Control computerized tomography in neoadjuvant chemotherapy for muscle invasive urinary bladder cancer has no value for treatment decisions and low correlation with nodal status.

BACKGROUND: Control computerized tomography (cCT) is routinely used in many cystectomy centres before the final treatment cycle in patients with muscle-invasive urinary bladder cancer (MIBC) undergoing neoadjuvant chemotherapy (NAC). This is for evaluating response or nonresponse to NAC treatment. In a real-world retrospective cohort, we intended to evaluate the frequency of changed individual treatment strategies following cCT and to investigate any discrepancies between cCT-results on nodal staging and final pN-stages. METHODS: We performed a retrospective data-based, multicenter study of 242 MIBC-patients, staged cT2N0M0-cT4aN0M0, having undergone NAC and radical cystectomy (RC) between 2008 and 2019 at four Swedish cystectomy centres. Statistical analysis was performed using IBM SPSS statistics 26. RESULTS: Overall, 139/242 patients were examined with cCT. Six patients were staged as progressive at cCT and 5/139 (3.6%) underwent a change of previously planned treatment strategy. 2/6 patients with suspected progression (33%) did not change strategy and underwent all preplanned NAC-cycles plus RC. Only 1/6 patients assigned as progressive at the cCT, showed progression in the postoperative pathology specimen. In total 133/139 patients were considered being without progress on cCT, yet 28/133 (21%) presented with nodal progression at postoperative pathology examinations. Only 1/29 patients with histopathologically verified nodal dissemination were detected with cCT, thus 28/29 (96.6%) with pN + were undetected. The sensitivity for cCT to predict pTNM was 17% CI [0%-64%] and the specificity was 78% CI [71%-86%]. CONCLUSIONS: CCT prior to the final treatment cycle of NAC in MIBC, leads to a low percentage of treatment strategy changes and cCT cannot accurately predict pN-status.

Targeting Epigenetics to Cure HIV-1: Lessons From (and for) Cancer Treatment.

The Human Immunodeficiency Virus type 1 (HIV-1) integrates in the host genome as a provirus resulting in a long-lived reservoir of infected CD4 cells. As a provirus, HIV-1 has several aspects in common with an oncogene. Both the HIV-1 provirus and oncogenes only cause disease when expressed. A successful cure of both cancer and HIV-1 includes elimination of all cells with potential to regenerate the disease. For over two decades, epigenetic drugs developed against cancer have been used in the HIV-1 field to modulate the state of the proviral chromatin. Cells with an intact HIV-1 provirus exist in three states of infection: productive, inducible latent, and non-inducible latent. Here focus is on HIV-1, transcription control and chromatin structure; how the inducible proviruses are maintained in a chromatin structure that allows reactivation of transcription; and how transcription switches between different stages to allow for an abundance of different transcripts from a single promoter. Recently it was shown that a functional cure of HIV can be achieved by encapsulating all intact HIV-1 proviruses in heterochromatin, giving hope that epigenetic interventions may be used to end the HIV-1 epidemic.

Chronic pain after open inguinal hernia repair: expertise-based randomized clinical trial of heavyweight or lightweight mesh.

BACKGROUND: There is a shortage of high-quality studies regarding choice of mesh in open anterior inguinal hernia repair in relation to long-term chronic pain. The authors hypothesized that heavyweight compared with lightweight mesh causes increased postoperative pain. METHODS: An RCT was undertaken between 2007 and 2009 at two sites in Sweden. Men aged 25 years or older with an inguinal hernia evaluated in the outpatient clinic were randomized in an unblinded fashion to heavyweight or lightweight mesh for open anterior inguinal hernia repair. Data on pain affecting daily activities, as measured by the Short-Form Inguinal Pain Questionnaire 9-12 years after surgery, were collected as the primary outcome. Differences between groups were evaluated by generalized odds and numbers needed to treat. RESULTS: A total of 412 patients were randomized; 363 were analysed with 320 questionnaires sent out. A total of 271 questionnaires (84.7 per cent) were returned; of these, 121 and 150 patients were in the heavyweight and lightweight mesh groups respectively. Pain affecting daily activities was more pronounced in patients randomized to heavyweight versus lightweight mesh (generalized odds 1.33, 95 per cent c.i. 1.10 to 1.61). This translated into a number needed to treat of 7.06 (95 per cent c.i. 4.28 to 21.44). Two reoperations for recurrence were noted in the heavyweight mesh group, and one in the lightweight mesh group. CONCLUSION: A large-pore lightweight mesh causes significantly less pain affecting daily activities a decade after open anterior inguinal hernia repair. Registration number: NCT00451893 (http://www.clinicaltrials.gov).

