Timing of treatment shapes the path to androgen receptor signaling inhibitor resistance in prostate cancer.

There is optimism that cancer drug resistance can be addressed through appropriate combination therapy, but success requires understanding the growing complexity of resistance mechanisms, including the evolution and population dynamics of drug-sensitive and drug-resistant clones over time. Using DNA barcoding to trace individual prostate tumor cells in vivo , we find that the evolutionary path to acquired resistance to androgen receptor signaling inhibition (ARSI) is dependent on the timing of treatment. In established tumors, resistance occurs through polyclonal adaptation of drug-sensitive clones, despite the presence of rare subclones with known, pre-existing ARSI resistance. Conversely, in an experimental setting designed to mimic minimal residual disease, resistance occurs through outgrowth of pre-existing resistant clones and not by adaptation. Despite these different evolutionary paths, the underlying mechanisms responsible for resistance are shared across the two evolutionary paths. Furthermore, mixing experiments reveal that the evolutionary path to adaptive resistance requires cooperativity between subclones. Thus, despite the presence of pre-existing ARSI-resistant subclones, acquired resistance in established tumors occurs primarily through cooperative, polyclonal adaptation of drug-sensitive cells. This tumor ecosystem model of resistance has new implications for developing effective combination therapy.

Improved charge-transfer resonance in graphene oxide/ZrO2 substrates for plasmonic-free SERS determination of methyl parathion.

This work reports a sensitive SERS substrate based on graphene oxide (GO) and quantum-sized ZrO2 nanoparticles (GO/ZrO2) for label-free determination of the organophosphate pesticide methyl parathion (MP). The enhanced light-matter interactions and the consequent SERS effect in these substrates resulted from the effective charge transfer (CT) mechanism attributed to synergistic contributions of three main factors: i) the strong molecular adherence of the MP molecules and the ZrO2 surface which allows the first layer-effect, ii) the relatively abundant surface defects in low dimensional ZrO2 semiconductor NPs, which act as intermediate electronic states that reduce the large bandgap barrier, and iii) the hindered charge recombination derived from the transference of the photoinduced holes to the GO layer. This mechanism allowed an enhancement factor of 8.78 × 104 for GO/ZrO2-based substrates, which is more than 5-fold higher than the enhancement observed for platforms without GO. A detection limit of 0.12 µM was achieved with an outstanding repeatability (variation ≤4.5%) and a linear range up to 10 µM, which is sensitive enough to determine the maximal MP concentration permissible in drinking water according to international regulations. Furthermore, recovery rates between 97.4 and 102.1% were determined in irrigation water runoffs, strawberry and black tea extracts, demonstrating the reliability of the hybrid GO/ZrO2 substrate for the organophosphate pesticides quantification in samples related to agri-food sectors and environmental monitoring.

Prenatal exposure to valproic acid and treatment with intranasal oxytocin have sex-specific effects on behavior in Long Evans rats.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social behaviors and communication. In rodents and humans, prenatal exposure to antiepileptic valproic acid is associated with an increased risk for autistic-like characteristics. One potential treatment is oxytocin, a prosocial neuropeptide that can be delivered intranasally. However, the sex-specific effects of valproic acid exposure and intranasal oxytocin treatment on behavior have not been fully explored. Pregnant Long Evans rats were administered valproic acid (500 mg/kg) or saline midday on gestational day 12, and after weaning, male and female pups were assigned to control (saline-saline), valproic acid-saline, or valproic acid-oxytocin groups. Oxytocin (0.8 IU/kg) or saline was delivered intranasally 30-60 min before tests for anxiety-like behaviors (elevated plus maze), social interactions (sociability) and sociosexual behaviors (partner preference, 50 kHz vocalizations and scent marking). Prenatal exposure to valproic acid resulted in sex-specific differences in behavior. When compared to controls, valproic acid males showed enhanced anxiety-like behaviors in adolescence and fewer scent marks in adulthood, while valproic acid females showed reduced sexual (partner) preference as adults. Intranasal oxytocin was anxiolytic for valproic acid males, but moderately anxiogenic for valproic acid females, and in both sexes it surprisingly impaired social interactions in the sociability test. Furthermore, intranasal oxytocin failed to improve sociosexual deficits in valproic acid rats. These findings highlight the importance of conducting preclinical studies in both sexes, and suggest that oxytocin may be an effective treatment in animal models with heightened anxiety-like behaviors.

