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Rapid development of high-throughput technologies has permitted the identification of an increasing number of disease-associated genes (DAGs), which are important for understanding disease initiation and developing precision therapeutics. However, DAGs often contain large amounts of redundant or false positive information, leading to difficulties in quantifying and prioritizing potential relationships between these DAGs and human diseases. In this study, a network-oriented gene entropy approach (NOGEA) is proposed for accurately inferring master genes that contribute to specific diseases by quantitatively calculating their perturbation abilities on directed disease-specific gene networks. In addition, we confirmed that the master genes identified by NOGEA have a high reliability for predicting disease-specific initiation events and progression risk. Master genes may also be used to extract the underlying information of different diseases, thus revealing mechanisms of disease comorbidity. More importantly, approved therapeutic targets are topologically localized in a small neighborhood of master genes in the interactome network, which provides a new way for predicting drug-disease associations. Through this method, 11 old drugs were newly identified and predicted to be effective for treating pancreatic cancer and then validated by in vitro experiments. Collectively, the NOGEA was useful for identifying master genes that control disease initiation and co-occurrence, thus providing a valuable strategy for drug efficacy screening and repositioning. NOGEA codes are publicly available at https://github.com/guozihuaa/NOGEA.

Objective To assess and compare the performance of fluorine-18-labeled fluorodeoxyglucose positron emission tomography (18 F-FDG-PET/ CT) and gallium-68-labeled tetraazacyclododecanetetraacetic acid-DPhe1-Tyr3-octreotate (68 Ga- DOTATATE) PET/CT in the targeted imaging of culprit tumors causing osteomalacia. Methods This was a clinical retrospective analysis. We analyzed 13 patients (five men, eight women; mean age, 49 years; range, 19-55 years) with suspicion of tumor-induced osteomalacia (TIO) between March 2017 and October 2019. All patients underwent two functional imaging methods to locate the culprittumors. Studies were performed on a PET/CT scanner. The injection doses of 18 F- FDG and 68 Ga-DOTATATE were 0.5mCi/kg and approximately 5.0mCi, respectively. In the two scans, the whole body was captured from head to toe 45 to 60 min after intravenous tracer injection. 68 Ga-DOTATATE PET/CT and 18 F-FDG PET/CT imaging results locate culprit tumors according to the following criteria: (i) abnormal foci uptake concentration was observed locally, and the uptake level was higher than the background level of the right lobe of the liver; (ii) combined CT showed or did not have obvious abnormal density changes; and (iii) non-specific ingestion lesions due to fracture, arthritis, necrosis of femoral head are excluded. Compared with the results of pathological examination and clinical follow-up, the sensitivity, specificity and accuracy of 68 Ga-DOTATATE PET/CT imaging and 18 F-FDG PET/CT imaging for TIO were analyzed. Results All patients had symptoms of osteomalacia and hypophosphatemia. The lag time (symptoms to PET diagnosis) ranged from 2 to 12 years. There were eight cases of TIO patients and five cases of non-TIO patients confirmed by surgery, pathology and follow-up. Among the eight TIO patients, there were six cases (75.0%) of PMTs, one case (12.5%) of giant cell tumor, one case (12.5%) of hemangiopericutoma. Most (n = 6, 75.0%) of the confirmed tumors in our patient population were in the lower extremities, followed by craniofacial regions (n = 1, 12.5%), and torso (n = 1, 12.5%), respectively. Among the five non-TIO patients, there were two cases of Fanconi syndrome, one case of rickets, and two cases of sporadic osteomalacia hypophosphorus. The culprit tumors could be located either in the bone (n = 5, 62.5%) or the soft tissue (n = 3, 37.5%). 18 F-FDG PET/CT was able to localize the tumor in six (6/13, 46.1%) patients. 68 Ga-DOTATATE PET/CT detected tumor in 8 (83.3%) of 13 patients. The sensitivity of 68 Ga-DOTATATE PET/CT imaging and 18 F-FDG PET/CT imaging in the evaluation of TIO in our patient population were 100% (8/8) vs 75% (6/8). The specificity of the two different methods was 80% (4/5). The overall accuracy was 92.3% (12/13) vs 76.9% (10/13). Conclusions 68 Ga-DOTATATE PET/CT is very effective in assessing hypophosphatemia patients with TIO typical symptoms compared with 18 F-FDG. Therefore, in clinically suspected cases of hypophosphatemic osteomalacia, 68 Ga-DOTATATE PET/CT should be preferred as an imaging modality investigation to avoid delay in the treatment of this disease.

Although different types of drugs are available for postmenopausal osteoporosis, the limitations of the current therapies including drug resistances and adverse effects require identification of novel anti-osteoporosis agents. Here, we defined that norlichexanthone (NOR), a natural product, is a ligand of estrogen receptor-alpha (ERα) and revealed its therapeutic potential for postmenopausal osteoporosis. We used mammalian-one hybrid assay to screen for ERα modulators from crude extracts of several plant endophytes. As a result, NOR purified from the extract of endophyte ARL-13 was identified as a selective ERα modulator. NOR directly bound to ERα with an affinity in nanomolar range, revealing that it is a natural ligand of ERα. NOR induced osteoblast formation in MC3T3-E1 precursor cells. Conversely, NOR inhibited receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclast formation in both RAW264.7 macrophages and mouse primary monocytes. Mechanistically, NOR inhibited RANKL-induced association of ERα and TRAF6 to prevent ERα-mediated TRAF6 activation via Lys63-linked ubiquitination. Importantly, NOR exhibited potent anti-osteoporosis efficacy in an ovariectomized mouse model. Comparing to estrogen, NOR was of much less capability in stimulating endometrial hyperplasia and promoting mammalian cancer cell proliferation. Taken together, our study identified NOR as a natural and high affinity ligand of ERα with substantial anti-osteoporosis but less estrogenic activity.

Cerebral β-amyloid deposits and regional glucose metabolism assessed by PET are used to distinguish between Alzheimer disease (AD) and other dementia syndromes. In the present multicenter study, we estimated the prevalence of β-amyloid deposits on PET imaging in a wide variety of dementia syndromes and mild cognitive impairment (MCI) within a memory clinic population. Methods: Of the 1,193 consecutive patients with cognitive impairment (CI) who received 1 11C-PIB PET or 18F-AV45 PET or both 11C-PIB PET and 18F-AV45 PET, 960 were diagnosed with AD, 36 with frontotemporal dementia (FTD), 5 with dementia with Lewy bodies, 144 with MCI, 29 with vascular dementia, 4 with corticobasal syndrome, and 15 with unclassifiable dementia. Baseline clinical diagnoses were independently established without access to PET imaging results. Apolipoprotein E (ApoE) genotype analysis was performed on CI patients and 231 sex- and age-matched controls. Results: Of the 1,193 CI patients, 860 (72.1%) were amyloid-positive. The prevalence of amyloid positivity in AD and MCI patients was 86.8% (833/960) and 9.7% (14/144), respectively. In FTD patients, the prevalence of β-amyloid deposits was 5.6% (2/36). In the 4 corticobasal syndrome patients, 2 were amyloid-positive. Three of the 5 patients with dementia with Lewy bodies showed amyloid positivity, as did 6 of the 29 vascular dementia (20.7%) patients. The ApoEe4 allele frequency was significantly increased in amyloid-positive CI patients (30.5%) as compared with other amyloid-negative CI patients (14%) or controls (7.3%). Conclusion: Amyloid imaging may potentially be the most helpful parameter for differential diagnosis in dementia, particularly to distinguish between AD and FTD. Amyloid PET can be used in conjunction with the ApoEe4 allele genetic risk test for amyloid deposits.

