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Abstract Background Interactive video games such as the Nintendo Wii Fit are increasingly used as a therapeutic tool in health and aged care settings however, their acceptability to older people is unclear. The aim of this study was to determine the acceptability of the Nintendo Wii Fit as a therapy tool for hospitalised older people using a discrete choice experiment (DCE) before and after exposure to the intervention. Methods A DCE was administered to 21 participants in an interview style format prior to, and following several sessions of using the Wii Fit in physiotherapy. The physiotherapist prescribed the Wii Fit activities, supervised and supported the patient during the therapy sessions. Attributes included in the DCE were: mode of therapy (traditional or using the Wii Fit), amount of therapy, cost of therapy program and percentage of recovery made. Data was analysed using conditional (fixed-effects) logistic regression. Results Prior to commencing the therapy program participants were most concerned about therapy time (avoiding programs that were too intensive), and the amount of recovery they would make. Following the therapy program, participants were more concerned with the mode of therapy and preferred traditional therapy programs over programs using the Wii Fit. Conclusions The usefulness of the Wii Fit as a therapy tool with hospitalised older people is limited not only by the small proportion of older people who are able to use it, but by older people's preferences for traditional approaches to therapy. Mainstream media portrayals of the popularity of the Wii Fit with older people may not reflect the true acceptability in the older hospitalised population.

WRN helicase is a promising target for treatment of cancers with microsatellite instability (MSI) due to its essential role in resolving deleterious non-canonical DNA structures that accumulate in cells with faulty mismatch repair mechanisms 1-5 . Currently there are no approved drugs directly targeting human DNA or RNA helicases, in part owing to the challenging nature of developing potent and selective compounds to this class of proteins. Here we describe the chemoproteomics-enabled discovery of a clinical-stage, covalent allosteric inhibitor of WRN, VVD-133214. This compound selectively engages a cysteine (C727) located in a region of the helicase domain subject to interdomain movement during DNA unwinding. VVD-133214 binds WRN protein cooperatively with nucleotide and stabilizes compact conformations lacking the dynamic flexibility necessary for proper helicase function, resulting in widespread double-stranded DNA breaks, nuclear swelling and cell death in MSI-high (MSI-H), but not in microsatellite-stable, cells. The compound was well tolerated in mice and led to robust tumour regression in multiple MSI-H colorectal cancer cell lines and patient-derived xenograft models. Our work shows an allosteric approach for inhibition of WRN function that circumvents competition from an endogenous ATP cofactor in cancer cells, and designates VVD-133214 as a promising drug candidate for patients with MSI-H cancers., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Few studies have derived data-driven dietary patterns in youth in the USA. This study examined data-driven dietary patterns and their associations with BMI measures in predominantly low-income, racial/ethnic minority US youth. Data were from baseline assessments of the four Childhood Obesity Prevention and Treatment Research (COPTR) Consortium trials: NET-Works (534 2-4-year-olds), GROW (610 3-5-year-olds), GOALS (241 7-11-year-olds) and IMPACT (360 10-13-year-olds). Weight and height were measured. Children/adult proxies completed three 24-h dietary recalls. Dietary patterns were derived for each site from twenty-four food/beverage groups using k-means cluster analysis. Multivariable linear regression models examined associations of dietary patterns with BMI and percentage of the 95th BMI percentile. Healthy (produce and whole grains) and Unhealthy (fried food, savoury snacks and desserts) patterns were found in NET-Works and GROW. GROW additionally had a dairy- and sugar-sweetened beverage-based pattern. GOALS had a similar Healthy pattern and a pattern resembling a traditional Mexican diet. Associations between dietary patterns and BMI were only observed in IMPACT. In IMPACT, youth in the Sandwich (cold cuts, refined grains, cheese and miscellaneous) compared with Mixed (whole grains and desserts) cluster had significantly higher BMI (β = 0·99 (95 % CI 0·01, 1·97)) and percentage of the 95th BMI percentile (β = 4·17 (95 % CI 0·11, 8·24)). Healthy and Unhealthy patterns were the most common dietary patterns in COPTR youth, but diets may differ according to age, race/ethnicity or geographic location. Public health messages focused on healthy dietary substitutions may help youth mimic a dietary pattern associated with lower BMI.

