Loading of p53-binding protein 1 (53BP1) and receptor-associated protein 80 (RAP80) at DNA double-strand breaks (DSBs) drives cell cycle checkpoint activation but is counterproductive to ...high-fidelity DNA repair. ring finger protein 169 (RNF169) maintains the balance by limiting the deposition of DNA damage mediator proteins at the damaged chromatin. We report here that this attribute is accomplished, in part, by a predicted nuclear localization signal (NLS) that not only shuttles RNF169 into the nucleus but also promotes its stability by mediating a direct interaction with the ubiquitin-specific protease USP7. Guided by the crystal structure of USP7 in complex with the RNF169 NLS, we uncoupled USP7 binding fromits nuclear import function and showed that perturbing the USP7–RNF169 complex destabilized RNF169, compromised high-fidelity DSB repair, and hypersensitized cells to poly (ADP-ribose) polymerase inhibition. Finally, expression of USP7 and RNF169 positively correlated in breast cancer specimens. Collectively, our findings uncover an NLS-mediated bipartite mechanism that supports the nuclear function of a DSB response protein.
Recent reviews recommended the use of the aldosterone/renin ratio (ARR) to screen for primary hyperaldosteronism. However, widely different cutoff levels have been proposed, and test characteristics ...of ARR under different conditions of sampling are not known. We conducted a retrospective review among 45 subjects with carefully validated diagnoses of primary hyperaldosteronism and 17 subjects with essential hypertension to study the utility of ARR. Sixty-two patients with 75 sets of plasma renin activity (PRA), aldosterone, and ARR values from a postural study and 48 sets of values from a saline suppression test were analyzed. Ninety-four percent of these subjects underwent investigations because of hypokalemic hypertension.
ARR yielded larger areas under the curve in the receiver-operating-characteristics curve than PRA or aldosterone under all conditions of testing. Our results confirmed the superiority of ARR to either aldosterone or PRA alone as a diagnostic test for primary hyperaldosteronism.
ARR cutoff levels were significantly affected by the condition of testing. Depending on posture and time of day, it varied from 13.1–35.0 ng/dl per ng/ml·h in our study population. When using ARR for screening primary hyperaldosteronism, posture and time of sampling should be standardized both within and between centers to minimize variability in cutoff levels.
Aim
Levels of branched‐chain amino acids (BCAAs, namely, isoleucine, leucine, and valine) are modulated by dietary intake and metabolic/genetic factors. BCAAs are associated with insulin resistance ...and increased risk of type 2 diabetes (T2D). Although insulin resistance predicts heart failure (HF), the relationship between BCAAs and HF in T2D remains unknown.
Methods
In this prospective observational study, we measured BCAAs in fasting serum samples collected at inception from 2139 T2D patients free of cardiovascular‐renal diseases. The study outcome was the first hospitalization for HF.
Results
During 29 103 person‐years of follow‐up, 115 primary events occurred (age: 54.8 ± 11.2 years, 48.2% men, median interquartile range diabetes duration: 5 years 1‐10). Patients with incident HF had 5.6% higher serum BCAAs than those without HF (median 639.3 561.3‐756.3 vs 605.2 524.8‐708.7 μmol/L; P = .01). Serum BCAAs had a positive linear association with incident HF (per‐SD increase in logarithmically transformed BCAAs: hazard ratio HR 1.22 95% CI 1.07‐1.39), adjusting for age, sex, and diabetes duration. The HR remained significant after sequential adjustment of risk factors including incident coronary heart disease (1.24, 1.09‐1.41); blood pressure, low‐density lipoprotein cholesterol, and baseline use of related medications (1.31, 1.14‐1.50); HbA1c, waist circumference, triglyceride, and baseline use of related medications (1.28, 1.11‐1.48); albuminuria and estimated glomerular filtration rate (1.28, 1.11‐1.48). The competing risk of death analyses showed similar results.
Conclusions
Circulating levels of BCAAs are independently associated with incident HF in patients with T2D. Prospective cohort analysis and randomized trials are needed to evaluate the long‐term safety and efficacy of using different interventions to optimize BCAAs levels in these patients.
Summary
Aim
To identify the barriers and facilitators to start insulin in patients with type 2 diabetes.
Method
This was a systematic review. We conducted a systematic search using PubMed, EMBASE, ...CINAHL and Web of Science (up to 5 June 2014) for original English articles using the terms ‘type 2 diabetes’, ‘insulin’, and free texts: ‘barrier’ or ‘facilitate’ and ‘initiate’. Two pairs of reviewers independently assessed and extracted the data. Study quality was assessed with Qualsyst.
