The importance of loop length on the stability of i-motif structures

Using UV and srCD spectroscopy it is found that loop length within the i-motif structure is important for both thermal and pH stability, but in contrast to previous statements, it is the shorter loops that exhibit the highest stability

The 2 × 2 Model of Perfectionism and Negative Experiences in Youth Sport

Objectives: Research has found that the four subtypes of perfectionism from the 2 × 2 model of perfectionism (i.e., Non-perfectionism, Pure PSP, Pure ECP, and Mixed perfectionism) are associated with different youth sport experiences. Extending this research, the current study examined the 2 × 2 model in regard to undesirable outcomes indicative of negative experiences in youth sport: negative (and positive) affect, anxiety, antisocial (and prosocial) behavior, and intentions to dropout of sport. Design: A cross-sectional design was employed. Method: Two hundred and twenty-two youth sports participants (65 males, 157 females, M age = 13.51 years, SD = 1.53 years, range = 11 – 18 years) were recruited from a variety of school- and community-based sports and completed a multi-section questionnaire. Results: Regression analyses revealed that, for the most part, Pure ECP was associated with the most negative experiences (higher negative affect, anxiety, and intentions to dropout and lower positive affect) and Pure PSP was, typically, associated with the least negative experiences (lower negative affect, anxiety, antisocial behavior, and intentions to dropout and higher positive affect) in youth sport. One notable exception was antisocial behavior towards teammates and competitors for which Mixed perfectionism was most problematic. Conclusion: The findings suggest that the four subtypes of perfectionism can be distinguished based on their association with both negative and positive experiences in youth sport

Estimates of Alpha/Beta (alpha/beta) Ratios for Individual Late Rectal Toxicity Endpoints: An Analysis of the CHHiP Trial

Purpose: Changes in fraction size of external beam radiation therapy exert nonlinear effects on subsequent toxicity. Commonly described by the linear-quadratic model, fraction size sensitivity of normal tissues is expressed by the α/β ratio. We sought to study individual α/β ratios for different late rectal effects after prostate external beam radiation therapy. Methods and Materials: The CHHiP trial (ISRCTN97182923) randomized men with nonmetastatic prostate cancer 1:1:1 to 74 Gy/37 fractions (Fr), 60 Gy/20 Fr, or 57 Gy/19 Fr. Patients in the study had full dosimetric data and zero baseline toxicity. Toxicity scales were amalgamated to 6 bowel endpoints: bleeding, diarrhea, pain, proctitis, sphincter control, and stricture. Lyman-Kutcher-Burman models with or without equivalent dose in 2 Gy/Fr correction were log-likelihood fitted by endpoint, estimating α/β ratios. The α/β ratio estimate sensitivity was assessed using sequential inclusion of dose modifying factors (DMFs): age, diabetes, hypertension, inflammatory bowel or diverticular disease (IBD/diverticular), and hemorrhoids. 95% confidence intervals (CIs) were bootstrapped. Likelihood ratio testing of 632 estimator log-likelihoods compared the models. Results: Late rectal α/β ratio estimates (without DMF) ranged from bleeding (G1 + α/β = 1.6 Gy; 95% CI, 0.9-2.5 Gy) to sphincter control (G1 + α/β = 3.1 Gy; 95% CI, 1.4-9.1 Gy). Bowel pain modelled poorly (α/β, 3.6 Gy; 95% CI, 0.0-840 Gy). Inclusion of IBD/diverticular disease as a DMF significantly improved fits for stool frequency G2+ (P = .00041) and proctitis G1+ (P = .00046). However, the α/β ratios were similar in these no-DMF versus DMF models for both stool frequency G2+ (α/β 2.7 Gy vs 2.5 Gy) and proctitis G1+ (α/β 2.7 Gy vs 2.6 Gy). Frequency-weighted averaging of endpoint α/β ratios produced: G1 + α/β ratio = 2.4 Gy; G2 + α/β ratio = 2.3 Gy. Conclusions: We estimated α/β ratios for several common late adverse effects of rectal radiation therapy. When comparing dose-fractionation schedules, we suggest using late a rectal α/β ratio ≤ 3 Gy

Structural studies reveal the enantiospecific recognition of a DNA G-quadruplex by a ruthenium polypyridyl complex

Using X-ray crystallography, we show an enantiospecificity in DNA G-quadruplex binding, using the complexes Λ/∆-[Ru(TAP)2(dppz-11-CN)]2+ (TAP=1,4,5,8-tetraazaphenanthrene) containing the dppz (dipyridophenazine) ligand, paralleling the specificity of the complexes with duplex DNA. The Λ complex crystallises with the normally parallel stranded d(TAGGGTTA) tetraplex to give the first such antiparallel strand assembly in which syn-guanosine is adjacent to the complex at the 5’ end of the quadruplex core. SRCD measurements confirm that the same conformational switch occurs in solution. The Δ enantiomer, by contrast, is present in the structure but stacked at the ends of the assembly. In addition, we report the structure of Λ-[Ru(phen)2(11-CN-dppz)]2+ bound to d(TCGGCGCCGA), a duplex forming sequence, and use both structural models to aid in the elucidation of the motif-specific luminescence response of the isostructural phen analogue enantiomers

Genitourinary α/β Ratios in the CHHiP Trial the Fraction Size Sensitivity of Late Genitourinary Toxicity: Analysis of Alpha/Beta (α/β) Ratios in the CHHiP Trial