Defining the therapeutic selective dependencies for distinct subtypes of PI3K pathway-altered prostate cancers.

Previous studies have suggested that PTEN loss is associated with p110ß signaling dependency, leading to the clinical development of p110ß-selective inhibitors. Here we use a panel pre-clinical models to reveal that PI3K isoform dependency is not governed by loss of PTEN and is impacted by feedback inhibition and concurrent PIK3CA/PIK3CB alterations. Furthermore, while pan-PI3K inhibition in PTEN-deficient tumors is efficacious, upregulation of Insulin Like Growth Factor 1 Receptor (IGF1R) promotes resistance. Importantly, we show that this resistance can be overcome through targeting AKT and we find that AKT inhibitors are superior to pan-PI3K inhibition in the context of PTEN loss. However, in the presence of wild-type PTEN and PIK3CA-activating mutations, p110α-dependent signaling is dominant and selectively inhibiting p110α is therapeutically superior to AKT inhibition. These discoveries reveal a more nuanced understanding of PI3K isoform dependency and unveil novel strategies to selectively target PI3K signaling nodes in a context-specific manner.

Rapid interrogation of cancer cell of origin through CRISPR editing.

The increasing complexity of different cell types revealed by single-cell analysis of tissues presents challenges in efficiently elucidating their functions. Here we show, using prostate as a model tissue, that primary organoids and freshly isolated epithelial cells can be CRISPR edited ex vivo using Cas9-sgRNA (guide RNA) ribotnucleoprotein complex technology, then orthotopically transferred in vivo into immunocompetent or immunodeficient mice to generate cancer models with phenotypes resembling those seen in traditional genetically engineered mouse models. Large intrachromosomal (∼2 Mb) or multigenic deletions can be engineered efficiently without the need for selection, including in isolated subpopulations to address cell-of-origin questions.

Native mitral valve endocarditis associated with KPC producing Serratia marcescens bacteremia successfully treated with mitral valve replacement and ceftazidime-avibactam.

Consistent with global trends of infections due to multiple-drug resistant Gram-negative bacteria, we report the first official case of native mitral valve endocarditis due to multi-resistant Klebsiella Pneumonia Carbapenemase (KPC) producing Serratia marcescens. The patient underwent mitral valve replacement and was successfully treated with monotherapy ceftazidime-avibactam.

Lymphoproliferative lung disorders: a radiologic-pathologic overview. Part II: Neoplastic disorders.

Lymphoproliferative pulmonary neoplasms can occur as primary pulmonary lymphomas or because of secondary pulmonary involvement. Neoplastic disorders may be difficult to differentiate from reactive pulmonary lymphoproliferative disorders, and immunohistochemical evaluation is often required to differentiate the 2 types of lesions. Neoplastic lymphoproliferative disorders are monoclonal lesions. Most affected patients present with systemic complaints, and imaging findings typically include nodules, masses, and lymphadenopathy. Primary pulmonary lymphomas are rare and account for less than 4% of the lymphomas that arise in extranodal sites. Secondary pulmonary lymphomas can affect the lung via hematogenous dissemination or by secondary involvement from tumor in adjacent or contiguous sites. Neoplastic lymphoproliferative lesions also include leukemia and plasma cell neoplasms. Posttransplantation lymphoproliferative disorders constitute a special type of lymphoid proliferation occurring in the setting of the chronic immunosuppression required for solid organ and bone marrow transplantation.

Lymphoproliferative lung disorders: a radiologic-pathologic overview. Part I: Reactive disorders.

