Deep learning based method for predicting DNA N6-methyladenosine sites.

DNA N6 methyladenine (6mA) plays an important role in many biological processes, and accurately identifying its sites helps one to understand its biological effects more comprehensively. Previous traditional experimental methods are very labor-intensive and traditional machine learning methods also seem to be somewhat insufficient as the database of 6mA methylation groups becomes progressively larger, so we propose a deep learning-based method called multi-scale convolutional model based on global response normalization (CG6mA) to solve the prediction problem of 6mA site. This method is tested with other methods on three different kinds of benchmark datasets, and the results show that our model can get more excellent prediction results.

One-Stage Intraoperative ERCP combined with Laparoscopic Cholecystectomy Versus Two-Stage Preoperative ERCP Followed by Laparoscopic Cholecystectomy in the Management of Gallbladder with Common Bile Duct Stones: A Meta-analysis.

INTRODUCTION: Concomitant gallbladder and common bile duct (CBD) stones, known as cholecystocholedocholithiasis, are clinically prevalent. There is currently no consensus on sequential versus simultaneous management approaches, and, if simultaneous, which approach to adopt. This meta-analysis evaluates the safety and efficacy of one-stage laparoscopic cholecystectomy (LC) with intraoperative endoscopic retrograde cholangiopancreatography (ERCP) versus two-stage ERCP followed by LC for treating concomitant gallbladder and CBD stones. METHODS: A comprehensive literature search was conducted in five databases, PubMed, Embase, Web of Science, VIP, and Wanfang, for all randomized controlled trials (RCTs), cohort and retrospective studies published up to February 2024. Data extraction was performed independently by two reviewers. The primary outcomes were CBD stone clearance rate and postoperative complications morbidity. Secondary outcomes included conversion to other procedures and length of hospital stay. Statistical analyses were performed using R (v.4.3.2) with weighted mean differences and odds ratios (ORs) calculated for continuous and dichotomous variables, respectively, with 95% confidence intervals (CIs). RESULTS: A total of 17 studies involving 2120 patients have been included, with 898 patients receiving single-stage and 1222 patients undergoing two-stage treatment. Of these studies, 9 were RCTs and 8 were retrospective cohort study. The one-stage group demonstrated superior outcomes in terms of CBD stone clearance (OR = 2.07, p = 0.0004), overall morbidity (OR = 0.35, p < 0.0001), post-operative pancreatitis (OR = 0.49, p = 0.006), conversion to other procedures (OR = 0.38, p = 0.0006), and length of hospital stay (MD = - 2.6456, 95% CI - 3.5776; - 1.7136, p < 0.0001). No significant differences were observed in post-operative cholangitis (OR = 0.44, p = 0.12), post-operative bleeding (OR = 0.76, p = 0.47), or bile leakage (OR = 1.28, p = 0.54). CONCLUSION: For patients with concomitant gallbladder and CBD stones, the one-stage approach combining ERCP and LC appears safer and more effective, with advantages including higher stone clearance rates, reduced postoperative complications (particularly pancreatitis), shorter hospital stays, fewer residual stones, and decreased need for additional procedures. However, additional high-quality clinical trials are needed to establish the optimal treatment approach for various patient scenarios.

Preclinical ImmunoPET Imaging Using a Zr-89-Labeled Anti-CD146 Monoclonal Antibody for Diagnosis of Melanoma.

