Timing of exercise therapy when initiating adjuvant chemotherapy for breast cancer: a randomized trial.

AIMS: The most appropriate timing of exercise therapy to improve cardiorespiratory fitness (CRF) among patients initiating chemotherapy is not known. The effects of exercise therapy administered during, following, or during and following chemotherapy were examined in patients with breast cancer. METHODS AND RESULTS: Using a parallel-group randomized trial design, 158 inactive women with breast cancer initiating (neo)adjuvant chemotherapy were allocated to receive (1:1 ratio): usual care or one of three exercise regimens-concurrent (during chemotherapy only), sequential (after chemotherapy only), or concurrent and sequential (continuous) (n = 39/40 per group). Exercise consisted of treadmill walking three sessions/week, 20-50 min at 55%-100% of peak oxygen consumption (VO2peak) for ≈16 (concurrent, sequential) or ≈32 (continuous) consecutive weeks. VO2peak was evaluated at baseline (pre-treatment), immediately post-chemotherapy, and ≈16 weeks after chemotherapy. In intention-to-treat analysis, there was no difference in the primary endpoint of VO2peak change between concurrent exercise and usual care during chemotherapy vs. VO2peak change between sequential exercise and usual care after chemotherapy [overall difference, -0.88 mL O2·kg-1·min-1; 95% confidence interval (CI): -3.36, 1.59, P = 0.48]. In secondary analysis, continuous exercise, approximately equal to twice the length of the other regimens, was well-tolerated and the only strategy associated with significant improvements in VO2peak from baseline to post-intervention (1.74 mL O2·kg-1·min-1, P < 0.001). CONCLUSION: There was no statistical difference in CRF improvement between concurrent vs. sequential exercise therapy relative to usual care in women with primary breast cancer. The promising tolerability and CRF benefit of ≈32 weeks of continuous exercise therapy warrant further evaluation in larger trials.

Generalization of an Early Intervention for Inhibited Preschoolers to the Classroom Setting.

Considerable evidence has accumulated supporting transactional influences between early childhood behavioral inhibition (BI), parent-child and child-peer relationships, and the development of anxiety disorders in adolescence and adulthood. Drawing from this literature, the Turtle Program was designed to treat children high in BI by intervening at the level of both parents and peers. In this pilot study, we sought to determine whether benefits of participating in the Turtle Program extended to children's classrooms in the form of increased positive social interactions with peers. Forty inhibited children (42-60 months) and their parent(s) were randomized to either the Turtle Program (n = 18) or a waitlist control group (WLC; n = 22). The Turtle Program involved 8 weeks of concurrent parent and child treatment. Trained research assistants, blind to treatment condition, coded participants' social interactions with peers during free play at each child's preschool at the beginning and end of treatment. Teachers unaware of group assignment also provided reports of social behaviors at these time points. Reliable change index scores revealed that both Turtle Program and WLC participants experienced relatively high rates of reliable increases in observed peer play interactions from pre- to post-treatment (73.3% and 42.1% respectively). Additionally, Turtle Program participants experienced high rates of reliable increase in observed initiations to peers (73.3%) as well as a moderate degree of reliable decrease in teacher-reported displays of fear/anxiety (33.3%). These data provide preliminary, but promising, evidence that increases in children's social behaviors as a result of participation in the Turtle Program generalize to their preschool classrooms.

A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/ sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801.