Establishment of a clinical SPECT/CT protocol for imaging of 161Tb.

BACKGROUND: It has been proposed, and preclinically demonstrated, that 161Tb is a better alternative to 177Lu for the treatment of small prostate cancer lesions due to its high emission of low-energy electrons. 161Tb also emits photons suitable for single-photon emission computed tomography (SPECT) imaging. This study aims to establish a SPECT protocol for 161Tb imaging in the clinic. MATERIALS AND METHODS: Optimal settings using various γ-camera collimators and energy windows were explored by imaging a Jaszczak phantom, including hollow-sphere inserts, filled with 161Tb. The collimators examined were extended low-energy general purpose (ELEGP), medium-energy general purpose (MEGP), and low-energy high resolution (LEHR), respectively. In addition, three ordered subset expectation maximization (OSEM) algorithms were investigated: attenuation-corrected OSEM (A-OSEM); attenuation and dual- or triple-energy window scatter-corrected OSEM (AS-OSEM); and attenuation, scatter, and collimator-detector response-corrected OSEM (ASC-OSEM), where the latter utilized Monte Carlo-based reconstruction. Uniformity corrections, using intrinsic and extrinsic correction maps, were also investigated. Image quality was assessed by estimated recovery coefficients (RC), noise, and signal-to-noise ratio (SNR). Sensitivity was determined using a circular flat phantom. RESULTS: The best RC and SNR were obtained at an energy window between 67.1 and 82.1 keV. Ring artifacts, caused by non-uniformity, were removed with extrinsic uniformity correction for the energy window between 67.1 and 82.1 keV, but not with intrinsic correction. Analyzing the lower energy window between 48.9 and 62.9 keV, the ring artifacts remained after uniformity corrections. The recovery was similar for the different collimators when using a specific OSEM reconstruction. Recovery and SNR were highest for ASC-OSEM, followed by AS-OSEM and A-OSEM. When using the optimized parameter setting, the resolution of 161Tb was higher than for 177Lu (8.4 ± 0.7 vs. 10.4 ± 0.6 mm, respectively). The sensitivities for 161Tb and 177Lu were 7.41 and 8.46 cps/MBq, respectively. CONCLUSION: SPECT with high resolution is feasible with 161Tb; however, extrinsic uniformity correction is recommended to avoid ring artifacts. The LEHR collimator was the best choice of the three tested to obtain a high-resolution image. Due to the complex emission spectrum of low-energy photons, window-based scatter correction had a minor impact on the image quality compared to using attenuation correction only. On the other hand, performing attenuation, scatter, and collimator-detector correction clearly improved image quality. Based on these data, SPECT-based dosimetry for 161Tb-labeled radiopharmaceuticals is feasible.

Regulation of bile acid metabolism in biliary atresia: reduction of FGF19 by Kasai portoenterostomy and possible relation to early outcome.

BACKGROUND: Fibroblast growth factor 19 (FGF19) is produced in the small intestine and is involved in suppression of hepatic bile acid (BA) synthesis. FGF19 is also expressed in the liver and serum levels are elevated in adults with cholestatic liver disease. This may reflect a rescue mechanism to dampen liver injury caused by increased intrahepatic BAs. OBJECTIVES: To examine circulating FGF19 at early stages of biliary atresia and at short-term follow-up post-Kasai portoenterostomy (KPE) in relation to noncholestatic infants. The relationship between FGF19, BAs and markers for BA synthesis and hepatic gene expression of factors involved in BA metabolism were also evaluated. METHODS: Liver tissue, portal and peripheral blood samples were obtained from fifteen patients at KPE; additional blood was collected 4-6 months after surgery. Two control groups were included; to examine possible changes related to surgery and to compare FGF19 in biliary atresia to noncholestatic infants. RESULTS: Circulating FGF19 levels correlated to its hepatic gene expression at time of KPE in biliary atresia and levels were elevated compared to noncholestatic infants. At follow-up, FGF19 levels were markedly reduced, and the decline coincided with reductions in bilirubin and conjugated chenodeoxycholic acid and with increased levels of the BA synthesis marker C4. CONCLUSION: Elevated circulating FGF19 in biliary atresia is of hepatic origin and reduced following KPE. Changes in serum FGF19 may reflect the level of restoration of the enterohepatic circulation, and this warrants further long-term studies on the role of FGF19 in the cholestatic liver.

