Gallbladder cancer: South American experience

Large differences in terms of incidence and mortality due to gallbladder cancer (GBC) have been reported worldwide. Moreover, it seems that GBC has unique characteristics in South America. We surveyed the literature looking for information about the epidemiology, basic and translational research, and clinical trials performed in South America in order to critically analyze the magnitude of this health problem in the region. Compared to other geographic areas, age-standardized mortality rates (ASMR) for GBC in women are very high, particularly in many western areas of South America. Genetic, as well as dietary and environmental factors likely contribute to the pathogenesis of this disease in the area. Compared to other regions the profile of abnormalities of key genes such as KRAS and TP53 in GBC seems to slightly differ in South America, while the clinical behavior appears to be similar with a median overall survival (OS) of 6.5 to 8 months in advanced GBC. In contrast to Europe and USA, prophylactic cholecystectomy is a common practice in western areas of South America. GBC particularly affects women in South America, and represents a significant public health problem. It appears to have peculiarities that pose an urgent need for additional research aimed to discover risk factors, molecular events associated with its development and new treatment options for this lethal disease.Fil: Arroyo, Gerardo F.. Intergrupo Latinoamericano de Oncología Gastrointestinal; ArgentinaFil: Gentile, Alberto. Provincia de Salta. Ministerio de Salud Pública; ArgentinaFil: Parada, Luis Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentin

A Molecular Basis for Estrogen-Induced Cryptorchidism

AbstractMale sexual differentiation relies upon testicular secretion of the hormones testosterone, Mullerian inhibiting substance, and insulin-3 (Insl3). Insl3 is responsible for testicular descent through virilization and outgrowth of the embryonic gubernaculum. In mouse, prenatal exposure to 17β-estradiol and the nonsteroidal synthetic estrogen diethylstilbestrol (DES) disturbs the endocrine balance, causing demasculinizing and feminizing effects in the male embryo, including impaired testicular descent (cryptorchidism). In the current study, we show that maternal exposure to estrogens, including 17α- and β-estradiol, as well as DES, specifically down regulates Insl3 expression in embryonic Leydig cells, thereby providing a mechanism for cryptorchidism. These experiments may have implications for the widespread use of estrogenic substances in agriculture and the environment

Neurofibromatosis type 1: Modeling CNS dysfunction

Neurofibromatosis type 1 (NF1) is the most common monogenic disorder in which individuals manifest central nervous system (CNS) abnormalities. Affected individuals develop glial neoplasms (optic gliomas, malignant astrocytomas) and neuronal dysfunction (learning disabilities, attention deficits). Nf1 genetically-engineered mouse models have revealed the molecular and cellular underpinnings of gliomagenesis, attention deficit, and learning problems with relevance to basic neurobiology. Using NF1 as a model system, these studies have revealed critical roles for the NF1 gene in non-neoplastic cells in the tumor microenvironment, the importance of brain region heterogeneity, novel mechanisms of glial growth regulation, the neurochemical bases for attention deficit and learning abnormalities, and new insights into neural stem cell function. Here we review recent studies, presented at a symposium at the 2012 Society for Neuroscience annual meeting, that highlight unexpected cell biology insights into RAS and cyclic AMP pathway effects on neural progenitor signaling, neuronal function, and oligodendrocyte lineage differentiation

Regulation of hippocampal progenitor cell survival, proliferation and dendritic development by BDNF

<p>Abstract</p> <p>Background</p> <p>Environmental enrichment (EE) is known to enhance BDNF levels and neurogenesis in the adult hippocampus. To examine the role of BDNF in modulating EE-mediated adult hippocampal neurogenesis, we conditionally ablated <it>BDNF </it>expression in the hippocampus (cKO mice) and have assessed proliferation, survival, differentiation and dendritic development of hippocampal progenitors.</p> <p>Results</p> <p>We show that while the extent of cell proliferation and neuronal fate differentiation in the hippocampus of cKO mice is not different from wild-type (WT) littermates maintained in either standard or enriched conditions, reduced BDNF levels significantly impaired the survival of newborn cells in both housing conditions. In addition, while highly active enriched WT mice exhibited a robust increase in progenitor cell proliferation, highly active cKO mice showed a modest increase in cell proliferation compared to standard housed or underactive cKO mice.</p> <p>Conclusions</p> <p>There results argue that while BDNF plays a role in exercise-induced cell proliferation, other factors must contribute to this phenomenon. We also show that dendritic development was impaired in cKO mice maintained in standard housing conditions, and that EE rescued this phenotype.</p

Isolation of bacteriocinogenic Enterococcus mundtii strain from Hemiodema spectabilis (sea cucumber)

