Monoallelic expression determines oncogenic progression and outcome in benign and malignant brain tumors

Although monoallelic expression (MAE) is a frequent genomic event in normal tissues, its role in tumorigenesis remains unclear. Here we carried out single-nucleotide polymorphism arrays on DNA and RNA from a large cohort of pediatric and adult brain tumor tissues to determine the genome-wide rate of MAE, its role in specific cancer-related genes, and the clinical consequences of MAE in brain tumors. We also used targeted genotyping to examine the role of tumor-related genes in brain tumor development and specifically examined the clinical consequences of MAE at TP53 and IDH1. The genome-wide rate of tumor MAE was higher than in previously described normal tissue and increased with specific tumor grade. Oncogenes, but not tumor suppressors, exhibited significantly higher MAE in high-grade compared with low-grade tumors. This method identified nine novel genes highly associated with MAE. Within cancer-related genes, MAE was gene specific; hTERT was most significantly affected, with a higher frequency of MAE in adult and advanced tumors. Clinically, MAE at TP53 exists only in mutated tumors and increases with tumor aggressiveness. MAE toward the normal allele at IDH1 conferred worse survival even in IDH1 mutated tumors. Taken together, our findings suggest that MAE is tumor and gene specific, frequent in brain tumor subtypes, and may be associated with tumor progression/aggressiveness. Further exploration of MAE at relevant genes may contribute to better understanding of tumor development and determine survival in brain tumor patients.     

Glioma morphology and tumor‐induced vascular alterations revealed in seven rodent glioma models by in vivo magnetic resonance imaging and angiography

Purpose:

To evaluate the added value of non–contrast‐enhanced MR angiography (MRA) to conventional MR imaging for a detailed characterization of different rodent glioma models.

Materials and Methods:

Intracerebral tumor cell implantation and chemical induction methods were implemented to obtain rat C6, 9L/LacZ, F98, RG2, and ethyl‐nitrosourea (ENU) ‐induced glioma models, a human U87 MG tumor model as well as a mouse GL261 glioma model. MR assessments were regularly conducted on a 7 Tesla Bruker BioSpin system. The tumor border sharpness and growth characteristics of each glioma model were assessed from T₂‐weighted images. Neovascularization and vascular alterations inherent to each model were characterized by assessing absolute blood volumes, vessel density, length, and diameter using Mathematica and Amira software.

Results:

The 9L/LacZ and ENU gliomas both presented flaws that hinder their use as reliable brain tumor models. C6 gliomas were slightly invasive and induced moderate vascular alterations, whereas GL261 tumors dramatically altered the brain vessels in the glioma region. F98, RG2, and U87 are infiltrative models that produced dramatic vascular alterations.

Conclusion:

MRI and MRA provided crucial in vivo information to identify a distinctive “fingerprint” for each of our seven rodent glioma models. J. Magn. Reson. Imaging 2010;32:267–275. © 2010 Wiley‐Liss, Inc.     

Clinical and pathogenetic features of early- and late-onset pre-eclampsia

Background: PE is present in ～2–8% of all pregnant women worldwide. Placental bed disorders at early and late PE have been not carried out yet. However, these studies help to explore details of the pathogenesis of PE, and to optimize the prognosis and obstetric management.

Objective: To identify clinical and morphological differences between early- and late-onset PE based on a comprehensive observation of pregnant women with regard to morphological and immunohistochemical characteristics of the placental bed.

Materials and methods: One hundred fifty patients aged 18–43 years old delivered by cesarean section due to severe PE. The samples of placental bed tissue were studied by morphological and immunohistochemical methods.

Results: The violation of invasion trophoblast, remodeling of spiral arteries were expressed in early onset PE; the degree of compensation of chronic hypoxia tissue in the area of the placental site was typical for late PE and was absent of an early onset PE.

Conclusion: Our studies confirm the need for separation of early- and late-onset PE, being justified in terms of different pathogenetic mechanisms of formation, and therefore the possibility of therapeutic effects, duration of pregnancy prolongation, forecasting, search early diagnostic markers of the disease, and personalized approaches.     

