Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies

A Recurrent Stop-Codon Mutation in Succinate Dehydrogenase Subunit B Gene in Normal Peripheral Blood and Childhood T-Cell Acute Leukemia

BACKGROUND: Somatic cytidine mutations in normal mammalian nuclear genes occur during antibody diversification in B lymphocytes and generate an isoform of apolipoprotein B in intestinal cells by RNA editing. Here, I describe that succinate dehydrogenase (SDH; mitochondrial complex II) subunit B gene (SDHB) is somatically mutated at a cytidine residue in normal peripheral blood mononuclear cells (PBMCs) and T-cell acute leukemia. Germ line mutations in the SDHB, SDHC or SDHD genes cause hereditary paraganglioma (PGL) tumors which show constitutive activation of homeostatic mechanisms induced by oxygen deprivation (hypoxia). PRINCIPAL FINDINGS: To determine the prevalence of a mutation identified in the SDHB mRNA, 180 samples are tested. An SDHB stop-codon mutation c.136C>T (R46X) is present in a significant fraction (average = 5.8%, range = less than 1 to 30%, n = 52) of the mRNAs obtained from PBMCs. In contrast, the R46X mutation is present in the genomic DNA of PBMCs at very low levels. Examination of the PBMC cell-type subsets identifies monocytes and natural killer (NK) cells as primary sources of the mutant transcript, although lesser contributions also come from B and T lymphocytes. Transcript sequence analyses in leukemic cell lines derived from monocyte, NK, T and B cells indicate that the mutational mechanism targeting SDHB is operational in T-cell acute leukemia. Accordingly, substantial levels (more than 3%) of the mutant SDHB transcripts are detected in five of 20 primary childhood T-cell acute lymphoblastic leukemia (T-ALL) bone marrow samples, but in none of 20 B-ALL samples. In addition, distinct heterozygous SDHB missense DNA mutations are identified in Jurkat and TALL-104 cell lines which are derived from T-ALLs. CONCLUSIONS: The identification of a recurrent, inactivating stop-codon mutation in the SDHB gene in normal blood cells suggests that SDHB is targeted by a cytidine deaminase enzyme. The SDHB mutations in normal PBMCs and leukemic T cells might play a role in cellular pre-adaptation to hypoxia

Predictive factors for skeletal complications in hormone-refractory prostate cancer patients with metastatic bone disease

Factors predictive of skeletal-related events (SREs) in bone metastatic prostate cancer patients with hormone-refractory disease were investigated. We evaluated the frequency of SREs in 200 hormone-refractory patients consecutively observed at our Institution and followed until death or the last follow-up. Baseline parameters were evaluated in univariate and multivariate analysis as potential predictive factors of SREs. Skeletal-related events were observed in 86 patients (43.0%), 10 of which (5.0%) occurred before the onset of hormone-refractory disease. In univariate analysis, patient performance status (P=0.002), disease extent (DE) in bone (P=0.0001), bone pain (P=0.0001), serum alkaline phosphatase (P=0.0001) and urinary N-telopeptide of type one collagen (P=0.0001) directly correlated with a greater risk to develop SREs, whereas Gleason score at diagnosis, serum PSA, Hb, serum albumin, serum calcium, types of bone lesions and duration of androgen deprivation therapy did not. Both DE in bone (hazard ratio (HR): 1.16, 95% confidence interval (CI): 1.07–1.25, P=0.000) and pain score (HR: 1.13, 95% CI: 1.06–1.20, P=0.000) were independent variables predicting for the onset of SREs in multivariate analysis. In patients with heavy tumour load in bone and great bone pain, the percentage of SREs was almost twice as high as (26 vs 52%, P<0.02) and occurred significantly earlier (P=0.000) than SREs in patients with limited DE in bone and low pain. Bone pain and DE in bone independently predict the occurrence of SREs in bone metastatic prostate cancer patients with hormone-refractory disease. These findings could help physicians in tailoring the skeletal follow-up most appropriate to individual patients and may prove useful for stratifying patients enrolled in bisphosphonate clinical trials

Brain Research to Ameliorate Impaired Neurodevelopment - Home-based Intervention Trial (BRAIN-HIT)

