Hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy for patients with locally advanced recurrent nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Reirradiation in standard fractionation for locally advanced recurrent nasopharyngeal carcinoma after a previous course of high-dose radiotherapy is often associated with substantial late toxicity, negating its overall benefit. We therefore aimed to investigate the efficacy and safety of hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy. METHODS: This multicentre, randomised, open-label, phase 3 trial was done in three centres in Guangzhou, China. Eligible patients were aged 18-65 years with histopathologically confirmed undifferentiated or differentiated, non-keratinising, advanced locally recurrent nasopharyngeal carcinoma. Participants were randomly assigned (1:1) to either receive hyperfractionation (65 Gy in 54 fractions, given twice daily with an interfractional time interval of at least 6 h) or standard fractionation (60 Gy in 27 fractions, given once a day). Intensity-modulated radiotherapy was used in both groups. A computer program generated the assignment sequence and randomisation was stratified by treatment centre, recurrent tumour stage (T2-T3 vs T4), and recurrent nodal stage (N0 vs N1-N2), determined at the time of randomisation. The two primary endpoints were the incidence of severe late complications defined as the incidence of grade 3 or worse late radiation-induced complications occurring 3 months after the completion of radiotherapy until the latest follow-up in the safety population, and overall survival defined as the time interval from randomisation to death due to any cause in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02456506. FINDINGS: Between July 10, 2015, and Dec 23, 2019, 178 patients were screened for eligibility, 144 of whom were enrolled and randomly assigned to hyperfractionation or standard fractionation (n=72 in each group). 35 (24%) participants were women and 109 (76%) were men. After a median follow-up of 45·0 months (IQR 37·3-53·3), there was a significantly lower incidence of grade 3 or worse late radiation-induced toxicity in the hyperfractionation group (23 [34%] of 68 patients) versus the standard fractionation group (39 [57%] of 68 patients; between-group difference -23% [95% CI -39 to -7]; p=0·023). Patients in the hyperfractionation group had better 3-year overall survival than those in the standard fractionation group (74·6% [95% CI 64·4 to 84·8] vs 55·0% [43·4 to 66·6]; hazard ratio for death 0·54 [95% CI 0·33 to 0·88]; p=0·014). There were fewer grade 5 late complications in the hyperfractionation group (five [7%] nasal haemorrhage) than in the standard fractionation group (16 [24%], including two [3%] nasopharyngeal necrosis, 11 [16%] nasal haemorrhage, and three [4%] temporal lobe necrosis). INTERPRETATION: Hyperfractionated intensity-modulated radiotherapy could significantly decrease the rate of severe late complications and improve overall survival among patients with locally advanced recurrent nasopharyngeal carcinoma. Our findings suggest that hyperfractionated intensity-modulated radiotherapy could be used as the standard of care for these patients. FUNDING: Key-Area Research and Development of Guangdong Province, the National Natural Science Foundation of China, the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project, and the National Ten Thousand Talents Program Science and Technology Innovation Leading Talents, Sun Yat-Sen University Clinical Research 5010 Program.

Unfolded Protein-Based Sandwich AIE Probe Imparts High Fluorescent Contrast for Pan-Cancer Surgical Navigation.

Fluorescence imaging-guided navigation for cancer surgery has a promising clinical application. However, pan-cancer encompasses a wide variety of cancer types with significant heterogeneity, resulting in the lack of universal and highly contrasted fluorescent probes for surgical navigation. Here, we developed an aggregation-induced emission (AIE) probe (MI-AIE-TsG, MAT) with dual activation for pan-cancer surgical navigation. MAT weakly activates fluorescence by targeting the SUR1 protein on the endoplasmic reticulum (ER) through the TsG group. Subsequently, the sulfhydryl groups on the unfolded proteins, which are highly enriched in cancer ER, react with the maleimide (MI) of MAT through the thiol-ene click reaction, further enhancing the fluorescence. The formation of a SUR1-MAT-unfolded protein sandwich complex reinforces the restriction of intramolecular motion and eliminates photoinduced electron transfer of MAT, leading to high signal-to-noise (9.2) fluorescence imaging and use for surgical navigation of pan-cancer. The generally high content of unfolded proteins in cancer cells makes MAT imaging generalizable, and it currently has proven feasibility in ovarian, cervical, and breast cancers. Meanwhile, MAT promotes cellular autophagy by hindering protein folding, thereby inhibiting cancer cell proliferation. This generalizable, high-contrast AIE fluorescent probe spans the heterogeneity of pancreatic cancer, enabling precise pancreatic cancer surgery navigation and treatment.

