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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.

We aimed to identify valid screening questions for adults regarding physical activity and dietary behaviours that (a) were correlated with BMI, (b) were deemed by patients and providers to be relevant to clinical care, and (c) have utility for longitudinal understanding of health behaviours in populations. The goal was to identify screening questions that could be implemented at annual health care visits. First, we identified dietary behaviour questions and solicited patient input. Next, we tested both physical activity and dietary behaviour questions in a large sample to test their potential utility. Finally, we used cognitive interviews with patients and physicians to narrow our assessment for clinical settings. We present a parsimonious and reliable six-question scale of physical activity and dietary behaviours for research settings, as well as a three-question scale for clinical settings. We demonstrate a robust relationship between these measures and obesity. Additionally, we present evidence that these measures may serve as a useful red flag for patients before they develop obesity. We provide a concise and useful tool for assessing patients' physical activity and dietary behaviours in a variety of research settings. We also highlight the importance of incorporating this tool into the clinical intake flow for inclusion in patients' Electronic Health Record., (© 2021 World Obesity Federation.)

In this article, we describe a personalized approach to meeting individual and community health needs that foregrounds relational learning. This article analyzes how relational approaches to learning expand participants' objectives and result in more enduring learning. We report on mixed methods data from interviews, focus groups, surveys, and goal setting and monitoring. Analyses reveal that relationships de confianza served as a central tool in supporting participants' agency to enact change across scales of practice to promote the health of themselves, their families, and their communities.

Objectives: A life-course perspective emphasizes healthy behaviors before, during, and after pregnancy to support a multi-generational risk reduction in obesity for mothers and infants. Optimal timing, content, and dose of such interventions is not well defined., Methods: We conducted a nested cohort within a randomized trial to evaluate whether a healthy lifestyle intervention around pregnancy led to a "spill-over effect," including a healthier rate (kg/week) of maternal gestational weight gain, and infant growth during the first year. Study enrollment began in 2012, follow-up data collection completed in 2018, and the data were analyzed in 2019. The intervention focused on healthy maternal diet and physical activity but not pregnancy weight or infant feeding. Outcome data were abstracted from electronic medical records., Results: Of the 165 women who became pregnant, 114 enrolled in the nested cohort. The average pre-pregnancy BMI was 29.6 (SD 5.1) kg/m 2 . Mixed effects models suggested clinically insignificant differences in both the rate of gestational weight gain (-0.02 kg/week; 95% CI -0.09, 0.06) and the rate of infant growth (difference at 1 year: -0.002 kg/cm; 95% CI -0.009, 0.005)., Conclusions for Practice: A behavioral intervention that focused on overall maternal health delivered in the time around pregnancy did not result in a "spill-over effect" on healthy gestational weight gain or healthy infant growth during the first year of life., Trial Registration: This study is registered at www.clinicaltrials.gov NCT01316653.

Background: To develop and test brief nutrition and physical activity screening questions for children ages 2-11 years that could be used as a pragmatic screening tool to tailor counseling, track behavior change, and improve population health. Methods: A literature review identified existing validated questions for nutrition and physical activity behaviors in children ages 2-11 years. Response variation and concurrent validity was then assessed using a mechanical Turk (MTurk) crowdsourcing survey employed in 2018. Additionally, cognitive interviews were conducted with both providers and parents of 2- to 11-year-old children to assess screening question priorities and perceived added value. Results: The literature review identified 260 questions, and 20 items were selected with expert guidance based on prespecified criteria (simplicity and potential utility for both clinical interactions during a well-child exam and population health). MTurk surveys yielded 1147 records that met eligibility criteria and revealed 6 items that had adequate response variation and were significantly correlated with parent-reported child BMI or BMI percentile, exhibiting concurrent validity. Cognitive interviews with 10 providers and 20 parents uncovered themes regarding suggestions and usability of the questions, eliminating 3 items due to parent and provider concerns. Combining quantitative and qualitative results, 3 nutrition and physical activity screening items remained for inclusion into the electronic health record (EHR). Conclusions: The three-pronged validation methodology produced a brief, 3-item child nutrition and physical activity screener to incorporate in the EHR, where it can inform tailored counseling for well-child care and be used to test associations with population health outcomes.

Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target's resurgence. As previously reported, the tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors of KRAS G12C that bind in the switch-II pocket of KRAS and make a covalent bond to cysteine 12. Using structure-based drug design in conjunction with a focused in vitro absorption, distribution, metabolism and excretion screening approach, analogues were synthesized to increase the potency and reduce metabolic liabilities of this series. The discovery of the clinical development candidate MRTX849 as a potent, selective covalent inhibitor of KRAS G12C is described.

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: Health behavior change interventions that target childhood obesity in minority populations have led to inconsistent and short-lived results. The purpose of this study was to test a novel intervention that was personalized and family-based in a Latino population to reduce childhood obesity. Methods: Competency-Based Approaches to Community Health (COACH) was a randomized controlled trial. Latino parent - child pairs were recruited from community settings in Nashville, TN. Child eligibility criteria included age 3-5 years and a BMI ≥50th percentile. The intervention included 15 weekly, 90-minute sessions followed by 3 months of twice-monthly health coaching calls. The control group was a twice-monthly school readiness curriculum for 3 months. Sessions were conducted by a health coach in local community centers, with groups of 8-11 parent - child pairs. The primary outcome was child BMI trajectory across 12 months, measured at four times. The intervention's effect was assessed by using a longitudinal, linear mixed-effects growth model, adjusting for child gender, baseline child and parent age, and baseline parent BMI and education. Results: Of the 305 parent - child pairs assessed for eligibility, 117 were randomized (59 intervention, 58 control). Child BMI was available for 91.5% at 1-year follow-up. Mean baseline child age was 4.2 [standard deviation (SD) = 0.8] years, and 53.8% of children were female. Mean baseline child BMI was 18.1 (SD = 2.6) kg/m 2 . After adjusting for covariates, the intervention's effect on linear child BMI growth was -0.41 kg/m 2 per year (95% confidence interval -0.82 to 0.01; p  = 0.05). Conclusions: Over 1-year follow-up, the intervention resulted in slower linear BMI growth for Latino preschool-aged children from poverty.

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.

Competency-Based Approaches to Community Health (COACH) is a randomized controlled trial of a family-centered, community-based, and individually-tailored behavioral intervention for childhood obesity among Latino pre-school children. COACH focuses on improving personal agency for health behavior change by tailoring content to overcome contextual barriers. The intervention focuses on diet, physical activity, sleep, media use, and engaged parenting. The content is individually adapted based on routine assessments of competency in specific health behaviors using a mobile health platform and novel measurement tools developed by our team. In response to these regular assessments, health coaches provide tailored health behavior change strategies to help families focus on the areas where they decide to improve the most. The intervention consists of a 15-week group-based intensive phase, with weekly sessions delivered by health coaches in community centers. Following weekly sessions, a 3-month maintenance phase of the intervention consists of twice monthly coaching calls for participants to focus on individual health goals for their families. The primary outcome of the trial is child body mass index trajectory over 1 year. Secondary outcomes include parent body mass index change, child waist circumference, child diet, child physical activity, and other psychosocial mediators of child health behavior change. The control arm consists of a school readiness intervention, delivered by the Nashville Public Library. By applying a personalized approach to child behavior change, in the setting of both family and community, COACH aims to develop sustainable solutions for childhood obesity by supporting healthy childhood growth in low-income, minority preschool children., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Importance: Prevention of obesity during childhood is critical for children in underserved populations, for whom obesity prevalence and risk of chronic disease are highest., Objective: To test the effect of a multicomponent behavioral intervention on child body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) growth trajectories over 36 months among preschool-age children at risk for obesity., Design, Setting, and Participants: A randomized clinical trial assigned 610 parent-child pairs from underserved communities in Nashville, Tennessee, to a 36-month intervention targeting health behaviors or a school-readiness control. Eligible children were between ages 3 and 5 years and at risk for obesity but not yet obese. Enrollment occurred from August 2012 to May 2014; 36-month follow-up occurred from October 2015 to June 2017., Interventions: The intervention (n = 304 pairs) was a 36-month family-based, community-centered program, consisting of 12 weekly skills-building sessions, followed by monthly coaching telephone calls for 9 months, and a 24-month sustainability phase providing cues to action. The control (n = 306 pairs) consisted of 6 school-readiness sessions delivered over the 36-month study, conducted by the Nashville Public Library., Main Outcomes and Measures: The primary outcome was child BMI trajectory over 36 months. Seven prespecified secondary outcomes included parent-reported child dietary intake and community center use. The Benjamini-Hochberg procedure corrected for multiple comparisons., Results: Participants were predominantly Latino (91.4%). At baseline, the mean (SD) child age was 4.3 (0.9) years; 51.9% were female. Household income was below $25 000 for 56.7% of families. Retention was 90.2%. At 36 months, the mean (SD) child BMI was 17.8 (2.2) in the intervention group and 17.8 (2.1) in the control group. No significant difference existed in the primary outcome of BMI trajectory over 36 months (P = .39). The intervention group children had a lower mean caloric intake (1227 kcal/d) compared with control group children (1323 kcal/d) (adjusted difference, -99.4 kcal [95% CI, -160.7 to -38.0]; corrected P = .003). Intervention group parents used community centers with their children more than control group parents (56.8% in intervention; 44.4% in control) (risk ratio, 1.29 [95% CI, 1.08 to 1.53]; corrected P = .006)., Conclusions and Relevance: A 36-month multicomponent behavioral intervention did not change BMI trajectory among underserved preschool-age children in Nashville, Tennessee, compared with a control program. Whether there would be effectiveness for other types of behavioral interventions or implementation in other cities would require further research., Trial Registration: ClinicalTrials.gov Identifier: NCT01316653.

