A Pathogenic Mosaic TP53 Mutation in Two Germ Layers Detected by Next Generation Sequencing

Background

Li-Fraumeni syndrome is caused by germline TP53 mutations and is clinically characterized by a predisposition to a range of cancers, most commonly sarcoma, brain tumours and leukemia. Pathogenic mosaic TP53 mutations have only rarely been described.

Methods and Findings

We describe a 2 years old child presenting with three separate cancers over a 6 month period; two soft tissue mesenchymal tumors and an aggressive metastatic neuroblastoma. As conventional testing of blood DNA by Sanger sequencing for mutations in TP53, ALK, and SDH was negative, whole exome sequencing of the blood DNA of the patient and both parents was performed to screen more widely for cancer predisposing mutations. In the patient''s but not the parents'' DNA we found a c.743 G>A, p.Arg248Gln (CCDS11118.1) TP53 mutation in 3–20% of sequencing reads, a level that would not generally be detectable by Sanger sequencing. Homozygosity for this mutation was detected in all tumor samples analyzed, and germline mosaicism was demonstrated by analysis of the child''s newborn blood spot DNA. The occurrence of separate tumors derived from different germ layers suggests that this de novo mutation occurred early in embryogenesis, prior to gastrulation.

Conclusion

The case demonstrates pathogenic mosaicim, detected by next generation deep sequencing, that arose in the early stages of embryogenesis.     

Associations between Lifetime Traumatic Events and Subsequent Chronic Physical Conditions: A Cross-National,Cross-Sectional Study

Background

Associations between lifetime traumatic event (LTE) exposures and subsequent physical ill-health are well established but it has remained unclear whether these are explained by PTSD or other mental disorders. This study examined this question and investigated whether associations varied by type and number of LTEs, across physical condition outcomes, or across countries.

Methods

Cross-sectional, face-to-face household surveys of adults (18+) were conducted in 14 countries (n = 38, 051). The Composite International Diagnostic Interview assessed lifetime LTEs and DSM-IV mental disorders. Chronic physical conditions were ascertained by self-report of physician''s diagnosis and year of diagnosis or onset. Survival analyses estimated associations between the number and type of LTEs with the subsequent onset of 11 physical conditions, with and without adjustment for mental disorders.

Findings

A dose-response association was found between increasing number of LTEs and odds of any physical condition onset (OR 1.5 [95% CI: 1.4–1.5] for 1 LTE; 2.1 [2.0–2.3] for 5+ LTEs), independent of all mental disorders. Associations did not vary greatly by type of LTE (except for combat and other war experience), nor across countries. A history of 1 LTE was associated with 7/11 of the physical conditions (ORs 1.3 [1.2–1.5] to 1.7 [1.4–2.0]) and a history of 5+ LTEs was associated with 9/11 physical conditions (ORs 1.8 [1.3–2.4] to 3.6 [2.0–6.5]), the exceptions being cancer and stroke.

Conclusions

Traumatic events are associated with adverse downstream effects on physical health, independent of PTSD and other mental disorders. Although the associations are modest they have public health implications due to the high prevalence of traumatic events and the range of common physical conditions affected. The effects of traumatic stress are a concern for all medical professionals and researchers, not just mental health specialists.     

Interferon and Interferon Inducers in the Treatment of Malignancies

The mechanism of the antitumor action of polyinosinic-polycytidylic acid is probably multifaceted. The compound induces the synthesis of interferon, and interferon probably is active against some tumors. Poly I:poly C alters protein and RNA synthesis in tissue culture. It specifically inhibits such macromolecule synthesis in tumors in vivo, while having less inhibitory action on synthesis in normal organs, or it may actually enhance. Finally, poly I:poly C strongly enhances graft vs. host rejection mechanisms, which may play a role in the rejection of some tumors.     