Background. The purpose of this study is to explore the correlation between the 18F-FDG PET/CT imaging maximum standardized uptake value (SUVmax) of preoperative colon cancer primary lesions and clinicopathological factors. Methods. 88 colon cancer patients diagnosed by histopathology were collected from January 2014 to December 2015. 18F-FDG PET/CT imaging was performed before surgery. Kaplan–Meier survival analysis was used to assess the prognosis of colon cancer patients. Results. The 18F-FDG PET/CT imaging SUVmax value of preoperative colon cancer primary lesion was significantly correlated with the length of the lesion, clinical stage, histopathological type, and the degree of tumor differentiation. The SUVmax value of tumors with long-diameter, ≥ 3 cm, clinically high-stage, adenocarcinoma, and poorly differentiated lesions was significantly high. In addition, the consistency between PET/CT and surgical pathological results at stage I and IV was higher. Stage II and III PET/CT are basically consistent with the pathological results of surgery. Kaplan–Meier survival analysis showed that the 5-year event-free survival rate of the SUVmax > 18.26 group was significantly lower than that of the SUVmax ≤ 18.26 group. Conclusion. 18F-FDG PET/CT imaging SUVmax of preoperative colon cancer primary lesions can not only reflect the proliferation and invasion ability but also monitor the recurrence and metastasis of colon cancer.

The ubiquitin-proteasome system plays important roles in various biological processes as it degrades the majority of cellular proteins. Adequate proteasomal degradation of crucial transcription regulators ensures the proper development of neutrophils. The ubiquitin E3 ligase of Growth factor independent 1 (GFI1), a key transcription repressor governing terminal granulopoiesis, remains obscure. Here we report that the deficiency of the ring finger protein Interferon regulatory factor 2 binding protein 2a (Irf2bp2a) leads to an impairment of neutrophils differentiation in zebrafish. Mechanistically, Irf2bp2a functions as a ubiquitin E3 ligase targeting Gfi1aa for proteasomal degradation. Moreover, irf2bp2a gene is repressed by Gfi1aa, thus forming a negative feedback loop between Irf2bp2a and Gfi1aa during neutrophils maturation. Different levels of GFI1 may turn it into a tumor suppressor or an oncogene in malignant myelopoiesis. Therefore, discovery of certain drug targets GFI1 for proteasomal degradation by IRF2BP2 might be an effective anti-cancer strategy., Author summary GFI1 is a key transcriptional repressor in hematopoiesis. The E3 ubiquitin ligase targeting GFI1 for proteasomal degradation remains obscure for many years. Here we show that the deficiency of the ring finger protein Irf2bp2a significantly impairs neutrophil maturation in zebrafish. Mechanistic studies reveal for the first time that instead of being a canonical transcription corepressor, Irf2bp2a functions as an E3 mediating the proteasomal degradation of Gfi1aa in neutrophil development.

For wide applications of the lacZ gene in cellular/molecular biology, small animal investigations, and clinical assessments, the improvement of noninvasive imaging approaches to precisely assay gene expression has garnered much attention. In this study, we investigate a novel molecular platform in which alizarin 2-O-β-d-galactopyranoside AZ-1 acts as a lacZ gene/β-gal responsive 1H-MRI probe to induce significant 1H-MRI contrast changes in relaxation times T1 and T2in situ as a concerted effect for the discovery of β-gal activity with the exposure of Fe3+. We also demonstrate the capability of this strategy for detecting β-gal activity with lacZ-transfected human MCF7 breast and PC3 prostate cancer cells by reaction-enhanced 1H-MRI T1 and T2 relaxation mapping.

Objectives Linezolid-resistant Enterococcus have spread worldwide. This study investigated the prevalence of linezolid-non-susceptible Enterococcus (LNSE) and the potential mechanism and molecular epidemiology of LNSE isolates from Nanjing, China. Methods Linezolid susceptibility of 2555 Enterococcus was retrospectively determined by Etest. Vancomycin and teicoplanin MICs were determined for LNSE by Etest. PCR and DNA sequencing were used to investigate the potential molecular mechanism. Clonal relatedness between LNSE isolates was analysed by MLST. WGS was also performed. Results A total of 27 Enterococcus isolates (24 Enterococcus faecalis, 3 Enterococcus faecium) with linezolid MICs of 4–48 μg/mL were identified, among which 20 E. faecalis and 3 E. faecium were positive for optrA. No mutations were found in genes encoding domain V of 23S rRNA or ribosomal proteins L3/L4; the cfr gene was not found. The 24 linezolid-non-susceptible E. faecalis were classified into eight STs (ST16, ST480, ST476, ST631, ST585, ST428, ST25 and ST689). The three linezolid-non-susceptible E. faecium were classified as ST17, ST400 and ST195. Comparison of the deduced OptrA amino acid sequences of the 23 optrA-positive isolates by PCR-based sequencing and WGS with that of the original OptrA from E. faecalis E349 revealed seven variants (KD, EDP, EDM, D, EDD, RDK and DP) in 16 isolates, with no mutations in the remaining 7 isolates. optrA was found downstream of fexA by searching the pE349 sequence based on WGS data. Conclusions Emergence of LNSE with optrA-mediated resistance and clonal dissemination of ST16 E. faecalis in our hospital may pose a potential public-health threat.

Aproper choice of neutrophil-macrophage progenitor cell fate is essential for the generation of adequate myeloid subpopulations during embryonic development and in adulthood. The network governing neutrophil-macrophage progenitor cell fate has several key determinants, such as myeloid master regulators CCAAT enhancer binding protein alpha (C/EBPα) and spleen focus forming virus proviral integration oncogene (PU.1). Nevertheless, more regulators remain to be identified and characterized. To ensure balanced commitment of neutrophil-macrophage progenitors toward each lineage, the interplay among these determinants is not only synergistic, but also antagonistic. Depletion of interferon regulatory factor 2 binding protein 2b (Irf2bp2b), a well-known negative transcription regulator, results in a bias in neutrophil-macrophage progenitor cell fate in favor of macrophages at the expense of neutrophils during the stage of definitive myelopoiesis in zebrafish embryos. Mechanistic studies indicate that Irf2bp2b acts as a downstream target of C/EBPα, repressing PU.1 expression, and that SUMOylation confers the repressive function of Irf2bp2b. Thus, Irf2bp2b is a novel determinant in the choice of fate of neutrophil-macrophage progenitor cells.