Diffusion tensor imaging and fiber tractography of C6 rat glioma

PURPOSE: To apply diffusion tensor images using 30 noncollinear directions for diffusion-weighted gradient schemes to characterize diffusion tensor imaging (DTI) features associated with C6 glioma-bearing rat brains, and ideally visualize fiber tractography datasets. MATERIALS AND METHODS: Fiber tractographies of normal male Fischer 344 rat brains were constructed from DTI datasets acquired with a 30 noncollinear diffusion gradient scheme. Cultured C6 cell were intracranially injected into the cortex of male Fischer 344 rats. The time course of the tumor growth was monitored with DTI and fiber tractography using diffusion-weighting gradients in 30 noncollinear directions. RESULTS: Fiber tractographies through the corpus callosum (CC) were easily visualized with the 30-direction gradient scheme, and the fiber trajectories of the motor cortex and striatum were well represented in normal rats. Fiber tractography indicated that the neuronal fibers of the CC were compressed or disappeared by growing C6 glioma, which affected surrounding brain tissue. CONCLUSION: We have demonstrated in this study that fiber tractography with the 30 noncollinear diffusion gradient scheme method can be used to help provide a better understanding regarding the influence of a tumor on the surrounding regions of normal brain tissue in vivo.     

Mature natural killer cells reset their responsiveness when exposed to an altered MHC environment

Some mature natural killer (NK) cells cannot be inhibited by major histocompatibility complex (MHC) I molecules, either because they lack corresponding inhibitory receptors or because the host lacks the corresponding MHC I ligands for the receptors. Such NK cells nevertheless remain self-tolerant and exhibit a generalized hyporesponsiveness to stimulation through activating receptors. To address whether NK cell responsiveness is set only during the NK cell differentiation process, we transferred mature NK cells from wild-type (WT) to MHC I–deficient hosts or vice versa. Remarkably, mature responsive NK cells from WT mice became hyporesponsive after transfer to MHC I–deficient mice, whereas mature hyporesponsive NK cells from MHC I–deficient mice became responsive after transfer to WT mice. Altered responsiveness was evident among mature NK cells that had not divided in the recipient animals, indicating that the cells were mature before transfer and that alterations in activity did not require cell division. Furthermore, the percentages of NK cells expressing KLRG1, CD11b, CD27, and Ly49 receptors specific for H-2^b were not markedly altered after transfer. Thus, the functional activity of mature NK cells can be reset when the cells are exposed to a changed MHC environment. These findings have important implications for how NK cell functions may be curtailed or enhanced in the context of disease.An important role of NK cells is to eliminate cells that extinguish or diminish expression of self-MHC class I molecules, which commonly occurs as a result of viral infection or cellular transformation (Herberman et al., 1975; Kiessling et al., 1975; Biron et al., 1999; Diefenbach and Raulet, 2002). This capacity arises because NK cells express stimulatory and inhibitory receptors that engage ligands on normal cells. The majority of inhibitory receptors belong to the KIR (in human), Ly49 (in mouse), and CD94/NKG2A (both in human and mouse) families and are specific for MHC I molecules (Raulet et al., 1997; Moretta et al., 2001; Lanier, 2005). When an NK cell encounters a normal cell, engagement of the inhibitory receptors conveys signals that counteract stimulatory signaling. Lysis occurs when inhibition is lost because the target cell lacks one or more self-MHC molecules or when target cells express high levels of stimulatory ligands that override inhibition (Raulet and Vance, 2006).NK cells vary in the number and specificity of MHC-specific inhibitory receptors that they express (Raulet et al., 1997). Recent studies demonstrate that NK cells vary in basal responsiveness to stimulatory receptor engagement depending on the number of expressed inhibitory receptors specific for self-MHC molecules (Yu et al., 2007; Brodin et al., 2009; Joncker et al., 2009). Cells with several self-MHC–specific receptors exhibit the greatest basal responsiveness and thus mediate the greatest activity against target cells that lose MHC. Cells with no self-MHC–specific receptors are the most hyporesponsive, to the extent that they fail to attack otherwise normal cells lacking MHC molecules. These data suggest that the responsiveness set point of individual NK cells is tuned depending on the balance of inhibitory and stimulatory ligands that each NK cell encounters on neighboring cells in the normal environment (Joncker and Raulet, 2008).An important unanswered question is whether the basal responsiveness of NK cells is set only once during NK cell development or, alternatively, can be readjusted when the fully mature NK cell is exposed to a changing MHC environment. Readjustments of NK cell responsiveness, if they occur, may account for instances under which NK cells fail to eliminate tumors or pathogen-infected cells and will be important to address when testing therapies designed to augment or suppress NK cell activity in the context of disease.     