Initial therapy of chronic graft-versus-host disease is prednisone ± a calcineurin-inhibitor, but most patients respond inadequately. In a randomized, adaptive, phase II/III, multicenter trial we studied whether prednisone/sirolimus or prednisone/sirolimus/photopheresis was more effective than prednisone/sirolimus/calcineurin-inhibitor for treating chronic graft-versus-host disease in treatment-naïve or early inadequate responders. Primary endpoints of this study were proportions of subjects alive without relapse or secondary therapy with 6-month complete or partial response in phase II, or with 2-year complete response in phase III. The prednisone/sirolimus/photopheresis arm closed prematurely because of slow accrual and the remaining two-drug versus three-drug study ended in phase II due to statistical futility with 138 evaluable subjects. The two-drug and three-drug arms did not differ in rates of 6-month complete or partial response (48.6% versus 50.0%, P=0.87), or 2-year complete response (14.7% versus 15.5%, P=0.90). Serum creatinine values >1.5 times baseline were less frequent in the calcineurin-inhibitor-free arm at 2 months (1.5% versus 11.7%, P=0.025) and 6 months (7.8% versus 24.0%, P=0.016). Higher adjusted Short Form-36 Physical Component Summary and Physical Functioning scores were seen in the two-drug arm at both 2 months (P=0.02 and P=0.04, respectively) and 6 months (P=0.007 and P=0.001, respectively). Failure-free survival and overall survival rates at 2 years were similar for patients in the the two-drug and three-drug arms (48.6% versus 46.2%, P=0.78; 81.5% versus 74%, P=0.28). Based on similar long-term outcomes, prednisone/sirolimus is a therapeutic alternative to prednisone/sirolimus/calcineurin-inhibitor for chronic graft-versus-host disease, being easier to administer and better tolerated. Clinicaltrials.gov identifier: NCT01106833.

Molecular convergence in ex vivo models of Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by erythroid hypoplasia, usually without perturbation of other hematopoietic lineages. Approximately 65% of DBA patients with autosomal dominant inheritance have heterozygous mutations or deletions in ribosomal protein (RP) genes while <1% of patients with X-linked inheritance have been identified with mutations in the transcription factor GATA1 Erythroid cells from patients with DBA have not been well characterized, and the mechanisms underlying the erythroid specific effects of either RP or GATA1 associated DBA remain unclear. We have developed an ex vivo culture system to expand peripheral blood CD34+ progenitor cells from patients with DBA and differentiate them into erythroid cells. Cells from patients with RP or GATA1 mutations showed decreased proliferation and delayed erythroid differentiation in comparison with controls. RNA transcript analyses of erythroid cells from controls and patients with RP or GATA1 mutations showed distinctive differences, with upregulation of heme biosynthesis genes prominently in RP-mediated DBA and failure to upregulate components of the translational apparatus in GATA1-mediated DBA. Our data show that dysregulation of translation is a common feature of DBA caused by both RP and GATA1 mutations. This trial was registered at www.clinicaltrials.gov as #NCT00106015.

Preliminary evaluation of a multimodal early intervention program for behaviorally inhibited preschoolers.

OBJECTIVE: Approximately 15%-20% of young children can be classified as having a behaviorally inhibited (BI) temperament. Stable BI predicts the development of later anxiety disorders (particularly social anxiety), but not all inhibited children develop anxiety. Parenting characterized by inappropriate warmth/sensitivity and/or intrusive control predicts the stability of BI and moderates risk for anxiety among high-BI children. For these reasons, we developed and examined the preliminary efficacy of the Turtle Program: a multimodal early intervention for inhibited preschool-age children. METHOD: Forty inhibited children between the ages of 42-60 months and their parent(s) were randomized to either the Turtle Program (n = 18) or a waitlist control (WLC; n = 22) condition. Participants randomized to the Turtle Program condition received 8 weeks of concurrent parent and child group treatment. Participants were assessed at baseline and posttreatment with multisource assessments, including parent and teacher report measures of child anxiety, diagnostic interviews, and observations of parenting behavior. RESULTS: The Turtle Program resulted in significant beneficial effects relative to the WLC condition on maternal-reported anxiety symptoms of medium to large magnitude; large effects on parent-reported BI; medium to large effects on teacher-rated school anxiety symptoms; and medium effects on observed maternal positive affect/sensitivity. CONCLUSIONS: This study provides encouraging preliminary support for the Turtle Program for young behaviorally inhibited children. Effects of the Turtle Program generalized to the school setting. Future studies should examine whether this early intervention program improves long-term developmental outcomes for this at-risk group.