Veramyosides A-J, eleven undescribed stigmastane-type steroids, including one aglycone and ten glycosides, along with three known homologues were isolated from the twigs of Vernonia amygdalina Delile (compositae). All compounds featured a stigmastane-type steroid skeleton with a unique conjugated Δ7,9(11) diene segment and highly oxygenated side chains with a γ-lactone or an α, β-unsaturated five-membered lactone ring. The structures of veramyosides A-J and their absolute configurations were unambiguously elucidated by HR-ESI-MS, extensive NMR spectroscopy, in situ dimolybdenum CD methods, modified Mosher's method, quantum chemical calculation of their ECD curves, and CD comparison methods on basis of their biogenetic pathway. In addition, all isolates were investigated for their effects on RXRα transcription, and their effects on the NF-κB signaling pathway were also evaluated.

Amyotrophic lateral sclerosis (ALS) patients suffer from difficulties in grasping objects in daily life. To help them regain impaired functionalities at a certain level, in this article, we present a visual feedback based eye tracking and EEG based human-machine interactive technique, in which the eye tracking system is used for locating user desired objects, and the EEG system is for instructing corresponding operations. A robotic arm is employed here to grasp the targeted objects. Experimental results demonstrate that the developed system can accurately reflect user’s intentions in terms of grasping surrounding objects.

Respiration is an essential human function. Common breath detectors include airflow testing and belt-wearing testing. However these techniques will bring discomfort to patients with back pressure sores or back burns caused by long-term bed rest. In order to solve the above problem, we designed a a large area piezoresistive array, which is made of graphite and silver paste. The force distribution and dynamic waveform of the resistance array are used to analyze the breathing rate and determine the prone position, so it helps the medical diagnosis and treatment in the hospital.This device is of great significance to improve patients' diagnosis and treatment experience.

Amyotrophic lateral sclerosis (ALS) patients will gradually lost their motion abilities and have huge inconvenience in their daily life. In this article, an artificial throat and eye tracking based smart assistive system is presented. Through detecting eye motions and throat vibrations, the established neural network can interpret the patient’s intention, and perform simple operations by a robotic arm (e.g. grasp an object). The experimental results demonstrate that the developed system can help patients obtain basic self-care ability.

Patients physically handicapped can't take care of themselves. Helping them easily control the objects around them will reduce their psychological burden and social pressure. In this article, a semi-autonomous grasping system based on eye movement and EEG is presented to achieve this goal. Patient just needs to gaze the target object and keep focused, the manipulator will automatically move to its position and grasp it. Experimental results verify the reliability of the system. This system promotes the development of human-computer interaction system based on multi-sensor fusion.

ObjectiveType 2 diabetes mellitus (T2DM) is often accompanied by cognitive decline and depressive symptoms. Numerous diffusion tensor imaging (DTI) studies revealed microstructural white matter (WM) abnormalities in T2DM but the findings were inconsistent. The present study aimed to conduct a coordinate‐based meta‐analysis (CBMA) to identify statistical consensus of DTI studies in T2DM.MethodsWe performed a systematic search on relevant studies that reported fractional anisotropy (FA) differences between T2DM patients and healthy controls (HC). The anisotropic effect size seed‐based d mapping (AES-SDM) approach was used to explore WM alterations in T2DM. A meta‐regression was then used to analyze potential influences of sample characteristics on regional FA changes.ResultsA total of eight studies that comprised 245 patients and 200 HC, along with 52 coordinates were extracted. The meta‐analysis identified FA reductions in three clusters including the left inferior network, the corpus callosum (CC), and the left olfactory cortex. Besides, FA in the CC was negatively correlated with body mass index (BMI) in the patients group.ConclusionsT2DM could lead to subtle WM microstructural alterations, which might be associated with cognitive deficits or emotional distress symptoms. This provides a better understanding of the pathophysiology of neurodegeneration and complications in T2DM.Systematic Review RegistrationRegistered at PROSPERO (http://www.crd.york.ac.uk/PROSPERO), registration number: CRD42020218737.

Aconitine (AC), one of the bioactive diterpenoid alkaloids extracted from Aconitum plants, is widely used in traditional herbal medicine to treat various diseases. Emerging evidence indicates that AC has attracted great interest for its wide cardiotoxicity and neurotoxicity. However, the toxic effects of AC on embryonic development and its underlying mechanisms remain unclear. Here, a developmental toxicity assay of AC was performed on zebrafish embryos from 4 to 96 h post fertilization (hpf), and its underlying mechanisms were discussed. AC exposure impaired the cardiac, liver, and neurodevelopment. Especially, a high dose of AC (7.27 and 8.23 μM) exposure resulted in malformations at 72 and 96 hpf, including reduced body length, curved body shape, pericardial edema, yolk retention, swim bladder and brain developmental deficiency, and degeneration of dopaminergic neurons. High-concentration AC exposure caused a deficient cardiovascular system with cardiac dysfunctions, increased heart rates at 72 and 96 hpf, and reduced locomotor behavior at 120 hpf. AC treatment significantly increased the ROS level and triggered cell apoptosis in the heart and brain regions of embryos at 96 hpf in 7.27 and 8.23 μM AC treatment zebrafish. Oxidative stress was confirmed by reduced levels of T-SOD activity associated with accumulation of lipid peroxidation in larvae. The expression levels of oxidative stress-related genes (Nrf2, HO-1, Cat, and Sod-1) Erk1/2 and Bcl-2 were significantly downregulated at 96 hpf. The expression pattern of JNK and mitochondrial apoptosis-related genes (Bad, Bax, Cyto C, Casp-9, and Casp-3) was significantly upregulated. Taken together, all these parameters collectively provide the first evidence of AC-induced developmental toxicity in zebrafish embryo/larvae through ROS-medicated mitochondrial apoptosis involving Nrf2/HO-1 and JNK/Erk pathways.

ObjectivesDental anxiety remains widespread among children, may continue into adulthood and affect their oral health-related quality of life and clinical management. The aim of the study was to explore the trend of children’s dental anxiety over time and potential risk factors.DesignLongitudinal study.MethodsChildren aged between 5 and 12 years were investigated with the Chinese version of face version of Children’s Fear Survey Schedule-Dental Subscale (CFSS-DS) and Frankl Behavior Rating scale from 2008 to 2017, and influential factors were explored.ResultsClinical data were available from 1061 children, including 533 (50.2%) male participants and 528 (49.8%) female participants. The total CFSS-DS scores ranged from 16 to 66, with a mean of 24.8±10.3. The prevalence of dental anxiety is 11.59%. No significant differences in total CFSS-DS scores between girls and boys were found. According to the Frankl scale, 238 children were allocated to the uncooperative group and the remaining 823 children were allocated to the cooperative group. Scores of CFSS-DS were negatively correlated with the clinical behaviour level of Frankl. Children aged 11–12 years old had significantly decreased scores compared with other age groups, and there was a decline in the scores of the group aged 8–10 years old over time. The factor analysis divided 15 items of CFSS-DS into four factors, and the total scores of ‘less invasive oral procedures’ items belonging to factor III decreased significantly over time in the group aged 8–10 years old.ConclusionsAge is a significant determinant for children’s dental anxiety, and dental anxiety outcomes have improved for Chinese children aged 8–10 years. This study is one of the few reports on changes of children’s dental anxiety in a new era of information, but the results may be extrapolated to other populations with caution.