A regulatory role for CHD2 in myelopoiesis.

The transcriptional program that dictates haematopoietic cell fate and differentiation requires an epigenetic regulatory and memory function, provided by a network of epigenetic factors that regulate DNA methylation, post-translational histone modifications and chromatin structure. Disturbed epigenetic regulation causes perturbations in the blood cell differentiation program that results in various types of haematopoietic disorders. Thus, accurate epigenetic regulation is essential for functional haematopoiesis. In this study, we used a CRISPR-Cas9 screening approach to identify new epigenetic regulators in myeloid differentiation. We designed a Chromatin-UMI CRISPR guide library targeting 1092 epigenetic regulators. Phorbol 12-myristate 13-acetate (PMA) treatment of the chronic myeloid leukaemia cell line K-562 was used as a megakaryocytic myeloid differentiation model. Both previously described developmental epigenetic regulators and novel factors were identified in our screen. In this study, we validated and characterized a role for the chromatin remodeller CHD2 in myeloid proliferation and megakaryocytic differentiation.

A nationwide study on the incidence of mesenteric ischaemia after surgery for rectal cancer demonstrates an association with high arterial ligation.

AIM: The incidence of mesenteric ischaemia after resection for rectal cancer has not been investigated in a population-based setting. The use of high ligation of the inferior mesenteric artery might cause such ischaemia, as the bowel left in situ depends on collateral blood supply after a high tie. METHOD: The Swedish Colorectal Cancer Registry was used to identify all patients subjected to an abdominal resection for rectal cancer during the years 2007-2017 inclusive. Mesenteric ischaemia within the first 30 postoperative days was recorded, classified as either stoma necrosis or colonic necrosis. Multivariable logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for mesenteric ischaemia in relation to high tie, with adjustment for confounding. RESULTS: Some 14 657 patients were included, of whom 59 (0.40%) had a reoperation for any type of mesenteric ischaemia, divided into 34 and 25 cases of stoma necrosis and colonic necrosis, respectively. Compared with patients who did not require reoperation for mesenteric ischaemia following rectal cancer surgery, the proportion having high tie was greater (54.2% vs 38.5%; P = 0.032). The adjusted OR for reoperation due to any mesenteric ischaemia with high tie was 2.26 (95% CI 1.34-3.79), while the corresponding estimates for stoma and colonic necrosis, respectively, were 1.60 (95% CI 0.81-3.17) and 3.69 (95% CI 1.57-8.66). CONCLUSION: The incidence of reoperation for mesenteric ischaemia after abdominal resection for rectal cancer is low, but the use of a high tie might increase the risk of colonic necrosis demanding surgery.

The mTOR Complex Controls HIV Latency.

A population of CD4 T lymphocytes harboring latent HIV genomes can persist in patients on antiretroviral therapy, posing a barrier to HIV eradication. To examine cellular complexes controlling HIV latency, we conducted a genome-wide screen with a pooled ultracomplex shRNA library and in vitro system modeling HIV latency and identified the mTOR complex as a modulator of HIV latency. Knockdown of mTOR complex subunits or pharmacological inhibition of mTOR activity suppresses reversal of latency in various HIV-1 latency models and HIV-infected patient cells. mTOR inhibitors suppress HIV transcription both through the viral transactivator Tat and via Tat-independent mechanisms. This inhibition occurs at least in part via blocking the phosphorylation of CDK9, a p-TEFb complex member that serves as a cofactor for Tat-mediated transcription. The control of HIV latency by mTOR signaling identifies a pathway that may have significant therapeutic opportunities.

A targeted proteomic multiplex CSF assay identifies increased malate dehydrogenase and other neurodegenerative biomarkers in individuals with Alzheimer's disease pathology.

