Despite being the most effective anti-inflammatory treatment for chronic inflammatory diseases, the mechanisms by which glucocorticoids (corticosteroids) effect repression of inflammatory gene ...expression remain incompletely understood. Direct interaction of the glucocorticoid receptor (NR3C1) with inflammatory transcription factors to repress transcriptional activity, i.e. transrepression, represents one mechanism of action. However, transcriptional activation, or transactivation, by NR3C1 also represents an important mechanism of glucocorticoid action. Glucocorticoids rapidly and profoundly increase expression of multiple genes, many with properties consistent with the repression of inflammatory gene expression. For example: the dual specificity phosphatase, DUSP1, reduces activation of mitogen-activated protein kinases; glucocorticoid-induced leucine zipper (TSC22D3) represses nuclear factor-κB (NF-κB) and activator protein 1 (AP-1) transcriptional responses; inhibitor of κBα (NFKBIA) inhibits NF-κB; tristraprolin (ZFP36) destabilises and translationally represses inflammatory mRNAs; CDKN1C, a cell cycle regulator, may attenuate JUN N-terminal kinase signalling; and regulator of G-protein signalling 2 (RGS2), by reducing signalling from Gαq-linked G protein-coupled receptors (GPCRs), is bronchoprotective. While glucocorticoid-dependent transrepression can co-exist with transactivation, transactivation may account for the greatest level and most potent repression of inflammatory genes. Equally, NR3C1 transactivation is enhanced by β2-adrenoceptor agonists and may explain the enhanced clinical efficacy of β2-adrenoceptor/glucocorticoid combination therapies in asthma and chronic obstructive pulmonary disease. Finally, NR3C1 transactivation is reduced by inflammatory stimuli, including respiratory syncytial virus and human rhinovirus. This provides an explanation for glucocorticoid resistance. Continuing efforts to understand roles for glucocorticoid-dependent transactivation will provide opportunities to improve glucocorticoid therapies.
Pemigatinib, a selective FGFR1-3 inhibitor, has demonstrated antitumor activity in FIGHT-202, a phase II study in patients with cholangiocarcinoma harboring
fusions/rearrangements, and has gained ...regulatory approval in the United States. Eligibility for FIGHT-202 was assessed using genomic profiling; here, these data were utilized to characterize the genomic landscape of cholangiocarcinoma and to uncover unique molecular features of patients harboring
rearrangements. The results highlight the high percentage of patients with cholangiocarcinoma harboring potentially actionable genomic alterations and the diversity in gene partners that rearrange with
. Clinicogenomic analysis of pemigatinib-treated patients identified mechanisms of primary and acquired resistance. Genomic subsets of patients with other potentially actionable
alterations were also identified. Our study provides a framework for molecularly guided clinical trials and underscores the importance of genomic profiling to enable a deeper understanding of the molecular basis for response and nonresponse to targeted therapy. SIGNIFICANCE: We utilized genomic profiling data from FIGHT-202 to gain insights into the genomic landscape of cholangiocarcinoma, to understand the molecular diversity of patients with
fusions or rearrangements, and to interrogate the clinicogenomics of patients treated with pemigatinib. Our study highlights the utility of genomic profiling in clinical trials.
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Although 10 000 steps per day is widely promoted to have health benefits, there is little evidence to support this recommendation. We aimed to determine the association between number of steps per ...day and stepping rate with all-cause mortality.
In this meta-analysis, we identified studies investigating the effect of daily step count on all-cause mortality in adults (aged ≥18 years), via a previously published systematic review and expert knowledge of the field. We asked participating study investigators to process their participant-level data following a standardised protocol. The primary outcome was all-cause mortality collected from death certificates and country registries. We analysed the dose–response association of steps per day and stepping rate with all-cause mortality. We did Cox proportional hazards regression analyses using study-specific quartiles of steps per day and calculated hazard ratios (HRs) with inverse-variance weighted random effects models.
We identified 15 studies, of which seven were published and eight were unpublished, with study start dates between 1999 and 2018. The total sample included 47 471 adults, among whom there were 3013 deaths (10·1 per 1000 participant-years) over a median follow-up of 7·1 years (IQR 4·3–9·9; total sum of follow-up across studies was 297 837 person-years). Quartile median steps per day were 3553 for quartile 1, 5801 for quartile 2, 7842 for quartile 3, and 10 901 for quartile 4. Compared with the lowest quartile, the adjusted HR for all-cause mortality was 0·60 (95% CI 0·51–0·71) for quartile 2, 0·55 (0·49–0·62) for quartile 3, and 0·47 (0·39–0·57) for quartile 4. Restricted cubic splines showed progressively decreasing risk of mortality among adults aged 60 years and older with increasing number of steps per day until 6000–8000 steps per day and among adults younger than 60 years until 8000–10 000 steps per day. Adjusting for number of steps per day, comparing quartile 1 with quartile 4, the association between higher stepping rates and mortality was attenuated but remained significant for a peak of 30 min (HR 0·67 95% CI 0·56–0·83) and a peak of 60 min (0·67 0·50–0·90), but not significant for time (min per day) spent walking at 40 steps per min or faster (1·12 0·96–1·32) and 100 steps per min or faster (0·86 0·58–1·28).
