A case of spinal cord abscess caused by Nocardia cyriacigeorgica is reported. The patient is an elderly man with a history of nephritic syndrome who presented with aggravating lower back pain and then gradually developed urinary retention, weakness and numbness in both lower extremities. Operative intervention was performed, and postoperative pathological findings suggested spinal cord abscess formation. Metagenomic next-generation sequencing of the cerebrospinal fluid identified Nocardia cyriacigeorgica as the causative pathogen. Although appropriate antibiotics were prescribed, the patient died 3 months later.

Protein neddylation is catalyzed by a three-enzyme cascade, namely an E1 NEDD8-activating enzyme (NAE), one of two E2 NEDD8 conjugation enzymes and one of several E3 NEDD8 ligases. The physiological substrates of neddylation are the family members of cullin, the scaffold component of cullin RING ligases (CRLs). Currently, a potent E1 inhibitor, MLN4924, also known as pevonedistat, is in several clinical trials for anti-cancer therapy. Here we report the discovery, through virtual screening and structural modifications, of a small molecule compound HA-1141 that directly binds to NAE in both

Chaperone-mediated autophagy (CMA) is a lysosome-dependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases. However, the mechanisms that regulate CMA are not fully understood. Here, using unbiased drug screening approaches, we discover Metformin, a drug that is commonly the first medication prescribed for type 2 diabetes, can induce CMA. We delineate the mechanism of CMA induction by Metformin to be via activation of TAK1-IKKα/β signaling that leads to phosphorylation of Ser85 of the key mediator of CMA, Hsc70, and its activation. Notably, we find that amyloid-beta precursor protein (APP) is a CMA substrate and that it binds to Hsc70 in an IKKα/β-dependent manner. The inhibition of CMA-mediated degradation of APP enhances its cytotoxicity. Importantly, we find that in the APP/PS1 mouse model of Alzheimer's disease (AD), activation of CMA by Hsc70 overexpression or Metformin potently reduces the accumulated brain Aβ plaque levels and reverses the molecular and behavioral AD phenotypes. Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/β-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases, such as AD, where such therapeutic intervention could be beneficial.

Androgen receptor (AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding of ligands to AR triggers the conformational changes in AR that may affect the recruitment of coactivators and downstream response of AR signaling pathway. Therefore, AR ligands have great potential to treat these diseases. In this study, we searched for novel AR ligands by performing a docking-based virtual screening (VS) on the basis of the crystal structure of the AR ligand binding domain (LBD) in complex with its agonist. A total of 58 structurally diverse compounds were selected and subjected to LBD affinity assay, with five of them (HBP1-3, HBP1-17, HBP1-38, HBP1-51, and HBP1-58) exhibiting strong binding to AR-LBD. The IC values of HBP1-51 and HBP1-58 are 3.96 µM and 4.92 µM, respectively, which are even lower than that of enzalutamide (Enz, IC = 13.87 µM), a marketed second-generation AR antagonist. Further bioactivity assays suggest that HBP1-51 is an AR agonist, whereas HBP1-58 is an AR antagonist. In addition, molecular dynamics (MD) simulations and principal components analysis (PCA) were carried out to reveal the binding principle of the newly-identified AR ligands toward AR. Our modeling results indicate that the conformational changes of helix 12 induced by the bindings of antagonist and agonist are visibly different. In summary, the current study provides a highly efficient way to discover novel AR ligands, which could serve as the starting point for development of new therapeutics for AR-related diseases.
Androgen Receptor Antagonists ; pharmacology ; Androgens ; metabolism ; pharmacology ; Biological Assay ; Cell Line, Tumor ; Drug Discovery ; methods ; Humans ; Ligands ; Male ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Phenylthiohydantoin ; analogs & derivatives ; pharmacology ; Principal Component Analysis ; Prostatic Neoplasms ; drug therapy ; Protein Binding ; physiology ; Protein Conformation ; drug effects ; Receptors, Androgen ; metabolism