The aim of this study was to evaluate the preclinical efficacy of [89Zr]Zr-DFO-Ab253 as a novel positron emission tomography (PET) tracer for CD146-positive malignant melanoma imaging. Considering the high expression of CD146 in malignant melanoma, this study investigated the effect of different CD146 expression levels on the tumor uptake of [89Zr]Zr-DFO-Ab253. CD146 selectivity was investigated by using the CD146-positive human melanoma cell A375 and the CD146-negative human alveolar epithelial cell A549. The cell uptake of [89Zr]Zr-DFO-Ab253 tracers was investigated, and receptor-binding affinities were measured by radioactive enzyme-linked immunosorbent assay. Biodistribution studies and micro-PET imaging of the radiotracers were performed on mice bearing A375 and A549 xenografts under baseline and blocking conditions. An immunohistochemical test was performed using A375 and A549 tissue sections for CD146 expression level analysis. [89Zr]Zr-DFO-Ab253 was obtained with a high radiochemical yield (87.86 ± 4.66%) and a satisfactory radiochemical purity (>98.0%). The specificity and affinity of [89Zr]Zr-DFO-Ab253 were confirmed in melanoma A375 cells and in vivo PET imaging of A375 tumor models. [89Zr]Zr-DFO-IgG and A549 lung tumors were prepared as control radiotracers and negative models to verify the specificity of [89Zr]Zr-DFO-Ab253 on CD146. [89Zr]Zr-DFO-Ab253 has a Kd of 4.01 ± 0.50 nM. PET imaging and biodistribution showed a higher uptake of [89Zr]Zr-DFO-Ab253 in A375 melanomas than that in A549 tumors (42.1 ± 4.04% vs 7.87 ± 1.30% ID/g at 120 h, P < 0.05). A low tumor uptake of [89Zr]Zr-DFO-IgG was observed with uptakes of 1.91 ± 0.41 and 2.80 ± 0.14 ID%/g when blocked at 120 h. The radiation-absorbed dose was calculated to be 0.13 mSv/MBq. This study demonstrates the synthesis and preclinical evaluation of [89Zr]Zr-DFO-Ab253 and indicates that the novel tracer has promising applications in malignant melanoma-specific PET imaging because of its high uptake and long-time retention in malignant melanoma. It also provides feasibility for the development of integrated molecular probes for diagnosis and treatment based on the CD146 target.

Impact of HER2-targeted PET/CT imaging in patients with breast cancer and therapeutic response monitoring.

BACKGROUND: Patients with breast cancer exhibit heterogeneity in the expression of the human epithelial growth factor receptor 2 (HER2). Clinically, re-biopsying recurrent or metastatic lesions presents substantial challenges. This study aimed to evaluate the efficacy of HER2-targeted PET/CT imaging in identifying HER2 expression in breast cancer lesions and monitoring therapeutic responses. PATIENTS AND METHODS: This exploratory analysis used data from a prospective study that included adult patients with breast cancer who underwent both Al18F-NOTA-HER2-BCH and 18F-FDG PET/CT imaging at Beijing Cancer Hospital between June 2020 and July 2023 (NCT04547309). RESULTS: Fifty-nine participants, with a median age of 55 years, were analyzed. Lesions imaged with HER2-targeted PET/CT before anti-HER2 therapy exhibited higher SUVmax values than after therapy in HER2 immunohistochemistry (IHC) 3 + lesions (19.9, 95% CI: 15.7-25.3 vs 9.8, 95% CI: 5.6-14.7; P = .006). A significant positive correlation was observed between SUVmax on HER2-targeted PET/CT and IHC before therapy (P = .034), with higher SUVmax values noted in lesions with positive HER2 pathology compared to those with negative HER2 status (17.9 ±â€…13.2 vs 1.1 ±â€…0.3; P = .007). HER2 expression heterogeneity was confirmed both between primary and metastatic lesions (22.9%) and among different metastatic sites (26.7%) as assessed by HER2-targeted PET/CT. A superior therapeutic response correlated with higher pretreatment SUVmax values. The HER2-targeted PET/CT procedure was well-tolerated by all patients. CONCLUSION: HER2-targeted PET/CT imaging offers a practical, non-invasive, and quantitative approach for assessing HER2 status in breast cancer patients, facilitating the optimization and personalization of therapeutic strategies by oncologists.

Prediction of hemifacial spasm re-appearing phenomenon after microvascular decompression surgery in patients with hemifacial spasm using dynamic susceptibility contrast perfusion MRI.

Objective: Hemifacial spasm (HFS) is treated by a surgical procedure called microvascular decompression (MVD). However, HFS re-appearing phenomenon after surgery, presenting as early recurrence, is experienced by some patients after MVD. Dynamic susceptibility contrast (DSC) perfusion MRI and two analytical methods: receiver operating characteristic (ROC) curve and machine learning, were used to predict early recurrence in this study. Methods: This study enrolled sixty patients who underwent MVD for HFS. They were divided into two groups: Group A consisted of 32 patients who had early recurrence, and Group B consisted of 28 patients who had no early recurrence of HFS. DSC perfusion MRI was undergone by all patients before the surgery to obtain the several parameters. ROC curve and machine learning methods were used to predict early recurrence using these parameters. Results: Group A had significantly lower relative cerebral blood flow (rCBF) than Group B in most of the selected brain regions, as shown by the region-of-interest (ROI)-based analysis. By combining three extraction fraction (EF) values at middle temporal gyrus, posterior cingulate, and brainstem, with age, using naive Bayes machine learning method, the best prediction model for early recurrence was obtained. This model had an area under the curve (AUC) value of 0.845. Conclusion: By combining EF values with age or sex using machine learning methods, DSC perfusion MRI can be used to predict early recurrence before MVD surgery. This may help neurosurgeons to identify patients who are at risk of HFS recurrence and provide appropriate postoperative care.