Taking more steps per day was associated with a progressively lower risk of all-cause mortality, up to a level that varied by age. The findings from this meta-analysis can be used to inform step guidelines for public health promotion of physical activity.
US Centers for Disease Control and Prevention.
Since Exercise and Sports Science Australia (ESSA) first published its position statement on exercise guidelines for people with cancer, there has been exponential growth in research evaluating the ...role of exercise pre-, during and post-cancer treatment.
The purpose of this report is to use the current scientific evidence, alongside clinical experience and exercise science principles to update ESSA’s position statement on cancer-specific exercise prescription.
Reported in this position statement is a summary of the benefits accrued through exercise following a cancer diagnosis and the strengths and limitations of this evidence-base. An exercise prescription framework is then proposed to enable the application of cancer-specific considerations for individualisation, specificity, safety, feasibility and progression of exercise for all patients. Additional specific exercise prescription considerations are provided for the presence of haematological, musculoskeletal, systemic, cardiovascular, lymphatic, gastrointestinal, genitourinary and neurological disease- and treatment-related concerns, as well as presence of co-morbid chronic disease. Further, we also identify and discuss cancer-specific pragmatic issues and barriers requiring consideration for exercise prescription.
While for the majority, multimodal, moderate to high intensity exercise will be appropriate, there is no set prescription and total weekly dosage that would be considered evidence-based for all cancer patients. Targeted exercise prescription, which includes the provision of behaviour change advice and support, is needed to ensure greatest benefit (as defined by the patient) in the short and longer term, with low risk of harm.
Evidence of the effectiveness of treatment for obesity delivered in primary care settings in underserved populations is lacking.
We conducted a cluster-randomized trial to test the effectiveness of a ...high-intensity, lifestyle-based program for obesity treatment delivered in primary care clinics in which a high percentage of the patients were from low-income populations. We randomly assigned 18 clinics to provide patients with either an intensive lifestyle intervention, which focused on reduced caloric intake and increased physical activity, or usual care. Patients in the intensive-lifestyle group participated in a high-intensity program delivered by health coaches embedded in the clinics. The program consisted of weekly sessions for the first 6 months, followed by monthly sessions for the remaining 18 months. Patients in the usual-care group received standard care from their primary care team. The primary outcome was the percent change from baseline in body weight at 24 months.
All 18 clinics (9 assigned to the intensive program and 9 assigned to usual care) completed 24 months of participation; a median of 40.5 patients were enrolled at each clinic. A total of 803 adults with obesity were enrolled: 452 were assigned to the intensive-lifestyle group, and 351 were assigned to the usual-care group; 67.2% of the patients were Black, and 65.5% had an annual household income of less than $40,000. Of the enrolled patients, 83.4% completed the 24-month trial. The percent weight loss at 24 months was significantly greater in the intensive-lifestyle group (change in body weight, -4.99%; 95% confidence interval CI, -6.02 to -3.96) than in the usual-care group (-0.48%; 95% CI, -1.57 to 0.61), with a mean between-group difference of -4.51 percentage points (95% CI, -5.93 to -3.10) (P<0.001). There were no significant between-group differences in serious adverse events.
A high-intensity, lifestyle-based treatment program for obesity delivered in an underserved primary care population resulted in clinically significant weight loss at 24 months. (Funded by the Patient-Centered Outcomes Research Institute and others; PROPEL ClinicalTrials.gov number, NCT02561221.).
Granulite facies metamorphism of the lower crust has decreased in scale since the Late Archean, but many of its definitive features have persisted: (1) Punctuated, sometimes relatively short-lived, ...episodes of high-grade metamorphism. These are recorded, in favorably simple cases, by discrete growth rims on zircons. (2) A consistent age gap of a few to several tens of millions of years between juvenile magmatism (crustal accretion) and high-temperature metamorphism. The secondary thermal pulse is an event distinct from primary crustal accretion. (3) Involvement of mineralizing pore fluids of lowered H2O activity, that is, with high CO2 and saline concentrations. Very high oxidation states of some granulites implicate sulfur as an important fluid component. (4) Transcurrent faulting as a conspicuous feature of synmetamorphic deformation. This gives rise to characteristic transposed foliation and lineation. (5) Emplacement of coeval postorogenic K-rich granites at midcrust levels. These features can be rationalized by concepts of modern plate tectonics. High-angle plate collision is succeeded by orogen-parallel transport. This change of plate motion necessarily detaches the underthrust portion of the lithosphere, liberating asthenospheric melts and/or fluids in a postorogenic resurgence. A generation of volatile-rich mafic magmas invades the continental margin; high CO2 and halogen contents cause outgassing and freezing of the magmas at depth. Liberated volatiles effect granulite facies metamorphism by leaching H2O and lithophile elements, importantly K, and transporting these components and heat upward. Extensive melting of the lower crust is inhibited by the low H2O activity of saline-carbonic pore fluids at high pressure. Melting of orthogneiss and supracrustal rocks occurs at midcrust levels by increase of H2O activity as pressure on alkali chloride solutions falls below 0.6–0.5 GPa. The foregoing hypothesis is an alternative to the classical view that granite results from fluid-absent partial melting of, and extraction from, the lower crust, leaving granulites.