Background and objective Arteriosclerosis can reflect the severity of hypertension, which is one of the main diseases threatening human life safety. But Arteriosclerosis retinopathy detection involves costly and time-consuming manual assessment. To meet the urgent needs of automation, this paper developed a novel arteriosclerosis retinopathy grading method based on convolutional neural network. Methods Firstly, we propose a good scheme for extracting features facing the fundus blood vessel background using image merging for contour enhancement. In this step, the original image is dealt with adaptive threshold processing to generate the new contour channel, which merge with the original three-channel image. Then, we employ the pre-trained convolutional neural network with transfer learning to speed up training and contour image channel parameter with Kaiming initialization. Moreover, ArcLoss is applied to increase inter-class differences and intra-class similarity aiming to the high similarity of images of different classes in the dataset. Results The accuracy of arteriosclerosis retinopathy grading achieved by the proposed method is up to 65.354%, which is nearly 4% higher than those of the exiting methods. The Kappa of our method is 0.508 in arteriosclerosis retinopathy grading. Conclusions An experimental study on multiple metrics demonstrates the superiority of our method, which will be a useful to the toolbox for arteriosclerosis retinopathy grading.

Objective This study aimed to differentiate the variations in the clinical characteristics, MRI irregularity, and glucose metabolism on 18F‐FDG‐PET for the differential diagnosis of Parkinson's Disease (PD), MSA with predominant Parkinsonism (MSA‐P), and MSA with predominant cerebellar features (MSA‐C). Methods Thirty PD patients, 22 MSA‐P patients, and 28 MSA‐C patients received an MRI and 20 PD patients, 11 MSA‐P patients, and 13 MSA‐C patients received 18F‐FDG‐PET. Results Firstly, we found that the clinical data presented a tremor at rest, bradykinesia, and postural instability that was predominated in PD (100%), MSA‐P (86.4%), and MSA‐C (53.6%) patients, respectively. Then, we used MRI analyses and found that putamina atrophy and hyperintensive rim (T2WI) were characteristic features in MSA‐P and cerebellar atrophy, the “hot cross bun” sign and signal rise in the middle cerebellar peduncle were more obvious in MSA‐C. To further explore the distinctions among the 3 diseases, we also used 18F‐FDG‐PET technology for our examination and found a decrease in glucose metabolism in the parietal area for Parkinson's Disease (PD), in the bilateral putamen for MSA‐P, and in the bilateral cerebellum for MSA‐C. Conclusion This study identified the distinctive features of the clinic symptoms, MRI irregularity, and glucose metabolism on 18F‐FDG‐PET, which provided a new basis for the differential diagnosis of Parkinson's Disease (PD), MSA with predominant Parkinsonism (MSA‐P), and MSA with predominant cerebellar features (MSA‐C)., This study identified the distinctive features of the clinic symptoms, MRI irregularity, and glucose metabolism on 18F‐FDG‐PET, which provided a new basis for the differential diagnosis of Parkinson's disease (PD), MSA with predominant Parkinsonism (MSA‐P), and MSA with predominant cerebellar features (MSA‐C).

Multidrug resistance (MDR) often leads to the failure of the anticancer treatment. Besides the blockage of those MDR pathways, the development of more potent drugs are of urgent needs but largely postponed due to imbalance between safety and efficacy. The prodrug strategy, especially with bioorthogonal activation has shown immerse potential to balance safety and efficacy, while recent studies focus on few drug entities such as doxorubicin and MMAE, leaving the vast collection of toxins undetermined. Here we have enumerated typical molecular entities ranging from FDA approved drugs (doxorubicin, paclitaxel) to a heated ADC warhead (MMAF-OMe) and a trichothecene toxin (Mytoxin A) to demonstrate that the trans-cyclooctene (TCO) caging may serve as a general prodrug design to increase the therapeutic index for bioactive molecules. These prodrugs can be efficiently activated on-demand by the bioorthogonal activators whose distribution is regulated by the cell specific enzymatic non-covalent synthesis of supramolecular self-assemblies. These cell-specific prodrugs activation could not only reduce the toxicology of drugs but also enhance the synergistic therapeutic effect within a broad range of dose ratio. More importantly, these prodrugs activation share the same activator bearing assemblies, which allows the flexible shift of drug identities to successfully combat MDR cancer in vivo. In general, this versatile bioorthogonal prodrug activation platform is readily applicable to enlarge the therapeutic window for various bioactive molecules. We envision that the spatiotemporal controlled prodrug activation should facilitate the drug discovery and development.

Background Vancomycin-resistant Enterococcus spp. (VRE) have spread all over the world. The present study aims to investigate the species distribution, specimen type and susceptibilities of Enterococcal species collected from Nanjing Drum Tower Hospital from 2013 to 2018. Additionally, distribution of VRE and prevalence of van gene among VRE isolates were also analyzed. Methods The susceptibilities of 3913 Enterococcus isolates were retrospectively investigated. Among these strains, 60 VRE strains were further anazlyed in this study. The minimum inhibitory concentrations (MICs) of the VRE strains towards vancomycin, teicoplanin and linezolid were determined by E-test. Polymerase chain reaction (PCR) and DNA sequencing were used to investigate the prevalence of van genes among VRE. Furthermore, the sequence types (STs) of VRE strains were explored by multi-locus sequence typing (MLST). Results Among the 3913 enterococci isolates, Enterococcus faecalis (n = 1870, 47.8%) and Enterococcus faecium (1738, 44.4%) were the main isolates. These Enterococcus strains were mainly isolated from urine (n = 1673, 42.8%), followed by secretions (n = 583, 14.9%) and ascites (n = 554, 14.2%). VRE displayed a decreasing trend year by year. Molecular analysis revealed that 49 out of 60 VRE isolates carried vanA gene, 10 carried vanM, and 1 carried both vanA and vanM genes. Sixteen distinct STs were identified among the 58 VREM, with ST78 (n = 16), ST192 (n = 8) and ST570 (n = 7) being the most dominant ones. Conclusions E. faecalis and E. faecium were the major enterococci strains which are the main pathogens of urinary traction infections; vanA and vanM were the main determinants conferring resistance to vancomycin; ST78, ST192 and ST570 were the leading STs of VREM which displayed a decreasing trend of prevalence year by year.

