Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia.

PURPOSE: Ataxia-Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear. METHODS: From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set. RESULTS: LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56-4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6-5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case-control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018). CONCLUSION: This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.

The biological functions and signaling mechanisms of the p75 neurotrophin receptor.

The p75 neurotrophin receptor (p75(NTR)) regulates a wide range of cellular functions, including programmed cell death, axonal growth and degeneration, cell proliferation, myelination, and synaptic plasticity. The multiplicity of cellular functions governed by the receptor arises from the variety of ligands and co-receptors which associate with p75(NTR) and regulate its signaling. P75(NTR) promotes survival through interactions with Trk receptors, inhibits axonal regeneration via partnerships with Nogo receptor (Nogo-R) and Lingo-1, and promotes apoptosis through association with Sortilin. Signals downstream of these interactions are further modulated through regulated intramembrane proteolysis (RIP) of p75(NTR) and by interactions with numerous cytosolic partners. In this chapter, we discuss the intricate signaling mechanisms of p75(NTR), emphasizing how these signals are differentially regulated to mediate these diverse cellular functions.

A multiplanet system of super-Earths orbiting the brightest red dwarf star GJ 887.

The closet exoplanets to the Sun provide opportunities for detailed characterization of planets outside the Solar System. We report the discovery, using radial velocity measurements, of a compact multiplanet system of super-Earth exoplanets orbiting the nearby red dwarf star GJ 887. The two planets have orbital periods of 9.3 and 21.8 days. Assuming an Earth-like albedo, the equilibrium temperature of the 21.8-day planet is ~350 kelvin. The planets are interior to, but close to the inner edge of, the liquid-water habitable zone. We also detect an unconfirmed signal with a period of ~50 days, which could correspond to a third super-Earth in a more temperate orbit. Our observations show that GJ 887 has photometric variability below 500 parts per million, which is unusually quiet for a red dwarf.

c-jun is essential for sympathetic neuronal death induced by NGF withdrawal but not by p75 activation.

Sympathetic neurons depend on NGF binding to TrkA for their survival during vertebrate development. NGF deprivation initiates a transcription-dependent apoptotic response, which is suggested to require activation of the transcription factor c-Jun. Similarly, apoptosis can also be induced by selective activation of the p75 neurotrophin receptor. The transcriptional dependency of p75-mediated cell death has not been determined; however, c-Jun NH2-terminal kinase has been implicated as an essential component. Because the c-jun-null mutation is early embryonic lethal, thereby hindering a genetic analysis, we used the Cre-lox system to conditionally delete this gene. Sympathetic neurons isolated from postnatal day 1 c-jun-floxed mice were infected with an adenovirus expressing Cre recombinase or GFP and analyzed for their dependence on NGF for survival. Cre immunopositive neurons survived NGF withdrawal, whereas those expressing GFP or those uninfected underwent apoptosis within 48 h, as determined by DAPI staining. In contrast, brain-derived neurotrophic factor (BDNF) binding to p75 resulted in an equivalent level of apoptosis in neurons expressing Cre, GFP, and uninfected cells. Nevertheless, cycloheximide treatment prevented BDNF-mediated apoptosis. These results indicate that whereas c-jun is required for apoptosis in sympathetic neurons on NGF withdrawal, an alternate signaling pathway must be induced on p75 activation.

Selective activation of NF-kappa B by nerve growth factor through the neurotrophin receptor p75.

Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) selectively bind to distinct members of the Trk family of tyrosine kinase receptors, but all three bind with similar affinities to the neurotrophin receptor p75 (p75NTR). The biological significance of neurotrophin binding to p75NTR in cells that also express Trk receptors has been difficult to ascertain. In the absence of TrkA, NGF binding to p75NGR activated the transcription factor nuclear factor kappa B (NF-kappa B) in rat Schwann cells. This activation was not observed in Schwann cells isolated from mice that lacked p75NTR. The effect was selective for NGF; NF-kappa B was not activated by BDNF or NT-3.

Case control study of chronic fatigue in pediatric patients.