To determine whether the magnitude of improvement in athletic performance and the mechanisms driving these adaptations differ in relatively weak individuals exposed to either ballistic power training ...or heavy strength training.
Relatively weak men (n = 24) who could perform the back squat with proficient technique were randomized into three groups: strength training (n = 8; ST), power training (n = 8; PT), or control (n = 8). Training involved three sessions per week for 10 wk in which subjects performed back squats with 75%-90% of one-repetition maximum (1RM; ST) or maximal-effort jump squats with 0%-30% 1RM (PT). Jump and sprint performances were assessed as well as measures of the force-velocity relationship, jumping mechanics, muscle architecture, and neural drive.
Both experimental groups showed significant (P < or = 0.05) improvements in jump and sprint performances after training with no significant between-group differences evident in either jump (peak power: ST = 17.7% +/- 9.3%, PT = 17.6% +/- 4.5%) or sprint performance (40-m sprint: ST = 2.2% +/- 1.9%, PT = 3.6% +/- 2.3%). ST also displayed a significant increase in maximal strength that was significantly greater than the PT group (squat 1RM: ST = 31.2% +/- 11.3%, PT = 4.5% +/- 7.1%). The mechanisms driving these improvements included significant (P < or = 0.05) changes in the force-velocity relationship, jump mechanics, muscle architecture, and neural activation that showed a degree of specificity to the different training stimuli.
Improvements in athletic performance were similar in relatively weak individuals exposed to either ballistic power training or heavy strength training for 10 wk. These performance improvements were mediated through neuromuscular adaptations specific to the training stimulus. The ability of strength training to render similar short-term improvements in athletic performance as ballistic power training, coupled with the potential long-term benefits of improved maximal strength, makes strength training a more effective training modality for relatively weak individuals.
Research has often examined the relationship between 1 or 2 measures of strength and change of direction (COD) ability reporting inconsistent relationships to performance. These inconsistencies may ...be the result of the strength assessment used and the assumption that 1 measure of strength can represent all "types" of strength required during a COD task. Therefore the purpose of this study was to determine the relationship between several lower-body strength and power measures, COD, and agility performance. Twelve (n = 12) elite female basketball athletes completed a maximal dynamic back squat, isometric midthigh pull, eccentric and concentric only back squat, and a countermovement jump, followed by 2 COD tests (505 and T-test) and a reactive agility test. Pearson product-moment correlation and stepwise regression analysis were performed on all variables. The percentage contribution of each strength measure to an athletes total strength score was also determined. Our results demonstrated that both COD tests were significantly correlated to maximal dynamic, isometric, concentric, and eccentric strength (r = -0.79 to -0.89), with eccentric strength identified as the sole predictor of COD performance. Agility performance did not correlate with any measure of strength (r = -0.08 to -0.36), whereas lower-body power demonstrated no correlation to either agility or COD performance (r = -0.19 to -0.46). These findings demonstrate the importance of multiple strength components for COD ability, highlighting eccentric strength as a deterministic factor of COD performance. Coaches should aim to develop a well-rounded strength base in athletes; ensuring eccentric strength is developed as effectively as the often-emphasized concentric or overall dynamic strength capacity.
Androgen suppression therapy (AST) results in musculoskeletal toxicity that reduces physical function and quality of life. This study examined the impact of a combined resistance and aerobic exercise ...program as a countermeasure to these AST-related toxicities.
Between 2007 and 2008, 57 patients with prostate cancer undergoing AST (commenced > 2 months prior) were randomly assigned to a program of resistance and aerobic exercise (n = 29) or usual care (n = 28) for 12 weeks. Primary end points were whole body and regional lean mass. Secondary end points were muscle strength and function, cardiorespiratory capacity, blood biomarkers, and quality of life.
Analysis of covariance was used to compare outcomes for groups at 12 weeks adjusted for baseline values and potential confounders. Patients undergoing exercise showed an increase in lean mass compared with usual care (total body, P = .047; upper limb, P < .001; lower limb, P = .019) and similarly better muscle strength (P < .01), 6-meter walk time (P = .024), and 6-meter backward walk time (P = .039). Exercise also improved several aspects of quality of life including general health (P = .022) and reduced fatigue (P = .021) and decreased levels of C-reactive protein (P = .008). There were no adverse events during the testing or exercise intervention program.
A relatively brief exposure to exercise significantly improved muscle mass, strength, physical function, and balance in hypogonadal men compared with normal care. The exercise regimen was well tolerated and could be recommended for patients undergoing AST as an effective countermeasure to these common treatment-related adverse effects.
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