Defects in DNA damage responses in SWI/SNF mutant cells and their impact on immune responses.

The mammalian SWI/SNF chromatin remodelling complexes are commonly dysregulated in cancer. These complexes contribute to maintaining genome stability through a variety of pathways. Recent research has highlighted an important interplay between genome instability and immune signalling, and evidence suggests that this interplay can modulate the response to immunotherapy. Here, we review emerging studies where direct evidence of this relationship has been uncovered in SWI/SNF deficient cells. We also highlight genome maintenance activities of SWI/SNF that could potentially shape immune responses and discuss potential therapeutic implications.

A recombinant approach for stapled peptide discovery yields inhibitors of the RAD51 recombinase.

Stapling is a macrocyclisation method that connects amino acid side chains of a peptide to improve its pharmacological properties. We describe an approach for stapled peptide preparation and biochemical evaluation that combines recombinant expression of fusion constructs of target peptides and cysteine-reactive divinyl-heteroaryl chemistry as an alternative to solid-phase synthesis. We then employ this workflow to prepare and evaluate BRC-repeat-derived inhibitors of the RAD51 recombinase, showing that a diverse range of secondary structure elements in the BRC repeat can be stapled without compromising binding and function. Using X-ray crystallography, we elucidate the atomic-level features of the staple moieties. We then demonstrate that BRC-repeat-derived stapled peptides can disrupt RAD51 function in cells following ionising radiation treatment.

PBAF loss leads to DNA damage-induced inflammatory signaling through defective G2/M checkpoint maintenance.

The PBRM1 subunit of the PBAF (SWI/SNF) chromatin remodeling complex is mutated in ∼40% of clear cell renal cancers. PBRM1 loss has been implicated in responses to immunotherapy in renal cancer, but the mechanism is unclear. DNA damage-induced inflammatory signaling is an important factor determining immunotherapy response. This response is kept in check by the G2/M checkpoint, which prevents progression through mitosis with unrepaired damage. We found that in the absence of PBRM1, p53-dependent p21 up-regulation is delayed after DNA damage, leading to defective transcriptional repression by the DREAM complex and premature entry into mitosis. Consequently, DNA damage-induced inflammatory signaling pathways are activated by cytosolic DNA. Notably, p53 is infrequently mutated in renal cancer, so PBRM1 mutational status is critical to G2/M checkpoint maintenance. Moreover, we found that the ability of PBRM1 deficiency to predict response to immunotherapy correlates with expression of the cytosolic DNA-sensing pathway in clinical samples. These findings have implications for therapeutic responses in renal cancer.

Aneuploidy tolerance caused by BRG1 loss allows chromosome gains and recovery of fitness.

Aneuploidy results in decreased cellular fitness in many species and model systems. However, aneuploidy is commonly found in cancer cells and often correlates with aggressive growth, suggesting that the impact of aneuploidy on cellular fitness is context dependent. The BRG1 (SMARCA4) subunit of the SWI/SNF chromatin remodelling complex is frequently lost in cancer. Here, we use a chromosomally stable cell line to test the effect of BRG1 loss on the evolution of aneuploidy. BRG1 deletion leads to an initial loss of fitness in this cell line that improves over time. Notably, we find increased tolerance to aneuploidy immediately upon loss of BRG1, and the fitness recovery over time correlates with chromosome gain. These data show that BRG1 loss creates an environment where karyotype changes can be explored without a fitness penalty. At least in some genetic backgrounds, therefore, BRG1 loss can affect the progression of tumourigenesis through tolerance of aneuploidy.

Improved RAD51 binders through motif shuffling based on the modularity of BRC repeats.