Comparison of an Affibody-based Molecular Probe and 18F-FDG for Detecting HER2-Positive Breast Cancer at PET/CT.

Background Human epidermal growth factor receptor 2 (HER2) affibody-based tracers could be an alternative to nonspecific radiotracers for noninvasive detection of HER2 expression in breast cancer lesions at PET/CT. Purpose To compare an affibody-based tracer, Al18F-NOTA-HER2-BCH, and fluorine 18 (18F) fluorodeoxyglucose (FDG) for detecting HER2-positive breast cancer lesions on PET/CT images. Materials and Methods In this prospective study conducted from June 2020 to July 2023, participants with HER2-positive breast cancer underwent both Al18F-NOTA-HER2-BCH and 18F-FDG PET/CT. HER2 positivity was confirmed with pathologic assessment (immunohistochemistry test results of 3+, or 2+ followed by fluorescence in situ hybridization, indicated HER2 amplification). Two independent readers visually assessed the uptake of tracers on images. Lesion uptake was quantified using the maximum standardized uptake value (SUVmax) and target to background ratio (TBR) and compared using a general linear mixed model. Results A total of 42 participants (mean age, 56.3 years ± 10.1 [SD]; 41 female) with HER2-positive breast cancer were included; 42 (100%) had tumors that were detected with Al18F-NOTA-HER2-BCH PET/CT and 40 (95.2%) had tumors detected with 18F-FDG PET/CT. Primary tumors in two of 21 participants, lymph node metastases in four of 21 participants, bone metastases in four of 15 participants, and liver metastases in three of nine participants were visualized only with Al18F-NOTA-HER2-BCH. Lung metastasis in one of nine participants was visualized only with 18F-FDG. Al18F-NOTA-HER2-BCH enabled depiction of more suspected HER2-positive primary tumors (26 vs 21) and lymph node (170 vs 130), bone (92 vs 66), and liver (55 vs 27) metastases than 18F-FDG. The SUVmax and TBR values of primary tumors and lymph node, bone, and liver metastases were all higher on Al18F-NOTA-HER2-BCH images than on 18F-FDG images (median SUVmax range, 10.4-13.5 vs 3.4-6.2; P value range, <.001 to .02; median TBR range, 2.7-17.6 vs 1.2-7.8; P value range, <.001 to .001). No evidence of differences in the SUVmax and TBR for chest wall or lung metastases was observed between Al18F-NOTA-HER2-BCH and 18F-FDG (P value range, .06 to .53). Conclusion PET/CT with the affibody-based tracer Al18F-NOTA-HER2-BCH enabled detection of more primary lesions and lymph node, bone, and liver metastases than PET/CT using 18F-FDG. ClinicalTrials.gov Identifier: NCT04547309 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Ulaner in this issue.

Sequence homology score-based deep fuzzy network for identifying therapeutic peptides.

The detection of therapeutic peptides is a topic of immense interest in the biomedical field. Conventional biochemical experiment-based detection techniques are tedious and time-consuming. Computational biology has become a useful tool for improving the detection efficiency of therapeutic peptides. Most computational methods do not consider the deviation caused by noise. To improve the generalization performance of therapeutic peptide prediction methods, this work presents a sequence homology score-based deep fuzzy echo-state network with maximizing mixture correntropy (SHS-DFESN-MMC) model. Our method is compared with the existing methods on eight types of therapeutic peptide datasets. The model parameters are determined by 10 fold cross-validation on their training sets and verified by independent test sets. Across the 8 datasets, the average area under the receiver operating characteristic curve (AUC) values of SHS-DFESN-MMC are the highest on both the training (0.926) and independent sets (0.923).

Grain Chalkiness Is Decreased by Balancing the Synthesis of Protein and Starch in Hybrid Indica Rice Grains under Nitrogen Fertilization.

