In Vitro and In Vivo Drug-Response Profiling Using Patient-Derived High-Grade Glioma.

BACKGROUND: Genomic profiling cannot solely predict the complexity of how tumor cells behave in their in vivo microenvironment and their susceptibility to therapies. The aim of the study was to establish a functional drug prediction model utilizing patient-derived GBM tumor samples for in vitro testing of drug efficacy followed by in vivo validation to overcome the disadvantages of a strict pharmacogenomics approach. METHODS: High-throughput in vitro pharmacologic testing of patient-derived GBM tumors cultured as 3D organoids offered a cost-effective, clinically and phenotypically relevant model, inclusive of tumor plasticity and stroma. RNAseq analysis supplemented this 128-compound screening to predict more efficacious and patient-specific drug combinations with additional tumor stemness evaluated using flow cytometry. In vivo PDX mouse models rapidly validated (50 days) and determined mutational influence alongside of drug efficacy. We present a representative GBM case of three tumors resected at initial presentation, at first recurrence without any treatment, and at a second recurrence following radiation and chemotherapy, all from the same patient. RESULTS: Molecular and in vitro screening helped identify effective drug targets against several pathways as well as synergistic drug combinations of cobimetinib and vemurafenib for this patient, supported in part by in vivo tumor growth assessment. Each tumor iteration showed significantly varying stemness and drug resistance. CONCLUSIONS: Our integrative model utilizing molecular, in vitro, and in vivo approaches provides direct evidence of a patient's tumor response drifting with treatment and time, as demonstrated by dynamic changes in their tumor profile, which may affect how one would address that drift pharmacologically.

The effects of strength training upon front foot contact ground reaction forces and ball release speed among high-level cricket pace bowlers.

The effects of an eight-week off-season strength training program upon lower-body strength, power, eccentric capacity, front foot contact (FFC) kinetics, and ball release speed (BRS) in pace bowlers were investigated. Ten elite-academy pace bowlers completed the intervention, and pre- and post-testing. Pre- and post-testing included: double (DLDL) and single leg (SLDL) drop landings; isometric mid-thigh pull (IMTP); countermovement jump; and pace bowling performance (two-over bowling spell measuring BRS and FFC kinetics). Changes from pre- to post-testing were assessed with paired sample t tests (p≤ 0.01), effects sizes and statistical parametrical mapping. Post-testing revealed a significant decrease in peak normalised vertical force during DLDL and SLDL with large effects and a significant, moderate effect increase in IMTP. There was no significant changes in BRS. Concomitantly, neither discrete scalar (p= 0.15-0.58) nor vector field analysis kinetics during FFC indicated significant changes. No significant alterations in FFC kinetics may explain the lack of improvement in BRS (pre = 31.55 ± 1.44 m/s; post = 31.79 ± 1.33 m/s). This study indicated an eight-week strength training program can improve strength and eccentric capacity in pace bowlers, and these changes when developed in the absence of skills training neither improved nor decreased pace bowling performance.

Does Delivery Length Impact Measures of Whole-Body Biomechanical Load During Pace Bowling?

PURPOSE: To investigate whether changes in delivery length (ie, short, good, and full) lead to alterations in whole-body biomechanical loading as determined by ground reaction force during front-foot contact of the delivery stride for pace bowlers. Current load-monitoring practices of pace bowling in cricket assume equivocal biomechanical loading as only the total number of deliveries are monitored irrespective of delivery length. METHODS: A total of 16 male pace bowlers completed a 2-over spell at maximum intensity while targeting different delivery lengths (short, 7-10 m; good, 4-7 m; and full, 0-4 m from the batter's stumps). In-ground force plates were used to determine discrete (vertical and braking force, impulse, and loading rates) and continuous front-foot contact ground reaction force. Repeated-measures analysis of variance (P < .05), effects size, and statistical parametrical mapping were used to determine differences between delivery lengths. RESULTS: There were no significant differences between short, good, and full delivery lengths for the discrete and continuous kinetic variables investigated (P = .19-1.00), with trivial to small effect sizes. CONCLUSION: There were minimal differences in front-foot contact biomechanics for deliveries of different lengths (ie, short, good, and full). These data reinforce current pace bowling load-monitoring practices (ie, counting the number of deliveries), as changes in delivery length do not affect the whole-body biomechanical loading experienced by pace bowlers. This is of practical importance as it retains simplicity in load-monitoring practice that is used widely across different competition levels and ages.