Results
A total of 9740 references were identified: 41 full‐text articles were assessed for eligibility. Twenty‐five articles (15 qualitative, 10 quantitative) were included in the review. Good inter‐rater reliability was observed for the Qualsyst score (weighted kappa 0.7). Three main themes identified were as follows: patient‐related, healthcare professional and system factors. The main patient‐related barriers were fear of pain and injection (n = 18), concerns about side effects of insulin (n = 12), perception that insulin indicated end stage of diabetes (n = 11), inconvenience (n = 10), difficulty in insulin administration (n = 7), punishment (n = 7) and stigma and discrimination (n = 7). Healthcare professionals’ barriers were as follows: poor knowledge and skills (n = 9), physician inertia (n = 5) and language barriers (n = 4). System barriers included lack of time (n = 5). The most common facilitators were understanding the benefits of insulin (n = 7), not being afraid of injections (n = 5), and patient education and information (n = 5).
Conclusion
Major barriers to insulin initiation persist despite availability of newer and safer insulin. Healthcare professionals should explore and address these barriers. Targeted interventions should be developed to overcome these barriers.
Aims
Growth differentiation factor 15 (GDF15), ST2, high‐sensitivity troponin T (hsTnT), and N‐terminal pro brain natriuretic peptide (NT‐proBNP) are biomarkers of distinct mechanisms that may ...contribute to the pathophysiology of heart failure (HF) inflammation (GDF15); ventricular remodelling (ST2); myonecrosis (hsTnT); and wall stress (NT‐proBNP).
Methods and results
We compared circulating levels of GDF15, ST2, hsTnT, and NT‐proBNP, as well as their combinations, in compensated patients with clinical HF with reduced ejection fraction (HFREF) (n = 51), HF with preserved ejection fraction (HFPEF) (n= 50), and community‐based controls (n = 50). Compared with controls, patients with HFPEF and HFREF had higher median levels of GDF15 (540 pg/mL vs. 2529 and 2672 pg/mL, respectively), hsTnT (3.7 pg/mL vs. 23.7 and 35.6 pg/mL), and NT‐proBNP (69 pg/mL vs. 942 and 2562 pg/mL), but not ST2 (27.6 ng/mL vs. 31.5 and 35.3 ng/mL), adjusting for clinical covariates. In receiver operating characteristic curve analyses, NT‐proBNP distinguished HFREF from controls with an area under the curve (AUC) of 0.987 (P < 0.001); GDF15 distinguished HFPEF from controls with an AUC of 0.936 (P < 0.001); and the combination of NT‐proBNP and GDF15 distinguished HFPEF from controls with an AUC of 0.956 (P < 0.001). NT‐proBNP and hsTnT levels were higher in HFREF than in HFPEF (adjusted P < 0.04). The NT‐proBNP:GDF15 ratio distinguished between HFPEF and HFREF with the largest AUC (0.709; P < 0.001).
Conclusions
Our study provides comparative data on physiologically distinct circulating biomarkers in HFPEF, HFREF, and controls from the same community. These data suggest a prominent role for myocardial injury (hsTnT) with increased wall stress (NT‐proBNP) in HFREF, and systemic inflammation (GDF15) in HFREF
New chemotherapeutic compounds against multidrug-resistant Mycobacterium tuberculosis (Mtb) are urgently needed to combat drug resistance in tuberculosis (TB). We have identified and characterized ...the indolcarboxamides as a new class of antitubercular bactericidal agent. Genetic and lipid profiling studies identified the likely molecular target of indolcarboxamides as MmpL3, a transporter of trehalose monomycolate that is essential for mycobacterial cell wall biosynthesis. Two lead candidates, NITD-304 and NITD-349, showed potent activity against both drug-sensitive and multidrug-resistant clinical isolates of Mtb. Promising pharmacokinetic profiles of both compounds after oral dosing in several species enabled further evaluation for efficacy and safety. NITD-304 and NITD-349 were efficacious in treating both acute and chronic Mtb infections in mouse efficacy models. Furthermore, dosing of NITD-304 and NITD-349 for 2 weeks in exploratory rat toxicology studies revealed a promising safety margin. Finally, neither compound inhibited the activity of major cytochrome P-450 enzymes or the hERG (human ether-a-go-go related gene) channel. These results suggest that NITD-304 and NITD-349 should undergo further development as a potential treatment for multidrug-resistant TB.