Lymphoid tissue is a normal component of the lung and manifests as intrapulmonary lymph nodes, bronchus-associated lymphoid tissue (BALT), peripheral lymphocytic aggregates, solitary lymphocytes, and phagocytic cells. Pulmonary lymphoid lesions are thought to develop as a consequence of anomalous stimulation and response of the bronchus-associated lymphoid tissue and manifests as a spectrum of lymphoproliferative disorders that may be reactive or neoplastic. Reactive disorders are polyclonal abnormalities and include nodular lymphoid hyperplasia, lymphocytic interstitial pneumonia, follicular bronchiolitis, angiofollicular hyperplasia, and enlarged intrapulmonary lymph nodes. Affected patients are often asymptomatic. Imaging findings include focal nodules, diffuse bilateral centrilobular nodules, and hilar or mediastinal masses.

Colecistectomía de urgencia por laparoscopia por colecistitis aguda en adultos mayores / Emergency laparoscopic cholecystectomy in the elderly

Introducción y objetivos. La colecistectomía de urgencia por laparoscopia en el adulto mayor con colecistitis aguda, ha aumentado en el mundo. En Colombia no existe información al respecto. En este estudio se evalúan los resultados del procedimiento, efectuando un análisis discriminado por subgrupos de edad. Métodos. Análisis descriptivo de los factores demográficos, clínicos, bioquímicos y de imágenes diagnósticas, en una población de adultos mayores sometidos a colecistectomía por laparoscopia de urgencia en comparación con la población general. Se evaluó la tasa de morbilidad, de mortalidad, conversión y estancia hospitalaria para cada grupo y en dos poblaciones de adultos mayores (mayores de 65 a 74 años y mayores de 75 años). Un valor p menor de 0,05 se consideró estadísticamente significativo. Resultados. Se incluyeron 703 pacientes (18,3% adultos mayores). La hipertensión, la diabetes, la colangitis, la coledocolitiasis y la clasificación ASA III-IV fueron factores significativamente estadísticos en los adultos mayores. Las tasas de reintervención, de conversión y de hemorragia fueron estadísticamente significativas en los adultos mayores. La diabetes y la tasa de conversión fueron superiores en los adultos mayores de 75 años, comparados con los de 65 a 74 años. Las tasas de lesión de la vía biliar, infección y mortalidad, no mostraron diferencia en ninguno de los grupos. La estancia hospitalaria fue de 4,5 días en promedio en los adultos mayores, contra 1,8 días en promedio en la población general (p<0,001). Conclusiones. La colecistectomía de urgencia por laparoscopia continúa siendo un procedimiento relevante en adultos mayores con colecistitis aguda. Se debe tener precaución pues las tasas de hemorragia, reintervención y conversión, son ligeramente superiores en este grupo.

Introduction: Laparoscopic cholecystectomy for acute cholecystitis in the elderly is increasing worldwide. Most trials report different results; however, their performance in Colombia is unknown. This study evaluates their results conducting a discriminative analysis in different aging populations. Methods: Prospective analysis of patients >65 years old with acute cholecystitis submitted to urgent laparoscopic cholecystectomy in a fourth level, teaching and referral center in Bogotá, Colombia. We performed a univariate analysis of demographic, clinical, biochemical and imaging characteristics to identify significant variables in the elderly, in comparison with general population. Then we compared two different elderly populations (65-74years and >75years). We identified morbidity, mortality, conversions and LOS for every group. A p<0.05 was statistically significant. Results: 703 patients were included. 18.3% were elderly. Hypertension (p<0.001), diabetes (p<0.001), cholangitis (p<0.001), choledocholithiasis (p<0.007), ASA III-IV (p<0.001) were significant factors for elderly. Reoperations [elderly:4.3%; general population:1.2% (p<0.001)], conversions [elderly:32.6%; general population:9.2% (p<0.001)] and bleeding [elderly:2.1%; general population:0.3%](p<0.01) were significant factors for elderly. Diabetes and conversions were identified as significant factors for patients >75 years compared with patients between 65-74 years. Biliary tract injury, surgical site infection and mortality did not show statistical significance. LOS was 4.5 days for elderly against 1.8 days in the general population (p<0.001). Conclusions: Laparoscopic cholecystectomy remains a valuable procedure for elderly patients with acute cholecystitis and could be recommended despite their epidemiologic profile. Precautions should be taken into account because bleeding, reoperation and conversion are slightly higher in these patients.