OBJECTIVE: To determine the demographic characteristics, medical features, psychological profile, and natural history of children with chronic fatigue. DESIGN: Case control study. SETTING: Pediatric Infectious Diseases Clinic of Kosair Children's Hospital, 1990 to 1992. PARTICIPANTS: Forty-four patients referred for persistent fatigue were evaluated. Twenty patients participated in a psychological study; 20 healthy controls of similar age and gender were recruited from community pediatric practices and 20 matched depressed controls were recruited from university psychiatry services (subjects were treated as groups in the analyses). MEASURES: Demographic data were obtained for all referred patients. Those with fatigue for at least 2 months and no alternative diagnosis received a detailed history, physical, and battery of laboratory tests (complete blood count, sedimentation rate, chemistry panel, chest X-ray thyroid stimulating hormone, thyroxine, anti-nuclear antibodies, urinalysis, immunoglobulins, and Epstein-Barr virus (EBV), toxoplasma, and cytomegalovirus serologies). Psychological study participants completed the following: background structured interview; Kaufman Brief Intelligence Test; Children's Depression Inventory; Child Behavior Checklist; Youth Self Report; Diagnostic Interview for Children and Adolescents-Revised; mail-in follow-up survey. RESULTS: The median age of fatigue patients was 14.3 years; 60% were female, 96% white, and 87% from the mid/upper socioeconomic status (SES). Fatigue patients were demographically similar to 21 patients referred for infectious mononucleosis (IM) but were older than other clinic patients (P < .0001). White race (P = .0568) and mid/upper SES (P = .0403) were over-represented among fatigue patients compared to patients referred for other diagnoses. Of 36 patients meeting criteria for further study, 5 had an IM-like illness including evidence of recent EBV infection. For the remaining 31 patients, clinical and laboratory evaluations were unrevealing. Psychological study subjects reported marked declines in quality-of-life and scored high on measures of internalizing, withdrawal, and social isolation. Nine met diagnostic criteria for depression, although depressive symptoms were not as prominent as those reported by depressed controls. Fatigue subjects scored higher on somatization than both control groups. The follow-up survey indicated symptomatic improvement in most patients. CONCLUSIONS: Chronic fatigue was a common reason for referral, with over-representation of white children from mid/upper SES. After exclusion of EBV-associated IM, screening laboratory tests were not helpful in establishing specific organic diagnoses. Whereas the natural history was favorable, chronic fatigue resulted in major quality-of-life changes and was associated with significant levels of psychosocial distress. IMPLICATIONS: Psychological evaluation is warranted in these patients, as some may have treatable psychological conditions. Given the absence of proved medical therapies, psychosocial interventions to improve quality-of-life should be studied.

Psychological symptoms in chronic fatigue and juvenile rheumatoid arthritis.

OBJECTIVE: To determine if psychological morbidity in youth with chronic fatigue is caused by the stress of coping with a chronic illness. STUDY DESIGN: Case-control study comparing pediatric patients with debilitating chronic fatigue and matched subjects with juvenile rheumatoid arthritis, a chronic medical illness with similar functional sequelae. SETTING: Pediatric Infectious Diseases Clinic and Juvenile Rheumatoid Arthritis Clinic of Kosair Children's Hospital. PARTICIPANTS: Nineteen children and adolescents with debilitating chronic fatigue and 19 age- and sex-matched peers with juvenile rheumatoid arthritis. Outcome. Structured Interview, Kaufman Brief Intelligence Test, Child Behavior Checklist, and Youth Self-Report. RESULTS: Intellectual functioning on the Kaufman Brief Intelligence Test Composite was average (103, standard score) for both groups. Pediatric patients with chronic fatigue had higher levels of internalizing psychological distress than patients suffering from juvenile rheumatoid arthritis, despite the fact that both groups had a similar pattern of decline in social and physical activities. Duration of illness did not explain the difference in psychological symptoms. CONCLUSIONS: Psychological factors may play a more active role in debilitating chronic fatigue in pediatric patients than can be explained by the stress of coping with a similar chronic, non-life-threatening illness.