The important reason for the commercial value of hybrid rice suffering is due to excessive chalkiness, and the biosynthesis of starch and proteins is critical for regulating chalkiness; however, it is currently unclear how the application of N fertilizer affects grains to reduce their chalkiness and improve their quality. The 2019, 2020, and 2021 trials were conducted in a split-plot design, with high and low chalky varieties as the main plot and N fertilizer rate as the split-plot. The effects of fertilization with 75, 150, and 225 kg N ha-1 on the dynamic synthesis of starch, protein, and endogenous hormones and on the amino acid of hybrid indica rice kernels with different degrees of chalkiness were investigated. Grain physiological activity was higher in low-chalky varieties than in high-chalky varieties, and these physiological parameters were strongly associated with chalkiness formation. Higher N fertilization (150 and 225 kg N ha-1) significantly reduced the proportion of chalky grains (8.93-28.02%) and chalkiness (8.61-33.99%) compared with 75 kg N ha-1. Increased N fertilization decreased the activities of granule-bound starch synthase and starch-debranching enzyme, but significantly increased adenosine diphosphate glucose pyrophosphorylase, soluble starch synthase, and starch-branching enzyme activities, synergistically improving glutamate synthetase and glutamine synthetase enzyme activities, which tended to support the synthesis of amylopectin, α-ketoglutarate, and 3-phosphoglyceric acid-derived amino acids in the endosperm cells of the grains; this favored starch and protein accumulation in the grains at 6-30 days after anthesis. Additionally, N application promoted the synthesis of endogenous hormones 1-aminocyclopropane-1-carboxylic acid, gibberellins, and abscisic acid in grains. Hence, N fertilization reduced the rice chalkiness in hybrid indica rice varieties by balancing grain protein and starch composition and enhancing some endogenous hormone synthesis.

P-tau217 correlates with neurodegeneration in Alzheimer's disease, and targeting p-tau217 with immunotherapy ameliorates murine tauopathy.

Neuronal loss is the central issue in Alzheimer's disease (AD), yet no treatment developed so far can halt AD-associated neurodegeneration. Here, we developed a monoclonal antibody (mAb2A7) against 217 site-phosphorylated human tau (p-tau217) and observed that p-tau217 levels positively correlated with brain atrophy and cognitive impairment in AD patients. Intranasal administration efficiently delivered mAb2A7 into male PS19 tauopathic mouse brain with target engagement and reduced tau pathology/aggregation with little effect on total soluble tau. Further, mAb2A7 treatment blocked apoptosis-associated neuronal loss and brain atrophy, reversed cognitive deficits, and improved motor function in male tauopathic mice. Proteomic analysis revealed that mAb2A7 treatment reversed alterations mainly in proteins associated with synaptic functions observed in murine tauopathy and AD brain. An antibody (13G4) targeting total tau also attenuated tau-associated pathology and neurodegeneration but impaired the motor function of male tauopathic mice. These results implicate p-tau217 as a potential therapeutic target for AD-associated neurodegeneration.

Passive immunotherapy for Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by cognitive impairment with few therapeutic options. Despite many failures in developing AD treatment during the past 20 years, significant advances have been achieved in passive immunotherapy of AD very recently. Here, we review characteristics, clinical trial data, and mechanisms of action for monoclonal antibodies (mAbs) targeting key players in AD pathogenesis, including amyloid-ß (Aß), tau and neuroinflammation modulators. We emphasized the efficacy of lecanemab and donanemab on cognition and amyloid clearance in AD patients in phase III clinical trials and discussed factors that may contribute to the efficacy and side effects of anti-Aß mAbs. In addition, we provided important information on mAbs targeting tau or inflammatory regulators in clinical trials, and indicated that mAbs against the mid-region of tau or pathogenic tau have therapeutic potential for AD. In conclusion, passive immunotherapy targeting key players in AD pathogenesis offers a promising strategy for effective AD treatment.

Detection and attribution of the start of the growing season changes in the Northern Hemisphere.

Global climate change has led to significant changes in land surface phenology. At present, research on the factors influencing the start of the growing season (SOS) mainly focuses on single factor effects, such as temperature and precipitation, ignoring the combined action of multiple factors. The impact of multiple factors on the spatial and temporal patterns of the SOS in the Northern Hemisphere is not clear, and it is necessary to combine multiple factors to quantify the degrees of influence of different factors on the SOS. Based on the GIMMS3g NDVI dataset, CRU climate data and other factor data, we used geographic detector model, random forest regression model, multiple linear regression, partial correlation analysis and Sen + Mann-Kendall trend analysis to explore the variation of the SOS in the Northern Hemisphere to reveal the main driving factors and impact threshold of 17 influencing factors on the SOS. The results showed that (1) during the past 34 years (1982-2015), the SOS in Europe and Asia mainly showed an advancing trend, whereas the SOS in North America mainly showed a delaying trend. (2) The SOS was mainly controlled by frost frequency, temperature and humidity. Increasing frost frequency inhibited the advancement of the SOS, and increasing temperature and humidity promoted the advancement of the SOS. (3) There were thresholds for the influences of the driving factors on the SOS. Outside the threshold ranges, the response mechanism of the SOS to driving factors changed. The results are important for understanding the response of the SOS to global climate change.