Objective To study the diagnostic value of endoscopic ultrasound guided fine needle aspiration (EUS-FNA) combined with the new category of papanicolaou society of cytopathology in solid pancreatic lesions (SPL) rapid on-site evaluation (ROSE).Methods From February 2011 to October 2014,225 patients with SPL who underwent EUS-FNA and obtained the cytological diagnosis were enrolled.The lesions were finally diagnosed according to pathological results,imaging and follow-up data,and then the sensitivity,specificity,and accuracy of EUS-FNA in the diagnosis of SPL were calculated based on the new papanicolaou society of cytopathology terminology.Logistic stepwise regression analysis was performed to analyze the risk factors.Results Among 225 patients with SPL,96 cases (42.7％)had uncertain cytological diagnosis,17.3％ (39/225) could not be diagnosed,8.0％ (18/225) were atypical lesions,and 17.3％ (39/225) were suspicious malignant carcinomas.Among 129 cases (57.3％)with certain cytological diagnosis,15.1％ (34/225) were benign lesions,14.7％ (33/225) were tumors (benign or others) and 27.6％ (62/225) were malignant tumors.When atypical lesions were added into non-tumor lesions or tumor lesions,the sensitivity,specificity and accuracy of diagnosis were 87.3 ％,91.7％,88.2％,and 94.7％,72.2％,90.3％,respectively.Serum CA125≥14 kU/L (odds ratio (OR) =7.13,95％ confidence interval (CI) 2.02 to 25.22,P=0.002) and history of biliary disease (OR=3.85,95％CI 1.22 to 12.51,P=0.022) were two independent risk factors of pancreatic tumors.Conclusions Despite of a high percentage of uncertain cytological diagnosis,EUS-FNA still has high diagnostic value in SPL when combined with the new papanicolaou society of cytopathology terminology.Furthermore,serum CA125≥14 kU/L and history of biliary disease may help to diagnose pancreatic tumors.

Objective To evaluate the prevalence of full thickness rotator cuff tear in patients with proximal humeral fractures,and the relationships between different risk factors.Methods Data of 113 patients with proximal humeral fractures from January 2014 to January 2016 who underwent surgical treatment were retrospectively analyzed.The general characteristics of patients (age,sex,cause of injury) were recorded and the rotator cuff was evaluated preoperatively on MRI and explored intra-operatively.We calculated and compared the incidence rate of age,sex in patients with and without rotator cuff tear.And the incidence rate of rotator cuff tear in different types of fracture according to Neer classification was calculated.Results The full thickness ro tator cuff tear were indentified in 28 patients (24.8％),and 21 of them had been confirmed by MRI preoperatively.Statistical significant difference was found between patients with rotator cuff tear group (average of 75.11± 10.89 years old) and without rotator cuff tear group (64.68± 13.43) for the age of the patient.Full thickness rotator cuff tear was most common in Neer 3 GT fracture (33.3％,8/54),followed by Neer 2 GT (26.67％,4/15) and Neer 2 SN (17.65,6/34),however,no full thickness rotator was found in Neer 4 type fracture.There were 4 patients with total rotator cuff tear who had symptom of shoulder before the operation.The other 24 patients had no symptom of shoulder.Conclusion Patient age was found as a risk factor for full thickness rotator cuff tear in humeral proximal fractures with the rate of 24.8％.Full thickness rotator cuff tear was most common in Neer 3 GT fracture.