Alzheimer's disease (AD) is the most common cause of dementia. Biomarkers are required to identify individuals in the preclinical phase, explain phenotypic diversity, measure progression and estimate prognosis. The development of assays to validate candidate biomarkers is costly and time-consuming. Targeted proteomics is an attractive means of quantifying novel proteins in cerebrospinal and other fluids, and has potential to help overcome this bottleneck in biomarker development. We used a previously validated multiplexed 10-min, targeted proteomic assay to assess 54 candidate cerebrospinal fluid (CSF) biomarkers in two independent cohorts comprising individuals with neurodegenerative dementias and healthy controls. Individuals were classified as 'AD' or 'non-AD' on the basis of their CSF T-tau and amyloid Aß1-42 profile measured using enzyme-linked immunosorbent assay; biomarkers of interest were compared using univariate and multivariate analyses. In all, 35/31 individuals in Cohort 1 and 46/36 in Cohort 2 fulfilled criteria for AD/non-AD profile CSF, respectively. After adjustment for multiple comparisons, five proteins were elevated significantly in AD CSF compared with non-AD CSF in both cohorts: malate dehydrogenase; total APOE; chitinase-3-like protein 1 (YKL-40); osteopontin and cystatin C. In an independent multivariate orthogonal projection to latent structures discriminant analysis (OPLS-DA), these proteins were also identified as major contributors to the separation between AD and non-AD in both cohorts. Independent of CSF Aß1-42 and tau, a combination of these biomarkers differentiated AD and non-AD with an area under curve (AUC)=0.88. This targeted proteomic multiple reaction monitoring (MRM)-based assay can simultaneously and rapidly measure multiple candidate CSF biomarkers. Applying this technique to AD we demonstrate differences in proteins involved in glucose metabolism and neuroinflammation that collectively have potential clinical diagnostic utility.

A novel statistical analysis method to improve the detection of hepatic foci of (111)In-octreotide in SPECT/CT imaging.

BACKGROUND: Low uptake ratios, high noise, poor resolution, and low contrast all combine to make the detection of neuroendocrine liver tumours by (111)In-octreotide single photon emission tomography (SPECT) imaging a challenge. The aim of this study was to develop a segmentation analysis method that could improve the accuracy of hepatic neuroendocrine tumour detection. METHODS: Our novel segmentation was benchmarked by a retrospective analysis of patients categorized as either (111)In-octreotide positive ((111)In-octreotide(+)) or (111)In-octreotide negative ((111)In-octreotide(-)) for liver tumours. Following a 3-year follow-up period, involving multiple imaging modalities, we further segregated (111)In-octreotide-negative patients into two groups: one with no confirmed liver tumours ((111)In-octreotide(-)/radtech(-)) and the other, now diagnosed with liver tumours ((111)In-octreotide(-)/radtech(+)). We retrospectively applied our segmentation analysis to see if it could have detected these previously missed tumours using (111)In-octreotide. Our methodology subdivided the liver and determined normalized numbers of uptake foci (nNUF), at various threshold values, using a connected-component labelling algorithm. Plots of nNUF against the threshold index (ThI) were generated. ThI was defined as follows: ThI = (c max - c thr)/c max, where c max is the maximal threshold value for obtaining at least one, two voxel sized, uptake focus; c thr is the voxel threshold value. The maximal divergence between the nNUF values for (111)In-octreotide(-)/radtech(-), and (111)In-octreotide(+) livers, was used as the optimal nNUF value for tumour detection. We also corrected for any influence of the mean activity concentration on ThI. The nNUF versus ThI method (nNUFTI) was then used to reanalyze the (111)In-octreotide(-)/radtech(-) and (111)In-octreotide(-)/radtech(+) groups. RESULTS: Of a total of 53 (111)In-octreotide(-) patients, 40 were categorized as (111)In-octreotide(-)/radtech(-) and 13 as (111)In-octreotide(-)/radtech(+) group. Optimal separation of the nNUF values for (111)In-octreotide(-)/radtech(-) and (111)In-octreotide(+) groups was defined at the nNUF value of 0.25, to the right of the bell shaped nNUFTI curve. ThIs at this nNUF value were dependent on the mean activity concentration and therefore normalized to generate nThI; a significant difference in nThI values was found between the (111)In-octreotide(-)/radtech(-) and the (111)In-octreotide(-)/radtech(+) groups (P < 0.01). As a result, four of the 13 (111)In-octreotide(-)/radtech(+) livers were redesigned as (111)In-octreotide(+). CONCLUSIONS: The nNUFTI method has the potential to improve the diagnosis of liver tumours using (111)In-octreotide.

Deaths among adult patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality.