Efficacy and complications of inoperable malignant distal biliary obstruction treatment by metallic stents: fully covered or uncovered?

Obstructive jaundice caused by malignant distal biliary obstruction is a common clinical symptom in patients with inoperable biliary-pancreatic cancer. Endoscopic retrograde cholangiopancreatography (ERCP)-guided stent implantation is an effective treatment for obstructive jaundice. Internal stent drainage is more physiologic and associated with a better quality of life than external stent drainage methods such as percutaneous transhepatic gallbladder drainage or percutaneous transhepatic cholangiodrainage. Self-expanding metallic stents, which may be covered and uncovered, are commonly used. However, some uncertainties remain regarding the selection of metallic stents, including drainage patency time, clinical effect, stent migration, and post-operative complications such as pancreatitis, bleeding, and cholecystitis. This review aims to summarize the current progress and controversies surrounding the use of covered or uncovered metallic stents in inoperable common biliary obstruction via ERCP.

Anti-Epstein-Barr Virus BNLF2b for Mass Screening for Nasopharyngeal Cancer.

BACKGROUND: Population screening of asymptomatic persons with Epstein-Barr virus (EBV) DNA or antibodies has improved the diagnosis of nasopharyngeal carcinoma and survival among affected persons. However, the positive predictive value of current screening strategies is unsatisfactory even in areas where nasopharyngeal carcinoma is endemic. METHODS: We designed a peptide library representing highly ranked B-cell epitopes of EBV coding sequences to identify novel serologic biomarkers for nasopharyngeal carcinoma. After a retrospective case-control study, the performance of the novel biomarker anti-BNLF2b total antibody (P85-Ab) was validated through a large-scale prospective screening program and compared with that of the standard two-antibody-based screening method (EBV nuclear antigen 1 [EBNA1]-IgA and EBV-specific viral capsid antigen [VCA]-IgA). RESULTS: P85-Ab was the most promising biomarker for nasopharyngeal carcinoma screening, with high sensitivity (94.4%; 95% confidence interval [CI], 86.4 to 97.8) and specificity (99.6%; 95% CI, 97.8 to 99.9) in the retrospective case-control study. Among the 24,852 eligible participants in the prospective cohort, 47 cases of nasopharyngeal carcinoma (38 at an early stage) were identified. P85-Ab showed higher sensitivity than the two-antibody method (97.9% vs. 72.3%; ratio, 1.4 [95% CI, 1.1 to 1.6]), higher specificity (98.3% vs. 97.0%; ratio, 1.01 [95% CI, 1.01 to 1.02]), and a higher positive predictive value (10.0% vs. 4.3%; ratio, 2.3 [95% CI, 1.8 to 2.8]). The combination of P85-Ab and the two-antibody method markedly increased the positive predictive value to 44.6% (95% CI, 33.8 to 55.9), with sensitivity of 70.2% (95% CI, 56.0 to 81.4). CONCLUSIONS: Our results suggest that P85-Ab is a promising novel biomarker for nasopharyngeal carcinoma screening, with higher sensitivity, specificity, and positive predictive value than the standard two-antibody method. (Funded by the National Key Research and Development Program of China and others; ClinicalTrials.gov number, NCT04085900.).

Preparation and Application of a Bioorganic Nanoparticle-Enhanced PDL1-Targeted Small-Molecule Probe.

