Improved Sleep Quality Is Associated with Reduced Insulin Resistance in Cancer Survivors Undertaking Circuit, Interval-Based Exercise.

PURPOSE: Cancer patients often experience poor sleep quality, typically induced by cancer-related treatments, a sedentary lifestyle, and psychological distress, leading to an increased risk of metabolic dysregulation such as obesity and insulin resistance. In this novel 16-week pilot study, we examined the effect of a circuit-based aerobic and resistance exercise intervention on self-reported sleep quality in breast, prostate, and colorectal cancer survivors and explored the association between changes in sleep quality and insulin resistance. METHODS: Survivors of breast, prostate or colorectal cancers who were sedentary, overweight or obese (BMI>25.0 kg/m2) were randomized to exercise (n=60) or usual care (n=30). The 16-week intervention included supervised moderate-vigorous aerobic (65-85% of VO2max) and resistance (65-85% of 1-repetition maximum) exercise performed in a circuit, interval fashion three times per week. Patient-reported sleep quality and insulin resistance were assessed at baseline and post-intervention using Pittsburgh Sleep Quality Index (PSQI) and Homeostasis Model of Assessment (HOMA-IR), respectively. Mean changes in PSQI score that are negative demonstrate improvements in sleep. Between-group differences were determined using repeated-measures analysis of variance. Associations between changes in PSQI and insulin resistance were computed using Pearson correlations. RESULTS: Participants were 63.2±10.8 years old, obese (87%), female (55%), and completed chemotherapy + radiation therapy (75%). Adherence to the intervention was 92% and the retention rate was 100%. Post-intervention, the PSQI global score improved significantly in the exercise group when compared to usual care (mean between-group difference, -2.7; 95% CI, -4.2 to -0.6). Change in PSQI was inversely associated with change in HOMA-IR (r=-0.91; p<0.01) among the exercise group. CONCLUSIONS: A circuit, interval-based aerobic and resistance exercise intervention improved patient-reported sleep quality in breast, prostate, and colorectal cancer survivors. Additionally, this exercise-induced improvement in sleep-quality may result in reduced insulin resistance.

Agonistic 4-1BB antibody fails to reduce disease burden during acute respiratory syncytial virus (RSV) infection.

Respiratory Syncytial Virus (RSV) remains a leading cause of infant morbidity and mortality worldwide. Despite this, there are limited therapeutic options. CD8 T cells have an integral role in controlling viral infections; strategies to enhance these responses may be clinically relevant. The T cell costimulatory receptor, 4-1BB, is known to play a role in expansion of antiviral CD8 T cells. In this study, we examined the effect of agonistic 4-1BB antibody at the time of RSV infection in mice. We show that this antibody did not improve outcomes in the setting of RSV infection but rather, led to increased weight loss and a reduction in RSV specific CD8 T cells in the lung. This work suggests caution in the use of agonistic 4-1BB antibody in the setting of viral infections.

Effects of resistance training frequency on physical functioning and quality of life in prostate cancer survivors: a pilot randomized controlled trial.

BACKGROUND: Resistance training (RT) improves muscular strength, physical functioning and quality of life in prostate cancer survivors, but the optimal frequency of RT is unknown. We conducted a pilot randomized controlled trial to compare the effects of 3 versus 2 days per week of RT in prostate cancer survivors diagnosed within the past 2 years. METHODS: Prostate cancer survivors (N=30) were randomized to 12 weeks of supervised RT performed either 3 days per week (n=16) or 2 days per week (n=14). The primary outcome was muscular strength assessed by a multiple repetition maximum test at baseline and postintervention. Secondary outcomes were objective physical functioning, quality of life and psychosocial functioning. RESULTS: A trend (P<0.10) and/or potentially meaningful effects (standardized effect size d⩾0.20) were found favoring 3 days per week over 2 days per week for the primary outcome of lower body strength (mean difference=27.8 kg; 95% confidence interval=-0.9 to 56.5; P=0.057; d=0.72) and for the secondary outcomes of 30-s chair stand (d=0.29; P=0.31), sit and reach (d=0.24; P=0.33), 6 -min walk (d=0.21; P=0.42) and the physical component summary (d=0.21; P=0.41). Conversely, a trend and/or potentially meaningful effects were found favoring 2 days per week over 3 days per week for the mental component summary (d=-0.38; P=0.10), mental health (d=-0.44; P=0.11), vitality (d=-0.31; P=0.28), role-emotional (d=-0.23; P=0.43), anxiety (d=0.32; P=0.29), happiness (d=-0.31; P=0.36) and perceived stress (d=0.23; P=0.39). CONCLUSIONS: This pilot randomized dose-comparison trial provides preliminary data to suggest that RT 3 days per week compared with 2 days per week may improve the strength and physical functioning in prostate cancer survivors, but may also blunt improvements in psychosocial functioning. Larger and more targeted phase II and III trials are needed to confirm the potentially complex effects of RT frequency in prostate cancer survivors.

