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Yoga therapy may have some potential in treating migraine, and thus this meta-analysis aims to explore the efficacy of yoga therapy for patients with migraine.PubMed, EMbase, Web of science, EBSCO and Cochrane library databases have been systematically searched and we included the randomized controlled trials (RCTs) reporting the efficacy of yoga therapy for migraine patients. The outcomes included.This meta-analysis included six RCTs. The results revealed that compared with control group for migraine, yoga therapy was associated with remarkably decreased pain intensity (SMD = -1.21; 95% CI = -2.17 to -0.25; P = 0.01), headache frequency (SMD = -1.43; 95% CI = -2.23 to -0.64; P = 0.0004), headache duration (SMD = -1.03; 95% CI = -1.85 to -0.21; P = 0.01), HIT-6 score (SMD = -2.28; 95% CI = -3.81 to -0.75; P = 0.003) and MIDAS score (SMD = -0.52; 95% CI = -0.77 to -0.27; P0.0001).Yoga therapy may be effective to treat migraine patients, but it should be recommended with caution because of heterogeneity.

Supplementary Methods, radiologist's reading of CT images, supplementary figure legends, supplementary references

microCT scans

SFigure 1: Histological examination of mouse lungs; SFigure 2: Tissue sections from human lung adenocarcinoma; SFigure 3: Cabozantinib (CBT) and vandetanib (VDT) resistant cells; SFigure 4: Comparison of in vitro inhibition of RET, RETV804L and RETV804M by ponatinib, cabozantinib, vandetanib, and lenvatinib; SFigure 5: Ponatinib treatment schedule and body weight measurements; SFigure 6: Lung section histology from Dox-induced C/KR mice and treated with vehicle or ponatinib for 1 months; SFigure 7: μCT examination of dox-induced C/KR mice with lung tumors before and after one month treatment with vehicle or ponatinib.

A ZnIn2S4 nanoflake-decorated 24-faceted concave MIL-88B(Fe) polyhedron S-scheme system was perfectly created, manifesting simultaneously enhanced photocatalytic cleanup of Cr(vi) and tetracycline.

Direct Z-scheme MgIn2S4/Bi2WO6 hierarchical heterostructures were simply fabricated via immobilising MgIn2S4 nanoflakes onto the surface of Bi2WO6 hierarchical nanosheet-like structures towards photocatalytic reduction of Cr(VI). The analyses of the energy band structure, UPS tests and DMPO-ESR spin-trap experiments confirm that the intimate MgIn2S4/Bi2WO6 heterointerface allows an efficient Z-scheme interfacial charge migration route between MgIn2S4 and Bi2WO6, leading to higher redox ability of photoexcited carriers, and thus favours the separation of photoexcited carriers, proved by the results of PL spectroscopy, photoluminescence decay traces, transient photocurrent densities and EIS. In addition, the MgIn2S4/Bi2WO6 heterostructures also exhibit obviously enhanced ultraviolet-visible-light absorption according to UV-vis DRS analysis, and can generate more electron–hole pairs under UV-visible light illumination, effectively improving the photocatalytic activity. Therefore, because of their synergistic effects, all the MgIn2S4/Bi2WO6 hierarchical heterostructures show distinctly improved photoreduction activities for Cr(VI), compared with pure Bi2WO6. The optimal hybrid (MIS/BWO-0.35) displays nearly 100% Cr(VI) reduction into Cr(III) after 40 min of simulated sunlight illumination, which is better than the majority of the reported Bi2WO6 and other semiconductor photocatalysts before. Its reaction rate constant for the photoreduction of Cr(VI) (0.1063 min−1) is about 4.5 times higher than that of the pristine Bi2WO6 (0.0237 min−1). This work provides a valid approach for developing efficient Z-scheme photocatalytic materials in removing Cr(VI).

