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A new approach decomposes aberrant signaling mediated by an oncogenic mutation into underlying core cellular states that may be more permissive to available therapeutic options.

The National Cancer Institute (NCI) Cancer Imaging Program organized two related workshops on June 26–27, 2013, entitled “Correlating Imaging Phenotypes with Genomics Signatures Research” and “Scalable Computational Resources as Required for Imaging-Genomics Decision Support Systems.” The first workshop focused on clinical and scientific requirements, exploring our knowledge of phenotypic characteristics of cancer biological properties to determine whether the field is sufficiently advanced to correlate with imaging phenotypes that underpin genomics and clinical outcomes, and exploring new scientific methods to extract phenotypic features from medical images and relate them to genomics analyses. The second workshop focused on computational methods that explore informatics and computational requirements to extract phenotypic features from medical images and relate them to genomics analyses and improve the accessibility and speed of dissemination of existing NIH resources. These workshops linked clinical and scientific requirements of currently known phenotypic and genotypic cancer biology characteristics with imaging phenotypes that underpin genomics and clinical outcomes. The group generated a set of recommendations to NCI leadership and the research community that encourage and support development of the emerging radiogenomics research field to address short-and longer-term goals in cancer research.

The disease course of patients with diffuse low-grade glioma is notoriously unpredictable. Temporal and spatially distinct samples may provide insight into the evolution of clinically relevant copy number aberrations (CNAs). The purpose of this study is to identify CNAs that are indicative of aggressive tumor behavior and can thereby complement the prognostically favorable 1p/19q co-deletion. Genome-wide, 50 base pair single-end sequencing was performed to detect CNAs in a clinically well-characterized cohort of 98 formalin-fixed paraffin-embedded low-grade gliomas. CNAs are correlated with overall survival as an endpoint. Seventy-five additional samples from spatially distinct regions and paired recurrent tumors of the discovery cohort were analyzed to interrogate the intratumoral heterogeneity and spatial evolution. Loss of 10q25.2-qter is a frequent subclonal event and significantly correlates with an unfavorable prognosis. A significant correlation is furthermore observed in a validation set of 126 and confirmation set of 184 patients. Loss of 10q25.2-qter arises in a longitudinal manner in paired recurrent tumor specimens, whereas the prognostically favorable 1p/19q co-deletion is the only CNA that is stable across spatial regions and recurrent tumors. CNAs in low-grade gliomas display extensive intratumoral heterogeneity. Distal loss of 10q is a late onset event and a marker for reduced overall survival in low-grade glioma patients. Intratumoral heterogeneity and higher frequencies of distal 10q loss in recurrences suggest this event is involved in outgrowth to the recurrent tumor.

Genomic, transcriptional, and proteomic analyses of brain tumors reveal subtypes that differ in pathway activity, progression, and response to therapy. However, a number of small molecule inhibitors under development vary in strength of subset and pathway‐specificity, with molecularly targeted experimental agents tending toward stronger specificity. The Notch signaling pathway is an evolutionarily conserved pathway that plays an important role in multiple cellular and developmental processes. We investigated the effects of Notch pathway inhibition in glioma tumor‐initiating cell (GIC, hereafter GIC) populations using γ secretase inhibitors. Drug cytotoxicity testing of 16 GICs showed differential growth responses to the inhibitors, stratifying GICs into responders and nonresponders. Responder GICs had an enriched proneural gene signature in comparison to nonresponders. Also gene set enrichment analysis revealed 17 genes set representing active Notch signaling components NOTCH1, NOTCH3, HES1, MAML1, DLL‐3, JAG2, and so on, enriched in responder group. Analysis of The Cancer Genome Atlas expression dataset identified a group (43.9%) of tumors with proneural signature showing high Notch pathway activation suggesting γ secretase inhibitors might be of potential value to treat that particular group of proneural glioblastoma (GBM). Inhibition of Notch pathway by γ secretase inhibitor treatment attenuated proliferation and self‐renewal of responder GICs and induces both neuronal and astrocytic differentiation. In vivo evaluation demonstrated prolongation of median survival in an intracranial mouse model. Our results suggest that proneural GBM characterized by high Notch pathway activation may exhibit greater sensitivity to γ secretase inhibitor treatment, holding a promise to improve the efficiency of current glioma therapy. StemCells2014;32:301–312