Low incidence of complications in computer assisted total knee arthroplasty--A retrospective review of 1596 cases.

BACKGROUND: Computer assisted total knee arthroplasty (CATKA) has its own unique complications. The aim of this study was to present our experience of early complications in a large consecutive series of CATKA. METHOD: We investigated retrospective data on the complications specific to computer navigation that were encountered with a consecutive series of 1596 CATKA. RESULTS: Intraoperatively, eight episodes of software failure occurred, two requiring conversion to conventional jig based TKA. There were four broken drill bits when positioning the pins for data entry. Repeat cuts of bone due to malalignment were required on two occasions. There were 17 episodes of superficial pin site infections at the tibial pin-site managed conservatively with antibiotics. One tibial fracture occurred through an old tibial tracker pin site hole. CONCLUSION: This large study shows a low complication rate related to CATKA which is reassuring to the orthopaedic community. CLINICAL RELEVANCE: Level of evidence: III.

An unexpected role for caspase-2 in neuroblastoma.

Caspase-2 has been implicated in various cellular functions, including cell death by apoptosis, oxidative stress response, maintenance of genomic stability and tumor suppression. The loss of the caspase-2 gene (Casp2) enhances oncogene-mediated tumorigenesis induced by E1A/Ras in athymic nude mice, and also in the Eµ-Myc lymphoma and MMTV/c-neu mammary tumor mouse models. To further investigate the function of caspase-2 in oncogene-mediated tumorigenesis, we extended our studies in the TH-MYCN transgenic mouse model of neuroblastoma. Surprisingly, we found that loss of caspase-2 delayed tumorigenesis in the TH-MYCN neuroblastoma model. In addition, tumors from TH-MYCN/Casp2(-/-) mice were predominantly thoracic paraspinal tumors and were less vascularized compared with tumors from their TH-MYCN/Casp2(+/+) counterparts. We did not detect any differences in the expression of neuroblastoma-associated genes in TH-MYCN/Casp2(-/-) tumors, or in the activation of Ras/MAPK signaling pathway that is involved in neuroblastoma progression. Analysis of expression array data from human neuroblastoma samples showed a correlation between low caspase-2 levels and increased survival. However, caspase-2 levels correlated with clinical outcome only in the subset of MYCN-non-amplified human neuroblastoma. These observations indicate that caspase-2 is not a suppressor in MYCN-induced neuroblastoma and suggest a tissue and context-specific role for caspase-2 in tumorigenesis.

Five-year follow-up of minimally invasive computer assisted total knee arthroplasty (MICATKA) versus conventional computer assisted total knee arthroplasty (CATKA) - A population matched study.

BACKGROUND: Minimally invasive surgery (MIS) has perceived advantages in the early post-operative stage such as reduced blood loss, decreased pain, earlier return to function and earlier discharge. The aim of our study was to confirm that longer term clinical outcome of TKA is not compromised when MIS is combined with computer assisted surgery. METHODS: Eighty patients matched for age, gender, pre-operative Knee Society Score (KSS) and mechanical axis were prospectively studied. Forty patients underwent minimally invasive computer assisted total knee arthroplasty (MICATKA) and 40 patients underwent conventional computer assisted TKA (CATKA). Functional scores were determined at 6 weeks, 6, 12, 18, and 24 months and 5 years post-surgery. Long-leg alignment views were obtained 3 months post-operatively. RESULTS: KSSs in the short term were significantly better in the MICATKA group than in the CATKA group (p<000.1). Tourniquet-time was 58 min in the MICTKA group and 60 min in the CATKA group (p=0.3). Straight leg raise was achieved by day one in 93% of the MICATKA group compared to 30% of the CATKA group (p<0.001). Length of stay for the MICATKA group has a mean of 3.25 days and a mean of 6 days for the CATKA group (p<0.001). KSSs up to 2-years were significantly better in the MICTKA group (p<0.001). At 5-years there was no significant difference in KSSs (p=0.46) in the MICATKA and CATKA groups. CONCLUSION: We confirm that the use of navigation in minimally invasive TKA permits a number of early post-operative advantages and that longer-term functional outcome is not compromised with its usage. LEVEL OF EVIDENCE: Level II.

Treatment of heavy metals by iron oxide coated and natural gravel media in Sustainable urban Drainage Systems.

