18F-FDG PET-CT uptake is a feature of both normal diameter and aneurysmal aortic wall and is not related to aneurysm size

Purpose

Aortic metabolic activity is suggested to correlate with presence and progression of aneurysmal disease, but has been inadequately studied. This study investigates the 2-[¹⁸F] fluoro-2-deoxy-D-glucose (¹⁸F-FDG) uptake in a population of infra-renal abdominal aortic aneurysms (AAA), compared to a matched non-aneurysmal control group.

Methods

The Positron Emission Tomography – Computed Tomography (PET/CT) database was searched for infra-renal AAA. Exclusion criteria were prior repair, vasculitis, and saccular/mycotic thoracic or thoraco-abdominal aneurysms. Matching of 159 non-aneurysmal (<3 cm diameter) controls from the same population was assessed. Infra-renal aortic wall FDG uptake was assessed using visual analysis; maximum standardized uptake value (SUV_max) and target to background mediastinal blood pool ratio (TBR) were documented. Predictors of FDG uptake (age, sex, aortic diameter, hypertension, statin use, and diabetes) were assessed using univariate analysis. Follow-up questionnaires were sent to referring clinicians.

Results

Aneurysms (n?=?151) and controls (n?=?159) were matched (p?>?0.05) for age, sex, diabetes, hypertension, smoking status, statin use, and indication for PET/CT. Median aneurysm diameter was 5.0 cm (range 3.2–10.4). On visual analysis there was no significant difference in the overall numbers with increased visual uptake 24 % (36/151) in the aneurysm group vs. 19 % (30/159) in the controls, p?=?ns. SUV_max was slightly lower in the aneurysm group vs. controls (mean (2 SD) 1.75(0.79) vs. 1.84(0.58), p?=?0.02). However there was no difference in TBR between the AAA group and controls (mean (2 SD) 1.03 (0.46) vs. 1.05(0.31), p?=?0.36). During a median 18 (interquartile range 8–35) months’ follow-up 20 were repaired and four were confirmed ruptured.

Conclusions

The level of metabolic activity as assessed by ¹⁸F-FDG PET/CT in infra-renal AAA does not correlate with aortic size and does not differ between aneurysms and matched controls.     