The relationship between inertial measurement unit-derived 'force signatures' and ground reaction forces during cricket pace bowling.

This study assessed the reliability and validity of segment measured accelerations in comparison to front foot contact (FFC) ground reaction force (GRF) during the delivery stride for cricket pace bowlers. Eleven recreational bowlers completed a 30-delivery bowling spell. Trunk- and tibia-mounted inertial measurement units (IMUs) were used to measure accelerations, converted to force, for comparisons to force plate GRF discrete measures. These measures included peak force, impulse and the continuous force-time curve in the vertical and braking (horizontal) planes. Reliability and validity was determined by intra-class correlation coefficients (ICC), coefficient of variation (CV), Bland-Altman plots, paired sample t-tests, Pearson's correlation and one-dimensional (1D) statistical parametrical mapping (SPM). All ICC (0.90-0.98) and CV (4.23-7.41%) were acceptable, except for tibia-mounted IMU braking peak force (CV = 12.44%) and impulse (CV = 18.17%) and trunk vertical impulse (CV = 17.93%). Bland-Altman plots revealed wide limits of agreement between discrete IMU force signatures and force plate GRF. The 1D SPM outlined numerous significant (p < 0.01) differences between trunk- and tibia-located IMU-derived measures and force plate GRF traces in vertical and braking (horizontal) planes. The trunk- and tibia-mounted IMUs appeared to not represent the GRF experienced during pace bowling FFC when compared to a gold-standard force plate.

The Effects of an Eight over Cricket Bowling Spell upon Pace Bowling Biomechanics and Performance within Different Delivery Lengths.

Pace bowlers must often perform extended bowling spells with maximal ball release speed (BRS) while targeting different delivery lengths when playing a multi-day match. This study investigated the effect of an eight over spell upon pace bowling biomechanics and performance at different delivery lengths. Nine male bowlers (age = 18.8 ± 1.7 years) completed an eight over spell, while targeting different lengths (short: 7-10 m, good: 4-7 m, full: 0-4 m from the batter's stumps, respectively) in a randomized order. Trunk, knee and shoulder kinematics and ground reaction forces at front foot contact (FFC), as well as run-up velocity and BRS were measured. Paired sample t-tests (p ≤ 0.01), Hedges' g effect sizes, and statistical parametrical mapping were used to assess differences between mean variables from the first and last three overs. No significant differences (p = 0.05-0.98) were found in any discrete or continuous variables, with the magnitude of difference being trivial-to-medium (g = 0.00-0.73) across all variables. Results suggest pace bowlers sustain BRS through a single eight over spell while tolerating the repeatedly high whole-body biomechanical loads as suggested by maintaining the kinematics or technique at the assessed joints during FFC. Practically, the findings are advantageous for bowling performance and support current bowling load monitoring practices.

Genome-Wide Structural Variation Detection by Genome Mapping on Nanochannel Arrays.

Comprehensive whole-genome structural variation detection is challenging with current approaches. With diploid cells as DNA source and the presence of numerous repetitive elements, short-read DNA sequencing cannot be used to detect structural variation efficiently. In this report, we show that genome mapping with long, fluorescently labeled DNA molecules imaged on nanochannel arrays can be used for whole-genome structural variation detection without sequencing. While whole-genome haplotyping is not achieved, local phasing (across >150-kb regions) is routine, as molecules from the parental chromosomes are examined separately. In one experiment, we generated genome maps from a trio from the 1000 Genomes Project, compared the maps against that derived from the reference human genome, and identified structural variations that are >5 kb in size. We find that these individuals have many more structural variants than those published, including some with the potential of disrupting gene function or regulation.

Rapid detection of structural variation in a human genome using nanochannel-based genome mapping technology.