<p>Abstract</p> <p>Background</p> <p>This randomized controlled trial aims to evaluate the effects of an early developmental intervention program on the development of young children in low- and low-middle-income countries who are at risk for neurodevelopmental disability because of birth asphyxia. A group of children without perinatal complications are evaluated in the same protocol to compare the effects of early developmental intervention in healthy infants in the same communities. Birth asphyxia is the leading specific cause of neonatal mortality in low- and low-middle-income countries and is also the main cause of neonatal and long-term morbidity including mental retardation, cerebral palsy, and other neurodevelopmental disorders. Mortality and morbidity from birth asphyxia disproportionately affect more infants in low- and low-middle-income countries, particularly those from the lowest socioeconomic groups. There is evidence that relatively inexpensive programs of early developmental intervention, delivered during home visit by parent trainers, are capable of improving neurodevelopment in infants following brain insult due to birth asphyxia.</p> <p>Methods/Design</p> <p>This trial is a block-randomized controlled trial that has enrolled 174 children with birth asphyxia and 257 without perinatal complications, comparing early developmental intervention plus health and safety counseling to the control intervention receiving health and safety counseling only, in sites in India, Pakistan, and Zambia. The interventions are delivered in home visits every two weeks by parent trainers from 2 weeks after birth until age 36 months. The primary outcome of the trial is cognitive development, and secondary outcomes include social-emotional and motor development. Child, parent, and family characteristics and number of home visits completed are evaluated as moderating factors.</p> <p>Discussion</p> <p>The trial is supervised by a trial steering committee, and an independent data monitoring committee monitors the trial. Findings from this trial have the potential to inform about strategies for reducing neurodevelopmental disabilities in at-risk young children in low and middle income countries.</p> <p>Trial Registration</p> <p>Clinicaltrials.gov NCT00639184</p

Developmental Trajectories in Siblings of Children with Autism: Cognition and Language from 4 Months to 7 Years

We compared the cognitive and language development at 4, 14, 24, 36, 54 months, and 7 years of siblings of children with autism (SIBS-A) to that of siblings of children with typical development (SIBS-TD) using growth curve analyses. At 7 years, 40% of the SIBS-A, compared to 16% of SIBS-TD, were identified with cognitive, language and/or academic difficulties, identified using direct tests and/or parental reports. This sub-group was identified as SIBS-A-broad phenotype (BP). Results indicated that early language scores (14–54 months), but not cognitive scores of SIBS-A-BP and SIBS-A-nonBP were significantly lower compared to the language scores of SIBS-TD, and that the rate of development was also significantly different, thus pinpointing language as a major area of difficulty for SIBS-A during the preschool years

Towards an understanding of contextual features that influence the linguistic formality of British Sign Language users

This paper seeks to understand linguistic formality through the identification and measurement of contextual features. Using an adapted sociometric methodology to combine systemic functional linguistics and sign linguistics, a survey identifies the elements of context that have an effect upon the level of linguistic formality employed by British Sign Language users. The responses of 51 participants are analysed in order to ascertain (i) the level of linguistic formality that would be employed in certain communicative scenarios, and (ii) the contextual features of these scenarios that have an influence on linguistic formality. The results obtained from this study posit that there is an overall agreement shared between British Sign Language users when choosing levels of linguistic formality based on broad contextual description alone. The people involved in the communication and their interpersonal relationships tend to be the biggest influence on the level of formality employed, whereas the topic of the interaction appears to show no significant influence upon linguistic formality on its own. This work contributes further evidence to the importance of studying language within communicative contexts and the importance of formality as an influential factor in linguistic production. It is hoped that this will encourage future studies to derive linguistic data of British Sign Language users, or indee

Randomized Controlled Trial of the Focus Parent Training for Toddlers with Autism: 1-Year Outcome

This randomized controlled trial compared results obtained after 12 months of nonintensive parent training plus care-as-usual and care-as-usual alone. The training focused on stimulating joint attention and language skills and was based on the intervention described by Drew et al. (Eur Child Adolesc Psychiatr 11:266–272, 2002). Seventy-five toddlers with autism spectrum disorder (65 autism, 10 PDD-NOS, mean age = 34.4 months, SD = 6.2) were enrolled. Analyses were conducted on a final sample of 67 children (lost to follow-up = 8). No significant intervention effects were found for any of the primary (language), secondary (global clinical improvement), or mediating (child engagement, early precursors of social communication, or parental skills) outcome variables, suggesting that the ‘Focus parent training’ was not of additional value to the more general care-as-usual

Satisfaction with care after total hip or knee replacement predicts self-perceived health status after surgery

<p>Abstract</p> <p>Background</p> <p>Inpatient satisfaction with care is a standard indicator of the quality of care delivered during hospitalization. Total hip and knee replacement (THR/TKR) for osteoarthritis (OA) are among the most successful orthopaedic interventions having a positive impact on health-related quality of life (HRQoL). The aim was to evaluate the effect of satisfaction shortly after hospital discharge on 1-month, 6-month and 1-year Medical Outcomes Study 36-item Short Form (SF-36) scores for OA patients after THR and TKR, controlling for patient characteristics, clinical presentation and preoperative SF-36 scores.</p> <p>Methods</p> <p>A multicenter prospective cohort study recruited 231 patients with OA scheduled to receive THR or TKR. Satisfaction was assessed by the Patients Judgment of Hospital Quality (PJHQ) questionnaire and HRQoL by the SF-36 questionnaire. Linear models for repeated measures assessed the relation between satisfaction (scores were dichotomized) and postoperative SF-36 scores.</p> <p>Results</p> <p>Of 231 participants, 189 were followed up 12 months after discharge (mean age 69 SD = 8; 42.6% male). The mean length of hospital stay was 13.5 (SD = 4) days. After adjustment for preoperative SF-36 scores, sociodemographic and clinical patient characteristics, satisfied patients (PJHQ score > 70) had higher SF-36 scores 1 year after surgery than did less-satisfied patients. Admission, medical care, and nursing and daily care scores mainly predicted bodily pain, mental health, social functioning, vitality and general health scores of the SF-36.</p> <p>Conclusion</p> <p>Besides being a quality-of-care indicator, immediate postoperative patient satisfaction with care may bring a new insight into clinical practice, as a predictor of self-perceived health status after surgery.</p