Coupling of the p75 neurotrophin receptor to sphingolipid signaling.

The neurotrophins are a family of growth factors involved in the survival and differentiation of specific populations of neurons and glial cells. Many of the trophic signals elicited by neurotrophins are initiated by the binding of these molecules to various Trk tyrosine kinase receptors. In contrast, recent data suggest that neurotrophin-mediated death signals are generated through the interaction of nerve growth factor with the low-affinity neurotrophin receptor, p75NTR, Neurotrophins may signal through p75NTR by stimulating sphingomyelin hydrolysis and generating ceramide in primary cultures of neurons and glial cells as well as in fibroblasts heterologously expressing p75NTR. The biochemical characteristics of p75NTR-dependent ceramide generation are discussed relative to the role of ceramide in p75NTR-dependent apoptosis and the activation of NF-kappa B.

Selectivity of ligand binding to opioid receptors in brain membranes from the rat, monkey and guinea pig.

Conditions for the equilibrium binding to opioid receptor of [3H]sufentanil (mu selective), [3H][D-Pen2,D-Pen5]enkephalin (delta selective), and [3H]U69,593 (kappa selective) were established in membranes from rat brain cerebrum, monkey cortex, or guinea pig cerebellum. The selectivity index of various opioid alkaloids and peptides in binding to the mu, delta, or kappa opioid receptors was expressed as the ratio of their EC50 values in displacing two selective radiolabeled ligands: [3H]sufentanil/[3H](D-Pen2,D-Pen5)enkephalin (selectivity: mu/delta), [3H]sufentanil/[3H]U69,593 (selectivity: mu/kappa), or [3H][D-Pen2,D-Pen5]enkephalin/[3H]U69,593 (selectivity: delta/kappa). High resolution in binding selectivity was observed: in rat brain the mu/delta selectivity for Tyr-D-Ala-Gly-(Me)Phe-Gly-ol and sufentanil were 0.02 and 0.03, whereas for [D-Pen2,D-Pen5]enkephalin and ICI 174,864 they were 1,200 and 998. Compared to mu opiates, the specific binding of delta and kappa agonists was less sensitive to sodium. The results describe a routinely applicable methodological approach for the assessment of selective ligand binding to the mu, delta and kappa opioid receptors in rodent and monkey brain membranes.

Differential diagnosis of chronic fatigue in children: behavioral and emotional dimensions.

A battery of self-report questionnaires and structured diagnostic interviews was administered to 20 children and adolescents who presented to a pediatric specialty clinic with chronic fatigue. Matched groups of healthy and depressed control subjects (aged 8 to 19 years) were also studied. Criteria were established to identify those items in the assessment battery that reliably differentiated among the three groups. Analysis of item content suggested several clusters of characteristics that discriminated among the subject groups, including life changes, cognitive difficulties, negative self-attributions, social relationship disruption, and somatic symptom presentation. The results suggest that certain psychological factors can discriminate chronic fatigue from depressive symptomatology, as well as normal functioning. Items discriminating among groups are presented in an organized questionnaire format to assist with the understanding and assessment of pediatric chronic fatigue cases.

Parent relationships and compliance in cystic fibrosis.

INTRODUCTION: Marital adjustment, family characteristics, and parent-child stress and compliance with treatment were investigated in 41 families with a preadolescent child (age 3 to 11 years) who had cystic fibrosis (CF). METHOD: Mothers completed the Dyadic Adjustment Scale, the Family Adaptability and Cohesion Evolution Scale, and the short form of the Parenting Stress Index. Parents and medical staff completed questionnaires assessing the child's compliance with diet/nutritional intake, vitamins, pancreatic enzymes, other medications (such as oral antibiotics), and chest physiotherapy. RESULTS: Preadolescents with CF were viewed as generally cooperative with most aspects of treatment. Parental ratings of compliance with dietary and nutritional intake were associated with increased marital consensus and decreased parenting stress. Medical staff ratings of dietary compliance, medication compliance, and chest physiotherapy compliance were associated with lower parenting stress. DISCUSSION: Parent-child stress and lack of agreement between parents is associated with problems in compliance with treatment, which may have an adverse impact on the disease and health status of the child with CF.