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.

Background: Recently, we reported ethyl nicotinates as antagonists of the P2Y12 receptor, which is an important target in antiplatelet therapies. A potential liability of these compounds was their generally high in vivo clearance due to ethyl ester hydrolysis., Results: Shape and electrostatic similarity matching was used to select five-membered heterocycles to replace the ethyl ester functionality. The 5-methyl and 5-ethyl-oxazole bioisosteres retained the sub-micromolar potency levels of the parent ethyl esters. Many oxazoles showed a higher CYP450 dependent microsomal metabolism than the corresponding ethyl esters. Structure activity relationship investigations supported by ab initio calculations suggested that a correctly positioned alkyl substituent and a strong hydrogen bond acceptor were necessary structural motifs for binding. In rat pharmacokinetics, the low clearance was retained upon replacement of an ethyl ester with a 5-ethyl-oxazole., Conclusion: The use of shape and electrostatic similarity led to the successful replacement of a metabolically labile ethyl ester functionality with 5-alkyl-oxazole bioisosteres.

The bradykinin B1 receptor is induced following tissue injury and/or inflammation. Antagonists of this receptor have been studied as promising candidates for treatment of chronic pain. We have identified aryl sulfonamides containing a chiral chroman diamine moiety that are potent antagonists of the human B1 receptor. Our previously communicated lead, compound 2, served as a proof-of-concept molecule, but suffered from poor pharmacokinetic properties. With guidance from metabolic profiling, we performed structure-activity relationship studies and have identified potent analogs of 2. Variation of the sulfonamide moiety revealed a preference for 3- and 3,4-disubstituted aryl sulfonamides, while bulky secondary and tertiary amines were preferred at the benzylic amine position for potency at the B1 receptor. Modifying the beta-amino acid core of the molecule lead to the discovery of highly potent compounds with improved in vitro pharmacokinetic properties. The most potent analog at the human receptor, compound 38, was also active in a rabbit B1 receptor cellular assay. Furthermore, compound 38 displayed in vivo activity in two rabbit models, a pharmacodynamic model with a blood pressure readout and an efficacy model of inflammatory pain.

Cholesteryl ester transfer protein is a plasma glycoprotein that transfers cholesterol ester between lipoprotein particles. Inhibition of this protein, in vitro and in vivo, produces an increase in plasma high density lipoprotein cholesterol (HDL-C). This communication will describe the SAR and synthesis of a series of substituted tetrahydroquinoxaline CETP inhibitors from early mu lead to advanced enantiomerically pure analogs.

We report the discovery of chroman 28, a potent and selective antagonist of human, nonhuman primate, rat, and rabbit bradykinin B1 receptors (0.4-17 nM). At 90 mg/kg s.c., 28 decreased plasma extravasation in two rodent models of inflammation. A novel method to calculate entropy is introduced and ascribed approximately 30% of the gained affinity between "flexible" 4 (Ki = 132 nM) and "rigid" 28 (Ki = 0.77 nM) to decreased conformational entropy.

A series of racemic and chiral, nonracemic lactams that display high binding affinities, functional chemotaxis antagonism, and selectivity toward CCR4 are described. Compound 41, which provides reasonably high blood levels in mice when dosed intraperitoneally, was identified as a useful pharmacological tool to explore the role of CCR4 antagonism in animal models of allergic disease.