A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylation

Monoallelic point mutations of the NADP⁺-dependent isocitrate dehydrogenases IDH1 and IDH2 occur frequently in gliomas, acute myeloid leukemias, and chondromas, and display robust association with specific DNA hypermethylation signatures. Here we show that heterozygous expression of the IDH1^R132H allele is sufficient to induce the genome-wide alterations in DNA methylation characteristic of these tumors. Using a gene-targeting approach, we knocked-in a single copy of the most frequently observed IDH1 mutation, R132H, into a human cancer cell line and profiled changes in DNA methylation at over 27,000 CpG dinucleotides relative to wild-type parental cells. We find that IDH1^R132H/WT mutation induces widespread alterations in DNA methylation, including hypermethylation of 2010 and hypomethylation of 842 CpG loci. We demonstrate that many of these alterations are consistent with those observed in IDH1-mutant and G-CIMP+ primary gliomas and can segregate IDH wild-type and mutated tumors as well as those exhibiting the G-CIMP phenotype in unsupervised analysis of two primary glioma cohorts. Further, we show that the direction of IDH1^R132H/WT-mediated DNA methylation change is largely dependent upon preexisting DNA methylation levels, resulting in depletion of moderately methylated loci. Additionally, whereas the levels of multiple histone H3 and H4 methylation modifications were globally increased, consistent with broad inhibition of histone demethylation, hypermethylation at H3K9 in particular accompanied locus-specific DNA hypermethylation at several genes down-regulated in IDH1^R132H/WT knock-in cells. These data provide insight on epigenetic alterations induced by IDH1 mutations and support a causal role for IDH1^R132H/WT mutants in driving epigenetic instability in human cancer cells.Mutations of the NADP⁺-dependent isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 occur in >70% of Grade II–III gliomas and secondary glioblastomas (sGBM) (Balss et al. 2008; Parsons et al. 2008; Bleeker et al. 2009; Hartmann et al. 2009; Yan et al. 2009a,b; Gravendeel et al 2010), 15%–30% of acute myeloid leukemias (AMLs) (Mardis et al. 2009; Marcucci et al. 2010; Paschka et al. 2010; Wagner et al. 2010; Ward et al. 2010), 56% of chondrosarcomas (Amary et al. 2011), 87% of enchondromas, 70% of spindle cell hemangiomas (Pansuriya et al. 2011), 22%–28% of cholangiocarcinomas of intrahepatic origin (Borger et al. 2012; Kipp et al. 2012), and at lower frequencies in other malignancies, including colorectal cancer (Sjoblom et al. 2006), prostate carcinoma, and B-acute lymphoblastic leukemia (B-ALL) (Kang et al. 2009). IDH mutations occur early in tumor development and may either cause or predispose cells to become malignant (Ichimura et al. 2009; Watanabe et al. 2009). In human tumors, IDH mutations give rise to single amino acid substitutions at specific conserved residues, arginine 132 (R132) of IDH1 and arginine 140 (R140) or arginine 172 (R172) of IDH2. These IDH point mutations primarily occur as somatically acquired heterozygous events, with tumor cells showing one mutant allele and retention of the second wild-type allele, suggesting that the ratio of mutant to wild-type enzyme may be critical to its oncogenic activity. The IDH mutation leads to an attenuation of the normal catalytic activity, the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) (Yan et al. 2009b; Zhao et al. 2009), while concurrently imparting a gain of novel enzymatic function wherein α-KG is reduced, leading to the aberrant accumulation of the onco-metabolite D-2-hydroxyglutarate (D-2-HG) (Dang et al. 2009). Both reduction of cellular α-KG levels and accumulation of D-2-HG have the potential to contribute to altered cellular phenotypes through the inhibition of multiple Fe(II)/2-oxoglutarate-dependent dioxygenases (W Xu et al. 2011), a superfamily of enzymes involved in a wide range of biological functions, including DNA repair and chromatin modification, such as the AlkB family of oxidative demethylases, the Jumonji-C domain family of histone demethylases (JHDMs), and the TET family of methylcytosine hydroxylases (Loenarz and Schofield 2008; Tahiliani et al. 2009; Figueroa et al. 2010a; Chowdhury et al. 2011).Recent large-scale studies of DNA methylation distribution in primary tumors have identified biologically distinct subgroups of glioblastomas (GBMs) and AMLs associated with aberrant DNA methylation (Figueroa et al. 2010b; Noushmehr et al. 2010). A subset of primary GBMs exhibit the “CpG island methylator phenotype” (CIMP) and show concordant hypermethylation of a large number of CpG islands (Toyota and Issa 1999; Toyota et al. 1999; Noushmehr et al. 2010). Interestingly, in gliomas, the CIMP phenotype (termed G-CIMP) has a striking association with IDH1 mutation (Noushmehr et al. 2010; Christensen et al. 2011; Laffaire et al. 2011; Turcan et al. 2012). Similarly, IDH1 and IDH2 mutations robustly associate with specific global DNA hypermethylation phenotypes in AMLs (Figueroa et al. 2010a), enchondromas (Pansuriya et al. 2011), and low-grade gliomas (LGGs) (Turcan et al. 2012). The evidence linking IDH1 and IDH2 mutations with distinct DNA methylation phenotypes in primary human tumors raises the question of whether these mutations can drive oncogenesis through epigenetic reprogramming of cancer cells. Such epigenetic changes, including DNA hypermethylation and hypomethylation, can play fundamental roles in the initiation and progression of human cancer through regulation of gene expression (Jones and Baylin 2002, 2007). In addition to epigenetic classifications, gene expression-based molecular classification systems have been developed in GBM to distinguish clinically relevant molecular subclasses (Phillips et al. 2006; Li et al. 2009; Verhaak et al. 2010). GBMs with IDH1 mutations were shown to primarily exhibit a proneural gene expression signature (Verhaak et al. 2010), although specific gene-expression alterations resulting from mutant IDH1 proteins have not been elucidated.Despite the apparent correlation between IDH mutations and CpG island hypermethylation, the contribution of heterozygous expression of IDH1 point mutations to this phenotype has not been addressed. One limitation of the field has been the lack of model systems that recapitulate naturally occurring monoallelic point mutations observed in human tumors. Previous studies have relied on ectopic overexpression in human and mouse cell lines to study the effects of mutant IDH proteins (Dang et al. 2009; Yan et al. 2009b; Figueroa et al. 2010a; Ward et al. 2010; G Jin et al. 2011; Reitman et al. 2011; Lu et al. 2012; Turcan et al. 2012). To address this issue, and to faithfully recapitulate the naturally occurring genetic alterations, we utilized gene targeting to introduce heterozygous IDH1^R132H/WT substitutions in the human colorectal cancer cell line, HCT116. We determined the impact of this mutation on the genome-wide distribution of CpG methylation in the isogenic IDH1^R132H/WT cells and identified differentially methylated CpGs induced by the IDH1^R132H/WT mutation, which include both hyper- and hypomethylation events. Our data indicate that IDH1^R132H/WT mutations play a causal role in the widespread alteration of DNA and histone methylation observed in human cancers and can impact gene expression.     