Background and Purpose: The acquired resistance to PARP inhibitors (PARPi) caused by point mutations in PARP1 protein is hard to overcome through current strategies. In order to explore modalities to conquer resistance and identify patients who are most likely to benefit from PARP1-targeted therapy, we developed a proteolysis-targeted-chimaera (PROTAC) to degrade mutant PARP1 in p53-mutant TNBC. Experimental Approach: Based on analysis of the resistant mutations, we attempted to use PROTAC strategy to increase the sensitivity of cells expressing PARPi-resistant proteins that identified from patients. The antineoplastic activity of our synthetic degrader was evaluated in multiple human cell lines, as well as the xenograft model with p53 mutation. The proteomics subsequently was used to reveal the potential mechanism of the degrader. Ferroptosis, as main mechanism, was assayed via detecting SLC7A11 signaling, glutathione and lipid peroxidation. Besides, according to genetic alteration analysis from patients, three common p53 mutations were selected to assess PARP1-related cell death. Key Results: We developed a PROTAC termed “NN3”, and this compound could trigger ubiquitination and proteasome-mediated PARP1 degradation. Interestingly, compared with other reported PARP1 degraders, NN3 has a unique antitumor mechanism and it promote ferroptosis effectively via decreasing the SLC7A11/GPX4 pathway in HR-proficient TNBC cells, whether or not these cells express drug resistance-related PARP1 mutations. More importantly, NN3 showed potent activity and low toxicity in vivo studies on mutant-p53 TNBC. Conclusion and Implications: We identify PROTAC-mediated degradation of PARP1 as a novel strategy against PARPi resistance and a paradigm for targeting mutant-p53 cancers by inducing ferroptosis.

Background: Depression is a prominent and highly prevalent nonmotor feature in patients with Parkinson’s disease (PD). The neural and pathophysiologic mechanisms of PD with depression (DPD) remain unclear. The current diagnosis of DPD largely depends on clinical evaluation. Methods: We proposed a new family of multinomial tensor regressions that leveraged whole-brain structural magnetic resonance imaging (MRI) data to discriminate among 196 non-depressed PD (NDPD) patients, 84 DPD patients, 200 healthy controls (HC), and to assess the special brain microstructures in NDPD and DPD. The method of maximum likelihood estimation coupled with state-of-art gradient descent algorithms was used to predict the individual diagnosis of PD and the development of DPD in PD patients. Results: The results reveal that the proposed efficient approach not only achieved a high prediction accuracy (0.94) with a multi-class AUC (0.98) for distinguishing between NDPD, DPD, and HC on the testing set but also located the most discriminative regions for NDPD and DPD, including cortical regions, the cerebellum, the brainstem, the bilateral basal ganglia, and the thalamus and limbic regions. Conclusions: The proposed imaging technique based on tensor regression performs well without any prior feature information, facilitates a deeper understanding into the abnormalities in DPD and PD, and plays an essential role in the statistical analysis of high-dimensional complex MRI imaging data to support the radiological diagnosis of comorbidity of depression with PD.

The three-dimensional electrode biological aerated filter (3DE-BAF) has the potential to overcome inherent limitations of conventional electrochemical and biofilm methods. Electrochemical means could enhance the performance and sustainability of biofilm technologies and stimulate the spread of new applications in (waste) water treatment. This paper describes the construction and performance of 3DE-BAF in the treatment of simulated wastewater represented by tetracycline (TC). This is followed by a discussion of electrode performance, the electron transport mechanism and the electrode's effect on the biological community of 3D-EBAF. Given the gap between experimental studies and practical applications, the enlarged anode 3DE-BAF named 3DEAE-BAF reactor was applied with good results to duck farm wastewater. This study could provide guidance as to developing new methods to construct a highly stable 3DE-BAF. The paper concludes that improved 3DE-BAF technology is promising for advanced treatment of livestock wastewater containing antibiotics.