Exchanges of protein sequence modules support leaps in function unavailable through point mutations during evolution. Here we study the role of the two RAD51-interacting modules within the eight binding BRC repeats of BRCA2. We created 64 chimeric repeats by shuffling these modules and measured their binding to RAD51. We found that certain shuffled module combinations were stronger binders than any of the module combinations in the natural repeats. Surprisingly, the contribution from the two modules was poorly correlated with affinities of natural repeats, with a weak BRC8 repeat containing the most effective N-terminal module. The binding of the strongest chimera, BRC8-2, to RAD51 was improved by -2.4 kCal/mol compared to the strongest natural repeat, BRC4. A crystal structure of RAD51:BRC8-2 complex shows an improved interface fit and an extended ß-hairpin in this repeat. BRC8-2 was shown to function in human cells, preventing the formation of nuclear RAD51 foci after ionizing radiation.

Comparison of Pelvis and Trunk Kinematics Between Youth and Collegiate Windmill Softball Pitchers.

BACKGROUND: The windmill softball pitch is a dynamic sporting movement that places softball pitchers at high risk of injury. Unlike baseball, there is limited research into the mechanical differences between softball pitchers of varying skill levels. PURPOSE/HYPOTHESIS: The purpose of this study was to compare pelvis and trunk kinematics between youth and collegiate softball pitchers. It was hypothesized that there would be significant differences in pelvis and trunk kinematics between these 2 groups. STUDY DESIGN: Descriptive laboratory study. METHODS: The pelvic and trunk kinematics of 90 softball pitchers were collected during full-effort pitching using a 3-dimensional motion capture system. Participants were grouped based on their age at the time of data collection (35 youth [mean age, 11 ± 1 years]; 55 collegiate [mean age, 20 ± 2 years]). We compared between-group differences in pelvic posterior tilt, lateral tilt, axial rotation, and axial rotation velocity as well as trunk extension, lateral flexion, axial rotation, and axial rotation velocity during the pitching phase between start of pitch and ball release (BR) using 1-dimensional statistical parametric mapping. Statistical significance was determined using Holmes-Sidák stepdown correction-adjusted P values (P '). RESULTS: Compared with youth pitchers, collegiate pitchers exhibited a more posteriorly tilted pelvis from the moment of start of pitch until 94% of the way between start of pitch and BR (P ' = .002) and a more laterally flexed trunk toward the glove side from the moment of start of pitch until 71% of the way between start of pitch and BR (P ' = .010). CONCLUSION: Collegiate pitchers displayed a more posteriorly tilted pelvis and more laterally flexed trunk toward the glove side during the windmill pitching motion when compared with youth pitchers. CLINICAL RELEVANCE: These findings add to the growing body of softball research and help elucidate mechanical differences between youth and collegiate softball pitchers.

Increased Upper Arm Length and Loading Rate Identified as Potential Risk Factors for Injury in Youth Baseball Pitchers.

BACKGROUND: In the throwing elbow, increased elbow torque has been correlated with increased injury risk. Additional insight into the relationships between anthropometric factors and elbow joint loading is warranted. PURPOSE: To investigate the relationship among physical limb length characteristics, elbow kinetics, and elbow kinematics in youth baseball pitchers and to examine the relationship between elbow varus loading rate and elbow kinetics. DESIGN: Descriptive laboratory study. METHODS: A total of 27 male youth baseball pitchers participated (mean ± SD: age, 15.8 ± 2.7 years; height, 176.3 ± 13.0 cm; weight, 71.7 ± 16.4 kg). Upper arm (UA) and forearm (FA) lengths were measured using a moveable sensor to digitize bony landmarks. Kinematic data were collected at 240 Hz using an electromagnetic tracking system. Participants threw 3 fastballs to a catcher at a regulation distance (60 ft 6 in), and the fastest velocity trial was used for analysis. Linear regression was used to determine the relationship among limb length characteristics, elbow kinetics, and elbow kinematics after accounting for the effects of body weight and height. RESULTS: Pitchers with longer UA length experienced increased maximum elbow varus torque (P = .005) and maximum net elbow force (P = .001). Pitchers with an increased forearm to UA ratio had decreased elbow compression force (P < .001) and exhibited a more flexed elbow at foot contact (P = .001). Pitchers with greater maximum loading rates experienced greater elbow varus torque (P = .002). CONCLUSION: In youth baseball pitchers, longer UA length and greater loading rate increase varus torque about the elbow during a fastball pitch. CLINICAL RELEVANCE: Longer UA length and greater loading rate may place pitchers at risk of injury because of their relationship with kinetic values.