En este estudio se evaluó la actividad antibacteriana de una cepa de Enterococcus mundtii tw278 productora de bacteriocina aislada del contenido intestinal de Hemiodema spectabilis (pepino de mar), recolectado en la costa patagónica de la Argentina. La cepa se identificó mediante pruebas bioquímicas y análisis filogenético del gen ARNr 16S. Además, se detectó el gen estructural que codifica para la mundticina KS mediante técnicas de PCR. La investigación de los factores de virulencia reveló que la cepa de E. mundtii tw278 no presentó actividad gelatinasa ni hemolítica y fue susceptible a todos los antibióticos analizados, excepto la cefalotina. La máxima actividad inhibitoria se logró al final de la fase logarítmica cuando se utilizó el caldo MRS como medio de cultivo a 35 °C. Luego de 12 h de incubación, el sobrenadante libre de células (SLC) alcanzó un título de 163 840 unidades arbitrarias por mililitro contra la cepa indicadora de Listeria innocua ATCC 33090. El SLC exhibió actividad contra todas las cepas de Listeria ensayadas, Enterococcus faecalis ATCC 29212, enterococos resistentes a vancomicina (Van A, Van B y Van C), Lactobacillus plantarum TwLb 5 y Vibrio anguilarum V10. Este sería el primer estudio que informa el aislamiento de una cepa bacteriocinogénica de E. mundtii aislada del contenido intestinal de Hemiodema spectabilis.This study was conducted to evaluate the antibacterial activity of a bacteriocinproducing Enterococcus mundtii tw278 strain isolated from the intestinal content of Hemiodema spectabilis (sea cucumber) sampled in the Patagonian coast of Argentine. The strain was identified by biochemical tests and 16S rRNA gene phylogenetic analyses. The structural gene that codifies mundticin KS was detected by PCR. Investigation of virulence factors revealed that E. mundtii tw278 did not display gelatinase or hemolytic activity and was susceptible to all antibiotics assayed, except cefalotin. Maximum inhibitory activity was achieved at the end of logarithmic phase when MRS broth was used as culture media at 35 °C. After 12 h of incubation, cell-free supernatant (CFS) reached a titre of 163 840 arbitrary units per mililitre against the target bacteria Listeria innocua ATCC 33090. CFS showed activity against all the Listeria strains assayed, Enterococcus faecalis ATCC 29212, vancomycin-resistant enterococci (Van A, Van B and Van C), Lactobacillus plantarum TwLb 5 and Vibrio anguilarum V10. This would be the first study to report the isolation of a bacteriocinogenic E. mundtii strain from intestinal content of Hemiodema spectabilis

Somatic PDGFRB activating variants in fusiform cerebral aneurysms

The role of somatic genetic variants in the pathogenesis of intracranial-aneurysm formation is unknown. We identified a 23-year-old man with progressive, right-sided intracranial aneurysms, ipsilateral to an impressive cutaneous phenotype. The index individual underwent a series of genetic evaluations for known connective-tissue disorders, but the evaluations were unrevealing. Paired-sample exome sequencing between blood and fibroblasts derived from the diseased areas detected a single novel variant predicted to cause a p.Tyr562Cys (g.149505130T>C [GRCh37/hg19]; c.1685A>G) change within the platelet-derived growth factor receptor β gene (PDGFRB), a juxtamembrane-coding region. Variant-allele fractions ranged from 18.75% to 53.33% within histologically abnormal tissue, suggesting post-zygotic or somatic mosaicism. In an independent cohort of aneurysm specimens, we detected somatic-activating PDGFRB variants in the juxtamembrane domain or the kinase activation loop in 4/6 fusiform aneurysms (and 0/38 saccular aneurysms; Fisher's exact test, p < 0.001). PDGFRB-variant, but not wild-type, patient cells were found to have overactive auto-phosphorylation with downstream activation of ERK, SRC, and AKT. The expression of discovered variants demonstrated non-ligand-dependent auto-phosphorylation, responsive to the kinase inhibitor sunitinib. Somatic gain-of-function variants in PDGFRB are a novel mechanism in the pathophysiology of fusiform cerebral aneurysms and suggest a potential role for targeted therapy with kinase inhibitors

Nf1-Dependent Tumors Require a Microenvironment Containing Nf1+/−- and c-kit-Dependent Bone Marrow

SummaryInteractions between tumorigenic cells and their surrounding microenvironment are critical for tumor progression yet remain incompletely understood. Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a common genetic disorder characterized by complex tumors called neurofibromas. Genetic studies indicate that biallelic loss of Nf1 is required in the tumorigenic cell of origin in the embryonic Schwann cell lineage. However, in the physiologic state, Schwann cell loss of heterozygosity is not sufficient for neurofibroma formation and Nf1 haploinsufficiency in at least one additional nonneoplastic lineage is required for tumor progression. Here, we establish that Nf1 heterozygosity of bone marrow-derived cells in the tumor microenvironment is sufficient to allow neurofibroma progression in the context of Schwann cell Nf1 deficiency. Further, genetic or pharmacologic attenuation of c-kit signaling in Nf1+/− hematopoietic cells diminishes neurofibroma initiation and progression. Finally, these studies implicate mast cells as critical mediators of tumor initiation

Association between T2-related co-morbidities and effectiveness of biologics in severe asthma

Acknowledgments The authors thank Mr. Joash Tan (BSc, Hons), of the Observational and Pragmatic Research Institute (OPRI), and Ms Andrea Lim (BSc, Hons) of the Observational Pragmatic Research Institute (OPRI) for their editorial and formatting assistance that supported the development of this publication. Funding statement: This study was conducted by the Observational and Pragmatic Research Institute (OPRI) Pte Ltd and was partially funded by Optimum Patient Care Global and AstraZeneca Ltd. AstraZeneca UK LimitedPeer reviewe