Background:Information is scarce concerning the perceived needs and the amount of health-care utilization of persons with suicidal ideation (SI) compared to those without SI. Aims:To describe the needs and health care use of persons with and without SI and to investigate whether these differences are associated with the severity of the axis-I symptomatology. Method:Data were obtained from 1,699 respondents with a depressive and/or anxiety disorder who participated in the Netherlands Study of Depression and Anxiety. Persons with and without SI were distinguished. Outcome variables were perceived needs and health-care utilization. We used multivariate regression in two models: (1) adjusted only for sociodemographic variables and (2) adjusted additionally for severity of axis-I symptomatology. Results:Persons with SI had higher odds for both unmet and met needs in almost all domains and made more intensive use of mental-health care. Differences in needs and health-care utilization of persons with and without SI were strongly associated with severity of axis I symptomatology. Conclusions:Our results validate previous findings about perceived needs and health-care use of persons with SI. The results also suggest that suicidal persons are more seriously ill, and that they need more professional care, dedication, and specialized expertise than anxious and depressed persons without SI, especially in the domains of information and referral.

Severe congenital neutropenia (SCN) is a BM failure syndrome with a high risk of progression to acute myeloid leukemia (AML). The underlying genetic changes involved in SCN evolution to AML are largely unknown. We obtained serial hematopoietic samples from an SCN patient who developed AML 17 years after the initiation of G-CSF treatment. Next- generation sequencing was performed to identify mutations during disease progression. In the AML phase, we found 12 acquired nonsynonymous mutations. Three of these, in CSF3R, LLGL2, and ZC3H18, co-occurred in a subpopulation of progenitor cells already in the early SCN phase. This population expanded over time, whereas clones harboring only CSF3Rmutations disappeared from the BM. The other 9 mutations were only apparent in the AML cells and affected known AML-associated genes (RUNX1and ASXL1) and chromatin remodelers (SUZ12and EP300). In addition, a novel CSF3Rmutation that conferred autonomous proliferation to myeloid progenitors was found. We conclude that progression from SCN to AML is a multistep process, with distinct mutations arising early during the SCN phase and others later in AML development. The sequential gain of 2 CSF3Rmutations implicates abnormal G-CSF signaling as a driver of leukemic transformation in this case of SCN.

Gene expression profiling of acute myeloid leukemia (AML) allows the discovery of previously unrecognized molecular entities. Here, we identified a specific subgroup of AML, defined by an expression profile resembling that of AMLs with mutations in the myeloid transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα), while lacking such mutations. We found that in these leukemias, the CEBPA gene was silenced, which was associated with frequent promoter hypermethylation. The leukemias phenotypically showed aberrant expression of T-cell genes, of which CD7 was most consistent. We identified 2 mechanisms that may contribute to this phenotype. First, absence of Cebpa led to up-regulation of specific T-cell transcripts (ie, Cd7 and Lck) in hematopoietic stem cells isolated from conditional Cebpa knockout mice. Second, the enhanced expression of TRIB2, which we identify here as a direct target of the T-cell commitment factor NOTCH1, suggested aberrantly activated Notch signaling. Putatively activating NOTCH1 mutations were found in several specimens of the newly identified subgroup, while a large set of control AMLs was mutation negative. A gene expression prediction signature allowed the detection of similar cases of leukemia in independent series of AML.

Gene expression profiling of acute myeloid leukemia (AML) allows the discovery of previously unrecognized molecular entities. Here, we identified a specific subgroup of AML, defined by an expression profile resembling that of AMLs with mutations in the myeloid transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα), while lacking such mutations. We found that in these leukemias, the CEBPAgene was silenced, which was associated with frequent promoter hypermethylation. The leukemias phenotypically showed aberrant expression of T-cell genes, of which CD7was most consistent. We identified 2 mechanisms that may contribute to this phenotype. First, absence of Cebpaled to up-regulation of specific T-cell transcripts (ie, Cd7and Lck) in hematopoietic stem cells isolated from conditional Cebpaknockout mice. Second, the enhanced expression of TRIB2, which we identify here as a direct target of the T-cell commitment factor NOTCH1, suggested aberrantly activated Notch signaling. Putatively activating NOTCH1mutations were found in several specimens of the newly identified subgroup, while a large set of control AMLs was mutation negative. A gene expression prediction signature allowed the detection of similar cases of leukemia in independent series of AML.