PBRM1 Deficiency Confers Synthetic Lethality to DNA Repair Inhibitors in Cancer.

Inactivation of Polybromo 1 (PBRM1), a specific subunit of the PBAF chromatin remodeling complex, occurs frequently in cancer, including 40% of clear cell renal cell carcinomas (ccRCC). To identify novel therapeutic approaches to targeting PBRM1-defective cancers, we used a series of orthogonal functional genomic screens that identified PARP and ATR inhibitors as being synthetic lethal with PBRM1 deficiency. The PBRM1/PARP inhibitor synthetic lethality was recapitulated using several clinical PARP inhibitors in a series of in vitro model systems and in vivo in a xenograft model of ccRCC. In the absence of exogenous DNA damage, PBRM1-defective cells exhibited elevated levels of replication stress, micronuclei, and R-loops. PARP inhibitor exposure exacerbated these phenotypes. Quantitative mass spectrometry revealed that multiple R-loop processing factors were downregulated in PBRM1-defective tumor cells. Exogenous expression of the R-loop resolution enzyme RNase H1 reversed the sensitivity of PBRM1-deficient cells to PARP inhibitors, suggesting that excessive levels of R-loops could be a cause of this synthetic lethality. PARP and ATR inhibitors also induced cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) innate immune signaling in PBRM1-defective tumor cells. Overall, these findings provide the preclinical basis for using PARP inhibitors in PBRM1-defective cancers. SIGNIFICANCE: This study demonstrates that PARP and ATR inhibitors are synthetic lethal with the loss of PBRM1, a PBAF-specific subunit, thus providing the rationale for assessing these inhibitors in patients with PBRM1-defective cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/11/2888/F1.large.jpg.

Differential and longitudinal immune gene patterns associated with reprogrammed microenvironment and viral mimicry in response to neoadjuvant radiotherapy in rectal cancer.

BACKGROUND: Rectal cancers show a highly varied response to neoadjuvant radiotherapy/chemoradiation (RT/CRT) and the impact of the tumor immune microenvironment on this response is poorly understood. Current clinical tumor regression grading systems attempt to measure radiotherapy response but are subject to interobserver variation. An unbiased and unique histopathological quantification method (change in tumor cell density (ΔTCD)) may improve classification of RT/CRT response. Furthermore, immune gene expression profiling (GEP) may identify differences in expression levels of genes relevant to different radiotherapy responses: (1) at baseline between poor and good responders, and (2) longitudinally from preradiotherapy to postradiotherapy samples. Overall, this may inform novel therapeutic RT/CRT combination strategies in rectal cancer. METHODS: We generated GEPs for 53 patients from biopsies taken prior to preoperative radiotherapy. TCD was used to assess rectal tumor response to neoadjuvant RT/CRT and ΔTCD was subjected to k-means clustering to classify patients into different response categories. Differential gene expression analysis was performed using statistical analysis of microarrays, pathway enrichment analysis and immune cell type analysis using single sample gene set enrichment analysis. Immunohistochemistry was performed to validate specific results. The results were validated using 220 pretreatment samples from publicly available datasets at metalevel of pathway and survival analyses. RESULTS: ΔTCD scores ranged from 12.4% to -47.7% and stratified patients into three response categories. At baseline, 40 genes were significantly upregulated in poor (n=12) versus good responders (n=21), including myeloid and stromal cell genes. Of several pathways showing significant enrichment at baseline in poor responders, epithelial to mesenchymal transition, coagulation, complement activation and apical junction pathways were validated in external cohorts. Unlike poor responders, good responders showed longitudinal (preradiotherapy vs postradiotherapy samples) upregulation of 198 immune genes, reflecting an increased T-cell-inflamed GEP, type-I interferon and macrophage populations. Longitudinal pathway analysis suggested viral-like pathogen responses occurred in post-treatment resected samples compared with pretreatment biopsies in good responders. CONCLUSION: This study suggests potentially druggable immune targets in poor responders at baseline and indicates that tumors with a good RT/CRT response reprogrammed from immune "cold" towards an immunologically "hot" phenotype on treatment with radiotherapy.

