Response assessment during chemoradiation using a hypercellular/hyperperfused imaging phenotype predicts survival in patients with newly diagnosed glioblastoma

BackgroundAdversely prognostic hypercellular and hyperperfused regions of glioblastoma (GBM) predict progression-free survival, and are a novel target for dose-intensified chemoradiation (chemoRT) recently implemented in a phase II clinical trial. As a secondary aim, we hypothesized that dose-intensified chemoRT would induce greater mid-treatment response of hypercellular/hyperperfused tumor regions vs standard chemoradiation, and that early response would improve overall survival (OS).MethodsForty-nine patients with newly diagnosed GBM underwent prospective, multiparametric high b value diffusion-weighted MRI (DW-MRI) and perfusion dynamic contrast-enhanced MRI (DCE-MRI) pre-RT and 3-4 weeks into RT. The hypercellular tumor volume (TV_HCV, mean contralateral normal brain + 2SD) and hyperperfused tumor volume (TV_CBV, contralateral normal frontal gray matter + 1SD) were generated using automated thresholding. Twenty-six patients were enrolled on a dose-escalation trial targeting TV_HCV/TV_CBV with 75 Gy in 30 fractions, and 23 non-trial patients comprised the control group. OS was estimated using the Kaplan-Meier method and compared using the log-rank test. The effect of TV_HCV/TV_CBV and Gd-enhanced tumor volume on OS was assessed using multivariable Cox proportional-hazard regression.ResultsMost patients had gross total (47%) or subtotal resection (37%), 25% were MGMT-methylated. Patients treated on the dose-escalation trial had significantly greater reduction in TV_HCV/TV_CBV (41% reduction, IQR 17%-75%) vs non-trial patients (6% reduction, IQR 6%-22%, P = .002). An increase in TV_HCV/TV_CBV during chemoRT was associated with worse OS (adjusted hazard ratio [aHR] 1.2, 95%CI 1.0-1.4, P = .02), while pre-treatment tumor volumes (P > .5) and changes in Gd-enhanced volume (P = .9) were not.ConclusionsMultiparametric MRI permits identification of therapeutic resistance during chemoRT and supports adaptive strategies in future trials.     

Hepatocyte-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice

Hepatic uptake and biosynthesis of fatty acids (FAs), as well as the partitioning of FAs into oxidative, storage, and secretory pathways, are tightly regulated processes. Dysregulation of one or more of these processes can promote excess hepatic lipid accumulation, ultimately leading to systemic metabolic dysfunction. Angiopoietin-like-4 (ANGPTL4) is a secretory protein that inhibits lipoprotein lipase (LPL) and modulates triacylglycerol (TAG) homeostasis. To understand the role of ANGPTL4 in liver lipid metabolism under normal and high-fat–fed conditions, we generated hepatocyte-specific Angptl4 mutant mice (Hmut). Using metabolic turnover studies, we demonstrate that hepatic Angptl4 deficiency facilitates catabolism of TAG-rich lipoprotein (TRL) remnants in the liver via increased hepatic lipase (HL) activity, which results in a significant reduction in circulating TAG and cholesterol levels. Consequently, depletion of hepatocyte Angptl4 protects against diet-induced obesity, glucose intolerance, liver steatosis, and atherogenesis. Mechanistically, we demonstrate that loss of Angptl4 in hepatocytes promotes FA uptake, which results in increased FA oxidation, ROS production, and AMPK activation. Finally, we demonstrate the utility of a targeted pharmacologic therapy that specifically inhibits Angptl4 gene expression in the liver and protects against diet-induced obesity, dyslipidemia, glucose intolerance, and liver damage, which likely occur via increased HL activity. Notably, this inhibition strategy does not cause any of the deleterious effects previously observed with neutralizing antibodies.     