Maternal Depression History Moderates Parenting Responses to Compliant and Noncompliant Behaviors of Children with ADHD.

Maternal depression and parenting are robust predictors of developmental outcomes for children with attention-deficit/hyperactivity disorder (ADHD). However, methods commonly used to examine parent-child interactions in these families do not account for temporal associations between child and parent behavior that have been theorized to maintain negative child behavior. Moreover, studies examining associations between maternal depression and parenting in families of children with ADHD have not compared mothers who were currently depressed, remitted, and never clinically depressed. This study utilized sequential analysis to examine how maternal reinforcement of compliant and noncompliant child behavior differs as a function of maternal depression history. Within the 82 participating mother-child dyads, 21 mothers were currently depressed, 29 mothers had a lifetime history of depression but were in remission for at least 1 month, and 32 mothers had never been clinically depressed. 24 girls (29.6 %) and 57 boys (70.4 %) between the ages of 6-12 years old (M = 8.7, SD = 2.0) and were diagnosed with ADHD. Results indicated that all mothers were less likely to respond optimally than non-optimally to child compliant and noncompliant behaviors during observed parent-child interactions; however, currently depressed mothers were least likely to reinforce child compliance and responded most coercively to child noncompliance relative to the other groups. Remitted mothers in this sample were more coercive than never clinically depressed mothers, but were more likely to follow through with commands than never clinically depressed mothers. Implications for behavioral parent training programs aimed at skill development for depressed mothers of children with ADHD are discussed.

Exploiting pre-rRNA processing in Diamond Blackfan anemia gene discovery and diagnosis.

Diamond Blackfan anemia (DBA), a syndrome primarily characterized by anemia and physical abnormalities, is one among a group of related inherited bone marrow failure syndromes (IBMFS) which share overlapping clinical features. Heterozygous mutations or single-copy deletions have been identified in 12 ribosomal protein genes in approximately 60% of DBA cases, with the genetic etiology unexplained in most remaining patients. Unlike many IBMFS, for which functional screening assays complement clinical and genetic findings, suspected DBA in the absence of typical alterations of the known genes must frequently be diagnosed after exclusion of other IBMFS. We report here a novel deletion in a child that presented such a diagnostic challenge and prompted development of a novel functional assay that can assist in the diagnosis of a significant fraction of patients with DBA. The ribosomal proteins affected in DBA are required for pre-rRNA processing, a process which can be interrogated to monitor steps in the maturation of 40S and 60S ribosomal subunits. In contrast to prior methods used to assess pre-rRNA processing, the assay reported here, based on capillary electrophoresis measurement of the maturation of rRNA in pre-60S ribosomal subunits, would be readily amenable to use in diagnostic laboratories. In addition to utility as a diagnostic tool, we applied this technique to gene discovery in DBA, resulting in the identification of RPL31 as a novel DBA gene.

A directional switch of integrin signalling and a new anti-thrombotic strategy.

Integrins have a critical role in thrombosis and haemostasis. Antagonists of the platelet integrin αIIbß3 are potent anti-thrombotic drugs, but also have the life-threatening adverse effect of causing bleeding. It is therefore desirable to develop new antagonists that do not cause bleeding. Integrins transmit signals bidirectionally. Inside-out signalling activates integrins through a talin-dependent mechanism. Integrin ligation mediates thrombus formation and outside-in signalling, which requires Gα13 and greatly expands thrombi. Here we show that Gα13 and talin bind to mutually exclusive but distinct sites within the integrin ß3 cytoplasmic domain in opposing waves. The first talin-binding wave mediates inside-out signalling and also ligand-induced integrin activation, but is not required for outside-in signalling. Integrin ligation induces transient talin dissociation and Gα13 binding to an EXE motif (in which X denotes any residue), which selectively mediates outside-in signalling and platelet spreading. The second talin-binding wave is associated with clot retraction. An EXE-motif-based inhibitor of Gα13-integrin interaction selectively abolishes outside-in signalling without affecting integrin ligation, and suppresses occlusive arterial thrombosis without affecting bleeding time. Thus, we have discovered a new mechanism for the directional switch of integrin signalling and, on the basis of this mechanism, designed a potent new anti-thrombotic drug that does not cause bleeding.

