Refining stereotactic body radiation therapy as a bridge to transplantation for hepatocellular carcinoma: An institutional experience.

BACKGROUND: Stereotactic body radiotherapy (SBRT) has been established as a safe and effective treatment for hepatocellular carcinoma (HCC). Currently, there are no consensus guidelines to advise optimal patient selection and radiotherapy planning parameters to minimise the risk of surgical and medical complications after liver transplant (LT) in patients who have had prior SBRT for HCC, whilst optimising treatment benefit. METHODS: We performed a retrospective analysis of all adult patients who received liver SBRT as a bridge to LT at a tertiary institution between 2017 and 2019. RESULTS: Nine patients received SBRT as bridging therapy to LT. HCC location varied from peripheral to central/hilar regions and HCC diameter was 13-54 mm. Median time between SBRT and LT was 141 days (range 27-461 days). Median operating time was 360 min (range 270-480 min). Four patients (44%) had visible SBRT reaction or fibrosis at the time of LT. SBRT reaction resulted in clinical impact in one patient (11%) only, where vascular clamping of the IVC was required for 10 min. CONCLUSION: SBRT is a safe and effective treatment for HCC enabling patients to remain within LT criteria, even for lesions not amenable to other more conventional bridging therapies. We describe a preliminary decision pathway to guide the optimal use of SBRT as a bridge to LT developed in our institution.

A Rare Case of Rhabdoid Pancreatic Carcinoma: Prolonged Disease-Free Survival Following Upfront Resection and Adjuvant Chemotherapy.

The rhabdoid subtype of undifferentiated pancreatic carcinoma is rarely reported. The clinical course of this disease is therefore poorly understood, although it is apparently an aggressive malignancy. We herein discuss the case of a 69-year-old man presenting with a rapidly enlarging mass of the pancreatic body and tail who was diagnosed with locally advanced SMARCB1-deficient undifferentiated pancreatic carcinoma with rhabdoid features, treated with radical resection and adjuvant chemotherapy, and has achieved 18-month disease-free survival ongoing at the time of article publication. We identify and contrast our case with 15 similar tumors reported in the English literature, briefly discuss the biology of this tumor, its relationship to malignant rhabdoid tumors of childhood, the role of SMARCB1 and its parent complex switch/sucrose-non-fermentable chromatin remodeling complex (SWI/SNF) in modulating the behavior of pancreatic malignancy, and the potential therapeutic avenues available for SWI/SNF-mutated malignancies.

Near-Fatal Hepatic Complication After Cardiac Catheter Ablation.

Radiofrequency cardiac ablation is increasingly performed for the management of dysrhythmias. Bleeding is a well-known complication of this procedure. We present a rare case of a near-fatal iatrogenic hepatic hemorrhage after cardiac catheter ablation. (Level of Difficulty: Advanced.).

Age Effects Aggressive Behavior: RNA-Seq Analysis in Cattle with Implications for Studying Neoteny Under Domestication.

The reactive type of aggression is regulated mostly by the brain's prefrontal cortex; however, the molecular changes underlying aggressiveness in adults have not been fully characterized. We used an RNA-seq approach to investigate differential gene expression in the prefrontal cortex of bovines from the aggressive Lidia breed at different ages: young three-year old and adult four-year-old bulls. A total of 50 up and 193 down-regulated genes in the adult group were identified. Furthermore, a cross-species comparative analysis retrieved 29 genes in common with previous studies on aggressive behaviors, representing an above-chance overlap with the differentially expressed genes in adult bulls. We detected changes in the regulation of networks such as synaptogenesis, involved in maintenance and refinement of synapses, and the glutamate receptor pathway, which acts as excitatory driver in aggressive responses. The reduced reactive aggression typical of domestication has been proposed to form part of a retention of juvenile traits as adults (neoteny).

Long term outcomes of hepatic resection following orthotopic liver transplant.

BACKGROUND: Liver resection is sometimes used as a graft saving procedure following orthotopic liver transplantation. METHODS: In this single centre retrospective cohort study, 12 adult patients underwent resection over a 20 year period, including recipients of split livers and second grafts. RESULTS: Indications for resection were vascular (portal vein obstruction and hepatic artery thrombus), biliary (ischaemic cholangiopathy, chronic biliary obstruction, biliary-vascular fistula and biloma) and recurrence of disease (primary sclerosing cholangitis [PSC] and hepatocellular carcinoma [HCC]). There was no perioperative mortality. Median follow up was 89 months. At the completion of the study 40% of patients had functioning grafts. One third required retransplantation with a median 1 year 6 months post resection. Three patients were deceased (recurrent HCC n = 1, PSC n = 1 and unspecified causes n = 1). Total graft survival was 91.7% at 1 year, 73.3% at 5 years and 64.2% at 10 years. CONCLUSIONS: Liver resection following liver transplant in select patients may salvage the graft or delay the need for retransplantation.