CONTEXT: Patients with hypopituitarism have an increased standardized mortality rate. The basis for this has not been fully clarified. OBJECTIVE: To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up. DESIGN AND METHODS: All-cause and cause-specific mortality in 1286 Swedish patients with hypopituitarism prospectively monitored in KIMS (Pfizer International Metabolic Database) 1995-2009 were compared to general population data in the Swedish National Cause of Death Registry. In addition, events reported in KIMS, medical records, and postmortem reports were reviewed. MAIN OUTCOME MEASURES: Standardized mortality ratios (SMR) were calculated, with stratification for gender, attained age, and calendar year during follow-up. RESULTS: An excess mortality was found, 120 deaths vs 84.3 expected, SMR 1.42 (95% confidence interval: 1.18-1.70). Infections, brain cancer, and sudden death were associated with significantly increased SMRs (6.32, 9.40, and 4.10, respectively). Fifteen patients, all ACTH-deficient, died from infections. Eight of these patients were considered to be in a state of adrenal crisis in connection with death (medical reports and post-mortem examinations). Another 8 patients died from de novo malignant brain tumors, 6 of which had had a benign pituitary lesion at baseline. Six of these 8 subjects had received prior radiation therapy. CONCLUSION: Two important causes of excess mortality were identified: first, adrenal crisis in response to acute stress and intercurrent illness; second, increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy. Both of these causes may be in part preventable by changes in the management of pituitary disease.

CHD1 remodelers regulate nucleosome spacing in vitro and align nucleosomal arrays over gene coding regions in S. pombe.

Nucleosome positioning governs access to eukaryotic genomes. Many genes show a stereotypic organisation at their 5'end: a nucleosome free region just upstream of the transcription start site (TSS) followed by a regular nucleosomal array over the coding region. The determinants for this pattern are unclear, but nucleosome remodelers are likely critical. Here we study the role of remodelers in global nucleosome positioning in S. pombe and the corresponding changes in expression. We find a striking evolutionary shift in remodeler usage between budding and fission yeast. The S. pombe RSC complex does not seem to be involved in nucleosome positioning, despite its prominent role in S. cerevisiae. While S. pombe lacks ISWI-type remodelers, it has two CHD1-type ATPases, Hrp1 and Hrp3. We demonstrate nucleosome spacing activity for Hrp1 and Hrp3 in vitro, and that together they are essential for linking regular genic arrays to most TSSs in vivo. Impaired arrays in the absence of either or both remodelers may lead to increased cryptic antisense transcription, but overall gene expression levels are only mildly affected.

A review of conservative treatment of acute appendicitis.

Appendicitis is a common condition in the pediatric population and appendectomy has been the traditional treatment. Both the urgency of the operation and the need for the appendectomy have recently been challenged. In children, this controversy focuses on operative management of perforated appendicitis and appendix abscesses. In adults, the debate has extended to management of nonperforated appendicitis. This review describes the evidence behind these challenges and updates a per-protocol meta-analysis of randomized controlled trials in adults. In the per-protocol meta-analysis, there was no difference between operative versus nonoperative management in failure of treatment. The complication rate was significantly lower in patients treated nonoperatively. However, in the nonoperative group, 10% of patients needed immediate surgery and 17% developed a recurrence during the 1-year follow-up. Overall, 73% of adults with suspected acute appendicitis may not need operative treatment. There are no data in the literature to support nonoperative treatment of acute appendicitis in children.

Podbat: a novel genomic tool reveals Swr1-independent H2A.Z incorporation at gene coding sequences through epigenetic meta-analysis.

