It is now recognized that internal global protein dynamics play an important role in the allosteric function of many proteins. Alterations of protein flexibility on effector binding affect the ...entropic cost of binding at a distant site. We present a coarse-grained model for a potential amplification of such entropic allostery due to coupling of fast, localized modes to the slow, global modes. We show how such coupling can give rise to large compensating entropic and enthalpic terms. The model corresponds to the pattern of calorimetry and NMR data from experiments on the Met repressor.
Male genital lichen sclerosus and filaggrin Shim, T. N.; Brown, S. J.; Francis, N. D. ...
Clinical and experimental dermatology,
January 2020, 2020-Jan, 2020-01-00, 20200101, Letnik:
45, Številka:
1
Journal Article
Dramatic responses are being observed in colorectal cancer liver metastases treated with newer chemotherapeutic regimens. These have been associated with normalization of ...(18)Ffluoro-2-deoxy-D-glucose (FDG) uptake (complete metabolic response) on follow-up Positron Emission Tomography with (18)Ffluoro-2-deoxy-D-glucose (FDG-PET) scans in some patients. It is unclear how often complete metabolic response is indicative of complete tumor destruction. We analyzed a subset of patients who had neoadjuvant chemotherapy for hepatic metastases from colorectal adenocarcinoma. Inclusion criteria were: (1) FDG-avid hepatic lesions before initiation of chemotherapy; (2) complete metabolic response of the same lesions after chemotherapy; and (3) histopathologic examination of hepatic lesions. Complete pathologic response was defined as no histologically identifiable viable tumor. Fourteen patients fit the inclusion criteria. All had synchronous, hepatic-only colorectal metastases. On microscopic examination, complete pathologic response to the neoadjuvant regimen was found in only 5 of 34 lesions (15%) and in only 3 of the 14 patients (21%). Seven lesions had complete metabolic response and disappeared on computed tomography (CT); of these, six still contained viable tumor. We conclude that complete metabolic response on FDG-PET after neoadjuvant chemotherapy is an unreliable indicator of complete pathologic response. Therefore, currently, curative resection of liver metastases in these patients should not be deferred on the basis of FDG-PET findings.
Aims
The non‐vitamin K antagonist oral anticoagulants (NOACs) have varying degrees of renal elimination which may be challenging in patients with heart failure (HF) and atrial fibrillation (AF). We ...examined the severity and variation in renal impairment, and the proportion of patients requiring NOAC cessation or dose reduction.
Methods and results
A retrospective analysis of patients with HF and AF in the Candesartan in Heart failure Assessment of Reduction in Mortality and Morbidity programme was carried out. Trends in renal impairment over 26 months were defined using Cockcroft–Gault (CG), simplified Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) equations. Mean estimated glomerular filtration rate (eGFR) was worse at every time point in patients with AF compared with those without AF, the difference being ∼11 mL/min (CG), 9 mL/min (CKD‐EPI), and 7 mL/min (MDRD). As renal function declined, CG classified a greater proportion of patients as having moderate or severe CKD and agreement with MDRD/CKD‐EPI declined. At least moderate renal impairment was present in a quarter of patients with AF at baseline, a third by study completion, and approaching a half at least once during follow‐up. The projected need for NOAC dose reduction was accordingly high, though it varied between individual NOACs due to different criteria for adjustment.
Conclusions
Renal impairment in patients with HF and AF is common, fluctuates, progresses, and frequently mandates NOAC dose reduction, though the need for cessation is rare. Baseline renal function, the method of estimating GFR, and intensity of monitoring should be considered when commencing oral anticoagulation.
Many signaling functions in molecular biology require proteins to bind to substrates such as DNA in response to environmental signals such as the simultaneous binding to a small molecule. Examples ...are repressor proteins which may transmit information via a conformational change in response to the ligand binding. An alternative entropic mechanism of "allostery" suggests that the inducer ligand changes the intramolecular vibrational entropy, not just the mean static structure. We present a quantitative, coarse-grained model of entropic allostery, which suggests design rules for internal cohesive potentials in proteins employing this effect. It also addresses the issue of how the signal information to bind or unbind is transmitted through the protein. The model may be applicable to a wide range of repressors and also to signaling in trans-membrane proteins.
Recent studies have shown that drug‐induced spatial alteration patterns in resting state functional activity as measured using magnetic resonance imaging (rsfMRI) are associated with the distribution ...of specific receptor systems targeted by respective compounds. Based on this approach, we introduce a toolbox (JuSpace) allowing for cross‐modal correlation of MRI‐based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, and GABAergic (gamma‐aminobutric acid) neurotransmission. We apply JuSpace to two datasets covering Parkinson's disease patients (PD) and risperidone‐induced changes in rsfMRI and cerebral blood flow (CBF). Consistently with the predominant neurodegeneration of dopaminergic and serotonergic system in PD, we find significant spatial associations between rsfMRI activity alterations in PD and dopaminergic (D2) and serotonergic systems (5‐HT1b). Risperidone induced CBF alterations were correlated with its main targets in serotonergic and dopaminergic systems. JuSpace provides a biologically meaningful framework for linking neuroimaging to underlying neurotransmitter information.
