Offspring of parents with chronic pain are at increased risk for pain and adverse mental and physical health outcomes (Higgins et al, 2015). Although the association between chronic pain in parents and offspring has been established, few studies have addressed why or how this relation occurs. Identifying mechanisms for the transmission of risk that leads to the development of chronic pain in offspring is important for developing preventive interventions targeted to decrease risk for chronic pain and related outcomes (eg, disability and internalizing symptoms). This review presents a conceptual model for the intergenerational transmission of chronic pain from parents to offspring with the goal of setting an agenda for future research and the development of preventive interventions. Our proposed model highlights 5 potential mechanisms for the relation between parental chronic pain and pediatric chronic pain and related adverse outcomes: (1) genetics, (2) alterations in early neurobiological development, (3) pain-specific social learning, (4), general parenting and family health, and (5) exposure to stressful environment. In addition, the model presents 3 potential moderators for the relation between parent and child chronic pain: (1) the presence of chronic pain in a second parent, (2) timing, course, and location of parental chronic pain, and (3) offspring’s characteristics (ie, sex, developmental stage, race or ethnicity, and temperament). Such a framework highlights chronic pain as inherently familial and intergenerational, opening up avenues for new models of intervention and prevention that can be family centered and include at-risk children.
WTX encodes a tumor suppressor gene inactivated in Wilms tumor and recently implicated in WNT signaling through enhancement of cytoplasmic ␤-catenin (CTNNB1) degradation. Here, we report that WTX translocates to the nucleus, a property that is modified by an endogenous splicing variant and is modulated by a nuclear export inhibitor. WTX is present in distinct subnuclear structures and co-localizes with the paraspeckle marker p54NRB/NONO, suggesting a role in transcriptional regulation. Notably, WTX binds WT1, another Wilms tumor suppressor and stem cell marker that encodes a zinc-finger transcription factor, and enhances WT1-mediated transcription of Amphiregulin, an endogenous target gene. Together, these observations suggest a role for WTX in nuclear pathways implicated in the transcriptional regulation of cellular differentiation programs.cancer biology ͉ subcellular localization ͉ tumor suppression W ilms tumor, the most common pediatric kidney cancer, is a pluripotent tumor that arises from a kidney-specific stem cell population (1). Genetic studies of Wilms tumor have consistently implicated genes that are critical mediators of differentiation, underscoring the link between normal kidney development and tumorigenesis. Loss of function mutations in WT1, a transcription factor with multiple roles in the developing kidney, are present in 5%-10% of cases (2-4), often in association with activating mutations in ␤-catenin (CTNNB1) (5, 6), a key regulator of WNT signaling. Loss of imprinting leading to increased expression of insulin-like growth factor 2 (IGF2) has also been implicated in approximately one-third of cases (7,8). In addition to these well-defined abnormalities, several other loci have been implicated by loss of heterozygosity studies, suggesting significant genetic heterogeneity in this disease (9).We have recently identified an X chromosome gene, WTX, which is targeted by deletions and truncations in up to 30% of Wilms tumors (10). All WTX mutations were somatic, targeting the single X chromosome in males or the active X chromosome in females and thus leading to complete inactivation in both sexes. WTX belongs to a gene family comprised of 3 genes with no significant homology to known functional domains. Biochemical studies of WTX have identified regions that mediate binding to APC and ␤-catenin and an N-terminal domain that mediates localization to the plasma membrane (11,12). Functional studies performed with a WTX ORF (ORF) predicted by automated database annotation (WTX-PRED, 804 aa from a transcript composed of 3 exons) indicated that WTX encodes a component of the ␤-catenin destruction complex that inhibits WNT signaling by increasing the degradation of ␤-catenin in the cytoplasm (12). However, our characterization of the endogenous 7.5-kb WTX mRNA transcript in diverse tissues does not confirm expression of the WTX-PRED third exon, revealing instead a larger 1135-aa ORF (WTX-WT) encoded by a longer second exon with an additional 350 aa in the C terminus compared to WTX-PRED (Fig. 1B) (10).H...
Having a parent with chronic pain (CP) may confer greater risk of persistence of CP from childhood into young adulthood. Social learning, such as parental modeling and reinforcement, represents one plausible mechanism for the transmission of risk of CP from parents to offspring. Based on a 7-day pain diary in 154 pediatric patients with functional abdominal CP, we tested a model in which parental CP predicted adolescents' daily average CP severity and functional impairment (distal outcomes) via parental modeling of pain behaviors and parental reinforcement of adolescent's pain behaviors (mediators) and adolescents' cognitive appraisals of pain threat (proximal outcome representing adolescents' encoding of parents' behaviors). Results indicated significant indirect pathways from parental CP status to adolescent average daily pain severity (b = 0.18, SE = 0.08, 95% confidence interval: 0.04-0.31, P = 0.03) and functional impairment (b = 0.08, SE = 0.04, 95% confidence interval: 0.02-0.15, P = 0.03) over the 7-day diary period via adolescents' observations of parent pain behaviors and adolescent pain threat appraisal. The indirect pathway through parental reinforcing responses to adolescents' pain did not reach significance for either adolescent pain severity or functional impairment. Identifying mechanisms of increased risk of pain and functional impairment in children of parents with CP ultimately could lead to targeted interventions aimed at improving functioning and quality of life in families with CP. Parental modeling of pain behaviors represents a potentially promising target for family-based interventions to ameliorate pediatric CP.