Gene expression profiles underlying aggressive behavior in the prefrontal cortex of cattle.

BACKGROUND: Aggressive behavior is an ancient and conserved trait, habitual for most animals in order to eat, protect themselves, compete for mating and defend their territories. Genetic factors have been shown to play an important role in the development of aggression both in animals and humans, displaying moderate to high heritability estimates. Although such types of behaviors have been studied in different animal models, the molecular architecture of aggressiveness remains poorly understood. This study compared gene expression profiles of 16 prefrontal cortex (PFC) samples from aggressive and non-aggressive cattle breeds: Lidia, selected for agonistic responses, and Wagyu, selected for tameness. RESULTS: A total of 918 up-regulated and 278 down-regulated differentially expressed genes (DEG) were identified, representing above-chance overlap with genes previously identified in studies of aggression across species, as well as those implicated in recent human evolution. The functional interpretation of the up-regulated genes in the aggressive cohort revealed enrichment of pathways such as Alzheimer disease-presenilin, integrins and the ERK/MAPK signaling cascade, all implicated in the development of abnormal aggressive behaviors and neurophysiological disorders. Moreover, gonadotropins, are up-regulated as natural mechanisms enhancing aggression. Concomitantly, heterotrimeric G-protein pathways, associated with low reactivity mental states, and the GAD2 gene, a repressor of agonistic reactions associated with PFC activity, are down-regulated, promoting the development of the aggressive responses selected for in Lidia cattle. We also identified six upstream regulators, whose functional activity fits with the etiology of abnormal behavioral responses associated with aggression. CONCLUSIONS: These transcriptional correlates of aggression, resulting, at least in part, from controlled artificial selection, can provide valuable insights into the complex architecture that underlies naturally developed agonistic behaviors. This analysis constitutes a first important step towards the identification of the genes and metabolic pathways that promote aggression in cattle and, providing a novel model species to disentangle the mechanisms underlying variability in aggressive behavior.

Capturing the Effects of Domestication on Vocal Learning Complexity.

Domesticated and vocal learning species can serve as informative model organisms for the reduction of reactive aggression and emergence of speech in our lineage. Amidst mounting evidence that domestication modifies vocal repertoires across different species, we focus on the domesticated Bengalese finch, which has a more complex song than the wild-type white-rumped munia. Our explanation for this effect revolves around the glutamate neurotransmitter system. Glutamate signaling (i) is implicated in birdsong learning, (ii) controls dopamine activity in neural circuits crucial for vocal learning, (iii) is disproportionately targeted in the evolution of domesticates, and (iv) regulates stress responses and aggressive behaviors attenuated under domestication. We propose that attenuated excitation of stress-related neural circuits potentiates vocal learning via altered dopaminergic signaling.

Names and their meanings: A dual-process account of proper-name encoding and retrieval.

The ability to pick out a unique entity with a proper name is an important component of human language. It has been a primary focus of research in the philosophy of language since the nineteenth century. Brain-based evidence has shed new light on this capacity, and an extensive literature indicates the involvement of distinct fronto-temporal and temporo-occipito-parietal association cortices in proper-name retrieval. However, comparatively few efforts have sought to explain how memory encoding processes lead to the later recruitment of these distinct regions at retrieval. Here, we provide a unified account of proper-name encoding and retrieval, reviewing evidence that socio-emotional and unitized encoding subserve the retrieval of proper names via anterior-temporal-prefrontal activations. Meanwhile, non-unitized item-item and item-context encoding support subsequent retrieval, largely dependent on the temporo-occipito-parietal cortex. We contend that this well-established divergence in encoding systems can explain how proper names are later retrieved from distinct neural structures. Furthermore, we explore how evidence reviewed here can inform a century-and-a-half-old debate about proper names and the meanings they pick out.

Glutamate receptors in domestication and modern human evolution.

There has been a recent resurgence of interest in the hypothesis that anatomically modern humans and domesticated species have followed convergent evolutionary paths. Here, we review results from domestication and modern-human evolutionary studies in order to evaluate evidence for shared changes to neurotransmission across these species. We compare genomic and, where available, brain-expression differences across 488 neurotransmitter receptor genes in 14 domesticated species and modern humans relative to their wild and archaic counterparts. This analysis highlights prevalent changes to glutamate - most notably kainate and metabotropic - receptor genes. We review evidence for these genes' expression and their respective receptor functions in the central nervous system, as well as phenotypes commonly associated with alterations to them. This evidence suggests an important role for kainate and metabotropic receptors in regulating hypothalamic-pituitary-adrenal axis excitation, and we provide a mechanistic account of their actions in attenuating the stress response. We assess the explanatory potential of such actions in contributing to the emergence of the (self-)domesticated phenotype, in particular to reduced reactive aggression.