Here, we introduce the JuSpace toolbox allowing for cross‐modal correlation of MRI‐based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, and GABAergic (gamma‐aminobutric acid) neurotransmission. The toolbox provides a biologically meaningful framework for linking neuroimaging to underlying neurotransmitter information.
Background: Electrocardiographic left ventricular hypertrophy (ECG LVH) is a powerful independent predictor of cardiovascular morbidity and mortality in hypertension. Objective: To determine the ...contemporary prevalence and prognostic implications of ECG LVH in a broad spectrum of patients with heart failure with and without reduced left ventricular ejection fraction (LVEF). Methods and outcome: The Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme randomised 7599 patients with symptomatic heart failure to receive candesartan or placebo. The primary outcome comprised cardiovascular death or hospital admission for worsening heart failure. The relative risk (RR) conveyed by ECG LVH compared with a normal ECG was examined in a Cox model, adjusting for as many as 31 covariates of prognostic importance. Results: The prevalence of ECG LVH was similar in all three CHARM trials (Alternative, 15.4%; Added, 17.1%; Preserved, 14.7%; Overall, 15.7%) despite a more frequent history of hypertension in CHARM-Preserved. ECG LVH was an independent predictor of worse prognosis in CHARM-Overall. RR for the primary outcome was 1.27 (95% confidence interval (CI) 1.04 to 1.55, p = 0.018). The risk of secondary end points was also increased: cardiovascular death, 1.50 (95% CI 1.13 to 1.99, p = 0.005); hospitalisation due to heart failure, 1.19 (95% CI 0.94 to 1.50, p = 0.148); and composite major cardiovascular events, 1.35 (95% CI 1.12 to 1.62, p = 0.002). Conclusion: ECG LVH is similarly prevalent in patients with symptomatic heart failure regardless of LVEF. The simple clinical finding of ECG LVH was an independent predictor of a worse clinical outcome in a broad spectrum of patients with heart failure receiving extensive contemporary treatment. Candesartan had similar benefits in patients with and without ECG LVH.
Purpose
The B-MaP-C study investigated changes to breast cancer care that were necessitated by the COVID-19 pandemic. Here we present a follow-up analysis of those patients commenced on bridging ...endocrine therapy (BrET), whilst they were awaiting surgery due to reprioritisation of resources.
Methods
This multicentre, multinational cohort study recruited 6045 patients from the UK, Spain and Portugal during the peak pandemic period (Feb–July 2020). Patients on BrET were followed up to investigate the duration of, and response to, BrET. This included changes in tumour size to reflect downstaging potential, and changes in cellular proliferation (Ki67), as a marker of prognosis.
Results
1094 patients were prescribed BrET, over a median period of 53 days (IQR 32–81 days). The majority of patients (95.6%) had strong ER expression (Allred score 7–8/8). Very few patients required expedited surgery, due to lack of response (1.2%) or due to lack of tolerance/compliance (0.8%). There were small reductions in median tumour size after 3 months’ treatment duration; median of 4 mm IQR − 20, 4. In a small subset of patients (
n
= 47), a drop in cellular proliferation (Ki67) occurred in 26 patients (55%), from high (Ki67 ≥ 10%) to low (< 10%), with at least one month’s duration of BrET.
Discussion
This study describes real-world usage of pre-operative endocrine therapy as necessitated by the pandemic. BrET was found to be tolerable and safe. The data support short-term (≤ 3 months) usage of pre-operative endocrine therapy. Longer-term use should be investigated in future trials.
Objective
Approximately 10% of stillbirths are attributed to fetal anomalies, but anomalies are also common in live births. We aimed to assess the relationship between anomalies, by system and ...stillbirth.
Design
Secondary analysis of a prospective, case–control study.
Setting
Multicentre, 59 hospitals in five regional catchment areas in the USA.
Population or sample
All stillbirths and representative live birth controls.
Methods
Standardised postmortem examinations performed in stillbirths, medical record ion for stillbirths and live births.
Main outcome measures
Incidence of major anomalies, by type, compared between stillbirths and live births with univariable and multivariable analyses using weighted analysis to account for study design and differential consent.
Results
Of 465 singleton stillbirths included, 23.4% had one or more major anomalies compared with 4.3% of 1871 live births. Having an anomaly increased the odds of stillbirth; an increasing number of anomalies was more highly associated with stillbirth. Regardless of organ system affected, the presence of an anomaly increased the odds of stillbirth. These relationships remained significant if stillbirths with known genetic abnormalities were excluded. After multivariable analyses, the adjusted odds ratio (aOR) of stillbirth for any anomaly was 4.33 (95% CI 2.80–6.70) and the systems most strongly associated with stillbirth were cystic hygroma (aOR 29.97, 95% CI 5.85–153.57), and thoracic (aOR16.18, 95% CI 4.30–60.94) and craniofacial (aOR 35.25, 95% CI 9.22–134.68) systems.
Conclusions
In pregnancies affected by anomalies, the odds of stillbirth are higher with increasing numbers of anomalies. Anomalies of nearly any organ system increased the odds of stillbirth even when adjusting for gestational age and maternal race.
Tweetable
Stillbirth risk increases with anomalies of nearly any organ system and with number of anomalies seen.
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Stillbirth risk increases with anomalies of nearly any organ system and with number of anomalies seen.
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