Mutations in nucleophosmin NPM1are the most frequent acquired molecular abnormalities in acute myeloid leukemia (AML). We determined the NPM1mutation status in a clinically and molecularly well-characterized patient cohort of 275 patients with newly diagnosed AML by denaturing high-performance liquid chromatography (dHPLC). We show that NPM1mutations are significantly underrepresented in patients younger than 35 years. NPM1mutations positively correlate with AML with high white blood cell counts, normal karyotypes, and fms-like tyrosine kinase-3 gene (FLT3)internal tandem duplication (ITD) mutations. NPM1mutations associate inversely with the occurrence of CCAAT/enhancer-binding protein-α (CEBPA)and NRASmutations. With respect to gene expression profiling, we show that AML cases with an NPM1mutation cluster in specific subtypes of AML with previously established gene expression signatures, are highly associated with a homeobox gene–specific expression signature, and can be predicted with high accuracy. We demonstrate that patients with intermediate cytogenetic risk AML without FLT3ITD mutations but with NPM1mutations have a significantly better overall survival (OS) and event-free survival (EFS) than those without NPM1mutations.Finally, in multivariable analysis NPM1mutations express independent favorable prognostic value with regard to OS, EFS, and disease-free survival (DFS).

Mutations in nucleophosmin NPM1 are the most frequent acquired molecular abnormalities in acute myeloid leukemia (AML). We determined the NPM1 mutation status in a clinically and molecularly well-characterized patient cohort of 275 patients with newly diagnosed AML by denaturing high-performance liquid chromatography (dHPLC). We show that NPM1 mutations are significantly underrepresented in patients younger than 35 years. NPM1 mutations positively correlate with AML with high white blood cell counts, normal karyotypes, and fms-like tyrosine kinase-3 gene (FLT3) internal tandem duplication (ITD) mutations. NPM1 mutations associate inversely with the occurrence of CCAAT/enhancer-binding protein-α (CEBPA) and NRAS mutations. With respect to gene expression profiling, we show that AML cases with an NPM1 mutation cluster in specific subtypes of AML with previously established gene expression signatures, are highly associated with a homeobox gene–specific expression signature, and can be predicted with high accuracy. We demonstrate that patients with intermediate cytogenetic risk AML without FLT3 ITD mutations but with NPM1 mutations have a significantly better overall survival (OS) and event-free survival (EFS) than those without NPM1 mutations. Finally, in multivariable analysis NPM1 mutations express independent favorable prognostic value with regard to OS, EFS, and disease-free survival (DFS).

BACKGROUND: The study aim was to clarify the role of anxiety and depression on the outcome in assisted reproductive treatment. Previous studies on this topic have shown contradicting results, which may have been caused by population characteristics, the design of the study, or small sample sizes. METHODS: In a multicentre prospective study, 291 out of 359 (81%) consecutively invited women agreed to participate. Before down-regulation by means of gonadotrophin-releasing hormone (GnRH) analogues in a long IVF protocol, patients were asked to complete the Dutch version of the State and Trait Anxiety Inventory to measure anxiety, and the Dutch version of the Beck Depression Inventory (BDI) to measure depression. Multiple logistic regression analysis was used to analyse known predictors of pregnancy and psychological factors and their relationship with treatment outcome. RESULTS: A significant relationship was shown between baseline psychological factors and the probability to become pregnant after IVF/intracytoplasmic sperm injection (ICSI) treatment, controlling for other factors. State anxiety had a slightly stronger correlation (P = 0.01) with treatment outcome than depression (P = 0.03). CONCLUSIONS: Pre-existing psychological factors are independently related to treatment outcome in IVF/ICSI, and should therefore be taken into account in patient counselling. Psychological factors may be improved by intervention, whereas demographic and gynaecological factors cannot. Future studies should be directed towards underlying mechanisms involved and the role of evidence-based distress reduction in order to improve treatment results.

The study aim was to clarify the role of anxiety and depression on the outcome in assisted reproductive treatment. Previous studies on this topic have shown contradicting results, which may have been caused by population characteristics, the design of the study, or small sample sizes.