PURPOSE: Moderately hypofractionated external beam intensity-modulated radiotherapy (IMRT) for prostate cancer is now standard-of-care. Normal tissue toxicity responses to fraction size alteration are non-linear: the linear-quadratic model is a widely-used framework accounting for this, through the α/β ratio. Few α/β ratio estimates exist for human late genitourinary endpoints; here we provide estimates derived from a hypofractionation trial. METHODS AND MATERIALS: The XXXXXX trial randomised 3216 men with localised prostate cancer 1:1:1 between conventionally fractionated IMRT (74Gy/37 fractions (Fr)) and two moderately hypofractionated regimens (60Gy/20Fr & 57Gy/19Fr). Radiotherapy plan and suitable follow-up assessment was available for 2206 men. Three prospectively assessed clinician-reported toxicity scales were amalgamated for common genitourinary endpoints: Dysuria, Haematuria, Incontinence, Reduced flow/Stricture, Urine Frequency. Per endpoint, only patients with baseline zero toxicity were included. Three models for endpoint grade ≥1 (G1+) and G2+ toxicity were fitted: Lyman Kutcher-Burman (LKB) without equivalent dose in 2Gy/Fr (EQD2) correction [LKB-NoEQD2]; LKB with EQD2-correction [LKB-EQD2]; LKB-EQD2 with dose-modifying-factor (DMF) inclusion [LKB-EQD2-DMF]. DMFs were: age, diabetes, hypertension, pelvic surgery, prior transurethral resection of prostate (TURP), overall treatment time and acute genitourinary toxicity (G2+). Bootstrapping generated 95% confidence intervals and unbiased performance estimates. Models were compared by likelihood ratio test. RESULTS: The LKB-EQD2 model significantly improved performance over LKB-NoEQD2 for just three endpoints: Dysuria G1+ (α/β=2.0 Gy, 95%CI 1.2-3.2Gy), Haematuria G1+ (α/β=0.9 Gy, 95%CI 0.1-2.2Gy) and Haematuria G2+ (α/β=0.6Gy, 95%CI 0.1-1.7Gy). For these three endpoints, further incorporation of two DMFs improved on LKB-EQD2: acute genitourinary toxicity and Prior TURP (Haematuria G1+ only), but α/β ratio estimates remained stable. CONCLUSIONS: Inclusion of EQD2-correction significantly improved model fitting for Dysuria and Haematuria endpoints, where fitted α/β ratio estimates were low: 0.6-2 Gy. This suggests therapeutic gain for clinician-reported GU toxicity, through hypofractionation, might be lower than expected by typical late α/β ratio assumptions of 3-5 Gy

Inter-cultural differences in response to a computer-based anti-bullying intervention

Background and purpose: Many holistic anti-bullying interventions have been attempted, with mixed success, while little work has been done to promote a 'self-help' approach to victimisation. The rise of the ICT curriculum and computer support in schools now allows for approaches that benefit from technology to be implemented. This study evaluates the cross-cultural effects of a computer-based anti-bullying intervention on primary school-aged children's knowledge about bullying and relevant coping strategies. Programme description: FearNot! is an interactive computer-based virtual learning environment designed for use as an anti-bullying intervention. It includes interactive virtual agents who assume the most common participant roles found in episodes of bullying. FearNot! was used by children over three consecutive weeks to allow its effectiveness to be evaluated in a longitudinal in situ programme. Sample: Two comparable samples were drawn from the UK and Germany. In the UK, 651 participants (aged 8-11) were recruited from primary schools in Hertfordshire, Coventry and Warwickshire, whereas the 535 German participants (aged 7-10) were sourced from Grundschulen in the Bayern and Hessen regions. Because of lack of parental consent, late joiners and absences/missing responses, data from 908 participants (UK 493; Germany 415) were analysed. Design and methods: A quasi-experimental, pre/post-tests control group design employed pre-published and bespoke questionnaires to collect data. Descriptive and inferential analyses were conducted. Results: UK students possessed higher coping strategy knowledge scores than German participants, but German children's scores improved over time and as a result of the FearNot! intervention. Conclusions: Overall, while not effective at increasing children's coping strategy knowledge in this study, the FearNot! intervention could prove a useful classroom tool to approach the issue of bullying as part of a wider initiative. Cultural differences at baseline and reactions to the intervention are discussed

A Bitter Taste Receptor as a Novel Molecular Target on Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma

Cancer-associated fibroblasts (CAFs) execute diverse and complex functions in cancer progression. While reprogramming the crosstalk between CAFs and cancer epithelial cells is a promising avenue to evade the adverse effects of stromal depletion, drugs are limited by their suboptimal pharmacokinetics and off-target effects. Thus, there is a need to elucidate CAF-selective cell surface markers that can improve drug delivery and efficacy. Here, functional proteomic pulldown with mass spectrometry was used to identify taste receptor type 2 member 9 (TAS2R9) as a CAF target. TAS2R9 target characterization included binding assays, immunofluorescence, flow cytometry, and database mining. Liposomes conjugated to a TAS2R9-specific peptide were generated, characterized, and compared to naked liposomes in a murine pancreatic xenograft model. Proof-of-concept drug delivery experiments demonstrate that TAS2R9-targeted liposomes bind with high specificity to TAS2R9 recombinant protein and exhibit stromal colocalization in a pancreatic cancer xenograft model. Furthermore, the delivery of a CXCR2 inhibitor by TAS2R9-targeted liposomes significantly reduced cancer cell proliferation and constrained tumor growth through the inhibition of the CXCL-CXCR2 axis. Taken together, TAS2R9 is a novel cell-surface CAF-selective target that can be leveraged to facilitate small-molecule drug delivery to CAFs, paving the way for new stromal therapies