Built to bite? Differences in cranial morphology and bite performance between narrow‐ and broad‐headed European glass eels

The presence of two phenotypes in a single species is a widespread phenomenon, also observed in European eel (Anguilla anguilla). This dimorphism has been related to dietary differences in the subadult elver and yellow eel stages, with broad‐heads generally feeding on harder and/or larger‐bodied prey items than narrow‐heads. Nevertheless, both broad‐ and narrow‐headed phenotypes can already be found among glass eels, the stage preceding the elver eel stage. As these glass eels are considered nonfeeding, we investigate here to what degree the observed variation in head width is reflected in variation in the musculoskeletal feeding system, as well as whether this reflects the same variation observed in the older, dimorphic yellow eels. Additionally, we investigate whether musculoskeletal differences between broad‐ and narrow‐headed glass eels have implications on their feeding performance and could thus impact prey preference when eels start feeding. Therefore, we compared the cranial musculoskeletal system of five broad‐ and narrow‐headed glass eels using 3D‐reconstructions and simulated the glass eel's bite force using the data of the muscle reconstructions. We found that the variation in the musculoskeletal system of glass eels indeed reflects that of the yellow eels. Broader heads were related to larger jaw muscles, responsible for mouth closure. Accordingly, broad‐heads could generate higher bite forces than narrow‐headed glass eels. In addition, broader heads were associated with higher coronoid processes and shorter hyomandibulae, beneficial for dealing with higher mechanical loadings and consequently, harder prey. We, thus, show that head width variation in glass eels is related to musculoskeletal differences which, in turn, can affect feeding performance. As such, differences in prey preference can already take place the moment the eels start feeding, potentially leading to the dimorphism observed in the elver and yellow eel stage.     

Investigation of the diversity of effector genes in the banana pathogen,Fusarium oxysporum f. sp. cubense,reveals evidence of horizontal gene transfer

It is hypothesized that the virulence of phytopathogenic fungi is mediated through the secretion of small effector proteins that interfere with the defence responses of the host plant. In Fusarium oxysporum, one family of effectors, the Secreted In Xylem (SIX) genes, has been identified. We sought to characterize the diversity and evolution of the SIX genes in the banana‐infecting lineages of F. oxysporum f. sp. cubense (Foc). Whole‐genome sequencing data were generated for the 23 genetic lineages of Foc, which were subsequently queried for the 14 known SIX genes (SIX1–SIX14). The sequences of the identified SIX genes were confirmed in a larger collection of Foc isolates. Genealogies were generated for each of the SIX genes identified in Foc to further investigate the evolution of the SIX genes in Foc. Within Foc, variation of the SIX gene profile, including the presence of specific SIX homologues, correlated with the pathogenic race structure of Foc. Furthermore, the topologies of the SIX gene trees were discordant with the topology of an infraspecies phylogeny inferred from EF‐1α/RPB1/RPB2 (translation elongation factor‐1α/RNA polymerase II subunit I/RNA polymerase II subunit II). A series of topological constraint models provided strong evidence for the horizontal transmission of SIX genes in Foc. The horizontal inheritance of pathogenicity genes in Foc counters previous assumptions that convergent evolution has driven the polyphyletic phylogeny of Foc. This work has significant implications for the management of Foc, including the improvement of diagnostics and breeding programmes.     

The Use of Vanilla Plantations by Lemurs: Encouraging Findings for both Lemur Conservation and Sustainable Agroforestry in the Sava Region,Northeast Madagascar

Extensive areas of forest are cleared every year to establish new agricultural land in the tropics, resulting in a catastrophic loss in habitat for the world’s primates. A prominent example of this process is Madagascar, where an increasing demand for arable land has led to the once-forested landscape to be now dominated by agricultural areas used for the cultivation of food and cash crops. Despite the prominence of these plantations throughout Madagascar, their suitability as a habitat to support endemic lemur populations remains unclear. Here, we assessed lemur presence in vanilla plantations, Madagascar’s principal export crop, within the northeastern Sava region with the use of line transects. We confirmed the presence of five lemur species, four of which were nocturnal cheirogaleids, in these vanilla plantations. Intensively farmed vanilla plantations and those in existing stands of vegetation supported at least one species of lemur. Furthermore, lemurs were significantly more likely to be present in plantations grown close or adjacent to natural forest fragments, compared to more intensively farmed, anthropogenic sites. In comparison, we observed eight lemur species in natural forest fragment sites in close proximity to the vanilla plantation sites, four of which we did not observe in any of the plantation sites. Our results provide evidence of lemurs using vanilla plantations and show that vanilla plantations may act as extensions of suitable habitat for lemurs, suggesting that they may also function as matrices between isolated forest fragments through which gene flow can occur. These are important and encouraging findings for both lemur conservation and for sustainable agroforestry undertaken by local farming communities.     