Background
Tumor spatial heterogeneity is an important prognostic factor, which may be reflected in medical images
Methods
Image texture analysis is an approach of quantifying heterogeneity that may ...not be appreciated by the naked eye. Different methods can be applied including statistical-, model-, and transform-based methods.
Results
Early evidence suggests that texture analysis has the potential to augment diagnosis and characterization as well as improve tumor staging and therapy response assessment in oncological practice.
Conclusion
This review provides an overview of the application of texture analysis with different imaging modalities, CT, MRI, and PET, to date and describes the technical challenges that have limited its widespread clinical implementation so far. With further efforts to refine its application, image texture analysis has the potential to develop into a valuable clinical tool for oncologic imaging.
Teaching Points
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Tumor spatial heterogeneity is an important prognostic factor.
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Image texture analysis is an approach of quantifying heterogeneity.
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Different methods can be applied, including statistical-, model-, and transform-based methods.
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Texture analysis could improve the diagnosis, tumor staging, and therapy response assessment.
African horse sickness (AHS) is a highly infectious and often fatal disease caused by 9 serotypes of the orbivirus African horse sickness virus (AHSV). In March 2020, an AHS outbreak was reported in ...Thailand in which AHSV serotype 1 was identified as the causative agent. Trivalent live attenuated vaccines serotype 1, 3, and 4 were used in a targeted vaccination campaign within a 50-km radius surrounding the infected cases, which promptly controlled the spread of the disease. However, AHS-like symptoms in vaccinated horses required laboratory diagnostic methods to differentiate infected horses from vaccinated horses, especially for postvaccination surveillance. We describe a real-time reverse transcription PCR-based assay for rapid characterization of the affecting field strain. The development and validation of this assay should imbue confidence in differentiating AHS-vaccinated horses from nonvaccinated horses. This method should be applied to determining the epidemiology of AHSV in future outbreaks.
BACKGROUNDDespite major advances in pharmacological treatment for patients with heart failure, residual mortality remains high. This suggests that important pathways are not yet targeted by current ...heart failure therapies.OBJECTIVESWe sought integration of genetic, transcriptomic, and proteomic data in a large cohort of patients with heart failure to detect major pathways related to progression of heart failure leading to death.METHODSWe used machine learning methodology based on stacked generalization framework and gradient boosting algorithms, using 54 clinical phenotypes, 403 circulating plasma proteins, 36,046 transcript expression levels in whole blood, and 6 million genomic markers to model all-cause mortality in 2,516 patients with heart failure from the BIOSTAT-CHF (Systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) study. Results were validated in an independent cohort of 1,738 patients.RESULTSThe mean age of the patients was 70 years (Q1-Q3: 61-78 years), 27% were female, median N-terminal pro-B-type natriuretic peptide was 4,275 ng/L (Q1-Q3: 2,360-8,486 ng/L), and 7% had heart failure with preserved ejection fraction. During a median follow-up of 21 months, 657 (26%) of patients died. The 4 major pathways with a significant association to all-cause mortality were: 1) the PI3K/Akt pathway; 2) the MAPK pathway; 3) the Ras signaling pathway; and 4) epidermal growth factor receptor tyrosine kinase inhibitor resistance. Results were validated in an independent cohort of 1,738 patients.CONCLUSIONSA systems biology approach integrating genomic, transcriptomic, and proteomic data identified 4 major pathways related to mortality. These pathways are related to decreased activation of the cardioprotective ERBB2 receptor, which can be modified by neuregulin.
ABSTRACT
The detection of coherent X-ray pulsations at ∼314 Hz (3.2 ms) classifies MAXI J1957+032 as a fast-rotating, accreting neutron star. We present the temporal and spectral analysis performed ...using NICER observations collected during the latest outburst of the source. Doppler modulation of the X-ray pulsation revealed the ultra-compact nature of the binary system characterized by an orbital period of ∼1 h and a projected semimajor axis of 14 lt-ms. The neutron star binary mass function suggests a minimum donor mass of 1.7 × 10−2 M⊙, assuming a neutron star mass of 1.4 M⊙ and a binary inclination angle lower than 60 deg. This assumption is supported by the lack of eclipses or dips in the X-ray light curve of the source. We characterized the 0.5–10 keV energy spectrum of the source in outburst as the superposition of a relatively cold black-body-like thermal emission compatible with the emission from the neutron star surface and a Comptonization component with photon index consistent with a typical hard state. We did not find evidence for iron K α lines or reflection components.
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