Sustainable urban Drainage Systems (SuDS) filter drains are simple, low-cost systems utilized as a first defence to treat road runoff by employing biogeochemical processes to reduce pollutants. However, the mechanisms involved in pollution attenuation are poorly understood. This work aims to develop a better understanding of these mechanisms to facilitate improved SuDS design. Since heavy metals are a large fraction of pollution in road runoff, this study aimed to enhance heavy metal removal of filter drain gravel with an iron oxide mineral amendment to increase surface area for heavy metal scavenging. Experiments showed that amendment-coated and uncoated (control) gravel removed similar quantities of heavy metals. Moreover, when normalized to surface area, iron oxide coated gravels (IOCGs) showed poorer metal removal capacities than uncoated gravel. Inspection of the uncoated microgabbro gravel indicated that clay particulates on the surface (a natural product of weathering of this material) augmented heavy metal removal, generating metal sequestration capacities that were competitive compared with IOCGs. Furthermore, when the weathered surface was scrubbed and removed, metal removal capacities were reduced by 20%. When compared with other lithologies, adsorption of heavy metals by microgabbro was 10-70% higher, indicating that both the lithology of the gravel, and the presence of a weathered surface, considerably influence its ability to immobilize heavy metals. These results contradict previous assumptions which suggest that gravel lithology is not a significant factor in SuDS design. Based upon these results, weathered microgabbro is suggested to be an ideal lithology for use in SuDS.

ß-blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms in neuroblastoma.

BACKGROUND: The use of ß-blockers for the management of hypertension has been recently associated with significant clinical benefits in cancer patients. Herein, we investigated whether ß-blockers could be used in combination with chemotherapy for the treatment of neuroblastoma. METHODS: Seven ß-blockers were tested for their antiproliferative and anti-angiogenic properties alone, and in combination with chemotherapy in vitro; the most potent drug combinations were evaluated in vivo in the TH-MYCN mouse model of neuroblastoma. RESULTS: Three ß-blockers (i.e., carvedilol, nebivolol and propranolol) exhibited potent anticancer properties in vitro and interacted synergistically with vincristine, independently of P-glycoprotein expression. ß-blockers potentiated the anti-angiogenic, antimitochondrial, antimitotic and ultimately pro-apoptotic effects of vincristine. In vivo, ß-blockers alone transiently slowed tumour growth as compared with vehicle only (P<0.01). More importantly, when used in combination, ß-blockers significantly increased the tumour regression induced by vincristine (P<0.05). This effect was associated with an increase in tumour angiogenesis inhibition (P<0.001) and ultimately resulted in a four-fold increase in median survival, as compared with vincristine alone (P<0.01). CONCLUSION: ß-blockers can increase treatment efficacy against neuroblastoma, and their combination with chemotherapy may prove beneficial for the treatment of this disease and other drug-refractory cancers.

High-risk childhood acute lymphoblastic leukemia in first remission treated with novel intensive chemotherapy and allogeneic transplantation.

Children with acute lymphoblastic leukemia (ALL) and high minimal residual disease (MRD) levels after initial chemotherapy have a poor clinical outcome. In this prospective, single arm, Phase 2 trial, 111 Dutch and Australian children aged 1-18 years with newly diagnosed, t(9;22)-negative ALL, were identified among 1041 consecutively enrolled patients as high risk (HR) based on clinical features or high MRD. The HR cohort received the AIEOP-BFM (Associazione Italiana di Ematologia ed Oncologia Pediatrica (Italy)-Berlin-Frankfurt-Münster ALL Study Group) 2000 ALL Protocol I, then three novel HR chemotherapy blocks, followed by allogeneic transplant or chemotherapy. Of the 111 HR patients, 91 began HR treatment blocks, while 79 completed the protocol. There were 3 remission failures, 12 relapses, 7 toxic deaths in remission and 10 patients who changed protocol due to toxicity or clinician/parent preference. For the 111 HR patients, 5-year event-free survival (EFS) was 66.8% (±5.5) and overall survival (OS) was 75.6% (±4.3). The 30 patients treated as HR solely on the basis of high MRD levels had a 5-year EFS of 63% (±9.4%). All patients experienced grade 3 or 4 toxicities during HR block therapy. Although cure rates were improved compared with previous studies, high treatment toxicity suggested that novel agents are needed to achieve further improvement.

Direct effects of Bmi1 on p53 protein stability inactivates oncoprotein stress responses in embryonal cancer precursor cells at tumor initiation.