Objective To investigate the effects of avastin combined with As2 O3 on rabbits corneal neovas-cularization (CNV)induced by alkali burn.Methods A total of 48 Japanese rabbits were induced the CNV models by middle alkali burns.The rabbits were randomly divided into four groups.A group was subconjunctivally injected 0.5mL 1mg/mL of As2 O3 and 0.5mL normal sodium,B group was subconjunctivally injected 0.5mL 25mg/mL of avastin and 0.5mL normal sodium,C group was subconjunctivally injected 0.5mL 1mg/mL of As2 O3 and 0.5mL 25mg/mL of avastin,D group was subconjunctivally injected 1.0mL normal sodium,after corneal alkali burn,respec-tively.CNV area at 6 days,12 days,15 days,21 days and 28 days after burns were calculated,the expression of IL -1β,VCAM-1 and VEGF in corneal tissue at 7 days,14 days,28 days after burns were detected by immunohisto-chemical staining.Results Alkali burn after 28 d,the CNV,IL -1β,VCAM-1,VEGF expression rates of A group were (50.28 ±30.26)mm2 ,(6.83 ±1.74)%,(1.52 ±0.91)%,(5.02 ±0.82)%,respectively,which of B group were (55.19 ±20.03)mm2 ,(6.88 ±1.94)%,(1.41 ±0.94)%,(2.91 ±0.84)%,respectively,which of C group were (10.03 ±5.98)mm2 ,(1.96 ±0.99)%,(0.38 ±0.57)%,(1.08 ±0.77)%,respectively,which of D group were (83.18 ±33.05)mm2 ,(10.16 ±2.17)%,(3.74 ±0.83)%,(7.69 ±1.33)%,respectively.The differences among four groups were statistically significant (F =25.33,3.64,13.13,7.23,all P <0.05 ).Compared with D group,the CNV area and the expressions of IL -1β,VCAM-1 and VEGF were significantly decreased in A,B,C group(qCNV =40.294,34.281,89.590,qIL -1β =4.078,4.017,10.043,qVCAM-1 =2.719,2.854,5.791,qVEGF =3.270,8.238,11.392,all P <0.05);Compared with C group,the CNV area and the expressions of IL -1β,VCAM-1 and VEGF were significantly decreased in A,B group (qCNV =49.296,55.309;qIL -1β =5.965,6.026;qVCAM-1 =1.965,1.775;qVEGF =6.790,22.413,all P <0.05);Compared with B group,the CNV area and the expressions of IL -1βand VCAM-1 were not significantly different in A group (P >0.05);Compared with B group,the expression of VEGF was significantly increased in A group (q =4.03,P <0.05).Conclusion Avastin combined with As2 O3 can inhibit the growth of CNV induced by alkali burning in rabbits effectively,and reduce the expressions of IL -1β, VCAM-1 and VEGF in CNV.It has better efficacy than single drug,and it opens up a new way for the prevention and treatment of CNV.

OBJECTIVE:To study protective effects of Ketorolac tromethamine ophthalmic gel against Staphylococcus aureus corneal ulcer in rabbits. METHODS:S. aureus corneal ulcer in rabbits model was induced by corneal substance layer inoculation, and then divided into model group,positive control group (Clarithromycin ophthalmic gel),gel high-dose,medium-dose and low-dose groups(Ketorolac tromethamine ophthalmic gel 120,80,40 mg/ml),with 20 rabbits in each group. They were given re-levant medicine,once a day for 2 weeks. The keratopathy of rabbits was observed;the clinical efficacy and keratopathy score were compared. The change of ratina was observed under micrescope. RESULTS:Compared with model group,the keratopathy score de-creased while total effective rate increased in positive control group and gel groups after medication, and the effects of gel high-dose and low-dose groups were significantly lower than that of positive control group,with statistical significance(P<0.05). The retina of rabbits had not affected by the experiment. CONCLUSIONS:Ketorolac tromethamine ophthalmic gel has protective effect against S. aureus corneal ulcer in rabbits.

The nano-structure TiN was modified on the laboratory self-made planar microelectrode array pMEA by magnetron sputtering method. The performance of modified pMEA was investigated. Research on neuroelectrical and neurochemical recording was studied in vitro. The impedance of the modified pMEA was decreased almost one order of magnitude, and the background noise level was reduced to ±6 μV. In the same testing environment, the signal-to-noise ratio (SNR) of modified electrodes was 1. 7 times of bare electrodes. The SNR of neuroelectrical recording on the brain slice of SD rats reached 10:1 , and the weak signal such as ±12 μV was separated easily. For neuroelectrical recordings, the detection limit of dopamine ( DA) solution reached 50 nmol/L with the 2:1 (S/N). During the concentration range of 0. 05-100 μmol/L, the linearly correlation coefficient of the DA oxidation currents was 0 . 998 . The modification of nano-structure TiN on pMEA reduced pMEA impedance and background noise level, meanwhile the SNR was increased. The weak signals of neuroelectrical and neurochemical recording were successfully recorded.