To analyze anthropometric and FF characteristics of non-disabled OA. METHODS: One hundred and sixteen subjects participated in the study. It was determined the prevalence of weight categories (Body Mass Index [BMI]) and cardiometabolic risk (CMR) (Waist Circumference [WC], Waist-Hip Ratio [WHR] and Waist-to-Height ratio [WHtR]). Additionally, "under the norm" physical performance and performance standards (Senior Fitness Test Battery [SFT]). Anthropometric and FF differences were analyzed according sex and age categories. RESULTS: A total of 63.8% and 73.5% of men and women respectively were overweight. The highest prevalence of CMR was obtained through WHtR and the tests with the highest prevalence of low performance were 2-minute step Test and Back scratch Test. The performance standard was reached in 29.7% and 17.3%, in men and women respectively. Men presented greater height, WHR, strength and aerobic capacity. Women had greater hip circumference, BMI, WHtR and flexibility. These results tends to be maintained in the analyzes according age categories. CONCLUSIONS: The studied sample presented a high prevalence of overweight, CMR and low physical performance especially in women. Due its low cost and complexity, it is proposed that integral evaluation of anthropometric and FF parameters should be implemented in primary care programs aimed to preserving functionality of OA.

Vitamin A-retinoid signaling in pulmonary development and disease.

Retinoic acid (RA), the active form of vitamin A, regulates key developmental processes in multiple organs. In the developing lung, RA is crucial for normal growth and differentiation of airways. Disruption in RA signaling or vitamin A deficiency (VAD) has been linked to aberrant development of the lung including alterations in the airway smooth muscle (SM) differentiation, development, and function. These alterations have been linked to disease states including asthma in both human and animal models.

Prenatal retinoid deficiency leads to airway hyperresponsiveness in adult mice.

There is increasing evidence that vitamin A deficiency in utero correlates with abnormal airway smooth muscle (SM) function in postnatal life. The bioactive vitamin A metabolite retinoic acid (RA) is essential for formation of the lung primordium; however, little is known about the impact of early fetal RA deficiency on postnatal lung structure and function. Here, we provide evidence that during murine lung development, endogenous RA has a key role in restricting the airway SM differentiation program during airway formation. Using murine models of pharmacological, genetic, and dietary vitamin A/RA deficiency, we found that disruption of RA signaling during embryonic development consistently resulted in an altered airway SM phenotype with markedly increased expression of SM markers. The aberrant phenotype persisted postnatally regardless of the adult vitamin A status and manifested as structural changes in the bronchial SM and hyperresponsiveness of the airway without evidence of inflammation. Our data reveal a role for endogenous RA signaling in restricting SM differentiation and preventing precocious and excessive SM differentiation when airways are forming.

Synergistic effects of targeted PI3K signaling inhibition and chemotherapy in liposarcoma.

While liposarcoma is the second most common soft tissue malignant tumor, the molecular pathogenesis in this malignancy is poorly understood. Our goal was therefore to expand the understanding of molecular mechanisms that drive liposarcoma and identify therapeutically-susceptible genetic alterations. We studied a cohort of high-grade liposarcomas and benign lipomas across multiple disease sites, as well as two liposarcoma cell lines, using multiplexed mutational analysis. Nucleic acids extracted from diagnostic patient tissue were simultaneously interrogated for 150 common mutations across 15 essential cancer genes using a clinically-validated platform for cancer genotyping. Western blot analysis was implemented to detect activation of downstream pathways. Liposarcoma cell lines were used to determine the effects of PI3K targeted drug treatment with or without chemotherapy. We identified mutations in the PIK3CA gene in 4 of 18 human liposarcoma patients (22%). No PIK3CA mutations were identified in benign lipomas. Western blot analysis confirmed downstream activation of AKT in both PIK3CA mutant and non-mutant liposarcoma samples. PI-103, a dual PI3K/mTOR inhibitor, effectively inhibited the activation of the PI3K/AKT in liposarcoma cell lines and induced apoptosis. Importantly, combination with PI-103 treatment strongly synergized the growth-inhibitory effects of the chemotherapy drugs doxorubicin and cisplatin in liposarcoma cells. Taken together, these findings suggest that activation of the PI3K/AKT pathway is an important cancer mechanism in liposarcoma. Targeting the PI3K/AKT/pathway with small molecule inhibitors in combination with chemotherapy could be exploited as a novel strategy in the treatment of liposarcoma.