Rapid and dynamic regulation of TGF-beta receptors on blood vessels and fibroblasts during ischemia-reperfusion injury

Thepathophysiological mechanisms involved in ischemia-reperfusioninjury are poorly understood. Although transforming growth factor(TGF)- has been shown to provide protection againstischemia-reperfusion injury in different organ systems, littleis known about the regulation of TGF- action during this process.Here we analyzed the effect of ischemia and reperfusion on theexpression of TGF- and its receptors in vivo with a pig skin flapmodel. Analysis of unoperated skin, nonischemic control flap,ischemic flap, and reperfused flap by immunohistochemistryindicates that ischemia and reperfusion result in rapid anddynamic regulation of type I, II, and III TGF- receptors andTGF-1 in a cell type-specific manner. Furthermore, hypoxiaupregulates type II TGF- receptor mRNA in skin fibroblasts inculture. Together, our results reveal that TGF- receptors andTGF-1 are markedly increased under acute ischemic conditions in the blood vessels and fibroblasts of the skin. We conclude thatTGF- action is enhanced under ischemic conditions and that it may represent an adaptive response to ischemic injury. The augmented TGF- responsiveness may be a critical determinant of theprotective effect of TGF- during ischemia-reperfusion injury.

     

Modeling perimenopause in Sprague-Dawley rats by chemical manipulation of the transition to ovarian failure

Various age-related diseases increase in incidence during perimenopause. However, our understanding of the effects of aging compared with hormonal changes of perimenopause in mediating these disease risks is incomplete, in part due to the lack of an experimental perimenopause model. We therefore aimed to determine whether manipulation of the transition to ovarian failure in rats via the use of 4-vinylcyclohexene diepoxide (VCD) could be used to model and accelerate hormonal changes characteristic of perimenopause. We examined long-term (11 to 20 mo), dose-dependent effects of VCD on reproductive function in 1- and 3-mo-old female Sprague-Dawley rats. Twenty-five daily doses of VCD (80 or 160 mg/kg daily compared with vehicle alone) depleted ovarian follicles in a dose-dependent fashion in rats of both ages, accelerated the onset of acyclicity, and caused dose-dependent increases in follicle-stimulating hormone that exceeded those naturally occurring with age in control rats but left serum levels of 17β-estradiol unchanged, with continued ovarian production of androstenedione. High-dose VCD caused considerable nonovarian toxicities in 3-mo-old Sprague-Dawley rats, making this an unsuitable model. In contrast, 1-mo-old rats had more robust dose-dependent increases in follicle-stimulating hormone without evidence of systemic toxicity in response to either VCD dose. Because perimenopause is characterized by an increase in follicle-stimulating hormone with continued secretion of ovarian steroids, VCD acceleration of an analogous hormonal milieu in 1-mo-old Sprague-Dawley rats may be useful for probing the hormonal effects of perimenopause on age-related disease risk.     

Disruption of rolandic gamma-band functional connectivity by seizures is associated with motor impairments in children with epilepsy

Although children with epilepsy exhibit numerous neurological and cognitive deficits, the mechanisms underlying these impairments remain unclear. Synchronization of oscillatory neural activity in the gamma frequency range (>30 Hz) is purported to be a mechanism mediating functional integration within neuronal networks supporting cognition, perception and action. Here, we tested the hypothesis that seizure-induced alterations in gamma synchronization are associated with functional deficits. By calculating synchrony among electrodes and performing graph theoretical analysis, we assessed functional connectivity and local network structure of the hand motor area of children with focal epilepsy from intracranial electroencephalographic recordings. A local decrease in inter-electrode phase synchrony in the gamma bands during ictal periods, relative to interictal periods, within the motor cortex was strongly associated with clinical motor weakness. Gamma-band ictal desychronization was a stronger predictor of deficits than the presence of the seizure-onset zone or lesion within the motor cortex. There was a positive correlation between the magnitude of ictal desychronization and impairment of motor dexterity in the contralateral, but not ipsilateral hand. There was no association between ictal desynchronization within the hand motor area and non-motor deficits. This study uniquely demonstrates that seizure-induced disturbances in cortical functional connectivity are associated with network-specific neurological deficits.