Análisis de los factores de conversión durante colecistectomía laparoscópica a abierta en una cohorte prospectiva de 703 pacientes con colecistitis aguda / Analysis of factors for conversion of laparoscopic to open cholecystectomy: a prospective study of 703 patients with acute cholecystitis

La conversión a cirugía abierta durante colecistectomía laparoscópica se presenta en el 20%. Este desenlace se relaciona con mayor morbilidad y costos. En este estudio se describen los factores predictivos de conversión, la estancia hospitalaria, morbimortalidad asociada. Materiales y métodos Cohorte prospectiva de pacientes sometidos a colecistectomía laparoscópica de urgencia con colecistitis aguda. Análisis uni- y multivariado de los factores predictivos de conversión a partir de variables socio-demográficas, clínicas, bioquímicas y de imágenes diagnósticas, identificación de la tasa de morbilidad, mortalidad y estancia hospitalaria en los dos grupos. Resultados 703 pacientes fueron incluidos en el análisis. La tasa de conversión fue 13,8%. Los factores identificados en el análisis univariado fueron: género masculino, edad >70 años, hipertensión arterial, colangitis, CPRE previa, coledocolitiasis, bilirrubina total >2mg/dl, ictericia, recuento de leucocitos >12.000mm3, ASA III-IV y engrosamiento de la pared de la vesícula por ecografía. Los factores independientes fueron: género masculino (p<0,02), edad>70 años (p<0,02), CPRE previa (p<0,05) y recuento de leucocitos>12.000mm3 (p<0,04). Los pacientes convertidos presentaron mayor tasa de morbilidad, reoperación y estancia hospitalaria (p<0,001). La mortalidad no mostró diferencias. Conclusiones Es importante reconocer al paciente con mayor riesgo de conversión para optimizar la planeación y ejecución del procedimiento quirúrgico y disminuir la morbilidad asociada a la laparotomía, dado que los factores independientes identificados no son modificables (AU)

Aims: Conversions to open surgery during laparoscopic cholecystectomy are performed in20% of patients with acute cholecystitis, and are associated with increased morbidity and costs. The aim of this study was to identify predictive factors for conversion and to evaluate morbidity, mortality and hospital stay. Methods: A prospective cohort of patients admitted to the emergency department with acute cholecystitis. We evaluated the statistical significance of the demographic, clinical, biochemical, imaging and surgical factors at admission, associated with conversion to open surgery using a univariate model. The associated factors evaluated during initial analysis were then included in a multivariate analysis. Finally a comparative analysis was made of the morbidity and mortality in both models. Results: A total of 703 patients were included. Conversion rate was 13.8%. Univariate analysis identified as factors: male gender, previous ERCP, leucocytes > 12,000 mm3,age > 70 years, hypertension, jaundice, cholangitis, total bilirubin > 2 mg/dl, ASA III-IV,gallbladder wall enlargement and choledocholithiasis. Logistic regression identified as predictive factors: previous ERCP, leucocytes, age > 70 years and male gender. Converted patients had a higher morbidity rate, further operations and longer hospital stays (P < .001).No difference was seen in mortality. Discussion: It is important to recognise patients with a higher risk of conversion in order to optimise planning and performing of the surgical procedure, and to decrease the morbidity associated with laparotomy, given that the independent factors identified are not modifiable (AU)

[Analysis of factors for conversion of laparoscopic to open cholecystectomy: a prospective study of 703 patients with acute cholecystitis]. / Análisis de los factores de conversión durante colecistectomía laparoscópica a abierta en una cohorte prospectiva de 703 pacientes con colecistitis aguda.