Embryonal cancer can arise from postnatally persistent embryonal remnant or rest cells, which are uniquely characterized by the absence of p53 mutations. Perinatal overexpression of the MycN oncoprotein in embryonal cancer precursor cells causes postnatal rests, and later tumor formation through unknown mechanisms. However, overexpression of Myc in adult tissues normally activates apoptosis and/or senescence signals as an organismal defense mechanism against cancer. Here, we show that perinatal neuroblastoma precursor cells exhibited a transiently diminished p53 response to MycN oncoprotein stress and resistance to trophic factor withdrawal, compared with their adult counterpart cells from the TH-MYCN(+/+) transgenic mouse model of neuroblastoma. The adult stem cell maintenance factor and Polycomb group protein, Bmi1 (B-cell-specific Moloney murine leukemia virus integration site), had a critical role at neuroblastoma initiation in the model, by repressing p53 responses in precursor cells. We further show in neuroblastoma tumor cells that Bmi1 could directly bind p53 in a complex with other Polycomb complex proteins, Ring1A or Ring1B, leading to increased p53 ubiquitination and degradation. Repressed p53 signal responses were also seen in precursor cells for other embryonal cancer types, medulloblastoma and acute lymphoblastic leukemia. Collectively, these date indicate a general mechanism for p53 inactivation in some embryonal cell types and consequent susceptibility to MycN oncogenesis at the point of embryonal tumor initiation.

FBXW7 regulates glucocorticoid response in T-cell acute lymphoblastic leukaemia by targeting the glucocorticoid receptor for degradation.

Loss of function mutation in FBXW7, an E3 ubiquitin ligase, is associated with good prognosis and early glucocorticoid treatment response in childhood T-cell acute lymphoblastic leukemia (T-ALL) by unknown mechanisms. Here, we show that FBXW7 targets the glucocorticoid receptor α (GRα) for ubiquitylation and proteasomal degradation in a manner dependent on glycogen synthase kinase 3 ß-mediated phsophorylation. FBXW7 inactivation caused elevated GRα levels, and enhanced the transcriptional response to glucocorticoids. There was significant enhancement of GR transcriptional responses in FBXW7-deficient cell lines and primary T-ALL samples, in particular, for those pro-apoptotic regulatory proteins, BIM and PUMA. Reduced FBXW7 expression or function promoted glucocorticoid sensitivity, but not sensitivity to other chemotherapeutic agents used in T-ALL. Moreover, this was a general feature of different cancer cell types. Taken together, our work defines GRα as a novel FBXW7 substrate and demonstrates that favorable patient prognosis in T-ALL is associated with FBXW7 mutations due to enhanced GRα levels and steroid sensitivity. These findings suggest that inactivation of FBXW7, a putative tumor suppressor protein, may create a synthetic lethal state in the presence of specific anticancer therapies.

The histone deacetylase SIRT2 stabilizes Myc oncoproteins.

Myc oncoproteins are commonly upregulated in human cancers of different organ origins, stabilized by Aurora A, degraded through ubiquitin-proteasome pathway-mediated proteolysis, and exert oncogenic effects by modulating gene and protein expression. Histone deacetylases are emerging as targets for cancer therapy. Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. Affymetrix gene array studies revealed that the gene most significantly repressed by SIRT2 was the ubiquitin-protein ligase NEDD4. Consistent with this finding, SIRT2 repressed NEDD4 gene expression by directly binding to the NEDD4 gene core promoter and deacetylating histone H4 lysine 16. Importantly, NEDD4 directly bound to Myc oncoproteins and targeted Myc oncoproteins for ubiquitination and degradation, and small-molecule SIRT2 inhibitors reactivated NEDD4 gene expression, reduced N-Myc and c-Myc protein expression, and suppressed neuroblastoma and pancreatic cancer cell proliferation. Additionally, SIRT2 upregulated and small-molecule SIRT2 inhibitors decreased Aurora A expression. Our data reveal a novel pathway critical for Myc oncoprotein stability, and provide important evidences for potential application of SIRT2 inhibitors for the prevention and therapy of Myc-induced malignancies.

HLA-G polymorphisms, genetic susceptibility, and clinical outcome in childhood neuroblastoma.