Evaluación de las pruebas de madurez fetal en líquido amniótico: perfil de fosfolípidos, prueba de Clements, y prueba de TAP / Evaluation of fetal maturity tests inamniotic fluid: phospholypids profile, Clements' test and TAP tests

En el servicio de Perinatología del Hospital Universitario Dr. José E. González de la U. A. N. L., se revisaron en forma prospectiva 51 estudios de líquido amniótico para determinación de madurez fetal en los que se practicó la prueba de TAP, perfil de fosfolípidos, y prueba de Clements. En este estudio, se obtubieron 37 recién nacidos vivos, en los cuales la edad gestacional fue estimada clínicamente por el método de Ballatrd, investigándose en ellos la presencia, no, de síndrome de insuficiencia respiratoria de la correlación con el perfil de fosfolípidos, 13.3% fueron resultados falsos negativos sin encontrar factores determinantes que alteraran el resultado. Los resultados falsos positivos ocuparon 9.9%. Respecto a la pruebaa de Clements, encontramos que 6.6% fueron falsos positivos, mientras que 41.6% fueron falsos negativos. En relación a la incidencia de síndrome de inbsuficiencia respiratoria, cuando la prueba de TAP fue inmadura, 50% de los productos desarrollaron insuficiencia respiratoria em cambio en los resultados de TAP maduros, tuvimos una incidencia corregida de 0%

Utilidad del diagnóstico de placenta grado III por ecografía en el manejo del embarazo prolongado / Usefulness of diagnosis of placenta stage III by echography in the management of prolonged pregnancy

Con el propósito de determinar la importancia de encontrar una placenta grado III por ecografía en embarazos prolongados se revisaron los resultados obtenidos en 75 pacientes con embarazos de 41 semanas, o más, por amenorrea, en los que se practicó eecografía con sistema de ultrasonido de tiempo real, lineal de 3.5 MHz en la Unidad de Perinatología del Hospital Universitario Dr. José E. González, U.A.N.L., del 27 de octubre de 1986 al 17 de febrero de 1987. Se formaron tres grupos según los grados I, II y III de imagen placentaria y se compararon los seguientes parámetros: Apgar, peso, Ballard y presencia de meconio en líquido amniótico. Los resultados obtenidos en nuestro grupo no mostraron diferencias estadísticamente significativas entre las pacientes con placenta grado III y las pacientes con placenta grados I y II respecto a Apgar, peso, Baillard y presencia de meconio; no por lo que consideramos que el diagnosticar una placenta grado III en pacientes con embarazo prolongado no constituye por sí sola una indicación para interrumpir éste. La incidencia de placenta grado III en nuestro grupo (27.3%) fue significativamente mayor que la reportada en la literatura (15%) para embarazos de término. En el grupo de placentas grado III no se presentó ningún producto pretérmino mientras que hubo cuatro prematuros en el resto de los casos; lo que concuerda con la literatura en lo que se especifica que una vez que la totalidad de la imagen placentaria es grado III se debe considerar al producto maduro

Registro nacional de comisurotomía mitral percutánea. Experiencia de 8 años / National Registry of percutaneous mitral commisurotomy. An eight years experience

De abril de 1986 a junio de 1994, en un estudio multicéntrico, se realizó comisurotomía mitral percutánea a 689 pacientes con el diagnóstico de estenosis mitral de etiología reumática. La edad promedio fue de 40ñ11 años. 84.9 por ciento del sexo femenino, 2.7 por ciento con tratamiento quirúrgico previo y 1.4 por ciento cursaban con embarazo. Se utilizó el balón de Inoue en 89.4 por ciento, doble balón 9.7 por ciento y monobalón en 0.9 por ciento. El área valvular mitral (AVM) predilatación se incrementó de 0.93ñ0.20 a 1.85ñ0.37 cm² (p<0.001), la presión media de la aúricula izquierda descendió de 20.9ñ8.1 a 10.0ñ5.9 mmHg (p<0.001), el gradiente transvalvular (GTVM) descendió de 15.4ñ6.4 a 3.4ñ3.1 mmHg (p<0.001). Se completó el procedimiento sin complicaciones mayores en 93.1 por ciento. Desarrollaron insuficiencia mitral (IM) severa el 3.9 por ciento. Resultado óptimo en 82.1 por ciento, subóptimo 8.2 por ciento y se fracasó en 9.7 por ciento. Complicaciones mayores 4.7 por ciento con mortalidad de 0.9 por ciento. A 6 meses de seguimiento el área valvular disminuyó a 1.77ñ0.38 (p<0.001), manteniéndose sin cambios a 24 meses (1.78ñ0.37 p ns). El 93.3 por ciento están en clase funcional (CF) 1 a 24 meses. Los únicos predictores de resultado óptimo, fueron el AVM(> 1cm²) y la CF(I y II). La IM se desarrolló con mayor frecuencia con fibrilación auricular y puntuación ecocardiográfica >8. Nuestros resultados son comparables a lo encontrado en la literatura mundial, confirmando la seguridad de efectividad del procedimiento