Substituted thiazolidinones were identified as CCR4 antagonists from high throughput screening. Subsequent lead optimization efforts resulted in defined structure-activity relationships and the identification of potent antagonists (compounds 90 and 91) that inhibited the chemotaxis of Th2 T-cells in vitro.

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.

Presence of mast cells and an increase in the concentration of their products has been reported in multiple sclerosis (MS) plaques. The most abundant secretory mediator of the human mast cell is the tetrameric protease tryptase. We demonstrate that tryptase can activate peripheral mononuclear cells (PBMCs), isolated from healthy donors as well as MS patients for the release of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and IL-1beta. Cytokine secretion was significantly higher in secondary progressive (SP) MS patients and healthy control (HC) individuals than in relapsing-remitting (RR) patients. Our findings suggest that tryptase is, most probably, an important mediator of inflammation in MS.

Allergic diseases such as atopic dermatitis, asthma, and allergic rhinitis represent a significant healthcare problem. Understanding these diseases as dysregulated inflammatory responses has led to many new targets for therapeutic intervention. Recent data concerning soluble IL-4 receptor, monoclonal antibodies against IL-5 and an antibody toward IgE have lead to an appreciation of the crucial role played by Th2 subset of CD4(+) T cells and their corresponding cytokines. While these potential drugs are presently in clinical trials and may be valuable therapeutics, orally bioavailable small molecule inhibitors of Th2 cell responses would be desirable for treatment of these chronic diseases. One strategy is to prevent effector cell migration (Th2 cells, mast cells, and eosinophils) via chemokine receptor antagonism with a suitable small molecule. Chemokine receptors are a subset of the seven transmembrane-spanning family, which mediate their effects through interaction with heterotrimeric G-proteins. The ligands are a structurally related set of proteins that are selectively expressed in certain disease settings. Three chemokine receptors CCR3, CCR4, and CCR8 are preferentially expressed by Th2 cells, mast cells and eosinophils and therefore represent therapeutic targets for allergy. This mini-review will focus on new research involving CCR3, CCR4 and CCR8. The cellular distribution of each receptor, the corresponding chemokine ligands, and various validation studies are discussed. Recent drug discovery advances concerning pharmacological tools and small molecule receptor antagonists will also be presented.

Human mast cell tryptase-beta, a tryptic serine protease with a unique structure, is an interesting therapeutic target that several companies and institutions have targeted for drug discovery. The catalytic activity of this tryptic enzyme has been linked to many disease states and proinflammatory events; however, the physical and physiological differences of tryptase across various species have made animal model data difficult to interpret, particularly in the context of human disease. Still, both protein and small-molecule tryptase inhibitors have been reported and the X-ray crystal structure of the enzyme aids in understanding how these compounds might bind. Three modes of inhibition exist: monofunctional inhibition, bifunctional inhibition and tetramer disruption. Many of these inhibitors have demonstrated activity in animal models. Human clinical studies have been conducted or are under way with certain tryptase inhibitors.

Emerging evidence suggests that mast cell tryptase is a therapeutic target for the treatment of asthma. The effects of this serine protease are associated with both pathophysiologic pulmonary responses and pathologic changes of the asthmatic airway. In this study, the tryptase inhibitor 1,5-bis-[4-[(3-carbamimidoyl-benzenesulfonylamino)-methyl]-p henoxy]-pentane (AMG-126737) was evaluated for its pharmacologic effects against allergen-induced airway responses. AMG-126737 is a potent inhibitor of human lung mast cell tryptase (Ki = 90 nM), with greater than 10- to 200-fold selectivity versus other serine proteases. Intratracheal administration of AMG-126737 inhibited the development of airway hyperresponsiveness in allergen-challenged guinea pigs with an ED50 of 0.015 mg/kg. In addition, the compound exhibited oral activity in the guinea pig model. The in vivo activity of AMG-126737 was confirmed in a sheep model of allergen-induced airway responses, where the compound inhibited early and late phase bronchoconstriction responses and the development of airway hyperresponsiveness. These results support the proposed role of tryptase in the pathology of asthma and suggest that AMG-126737 has potential therapeutic utility in this pulmonary disorder.

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.

The renal microvasculature was studied in normotensive rats and in rats with spontaneous hypertension. The microvascular pattern was normal in both groups of animals, suggesting normal renin secretion. This may or may not indicate a role for renin in the cause of spontaneous hypertension.