Cancer is a leading cause of death worldwide and an estimated 1 in 4 deaths in the United States is due to cancer. Despite recent advances in cancer treatment, adverse effects related to cancer therapy remain a limiting factor for many patients. The ideal cancer treatment would selectively target cancerous cells while sparing normal, healthy cells to offer maximal therapeutic benefit while minimizing toxicity. Telomeres are structurally unique DNA sequences at the end of human chromosomes, which play an integral role in the cellular mortality of normal cells. As telomeres shorten with successive cellular divisions, cells develop chromosomal instability and undergo either apoptosis or senescence. In many cancers, this apoptosis or senescence is avoided as normal telomere length is maintained by a ribonucleoprotein reverse transcriptase called telomerase. Telomerase is expressed in more than 85% of all cancers and confers cancerous cells with a replicative immortality, which is a hallmark of malignant tumors. In contrast, telomerase activity is not detectable in the majority of normal somatic cell populations. Therefore, the targeting of telomerase and telomere maintenance mechanisms represent a potentially promising therapeutic approach for various types of cancer. This review evaluates the roles of GRN163L, T-oligo and small molecule G-quadruplex stabilizers as potential anticancer therapies by targeting telomerase and other telomere maintenance mechanisms.
Aerobic exercise is believed to be an effective chronic low back pain (CLBP) intervention, although its mechanisms remain largely untested. This study evaluated whether endogenous opioid (EO) mechanisms contributed to the analgesic effects of an aerobic exercise intervention for CLBP. Individuals with CLBP were randomized to a 6-week, 18-session aerobic exercise intervention (n = 38) or usual activity control (n = 44). Before and after the intervention, participants underwent separate laboratory sessions to assess responses to evoked heat pain after receiving saline placebo or intravenous naloxone (opioid antagonist) in a double-blinded, crossover fashion. Chronic pain intensity and interference were assessed before and after the intervention. Endogenous opioid analgesia was indexed by naloxone–placebo condition differences in evoked pain responses (blockade effects). Relative to controls, exercise participants reported significantly greater pre–post intervention decreases in chronic pain intensity and interference (Ps < 0.04) and larger reductions in placebo condition evoked pain responsiveness (McGill Pain Questionnaire—Short Form [MPQ]-Total). At the group level, EO analgesia (MPQ-Total blockade effects) increased significantly pre–post intervention only among female exercisers (P = 0.03). Dose–response effects were suggested by a significant positive association in the exercise group between exercise intensity (based on meeting heart rate targets) and EO increases (MPQ-Present Pain Intensity; P = 0.04). Enhanced EO analgesia (MPQ-Total) was associated with a significantly greater improvement in average chronic pain intensity (P = 0.009). Aerobic exercise training in the absence of other interventions appears effective for CLBP management. Aerobic exercise–related enhancements in endogenous pain inhibition, in part EO-related, likely contribute to these benefits.
Background & Aims Nausea is common among children with functional abdominal pain (FAP). We evaluated the relation of nausea to short- and long-term morbidity in pediatric patients with FAP. Methods We performed a prospective study of 871 children with FAP (8–17 years old) seen in a pediatric gastroenterology practice; follow-up data were collected from 396 of the patients 8.7±3.3 years later. Participants were defined as having significant nausea if they reported nausea “a lot” or “a whole lot” within the past 2 weeks. Validated questionnaires assessed abdominal pain, gastrointestinal and somatic symptoms, and depression. Baseline measures, anxiety, and the Rome III criteria were assessed in the follow-up evaluation. Results At baseline, 44.8% of the patients reported significant nausea. Those with nausea reported worse abdominal pain, gastrointestinal symptoms, somatic symptoms, and depression than those without nausea (P< .001 for all). When the children had reached young adulthood, those with nausea in childhood continued to have more severe gastrointestinal (P< .001) and somatic symptoms (P= .003) than patients without nausea in childhood, as well as higher levels of anxiety (P = .02) and depression (P = .02). In the follow-up evaluation, somatic symptoms, depression, and anxiety remained significant after controlling for baseline abdominal pain severity. Conclusions Pediatric patients with FAP and nausea have more severe short- and long-term gastrointestinal and somatic symptoms than patients with FAP without nausea, as well as reductions mental health and daily function. Pediatric patients with FAP and nausea therefore need intensive treatment and follow up.
Numerous tyrosine kinase inhibitors (TKIs) targeting c-Met are currently in clinical trials for several cancers. Their efficacy is limited due to the development of resistance. The present study aims to elucidate this mechanism of c-Met TKI resistance by investigating key mTOR and Wnt signaling proteins in melanoma cell lines resistant to SU11274, a c-Met TKI. Xenografts from RU melanoma cells treated with c-Met TKIs SU11274 and JNJ38877605 showed a 7- and 6-fold reduction in tumor size, respectively. Resistant cells displayed upregulation of phosphorylated c-Met, mTOR, p70S6Kinase, 4E-BP1, ERK, LRP6, and active β-catenin. In addition, GATA-6, a Wnt signaling regulator, was upregulated, and Axin, a negative regulator of the Wnt pathway, was downregulated in resistant cells. Modulation of these mTOR and Wnt pathway proteins was also prevented by combination treatment with SU11274, everolimus, an mTOR inhibitor, and XAV939, a Wnt inhibitor. Treatment with everolimus, resulted in 56% growth inhibition, and a triple combination of SU11274, everolimus and XAV939, resulted in 95% growth inhibition in RU cells. The V600E BRAF mutation was found to be positive only in MU cells. Combination treatment with a c-Met TKI and a BRAF inhibitor displayed a synergistic effect in reducing MU cell viability. These studies indicate activation of mTOR and Wnt signaling pathways in c-Met TKI resistant melanoma cells and suggest that concurrent targeting of c-Met, mTOR, and Wnt pathways and BRAF may improve efficacy over traditional TKI monotherapy in melanoma patients.
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