TP53 modulates radiotherapy fraction size sensitivity in normal and malignant cells.

Recent clinical trials in breast and prostate cancer have established that fewer, larger daily doses (fractions) of radiotherapy are safe and effective, but these do not represent personalised dosing on a patient-by-patient basis. Understanding cell and molecular mechanisms determining fraction size sensitivity is essential to fully exploit this therapeutic variable for patient benefit. The hypothesis under test in this study is that fraction size sensitivity is dependent on the presence of wild-type (WT) p53 and intact non-homologous end-joining (NHEJ). Using single or split-doses of radiation in a range of normal and malignant cells, split-dose recovery was determined using colony-survival assays. Both normal and tumour cells with WT p53 demonstrated significant split-dose recovery, whereas Li-Fraumeni fibroblasts and tumour cells with defective G1/S checkpoint had a large S/G2 component and lost the sparing effect of smaller fractions. There was lack of split-dose recovery in NHEJ-deficient cells and DNA-PKcs inhibitor increased sensitivity to split-doses in glioma cells. Furthermore, siRNA knockdown of p53 in fibroblasts reduced split-dose recovery. In summary, cells defective in p53 are less sensitive to radiotherapy fraction size and lack of split-dose recovery in DNA ligase IV and DNA-PKcs mutant cells suggests the dependence of fraction size sensitivity on intact NHEJ.

Hip Range of Motion and Strength and Energy Flow During Windmill Softball Pitching.

CONTEXT: Inadequate hip range of motion (ROM) and isometric strength (ISO) may interfere with energy flow through the kinetic chain and result in increased injury susceptibility. OBJECTIVE: To examine the relationship of hip ROM and ISO with energy flow through the trunk and pitching-arm segments during the windmill softball pitch in youth athletes. A subsequent purpose was to examine the relationship between energy flow and pitch speed. DESIGN: Descriptive laboratory study. SETTING: University research laboratory. PATIENTS OR OTHER PARTICIPANTS: A sample of 29 youth softball pitchers (age = 11.2 ± 1.3 years, height = 155.0 ± 10.4 cm, mass = 53.2 ± 12.6 kg). MAIN OUTCOME MEASURE(S): Bilateral hip internal-rotation and external-rotation (ER) ROM and ISO were measured. Net energy outflow and peak rates of energy outflow from the distal ends of the trunk, humerus, and forearm were calculated for the acceleration phase of the windmill softball pitch, and pitch speed was measured. RESULTS: Regression analysis revealed an effect of drive-hip ER ISO on the net energy flow out of the distal ends of the trunk (P = .045) and humerus (P = .002). Specifically, increased drive-hip ER ISO was associated with increased net energy outflow from the trunk to the humerus and from the humerus to the forearm. No significant effects of hip ROM or other hip ISO measures were observed. Additionally, pitchers who achieved higher peak rates of distal outflow tended to achieve higher pitch speeds. CONCLUSIONS: An association was present between drive-hip ER ISO and the net energy flow out of the distal ends of the trunk and humerus during the acceleration phase of the windmill softball pitch, emphasizing the importance of hip and lower body strength in executing the whole-body windmill pitch. Overall, energy-flow analysis is an interesting new way to analyze pitching mechanics and will aid in furthering our understanding of performance and injury risk in windmill softball pitching.

Kinematic Differences Exist Between the Fastball, Changeup, Curveball, and Dropball Pitch Types in Collegiate Softball Pitchers.