A Universal and Programmable Platform based on Fluorescent Peptide-Conjugated Probes for Detection of Proteins in Organelles of Living Cells.

Realizing protein analysis in organelles of living cells is of great significance for developing diagnostic and therapeutic methods of diseases. Fluorescent-labeled antibodies with well imaging performance and high affinity are classical biochemical tools for protein analysis, while due to the inability to effectively enter into cells, not to mention organelles and the uncontrollable reaction sites that might cause antibodies inactivation when chemically modification, they are hard to apply to living cells. Inspired by the structure of fluorescent-labeled antibodies, we designed as a universal detection platform that was based on the peptide-conjugated probes (PCPs) and consisted of three parts: a) a rotor type fluorescent molecular scaffold for conjugation and signal output; b) the cell penetration protein recognition unit; c) the subcellular organelle targeting unit. In living cells, PCPs could firstly localize at organelles and then proceed protein specific recognition, thus jointly leading to the restriction of twisted intramolecular charge transfer and activation of fluorescence signal. As a proof-of-concept, six different proteins in three typical intracellular organelles could be detected by our platform through simply replacing the recognition sequence of proteins and matching organelle targeting units. The position and intensity of fluorescence signals demonstrated specificity of PCPs and universality of the platform.

The function of astrocytes and their role in neurological diseases.

Astrocytes have countless links with neurons. Previously, astrocytes were only considered a scaffold of neurons; in fact, astrocytes perform a variety of functions, including providing support for neuronal structures and energy metabolism, offering isolation and protection and influencing the formation, function and elimination of synapses. Because of these functions, astrocytes play an critical role in central nervous system (CNS) diseases. The regulation of the secretiory factors, receptors, channels and pathways of astrocytes can effectively inhibit the occurrence and development of CNS diseases, such as neuromyelitis optica (NMO), multiple sclerosis, Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease. The expression of aquaporin 4 in AS is directly related to NMO and indirectly involved in the clearance of Aß and tau proteins in AD. Connexin 43 has a bidirectional effect on glutamate diffusion at different stages of stroke. Interestingly, astrocytes reduce the occurrence of PD through multiple effects such as secretion of related factors, mitochondrial autophagy and aquaporin 4. Therefore, this review is focused on the structure and function of astrocytes and the correlation between astrocytes and CNS diseases and drug treatment to explore the new functions of astrocytes with the astrocytes as the target. This, in turn, would provide a reference for the development of new drugs to protect neurons and promote the recovery of nerve function.

Regulating the Membrane Affinity of Multi-module Probes to Address the Trade-off between Anchoring and Internalization.

Cell membrane transport is the first and crucial step for bioprobes to realize the diagnosis, imaging, and therapy in cells. However, during this transport, there is a trade-off between anchoring and internalization steps, which will seriously affect the membrane transport efficiency. In the past, because the interaction between probes and cell membrane is constant, this challenge is hard to solve. Here, we proposed a strategy to regulate the membrane affinity of multi-module probes that enabled probe to have strong affinity during cell membrane anchoring and weak affinity during internalization. Specifically, a multi-module probe defined as LK-M-NA was constructed, which consisted of three main parts, membrane-anchoring α-helix peptide (LK), anchoring regulator (M), and therapeutic module (NA). With the α-helix module, LK-M-NA was able to rapidly anchor on the cell membrane and the binding energy was -1450.90 kcal/mol. However, after pericellular cleavage by the highly active matrix metalloproteinase-2 , LK could be removed due to the breakage of M and the binding energy reduced to -869.95 kcal/mol. Thus, the internalization restriction caused by high affinity was relieved. Owing to the alterable affinity, the membrane transport efficiency of LK-M-NA increased to 14.58%, well addressing the trade-off problem.