Epigenetic regulation consists of a multitude of different modifications that determine active and inactive states of chromatin. Conditions such as cell differentiation or exposure to environmental stress require concerted changes in gene expression. To interpret epigenomics data, a spectrum of different interconnected datasets is needed, ranging from the genome sequence and positions of histones, together with their modifications and variants, to the transcriptional output of genomic regions. Here we present a tool, Podbat (Positioning database and analysis tool), that incorporates data from various sources and allows detailed dissection of the entire range of chromatin modifications simultaneously. Podbat can be used to analyze, visualize, store and share epigenomics data. Among other functions, Podbat allows data-driven determination of genome regions of differential protein occupancy or RNA expression using Hidden Markov Models. Comparisons between datasets are facilitated to enable the study of the comprehensive chromatin modification system simultaneously, irrespective of data-generating technique. Any organism with a sequenced genome can be accommodated. We exemplify the power of Podbat by reanalyzing all to-date published genome-wide data for the histone variant H2A.Z in fission yeast together with other histone marks and also phenotypic response data from several sources. This meta-analysis led to the unexpected finding of H2A.Z incorporation in the coding regions of genes encoding proteins involved in the regulation of meiosis and genotoxic stress responses. This incorporation was partly independent of the H2A.Z-incorporating remodeller Swr1. We verified an Swr1-independent role for H2A.Z following genotoxic stress in vivo. Podbat is open source software freely downloadable from www.podbat.org, distributed under the GNU LGPL license. User manuals, test data and instructions are available at the website, as well as a repository for third party-developed plug-in modules. Podbat requires Java version 1.6 or higher.

Maternal autoimmune thyroid disease and the fetal immune system.

OBJECTIVE: Several studies indicate that in utero exposure to maternal autoimmune diseases and transplacental passage of autoantibodies affect the risk of autoimmunity in the offspring, e. g., maternally derived GAD65 autoantibody correlates with decreased risk of type 1 diabetes, whereas thyroid peroxidase autoantibody (TPOAb) positivity at birth is associated with increased incidence of autoimmune thyroid disease later in life. The aim of this study was to identify immunological changes in children born to mothers with thyroid autoimmunity that may be related to in utero exposure to autoantibodies. DESIGN AND METHOD: Open label prospective analysis of cord blood lymphocytes and serum cytokines by Flow Cytometry in children born to mothers with autoimmune thyroiditis (AIT) (n=31) and to healthy mothers (n=76) and titers of thyroid autoantibodies were determined in cord blood and in maternal peripheral blood at delivery. RESULTS: We found an increase (almost 30%) in the frequency of cord blood natural killer (NK) cells (p=0.0016) and a minor increase in the subset of T cells expressing NK markers (p=0.028), in children born to AIT mothers. There were no detectable differences in the phenotype or frequency of cord blood memory/activated T cells, including CD4 (+)CD25 (+) T cells, between the 2 groups. The levels of pro-inflammatory cytokines TNF-α, IL-10, IL-12p70, IFN-γ and IL-1ß were significantly decreased in offspring of AIT mothers as compared to healthy controls. CONCLUSIONS: Maternal thyroid autoimmunity and transplacental passage of autoantibodies against thyroid antigens may affect the generation or expansion of cells with NK activity and the secretion of inflammatory cytokines.

Efficient use of automatic exposure control systems in computed tomography requires correct patient positioning.

BACKGROUND: Image quality and radiation dose to the patient are important factors in computed tomography (CT). To provide constant image quality, tube current modulation (TCM) performed by automatic exposure control (AEC) adjusts the tube current to the patient's size and shape. PURPOSE: To evaluate the effects of patient centering on tube current-time product (mAs) and image noise. MATERIAL AND METHODS: An oval-shaped acrylic phantom was scanned in various off-center positions, at 30-mm intervals within a 500-mm field of view, using three different CT scanners. Acquisition parameters were similar to routine abdomen examinations at each site. The mAs was recorded and noise measured in the images. The correlation of mAs and noise with position was calculated using Pearson correlation. RESULTS: In all three scanners, the mAs delivered by the AEC changed with y-position of the phantom (P<0.001), with correlation values of 0.98 for scanners A and B and -0.98 for scanner C. With x-position, mAs changes were 4.9% or less. As the phantom moved into the y-positions, compared with the iso-center, the mAs varied by up to +70%, -34%, and +56% in scanners A, B, and C, respectively. For scanners A and B, noise in two regions of interest in the lower part of the phantom decreased with elevation, with correlation factors from -0.95 to -0.86 (P<0.02). In the x-direction, significant noise relationships (P<0.005) were only seen in scanner A. CONCLUSION: This study demonstrates that patient centering markedly affects the efficacy of AEC function and that tube current changes vary between scanners. Tube position when acquiring the scout projection radiograph is decisive for the direction of the mAs change. Off-center patient positions cause errors in tube current modulation that can outweigh the dose reduction gained by AEC use, and image quality is affected.

Genomic predictors of interindividual differences in response to DNA damaging agents.