BACKGROUND: A majority of softball literature focuses on the mechanics associated with pain and injury within a single pitch type per study; however, the generalizability of these findings is unknown since a kinematic comparison has yet to be performed between pitch types. Understanding kinematic differences between pitch types can be used to identify risk factors for injury, improve safety guidelines, and improve performance by linking specific mechanics with desired pitch outcomes. HYPOTHESIS/PURPOSE: The purpose of this study was to compare kinematics between the fastball, changeup, curveball, and dropball pitch types in collegiate softball pitchers. It was hypothesized that there would be significant kinematic differences between pitch types. STUDY DESIGN: Descriptive laboratory study. METHODS: A total of 28 female collegiate softball pitchers pitched 3 trials of each pitch type to a catcher at regulation distance. Pitch speed, stride length, trunk extension, trunk rotation, trunk lateral flexion, elbow flexion, and center of mass for each trial were calculated using an electromagnetic motion capture system and were averaged for analysis. A 1-way analysis of variance (ANOVA) was used to investigate pitch speed differences between the 4 pitch types. A 4 (pitch type) × 5 (event) within-athlete multivariate ANOVA was also used to determine kinematic differences. RESULTS: The results revealed a significant difference in pitch speed between pitch types; a pitch type main effect for trunk extension, trunk rotation, trunk lateral flexion, and center of mass; and an event main effect for all variables except stride length. The results also revealed a pitch type by event interaction for trunk flexion, trunk lateral flexion, and center of mass. Specifically, the dropball type had less trunk extension than the fastball at all pitching events. Similarly, the curveball type had a more posteriorly shifted center of mass than the dropball at the last 3 pitching events of foot contact, ball release and follow-through. CONCLUSION: Significant kinematic differences exist between pitch types, but these differences may be necessary to execute desired pitch outcomes. CLINICAL RELEVANCE: This is the first study to analyze kinematic differences between pitch types in softball pitchers. Understanding the effects of different pitch types on kinematic parameters may enhance injury prevention and performance strategies for softball pitchers.

Effects of Hip Range of Motion and Isometric Strength on Energy Flow during Windmill Softball Pitching.

CONTEXT: Inadequate hip range of motion (ROM) and isometric strength (ISO) may interfere with energy flow through the kinetic chain and result in increased injury susceptibility. OBJECTIVE: To examine the relationship of hip ROM and ISO with energy flow through the trunk and pitching arm segments during the windmill softball pitch in youth athletes. A subsequent purpose was to examine the relationship between energy flow and pitch speed. DESIGN: Descriptive laboratory study. SETTING: University research laboratory. PARTICIPANTS: A sample of 29 youth softball pitchers (11.2±1.3 yrs.; 155.0±10.4 cm; 53.2±12.6 kg). MAIN OUTCOME MEASURE(S): Bilateral hip internal rotation (IR) and external rotation (ER) ROM and ISO were measured. Net energy outflow and peak rates of energy outflow from the distal ends of the trunk, humerus, and forearm were calculated for the acceleration phase of the windmill softball pitch, and pitch speed was measured. RESULTS: Regression analysis revealed a significant effect of drive hip ER ISO on the net energy flow out of the distal ends of the trunk (p=0.045) and humerus (p=0.002). Specifically, increased drive hip ER ISO was associated with increased net energy outflow from the trunk to the humerus and from the humerus to the forearm. No significant effects of hip ROM or other hip ISO measures were observed. Additionally, pitchers who achieved higher peak rates of distal outflow tended to also achieve higher pitch speeds. CONCLUSIONS: There is an association between drive hip ER ISO and the net energy flow out of the distal ends of the trunk and humerus during the acceleration phase of the windmill softball pitch, emphasizing the importance of hip and lower body strength in the execution of the whole-body windmill pitch. Overall, energy flow analysis is an interesting new way to analyze pitching mechanics and will aid in further understanding of performance and injury risk in windmill softball pitching.

Histone isoforms and the oncohistone code.

Recent studies have highlighted the potential for missense mutations in histones to act as oncogenic drivers, leading to the term 'oncohistones'. While histone proteins are highly conserved, they are encoded by multigene families. There is heterogeneity among these genes at the level of the underlying sequence, the amino acid composition of the encoded histone isoform, and the expression levels. One question that arises, therefore, is whether all histone-encoding genes function equally as oncohistones. In this review, we consider this question and explore what this means in terms of the mechanisms by which oncohistones can exert their effects in chromatin.