Programmed death ligand 1 (PDL1) is a specific molecular target for the diagnosis and immunotherapy of solid tumors. PET imaging can be used for noninvasive assessments of PDL1 expression in tumors to aid in therapy selection. The most frequently reported small-molecule radiotracer of PDL1 is limited by low imaging specificity, short residence time, and singular functionality. Here, we combined a biocompatible melanin nanoprobe with the PDL1-binding peptide WL12 to construct a novel radiotracer, 124I-WPMN, to enhance PDL1 targeting. The radiochemical purity of 124I-WPMN was >95%, and uptake in A549PDL1 cells was 1.49 ± 0.08% at 2 h. The uptake was blocked by WL12 (0.39 ± 0.03%, P < 0.0001). This novel radiotracer showed a higher affinity for PDL1 (Kd = 18.5 nM) than 68Ga-NOTA-WL12 (Kd = 24.0 nM). Micro-PET/CT imaging demonstrated specific uptake and a high signal-to-noise ratio in an A549PDL1 xenograft mouse model with a tumor-to-muscle ratio of 27.31 ± 7.03 at 2 h. The levels increased or remained steady for more than 72 h, and tumor uptake was significantly higher than 68Ga-NOTA-WL12, at 6.08 ± 0.62 at 2 h. Prolonged retention of 124I-WPMN makes it possible to conduct PET/MRI imaging over long periods and to perform various imaging techniques. A clear advantage of 124I-WPMN over 68Ga-NOTA-WL12 was observed for PDL1-targeted PET imaging after nanoparticle modification, supporting the utility of 124I-WPMN PET imaging as an effective diagnostic tool for optimizing PDL1-targeted therapies.

The mechanism of chronic intracellular infection with Brucella spp.

Globally, brucellosis is a widespread zoonotic disease. It is prevalent in more than 170 countries and regions. It mostly damages an animal's reproductive system and causes extreme economic losses to the animal husbandry industry. Once inside cells, Brucella resides in a vacuole, designated the BCV, which interacts with components of the endocytic and secretory pathways to ensure bacterial survival. Numerous studies conducted recently have revealed that Brucella's ability to cause a chronic infection depends on how it interacts with the host. This paper describes the immune system, apoptosis, and metabolic control of host cells as part of the mechanism of Brucella survival in host cells. Brucella contributes to both the body's non-specific and specific immunity during chronic infection, and it can aid in its survival by causing the body's immune system to become suppressed. In addition, Brucella regulates apoptosis to avoid being detected by the host immune system. The BvrR/BvrS, VjbR, BlxR, and BPE123 proteins enable Brucella to fine-tune its metabolism while also ensuring its survival and replication and improving its ability to adapt to the intracellular environment.

Comparison of renal clearance of [18F]AlF-RESCA-HER2-BCH and [18F]AlF-NOTA-HER2-BCH in mice and breast cancer patients.

PURPOSE: A novel HER2 affibody-based molecular probe, [18F]AlF-RESCA-HER2-BCH, was developed for reducing renal uptake, evaluated, and compared with [18F]AlF-NOTA-HER2-BCH. METHODS: In preclinical studies, micro-PET/CT was performed using HER2-positive gastric cancer patient-derived xenografts (PDX) model at 0.5-1 (dynamic), 2, 4, and 6 h post-injection. For blocking experiment, 0.5 mg cold affibody was co-injected with probes. Biodistribution were performed on HER2-positive PDX models at 2 h post-injection. For clinical study, PET/CT images were acquired at 2 h and 4 h after injection of 231.29 ± 17.77 MBq [18F]AlF-NOTA-HER2-BCH or [18F]AlF-RESCA-HER2-BCH in five breast cancer patients (4 HER2-positive and 1 HER2-low). Standardized uptake values (SUVs) were measured in tumors and source-organs for semi-quantitative analysis. The OLINDA/EXM software (version 1.2) was used to calculate the radiation doses. RESULTS: [18F]AlF-NOTA-HER2-BCH and [18F]AlF-RESCA-HER2-BCH were stably labeled with [18F]F, with high binding specificity and affinity to HER2. Micro-PET/CT of both tracers could clearly visualize HER2-positive PDX tumors with high uptake of 16.24 ± 1.74% ID/g and 14.39 ± 2.45% ID/g at 2 h post-injection. The renal accumulation of [18F]AlF-RESCA-HER2-BCH was significantly lower than that of [18F]AlF-NOTA-HER2-BCH (5.16 ± 0.22% ID/g vs. 158.73 ± 5.44% ID/g at 2 h, p < 0.0001). In the clinical study, both [18F]AlF-NOTA-HER2-BCH and [18F]AlF-RESCA-HER2-BCH demonstrated favorable tumor targeting and image contrast. [18F]AlF-RESCA-HER2-BCH showed a higher SUVmax in both primary tumor and metastases, and a significantly higher target-to-nontarget ratio in metastases than [18F]AlF-NOTA-HER2-BCH. Moreover, [18F]AlF-RESCA-HER2-BCH had lower renal accumulation (43.56 ± 7.88 vs. 79.81 ± 3.81 at 2 h, p < 0.0001; 33.23 ± 6.89 vs. 78.63 ± 4.00 at 4 h, p < 0.0001) as well as a significantly lower renal absorbed dose than [18F]AlF-NOTA-HER2-BCH (0.4450 ± 0.1117 mGy/MBq vs. 0.8030 ± 0.1604 mGy/MBq, p < 0.01). CONCLUSIONS: [18F]AlF-RESCA-HER2-BCH tended to provide better image contrast than [18F]AlF-NOTA-HER2-BCH with a higher target-to-nontarget ratio in detection of metastases. Notably, [18F]AlF-RESCA-HER2-BCH had lower renal accumulation than [18F]AlF-NOTA-HER2-BCH.