Expression of 4 genes between chromosome 15 breakpoints 1 and 2 and behavioral outcomes in Prader-Willi syndrome

Prader-Willi syndrome is a neurodevelopmental disorder that is characterized by infantile hypotonia, feeding difficulties, hypogonadism, mental deficiency, hyperphagia (leading to obesity in early childhood), learning problems, and behavioral difficulties. A paternal 15q11-q13 deletion is found in approximately 70% of patients with Prader-Willi syndrome, approximately 25% have uniparental maternal disomy 15, and the remaining 2% to 5% have imprinting defects. The proximal deletion breakpoint in the 15q11-q13 region occurs at 1 of 2 sites located within either of 2 large duplicons allowing for the identification of 2 deletion subgroups. The larger, type I (TI) deletion involves breakpoint 1, which is close to the centromere, whereas the smaller, type II (TII) deletion involves breakpoint 2, located approximately 500 kilobases distal to breakpoint 1. Breakpoint 3 is located at the distal end of the 15q11-q13 region and common to both typical deletion subgroups. Analyses of the genetic subtypes of Prader-Willi syndrome to date have primarily compared individuals with typical deletion and uniparental maternal disomy 15 without grouping the individuals with a deletion into TI or TII. Distinct differences have been reported between individuals with Prader-Willi syndrome resulting from deletion compared with uniparental maternal disomy 15 in physical, cognitive, and behavioral parameters. We previously presented the first assessment of clinical differences in individuals with Prader-Willi syndrome categorized as having type I or II deletions. Adaptive behavior, obsessive-compulsive behaviors, reading, math, and visual-motor integration assessments were generally poorer in individuals with Prader-Willi syndrome and the TI deletion compared with subjects with Prader-Willi syndrome with the TII deletion or uniparental maternal disomy 15. Four genes (NIPA1, NIPA2, CYFIP1, and GCP5) have been identified in the chromosomal region between breakpoints 1 and 2 and are implicated in compulsive behavior and lower intellectual ability observed in individuals with Prader-Willi syndrome with TI versus TII deletions. We quantified messenger-RNA levels of these 4 genes in actively growing lymphoblastoid cells derived from 8 subjects with Prader-Willi syndrome with the TI deletion (4 males, 4 females; mean: age 25.2 +/- 8.9 years) and 9 with the TII deletion (3 males, 6 females; mean age: 19.5 +/- 5.8 years). Messenger-RNA levels were correlated with validated psychological and behavioral scales administered by trained psychologists blinded to genotype status. Messenger RNA from NIPA1, NIPA2, CYFIP1, and GCP5 was reduced but detectable in the subjects with Prader-Willi syndrome with the TI deletion, supporting biallelic expression. For the most part, messenger-RNA values were positively correlated with assessment parameters, indicating a direct relationship between messenger-RNA levels and better assessment scores, with the highest correlation for NIPA2. The coefficient of determination indicated the quantity of messenger RNA of the 4 genes explained from 24% to 99% of the variation of the behavioral and academic parameters measured. By comparison, the coefficient of determination for deletion type alone explained 5% to 50% of the variation in the assessed parameters. Understanding the influence of gene expression on behavioral and cognitive characteristics in humans is in the early stage of research development. Additional research is needed to identify the function of these genes and their interaction with gene networks to clarify the potential role they play in central nervous system development and function.     

