Analysis of high and low physical functioning breast cancer survivors within two years of treatment

The five year survivorship rate of females diagnosed with breast cancer is 88% across Canada (Canadian Cancer Society, 2015). Often, treatments can cause damage to the tissue which may lead to impairment of upper limb function, specifically range of motion and strength. There have been several attempts to quantify these changes, but to inconclusive extents. This study investigated differences between breast cancer survivors with low and high self-reported physical functioning scores, differences between affected and unaffected limbs, as well as differences after 4 months of usual care. Ten female breast cancer survivors (between 3 months and 2 years post treatment) completed six maximal strength trials (flexion, extension, abduction, adduction, internal and external rotation) per limb and six maximal range of motion trials (flexion, extension, abduction, scapular plane abduction, and internal and external rotation), along with three questionnaires. Groups were split based on scores from the disability of arm, shoulder and hand (DASH) questionnaire. Maximal strength was compared for strength trials, and glenohumeral elevation was compared for range of motion trials. For both sets of trials, peak, median and static muscular activity was compared for high and low physical function scores as well as between affected and unaffected limbs. No differences were found between affected and unaffected limbs for either strength or range of motion. However, flexion, extension, abduction, and adduction strength were 32-52% higher in the group with higher self-reported physical functioning scores compared to the group with lower self-reported physical function scores. Correspondingly, internal rotation range of motion was 1.92 times higher in the group with higher physical function scores (effect size =1.98). The other five range of motion tasks (abduction, flexion, extension, scapular plane abduction and external rotation) were not statistically different between groups of high and low physical function scores but had moderate to large effect sizes (0.42-0.94). Several measures were correlated with DASH scores, indicating that increased strength and range of motion relate to self-reported physical functioning in breast cancer survivors. Between baseline and follow up, none of the six measured strengths changed, with only one of the six range of motion measures increased over the four month period. Extension range of motion increased by 112% during this period of usual care. Overall, this thesis provides insight into the period of time immediately following treatment. These variables had not been evaluated within the first two years of survivorship. Additionally, this work suggests breast cancer survivors are not a homogeneous group, and that function (range of motion and strength) differ. In previous literature, all outcomes are reported from one group and have been inconclusive. However this work shows that there may be a difference in survivors’ function. This can help refine future rehabilitation strategies as the deficits for these individuals can be quantified more accurately

Breast cancer survivor functional changes immediately following treatment: quantifying mechanisms of strength deficits and compensatory kinematic and muscular strategy adaptations

Breast cancer is prevalent among Canadian women, but treatments may cause functional impairments among survivors. Over 22,000 Canadian women join the survivor population yearly (Brenner et al., 2020). Despite this substantial number, minimal research has approached the challenges faced by this population after primary treatment. Particularly, decreases in strength, range of motion and shoulder-related quality of life are widely reported (Harrington, Padua, Battaglini, & Michener, 2013; Lee, Kilbreath, Refshauge, Herbert, & Beith, 2008; Rietman et al., 2004). These factors, linked with changes in kinematics and muscular activation may result in further complications (Brookham, Cudlip, & Dickerson, 2018a, 2018b). Variability in previous studies, in both the population sampled and results make it difficult to isolate potential mechanism disrupting function. Further, this complicates the determination of key deficits to target in the early years of survivorship. Therefore, the purpose of this dissertation was to determine which factors affect breast cancer survivors in the first two years following the conclusion of treatment, if these factors translate to differences during low load functional tasks, and to investigate the feasibility of increasing strength (as a surrogate for function) to help mitigate these factors and increase function. Study 1 and 2 shared an in vivo experimental collection, with Study 3 using input from the collection in an in-silico approach. Briefly, 35 breast cancer survivors within two years since the conclusion of their treatment participated in the experiment. Participants completed a general questionnaire about their diagnosis, three shoulder-related quality of life questionnaires, and a Godin-Shephard leisure-time physical activity questionnaire, followed by a dual energy x-ray absorptiometry (DXA) scan. Eight muscles were monitored on the affected limb (pectoralis major (sternal and clavicular), deltoids (anterior, middle and posterior), infraspinatus, supraspinatus, and latissimus dorsi). Six maximal isometric strength trials were completed (flexion, extension, abduction, adduction, internal rotation and external rotation). Kinematics of the affected limb were collected for the remaining trials. These consisted of 6 maximal range of motion trials (flexion, extension, abduction, scapular abduction, internal rotation and external rotation), as well as 8 activities of daily living. Study 1 clustered participants into two distinct groups, the low score cluster (LSC) and high score cluster (HSC). The variance in treatment, force production, range of motion, body composition and shoulder-related quality of life is well documented in literature, however there is no distinguishing characteristics that separate survivors who may need rehabilitation following treatment. This study determined, through feature reduction, that internal rotation force production, active extension range of motion and 3 shoulder related quality of life variables (energy/fatigue, social functioning and pain) separated survivors within 2 years of treatment into two clusters (LSC and HSC). The LSC participants had higher self-reported disability, role limitations (health and emotion), fatigue, and lower self reported physical well-being, along with lower abduction, adduction, extension and flexion force production (p<0.001). Several other factors differed between groups (p<0.05); the HSC group had more lean mass of the affected arm, internal and external force production and active flexion range of motion. These factors highlight potentially important factors to address in a rehabilitation program, as survivors finish treatment, specifically that lower force production likely corresponds to lower self-reported shoulder-related quality of life. Study 2 contrasted the muscular activation and kinematics of the LSC and HSC during various activities of daily living. The selected low load functional tasks can indicate survivors’ ability to complete daily tasks and return to work. The LSC used lower range of angles, and increased muscular activation. Range of angles differed 6.5-16.1° across elevation angle, axial rotation and plane of elevation during the shelf reach, forward reach, pitcher pour and tray transfer tasks. Additionally, the LSC had 0.89-12.73% MVC more muscular activation than the HSC across all muscles and tasks. At least one muscle differed between groups during each of the 8 tasks investigated. Finally, study 3 simulated various treatment scenarios to find a maximal producible force and the internal muscle forces required to produce that force in a compromised system with an in-silico approach. Beginning with the force from the LSC, and increasing capacity of muscles based on given treatment scenarios (permanent damage of a subset of muscles from radiation, or overall reduction in capacity due to chemotherapy, or a combination of both), 70-80% of strength in adduction and internal rotation is recoverable if retraining of muscles can be achieved. Specifically, for adduction rhomboid (major and minor), upper trapezius, subscapularis (lower), and triceps (long), latissimus dorsi (upper and lower), pectoralis minor, middle deltoid, middle trapezius and biceps (short) increased during the various simulations to increase force output compared to the LSC group. During internal rotation, latissimus dorsi, rhomboid (major and minor), upper trapezius, posterior deltoid, subscapularis (middle and lower), triceps (long), pectoralis minor, middle deltoid, and middle trapezius estimation increased from the LSC group levels in each of the simulations. Although no scenario reached reference control population force levels, achieving 70-80% of force would be meaningful for enabling daily task performance, returning to work and enhancing physical self-efficacy. Taken together, these studies point towards novel strategies and valuable considerations in creating rehabilitation foci that enable improved arm function for breast cancer survivors