Somatic missense mutations of the CSNK1A1 gene encoding casein kinase 1 alpha (CK1α) occur in a subset of myelodysplastic syndrome (MDS) with del(5q) karyotype. The chromosomal deletion causes CSNK1A1 haplo-insufficiency. CK1α mutations have also been observed in a variety of solid and hematopoietic tumors at low frequency. The functional consequence of CK1α mutation remains unknown. Here we show that tumor-associated CK1α mutations exclusively localize to the substrate-binding cleft. Functional analysis of recurrent mutants E98K and D140A revealed enhanced binding to the p53 inhibitor MDMX, increased ability to stimulate MDMX-p53 binding, and increased suppression of p21 expression. Furthermore, E98K and D140A mutants have reduced ability to promote phosphorylation of β-catenin, resulting in enhanced Wnt signaling. The results suggest that the CK1α mutations observed in tumors cause gain-of-function in cooperating with MDMX and inhibiting p53, and partial loss-of-function in suppressing Wnt signaling. These functional changes may promote expansion of abnormal myeloid progenitors in del(5q) MDS, and in rare cases drive the progression of other tumors.

Objective We review the radiological imaging features and report histopathological findings of 7 adult patients with epithelioid glioblastoma (eGBM), which was a newly revised subtype of glioblastoma. Methods Seven adult patients with a diagnosis of eGBM on a brain tissue specimen were retrospectively confirmed by pathology. The tumor magnetic resonance imaging characteristics such as location, number, edema, necrosis, hemorrhage, enhancement, diffusion-weighted image, apparent diffusion coefficient, magnetic resonance spectroscopy, dynamic susceptibility contrast-perfusion–weighted imaging, and histopathological findings were documented. Results The tumors of these patients exhibited iso-hyperintensive signal on the T2-weighted image and iso-hypointensive signal on the T1-weighted image. All the lesions manifested iso-hypointensive signal on the diffusion-weighted image, and 2 cases showed significantly restricted hyperintensive signal (2/7). Peritumoral edema in all cases was mild. Five cases were located in the cortical lobe (5/7) and the other 2 were multifocal (2/7). Four cases showed white matter collapse sign (4/7). These tumors revealed apparent enhancement after contrast injection. In particular, 4 cases displayed capsuled sign (4/7), 2 cases showed dura mater tail sign (2/7), and 1 case showed hemorrhage (1/7). The mean value of apparent diffusion coefficient in 6 cases was 1.09 × 10−3 mm2/s. The mean value of relative cerebral blood volume in 3 cases was 2.84 × 10−3 mm2/s on dynamic susceptibility contrast-perfusion–weighted imaging. The average value of the choline/N-acetyl aspartate ratio in 4 cases was 6.47 × 10−3 mm2/s on magnetic resonance spectroscopy. All cases expressed a BRAF V600E mutation according to molecular characteristics. Conclusions eGBMs that were predominantly located in cortex with mild peritumoral edema, white matter collapse, encapsular sign, and dura mater tail sign could be easily misdiagnosed as cortex-involved intracranial brain tumor such as meningioma, whereas multifocal tumors could be easily misdiagnosed as metastatic tumor and lymphoma. Multimodal images were helpful for the differential diagnosis.

Introduction The current diagnosis of Parkinson's disease (PD) comorbidity with depression (DPD) largely depends on clinical evaluation. However, the modality may tend to lack precision in detecting PD with depression. A radiomic approach that combines functional connectivity and activity with clinical scores has the potential to achieve accurate and differential diagnosis between PD and DPD. Methods In this study, we aimed to employ the radiomic approach to extract large‐scale features of functional connectivity and activity for differentiating among DPD, PD with no depression (NDPD), and healthy controls (HC). We extracted 6,557 features of five types from all subjects including clinical characteristics, resting‐state functional connectivity (RSFC), amplitude of low‐frequency fluctuation (ALFF), regional homogeneity (ReHo), and voxel‐mirrored homotopic connectivity (VMHC). Lasso, random forest, and support vector machine (SVM) were implemented for feature selection and dimension reduction based on the training sets, and the prediction performance for different methods in the testing sets was compared. Results The results showed that nineteen features were selected for the group of DPD versus HC, 34 features were selected for the group of NDPD versus HC, and 17 features were retained for the group of DPD versus NDPD. In the testing sets, Lasso prediction achieved the accuracies of 0.95, 0.96, and 0.85 for distinguishing between DPD and HC, NDPD and HC, and DPD and NDPD, respectively. Random forest achieved the accuracies of 0.90, 0.82, and 0.90 for distinguishing between DPD and HC, NDPD and HC, and DPD and NDPD, respectively, while SVM yielded the accuracies of 1, 0.86 and 0.65 for distinguishing between DPD and HC, NDPD and HC, and DPD and NDPD, respectively. Conclusions By identifying aberrant functional connectivity and activity as potential biomarkers, the radiomic approach facilitates a deeper understanding and provides new insights into the pathophysiology of DPD to support the clinical diagnosis with high prediction accuracy., By identifying aberrant functional connectivity and activity as potential biomarkers, the radiomics approach facilitates a deeper understanding and provides new insights into the pathophysiology of DPD to support the clinical diagnosis with high prediction accuracy.