Microvascular morphology alteration using relaxation rate change with gadolinium-based magnetic resonance imaging contrast agent in patients with Alzheimer's disease.

Background: Conventional magnetic resonance imaging (MRI) techniques cannot demonstrate microvascular alterations in mild Alzheimer's disease (AD). Thus, the diagnosis of microvascular pathology commonly relies on postmortem. The purpose of this study was to evaluate alterations of microvascular structures in patients with AD using a 3T clinical MRI system with a commercially available contrast agent. Methods: Eleven patients with AD and 11 cognitively normal (CN) controls were included in this cross-sectional prospective study. R2 and R2* relaxation rate changes (∆R2 and ∆R2*) before and after a Gadolinium (Gd)-based contrast agent injection were calculated from images obtained with a multi-echo turbo spin-echo sequence and multi-echo gradient-echo sequence to obtain microvascular index maps of blood volume fraction (BVf), mean vessel diameter (mVD), vessel size index (VSI), mean vessel density (Q), and microvessel-weighted imaging (MvWI). Two-sample t-test was used to compare those values between the two groups. Correlation analysis was performed to evaluate the relationship between those values and age. Results: BVfs at the corpus callosum and at the thalamus were significantly increased in the AD group (P=0.024 and P=0.005, respectively). BVf at the gray matter (P=0.020) and white matter area (P=0.012) were also significantly increased in the AD group compared with the CN group. MvWIs at the hippocampus and parahippocampal gyrus were significantly increased in the AD group compared with the CN group (P=0.020 and P=0.006, respectively). Voxel-based analysis showed both mVD and VSI were significantly decreased at the prefrontal lobe in the AD group. Q were not significant difference between CN and AD groups. MvWI were significantly positively correlated with age. Conclusions: Microvascular index was a useful non-invasive method to evaluate microvascular morphology alteration. The microvascular morphology of AD was manifested as increasing BVf and microvessel-weighted.

High in-vivo stability in preclinical and first-in-human experiments with [18F]AlF-RESCA-MIRC213: a 18F-labeled nanobody as PET radiotracer for diagnosis of HER2-positive cancers.