Background Progressive supranuclear palsy (PSP) is a kind of neurodegenerative disease. In the present study, the clinical and magnetic resonance imaging (MRI) features of PSP were analyzed, and fluorodeoxyglucose positron emission tomography (FDG PET) brain imaging was performed to preliminarily explore the characteristics of cerebral glucose metabolism, so as to make a more accurate and differential diagnosis. Methods In accordance with the diagnostic criteria, the clinical symptoms, the unified Parkinson’s disease rating scale (UPDRS), the mini-mental state examination (MMSE), the activities of daily living (ADL), and the magnetic resonance image (MRI) of 19 patients with PSP were examined and FDG-PET brain imaging was performed. Visual analysis and statistical parameter diagram were used to analyze the characteristics. Results Concerning the clinical characteristics, 84.21% of the patients with PSP had early recurrent falls, 63.15% had vertical supranuclear ophthalmoplegia, and 47.37% had symptoms of dementia. The MRI scans showed that 57.89% of the patients had a “hummingbird” sign in the middle sagittal position. The FDG-PET imaging indicated that glucose metabolism in the midbrain and frontal lobe was decreased in patients with PSP. Conclusions Studying the clinical and MRI features of patients with PSP can be helpful in the diagnosis, especially as some signs could be found in the early stage by FDG PET, enhancing early diagnosis and differentiation.

Rapid development of high-throughput technologies has permitted the identification of an increasing number of disease-associated genes (DAGs), which are important for understanding disease initiation and developing precision therapeutics. However, DAGs often contain large amounts of redundant or false positive information, leading to difficulties in quantifying and prioritizing potential relationships between these DAGs and human diseases. In this study, a network-oriented gene entropy approach (NOGEA) is proposed for accurately inferring master genes that contribute to specific diseases by quantitatively calculating their perturbation abilities on directed disease-specific gene networks. In addition, we confirmed that the master genes identified by NOGEA have a high reliability for predicting disease-specific initiation events and progression risk. Master genes may also be used to extract the underlying information of different diseases, thus revealing mechanisms of disease comorbidity. More importantly, approved therapeutic targets are topologically localized in a small neighborhood of master genes on the interactome network, which provides a new way for predicting new drug-disease associations. Through this method, 11 old drugs were newly identified and predicted to be effective for treating pancreatic cancer and then validated by in vitro experiments. Collectively, the NOGEA was useful for identifying master genes that control disease initiation and co-occurrence, thus providing a valuable strategy for drug efficacy screening and repositioning. NOGEA codes are publicly available at https://github.com/guozihuaa/NOGEA.

Two experiments were conducted to investigate the effects of dietary supplementation with protease and phytase on growth performance, serum physiochemical parameters, and activities of digestive enzymes in jejunal digesta of meat ducks. Experiment 1 was carried out to determine the effects of different protease or phytase on growth performance, serum physiochemical parameter, and activities of digestive enzymes in jejunal digesta of meat ducks to select the optimal phytase or protease. According to the hatching age and initial weight, a total of 5040 Cherry Valley ducks (15 days of age) were randomly assigned into six treatments. Treatments included a basal control diet (CON) and 5 basal diets supplemented with different enzyme preparations, which were phytase preparation A (PA, 160 g/t), phytase preparation B (PB, 800 g/t), protease preparation A (PTA, 80 g/t), protease preparation B (PTB, 300 g/t) and protease preparation C (PTC, 200 g/t). The enzyme activities were as follows: Phytase A and B as well as protease A, B, and C were 50,000, 10,000, 250,000, 50,000, and 60,000 U/g, respectively. Each treatment had 7 replicates with 120 meat ducks per replicate. Experiment 1 lasted for 28 days. The results showed that: compared with the CON group, the PA group significantly decreased contents of serum phosphorus and calcium (p &lt, 0.05), and the PTA, PTB, and PTC groups had higher activities of trypsin in jejunal digesta (p &lt, 0.05), and the activity of jejunal chymotrypsin in PTA group was greater (p &lt, 0.05). Experiment 2 was carried out to determine the effects of dietary supplementation with protease and phytase in low-energy and low-protein diet on growth performance, serum physiochemical parameters, and activities of digestive enzymes in jejunal digesta of meat ducks. According to the hatching age and initial weight, a total of 5760 Cherry Valley ducks (15 days of age) were randomly assigned into four treatments on the basis of a trial of 2 &times, 2 factorial design. Treatments included a basal control diet (PC), basal diet supplemented with enzymes (PCE), low-energy and low-protein diet (LEP), and low-energy and low-protein diet supplemented with enzymes (LEPE), the nutrient levels of energy and CP of basal diet were 2747.2 cal&middot, ME/kg and 16.80%, respectively, and the nutrient levels of energy and CP of low-energy and low-protein diet decreased 45.90 kcal&middot, ME/kg and 0.52% on the basis of basal diet, respectively. According to the results of experiment 1, phytase A and protease A were determined as the optimal enzyme combination of Experiment 2, and additional dosage of which were identical with Experiment 1. Each treatment had 6 replicates with 240 meat ducks per replicate. Experiment 2 lasted for 28 days. The results showed that: compared with PC and LEP groups, PCE and LEPE groups had higher final weight and average daily gain (ADG) (p &lt, 0.05), higher activities of trypsin and chymotrypsin in jejunal digesta (p &lt, 0.05), lower contents of serum calcium and phosphorus as well as higher levels of high-density lipoprotein in the serum (p &lt, 0.05). In conclusion, dietary supplementation with phytase and protease in different energy and protein diets could increase digestive enzymes in jejunal digesta, effect serum physiochemical parameters, improve metabolic status, and increase the growth performance of meat ducks. Meanwhile, with the dietary supplementation with phytase and protease in the lower energy and protein diet, the growth performance could reach to the degree of the higher energy and increased protein diet, but without the addition of phytase and protease.

