Targeting Histone Demethylases in MYC-Driven Neuroblastomas with Ciclopirox

Histone lysine demethylases facilitate the activity of oncogenic transcription factors, including possibly MYC. Here we show that multiple histone demethylases influence the viability and poor prognosis of neuroblastoma cells, where MYC is often overexpressed. We also identified the approved small-molecule antifungal agent ciclopirox as a novel pan-histone demethylase inhibitor. Ciclopirox targeted several histone demethylases, including KDM4B implicated in MYC function. Accordingly, ciclopirox inhibited Myc signaling in parallel with mitochondrial oxidative phosphorylation, resulting in suppression of neuroblastoma cell viability and inhibition of tumor growth associated with an induction of differentiation. Our findings provide new insights into epigenetic regulation of MYC function and suggest a novel pharmacologic basis to target histone demethylases as an indirect MYC-targeting approach for cancer therapy

Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)

Background: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods: CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results: This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion: CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic

Estudio de Factibilidad para la Producción y Comercialización de Tomate Hidropónico en Tegucigalpa, Honduras C.A.

47 p.Interiano, Rodolfo Eugenio; Villar, Marco Antonio. 2004. Estudio de Factibilidad para la Producción y Comercialización de Tomate Hidropónico en Tegucigalpa, Honduras. Tendencias a nivel mundial como altos costos de insumos para la producción convencional de cultivos hortícola en Honduras, son uno de los factores que exigen a los productores actuales ser más eficientes en sus métodos de producción y así poder disminuir el riesgo e incertidumbre para que puedan aumentar sus ingresos. El tomate se ha convertido una hortaliza importante ya que por su popularidad se ha transformado en una de las principales fuentes de vitaminas y minerales de muchos países y con una participación anual creciente en el mercado internacional, por lo que se esta exigiendo a sus productores métodos de producción cada vez más eficientes y es donde las técnicas hidropónicas, no sólo en tomate sino en cualquier tipo de cultivos, ha ganado importancia y atención al convertirse en una opción efectiva de producción. Los productos hidropónicos son considerados productos vanguardistas e innovadores, debido a su reciente incursión en los mercados mundiales, sin embargo es aún un producto ajeno para los mercados de Honduras. El mercado meta esta constituido por personas con un ingreso mayor a L. 30,000, que se preocupan por su salud y que ponen énfasis en la calidad de los productos que consumen. Esto es equivalente a 48,294 personas en Tegucigalpa. Los factores de compra que el cliente toma en cuenta a la hora de la elección son firmeza y color. Se ofertará un 12% de la demanda potencial total (29,244 kg /semana) de tomate fresco en los supermercados y clubes de bodega de Tegucigalpa, debido a la capacidad productiva del proyecto. Con una tasa de descuento del 15%, se tiene un VAN de L.488, 950.00 una tasa interna de retorno (TIR) de 36%, y un período de recuperación de 2.5 años, cumpliendo todos los indicadores los criterios de aceptación. Se concluye que el proyecto es financieramente rentable. Los requerimientos de inversión para el proyecto son de L. 1,396,750, de los cuales cada uno de los dos inversionistas invertirá L. 370,000 y el restante de L. 656,750 serán financiados por una entidad bancaria nacional. El capital de trabajo representará L. 74,000 el cual está incluido en la inversión inicial del proyecto

Molecular heterogeneity in a patient-derived glioblastoma xenoline is regulated by different cancer stem cell populations.

Malignant glioblastoma (GBM) is a highly aggressive brain tumor with a dismal prognosis and limited therapeutic options. Genomic profiling of GBM samples has identified four molecular subtypes (Proneural, Neural, Classical and Mesenchymal), which may arise from different glioblastoma stem-like cell (GSC) populations. We previously showed that adherent cultures of GSCs grown on laminin-coated plates (Ad-GSCs) and spheroid cultures of GSCs (Sp-GSCs) had high expression of stem cell markers (CD133, Sox2 and Nestin), but low expression of differentiation markers (βIII-tubulin and glial fibrillary acid protein). In the present study, we characterized GBM tumors produced by subcutaneous and intracranial injection of Ad-GSCs and Sp-GSCs isolated from a patient-derived xenoline. Although they formed tumors with identical histological features, gene expression analysis revealed that xenografts of Sp-GSCs had a Classical molecular subtype similar to that of bulk tumor cells. In contrast xenografts of Ad-GSCs expressed a Mesenchymal gene signature. Adherent GSC-derived xenografts had high STAT3 and ANGPTL4 expression, and enrichment for stem cell markers, transcriptional networks and pro-angiogenic markers characteristic of the Mesenchymal subtype. Examination of clinical samples from GBM patients showed that STAT3 expression was directly correlated with ANGPTL4 expression, and that increased expression of these genes correlated with poor patient survival and performance. A pharmacological STAT3 inhibitor abrogated STAT3 binding to the ANGPTL4 promoter and exhibited anticancer activity in vivo. Therefore, Ad-GSCs and Sp-GSCs produced histologically identical tumors with different gene expression patterns, and a STAT3/ANGPTL4 pathway is identified in glioblastoma that may serve as a target for therapeutic intervention

Overall survival and renal function of patients with synchronous bilateral Wilms tumor undergoing surgery at a single institution

Objectives: Wilms tumor is the most common renal cancer in children. Approximately 5% of children with Wilms tumor present with disease in both kidneys. The treatment challenge is to achieve a high cure rate while maintaining long-term renal function. We retrospectively reviewed our institutional experience with nephron sparing surgery (NSS) in patients with synchronous bilateral Wilms tumor (BWT) operated on between 2001 and 2014. Methods: Imaging studies, surgical approach, adjuvant therapy, and pathology reports were reviewed. Outcomes evaluated included surgical complications, tumor recurrence, patient survival, and renal function, as assessed by estimated glomerular filtration rate. Results: A total of 42 patients with BWT were identified: 39 (92.9%) patients underwent bilateral NSS; only 3 patients (7.1%) underwent unilateral nephrectomy with contralateral NSS. Postoperative complications included prolonged urine leak (10), infection (6), intussusception (2), and transient renal insufficiency (1). Three patients required early (within 4 months) repeat of NSS for residual tumor. In the long-term, 7 (16.7%) patients had local tumor recurrence (managed with repeat NSS in 6 and completion nephrectomy in 1) and 3 had an episode of intestinal obstruction requiring surgical intervention. Overall survival was 85.7% (mean follow-up, 4.1 years). Of the 6 patients who died, 5 had diffuse anaplastic histology. All of the patients had an estimated glomerular filtration rate more than 60 mL/min/1.73 m2 at the last follow-up; no patient developed end-stage renal disease. Conclusions: In patients with synchronous, BWT, bilateral NSS is safe and almost always feasible, thereby preserving maximal renal parenchyma. With this approach, survival was excellent, as was maintenance of the renal function