Human lymphoblastoid cells derived from different healthy individuals display considerable variation in their transcription profiles. Here we show that such variation in gene expression underlies interindividual susceptibility to DNA damaging agents. The results demonstrate the massive differences in sensitivity across a diverse cell line panel exposed to an alkylating agent. Computational models identified 48 genes with basal expression that predicts susceptibility with 94% accuracy. Modulating transcript levels for two member genes, MYH and C21ORF56, confirmed that their expression does indeed influence alkylation sensitivity. Many proteins encoded by these genes are interconnected in cellular networks related to human cancer and tumorigenesis.

Perfusion Weighted MR Imaging may Differentiate Primary CNS Lymphoma from other Homogeneously Enhancing Brain Tumors.

Primary central nervous system lymphoma (PCNSL), glioblastoma multiforme (GBM) and metastases may be difficult to differentiate based on conventional imaging alone. The aim of this study was to investigate the value of perfusion weighted imaging (PWI) in differentiating homogeneously enhancing PCNSL from homogeneously enhancing GBM and metastases. Seven consecutive patients presenting with homogeneously enhancing intraaxial tumors on MRI were retrospectively analyzed. All seven patients (three immunocompetent patients with PCNSL, three with GBM, and one with cerebral metastases) were examined with identical MR-sequences including PWI. The relative regional Cerebral Blood Volume (rrCBV) and the rrCBV ratio (rrCBVratio) were calculated. In lymphomas rrCBVratio was 0.93 ± 0.42 (mean ± SD) compared with 7.93 ± 1.44 in GBM and metastases. All lymphomas had rrCBVratio < 1.43 while all GBM and metastases had rrCBVratio > 1.43 (Fischer exact test; p < 0.001). PWI may be a valuable method in differentiating homogenously enhancing PCNSL from GBM and metastases.

Activation of inflammation/NF-kappaB signaling in infants born to arsenic-exposed mothers.

The long-term health outcome of prenatal exposure to arsenic has been associated with increased mortality in human populations. In this study, the extent to which maternal arsenic exposure impacts gene expression in the newborn was addressed. We monitored gene expression profiles in a population of newborns whose mothers experienced varying levels of arsenic exposure during pregnancy. Through the application of machine learning-based two-class prediction algorithms, we identified expression signatures from babies born to arsenic-unexposed and -exposed mothers that were highly predictive of prenatal arsenic exposure in a subsequent test population. Furthermore, 11 transcripts were identified that captured the maximal predictive capacity to classify prenatal arsenic exposure. Network analysis of the arsenic-modulated transcripts identified the activation of extensive molecular networks that are indicative of stress, inflammation, metal exposure, and apoptosis in the newborn. Exposure to arsenic is an important health hazard both in the United States and around the world, and is associated with increased risk for several types of cancer and other chronic diseases. These studies clearly demonstrate the robust impact of a mother's arsenic consumption on fetal gene expression as evidenced by transcript levels in newborn cord blood.

A portrait of cisplatin-induced transcriptional changes in mouse embryonic stem cells reveals a dominant p53-like response.

Accumulation of damage in undifferentiated cells may threaten homeostasis and regenerative capacity. Remarkably, p53 has been suggested to be transcriptionally inactive in these cells. To gain insight in the kinetics and interplay of the predominant transcriptional responses of DNA damage signalling pathways in undifferentiated cells, mouse embryonic stem cells were exposed to cisplatin at four different time points (2, 4, 8 and 24h) and concentrations (1, 2, 5 and 10 microM). RNA was isolated and subjected to genome-wide expression profiling. Up to one fourth of the tested genes could be identified as being differentially expressed (false discovery rate=10%) after the cisplatin treatment. Clustering of the expression changes showed a strong time dependency. To investigate the relationship between affected genes, a gene set analysis method was used. Functionally related gene sets were defined using gene ontologies or transcription factor binding sites and were tested for overrepresentation within the differentially expressed genes. A variety of gene sets were clearly enriched among which 'apoptosis' and 'cell cycle' were the most pronounced. Furthermore, there was a strong enrichment of genes with a p53-binding motif. The involvement of the 'cell cycle' and 'apoptosis' gene sets in the cisplatin response was detected at concentrations and time points where the respective biological assays were still negative. The results reveal novel insights into the mechanisms which maintain the genomic integrity in undifferentiated cells. Additionally the results illustrate that gene set analysis of genome-wide expression changes provides a sensitive instrument to detect cellular stress responses to DNA damage.