Background Cancer-associated fibroblasts (CAFs) play an important role in regulating tumor progression by transferring exosomes to neighboring cells. Our aim was to clarify the role of microRNA encapsulated in the exosomes derived from CAFs in oral squamous cell carcinoma (OSCC). Methods We examined the microRNA expression profiles of exosomes derived from CAFs and donor-matched normal fibroblasts (NFs) from patients with OSCC. We used confocal microscopy to examine the transportation of exosomal miR-34a-5p between CAFs and OSCC cells. Next, luciferase reporter and its mutant plasmids were used to confirm direct target gene of miR-34a-5p. Phenotypic assays and in vivo tumor growth experiments were used to investigate the functional significance of exosomal miR-34a-5p. Findings We found that the expression of miR-34a-5p in CAF-derived exosomes was significantly reduced, and fibroblasts could transfer exosomal miR-34a-5p to OSCC cells. In xenograft experiments, miR-34a-5p overexpression in CAFs could inhibit the tumorigenesis of OSCC cells. We further revealed that miR-34a-5p binds to its direct downstream target AXL to suppress OSCC cell proliferation and metastasis. Stable ectopic expression of AXL in OSCC cells overexpressing miR-34a-5p restored proliferation and motility abolished by the miRNA. The miR-34a-5p/AXL axis promoted OSCC progression via the AKT/GSK-3β/β-catenin signaling pathway, which could induce the epithelial-mesenchymal transition (EMT) to promote cancer cells metastasis. The miR-34a-5p/AXL axis enhanced nuclear translocation of β-catenin and then induced transcriptional upregulation of SNAIL, which in turn activated both MMP-2 and MMP-9. Interpretation The miR-34a-5p/AXL axis confers aggressiveness in oral cancer cells through the AKT/GSK-3β/β-catenin/Snail signaling cascade and might represent a therapeutic target for OSCC. Fund National Natural Science Foundation of China., Graphical abstract Unlabelled Image, Highlights • CAFs transfer miR-34a-5p-devoid exosomes to OSCC cells. • Exosomal miR-34a-5p mediates the proliferation and motility of OSCC cells through regulating AXL. • MiR-34a-5p/AXL axis confers aggressiveness in OSCC through AKT/GSK-3β/β-catenin/Snail signaling cascade.

To identify the most vulnerable network among typical and three variants of Alzheimer’s disease (AD) and to link amyloid-β (Aβ) deposition and downstream network dysfunction. In this study, 38 typical AD, 11 frontal variants, 8 logopenic variants, 6 posterior variants, and 20 normal controls were enrolled. 2-(4′-[11C] Methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB) and 2-deoxy-2-[18]fluoro-d-glucose ([18F]FDG) positron emission tomography (PET) imaging were performed. Voxel-wise statistical analysis was used for [18F]FDG analysis, whereas two-sample t test was performed between each AD group and control group. Moreover, the goodness of fit (GOF) of t-maps with brain functional network templates was assessed, and the most vulnerable network in each phenotypic of AD was chosen as volume of interests (VOIs). [11C]PIB binding potential (BPND) of VOIs were generated by using PMOD software. In addition, statistical analysis of BPND among four types of AD in each specific network was calculated by SPSS software. The hypometabolism patterns indicated that in typical and frontal variants of AD, the most vulnerable network was the left executive control network (GOF score = 4.3, 5.0). For the logopenic variant, the highest GOF score (1.9) belonged to the auditory network. For the posterior variant, the higher visual network was the most vulnerable (GOF score = 6.0). The [11C]PIB BPND showed that there were no significant differences (p > 0.05) among AD groups within the specific networks. The phenotypic diversity of AD correlates with specific functional network failure; however, Aβ plaques do not associate with specific network vulnerability.

Multi-drug resistance (MDR) is one of the leading causes of the anticancer failures. Besides the blockage of the MDR pathways, the development of more potent drugs is with urgent needs, but has been postponed mainly due to an imbalance between safety and efficacy. The recent development of the bioorthogonal prodrug activation strategy has shown immense potential to balance safety and efficacy, while recent studies only focused on few drug entities such as doxorubicin and monomethyl auristatin E, leaving the vast collection of toxins undetermined. Here we have enumerated typical molecular entities ranging from food and drug administration (FDA) approved drugs to a heated antibody drug conjugates (ADC) warhead and a trichothecene toxin to demonstrate that the bioorthogonal caging and specific activation could serve as a general design to increase the therapeutic index of bioactive molecules. These prodrugs can be efficiently activated on-demand by the bioorthogonal activators whose distribution was regulated by the cancer cell specific enzymatic non-covalent synthesis of supramolecular self-assemblies. The prodrug activation not only enhanced the synergistic therapeutic effect within a broad range of dose ratios but also allowed the convenient switching of drug identities to successfully combat MDR tumor in vivo. In general, this strategy might serve as a general platform, which can be readily applicable to enlarge the therapeutic window for various bioactive molecules. We envision that the spatiotemporal controlled bioorthogonal prodrug activation would facilitate the discovery of anticancer drugs.

A series of 17β-amide-2-methoxyestradiol compounds were synthesized with an aim to enhance the antiproliferative effect of 2-methoxyestradiol. The antiproliferative activity of 2-methoxyestradiol analogs against human cancer cells was investigated. 2-methoxy-3-benzyloxy-17β-chloroacetamide-1,3,5(10)-triene (5e) and 2-methoxy-3-hydroxy-17β-butyramide-1,3,5(10)-triene (6c) had comparable or better antitumor activity than 2-methoxyestradiol. The elimination half-life of 6c (t1/2β=240.93min) is ten times longer than 2-ME and the area under the curve was seven times (AUC0-tmin=2068.20±315.74μgmL-1min) higher than 2-ME, respectively. Whereas 5e had similar pharmacokinetic behavior with 2-ME (t1/2β=22.28min) with a t1/2β of 29.5 min. 6c had higher blood concentration, longer actuation duration and better suppression rate against S180 mouse ascites tumor than 2-methoxyestradiol.

Hepatitis-hydropericardium syndrome (HHS) is an acute infectious disease caused by fowl adenovirus serotype 4 (FAdV-4), which mainly infects broilers aged 3–5 weeks. In March 2018, a pathogenic disease, which was characterized by symptoms similar to HHS, broke out in 10-day-old broiler flocks in Shandong province. In this study, a strain of FAdV-4 (SDSG) was isolated from naturally infected broilers. To assess its pathogenicity, 10-day-old and 20-day-old specific pathogen-free (SPF) chickens were inoculated separately with the FAdV-4 virus fluid via oral and intramuscular injection routes. The results show that typical hydropericardium and hepatitis were observed in experimental chickens. The titer levels of the virus antibody and the levels of inflammatory cytokines were upregulated, which may be caused by the infection and innate immune response. The detection of viral load showed that the presence of virus was detected in multiple organs, in which the liver contained the highest concentration of viral DNA, and the virus content in the intramuscular injection group was higher than that of the oral injection group. In summary, these findings increase our understanding of the pathogenicity of FAdV-4 (SDSG) in chickens. The established model will be valuable for anti-viral drug testing and vaccine evaluation, which can prevent and reduce the spread of HHS in the poultry industry.

Stenotrophomonas maltophilia is an opportunistic pathogen which causes an increasing frequency of infections in hospitalized patients. Here, we present the complete genome sequence of Stenotrophomonas maltophilia SM7059, an oxidase-positive strain isolated from a female patient with hepatolithiasis in China.