Comparative effectiveness of prophylactic strategies for preeclampsia: a network meta-analysis of randomized controlled trials.

OBJECTIVE: Preeclampsia is a common disease during pregnancy that leads to fetal and maternal adverse events. Few head-to-head clinical trials are currently comparing the effectiveness of prophylactic strategies for preeclampsia. In this network meta-analysis, we aimed to compare the efficacy of prophylactic strategies for preventing preeclampsia in pregnant women at risk. DATA SOURCES: Articles published in or before September 2021 from PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov, references of key articles, and previous meta-analyses were manually searched. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials comparing prophylactic strategies preventing preeclampsia with each other or with negative controls were included. METHODS: Two reviewers independently extracted data, assessed the risk of bias, and assessed evidence certainty. The efficacy of prophylactic strategies was estimated by frequentist and Bayesian network meta-analysis models. The primary composite outcome was preeclampsia/ pregnancy-induced hypertension. RESULTS: In total, 130 trials with a total of 112,916 patients were included to assess 13 prophylactic strategies. Low-molecular-weight heparin (0.60; 95% confidence interval, 0.42-0.87), vitamin D supplementation (0.65; 95% confidence interval, 0.45-0.95), and exercise (0.68; 95% confidence interval, 0.50-0.92) were as efficacious as calcium supplementation (0.71; 95% confidence interval, 0.62-0.82) and aspirin (0.79; 95% confidence interval, 0.72-0.86) in preventing preeclampsia/pregnancy-induced hypertension, with a P score ranking of 85%, 79%, 76%, 74%, and 61%, respectively. In the head-to-head comparison, no differences were found between these effective prophylactic strategies for preventing preeclampsia and pregnancy-induced hypertension, except with regard to exercise, which tended to be superior to aspirin and calcium supplementation in preventing pregnancy-induced hypertension. Furthermore, the prophylactic effects of aspirin and calcium supplementation were robust across subgroups. However, the prophylactic effects of low-molecular-weight heparin, exercise, and vitamin D supplementation on preeclampsia and pregnancy-induced hypertension varied with different risk populations, dosages, areas, etc. The certainty of the evidence was moderate to very low. CONCLUSION: Low-molecular-weight heparin, vitamin D supplementation, exercise, calcium supplementation, and aspirin reduce the risk of preeclampsia/pregnancy-induced hypertension. No significant differences between effective prophylactic strategies were found in preventing preeclampsia. These findings raise the necessity to reevaluate the prophylactic effects of low-molecular-weight heparin, vitamin D supplementation, and exercise on preeclampsia.

Detection of Unfolded Cellular Proteins Using Nanochannel Arrays with Probe-Functionalized Outer Surfaces.

Nanochannel technology has emerged as a powerful tool for label-free and highly sensitive detection of protein folding/unfolding status. However, utilizing the inner walls of a nanochannel array may cause multiple events even for proteins with the same conformation, posing challenges for accurate identification. Herein, we present a platform to detect unfolded proteins through electrical and optical signals using nanochannel arrays with outer-surface probes. The detection principle relies on the specific binding between the maleimide groups in outer-surface probes and the protein cysteine thiols that induce changes in the ionic current and fluorescence intensity responses of the nanochannel array. By taking advantage of this mechanism, the platform has the ability to differentiate folded and unfolded state of proteins based on the exposure of a single cysteine thiol group. The integration of these two signals enhances the reliability and sensitivity of the identification of unfolded protein states and enables the distinction between normal cells and Huntington's disease mutant cells. This study provides an effective approach for the precise analysis of proteins with distinct conformations and holds promise for facilitating the diagnoses of protein conformation-related diseases.