Validity of affect measurements in evaluating symptom reporting in athletes

Identifying factors that improve the assessment of athletes' psychological functioning is imperative to make proper return-to-play decisions following concussion. Prior research indicates that an individual's affect is related to symptom reporting. The present study examines two novel methods of affect assessment in college athletes at baseline participating in a sports-concussion management program. A total of 256 athletes completed a neuropsychological baseline battery with measurements of psychological symptoms (BDI-Fast Screen, Post-Concussion Symptom Scale, and ImPact Total Symptom Score) and a measure of affective memory bias (the Affective Verbal Learning Test; AVLT). Examiners completed an observation-based rating of affect. Multivariate analysis of variance and χ2 analyses were conducted to examine the effect of affect on symptom reports. Examiners' Affect Ratings were predictive of broad symptom reporting, while the performance based index of affect (Affective Verbal Learning Test, AVLT) was more predictive of depressive symptoms. These findings suggest that performance on the AVLT may be a useful indicator of self-reported depression in a collegiate athlete sample. Additionally, these results demonstrate that examiners' behavioral assessments of affect are important in the assessment of psychological functioning in athletes. Continued work should focus on developing objective measures that are sensitive and valid for the evaluation of outcomes from concussion.     

Downregulation of PA28α induces proteasome remodeling and results in resistance to proteasome inhibitors in multiple myeloma

Protein homeostasis is critical for maintaining eukaryotic cell function as well as responses to intrinsic and extrinsic stress. The proteasome is a major portion of the proteolytic machinery in mammalian cells and plays an important role in protein homeostasis. Multiple myeloma (MM) is a plasma cell malignancy with high production of immunoglobulins and is especially sensitive to treatments that impact protein catabolism. Therapeutic agents such as proteasome inhibitors have demonstrated significant benefit for myeloma patients in all treatment phases. Here, we demonstrate that the 11S proteasome activator PA28α is upregulated in MM cells and is key for myeloma cell growth and proliferation. PA28α also regulates MM cell sensitivity to proteasome inhibitors. Downregulation of PA28α inhibits both proteasomal load and activity, resulting in a change in protein homeostasis less dependent on the proteasome and leads to cell resistance to proteasome inhibitors. Thus, our findings suggest an important role of PA28α in MM biology, and also provides a new approach for targeting the ubiquitin-proteasome system and ultimately sensitivity to proteasome inhibitors.Subject terms: Myeloma, Translational research     

Renin in angiolymphoid hyperplasia with eosinophilia. Its possible effect on vascular proliferation