Background: Current recommendations for intensive behavioral interventions for childhood obesity treatment do not account for variable participant attendance, optimal duration of the intervention, mode of delivery (phone vs. face-to-face), or address obesity prevention among young children. A secondary analysis of an active one-year behavioral intervention for childhood obesity prevention was conducted to test how "dose delivered" was associated with body mass index z-score (BMI-Z) across 3 years of follow-up., Methods: Parent-child pairs were eligible if they qualified for government assistance and spoke English or Spanish. Children were between three and 5 years old and were at risk for but not yet obese (BMI percentiles ≥50th and < 95th). The intended intervention dose was 18 h over 3-months via 12 face-to-face "intensive sessions" (90 min each) and 6.75 h over the next 9 months via 9 "maintenance phone calls" (45 min each). Ordinary least-squares multivariable regression was utilized to test for associations between dose delivered and child BMI-Z immediately after the 1-year intervention, and at 2-, and 3-year follow-up, including participants who were initially randomized to the control group as having "zero" dose., Results: Among 610 parent-child pairs (intervention n = 304, control n = 306), mean child age was 4.3 (SD = 0.9) years and 51.8% were female. Mean dose delivered was 10.9 (SD = 2.5) of 12 intensive sessions and 7.7 (SD = 2.4) of 9 maintenance calls. Multivariable linear regression models indicated statistically significant associations of intensive face-to-face contacts (B = -0.011; 95% CI [- 0.021, - 0.001]; p = 0.029) and maintenance calls (B = -0.015; 95% CI [- 0.026, - 0.004]; p = 0.006) with lower BMI-Z immediately following the 1-year intervention. Their interaction was also significant (p = 0.04), such that parent-child pairs who received higher numbers of both face-to-face intensive sessions (> 6) and maintenance calls (> 8) were predicted to have lower BMI-Z. Sustained impacts were not statistically significant at 2- or 3-year follow-up., Conclusions: In a behavioral intervention for childhood obesity prevention, the combination of a modest dose of face-to-face sessions (> 6 h over 3 months) with sustained maintenance calls (> 8 calls over 9 months) was associated with improved BMI-Z at 1-year for underserved preschool aged children, but sustained impacts were not statistically significant at 2 or 3 year follow-up., Clinical Trial Registration: The trial was registered on ClinicalTrials.gov (NCT01316653) on March 16, 2011, which was prior to participant enrollment.

Background: The purpose of this study was to conduct a qualitative evaluation of a behavioral intervention to prevent and treat childhood obesity in minority children. Using qualitative methods to augment understanding of intervention success may be one way to gain insight into the types of behavior change strategies that are most effective in childhood obesity interventions., Methods: COACH was a randomized controlled trial of 117 Latino parent-child (ages 3-5) pairs in Nashville, TN that resulted in improved child BMI in intervention vs. control families at 1-year follow-up. All participant parents were invited to focus groups after the trial. Discussions were audiotaped, transcribed, and translated into English. A hierarchical coding scheme was generated, and qualitative analysis done using an inductive/deductive approach. Both theme saturation and consensus between the coders were achieved. Responses were compared between intervention and control groups., Results: We conducted seven focus groups with 43 participants. 4 themes emerged from the intervention group: 1) perceived barriers to health behavior change; 2) strategies learned to overcome perceived barriers; 3) behavioral changes made in response to the program; and 4) knowledge, skills, and agency for family health behaviors. 4 themes emerged from the control group: 1) a desire to engage in health behaviors without specific strategies; 2) common set of barriers to health behavior change; 3) engagement in literacy activities, including creative problem-solving strategies; and 4) changes made in response to study visits. Analysis of coded data showed the intervention increased healthy behaviors (e.g., fruit/vegetable consumption) despite barriers (e.g., time, cost, culture, family dynamics). Intervention participants described using specific behavior change strategies promoted by the intervention including: substituting ingredients in culturally-normative recipes; avoiding grocery shopping when hungry; and coping with inability to meet goals with acceptance and problem-solving. Control participants reported little success in achieving healthy changes for their family. Intervention participants described successful health behavior changes that were shared across generations and were maintained after the program. Intervention participants reported increased awareness of their own agency in promoting their health., Conclusions: Qualitative evaluation of COACH provides a more detailed understanding of the intervention's quantitative effectiveness: child and adult health behaviors and personal agency were improved., (© 2019 The Author(s).)

KRAS is the most frequently mutated driver oncogene in human cancer, and KRAS mutations are commonly associated with poor prognosis and resistance to standard treatment. The ability to effectively target and block the function of mutated KRAS has remained elusive despite decades of research. Recent findings have demonstrated that directly targeting KRAS-G12C with electrophilic small molecules that covalently modify the mutated codon 12 cysteine is feasible. We have discovered a series of tetrahydropyridopyrimidines as irreversible covalent inhibitors of KRAS-G12C with in vivo activity. The PK/PD and efficacy of compound 13 will be highlighted., Competing Interests: The authors declare no competing financial interest.