Neuroblastoma is the most common solid tumor in children less than 5 years of age. The early onset of neuroblastoma suggests that genes involved in fetal development and pregnancy may have a putative role in the etiology of neuroblastoma. The human leukocyte antigen subtype G (HLA-G) molecule plays an important role in immune response regulation and appears to regulate immune tolerance during early pregnancy as well as tumor immunosurveillance. Elevated levels of soluble HLA-G (sHLA-G) have been detected in a number of malignancies including serum samples from neuroblastoma and have been reported to be predictive of tumor relapse in neuroblastoma. In light of previous investigations suggesting that single nucleotide polymorphisms in the HLA-G gene may impact on protein expression levels and isoform production, we examined the influence of HLA-G polymorphisms on the susceptibility and clinical outcome of neuroblastoma in 163 neuroblastoma patients and 404 healthy controls. The distribution of HLA-G polymorphisms, alleles, or allelic groups did not differ between children diagnosed with neuroblastoma and healthy controls. Our analyses did not detect an association between common HLA-G polymorphisms and clinical outcome in patients treated for neuroblastoma.

Effects of neurofibromatosis type 1 on children's development.

In-depth study of the human genome holds the potential to provide needed focus on genetic disorders that affect hundreds of thousands of children and significantly affect their development. Neurofibromatosis Type-1 (NF-1) is one of the most common genetic disorders that affect neurological, cognitive, social, and physical development. NF-1 affects all racial groups and both genders equally. NF-1 occurs in about 1 in 2,500 to 3,300 individuals in the population. The incidence rate at birth is about 0.0004 births in the United States and is growing in prevalence. Children with NF-1 experience a range of psychomotor and cognitive impairments that affect the quality of their social lives and their learning and academic achievements. Interventions to address the psychosocial and educational needs of children with NF-1 include a range of social and academic support services, which are most effective when they are comprehensive, involve a multidisciplinary team of educational and health experts, and include a focus on supporting and empowering family members to be effective caregivers. Efforts to address the needs of children with NF-1 and to provide adequate support to their families have significant policy implications for local, state, and federal officials.

Transcriptional upregulation of histone deacetylase 2 promotes Myc-induced oncogenic effects.

Myc oncoproteins and histone deacetylases (HDACs) modulate gene transcription and enhance cancer cell proliferation, and HDAC inhibitors are among the most promising new classes of anticancer drugs. Here, we show that N-Myc and c-Myc upregulated HDAC2 gene expression in neuroblastoma and pancreatic cancer cells, respectively, which contributed to N-Myc- and c-Myc-induced cell proliferation. Cyclin G2 (CCNG2) was commonly repressed by N-Myc and HDAC2 in neuroblastoma cells and by c-Myc and HDAC2 in pancreatic cancer cells, and could be reactivated by HDAC inhibitors. 5-bromo-2'-deoxyuridine incorporation assays showed that transcriptional repression of CCNG2 was, in part, responsible for N-Myc-, c-Myc- and HDAC2-induced cell proliferation. Dual crosslinking chromatin immunoprecipitation assay demonstrated that N-Myc acted as a transrepressor by recruiting the HDAC2 protein to Sp1-binding sites at the CCNG2 gene core promoter. Moreover, HDAC2 was upregulated, and CCNG2 downregulated, in pre-cancerous and neuroblastoma tissues from N-Myc transgenic mice, and c-Myc overexpression correlated with upregulation of HDAC2 and repression of CCNG2 in tumour tissues from pancreatic cancer patients. Taken together, our data indicate the critical roles of upregulation of HDAC2 and suppression of CCNG2 in Myc-induced oncogenesis, and have significant implications for the application of HDAC inhibitors in the prevention and treatment of Myc-driven cancers.

TRIM16 acts as a tumour suppressor by inhibitory effects on cytoplasmic vimentin and nuclear E2F1 in neuroblastoma cells.

The family of tripartite-motif (TRIM) proteins are involved in diverse cellular processes, but are often characterized by critical protein-protein interactions necessary for their function. TRIM16 is induced in different cancer types, when the cancer cell is forced to proceed down a differentiation pathway. We have identified TRIM16 as a DNA-binding protein with histone acetylase activity, which is required for the retinoic acid receptor ß(2) transcriptional response in retinoid-treated cancer cells. In this study, we show that overexpressed TRIM16 reduced neuroblastoma cell growth, enhanced retinoid-induced differentiation and reduced tumourigenicity in vivo. TRIM16 was only expressed in the differentiated ganglion cell component of primary human neuroblastoma tumour tissues. TRIM16 bound directly to cytoplasmic vimentin and nuclear E2F1 in neuroblastoma cells. TRIM16 reduced cell motility and this required downregulation of vimentin. Retinoid treatment and enforced overexpression caused TRIM16 to translocate to the nucleus, and bind to and downregulate nuclear E2F1, required for cell replication. This study, for the first time, demonstrates that TRIM16 acts as a tumour suppressor, affecting neuritic differentiation, cell migration and replication through interactions with cytoplasmic vimentin and nuclear E2F1 in neuroblastoma cells.