BACKGROUND: Structural variants (SVs) are less common than single nucleotide polymorphisms and indels in the population, but collectively account for a significant fraction of genetic polymorphism and diseases. Base pair differences arising from SVs are on a much higher order (>100 fold) than point mutations; however, none of the current detection methods are comprehensive, and currently available methodologies are incapable of providing sufficient resolution and unambiguous information across complex regions in the human genome. To address these challenges, we applied a high-throughput, cost-effective genome mapping technology to comprehensively discover genome-wide SVs and characterize complex regions of the YH genome using long single molecules (>150 kb) in a global fashion. RESULTS: Utilizing nanochannel-based genome mapping technology, we obtained 708 insertions/deletions and 17 inversions larger than 1 kb. Excluding the 59 SVs (54 insertions/deletions, 5 inversions) that overlap with N-base gaps in the reference assembly hg19, 666 non-gap SVs remained, and 396 of them (60%) were verified by paired-end data from whole-genome sequencing-based re-sequencing or de novo assembly sequence from fosmid data. Of the remaining 270 SVs, 260 are insertions and 213 overlap known SVs in the Database of Genomic Variants. Overall, 609 out of 666 (90%) variants were supported by experimental orthogonal methods or historical evidence in public databases. At the same time, genome mapping also provides valuable information for complex regions with haplotypes in a straightforward fashion. In addition, with long single-molecule labeling patterns, exogenous viral sequences were mapped on a whole-genome scale, and sample heterogeneity was analyzed at a new level. CONCLUSION: Our study highlights genome mapping technology as a comprehensive and cost-effective method for detecting structural variation and studying complex regions in the human genome, as well as deciphering viral integration into the host genome.

Can a Specific Neck Strengthening Program Decrease Cervical Spine Injuries in a Men's Professional Rugby Union Team? A Retrospective Analysis.

Cervical spine injuries in Rugby Union are a concerning issue at all levels of the game. The primary aim of this retrospective analysis conducted in a professional Rugby Union squad was to determine whether a 26-week isometric neck strengthening intervention program (13-week strengthening phase and 13-week maintenance phase) was effective in reducing the number and severity of cervical spine injuries. The secondary aim was to determine whether at week five, where the program had been the similar for all players, there was increased isometric neck strength. All 27 players who were common to both the 2007-2008 and 2008-2009 seasons were included in this analysis and data was extracted from a Sports Medicine/Sports Science database which included the squad's injury records. Primary outcome variables included; the number of cervical spine injuries and the severity of these injuries as determined by the total number of days lost from training and competition. Secondary outcome variables included isometric neck strength in flexion, extension and left and right lateral flexion. Using non-parametric statistical methods, no significant differences were evident for the total number of cervical spine injuries (n = 8 in 2007-2008, n = 6 in 2008-2009) or time loss due to these injuries (100 days in 2007-2008, 40 days in 2008-2009). However, a significant (p = 0.03) reduction in the number of match injuries was evident from 2007-2008 (n = 11) to 2008-09 (n = 2). Non-significant increases in isometric neck strength were found in all directions examined. A significant reduction in the number of match injuries was evident in this study. However, no other significant changes to primary outcome variables were achieved. Further, no significant increases in isometric neck strength were found in this well-trained group of professional athletes. Key PointsWhile many authors have proposed that neck strengthening could be an effective strategy in preventing cervical spine injuries in Rugby Union, there is currently little information in the literature pertaining to how such a study might be conducted.A significant decrease in the number of injuries recorded in matches can be achieved using a specific neck strengthening program at the elite level.In an elite rugby union team as investigated in this study a significant increase in neck strength is difficult to achieve in a short period of time such as five weeks.

Does performance of hang power clean differentiate performance of jumping, sprinting, and changing of direction?