Parkinson’s disease is a progressive, chronic, and neurodegenerative disorder that is primarily diagnosed by clinical examinations and magnetic resonance imaging (MRI). In this paper, we propose a Bayesian model to predict Parkinson’s disease employing a functional MRI (fMRI) based radiomics approach. We consider a spike and slab prior for variable selection in high-dimensional logistic regression models, and present an approximate Gibbs sampler by replacing a logistic distribution with a t-distribution. Under mild conditions, we establish model selection consistency of the induced posterior and illustrate the performance of the proposed method outperforms existing state-of-the-art methods through simulation studies. In fMRI analysis, 6216 whole-brain functional connectivity features are extracted for 50 healthy controls along with 70 Parkinson’s disease patients. We apply our method to the resulting dataset and further show its benefits with a higher average prediction accuracy of 0.83 compared to other contenders based on 10 random splits. The model fitting procedure also reveals the most discriminative brain regions for Parkinson’s disease. These findings demonstrate that the proposed Bayesian variable selection method has the potential to support radiological diagnosis for patients with Parkinson’s disease.

Background: An early and correct diagnosis is crucial for treatment of unipolar depression (UD) and bipolar disorder (BD). The fractional amplitude of low-frequency fluctuations (fALFFs) has been widely used in the study of neuropsychiatric diseases, as it can detect spontaneous brain activities. This study was conducted to survey changes of fALFF within various frequency bands of the UD and BD patients, as well as to explore the effects on changes in fALFF on cognitive function. Methods: In total, 58 drug-naive first-episode patients, including 32 UD and 26 BD, were enrolled in the study. The fALFF values were calculated under slow-5 band (0.01-0.027 Hz) and slow-4 band (0.027-0.073 Hz) among UD patients, BD patients, and healthy control (HC). Additionally, we conducted correlation analyses to examine the association between altered fALFF values and cognitive function. Results: Under the slow-5 band, compared to the HC group, the UD group showed increased fALFF values in the right cerebellum posterior lobe, whereas the BD group showed increased fALFF values in the left middle temporal gyrus (MTG). Under the slow-4 band, in comparison to HC, the UD group showed increased fALFF values in the left superior temporal gyrus, whereas the right inferior parietal lobule (IPL) and BD group showed increased fALFF values in the bilateral postcentral gyrus. Notably, compared to BD, the UD group showed increased fALFF values in the right IPL under the slow-4 band. Furthermore, altered fALFF values in the left MTG and the right IPL were significantly positively correlated with Verbal Fluency Test scores. Conclusions: This current study indicated that there were changes in brain activities in the early UD and BD groups, and changes were related to executive function. The fALFF values can serve as potential biomarker to diagnose and differentiate UD and BD patients.