The Cues and Care Trial: A randomized controlled trial of an intervention to reduce maternal anxiety and improve developmental outcomes in very low birthweight infants

Abstract Background Very low birthweight infants are at risk for deficits in cognitive and language development, as well as attention and behaviour problems. Maternal sensitive behaviour (i.e. awareness of infant cues and appropriate responsiveness to those cues) in interaction with her very low birthweight infant is associated with better outcomes in these domains; however, maternal anxiety interferes with the mother's ability to interact sensitively with her very low birthweight infant. There is a need for brief, cost-effective and timely interventions that address both maternal psychological distress and interactive behaviour. The Cues and Care trial is a randomized controlled trial of an intervention designed to reduce maternal anxiety and promote sensitive interaction in mothers of very low birthweight infants. Methods and design Mothers of singleton infants born at weights below 1500 g are recruited in the neonatal intensive care units of 2 tertiary care hospitals, and are randomly assigned to the experimental (Cues) intervention or to an attention control (Care) condition. The Cues intervention teaches mothers to attend to their own physiological, cognitive, and emotional cues that signal anxiety and worry, and to use cognitive-behavioural strategies to reduce distress. Mothers are also taught to understand infant cues and to respond sensitively to those cues. Mothers in the Care group receive general information about infant care. Both groups have 6 contacts with a trained intervener; 5 of the 6 sessions take place during the infant's hospitalization, and the sixth contact occurs after discharge, in the participant mother's home. The primary outcome is maternal symptoms of anxiety, assessed via self-report questionnaire immediately post-intervention. Secondary outcomes include maternal sensitive behaviour, maternal symptoms of posttraumatic stress, and infant development at 6 months corrected age. Discussion The Cues and Care trial will provide important information on the efficacy of a brief, skills-based intervention to reduce anxiety and increase sensitivity in mothers of very low birthweight infants. A brief intervention of this nature may be more readily implemented as part of standard neonatal intensive care than broad-based, multi-component interventions. By intervening early, we aim to optimize developmental outcomes in these high risk infants. Trial Registration Current Controlled Trials ISRCTN00918472 The Cues and Care Trial: A randomized controlled trial of an intervention to reduce maternal anxiety and improve developmental outcomes in very low birthweight infant

LEARN 2 MOVE 2-3: a randomized controlled trial on the efficacy of child-focused intervention and context-focused intervention in preschool children with cerebral palsy

<p>Abstract</p> <p>Background</p> <p>Little is known about the efficacy and the working mechanisms of physical and occupational therapy interventions for children with cerebral palsy (CP). In recent years a shift from a child-focused intervention approach to a more context-focused intervention approach can be recognized. Until now the evidence on the efficacy and the working mechanisms of these interventions for children with CP is inconclusive. This study aims to evaluate the efficacy and working mechanisms of two intervention approaches compared to regular care intervention in improving mobility and self-care skills of children (2-3 years) with CP and their families: a child-focused intervention approach and a context-focused intervention approach.</p> <p>Methods/Design</p> <p>A multi-centre, randomized controlled trial research design will be used. Ninety-four children with CP (Gross Motor Function Classification System (GMFCS) level I-IV; age 2 to 3 years), their parents, and service providers (physical and occupational therapists) will be included. During a period of six months children will receive child-focused, context-focused or regular care intervention. Therapists will be randomly assigned to deliver either a child-focused intervention approach, a context-focused intervention approach or regular care intervention. Children follow their therapist into the allocated intervention arm. After the six months study-intervention period, all participants return to regular care intervention. Outcomes will be evaluated at baseline, after six months and at a three months follow-up period. Primary outcome is the capability of functional skills in self-care and mobility, using the Functional Skills Scale of the Pediatric Evaluation of Disability Inventory (PEDI). Other outcomes will be quality of life and the domains of the International Classification of Functioning, Disability and Health - for Children and Youth (ICF-CY), including body function and structure, activities (gross motor capacity and performance of daily activities), social participation, environmental variables (family functioning, parental empowerment).</p> <p>Discussion</p> <p>This paper presents the background information, design, description of interventions and protocol for this study on the efficacy and working mechanisms of child-focused intervention approach and context-focused intervention approach compared to regular care intervention in mobility and self-care skills of children (2-3 years) with CP.</p> <p>Trial registration</p> <p>This study is registered in the Dutch Trial Register as NTR1900</p