Background
Neuroendocrine tumors are becoming increasingly prevalent, with many patients presenting with or developing metastatic disease to the liver.
Methods
In this landmark series paper, we ...highlight the critical studies that have defined the surgical management of neuroendocrine tumor liver metastases, as well as several randomized control trials which have investigated strategies for systemic control of metastatic disease.
Results
Liver-directed surgical approaches and locally ablative procedures are recommended for patients with limited, resectable, and in some cases, nonresectable tumor burden. Angiographic liver-directed techniques, such as transarterial embolization, chemoembolization, and radioembolization, offer another approach for management in patients with liver-predominant disease. Peptide receptor radionuclide therapy is a promising therapy for patients with hepatic and/or extrahepatic metastases. Various systemic medical therapies are also available as adjunct or definitive therapy for patients with metastatic disease.
Conclusions
This article reviews current data regarding management of neuroendocrine liver metastases and highlights areas for future study.
Autism spectrum disorder (ASD) is a disorder of brain development. Most cases lack a clear etiology or genetic basis, and the difficulty of re-enacting human brain development has precluded ...understanding of ASD pathophysiology. Here we use three-dimensional neural cultures (organoids) derived from induced pluripotent stem cells (iPSCs) to investigate neurodevelopmental alterations in individuals with severe idiopathic ASD. While no known underlying genomic mutation could be identified, transcriptome and gene network analyses revealed upregulation of genes involved in cell proliferation, neuronal differentiation, and synaptic assembly. ASD-derived organoids exhibit an accelerated cell cycle and overproduction of GABAergic inhibitory neurons. Using RNA interference, we show that overexpression of the transcription factor FOXG1 is responsible for the overproduction of GABAergic neurons. Altered expression of gene network modules and FOXG1 are positively correlated with symptom severity. Our data suggest that a shift toward GABAergic neuron fate caused by FOXG1 is a developmental precursor of ASD.
Display omitted
•iPSC-derived telencephalic organoids reflect human midfetal telencephalic development•Inhibitory neurons are overproduced in organoids from patients with idiopathic autism•Overproduction of inhibitory neurons is caused by increased FOXG1 gene expression
iPSC-derived brain organoids from autism patients reveal increased production of inhibitory neurons caused by increased FOXG1 gene expression, identifying this gene as a molecular signature of idiopathic ASD and a potential drug target.
The high-throughput antibiotic resistance gene (ARG) qPCR array, initially published in 2012, is increasingly used to quantify resistance and mobile determinants in environmental matrices. Continued ...utility of the array; however, necessitates improvements such as removing or redesigning questionable primer sets, updating targeted genes and coverage of available sequences. Towards this goal, a new primer design tool (EcoFunPrimer) was used to aid in identification of conserved regions of diverse genes. The total number of assays used for diverse genes was reduced from 91 old primer sets to 52 new primer sets, with only a 10% loss in sequence coverage. While the old and new array both contain 384 primer sets, a reduction in old primer sets permitted 147 additional ARGs and mobile genetic elements to be targeted. Results of validating the updated array with a mock community of strains resulted in over 98% of tested instances incurring true positive/negative calls. Common queries related to sensitivity, quantification and conventional data analysis (e.g. Ct cutoff value, and estimated genomic copies without standard curves) were also explored. A combined list of new and previously used primer sets is provided with a recommended set based on redesign of primer sets and results of validation.
This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the surgical management of pancreatic neuroendocrine tumors from July 19 to 20, 2018. The ...group reviewed a series of questions of specific interest to surgeons taking care of patients with pancreatic neuroendocrine tumors, and for each, the available literature was reviewed. What follows are these reviews for each question followed by recommendations of the panel.
Phosphatase and tensin homolog (PTEN) is a major negative regulator of the phosphatidylinositol-3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway. Loss-of-function mutations in
have ...been found in a subset of patients with macrocephaly and autism spectrum disorder (ASD). PTEN loss in neurons leads to somal hypertrophy, aberrant migration, dendritic overgrowth, increased spine density, and hyperactivity of neuronal circuits. These neuronal overgrowth phenotypes are present on
knock-out (KO) and reconstitution with autism-associated point mutations. The mechanism underlying dendritic overgrowth in
deficient neurons is unclear. In this study, we examined how
loss impacts microtubule (MT) dynamics in both sexes using retroviral infection and transfection strategies to manipulate PTEN expression and tag the plus-end MT binding protein, end-binding protein 3 (EB3). We found
KO neurons sprout more new processes over time compared with wild-type (WT) neurons. We also found an increase in MT polymerization rate in
KO dendritic growth cones. Reducing MT polymerization rate to the WT level was sufficient to reduce dendritic overgrowth in
KO neurons
and
Finally, we found that rescue of dendritic overgrowth via inhibition of MT polymerization was sufficient to improve the performance of
KO mice in a spatial memory task. Taken together, our data suggests that one factor underlying PTEN loss dependent dendritic overgrowth is increased MT polymerization. This opens the possibility for an intersectional approach targeting MT polymerization and mTOR with low doses of inhibitors to achieve therapeutic gains with minimal side effects in pathologies associated with loss of neuronal PTEN function.
Loss of
function because of genetic deletion or expression of mutations associated with autism spectrum disorder (ASD), results in overgrowth of neurons including increased total dendritic length and branching. We have discovered that this overgrowth is accompanied by increased rate of microtubule (MT) polymerization. The increased polymerization rate is insensitive to acute inhibition of mechanistic target of rapamycin (mTOR)C1 or protein synthesis. Direct pharmacological inhibition of MT polymerization can slow the polymerization rate in
knock-out (KO) neurons to rates seen in wild-type (WT) neurons. Correction of the MT polymerization rate rescues increased total dendritic arborization and spatial memory. Our studies suggest that phosphatase and tensin homolog (PTEN) inhibits dendritic growth through parallel regulation of protein synthesis and cytoskeletal polymerization.
Pancreatic neuroendocrine tumors are a diverse group of neoplasms with a generally favorable prognosis. Although they exhibit indolent growth, metastases are seen in roughly 60% of patients. ...Pancreatic neuroendocrine tumors may produce a wide variety of hormones, which are associated with dramatic symptoms, but the majority are nonfunctional. The diagnosis and treatment of these tumors is a multidisciplinary effort, and management guidelines continue to evolve. This review provides a concise summary of the presentation, diagnosis, surgical management, and systemic treatment of pancreatic neuroendocrine tumors.
PDF