Fully automated mouse echocardiography analysis using deep convolutional neural networks.

Echocardiography (echo) is a translationally relevant ultrasound imaging modality widely used to assess cardiac structure and function in preclinical models of heart failure (HF) during research and drug development. Although echo is a very valuable tool, the image analysis is a time-consuming, resource-demanding process, and is susceptible to interreader variability. Recent advancements in deep learning have enabled researchers to automate image processing and reduce analysis time and interreader variability in the field of medical imaging. In the present study, we developed a fully automated tool, mouse-echocardiography neural net (MENN), for the analysis of both long-axis brightness (B)-mode and short-axis motion (M)-mode images of left ventricle. MENN is a series of fully convolutional neural networks that were trained and validated using manually segmented B-mode and M-mode echo images of the left ventricle. The segmented images were then used to compute cardiac structural and functional metrics. The performance of MENN was further validated in two preclinical models of HF. MENN achieved excellent correlations (Pearson's r = 0.85-0.99) and good-to-excellent agreement between automated and manual analyses. Further interreader variability analysis showed that MENN has better agreements with an expert analyst than both a trained analyst and a novice. Notably, the use of MENN reduced manual analysis time by >92%. In conclusion, we developed an automated echocardiography analysis tool that allows for fast and accurate analysis of B-mode and M-mode mouse echo data and mitigates the issue of interreader variability in manual analysis.NEW & NOTEWORTHY Echocardiography is commonly used in preclinical research to evaluate cardiac structure and function. Despite the broad applications across therapeutic areas, the analysis of echo data is laborious and susceptible to interreader variability. In this study, we developed a fully automated mouse-echocardiography neural net (MENN). Cardiac measurements from MENN showed excellent correlations with manual analysis. Furthermore, the use of MENN leads to >92% reduction in analysis time and potentially eliminates the interobserver variability issue.

The association of baseline N-terminal pro-B-type natriuretic peptide with short and long-term prognosis following percutaneous coronary intervention in non-ST segment elevation acute coronary syndrome with multivessel coronary artery disease: a retrospective cohort study.

BACKGROUND: Several studies have shown that N-terminal pro-B-type natriuretic peptide (NT-proBNP) is strongly correlated with the complexity of coronary artery disease and the prognosis of patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS), However, it remains unclear about the prognostic value of NT-proBNP in patients with NSTE-ACS and multivessel coronary artery disease (MCAD) undergoing percutaneous coronary intervention (PCI). Therefore, this study aimed to reveal the relationship between NT-proBNP levels and the prognosis for NSTE-ACS patients with MCAD undergoing successful PCI. METHODS: This study enrolled 1022 consecutive NSTE-ACS patients with MCAD from January 2010 to December 2014. The information of NT-proBNP levels was available from these patients. The primary outcome was in-hospital all-cause death. In addition, the 3-year follow-up all-cause death was also ascertained. RESULTS: A total of 12 (1.2%) deaths were reported during hospitalization. The 4th quartile group of NT-proBNP (> 1287 pg/ml) showed the highest in-hospital all-cause death rate (4.3%) (P < 0.001). Besides, logistic analyses revealed that the increasing NT-proBNP level was robustly associated with an increased risk of in-hospital all-cause death (adjusted odds ratio (OR): 2.86, 95% confidence interval (CI) = 1.16-7.03, P = 0.022). NT-proBNP was able to predict the in-hospital all-cause death (area under the curve (AUC) = 0.888, 95% CI = 0.834-0.941, P < 0.001; cutoff: 1568 pg/ml). Moreover, as revealed by cumulative event analyses, a higher NT-proBNP level was significantly related to a higher long-term all-cause death rate compared with a lower NT-proBNP level (P < 0.0001). CONCLUSIONS: The increasing NT-proBNP level is significantly associated with the increased risks of in-hospital and long-term all-cause deaths among NSTE-ACS patients with MCAD undergoing PCI. Typically, NT-proBN P > 1568 pg/ml is related to the all-cause and in-hospital deaths.