Casein kinase 1 alpha (CK1α) is a serine/threonine kinase with numerous functions, including regulating the Wnt/β‐catenin and p53 pathways. CK1α has a well‐established role in inhibiting the p53 tumor suppressor by binding to MDMX and stimulating MDMX‐p53 interaction. MDMX purified from cells contains near‐stoichiometric amounts of CK1α, suggesting that MDMX may in turn regulate CK1α function. We present evidence that MDMX is a potent competitive inhibitor of CK1α kinase activity (K (i) = 8 nM). Depletion of MDMX increases CK1α activity and β‐catenin S45 phosphorylation, whereas ectopic MDMX expression inhibits CK1α activity and β‐catenin phosphorylation. The MDMX acidic domain and zinc finger are necessary and sufficient for binding and inhibition of CK1α. P53 binding to MDMX disrupts an intramolecular auto‐regulatory interaction and enhances its ability to inhibit CK1α. P53‐null mice expressing the MDMX(W) (200S/W201G) mutant, defective in CK1α binding, exhibit reduced Wnt/β‐catenin target gene expression and delayed tumor development. Therefore, MDMX is a physiological inhibitor of CK1α and has a role in modulating cellular response to Wnt signaling. The MDMX‐CK1α interaction may account for certain p53‐independent functions of MDMX.

Parkinson's disease (PD) is a progressive, chronic, and neurodegenerative disorder that is primarily diagnosed by clinical examinations and magnetic resonance imaging (MRI). In this study, we proposed a machine learning based radiomics method to predict PD. Fifty healthy controls (HC) along with 70 PD patients underwent resting-state magnetic resonance imaging (rs-fMRI). For all subjects, we extracted five types of 6664 features, including mean amplitude of low-frequency fluctuation (mALFF), mean regional homogeneity (mReHo), resting-state functional connectivity (RSFC), voxel-mirrored homotopic connectivity (VMHC) and gray matter (GM) volume. After conducting dimension reduction utilizing Least absolute shrinkage and selection operator (LASSO), fifty-three radiomic features including 46 RSFCs, 1 mALFF, 3 mReHos, 1 VMHC, 2 GM volumes and 1 clinical factor were retained. The selected features also indicated the most discriminative regions for PD. We further conducted model fitting procedure for classifying subjects in the training set employing random forest and support volume machine (SVM) to evaluate the performance of the two methods. After cross-validation, both methods achieved 100% accuracy and area under curve (AUC) for distinguishing between PD and HC in the training set. In the testing set, SVM performed better than random forest with the accuracy, true positive rate (TPR) and AUC being 85%, 1 and 0.97, respectively. These findings demonstrate the radiomics technique has the potential to support radiological diagnosis and to achieve high classification accuracy for clinical diagnostic systems for patients with PD.

Ionic liquids (ILs) have been a hot topic in the past decades because of their unique properties and promising applications in various areas. However, the toxicity of ILs and their possible risk to the environment and aquatic organisms have also been confirmed. Therefore, it is imperative to seek an efficient way to remove or degrade ILs in the polluted aqueous system. In this work, Ag nanocubes/ZnO microspheres composites have been designed, prepared, and used for the photocatalytic degradation of eight commonly used imidazolium-based ILs in aqueous solution. It is found that ZnO semiconductor photocatalyst with an Ag content of 1.12 at. % can degrade 90% of all these ILs within 7 h. The structural characterization, photoluminescence analysis, and discrete dipole approximation calculations showed that the loading of Ag nanocubes onto ZnO microspheres significantly improves the performance of ZnO for the IL degradation through hot electron transfer and electrical field enhancement. In addition, the formed...