Fourier transform infrared spectroscopy for analysis of the composition of kidney stones

Kamica nerkowa jest jedną z najczęstszych chorób układu moczowego, której przyczyną są zaburzenia metaboliczne i wydalnicze. Identyfikacja składników kamieni nerkowych jest niezbędna do określenia przyczyny powstawania złogów i doboru odpowiedniej terapii leczenia. Celem badań było określenie składu chemicznego kamieni nerkowych. Kamienie nerkowe pobrane od 46 pacjentów analizowano pod kątem składu chemicznego, za pomocą spektroskopii w podczerwieni z transformatą Fouriera (FTIR). Otrzymane widma FTIR kamieni nerkowych porównano ze standardami. Z 46 próbek 58,3% stanowiły kamienie zbudowane ze szczawianu wapnia, 28,3% - kamienie struwitowe, a 10,9% - kamienie kwasu moczowego. Analiza względem płci pokazała, że 69,6% badanych kamieni pochodziło od mężczyzn, a 30,4% od kobiet. Porównanie względem wieku ujawniło, że najwięcej badanych znajduje się w przedziale wiekowym 30-44 lat. Szczawian wapnia, struwit i kwas moczowy są powszechnie spotykanymi kamieniami nerkowymi.Kidney stones are one of the most common diseases of the urinary tract, caused by metabolic and excretory disorders. Identification of the components of the stone is necessary to determine the cause of the formation of deposits and to choose the appropriate therapy. The aim of the study was to determine the chemical composition of the kidney stones. Kidney stones recovered from 46 patients were analyzed for their chemical composition by Fourier transform infrared spectroscopy (FTIR). The resulting FTIR spectra of the kidney stones were compared to standards. Of the 46 samples, 58.3% were comprised calcium oxalate, 28.3% struvites and 10.9% uric acid. Gender analysis showed that 69.6% of the examined stones were from men and 30.4% from women. Comparison with age revealed that the majority of respondents are people aged 30-44. Calcium oxalate, struvites and uric acid are commonly occurring kidney stones

The histone acetyl transferases CBP and p300 regulate stress response pathways in synovial fibroblasts at transcriptional and functional levels.

The activation of stress response pathways in synovial fibroblasts (SF) is a hallmark of rheumatoid arthritis (RA). CBP and p300 are two highly homologous histone acetyl transferases and writers of activating histone 3 lysine 27 acetylation (H3K27ac) marks. Furthermore, they serve as co-factors for transcription factors and acetylate many non-histone proteins. Here we showed that p300 but not CBP protein expression was down regulated by TNF and 4-hydroxynonenal, two factors that mimic inflammation and oxidative stress in the synovial microenvironment. We used existing RNA-sequencing data sets as a basis for a further in-depth investigation of individual functions of CBP and p300 in regulating different stress response pathways in SF. Pathway enrichment analysis pointed to a profound role of CBP and/ or p300 in regulating stress response-related gene expression, with an enrichment of pathways associated with oxidative stress, hypoxia, autophagy and proteasome function. We silenced CBP or p300, and performed confirmatory experiments on transcriptome, protein and functional levels. We have identified some overlap of CBP and p300 target genes in the oxidative stress response pathway, however, with several genes being regulated in opposite directions. The majority of stress response genes was regulated by p300, with a specific function of p300 in regulating hypoxia response genes and genes encoding proteasome subunits. Silencing of p300 suppressed proteasome enzymatic activities. CBP and p300 regulated autophagy on transcriptome and functional levels. Whereas CBP was indispensable for autophagy synthesis, silencing of p300 affected late-stage autophagy. In line with impaired autophagy and proteasome function, poly-ubiquitinated proteins accumulated after silencing of p300