The primary purpose of this study was to investigate whether the athlete who has high performance in hang power clean, a common weightlifting exercise, has high performances in sprinting, jumping, and changing of direction (COD). As the secondary purpose, relationships between hang power clean performance, maximum strength, power and performance of jumping, sprinting, and COD also were investigated. Twenty-nine semiprofessional Australian Rules football players (age, height, and body mass [mean +/- SD]: 21.3 +/- 2.7 years, 1.8 +/- 0.1 m, and 83.6 +/- 8.2 kg) were tested for one repetition maximum (1RM) hang power clean, 1RM front squat, power output during countermovement jump with 40-kg barbell and without external load (CMJ), height of CMJ, 20-m sprint time, and 5-5 COD time. The subjects were divided into top and bottom half groups (n = 14 for each group) based on their 1RM hang power clean score relative to body mass, then measures from all other tests were compared with one-way analyses of variance. In addition, Pearson's product moment correlations between measurements were calculated among all subjects (n = 29). The top half group possessed higher maximum strength (P < 0.01), power (P < 0.01), performance of jumping (P < 0.05), and sprinting (P < 0.01). However, there was no significant difference between groups in 5-5 COD time, possibly because of important contributing factors other than strength and power. There were significant correlations between most of, but not all, combinations of performances of hang power clean, jumping, sprinting, COD, maximum strength, and power. Therefore, it seems likely there are underlying strength qualities that are common to the hang power clean, jumping, and sprinting.

Comparison of weighted jump squat training with and without eccentric braking.

The purpose of this study was to investigate the effect of weighted jump squat training with and without eccentric braking. Twenty male subjects were divided into two groups (n = 10 per group), Non-Braking Group and Braking Group. The subjects were physically active, but not highly trained. The program for Non-Braking Group consisted of 6 sets of 6 repetitions of weighted jump squats without reduction of eccentric load for 8 weeks. The training program for the Braking Group consisted of the same sets and repetitions, but eccentric load was reduced by using an electromagnetic braking mechanism. Jump and reach, countermovement jump, static jump, drop jump, one repetition maximum half squat, weighted jump squat, and isometric/isokinetic knee extension/flexion at several different positions/angular velocities were tested pre- and posttraining intervention. The Non-Braking Group exhibited greater improvement in peak torque during isokinetic concentric knee flexion at 300 degrees/s [Non-Braking Group: (mean +/- SD) 124.0 +/- 22.6 Nm at pre- and 134.1 +/- 18.4 Nm at posttraining, and Braking Group: 118.5 +/- 32.7 Nm at pre- and 113.2 +/- 26.7 Nm at posttraining]. Braking Group exhibited superior adaptations in peak power relative to body mass during weighted jump squat [Non-Braking Group: (mean +/- SD) 49.1 +/- 8.6 W/kg at pre- and 50.9 +/- 6.2 W/kg at posttraining, and Braking Group: 47.9 +/- 6.9 W/kg at pre- and 53.7 +/- 7.3 W/kg at posttraining]. It appears that power output in relatively slow movement (weighted jump squat) was improved more in the Braking Group, however strength in high velocity movements (isokinetic knee flexion at 300 degrees/s) was improved more in Non-Braking Group. This study supports load and velocity specific effects of weighted jump squat training.

Comparison of four different methods to measure power output during the hang power clean and the weighted jump squat.

Measurement of power output during resistance training is becoming ubiquitous in strength and conditioning programs, but there is great variation in the methods used. The main purposes of this study were to compare the power output values obtained from 4 different methods and to examine the relationships between these values. Male semiprofessional Australian rules football players (n = 30) performed hang power clean and weighted jump squat while ground reaction force (GRF)-time data and barbell displacement-time data were sampled simultaneously using a force platform and a linear position transducer attached to the barbell. Peak and mean power applied to the barbell was obtained from barbell displacement-time data (method 1). Peak and mean power applied to the system (barbell + lifter) was obtained from 3 other methods: (a) using GRF-time data (method 2), (b) using barbell displacement-time data (method 3), and (c) using both barbell displacement-time data and GRF-time data (method 4). The peak power values (W) obtained from methods 1, 2, 3, and 4 were (mean +/- SD) 1,644 +/- 295, 3,079 +/- 638, 3,821 +/- 917, and 4,017 +/- 833 in hang power clean and 1,184 +/- 115, 3,866 +/- 451, 3,567 +/- 494, and 4,427 +/- 557 in weighted jump squat. There were significant differences between power output values obtained from method 1 vs. methods 2, 3, and 4, as well as method 2 vs. methods 3 and 4. The power output applied to the barbell and that applied to the system was significantly correlated (r = 0.65-0.81). As a practical application, it is important to understand the characteristics of each method and consider how power output should be measured during the hang power clean and the weighted jump squat.