PURPOSE: [18F]AlF-RESCA was introduced as a core particularly useful for 18F-labeling of heat-sensitive biomolecules. However, no translational studies have been reported up to now. Herein, we reported the first-in-human evaluation of an 18F-labeled anti-HER2 nanobody MIRC213 as a PET radiotracer for imaging HER2-positive cancers. METHODS: MIRC213 was produced by E. coli and conjugated with ( ±)-H3RESCA-Mal. [18F]AlF-RESCA-MIRC213 was prepared at room temperature. Its radiochemical purity and stability of were determined by radio-HPLC with the size-exclusion chromatographic column. Cell uptake was performed in NCI-N87 (HER2 +) and MCF-7 (HER2-) cells and the cell-binding affinity was verified in SK-OV-3 (HER2 +) cells. Small-animal PET/CT was performed using SK-OV-3, NCI-N87, and MCF-7 tumor-bearing mice at 30 min, 1 h, and 2 h post-injection. For blocking experiment, excess MIRC213 was co-injected with radiotracer. Biodistribution were performed on SKOV-3 and MCF-7 tumor-bearing mice at 2 h post-injection. For clinical study, PET/CT images were acquired at 2 h and 4 h after injection of [18F]AlF-RESCA-MIRC213 (1.85-3.7 MBq/kg) in six breast cancer patients (3 HER2-positive and 3 HER2-negative). All patients underwent [18F]-FDG PET/CT within a week for tissue selection purpose. Distribution and dosimetry were calculated. Standardized uptake values (SUV) were measured in tumors and normal organs. RESULTS: MIRC213 was produced with > 95% purity and modified with RESCA to obtain RESCA-MIRC213. [18F]AlF-RESCA-MIRC213 was prepared within 20 min at room temperature with the radiochemical yield of 50.48 ± 7.6% and radiochemical purity of > 98% (n > 10), and remained stable in both PBS (88%) and 5% HSA (92%) after 6 h. The 2 h cellular uptake of [18F]AlF-RESCA-MIRC213 in NCI-N87 cells was 11.22 ± 0.60 AD%/105 cells. Its binding affinity Kd value was determined to be 1.23 ± 0.58 nM. Small-animal PET/CT with [18F]AlF-RESCA-MIRC213 can clearly differentiate SK-OV-3 and NCI-N87 tumors from MCF-7 tumors and background with a high uptake of 4.73 ± 1.18 ID%/g and substantially reduced to 1.70 ± 0.13 ID%/g for the blocking group (p < 0.05) in SK-OV-3 tumors at 2 h post-injection. No significant bone radioactivity was seen in the tumor-bearing animals. In all six breast cancer patients, there was no adverse reaction during study. The uptake of [18F]AlF-RESCA-MIRC213 was mainly in lacrimal gland, parotid gland, submandibular gland, thyroid gland, gallbladder, kidneys, liver, and intestines. There was no significant bone radioactivity accumulation in cancer patients. [18F]AlF-RESCA-MIRC213 had significantly higher tumor uptake in lesions from HER2-positive patients than that lesions from HER2-negative patients (SUVmax of 3.62 ± 1.56 vs. 1.41 ± 0.41, p = 0.0012) at 2 h post-injection. The kidneys received the highest radiation dose of 2.42 × 10-1 mGy/MBq, and the effective dose was 1.56 × 10-2 mSv/MBq. CONCLUSIONS: [18F]AlF-RESCA-MIRC213 could be prepared with high radiolabeling yield under mild conditions. [18F]AlF-RESCA-MIRC213 has relatively high stability both in vitro and in vivo. The results from clinical transformation suggest that [18F]AlF-RESCA-MIRC213 PET/CT is a safe procedure with favorable pharmacokinetics and dosimetry profile, and it is a promising new PET radiotracer for noninvasive diagnosis of HER2-positive cancers.

Fabricating Ultra-Narrow Precision Slit Structures with Periodically Reducing Current Over-Growth Electroforming.

An ultra-narrow precision slit with a width of less than ten micrometers is the key structure of some optical components, but the fabrication of these structures is still very difficult to accomplish. To fabricate these slits, this paper proposed a periodically reducing current over-growth electroforming process. In the periodically reducing current over-growth electroforming, the electric current applied to the electrodeposition process is periodically stepped down rather than being constant. Simulations and experimentation studies were carried out to verify the feasibility of the proposed process, and further optimization of process parameters was implemented experimentally to achieve the desired ultra-narrow precision slits. The current values were: I1=Iinitial, I2=0.75Iinitial at Qc=0.5Qt, I3=0.5Iinitial at Qc=0.75Qt,respectively. It was shown that, compared with conventional constant current over-growth electroforming, the proposed process can significantly improve the surface quality and geometrical accuracy of the fabricated slits and can markedly enhance the achievement of the formed ultra-narrow slits. With the proposed process, slits with a width of down to 5 ± 0.1 µm and a surface roughness of less than 62.8 nm can be easily achieved. This can improve the determination sensitivity and linear range of the calibration curves of spectral imagers and food and chemical analysis instruments. Periodically reducing current over-growth electroforming is effective and advantageous in fabricating ultra-narrow precision slits.

Random Fourier features-based sparse representation classifier for identifying DNA-binding proteins.

DNA-binding proteins (DBPs) protect DNA from nuclease hydrolysis, inhibit the action of RNA polymerase, prevents replication and transcription from occurring simultaneously on a piece of DNA. Most of the conventional methods for detecting DBPs are biochemical methods, but the time cost is high. In recent years, a variety of machine learning-based methods that have been used on a large scale for large-scale screening of DBPs. To improve the prediction performance of DBPs, we propose a random Fourier features-based sparse representation classifier (RFF-SRC), which randomly map the features into a high-dimensional space to solve nonlinear classification problems. And L2,1-matrix norm is introduced to get sparse solution of model. To evaluate performance, our model is tested on several benchmark data sets of DBPs and 8 UCI data sets. RFF-SRC achieves better performance in experimental results.