LIM kinase-1 selectively promotes glycoprotein Ib-IX-mediated TXA2 synthesis, platelet activation, and thrombosis.

Current antithrombotic drugs have an adverse effect on bleeding, highlighting the need for new molecular targets for developing antithrombotic drugs that minimally affect hemostasis. Here we show that LIMK1(-/-) mice have defective arterial thrombosis in vivo but do not differ from wild-type mice with respect to bleeding time. LIMK1(-/-) mice show a selective defect in platelet activation induced through the von Willebrand Factor (VWF) receptor, the glycoprotein Ib-IX-V complex (GPIb-IX), but not by GPIb-IX-independent platelet agonists. In fact, LIMK1(-/-) platelets show an enhanced reaction to certain GPIb-IX-independent agonists. The defect of LIMK1(-/-) platelets in GPIb-IX-mediated platelet activation is attributed to a selective inhibition in VWF/GPIb-IX-induced phosphorylation of cytosolic phospholipase A2 (cPLA2) and consequent thromboxane A2 (TXA2) production. Supplementing a TXA2 analog, U46619, corrected the defect of LIMK1(-/-) platelets in VWF-induced stable platelet adhesion. Although LIMK1(-/-) platelets also showed reduced actin polymerization after GPIb-IX-mediated platelet aggregation, actin polymerization inhibitors did not reduce TXA2 generation, but rather accelerated platelet aggregation, suggesting that the role of LIMK1 in GPIb-mediated platelet activation is independent of actin polymerization. Thus, LIMK1 plays a novel role in selectively mediating GPIb-IX-dependent TXA2 synthesis and thrombosis and represents a potential target for developing antithrombotic drugs with minimal bleeding side effect.

Development and preliminary evaluation of an integrated treatment targeting parenting and depressive symptoms in mothers of children with attention-deficit/hyperactivity disorder.

OBJECTIVE: More than 50% of mothers of children with attention-deficit/hyperactivity disorder (ADHD) have a lifetime history of major depressive disorder (MDD). Maternal depressive symptoms are associated with impaired parenting and predict adverse developmental and treatment outcomes for children with ADHD. For these reasons, we developed and examined the preliminary efficacy of an integrated treatment targeting parenting and depressive symptoms for mothers of children with ADHD. This integrated intervention incorporated elements of 2 evidence-based treatments: behavioral parent training (BPT) and cognitive behavioral depression treatment. METHOD: Ninety-eight mothers with at least mild depressive symptoms were randomized to receive either standard BPT (n = 51) or the integrated parenting intervention for ADHD (IPI-A; n = 47). Participants were assessed at baseline, posttreatment, and 3- to 6-month follow-up on measures of (a) self-reported maternal depressive symptoms, (b) observed positive and negative parenting, and (c) observed and mother-reported child disruptive behavior and mother-reported child and family impairment. RESULTS: The IPI-A produced effects of small to moderate magnitude relative to BPT on maternal depressive symptoms, observed negative parenting, observed child deviance, and child impairment at posttreatment and on maternal depressive symptoms, child disruptive behavior, child impairment and family functioning at follow-up. Contrary to expectations, the BPT group demonstrated moderate to large effects relative to IPI-A on observed positive parenting at follow-up. CONCLUSIONS: This treatment development study provides encouraging preliminary support for the integrated intervention targeting parenting and depressive symptoms in mothers of children with ADHD. Future studies should examine whether this integrated intervention improves long-term developmental outcomes for children with ADHD. (PsycINFO Database Record (c) 2013 APA, all rights reserved).