Background: This study aimed to evaluate the value of 3-dimensional pseudocontinuous arterial spin labeling (3D-pcASL) and susceptibility-weighted imaging (SWI) for the early disease-sensitive markers of conversion from amnestic MCI (aMCI) to Alzheimer disease (AD) in this process. Methods: Forty patients with aMCI and AD respectively were recruited in the study, and 40 healthy subjects were taken as controls. Data were recorded using 3T MR scanner. We assessed the cerebral blood flow (CBF) in 11 different regions of interest, and counted number of microhemorrhages (MB) in 3 regions of brain lobes, bilateral basal ganglia/thalamus, and brain stem/cerebellum, and then investigated correlations between Montreal Cognitive Assessment (MoCA) scores, CBF, and susceptibility-weighted imaging (SWI) features in these 3 groups. Results: The results revealed that for AD patients, the MoCA scores and CBF values in frontal gray matter (FGM), occipital gray matter (OGM), temporal gray matter (TGM), parietal gray matter (PGM), hippocampus, anterior cingulate cortex (ACC), precuneus, posterior cingulate cortex (PCC), precuneus, basal ganglia and thalamus decreased compared with aMCI patients and control group, and significant difference was revealed among the 3 groups. While in cerebellum, statistical significance was only found between AD patients and control group. On SWI, the average numbers of hemorrhage in regions of lobes for AD patients were significantly higher than aMCI patients and control group. The same results occurred in the bilateral basal ganglia/thalamus. We further found the MoCA score was positively correlated with CBF, but negatively correlated with hypointense signal on SWI. Conclusion: 3D-pCASL and SWI have promising potential to be biomarkers for conversion from aMCI to AD in this process.

RET is a transmembrane growth factor receptor. Aberrantly activated RET is found in several types of human cancer and is a target for treating RET aberration-associated cancer. Multiple clinically relevant RET protein-tyrosine kinase inhibitors (TKIs) have been identified, but how TKIs bind to RET is unknown except for vandetanib. Nintedanib is a RET TKI that inhibits the vandetanib-resistant RET(G810A) mutant. Here, we determined the X-ray co-crystal structure of RET kinase domain–nintedanib complex to 1.87 Å resolution and a RET(G810A) kinase domain crystal structure to 1.99 Å resolution. We also identified a vandetanib-resistant RET(L881V) mutation previously found in familial medullary thyroid carcinoma. Drug-sensitivity profiling of RET(L881V) revealed that it remains sensitive to nintedanib. The RET–nintedanib co-crystal structure disclosed that Leu-730 in RET engages in hydrophobic interactions with the piperazine, anilino, and phenyl groups of nintedanib, providing a structural basis for explaining that the p.L730V mutation identified in nine independently isolated cell lines resistant to nintedanib. Comparisons of RET–nintedanib, RET(G810A), and RET–vandetanib crystal structures suggested that the solvent-front Ala-810 makes hydrophobic contacts with a methyl group and aniline in nintedanib and blocks water access to two oxygen atoms of vandetanib, resulting in an energetic penalty for burying polar groups. Of note, even though the p.L881V mutation did not affect sensitivity to nintedanib, RET(L881V) was resistant to nintedanib analogs lacking a phenyl group. These results provide structural insights into resistance of RET mutants against the TKIs nintedanib and vandetanib.

RET fusions have been found in lung adenocarcinoma, of which KIF5B–RET is the most prevalent. We established inducible KIF5B-RET transgenic mice and KIF5B–RET-dependent cell lines for preclinical modeling of KIF5B–RET-associated lung adenocarcinoma. Doxycycline-induced CCSP-rtTA/tetO-KIF5B-RET transgenic mice developed invasive lung adenocarcinoma with desmoplastic reaction. Tumors regressed upon suppression of KIF5B–RET expression. By culturing KIF5B–RET-dependent BaF3 (B/KR) cells with increasing concentrations of cabozantinib or vandetanib, we identified cabozantinib-resistant RETV804L mutation and vandetanib-resistant-RETG810A mutation. Among cabozantinib, lenvatinib, ponatinib, and vandetanib, ponatinib was identified as the most potent inhibitor against KIF5B–RET and its drug-resistant mutants. Interestingly, the vandetanib-resistant KIF5B-RETG810A mutant displayed gain-of-sensitivity (GOS) to ponatinib and lenvatinib. Treatment of doxycycline-induced CCSP-rtTA/tetO-KIF5B-RET bitransgenic mice with ponatinib effectively induced tumor regression. These results indicate that KIF5B-RET–associated lung tumors are addicted to the fusion oncogene and ponatinib is the most effective inhibitor for targeting KIF5B–RET in lung adenocarcinoma. Moreover, this study finds a novel vandetanib-resistant RETG810A mutation and identifies lenvatinib and ponatinib as the secondary drugs to overcome this vandetanib resistance mechanism. Mol Cancer Ther; 15(10); 2521–9. ©2016 AACR.