Spatial Order of Functional Modules Enabling Diverse Intracellular Performance of Fluorescent Probes.

To overcome a series of challenges in tumor therapy, modular-agent probes (MAPs) comprised of various functional modules have been proposed. Researchers have tried to optimize the MAPs by exploiting the new modules or increasing the numbers of module, while neglecting the configuration of various modules. Here, we focus on the different spatial arrangements of existing modules. By utilizing a tetraphenylethylene (TPE) derivative with stereochemical structure and dual modifiable end-group sites as small molecule scaffold, two MAPs with same modular agents (module T for enhancing the internalization of MAPs by tumor cells and module M for causing mitochondrial dysfunction) but different spatial arrangements (on the one side, TM-AIE, and two sides, T-AIE-M, of the molecule scaffold) are designed. T-AIE-M with larger RGD binding angle performed higher specificity, while TM-AIE characterizing longer α-helix structure displayed superior toxicity.

Incidence, Risk Factors and Subsequent Prognostic Impact of New-Onset Atrial Fibrillation in Infective Endocarditis.

BACKGROUND: Few studies with a large sample size have been performed to evaluate the incidence, risk factors and prognostic value of new-onset atrial fibrillation (AF) in patients with infective endocarditis (IE).Methods and Results:A total of 1,063 IE patients were included and 83 developed new AF. Compared with no-AF, the incidence of in-hospital death (6.0% vs. 22.9%, P<0.001) was higher in patients with new-onset AF. New-onset AF was independently associated with increased risk of in-hospital (adjusted odds ratio [OR]=3.92, P=0.001) and 1-year death (adjusted hazard ratio=2.91, P=0.001), while prior AF was not an independent factor. Kaplan-Meier curve analysis demonstrated new-onset AF mainly affected short-term death (180 days). Age (OR=1.04, P<0.001), rheumatic heart disease (OR=1.88, P=0.022), NYHA Class III or IV (OR=2.09, P=0.003), and left atrial diameter (LAD; OR=1.05, P=0.006) were independent risk factors for development of new AF. CONCLUSIONS: New-onset AF, not prior AF, was a prognostic factor in IE patients, which was mainly associated with increased risk of short-term death. Patients with concomitant rheumatic heart disease, poor cardiac function, and larger LAD had higher risk of developing new AF.

Association of in-hospital intensive statins dosage and death in arteriosclerotic cardiovascular disease with percutaneous coronary intervention: insights of multicentre cohort from China.

PURPOSE: In-hospital statin dosage-related effect remains unknown for patients with arteriosclerotic cardiovascular disease (ASCVD). This study aimed to determine the associations of different in-hospital intensive statins dosages with the prognosis for patients in the era of percutaneous coronary intervention (PCI). METHODS: From January 2010 to December 2014, consecutive ASCVD patients receiving PCI were enrolled from five centres in China. All the enrolled patients were classified into high-dose (40 mg atorvastatin or 20 mg rosuvastatin) or low-dose (20 mg atorvastatin or 10 mg rosuvastatin) intensive statin group. In-hospital all-cause death was the primary outcome. RESULTS: Of the 7008 patients included in this study, 5248 received low-dose intensive statins (mean age, 64.28 ± 10.39; female, 25.2%), whereas 1760 received high-dose intensive statins (mean age, 63.68 ± 10.59; female, 23.1%). There was no significant difference in the in-hospital all-cause death between the two groups (adjusted OR, 1.27; 95% CI, 0.43-3.72; P = 0.665). All-cause death was similar between the two groups during the 30-day follow-up period (adjusted HR, 1.28; 95% CI, 0.55-2.97; P = 0.571). However, the high-dose intensive statins were tightly associated with the reduction in in-hospital dialysis (adjusted OR, 0.11; 95% CI, 0.01-0.81; P = 0.030). Besides, primary analyses were confirmed by subgroup analyses. CONCLUSIONS: The in-hospital high-dose intensive statins are not associated with the lower risk of in-hospital or 30-day all-cause death among ASCVD patients undergoing PCI. Given the robust beneficial effect of high-dose intensive statins with in-hospital dialysis, an individualized high-dose intensive statin therapy can be rational in specified populations.