ADP-stimulated activation of Akt during integrin outside-in signaling promotes platelet spreading by inhibiting glycogen synthase kinase-3ß.

OBJECTIVE: Integrins mediate platelet adhesion and transmit outside-in signals leading to platelet spreading. Phosphoinositide 3-kinases (PI3Ks) play a critical role in outside-in signaling and platelet spreading; however, the mechanisms of PI3K activation and function in outside-in signaling are unclear. We sought to determine the role of the Akt family of serine/threonine kinases and activation mechanisms of the PI3K/Akt pathway in outside-in signaling. METHODS AND RESULTS: Akt inhibitors and Akt3 knockout inhibited platelet spreading on fibrinogen, indicating that Akt is important in integrin outside-in signaling. Akt inhibitors and Akt3 knockout also diminished integrin-dependent phosphorylation of glycogen synthase kinase-3ß. Inhibition of glycogen synthase kinase-3ß reversed the inhibitory effects of Akt3 knockout and inhibitors of Akt or PI3K on platelet spreading, indicating that glycogen synthase kinase-3ß is a downstream target of Akt in outside-in signaling. Integrin-dependent activation of the PI3K-Akt pathway requires Src family kinase. Akt phosphorylation is also significantly inhibited in ADP receptor P2Y12 knockout platelets and further inhibited in P2Y12 knockout platelets treated with a P2Y1 antagonist. Consistently, P2Y12 knockout and P2Y1 inhibition together reduced platelet spreading. CONCLUSIONS: These results demonstrate that integrin outside-in signaling and platelet spreading requires Src family kinase-dependent and ADP receptor-amplified activation of the PI3K-Akt-GSK-3ß pathway.

An important role for Akt3 in platelet activation and thrombosis.

The Akt family of serine/threonine kinases includes Akt1, Akt2, and Akt3 isoforms. Prior studies have reported that Akt1 and Akt2, but not Akt3, are expressed in platelets. Here, we show that Akt3 is expressed in substantial amounts in platelets. Akt3(-/-) mouse platelets selectively exhibit impaired platelet aggregation and secretion in response to low concentrations of thrombin receptor agonists and thromboxane A2 (TXA2), but not collagen or VWF. In contrast, platelets from Akt1(-/-) or Akt2(-/-) mice are defective in platelet activation induced by thrombin, TXA2, and VWF, but only Akt1(-/-) platelets show significant defects in response to collagen, indicating differences among Akt isoforms. Akt3(-/-) platelets exhibit a significant reduction in thrombin-induced phosphorylation of glycogen synthase kinase 3ß (GSK-3ß) at Ser9, which is known to inhibit GSK-3ß function. Thus, Akt3 is important in inhibiting GSK-3ß. Accordingly, treatment of Akt3(-/-) platelets with a GSK-3ß inhibitor rescued the defect of Akt3(-/-) platelets in thrombin-induced aggregation, suggesting that negatively regulating GSK-3ß may be a mechanism by which Akt3 promotes platelet activation. Importantly, Akt3(-/-) mice showed retardation in FeCl3-induced carotid artery thrombosis in vivo. Thus, Akt3 plays an important and distinct role in platelet activation and in thrombosis.

The relation between maternal ADHD symptoms & improvement in child behavior following brief behavioral parent training is mediated by change in negative parenting.