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) suppress normal hematopoietic activity in part by enabling a pathogenic inflammatory milieu in the bone marrow. In this report, we show that elevation of angiopoietin-1 in myelodysplastic CD34(+) stem-like cells is associated with higher risk disease and reduced overall survival in MDS and AML patients. Increased angiopoietin-1 expression was associated with a transcriptomic signature similar to known MDS/AML stem-like cell profiles. In seeking a small-molecule inhibitor of this pathway, we discovered and validated pexmetinib (ARRY-614), an inhibitor of the angiopoietin-1 receptor Tie-2, which was also found to inhibit the proinflammatory kinase p38 MAPK (which is overactivated in MDS). Pexmetinib inhibited leukemic proliferation, prevented activation of downstream effector kinases, and abrogated the effects of TNFα on healthy hematopoietic stem cells. Notably, treatment of primary MDS specimens with this compound stimulated hematopoiesis. Our results provide preclinical proof of concept for pexmetinib as a Tie-2/p38 MAPK dual inhibitor applicable to the treatment of MDS/AML. Cancer Res; 76(16); 4841-9. ©2016 AACR., (©2016 American Association for Cancer Research.)

The in silico construction of a PDGFRβ kinase homology model and ensuing medicinal chemistry guided by molecular modeling, led to the identification of potent, small molecule inhibitors of PDGFR. Subsequent exploration of structure-activity relationships (SAR) led to the incorporation of a constrained secondary amine to enhance selectivity. Further refinements led to the integration of a fluorine substituted piperidine, which resulted in significant reduction of P-glycoprotein (Pgp) mediated efflux and improved bioavailability. Compound 28 displayed oral exposure in rodents and had a pronounced effect in a pharmacokinetic-pharmacodynamic (PKPD) assay.

Cancer presents a difficult challenge for oncologists, as there are few therapies that specifically target disease cells. Existing treatment strategies rely heavily on physical and chemical agents that nonspecifically affect DNA metabolism. To improve the effectiveness of these treatments, we have identified a new class of protein kinase inhibitor that targets a major DNA repair pathway. A representative of this class, 1-(2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone, inhibits the DNA-dependent protein kinase (DNA-PK) and differs significantly from previously studied DNA-PK inhibitors both structurally and functionally. DNA-PK participates in the cellular response to and repair of chromosomal DNA double-strand breaks (DSBs). These new selective inhibitors recapitulate the phenotype of DNA-PK defective cell lines including those from SCID mice. These compounds directly inhibit the repair of DNA DSBs and consequently enhance the cytotoxicity of physical and chemical agents that induce DSBs but not other DNA lesions. In contrast to previously studied DNA-PK inhibitors, these compounds appear benign, exhibiting no toxic effects in the absence of DSB-inducing treatments. Most importantly, 1-(2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone synergistically enhances radiation-induced tumor control in a mouse-human xenograft assay. These studies validate DNA-PK as a cancer drug target and suggest a new approach for enhancing the effects of existing cancer therapies.

Human lung tryptase, a homotetrameric serine protease unique to mast cell secretory granules, has been implicated in the pathogenesis of asthma. A hypothesis that tethered symmetrical inhibitors might bridge two adjacent active sites was explored via a rationally designed series of bisbenzamidines. These compounds demonstrated a remarkable distanced-defined structure-activity relationship against human tryptase with one series possessing subnanomolar potencies. Additional evidence supporting the concept of active-site bridging is also presented.

1. UK-78,282, a novel piperidine blocker of the T lymphocyte voltage-gated K+ channel, Kv1.3, was discovered by screening a large compound file using a high-throughput 86Rb efflux assay. This compound blocks Kv1.3 with a IC50 of approximately 200 nM and 1:1 stoichiometry. A closely related compound, CP-190,325, containing a benzyl moiety in place of the benzhydryl in UK-78,282, is significantly less potent. 2 Three lines of evidence indicate that UK-78,282 inhibits Kv1.3 in a use-dependent manner by preferentially blocking and binding to the C-type inactivated state of the channel. Increasing the fraction of inactivated channels by holding the membrane potential at - 50 mV enhances the channel's sensitivity to UK-78,282. Decreasing the number of inactivated channels by exposure to approximately 160 mM external K+ decreases the sensitivity to UK-78,282. Mutations that alter the rate of C-type inactivation also change the channel's sensitivity to UK-78,282 and there is a direct correlation between tau(h) and IC50 values. 3. Competition experiments suggest that UK-78,282 binds to residues at the inner surface of the channel overlapping the site of action of verapamil. Internal tetraethylammonium and external charybdotoxin do not compete UK-78,282's action on the channel. 4. UK-78,282 displays marked selectivity for Kv1.3 over several other closely related K+ channels, the only exception being the rapidly inactivating voltage-gated K+ channel, Kv1.4. 5. UK-78,282 effectively suppresses human T-lymphocyte activation.