Structural determination and in vitro tumor cytotoxicity evaluation of five new cycloartane glycosides from Asplenium ruprechtii Sa. Kurata.

Five new cycloartane glycosides, named aspleniumside A - E, were discovered and characterized by re-investigated the remaining extracts of the whole plant of Asplenium ruprechtii Sa. Kurata, a famous folk medicine for treating thromboangitis obliterans in China, Japan, and Korea. Compounds 3-5 possessed the 9,19-seco-cycloartane-9,11-en triterpene aglycone with 3,7(or 23),24,25,30-highly oxidized methylene, methylene or quaternary carbons, that was found in this species for the first time. The stereo-chemistry of all new compounds were fully discussed by extensive analysis of the 1D and 2D NMR data, and comparisons with those data of known compounds. 24R configuration was determined here which indicated the different growing areas of the same species could influence the secondary metabolic behavior, leading to the differences in chemical composition. All glycoside groups were determined as ß-d-glucopyranosyl by 1H coupling constant of anomeric protons and co-TLC of the acid hydrolysate with d-glucose. All the cycloartane glycosides were evaluated against HL-60 and HepG2 cells for cytotoxicity, compounds 1-3, showed potential cytotoxicity with the IC50 in range of 18-60 µM, while the standard sorafenib showed IC50 value of 10.61 ± 0.43 and 13.43 ± 1.12 µM against HL-60 and HepG2, respectively. The results attained in this study indicated that cycloartane glycosides should be the cytotoxicity substance in A. ruprechtii Sa. Kurata, and had the potential to be developed as tumor cytotoxicity agent applied in clinic.

In Vivo Imaging of Endogenously Produced HClO in Zebrafish and Mice Using a Bright, Photostable Ratiometric Fluorescent Probe.

A high brightness red fluorescent probe (S-BODIPY) has been developed for the sensitive and specific imaging of HClO/ClO- in vitro and in vivo. This probe exhibits some distinctive features such as excellent resistance to photobleaching, a high fluorescence brightness, high selectivity, as well as a good biocompatibility. Upon oxidation of the thio-ether group into sulfoxide, the probe showed a noticeable ratiometric fluorescence response toward ClO- with fast response (within 30 s) and a low detection limit (59 nM). The probe demonstrated the successful imaging of exogenous and endogenous HClO/ClO- in living HeLa cells, zebrafish, and mice with high signal-to-noise ratios. S-BODIPY allows for the real-time monitoring the level of ClO- in living cells by ratiometric fluorescence imaging, opening up exciting prospects to develop red and even near-infrared BODIPYs with high brightness and good photostability for in vivo imaging.

Integrated motion correction and dictionary learning for free-breathing myocardial T1 mapping.