A hypertensive man became normotensive after the surgical removal of two subcutaneous masses of angiolymphoid hyperplasia with eosinophilia. To demonstrate that angiolymphoid hyperplasia with eosinophilia is a renin-producing pathologic condition, Bowie stain for juxtaglomerular cell granules and immunohistochemistry for human renin were used. Bowie stain was positive in cells showing cytoplasmic granules similar to those found in the juxtaglomerular cells of the kidney. Immunohistochemical staining using antiserum against human renin showed the presence of renin-containing cells. This staining was not seen after substitution of the specific renin antiserum by preimmune serum, by the renin antiserum preabsorbed with pure human renin, or with plasma from a patient with high-plasma renin activity. Renin-containing cells were located in areas surrounding vascular structures and were apparently neither endothelial, mast, nor lymphoid cells. Six of eight additional cases of angiolymphoid hyperplasia with eosinophilia were positive for renin-containing cells. Renin has been described in several other histologically highly vascularized tumors. Since a product of renin, angiotensin II, has been found to have angiogenic properties, it is possible to postulate that renin, through angiotensin II, may stimulate the proliferation of vessels and, therefore, may be involved in the pathogenesis of angiolymphoid hyperplasia with eosinophilia.     

4D visualization of embryonic, structural crystallization by single-pulse microscopy

In many physical and biological systems the transition from an amorphous to ordered native structure involves complex energy landscapes, and understanding such transformations requires not only their thermodynamics but also the structural dynamics during the process. Here, we extend our 4D visualization method with electron imaging to include the study of irreversible processes with a single pulse in the same ultrafast electron microscope (UEM) as used before in the single-electron mode for the study of reversible processes. With this augmentation, we report on the transformation of amorphous to crystalline structure with silicon as an example. A single heating pulse was used to initiate crystallization from the amorphous phase while a single packet of electrons imaged selectively in space the transformation as the structure continuously changes with time. From the evolution of crystallinity in real time and the changes in morphology, for nanosecond and femtosecond pulse heating, we describe two types of processes, one that occurs at early time and involves a nondiffusive motion and another that takes place on a longer time scale. Similar mechanisms of two distinct time scales may perhaps be important in biomolecular folding.     

Follow‐up after systemic adverse reactions of immunotherapy

Out of 280 immunotherapy (IT)-treated patients in our allergy clinic, 37 (13%) developed systemic adverse reactions. Parietaria judaica (Pj) extract, a highly allergenic pollen in northern Israel, was part of the IT regimen in 46% of treated patients who developed systemic adverse reactions. Twenty-six (70%) of systemic adverse reactions occurred during the buildup phase, whereas 11 (30%) occurred in the maintenance phase of treatment. Mild systemic reactions developed in 15/37 (40%), moderate in 20/37 (54%), and severe in 2/37 (5%) of patients. In 22/37 (59% of our IT-treated patients, adverse reactions developed within 30 min after injection. Among these were the two patients with severe systemic reactions. In 19%, moderate adverse reactions appeared at 30-60 min; in 22%, mild to moderate reactions appeared after 1-2 h. Our study concludes that severe systemic reactions to IT usually appear within 30 min after injection. In Israel, IT with highly allergenic pollens such as Pj frequently causes systemic reactions, even during the maintenance phase of treatment. In such cases, the reduction of IT dosage should be more than 50% during the pollen season, and a waiting period of 1 h should also be considered.     

氯喹对烟雾吸入伤大鼠肺细胞膜ATP酶活性和丙二醛含量的影响

目的：探讨氯喹对烟雾吸入伤大鼠肺细胞膜ＡＴＰ酶活性及丙二醛含量的影响,方法：８０只Ｗｉｓｔａｒ大鼠随机分成正常对照组,烟雾吸入伤１,３,６,１２和２４ｈ组以及氯喹治疗６ｈ和１２ｈ组,分别于各时相点活杀动物,取肺制备膜制剂,用生化比色法测定膜上Ｎａ＾＋,Ｋ＾＋－ＡＴＰ酶Ｍｇ＾２＋－ＡＴＰ酶和Ｃａ＾２＋－ＡＴＰ酶活性,用比色法测定膜上丙醛含量,并用定磷法测定膜总磷脂含量,结果：烟雾吸入伤后,肺细胞膜３