AIMS: Conversions to open surgery during laparoscopic cholecystectomy are performed in 20% of patients with acute cholecystitis, and are associated with increased morbidity and costs. The aim of this study was to identify predictive factors for conversion and to evaluate morbidity, mortality and hospital stay. METHODS: A prospective cohort of patients admitted to the emergency department with acute cholecystitis. We evaluated the statistical significance of the demographic, clinical, biochemical, imaging and surgical factors at admission, associated with conversion to open surgery using a univariate model. The associated factors evaluated during initial analysis were then included in a multivariate analysis. Finally a comparative analysis was made of the morbidity and mortality in both models. RESULTS: A total of 703 patients were included. Conversion rate was 13.8%. Univariate analysis identified as factors: male gender, previous ERCP, leucocytes>12,000 mm(3), age>70 years, hypertension, jaundice, cholangitis, total bilirubin>2mg/dl, ASA III-IV, gallbladder wall enlargement and choledocholithiasis. Logistic regression identified as predictive factors: previous ERCP, leucocytes, age>70 years and male gender. Converted patients had a higher morbidity rate, further operations and longer hospital stays (P<.001). No difference was seen in mortality. DISCUSSION: It is important to recognise patients with a higher risk of conversion in order to optimise planning and performing of the surgical procedure, and to decrease the morbidity associated with laparotomy, given that the independent factors identified are not modifiable.

Tratamiento quirúrgico del aneurisma del tronco celíaco, reporte de un caso / Surgical treatment of aneurysm of the celiac trunk: case report

Los aneurismas del tronco celíaco son un problema clínico infrecuente. La mayoría de los pacientes son sintomáticos al momento del diagnóstico; sin embargo, ocasionalmente se detectan de manera incidental durante estudios imagenológicos para otras enfermedades. Se presenta el caso de un paciente de 54 años con aneurisma sintomático del tronco celíaco, diagnosticado por tomografía e intervenido quirúrgicamente de manera satisfactoria.

Aneurysm of the celiac artery is an uncommon clinical problem; fewer than 180 cases have been reported in the world's medical literature. Most patients are symptomatic at the time of diagnosis. However, occasionally such aneurysms are detected incidentally during diagnostic imaging for other diseases. We present of a 54 years-old man who had a symptomatic celiac artery aneurysm detected by Computed tomography. The patient underwent successful resection of the aneurysm and revascularization of the celiac artery – common hepatic and splenic arteries with use of an PTFE graft.

Diagnóstico nutricional antropométrico y coefi ciente intelectual en escolares / No disponible

El estado nutricional influye en el desarrollo físico del individuo,así como en la conducta y la actividad intelectual.Objetivo: Relacionar el Diagnóstico Nutricional Antropométrico(DNA) y el Coeficiente Intelectual (CI) en escolares dela escuela básica Las Agüitas III del Municipio Los Guayos,Estado Carabobo, Venezuela.Metodología: Se realizó un estudio descriptivo y transversalen 334 escolares de ambos sexos entre 6 y 12 años deedad, seleccionados por muestreo probabilístico estratificado,teniendo en cuenta edad, sexo, estrato social. Parasu evaluación antropométrica se utilizaron los indicadoresPeso/Talla (P/T), Talla/Edad (T/E). Así mismo, fue aplicadala Batería de Kaufman (K-ABC) que mide el CI.Resultados: Según el estrato social 82,64% de los niños estabanen pobreza; según el DNA un 57,49% de los escolareseran eutróficos, con mayor porcentaje en el sexo femenino.El 24,25% eran desnutridos con mayor porcentaje en elsexo masculino. El sobrepeso fue de 18,26% con mayortendencia en el sexo femenino. Los escolares eutróficos ycon sobrepeso presentaron una tendencia a un CI superiory medio, mientras los desnutridos un CI medio; no huboasociación estadística significativa.Conclusión: Los escolares desnutridos tuvieron mayortendencia a un CI medio, mientras que los eutróficos y consobrepeso a un CI medio y superior(AU)