Biceps Tendon Changes and Pitching Mechanics in Youth Softball Pitchers.

With the lack of pitch count regulation, youth softball pitchers are experiencing unremitting high stresses on the anterior shoulder. The purpose of this study was to examine the association of acute changes in the long head of the biceps tendon with pitching kinematics and kinetics in youth softball pitchers following an acute bout of pitching. Twenty-three softball pitchers (12.17±1.50 yrs.; 160.32±9.41 cm; 60.40±15.97 kg) participated. To investigate the association between biceps tendon changes and kinematic and kinetic changes from pre- to post-simulated game, each biceps tendon measure was split into those whose biceps tendon thickness, width, and/or area increased pre- to post-simulated game, and those whose did not. There were significant differences in biceps tendon longitudinal thickness (Z=- 2.739, p=0.006) and pitch speed; as well as a difference between groups in biceps tendon transverse thickness and the amount of change in trunk rotation at the start of the pitching motion (p=0.017) and the amount of change in trunk flexion at ball release (p=0.030). This study illustrates the association of trunk and lower extremity kinematics and shoulder kinetics with morphologic changes in the biceps tendon with an acute bout of windmill softball pitching.

Influence of a Pre-throwing Protocol on Range of Motion and Strength in Baseball Athletes.

Though chronic overhand throwing is known to result in range of motion and strength adaptations, there is limited research regarding interventions for maintenance of these characteristics. Therefore, the purposes of this study were to explore the use of a pre-throwing protocol focusing on lumbopelvic-hip complex musculature in high school baseball players and examine its effects on shoulder and hip range of motion and isometric strength over the course of a season. Four exercises were added to the intervention team's warm-up routine. The control and intervention teams' passive bilateral hip and shoulder range of motion and isometric strength were assessed pre/post-season. A multivariate analysis of variance revealed significant differences in delta scores between the teams for multiple shoulder and hip range of motion and isometric strength variables. Key results were the intervention team lost significantly more stride hip external rotation but gained more isometric strength than the control team. The intervention team was also able to better maintain shoulder range of motion than the control team. Practitioners should use the results of this study and consider incorporating exercises that target lumbopelvic-hip complex musculature into their current training program.

DESCRIPTIVE PROFILE OF SHOULDER RANGE OF MOTION AND STRENGTH IN YOUTH ATHLETES PARTICIPATING IN OVERHEAD SPORTS.

BACKGROUND: The unilateral and repetitive nature of overhead sports, often result in a biomechanical overload of the upper extremity. Understanding the musculoskeletal shoulder range of motion (ROM) and strength patterns in the youth sports of baseball, softball, and tennis could assist injury prevention screening and further the development of conditioning and rehabilitation programs. PURPOSE: To generate a descriptive profile of shoulder musculoskeletal characteristics and determine whether bilateral differences in shoulder ROM exist in youth baseball, softball, and tennis athletes. A secondary aim was to determine whether shoulder rotational adaptations are correlated with playing position, sport, or years of experience. STUDY DESIGN: Descriptive Laboratory. METHODS: A total of 136 competitive youth overhead athletes (baseball: n = 51,12.8 ± 0.9yrs; softball: n = 63,12.3 ± 1.1yrs; and tennis: n = 22,12.5 ± 0.9yrs) participated. Bilateral shoulder internal (IR) and external (ER) passive ROM and external rotation strength were measured using an inclinometer and handheld dynamometer. RESULTS: Significant differences (p<.001) in bilateral shoulder ROM and ER strength were found between the athletes in the three sports. Post-hoc test revealed tennis athletes had greater bilateral shoulder ROM than both baseball and softball athletes, but baseball and softball athletes had greater bilateral ER strength than tennis athletes. There were no differences between baseball and softball athletes. Additionally, tennis athletes had greater bilateral internal rotation and total ROM but less ER strength than baseball pitchers, baseball positional athletes, softball pitchers, and softball positional athletes. There were no significant differences between positions and baseball and softball athletes. There were no significant correlations between playing position, sport, or years of experience. CONCLUSION: The results of this study showed differences in shoulder passive ROM and strength adaptations between youth tennis, baseball, and softball athletes. The descriptive nature of this study is impactful as it presents specific ROM adaptions seen in this population. Future research is needed to further evaluate if the "at risk" ROM identified in older populations holds true in the youth population. LEVEL OF EVIDENCE: Diagnosis, Level 3b.