PURPOSE: To develop and evaluate an integrated motion correction and dictionary learning (MoDic) technique to accelerate data acquisition for myocardial T1 mapping with improved accuracy. METHODS: MoDic integrates motion correction with dictionary learning-based reconstruction. A random undersampling scheme was implemented for slice-interleaved T1 mapping sequence to allow prospective undersampled data acquisition. Phantom experiments were performed to evaluate the effect of reconstruction on T1 measurement. In vivo T1 mappings were acquired in 8 healthy subjects using 6 different acceleration approaches: uniform or randomly undersampled k-space data with reduction factors (R) of 2, 3, and 4. Uniform undersampled data were reconstructed with SENSE, and randomly undersampled k-space data were reconstructed using dictionary learning, compressed sensing SENSE, and MoDic methods. Three expert readers subjectively evaluated the quality of T1 maps using a 4-point scoring system. The agreement between T1 values was assessed by Bland-Altman analysis. RESULTS: In the phantom study, the accuracy of T1 measurements improved with increasing reduction factors ( - 31 ± 35 ms, - 13 ± 18 ms, and - 5 ± 11 ms for reduction factor (R) = 2 to 4, respectively). The image quality of in vivo T1 maps assessed by subjective scoring using MoDic was similar to that of SENSE at R = 2 (P = .61) but improved at R = 3 and 4 (P < .01). The scores of dictionary learning (2.98 ± 0.71, 2.91 ± 0.60, and 2.67 ± 0.71 for R = 2 to 4) and CS-SENSE (3.32 ± 0.42, 3.05 ± 0.43, and 2.53 ± 0.43) were lower than those of MoDic (3.48 ± 0.46, 3.38 ± 0.52, and 2.9 ± 0.60) for all reduction factors (P < .05 for all). CONCLUSION: The MoDic method accelerates data acquisition for myocardial T1 mapping with improved T1 measurement accuracy.

Non-contrast myocardial infarct scar assessment using a hybrid native T1 and magnetization transfer imaging sequence at 1.5T.

PURPOSE: To develop a gadolinium-free cardiac MR technique that simultaneously exploits native T1 and magnetization transfer (MT) contrast for the imaging of myocardial infarction. METHODS: A novel hybrid T one and magnetization transfer (HYTOM) method was developed based on the modified look-locker inversion recovery (MOLLI) sequence, with a train of MT-prep pulses placed before the balanced SSFP (bSSFP) readout pulses. Numerical simulations, based on Bloch-McConnell equations, were performed to investigate the effects of MT induced by (1) the bSSFP readout pulses, and (2) the MT-prep pulses, on the measured, "apparent," native T1 values. The HYTOM method was then tested on 8 healthy adult subjects, 6 patients, and a swine with prior myocardial infarction (MI). The resulting imaging contrast between normal myocardium and infarcted tissues was compared with that of MOLLI. Late gadolinium enhancement (LGE) images were also obtained for infarct assessment in patients and swine. RESULTS: Numerical simulation and in vivo studies in healthy volunteers demonstrated that MT effects, resulting from on-resonance bSSFP excitation pulses and off-resonance MT-prep pulses, reduce the measured T1 in both MOLLI and HTYOM. In vivo studies in patients and swine showed that the HYTOM sequence can identify locations of MI, as seen on LGE. Furthermore, the HYTOM method yields higher myocardium-to-scar contrast than MOLLI (contrast-to-noise ratio: 7.33 ± 1.67 vs. 3.77 ± 0.66, P < 0.01). CONCLUSION: The proposed HYTOM method simultaneously exploits native T1 and MT contrast and significantly boosts the imaging contrast for myocardial infarction.

Colorimetric and Ratiometric Chemosensor for Visual Detection of Gaseous Phosgene Based on Anthracene Carboxyimide Membrane.

In this work, we reported an anthracene carboxyimide-based chemosensor (AC-Phos) for colorimetric and ratiometric fluorescence detection of highly toxic phosgene, which displayed rapid response (<5 min) toward phosgene with a high selectivity and a low detection limit (2.3 nM). Furthermore, a facile testing membrane with a polystyrene immobilizing chemosensor has been fabricated for real-time visualizing of gaseous phosgene.

Bayesian Modeling of NMR Data: Quantifying Longitudinal Relaxation in Vivo, and in Vitro with a Tissue-Water-Relaxation Mimic (Crosslinked Bovine Serum Albumin).