The histone acetyl transferases CBP and p300 regulate stress response pathways in synovial fibroblasts at transcriptional and functional levels

The activation of stress response pathways in synovial fibroblasts (SF) is a hallmark of rheumatoid arthritis (RA). CBP and p300 are two highly homologous histone acetyl transferases and writers of activating histone 3 lysine 27 acetylation (H3K27ac) marks. Furthermore, they serve as co-factors for transcription factors and acetylate many non-histone proteins. Here we showed that p300 but not CBP protein expression was down regulated by TNF and 4-hydroxynonenal, two factors that mimic inflammation and oxidative stress in the synovial microenvironment. We used existing RNA-sequencing data sets as a basis for a further in-depth investigation of individual functions of CBP and p300 in regulating different stress response pathways in SF. Pathway enrichment analysis pointed to a profound role of CBP and/ or p300 in regulating stress response-related gene expression, with an enrichment of pathways associated with oxidative stress, hypoxia, autophagy and proteasome function. We silenced CBP or p300, and performed confirmatory experiments on transcriptome, protein and functional levels. We have identified some overlap of CBP and p300 target genes in the oxidative stress response pathway, however, with several genes being regulated in opposite directions. The majority of stress response genes was regulated by p300, with a specific function of p300 in regulating hypoxia response genes and genes encoding proteasome subunits. Silencing of p300 suppressed proteasome enzymatic activities. CBP and p300 regulated autophagy on transcriptome and functional levels. Whereas CBP was indispensable for autophagy synthesis, silencing of p300 affected late-stage autophagy. In line with impaired autophagy and proteasome function, poly-ubiquitinated proteins accumulated after silencing of p300

BRD3 Regulates the Inflammatory and Stress Response in Rheumatoid Arthritis Synovial Fibroblasts

BACKGROUND Individual functions of members of the bromodomain (BRD) and extra-terminal (BET) protein family underlying the anti-inflammatory effects of BET inhibitors in rheumatoid arthritis (RA) are incompletely understood. Here, we aimed to analyze the regulatory functions of BRD3, an understudied member of the BET protein family, in RA synovial fibroblasts (FLS). METHODS BRD3 was silenced in FLS prior to stimulation with TNF. Alternatively, FLS were treated with I-BET. Transcriptomes were analyzed by RNA sequencing (RNAseq), followed by pathway enrichment analysis. We confirmed results for selective target genes by real-time PCR, ELISA, and Western blotting. RESULTS BRD3 regulates the expression of several cytokines and chemokines in FLS, and positively correlates with inflammatory scores in the RA synovium. In addition, RNAseq pointed to a profound role of BRD3 in regulating FLS proliferation, metabolic adaption, and response to stress, including oxidative stress, and autophagy. CONCLUSIONS BRD3 acts as an upstream regulatory factor that integrates the response to inflammatory stimuli and stress conditions in FLS and executes many functions of BET proteins that have previously been identified using pan-BET inhibitors

ASSOCIATION OF THE GLUCOCORTICOID RECEPTOR GENE POLYMORPHISMS AND THEIR INTERACTION WITH STRESSFUL LIFE EVENTS IN POLISH ADOLESCENT GIRLS WITH ANOREXIA NERVOSA

Background: Disturbances in stress response mechanisms and hypothalamic-pituitary-adrenal axis (HPA) functioning are considered important factors involved in the pathophysiology of anorexia nervosa (AN). Thus, genetic variations in the end effector of HPA - glucocorticoid receptor gene and relationships to stressful life events (SLE) may be connected to a higher risk of illness. The aim of the study was examining the association between glucocorticoid receptor gene (NR3C1) polymorphisms and risk factors among stressful life events in AN patients. Subjects and methods: This study comprised 256 patients with AN and 167 control subjects. The questionnaires examining brief history of the mother’s pregnancy and long-acting stress factors, as well as life events checklist to assess stressful life events during the 6 months prior to hospitalization were used. The eight common SNPs (rs6198, rs6191, rs6196, rs258813, rs33388, rs41423247, rs56149945 and rs10052957) of NR3C1 gene were genotyped. Results: The association of five polymorphisms (rs6191, rs258813, rs33388, rs41423247 and rs10052957) and one complex allele (TCAGT) of NR3C1 gene with increased risk of AN were found. However, no significant correlations between early, longacting and predicting hospitalization SLE and any of the analyzed polymorphisms were observed. Conclusions: The results confirm that the NR3C1 gene is associated with AN risk regardless of the type of stressful triggering factors