Hereditary Diffuse Gastric Cancer: A Family Diagnosis and Treatment

Hereditary diffuse gastric cancer (HDGC) is a rare cancer representing approximately 2% of all gastric cancers. It is caused by CDHI gene mutations, inherited in an autosomal dominant fashion, that affect the function of E-cadherin. Approximately 38% of HDGC families have a CDHI gene mutation. With an estimated 75% penetrance rate, carriers are at high risk for HDGC. We describe the case of a Caucasian male of German-Russian ancestry, carrying a CDHI gene mutation, who survived for 18 months after being diagnosed with HDGC. The results of genetic testing undergone by his family members are also reported, along with a review of the current literature. Since surveillance methods for HDGC are ineffective and unreliable, total prophylactic gastrectomy is advised for individuals with the gene mutation. Additionally, a diagnosis of HDGC should lead to genetic evaluation of family members followed by preventative measures.     

Peritumoral tissue compression is predictive of exudate flux in a rat model of cerebral tumor: an MRI study in an embedded tumor

MRI estimates of extracellular volume and tumor exudate flux in peritumoral tissue are demonstrated in an experimental model of cerebral tumor. Peritumoral extracellular volume predicted the tumor exudate flux. Eighteen RNU athymic rats were inoculated intracerebrally with U251MG tumor cells and studied with dynamic contrast enhanced MRI (DCE‐MRI) approximately 18 days post implantation. Using a model selection paradigm and a novel application of Patlak and Logan plots to DCE‐MRI data, the distribution volume (i.e. tissue porosity) in the leaky rim of the tumor and that in the tissue external to the rim (the outer rim) were estimated, as was the tumor exudate flow from the inner rim of the tumor through the outer rim. Distribution volume in the outer rim was approximately half that of the inner adjacent region (p < 1 × 10^?4). The distribution volume of the outer ring was significantly correlated (R² = 0.9) with tumor exudate flow from the inner rim. Thus, peritumoral extracellular volume predicted the rate of tumor exudate flux. One explanation for these data is that perfusion, i.e. the delivery of blood to the tumor, was regulated by the compression of the mostly normal tissue of the tumor rim, and that the tumor exudate flow was limited by tumor perfusion. Copyright © 2015 John Wiley & Sons, Ltd.     

Cerebral cavernous malformations in the setting of focal epilepsies: pathological findings,clinical characteristics,and surgical treatment principles

Cavernous cerebral malformations (CCMs) are a well-defined epilepsy-associated pathology. They represent lesions/conglomerates of abnormally configured vessels leading to seizures either as a result of physiological changes affecting the cerebral cortex immediately surrounding the CCM (an epileptogenic mechanism that is relevant for both temporal and extratemporal lesions), or as a result of promoting epileptogenicity in remote but anatomo-functionally connected brain regions (a mechanism that is particularly relevant for temporal lobe lesions). This review details the pathological findings in CCMs and discusses the mechanisms of epileptogenicity in this context. The bulk of the review will focus on therapeutic strategies. Medical therapy using antiepileptic drugs is recommended as a first-line therapy, but surgical removal of the CCM with the surrounding cortex should be pursued if seizures prove to be drug resistant. Early timing of the resection and complete removal of any associated epileptic pathology are critical for best outcomes. In addition to reviewing the available data from prior series, we present original research from two specialized epilepsy centers targeted at answering particularly pressing clinical questions mainly related to the ideal timing and extent of surgery. Further research is needed to define the best surgical strategies in patients with temporal lobe CCMs and structurally normal hippocampi.     

Alteration of Striatal Tetrahydrobiopterin in Iron-Induced Unilateral Model of Parkinson's Disease

It has been suggested that transition metal ions such as iron can produce an oxidative injuries to nigrostriatal dopaminergic neurons, like Parkinson''s disease (PD) and subsequent compensative increase of tetrahydrobiopterin (BH₄) during the disease progression induces the aggravation of dopaminergic neurodegeneration in striatum. It had been established that the direct administration of BH₄ into neuron would induce the neuronal toxicity in vitro. To elucidate a role of BH₄ in pathogenesis in the PD in vivo, we assessed the changes of dopamine (DA) and BH₄ at striatum in unilateral intranigral iron infused PD rat model. The ipsistriatal DA and BH₄ levels were significantly increased at 0.5 to 1 d and were continually depleting during 2 to 7 d after intranigral iron infusion. The turnover rate of BH₄ was higher than that of DA in early phase. However, the expression level of GTP-cyclohydrolase I mRNA in striatum was steadily increased after iron administration. These results suggest that the accumulation of intranigral iron leads to generation of oxidative stress which damage to dopaminergic neurons and causes increased release of BH₄ in the dopaminergic neuron. The degenerating dopaminergic neurons decrease the synthesis and release of both BH4 and DA in vivo that are relevance to the progression of PD. Based on these data, we propose that the increase of BH₄ can deteriorate the disease progression in early phase of PD, and the inhibition of BH4 increase could be a strategy for PD treatment.     