Recently, a number of MRI protocols have been reported that seek to exploit the effect of dissolved oxygen (O2, paramagnetic) on the longitudinal 1H relaxation of tissue water, thus providing image contrast related to tissue oxygen content. However, tissue water relaxation is dependent on a number of mechanisms, and this raises the issue of how best to model the relaxation data. This problem, the model selection problem, occurs in many branches of science and is optimally addressed by Bayesian probability theory. High signal-to-noise, densely sampled, longitudinal 1H relaxation data were acquired from rat brain in vivo and from a cross-linked bovine serum albumin (xBSA) phantom, a sample that recapitulates the relaxation characteristics of tissue water in vivo. Bayesian-based model selection was applied to a cohort of five competing relaxation models: (i) monoexponential, (ii) stretched-exponential, (iii) biexponential, (iv) Gaussian (normal) R1-distribution, and (v) gamma R1-distribution. Bayesian joint analysis of multiple replicate datasets revealed that water relaxation of both the xBSA phantom and in vivo rat brain was best described by a biexponential model, while xBSA relaxation datasets truncated to remove evidence of the fast relaxation component were best modeled as a stretched exponential. In all cases, estimated model parameters were compared to the commonly used monoexponential model. Reducing the sampling density of the relaxation data and adding Gaussian-distributed noise served to simulate cases in which the data are acquisition-time or signal-to-noise restricted, respectively. As expected, reducing either the number of data points or the signal-to-noise increases the uncertainty in estimated parameters and, ultimately, reduces support for more complex relaxation models.

Are complex DCE-MRI models supported by clinical data?

PURPOSE: To ascertain whether complex dynamic contrast enhanced (DCE) MRI tracer kinetic models are supported by data acquired in the clinic and to determine the consequences of limited contrast-to-noise. METHODS: Generically representative in silico and clinical (cervical cancer) DCE-MRI data were examined. Bayesian model selection evaluated support for four compartmental DCE-MRI models: the Tofts model (TM), Extended Tofts model, Compartmental Tissue Uptake model (CTUM), and Two-Compartment Exchange model. RESULTS: Complex DCE-MRI models were more sensitive to noise than simpler models with respect to both model selection and parameter estimation. Indeed, as contrast-to-noise decreased, complex DCE models became less probable and simpler models more probable. The less complex TM and CTUM were the optimal models for the DCE-MRI data acquired in the clinic. [In cervical tumors, Ktrans, Fp, and PS increased after radiotherapy (P = 0.004, 0.002, and 0.014, respectively)]. CONCLUSION: Caution is advised when considering application of complex DCE-MRI kinetic models to data acquired in the clinic. It follows that data-driven model selection is an important prerequisite to DCE-MRI analysis. Model selection is particularly important when high-order, multiparametric models are under consideration. (Parameters obtained from kinetic modeling of cervical cancer clinical DCE-MRI data showed significant changes at an early stage of radiotherapy.) Magn Reson Med 77:1329-1339, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Can anti-vascular endothelial growth factor antibody reverse radiation necrosis? A preclinical investigation.

Anti-vascular endothelial growth factor (anti-VEGF) antibodies are a promising new treatment for late time-to-onset radiation-induced necrosis (RN). We sought to evaluate and validate the response to anti-VEGF antibody in a mouse model of RN. Mice were irradiated with the Leksell Gamma Knife Perfexion™ and then treated with anti-VEGF antibody, beginning at post-irradiation (PIR) week 8. RN progression was monitored via anatomic and diffusion MRI from weeks 4-12 PIR. Standard histology, using haematoxylin and eosin (H&E), and immunohistochemistry staining were used to validate the response to treatment. After treatment, both post-contrast T1-weighted and T2-weighted image-derived lesion volumes decreased (P < 0.001), while the lesion volumes for the control group increased. The abnormally high apparent diffusion coefficient (ADC) for RN also returned to the ADC range for normal brain following treatment (P < 0.001). However, typical RN pathology was still present histologically. Large areas of focal calcification were observed in ~50% of treated mouse brains. Additionally, VEGF and hypoxia-inducible factor 1-alpha (HIF-1α) were continually upregulated in both the anti-VEGF and control groups. Despite improvements observed radiographically following anti-VEGF treatment, lesions were not completely resolved histologically. The subsequent calcification and the continued upregulation of VEGF and HIF-1α merit further preclinical/clinical investigation.