Dosage analysis of the 7q11.23 Williams region identifies BAZ1B as a major human gene patterning the modern human face and underlying self-domestication.

We undertook a functional dissection of chromatin remodeler BAZ1B in neural crest (NC) stem cells (NCSCs) from a uniquely informative cohort of typical and atypical patients harboring 7q11.23 copy number variants. Our results reveal a key contribution of BAZ1B to NCSC in vitro induction and migration, coupled with a crucial involvement in NC-specific transcriptional circuits and distal regulation. By intersecting our experimental data with new paleogenetic analyses comparing modern and archaic humans, we found a modern-specific enrichment for regulatory changes both in BAZ1B and its experimentally defined downstream targets, thereby providing the first empirical validation of the human self-domestication hypothesis and positioning BAZ1B as a master regulator of the modern human face. In so doing, we provide experimental evidence that the craniofacial and cognitive/behavioral phenotypes caused by alterations of the Williams-Beuren syndrome critical region can serve as a powerful entry point into the evolution of the modern human face and prosociality.

Increasing Community Resilience Through Improved Lifeline Infrastructure Performance.

The concept of community resilience is complex and multidimensional, relying on engineering and other disciplines to help communities break the cycle of destruction and recovery and reduce the impacts of earthquakes and other hazards. This article presents proposed prioritized actions to improve lifeline infrastructure resilience based on an assessment of lifeline infrastructure performance commissioned and funded by the National Institute of Standards and Technology (NIST).

Nab3's localization to a nuclear granule in response to nutrient deprivation is determined by its essential prion-like domain.

Ribonucleoprotein (RNP) granules are higher order assemblies of RNA, RNA-binding proteins, and other proteins, that regulate the transcriptome and protect RNAs from environmental challenge. There is a diverse range of RNP granules, many cytoplasmic, which provide various levels of regulation of RNA metabolism. Here we present evidence that the yeast transcription termination factor, Nab3, is targeted to intranuclear granules in response to glucose starvation by Nab3's proline/glutamine-rich, prion-like domain (PrLD) which can assemble into amyloid in vitro. Localization to the granule is reversible and sensitive to the chemical probe 1,6 hexanediol suggesting condensation is driven by phase separation. Nab3's RNA recognition motif is also required for localization as seen for other PrLD-containing RNA-binding proteins that phase separate. Although the PrLD is necessary, it is not sufficient to localize to the granule. A heterologous PrLD that functionally replaces Nab3's essential PrLD, directed localization to the nuclear granule, however a chimeric Nab3 molecule with a heterologous PrLD that cannot restore termination function or viability, does not form granules. The Nab3 nuclear granule shows properties similar to well characterized cytoplasmic compartments formed by phase separation, suggesting that, as seen for other elements of the transcription machinery, termination factor condensation is functionally important.

Correction: Self-domestication in Homo sapiens: Insights from comparative genomics.

[This corrects the article DOI: 10.1371/journal.pone.0185306.].

Self-domestication in Homo sapiens: Insights from comparative genomics.

This study identifies and analyzes statistically significant overlaps between selective sweep screens in anatomically modern humans and several domesticated species. The results obtained suggest that (paleo-)genomic data can be exploited to complement the fossil record and support the idea of self-domestication in Homo sapiens, a process that likely intensified as our species populated its niche. Our analysis lends support to attempts to capture the "domestication syndrome" in terms of alterations to certain signaling pathways and cell lineages, such as the neural crest.

The hnRNP-like Nab3 termination factor can employ heterologous prion-like domains in place of its own essential low complexity domain.

Many RNA-binding proteins possess domains with a biased amino acid content. A common property of these low complexity domains (LCDs) is that they assemble into an ordered amyloid form, juxtaposing RNA recognition motifs in a subcellular compartment in which RNA metabolism is focused. Yeast Nab3 is one such protein that contains RNA-binding domains and a low complexity, glutamine/proline-rich, prion-like domain that can self-assemble. Nab3 also contains a region of structural homology to human hnRNP-C that resembles a leucine zipper which can oligomerize. Here we show that the LCD and the human hnRNP-C homology domains of Nab3 were experimentally separable, as cells were viable with either segment, but not when both were missing. In exploiting the lethality of deleting these regions of Nab3, we were able to test if heterologous prion-like domains known to assemble into amyloid, could substitute for the native sequence. Those from the hnRNP-like protein Hrp1, the canonical prion Sup35, or the epsin-related protein Ent2, could rescue viability and enable the new Nab3 chimeric protein to support transcription termination. Other low complexity domains from RNA-binding, termination-related proteins or a yeast prion, could not. As well, an unbiased genetic selection revealed a new protein sequence that could rescue the loss of Nab3's essential domain via multimerization. This new sequence and Sup35's prion domain could also rescue the lethal loss of Hrp1's prion-like domain when substituted for it. This suggests there are different cross-functional classes of amyloid-forming LCDs and that appending merely any assembly-competent LCD to Nab3 does not restore function or rescue viability. The analysis has revealed the functional complexity of LCDs and provides a means by which the differing classes of LCD can be dissected and understood.