Origin and domestication of papaya Yh chromosome

Sex in papaya is controlled by a pair of nascent sex chromosomes. Females are XX, and two slightly different Y chromosomes distinguish males (XY) and hermaphrodites (XY^h). The hermaphrodite-specific region of the Y^h chromosome (HSY) and its X chromosome counterpart were sequenced and analyzed previously. We now report the sequence of the entire male-specific region of the Y (MSY). We used a BAC-by-BAC approach to sequence the MSY and resequence the Y regions of 24 wild males and the Y^h regions of 12 cultivated hermaphrodites. The MSY and HSY regions have highly similar gene content and structure, and only 0.4% sequence divergence. The MSY sequences from wild males include three distinct haplotypes, associated with the populations’ geographic locations, but gene flow is detected for other genomic regions. The Y^h sequence is highly similar to one Y haplotype (MSY3) found only in wild dioecious populations from the north Pacific region of Costa Rica. The low MSY3-Y^h divergence supports the hypothesis that hermaphrodite papaya is a product of human domestication. We estimate that Y^h arose only ∼4000 yr ago, well after crop plant domestication in Mesoamerica >6200 yr ago but coinciding with the rise of the Maya civilization. The Y^h chromosome has lower nucleotide diversity than the Y, or the genome regions that are not fully sex-linked, consistent with a domestication bottleneck. The identification of the ancestral MSY3 haplotype will expedite investigation of the mutation leading to the domestication of the hermaphrodite Y^h chromosome. In turn, this mutation should identify the gene that was affected by the carpel-suppressing mutation that was involved in the evolution of males.Gender in papaya is genetically controlled by a sex-linked region that behaves like an XY sex chromosome, and maleness versus hermaphroditism is controlled by slightly different sex-specific Y chromosome regions, Y^h (HSY) in hermaphrodites and Y (MSY) in males. Both the HSY and MSY are ∼8.1 Mb (∼15% of the largest papaya chromosome, Chromosome 1), and recombination with the X is suppressed, so that hermaphrodite- and male-specific regions can be defined (Liu et al. 2004; Wang et al. 2012). The corresponding region of the X is only 3.5 Mb, and both the Y and Y^h have increased repeat sequence content, changed physical structure, and different gene content (Wang et al. 2012). Any combination of the Y and Y^h chromosomes (YY, YY^h, or Y^hY^h) is inviable, and the embryos abort 25–50 d after pollination, suggesting that the Y chromosome types are similar and that both are missing an essential gene that is functional in the X.Wild papaya populations are dioecious, with one-half male and one-half female plants, whereas cultivated papaya is predominantly gynodioecious, with two-thirds hermaphrodite and one-third female plants, though dioecious varieties do exist. There is no direct archaeological evidence for the center of origin of papaya, but the presence of natural populations in Mexico and Central America and the cultivation in Mexico and Belize predating the Spaniards suggest a Mesoamerican origin (Colunga-GarcíaMarín and Zizumbo-Villarreal 2004). William Storey (1976) wrote, “Since dioecism seems to be the evolutionary norm in Caricaceae, it is possible that ambisexual forms owe their continued existence to human selection.” This hypothesis was previously rejected after analysis of a pair of X- and Y-specific bacterial artificial chromosomes (BACs) from an improved (but not cultivated) dioecious variety, AU9, and their homologous BAC from the gynodioecious cultivar SunUp. The resulting molecular dating estimate suggested that the Y chromosomes of males and hermaphrodites diverged ∼73,000 yr ago (Yu et al. 2008), long before the origin of agriculture in Mesoamerica ∼6200 yr ago (Pope et al. 2001). It is worth further testing to establish the age of the HSY, because if the HSY diverged very recently from the MSY, papaya could offer the opportunity to identify the gene or genes responsible for the gender difference. Such genes would be candidates for the female suppressor involved in the early stages of sex chromosome evolution in this species. The sex chromosomes in other organisms, such as mammals, are ancient (Veyrunes et al. 2008; Bellott et al. 2014; Cortez et al. 2014), and the genes involved in their initial evolution cannot be identified, because many subsequent changes, including gene gains and losses, have occurred (Hughes et al. 2010, 2012; Zhou et al. 2014). The younger sex chromosomes of some species of plants, fish, and insects may provide insights into the mechanisms involved in the early stages of the evolution of separate sexes and of sex chromosomes (Delph et al. 2010; Zhou and Bachtrog 2012).To understand the origin and accurately estimate the divergence time of the HSY and MSY, sequencing of HSY and MSY sequences is needed. Here, we describe complete sequencing of the AU9 MSY. Moreover, sequencing multiple individuals of both males and hermaphrodites is necessary, because the origin or origins of hermaphrodites are unknown, and the AU9 MSY might not be closely related to the ancestor of the HSY, as we indeed show to be the case. Moreover, sequences from multiple individuals are needed, because the HSY and MSY of any single varieties may include mutations in genes that are not responsible for the phenotypic difference in their gender; only fixed differences between the Y^h and Y are candidates for causing the functional difference (though variants in individual varieties can help exclude candidate genes because the female-suppressor is dominant, causing maleness or hermaphroditism in the heterozygous XY or XY^h state, respectively). The objectives of this study were to (1) sequence the MSY as a necessary step toward identifying the genes distinguishing the Y and Y^h chromosome; (2) determine which Y chromosome, the Y or Y^h, is ancestral in papaya and identify the origin of the derived MSY or HSY by resequencing male and hermaphrodite genomes sampled from wild and domesticated populations; (3) use the sequences from wild populations to estimate diversity and thus test the domestication hypothesis independently of the molecular dating based on MSY–HSY divergence; and (4) use the sequences from wild populations to discover genes with fixed differences between the sets of Y-specific sequences of males and hermaphrodites, where the differences may affect gene functions, to generate candidate genes for the Y-linked carpel suppressor. The Y^h chromosome of hermaphrodites differs from the Y of males by lacking a female suppressor. The finding that the papaya Y^h and Y diverged very recently is therefore important, because it suggests that the number of fixed differences between the two chromosomes may be small. Sequences from papaya males from natural populations therefore offer the opportunity to identify the gene or genes responsible for the gender difference.     