Background and Purpose. The treatment of people with low back pain often includes giving a variety of instructions about back care. The objective of our study was to explore the content and sequence of these instructions. Subjects. Our database contained information on 1,151 therapy sessions for 132 patients who were treated by 21 therapists. Methods. Hierarchical linear modeling was used to establish trends in instructions during the course of treatment. Instructions were measured by means of a registration form. Results. Pain management instructions were given at the start of treatment and then decreased in later sessions. Instructions about taking care of the back in daily activities followed the same course. Exercise instructions were introduced after the start of treatment and were spread evenly across the visits. The number of recommendations about general fitness decreased during treatment. Conclusion and Discussion. The majority of back care instructions were spread evenly across therapy visits. Relatively little variation in instructions among patients was seen, which may indicate a lack of individualization of the back care programs.

Objective: The purpose of the study was to assess the feasibility of a psychiatric consultation intervention for somatizing patients in the family practice setting in terms of 1) patient compliance, 2) patient satisfaction, and 3) compliance and satisfaction of general practitioners (GPs).Method: In a period of nine months, forty-six patients were selected for psychiatric consultation in six solo family practices in a semi-urban area in the Netherlands. The consultation included an interview with the consulting psychiatrist, the patient, and the GP. A written summary of the consultation was provided to the GP and the patient. A booster session with a GP and psychiatrist was included to evaluate and reinforce the recommendations.Results: The majority of the selected patients agreed to participate after informed consent. An intervention was implemented containing interpersonal techniques, reattribution, clarification, and structuring. GP compliance with recommendations was 100 percent, patient compliance 75 percent.Conclusion: A standardized psychiatric consultation for somatizing patients in a family practice setting can be implemented. Several levels of implementation can be distinguished.

The aim of this study was to describe the disorders and the treatment of patients whose complaints were evaluated as being solely somatic in nature, as being somatic and having psychosocial consequences, or as being (at least partially) of a psychosocial origin. Data were used from a survey on physical therapy in Dutch primary health care, in which physical therapists collected data on their patients using a standardised registration form. The therapists evaluated approximately two-thirds of their patients' complaints as solely somatic, about one-sixth as having psychosocial consequences and about one-sixth as being at least partially of psychosocial origin. Systematic differences were found between these categories of patients with regard to the medical diagnosis, the physical therapist's diagnosis (in terms of impairments and disabilities) and the treatment. It is concluded that, in addressing the issue of physical therapy in patients with psychosocial complaints, one should make a distinction between complaints of psychosocial origin and complaints with psychosocial consequences. Furthermore, the therapeutic goals and interventions applied in patients with psychosocial complaints clearly belong to the domain of physical therapy.

Nickel catalysts tend to deactivate in the hydrogenation of acetonitrile. Using temperature-programmed techniques, combined with a number of different analytical procedures, including mass spectrometry, it was established that the formation of surface nickel carbides was the major cause of the loss of activity with time on stream. The presence of partly dehydrogenated species was a second factor causing the loss of activity. Even in the presence of hydrogen adsorbed nitrile molecules were partly dehydrogenated during the process. The resulting species were strongly adsorbed on the nickel surface and blocked some of the active sites for hydrogenation. Treatment of the deactivated catalyst with hydrogen at an elevated temperature (>200°C) restored both the catalytic activity and the selectivity of the catalyst. The influence of the hydrogen partial pressure on the rate of deactivation was assessed by performing the hydrogenation at several different molar hydrogen-to-acetonitrile (H/C) ratios. It was found that the performance of the catalyst could be maintained when a large excess of hydrogen was present in the feed. Under the experimental conditions, a H/C ratio higher than about 25 was required to maintain productivity.

Genome analysis which takes into account tumor purity leads to discovery of PTENas a tumor suppressor gene in high-grade serous ovarian cancer. See related research, http://genomebiology.com/2014/15/12/526

The molecular basis for the clinical heterogeneity observed in patients with malignant rhabdoid tumors is unknown. Recently, two reports revealed molecular intertumor heterogeneity in teratoid/rhabdoid tumors (ATRTs) and extra-cranial MRTs (ecMRTs) using genomic, transcriptomic, and epigenomic profiling. Distinct molecular subgroups were identified and new therapeutic targets were revealed.

Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem cell niche. Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53mutant sonic hedgehog (SHH) medulloblastomas with GLI2and/or N-MYCamplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and the developing brain, promoting malignant gliomas and suppressing SHH-medulloblastoma formation, respectively.

Genomic markers provide unbiased information that is increasingly being used to enhance traditional histopathology approaches for classification of cancer samples.