The MDM2 homolog MDMX oncoprotein is indispensable for inhibition of p53 during normal embryonic development and malignant transformation, yet how MDMX harnesses p53 functions is unclear. In addition to a canonical N-terminal p53-binding domain, recent work suggests the central acidic domain of MDMX regulates p53 interaction through intramolecular mimicry and engages in second-site interaction with the p53 core domain in vitro. To test the physiological relevance of these interactions, we generated an MDMX knockin mouse having substitutions in a conserved WW motif necessary for these functions (W201S/W202G). Notably, MDMXSG cells have normal p53 level but increased p53 DNA binding and target gene expression, and rapidly senesce. In vivo, MDMXSG inhibits early-phase disease in Eµ-Myc transgenic mice but accelerates the onset of lethal lymphoma and shortens overall survival. Therefore, MDMX is an important regulator of p53 DNA binding, which complements the role of MDM2 in regulating p53 level. Furthermore, the results suggest that the WW motif has dual functions that regulate p53 and inhibit Myc-driven lymphomas independent of p53.

Epidermal growth factor receptor (EGFR) mutants drive lung tumorigenesis and are targeted for therapy. However, resistance to EGFR inhibitors has been observed, in which the mutant EGFR remains active. Thus, it is important to uncover mediators of EGFR mutant-driven lung tumors to develop new treatment strategies. The protein tyrosine phosphatase (PTP) Shp2 mediates EGF signaling. Nevertheless, it is unclear if Shp2 is activated by oncogenic EGFR mutants in lung carcinoma or if inhibiting the Shp2 PTP activity can suppress EGFR mutant-induced lung adenocarcinoma. Here, we generated transgenic mice containing a doxycycline (Dox)-inducible PTP-defective Shp2 mutant (tetO-Shp2CSDA). Using the rat Clara cell secretory protein (CCSP)-rtTA-directed transgene expression in the type II lung pneumocytes of transgenic mice, we found that the Gab1-Shp2 pathway was activated by EGFRL858R in the lungs of transgenic mice. Consistently, the Gab1-Shp2 pathway was activated in human lung adenocarcinoma cells containing mutant EGFR. Importantly, Shp2CSDA inhibited EGFRL858R-induced lung adenocarcinoma in transgenic animals. Analysis of lung tissues showed that Shp2CSDA suppressed Gab1 tyrosine phosphorylation and Gab1-Shp2 association, suggesting that Shp2 modulates a positive feedback loop to regulate its own activity. These results show that inhibition of the Shp2 PTP activity impairs mutant EGFR signaling and suppresses EGFRL858R-driven lung adenocarcinoma.

Lesions of the cerebellum lead to motor and non-motor deficits by influencing cerebral cortex activity via cerebello-cortical circuits. It remains unknown whether the cerebello-cortical "disconnection" underlies motor and non-motor impairments both in the parkinsonian variant of multiple system atrophy (MSA-P) and Parkinson's disease (PD). In this study, we investigated both the functional and effective connectivity of the cerebello-cortical circuits from resting-state functional magnetic resonance imaging (rs-fMRI) data of three groups (26 MSA-P patients, 31 PD patients and 30 controls). Correlation analysis was performed between the causal connectivity and clinical scores. PD patients showed a weakened cerebellar dentate nucleus (DN) functional coupling in the posterior cingulate cortex and inferior parietal lobe compared with MSA-P or controls. MSA-P patients exhibited significantly enhanced effective connectivity from the DN to posterior cingulate cortex compared with PD patients or controls, as well as declined causal connectivity from the left precentral gyrus to right DN compared with the controls, and this value is significantly correlated with the motor symptom scores. Our findings demonstrated a crucial role for the cerebello-cortical networks in both MSA-P and PD patients in addition to striatal-thalamo-cortical (STC) networks and indicated that different patterns of cerebello-cortical loop degeneration are involved in the development of the diseases.