Determinants of Amyloid Formation for the Yeast Termination Factor Nab3.

Low complexity protein sequences are often intrinsically unstructured and many have the potential to polymerize into amyloid aggregates including filaments and hydrogels. RNA-binding proteins are unusually enriched in such sequences raising the question as to what function these domains serve in RNA metabolism. One such yeast protein, Nab3, is an 802 amino acid termination factor that contains an RNA recognition motif and a glutamine/proline rich domain adjacent to a region with structural similarity to a human hnRNP. A portion of the C-terminal glutamine/proline-rich domain assembles into filaments that organize into a hydrogel. Here we analyze the determinants of filament formation of the isolated low complexity domain as well as examine the polymerization properties of full-length Nab3. We found that the C-terminal region with structural homology to hnRNP-C is not required for assembly, nor is an adjacent stretch of 16 glutamines. However, reducing the overall glutamine composition of this 134-amino acid segment from 32% to 14% destroys its polymerization ability. Importantly, full-length wildtype Nab3 also formed filaments with a characteristic cross-ß structure which was dependent upon the glutamine/proline-rich region. When full length Nab3 with reduced glutamine content in its low complexity domain was exchanged for wildtype Nab3, cells were not viable. This suggests that polymerization of Nab3 is normally required for its function. In an extension of this idea, we show that the low complexity domain of another yeast termination factor, Pcf11, polymerizes into amyloid fibers and a hydrogel. These findings suggest that, like many other RNA binding proteins, termination factors share a common biophysical trait that may be important for their function.

Amyloid-like assembly of the low complexity domain of yeast Nab3.

Termination of transcription of short non-coding RNAs is carried out in yeast by the Nab3-Nrd1-Sen1 complex. Nab3 and Nrd1 are hnRNP-like proteins that dimerize and bind RNA with sequence specificity. We show here that an essential region of Nab3 that is predicted to be prion-like based upon its sequence bias, formed amyloid-like filaments. A similar region from Nrd1 also assembled into filaments in vitro. The purified Nab3 domain formed a macroscopic gel whose lattice organization was observed by X-ray fiber diffraction. Filaments were resistant to dissociation in anionic detergent, bound the fluorescent dye thioflavin T, and showed a ß-sheet rich structure by circular dichroism spectroscopy, similar to human amyloid ß which served as a reference amyloid. A version of the Nab3 domain with a mutation that impairs its termination function, also formed fibers as observed by electron microscopy. Using a protein fragment interaction assay, the purified Nab3 domain was seen to interact with itself in living yeast. A similar observation was made for full length Nab3. These results suggest that the Nab3 and Nrd1 RNA-binding proteins can attain a complex polymeric form and raise the possibility that this property is important for organizing their functional state during termination. These findings are congruent with recent work showing that RNA binding proteins with low complexity domains form a dynamic subcellular matrix in which RNA metabolism takes place but can also aberrantly yield pathological aggregated particles.

Spontaneous intrahepatic haemorrhage: two cases of segmental arterial mediolysis.

BACKGROUND: Segmental arterial mediolysis (SAM) is an under-recognized degenerative vascular disorder with variable clinical presentations. It affects medium to large calibre arteries, typically those arising from the coeliac axis, and its diagnosis is complicated by overlap with other clinical entities like fibromuscular dysplasia. Diagnosis requires histopathological examination of the affected tissue, although radiographic appearances can be suggestive of SAM. METHODS: We report on two patients presenting with acute rupture of an intrahepatic artery affected by SAM. RESULTS: Both patients ultimately required right hemi-hepatectomy in order to either control ongoing bleeding or for removal of liver rendered ischaemic by intra-arterial embolization. This was achieved safely despite additional SAM lesions present throughout the vasculature. CONCLUSION: In both cases described, presentation followed recent, unrelated abdominal surgery and we propose a link between these two events. Recent research has identified the potential role of noradrenaline in the development of SAM lesions in greyhounds, with levels of endogenous noradrenaline known to rise in the setting of surgery.