The Reticuloendotheliosis virus (REV) primarily causes avian severe immunosuppression, in addition to other symptoms, which include avian dwarfing syndrome and chronic tumors in lymphoid and other tissue. To date, REV&rsquo, s molecular mechanisms leading to immunosuppression have not been fully elucidated. In the current study, we aimed to elucidate the role of microRNAs (miRNA) in regulating gene expression during REV infections. Therefore, we used a high-dose spleen necrosis virus (SNV) model of REV to inoculate one-day-old specific pathogen-free (SPF) chickens, thereby inducing congenital infections. We analyzed miRNA and mRNA expression profiles using Next Generation Sequencing (NGS) in a total of 19 spleen samples that were collected at 7, 14, and 21 days post infection (dpi). The results showed that 63 differentially expressed miRNAs (DEmiRNAs) (30 known miRNAs and 33 novel miRNAs) and 482 differentially expressed target genes (DETGs) were identified. Integration analysis identified 886 known miRNA&ndash, mRNA and 580 novel miRNA&ndash, mRNA interaction pairs, which involved miRNAs that were inversely correlated with the above DETGs. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the DETGs were considerably enriched in the immune-relevant pathways category, such as immune system, cell growth and death, signaling molecules and interaction, signal transduction, etc. We further verified selected immune-relevant miRNA and their DETGs while using quantitative RT-PCR (qRT-PCR). Overall, our data revealed valuable immune-related miRNA&ndash, mRNA interaction information that occurred during REV infections, thereby broadening our understanding of the REV-induced immunosuppression.

Antrodia camphorata, a well-known and highly valued edible medicinal mushroom with intriguing activities like liver protection, has been traditionally used for the treatment of alcoholic liver disease. A. camphorata shows highly medicinal and commercial values with the demand far exceeds the available supply. Thus, the petri-dish cultured A. camphorata (PDCA) is expected to develope as a substitute. In this paper, nineteen triterpenes were isolated from PDCA, and thirteen of them were the unique anthroic acids in A. camphorata, including the main content antcin K, which suggested that PDCA produced a large array of the same anthroic acids as the wild one. Furthermore, no obvious acute toxicity was found suggesting the edible safety of PDCA. In mice alcohol-induced liver injury model, triglyceride (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA) had been reduced by the PDCA powder as well as the main content antcin K, which indicated that the PDCA could protect alcoholic liver injury in mice model and antcin K could be the effective component responsible for the hepatoprotective activities of PDCA against alcoholic liver diseases.

Timely and efficient reperfusion of the occluded coronary artery is the best strategy for decreasing myocardial infarct size in patients with a ST-segment elevated myocardial infarction. However, reperfusion per se can result in further cardiomyocyte death, a phenomenon known as reperfusion injury. The opening of the mitochondrial permeability transition pore (mPTP), with the decrease of the mitochondrial membrane potential (MMP), or mitochondrial depolarization, is universally recognized as the final step of reperfusion injury and is responsible for mitochondrial and cardiomyocyte death. JC-1 is a lipophilic cationic dye that accumulates in mitochondria depending on the value of MMP. The higher the MMP is, the more JC-1 accumulates in the mitochondria. The increasing amounts of JC-1 in mitochondria can be reflected by a fluorescence emission shift from green (~530 nm) to red (~590 nm). Therefore, the reduction of the red/green fluorescence intensity ratio can indicate the depolarization of mitochondria. Here, we take advantage of JC-1 to measure MMP, or the opening of mPTP in human cardiac myocytes after hypoxia/reoxygenation, detected by flow cytometry.

Background: Alzheimer's disease (AD) and frontotemporal dementia (FTD) are two common forms of primary neurodegenerative dementia. Mutations in 3 genes (PSEN1, PSEN2, and APP) have been identified in patients with early-onset AD. Methods: We performed gene sequencing in PSEN1, PSEN2, and APP in 61 AD and 35 FTD Chinese patients. Amyloid load using 11C-labeled Pittsburgh compound B (11C-PIB) positron emission tomography (PET) and cerebral glucose metabolism using 18F-fludeoxyglucose PET were evaluated in patients carrying mutations. Results: We identified 1 known pathogenic PSEN1 (p.His163Arg, c.488A>G) mutation and 3 novel PSEN2 mutations in 6 patients. The novel mutation PSEN2 (p.His169Asn, c.505C>A) was identified in 1 patient with familial late-onset AD and in 1 sporadic FTD patient. The PSEN2 (p.Val214Leu, c.640G>T; p.Lys82Arg, c.245A>G) mutations were identified in 2 early-onset AD patients and 1 early-onset AD patient, respectively. Three patients with PSEN2 mutations were observed to have PIB retention on the cortex and striatum. One patient with the FTD phenotype was not observed to have PIB retention. Conclusion: PSEN2 mutations are common in the Chinese Han population with a history of AD and FTD. Pathogenic mutations or risk variants in the PSEN2 gene can influence both FTD and AD phenotypic traits and show variations in neuroimaging characterization. © 2014 S. Karger AG, Basel

Dental care is consistently reported as one of the primary medical needs of children with disabilities (IDC). The aim of the present study was to explore the influence of oral health behaviors on the caries experience in children with intellectual disabilities in Guangzhou, China. A cross-sectional study was carried out in 477 intellectually disabled children, 12 to 17 years old, who were randomly selected from special educational schools in Guangzhou. A self-administered parental questionnaire was used to collect data on socio-demographic characteristics and oral health behavior variables, and 450 valid questionnaires were returned. Multiple regression analysis was used to examine the factors associated with dental caries. The average age of those in the sample was 14.6 years (SD = 1.3), 68.4% of whom were male, and the caries prevalence rate was 53.5% (DMFT = 1.5 ± 2.0). The factors significantly affecting the development of dental caries in IDC included gender, the presence or absence of cerebral palsy, and the frequency of dental visits and toothbrushing. In conclusion, the presence of cerebral palsy contributed to an increase risk of caries experience in intellectually disabled children, while toothbrushing more than twice a day and routine dental visits were caries-protective factors. Oral health promotion action may lead to a reduction in dental caries levels in IDC.

Genotype-phenotype correlation of hypertrophic cardiomyopathy (HCM) has been challenging because of the genetic and clinical heterogeneity. To determine the mutation profile of Chinese patients with HCM and to correlate genotypes with phenotypes, we performed a systematic mutation screening of the eight most commonly mutated genes encoding sarcomere proteins in 200 unrelated Chinese adult patients using direct DNA sequencing. A total of 98 mutations were identified in 102 mutation carriers. The frequency of mutations in MYH7, MYBPC3, TNNT2 and TNNI3 was 26.0, 18.0, 4.0 and 3.5 % respectively. Among the 200 genotyped HCM patients, 83 harbored a single mutation, and 19 (9.5 %) harbored multiple mutations. The number of mutations was positively correlated with the maximum wall thickness. We found that neither particular gene nor specific mutation was correlated to clinical phenotype. In summary, the frequency of multiple mutations was greater in Chinese HCM patients than in the Caucasian population. Multiple mutations in sarcomere protein may be a risk factor for left ventricular wall thickness.