CHD7 and 53BP1 regulate distinct pathways for the re-ligation of DNA double-strand breaks.

Chromatin structure is dynamically reorganized at multiple levels in response to DNA double-strand breaks (DSBs). Yet, how the different steps of chromatin reorganization are coordinated in space and time to differentially regulate DNA repair pathways is insufficiently understood. Here, we identify the Chromodomain Helicase DNA Binding Protein 7 (CHD7), which is frequently mutated in CHARGE syndrome, as an integral component of the non-homologous end-joining (NHEJ) DSB repair pathway. Upon recruitment via PARP1-triggered chromatin remodeling, CHD7 stimulates further chromatin relaxation around DNA break sites and brings in HDAC1/2 for localized chromatin de-acetylation. This counteracts the CHD7-induced chromatin expansion, thereby ensuring temporally and spatially controlled 'chromatin breathing' upon DNA damage, which we demonstrate fosters efficient and accurate DSB repair by controlling Ku and LIG4/XRCC4 activities. Loss of CHD7-HDAC1/2-dependent cNHEJ reinforces 53BP1 assembly at the damaged chromatin and shifts DSB repair to mutagenic NHEJ, revealing a backup function of 53BP1 when cNHEJ fails.

The role of the SWI/SNF chromatin remodelling complex in the response to DNA double strand breaks.

Mammalian cells possess multiple closely related SWI/SNF chromatin remodelling complexes. These complexes have been implicated in the cellular response to DNA double strand breaks (DSBs). Evidence suggests that SWI/SNF complexes contribute to successful repair via both the homologous recombination and non-homologous end joining pathways. In addition, repressing transcription near DSBs is dependent on SWI/SNF activity. Understanding these roles is important because SWI/SNF complexes are frequently dysregulated in cancer, and DNA DSB repair defects have the potential to be therapeutically exploited. In this graphical review, we summarise what is known about SWI/SNF contribution to DNA DSB responses in mammalian cells and provide an overview of the SWI/SNF-encoding gene alteration spectrum in human cancers.

Effects of a Simulated Game on Pitching Kinematics in Youth Softball Pitcher.

Despite evidence that overuse is the most common mechanism of injury, softball pitchers currently have no pitch count regulations. Pain has been associated with certain pitching pathomechanics, and some reports indicate increased pain following a single pitching bout. Therefore, the purpose of this study was to examine trunk and lower extremity kinematics during the first and last inning of a game, as well as last inning pitch volume in youth softball pitchers. Thirty-two youth softball pitchers (12.4±1.6 years, 159.4±8.9 cm, 62.0±13.6 kg) pitched a simulated game. Three fastballs were averaged and analyzed from the first and last inning. Kinematic data were collected at 100Hz using an electromagnetic system, synced with motion analysis software. A Wilcoxon signed rank test revealed pitchers exhibited less trunk rotation toward their pitching arm side in the last inning. A bivariate Pearson's correlation showed volume of pitches was correlated with stride length (r=0.367, p=0.039) and center of mass (r=0.364, p=0.041) at the start of the pitch, and trunk flexion at top of pitch (r=-0.392, p=0.026), foot contact (r=-0.413, p=0.019), and follow-through (r=-0.436, p=0.013). This study found that pitching a simulated game did result in altered pitching mechanics, meanwhile pitch volume was also correlated with pitching mechanics.