The nutritional status influences in the physical developmentof the individual, on its behavior and intellectual activity.Objective: To relate Anthropometric Nutritional Diagnosis(AND) and the Intellectual Coefficient (IC) in students ofthe basic school Agüitas III in the Municipality the Guayos,Carabobo State, Venezuela.Methodology: A descriptive and cross-sectional study wasconducted in 334 students of both sexes between 6 and 12years of age, selected by stratified probabilistic sampling,considering age, sex, social layer. The anthropometric indicatorsused were Weight/Height (W/H), Height/Age (H/A).To measure IC the Battery of Kaufman was applied (K-ABC).Results: According to social layer 82,64% of the childrenwere in poverty; according to the AND 57,49% of thestudents were normal, with greater percentage in femalesex. 24,25% were undernourished with greater percentagein masculine sex. The overweight was of 18,26% withgreater tendency in female sex. The normal and overweightstudents showed a trend to score on IC medium or high,while the undernourished score on medium IC, althoughthe association was not significant.Conclusion: The undernourished students had greatertendency to a medium IC score, whereas the normal andoverweight to a medium and high IC scorer(AU)

Silicone pulmonary embolism: report of 10 cases and review of the literature.

OBJECTIVE: To assess patient outcome and imaging findings of patients with pulmonary embolism of fluid silicone. METHODS: Medical records and imaging examinations of 10 patients with respiratory distress after illicit injection of fluid silicone were reviewed. Population consisted of 8 male (6 male-to-female transsexuals) and 2 female subjects. RESULTS: Average age was 29 years. Most common injection sites were gluteal and trochanteric. Respiratory symptoms developed between 15 minutes and 2 days after silicone injection. Five referred fever, 6 developed adult respiratory distress syndrome, and 2 subsequently died. Alveolar hemorrhage was demonstrated on pathological examination in 6, with silicone vacuoles in the lung parenchyma in 3. Computed tomography demonstrated peripheral ground glass opacities with interlobular septal thickening in all and peripheral airspace disease in 7. CONCLUSIONS: Illicit injection of large volumes of fluid silicone for cosmetic purposes is associated with pulmonary embolism and acute alveolar hemorrhage and is associated with a significant mortality.

Gas extraluminal abdominal en imagen: causas y significado clínico / Extraluminal abdominal gas in image: causes and clinical significance

El gas extraluminal abdominal hace referencia a la presencia de gas fuera de la luz del tracto gastrointestinal. Este hallazgo acompaña a un amplio espectro de situaciones clínicas que pueden ser desde asintomáticas hasta potencialmente mortales. El neumoperitoneo, el retroneumoperitoneo, la neumatosis cistoide intestinal, la colecistitis y cistitis enfisematosas, el gas portomesentérico, la neumobilia y el gas dentro de un órgano sólido constituyen los signos radiológicos de gas extraluminal. El abordaje imaginológico inicial del gas extraluminal se hace con radiografía convencional, sin embargo, la tomografía computada (TC) tiene mayor sensibilidad, y aporta mayor información. el ultrasonido (US) cumple también un papel importante en el estudio de estos pacientes. la interpretación de las imágenes debe considerar la historia clínica, ya que una misma apariencia radiológica puede tener significado diferente en pacientes con cuadros clínicos distintos.

Pulmonary complications from cocaine and cocaine-based substances: imaging manifestations.

Cocaine is the illicit drug whose abuse most often results in cardiopulmonary symptoms and emergency treatment. Habitual smoking of alkaloidal cocaine ("freebase," "crack") has replaced nasal insufflation as the most common method of abuse. Smoking of cocaine exposes the lung directly to the volatilized drug as well as to the other combustion products of the smoked mixture, thereby increasing the risk of adverse pulmonary effects. A wide variety of pulmonary complications including interstitial pneumonitis, fibrosis, pulmonary hypertension, alveolar hemorrhage, asthma exacerbation, barotrauma, thermal airway injury, hilar lymphadenopathies, and bullous emphysema may be associated with the inhalation of crack cocaine or of associated substances such as talc, silica, and lactose. Cocaine abuse represents one of the most serious medical and social problems of our time. Radiologists should be familiar with the various pleuropulmonary complications associated with the abuse of illicit drugs in general and of cocaine in particular to ensure correct diagnosis and appropriate treatment planning in patients with respiratory manifestations associated with such abuse.