Background: The beneficial health effects associated with Universal Salt Iodization are well known. Yet, little is known about the possible adverse health effects in people with high iodine intake and the safe daily intake upper limit in the Chinese population. Objective: The objective of this study was to explore the safe upper level of total daily iodine intake among adults in China. Design: A 4-wk, double-blind, placebo-controlled, randomized controlled trial was conducted in 256 euthyroid adults. Participants were randomly assigned to 12 intervention groups with various iodine supplement doses ranging from 0 to 2000 lg/d. Total iodine intake included iodine from both supplements and diet. Multiple outcome measures were used to evaluate possible adverse effects, including thyroid function, thyroid size, and urinary iodine. Results: The mean iodine intake from the diets and salt intake of the participants were 105 6 25 and 258 6 101 lg/d, respectively. In comparison with the placebo group, all iodide-supplemented groups responded with significant increases in median urinary iodine concentrations (P , 0.05) and in thyroid-stimulating hormone concentration (P , 0.05). Thyroid volume decreased after 4 wk in the high-iodine intervention groups (1500‐2000 lg). Subclinical hypothyroidism appeared in the groups that received 400 lg I (5%) and 500‐2000 lg I (15‐47%). Conclusions: This study showed that subclinical hypothyroidism appeared in the participants who took the 400-lg I supplement, which provided a total iodine intake of ;800 lg/d. Thus, we caution against a total daily iodine intake that exceeds 800 lg/d in China and recommend further research to determine a safe daily upper limit. Am J Clin Nutr 2012;95:367‐73.

To investigate the genotype-phenotype correlation in Chinese familial hypertrophic cardiomyopathy (HCM), peripheral blood samples were collected from 7 members of a Chinese HCM family, and 120 normal subjects were recruited as control. The full encoding exons and flanking sequences of the cardiac troponin T (TNNT2) gene, beta-myosin heavy chain (MYH7) gene and myosin binding protein C (MYBPC3) gene were amplified and the products were sequenced directly to detect the mutations. A missense mutation, c.1273G>A, was identified in exon 14 of the MYH7 gene in 4 members of the Chinese HCM family, which resulted a glycine (Gly) to arginine (Arg) exchange at amino acid residue 425. The 425th glycine amino acid residue is highly conservative across the different species. The clinical phenotypes among the family members who carried this mutation presented significant individual differences. The c.1273G>A mutation of the MYH7 gene might be the causal mutation of the familial HCM. The heterogeneity of phenotypes suggested that multiple factors may be involved in the pathogenesis of HCM.

Primary adrenal lymphoma (PAL) is an extremely rare entity and primary adrenal insufficiency (PAI) is a common complication. The majority of cases reported previously were of B-cell origin. Here, we describe an additional PAL of B-cell origin with 18 F-FDG PET/CT images. The patient was a 74-year-old man who presented with clinical and laboratory features of PAI. Abdominal ultrasonography (US) showed bilateral adrenal masses. Whole-body 18 F-FDG PET/CT showed intensely increased glucose metabolism in bilateral bulky adrenal masses. Pathological diagnosis was non-Hodgkin lymphoma of B-cell origin. Combination chemotherapy was unsuccessful and our patient died of CNS involvement 6 months later. The present case indicated that PAL should be included in the differential diagnosis of bilateral adrenal masses, especially in patients with PAI. We report the case and review the literature for this disease in detail.

A rapid, selective and convenient liquid chromatography–mass spectrometric method for the simultaneous determination of paracetamol and caffeine in human plasma was developed and validated. Analytes and theophylline [internal standard (I.S.)] were extracted from plasma samples with diethyl ether-dichloromethane (3:2, v/v) and separated on a C18 column (150 × 4.6 mm ID, 5 μm particle size, 100 A pore size). The mobile phase consisted of 0.2% formic acid–methanol (60:40, v/v). The assay was linear in the concentration range between 0.05 and 25 μg mL−1 for paracetamol and 10–5,000 ng mL−1 for caffeine, with the lower limit of quantification of 0.05 μg mL−1 and 10 ng mL−1, respectively. The intra- and inter-day precision for both drugs was less than 8.1%, and the accuracy was within ±6.5%. The single chromatographic analysis of plasma samples was achieved within 4.5 min. This validated method was successfully applied to study the pharmacokinetics of paracetamol and caffeine in human plasma.

The numerous natural products and their bioactivity potentially afford an extraordinary resource for new drug discovery and have been employed in cancer treatment. However, the underlying pharmacological mechanisms of most natural anticancer compounds remain elusive, which has become one of the major obstacles in developing novel effective anticancer agents. Here, to address these unmet needs, we developed an anticancer herbs database of systems pharmacology (CancerHSP), which records anticancer herbs related information through manual curation. Currently, CancerHSP contains 2439 anticancer herbal medicines with 3575 anticancer ingredients. For each ingredient, the molecular structure and nine key ADME parameters are provided. Moreover, we also provide the anticancer activities of these compounds based on 492 different cancer cell lines. Further, the protein targets of the compounds are predicted by state-of-art methods or collected from literatures. CancerHSP will help reveal the molecular mechanisms of natural anticancer products and accelerate anticancer drug development, especially facilitate future investigations on drug repositioning and drug discovery. CancerHSP is freely available on the web at http://lsp.nwsuaf.edu.cn/CancerHSP.php.

The aim of the study was to obtain an overview of the clinical and neuroimaging features of Chinese patients with subtypes of frontotemporal lobe degeneration (FTLD). We evaluated the demographic features, clinical presentation, and lobe atrophy depicted by magnetic resonance imaging (MRI) in 133 patients with FTLD. Two positron emission tomography (PET) scans were performed at baseline: [11C]Pittsburgh compound B PET to assess amyloid-β plaque load and [18F]fluorodeoxyglucose (FDG) PET to assess glucose metabolism. The behavioral variant of FTD (bvFTD) was the most common subtype (67.7%) of FTLD. The percentages of progressive nonfluent aphasia (PNFA) and semantic dementia (SD) were similar. Cerebral lobe atrophy was seen in 87.7% of the cases. The Activities of Daily Living scale, Mini-Mental State Examination, and Montreal Cognitive Assessment scores were significantly correlated with the degree of overall atrophy. The severity of abnormal behavior was correlated with right anterior and right posterior temporal atrophy scores. The overall atrophy scores and atrophy score in the left temporal region were related to cognitive outcomes and Activities of Daily Living scores. Most of the bvFTD patients presented symmetric/asymmetric hypometabolism in the bilateral temporal cortex, frontal cortex, anterior cingulate cortex, insula, and caudate nucleus. All the PNFA patients presented left dominant hypometabolism in the frontal cortex. All the SD patients presented left dominant hypometabolism in the anterior temporal cortex. FTLD is not rare in cognitive clinics, and the ratios of subtypes in Chinese patients are similar to other ethnic groups. Overall atrophy scores, determined by MRI, were related to the severity of cognitive dysfunction and deficits in Activities of Daily Living. Patterns of hypometabolism, determined by [18F]FDG PET, were more specific to subtypes of FTLD and may help provide differential diagnoses of variants of FTLD.