The challenges of using medication event monitoring technology with pediatric transplant patients

This study investigated the advantages and challenges of using Medication Electronic Monitoring System (MEMS) technology to examine adherence among pediatric kidney transplant patients. Twenty-nine patients participated in the study, with a mean age of 14.03 yr (SD = 3.34, range 8-19 yr). Patients were given a MEMS bottle and cap to be used with their primary immunosuppressant medication over a three-month period. Issues related to study eligibility, recruitment, and participant maintenance were recorded. Patients completed the Debriefing Form regarding their experiences with the MEMS. Many younger patients were on liquid medications affecting the feasibility of this technology across ages. Acceptance of this technology proved difficult, as many patients either declined upfront or dropped out because they did not want to use the MEMS. Of the final sample, 41% found transferring medication into the MEMS bottle difficult and 27.2% reported that the MEMS was a burden and/or difficult to transport. Another 22% of the patients reported that using the MEMS changed their routine, and 10.2% worried about missing their medications. Pediatric transplant centers should be cautious about solely relying on MEMS to examine adherence until more research is conducted on the feasibility, acceptance, and utility of this technology.     

Overview on the Evaluation of the Elastic Properties of Non-Carbon Nanotubes by Theoretical Approaches

Low-dimensional structures, such as nanotubes, have been the focus of research interest for approximately three decades due to their potential for use in numerous applications in engineering and technology. In addition to extensive investigation of carbon nanotubes, those composed of elements other than carbon, the so-called non-carbon nanotubes, have also begun to be studied, since they can be more suitable for electronic and optical nano-devices than their carbon counterparts. As in the case of carbon nanotubes, theoretical (numerical and analytical) approaches have been established predominantly to study non-carbon nanotubes. So far, most of work has dealt with the investigation of the structural and electrical properties of non-carbon nanotubes, paying less attention to the evaluation of their mechanical properties. As the understanding of the mechanical behaviour of the constituents is fundamental to ensure the effective performance of nanotube-based devices, this overview aims to analyse and systematize the literature results on the elastic properties of inorganic non-carbon nanotubes.     

Cardiovascular adverse events in patients with chronic lymphocytic leukemia receiving acalabrutinib monotherapy: pooled analysis of 762 patients

Cardiovascular (CV) toxicities of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib may limit use of this effective therapy in patients with chronic lymphocytic leukemia (CLL). Acalabrutinib is a second-generation BTK inhibitor with greater BTK selectivity. This analysis characterizes pooled CV adverse events (AE) data in patients with CLL who received acalabrutinib monotherapy in clinical trials (clinicaltrials gov. Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02029443","term_id":"NCT02029443"}}NCT02029443, {"type":"clinical-trial","attrs":{"text":"NCT02475681","term_id":"NCT02475681"}}NCT02475681, {"type":"clinical-trial","attrs":{"text":"NCT02970318","term_id":"NCT02970318"}}NCT02970318 and {"type":"clinical-trial","attrs":{"text":"NCT02337829","term_id":"NCT02337829"}}NCT02337829). Acalabrutinib was given orally at total daily doses of 100–400 mg, later switched to 100 mg twice daily, and continued until disease progression or toxicity. Data from 762 patients (median age: 67 years [range, 32–89]; median follow-up: 25.9 months [range, 0–58.5]) were analyzed. Cardiac AE of any grade were reported in 129 patients (17%; grade ≥3, n=37 [5%]) and led to treatment discontinuation in seven patients (1%). The most common any-grade cardiac AE were atrial fibrillation/flutter (5%), palpitations (3%), and tachycardia (2%). Overall, 91% of patients with cardiac AE had CV risk factors before acalabrutinib treatment. Among 38 patients with atrial fibrillation/flutter events, seven (18%) had prior history of arrhythmia or atrial fibrillation/flutter. Hypertension AE were reported in 67 patients (9%), 43 (64%) of whom had a preexisting history of hypertension; no patients discontinued treatment due to hypertension. No sudden cardiac deaths were reported. Overall, these data demonstrate a low incidence of new-onset cardiac AE with acalabrutinib in patients with CLL. Findings from the head-to-head, randomized trial of ibrutinib and acalabrutinib in patients with high-risk CLL (clinicaltrials gov. Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02477696","term_id":"NCT02477696"}}NCT02477696) prospectively assess differences in CV toxicity between the two agents.