The p53 inhibitor Mdm4 cooperates with multiple genetic lesions in tumourigenesis

The p53 inhibitor Mdm4 is present at high levels in multiple human cancers. Overexpression of Mdm4 in mice drives the spontaneous development of mostly lymphomas and sarcomas. In this study, we explored the ability of Mdm4 to cooperate with lesions in tumour development. The Mdm4 transgene contributed to mammary tumour development in a BALB/cJ background. High levels of Mdm4 enhanced tumour development in a mutant p53R172H heterozygous background, and reduced the need to lose the wild‐type p53 allele, as compared with mice heterozygous only for the p53R172H mutation. Additionally, high levels of Mdm4 cooperated with an oncogenic K‐ras mutation to drive lung tumourigenesis in vivo. Finally, we examined p53‐independent functions of Mdm4 by studying the contribution of Mdm4 to tumour development in the absence of p53. Whereas the overall survival times of p53‐null mice with and without the Mdm4 transgene were similar, male mice with both alterations showed significantly shorter survival than p53‐null male mice, and showed differences in tumour spectrum, demonstrating a p53‐independent function of Mdm4 in tumourigenesis. Furthermore, p53‐null mice with the highest level of Mdm4 tended to have multiple tumours. Thus, a detailed analysis of Mdm4 transgenic mice in various genetic backgrounds shows synergy in tumour development in vivo. Mdm4 may thus serve as a therapeutic target in cancers. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.