This study examined the extent to which maternal attention-deficit/hyperactivity disorder (ADHD) symptoms predict improvement in child behavior following brief behavioral parent training. Change in parenting was examined as a potential mediator of the negative relationship between maternal ADHD symptoms and improvement in child behavior. Seventy mothers of 6-10 year old children with ADHD underwent a comprehensive assessment of adult ADHD prior to participating in an abbreviated parent training program. Before and after treatment, parenting was assessed via maternal reports and observations and child disruptive behavior was measured via maternal report. Controlling for pre-treatment levels, maternal ADHD symptomatology predicted post-treatment child disruptive behavior problems. The relation between maternal ADHD symptomatology and improvement in child behavior was mediated by change in observed maternal negative parenting. This study replicated findings linking maternal ADHD symptoms with attenuated child improvement following parent training, and is the first to demonstrate that negative parenting at least partially explains this relationship. Innovative approaches combining evidence-based treatment for adult ADHD with parent training may therefore be necessary for families in which both the mother and child have ADHD. Larger-scale studies using a full evidence-based parent training program are needed to replicate these findings.

Signaling during platelet adhesion and activation.

Upon vascular injury, platelets are activated by adhesion to adhesive proteins, such as von Willebrand factor and collagen, or by soluble platelet agonists, such as ADP, thrombin, and thromboxane A(2). These adhesive proteins and soluble agonists induce signal transduction via their respective receptors. The various receptor-specific platelet activation signaling pathways converge into common signaling events that stimulate platelet shape change and granule secretion and ultimately induce the "inside-out" signaling process leading to activation of the ligand-binding function of integrin α(IIb)ß(3). Ligand binding to integrin α(IIb)ß(3) mediates platelet adhesion and aggregation and triggers "outside-in" signaling, resulting in platelet spreading, additional granule secretion, stabilization of platelet adhesion and aggregation, and clot retraction. It has become increasingly evident that agonist-induced platelet activation signals also cross talk with integrin outside-in signals to regulate platelet responses. Platelet activation involves a series of rapid positive feedback loops that greatly amplify initial activation signals and enable robust platelet recruitment and thrombus stabilization. Recent studies have provided novel insight into the molecular mechanisms of these processes.

Early identification and intervention for behavior problems in primary care: a comparison of two abbreviated versions of parent-child interaction therapy.

Behavioral screening and preventive intervention were implemented for 3- to 6-year-olds in pediatric primary care with subclinical behavior problems. One hundred eleven children were screened with the Eyberg Child Behavior Inventory. Thirty children who scored within one standard deviation of the normative mean whose mothers indicated wanting help for their child's behavior were randomized to one of two abbreviated versions of Parent-Child Interaction Therapy (PCIT) for use in pediatric primary care: (a) a 4-session group preventive intervention called Primary Care PCIT (PC-PCIT); or (b) written materials describing basic steps of PCIT and guidelines for practice, called PCIT Anticipatory Guidance (PCIT-AG). Decreases in child problem behaviors and ineffective parenting strategies, and increases in parental feelings of control were not significantly different between versions at post-intervention or 6-month follow-up. Changes during intervention were significantly larger for both groups than changes during pretreatment baseline, with moderate to large effect sizes. These brief versions of PCIT are both promising primary care preventive interventions that deserve further study.

Mental health services for preschool children in primary care: a survey of maternal attitudes and beliefs.

OBJECTIVE: This study examined maternal attitudes and practices that may prevent preschoolers from receiving needed mental health services. METHODS: Mothers of 110 children ages 3-6 completed a survey of maternal attitudes and practices and the Eyberg Child Behavior Inventory (ECBI). RESULTS: Mothers wanted pediatrician assistance with child behavior concerns. Mothers of children with elevated ECBI scores reported most often discussing disruptive behaviors with their pediatrician, and preferred clinician-provided services, whereas mothers of children with normal range ECBI scores most often discussed developmental issues with the pediatrician and preferred parenting help from handouts and books. Mothers reported receiving clinician-provided services almost never. CONCLUSIONS: Mothers were open to psychosocial services for child behavior problems, particularly via primary care, and ratings of barriers were relatively low despite reporting infrequent service use. Mothers' responses highlight the need for mental health providers in primary care to ensure accessibility of desired services.