NRAGE, a p75NTR adaptor protein, is required for developmental apoptosis in vivo.

NRAGE (also known as Maged1, Dlxin) is a member of the MAGE gene family that may play a role in the neuronal apoptosis that is regulated by the p75 neurotrophin receptor (p75NTR). To test this hypothesis in vivo, we generated NRAGE knockout mice and found that NRAGE deletion caused a defect in developmental apoptosis of sympathetic neurons of the superior cervical ganglia, similar to that observed in p75NTR knockout mice. Primary sympathetic neurons derived from NRAGE knockout mice were resistant to apoptosis induced by brain-derived neurotrophic factor (BDNF), a pro-apoptotic p75NTR ligand, and NRAGE-deficient sympathetic neurons show attenuated BDNF-dependent JNK activation. Hair follicle catagen is an apoptosis-like process that is dependent on p75NTR signaling; we show that NRAGE and p75NTR show regulated co-expression in the hair follicle and that identical defects in hair follicle catagen are present in NRAGE and p75NTR knockout mice. Interestingly, NRAGE knockout mice have severe defects in motoneuron apoptosis that are not observed in p75NTR knockout animals, raising the possibility that NRAGE may facilitate apoptosis induced by receptors other than p75NTR. Together, these studies demonstrate that NRAGE plays an important role in apoptotic-signaling in vivo.

Pediatric limb amputation: aspects of coping and psychotherapeutic intervention.

This paper addresses the assessment of and intervention with pediatric patients undergoing limb amputation. A multicomponent treatment package is advocated including the use of play and cognitive-behavioral strategies to enhance coping and adjustment to the loss of a limb.

Opioid signal transduction in intact and fragmented SH-SY5Y neural cells.

Parameters of ligand binding, stimulation of low-Km GTPase, and inhibition of adenylate cyclase were determined in intact human neuroblastoma SH-SY5Y cells and in their isolated membranes, both suspended in identical physiological buffer medium. In cells, the mu-selective opioid agonist [3H]Tyr-D-Ala-Gly(Me)Phe-Gly-ol ([3H]DAMGO) bound to two populations of sites with KD values of 3.9 and 160 nM, with less than 10% of the sites in the high-affinity state. Both sites were also detected at 4 degrees C and were displaced by various opioids, including quaternary naltrexone. The opioid antagonist [3H]naltrexone bound to a single population of sites, and in cells treated with pertussis toxin the biphasic displacement of [3H]naltrexone by DAMGO became monophasic with only low-affinity binding present. The toxin specifically reduced high-affinity agonist binding but had no effect on the binding of [3H]naltrexone. In isolated membranes, both agonist and antagonist bound to a single population of receptor sites with affinities similar to that of the high-affinity binding component in cells. Addition of GTP to membranes reduced the Bmax for [3H]DAMGO by 87% and induced a linear ligand binding component; a low-affinity binding site, however, could not be saturated. Compared with results obtained with membranes suspended in Tris buffer, agonist binding, including both receptor density and affinity, in the physiological medium was attenuated. The results suggest that high-affinity opioid agonist binding represents the ligand-receptor-guanine nucleotide binding protein (G protein) complex present in cells at low density due to modulation by endogenous GTP.(ABSTRACT TRUNCATED AT 250 WORDS)

p75 neurotrophin receptor signaling: mechanisms for neurotrophic modulation of cell stress?

The recent recognition that the p75 neurotrophin receptor, p75((NTR)), can induce apoptotic signals has contributed to the perception that it acts primarily as a death receptor. Although the molecular mechanisms of p75(NTR) signaling remain to be fully characterized, many of the currently identified pathways activated by p75(NTR) may be generally characterized as stress response signals. This review describes recent advances in identifying the molecular components involved in p75(NTR) signal transduction and suggests that p75(NTR) signaling may more aptly serve as a general mechanism for the transduction and modulation of stress signals.