Rationale: Consumption of oral contraceptive pills (OCP) is a known risk factor for cerebral venous sinus thrombosis (CVST) among women. Development of dural arteriovenous fistula (dAVF) afterwards was very uncommon. We present a rare chronic complication of development of dAVF after CVST. Patient concerns: A 22-year-old woman suffered headache for a week. She was then admitted into our hospital. Diagnosis: Contrast enhanced magnetic resonance venography (MRV) demonstrated the thrombosis of the left transverse-sigmoid sinus the second day. Interventions: The intravenous thrombolysis was carried out. As the symptoms improved, the patient was discharged, while the treatment with oral dabigatran continued. However, 3 months after the onset, magnetic resonance imaging (MRI) showed swelling brainstem, and digital subtraction angiography (DSA) confirmed a dAVF. Clipping of the fistula was conducted, and her clinical symptoms improved gradually. Outcomes: The patient was transferred to rehabilitation center later, and received follow-up care. Lessons: When a patient taking OCP and suffering from a sudden headache, a clinical suspicion of possible CVST should always arise to avoid the onset of dAVF as soon as possible.

The RET protein tyrosine kinase (PTK) is a clinically validated target of therapy in non-small cell lung cancer (NSCLC) and thyroid cancer. Mutations in the targeted PTKs is a mechanism of drug resistance in cancer therapy with tyrosine kinase inhibitors (TKIs). Mutation-sensitive secondary drugs have been used successfully to overcome acquired drug-resistance to the first line TKIs. Cabozantinib, lenvatinib, vandetanib, and nintedanib are FDA-approved multikinase TKIs with anti-RET activity. Using RET kinase-dependent BaF3/KIF5B-RET cells, we isolated thirteen mutations resistant to one of these TKIs. Cross-analysis of sensitivities of these four TKIs on these drug-resistant RET mutants and the RETM918T mutant, which is found in medullary thyroid carcinoma, revealed different TKI resistance-sensitivity profiles. In particular, the RETM918T mutant was resistant to cabozantinib, lenvatinib, and vandetanib but did not affect the potency of nintedanib. RETL881V was isolated as a vandetanib-resistant mutation. The RETL881V mutation also induced resistance to cabozantinib and lenvatinib but did not affect the nintedanib sensitivity. Examination of the RET-vandetanib co-crystal structure and the chemical structures of vandetanib and nintedanib suggested that a phenyl group in nintedanib, which corresponds to a methoxy group in vandetanib, may form hydrophobic interaction with the shorter side chain of Val881 and thus allows nintedanib to inhibit RETL881V. To test this possibility, we synthesized two nintedanib analogs (Compound 1 and Compound 2) without the phenyl group and tested their activities. The data showed that RETL881V was resistant to Compound 1 and Compound 2, supporting a role of the phenyl group of nintedanib in mediating inhibition of RETL881V. Taken together, we have identified 13 RET mutations that display different resistance-sensitivity profiles against four anti-RET TKIs. Moreover, nintedanib is effective in inhibiting RETM918T and RETL881V mutants that are resistant to the other three TKIs. Citation Format: Xuan Liu, Tao Shen, Qingling Huang, Teng Peng, Frank Hilberg, Jianfeng Cai, Blaine H. Mooers, Jie Wu. Different sensitivities of four protein tyrosine kinase inhibitors towards drug-resistant RET mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2117.

The development of a simple, template-free, and one-step strategy to synthesize nanostructured Au architectures with fascinating morphology is highly desirable and technically important due to their valuable applications in varied fields. In this work, the “green” strategy of “tunable ionic liquids-water (ILs-H2O) interfacial synthesis” developed previously by us is utilized for feasible synthesis of gold needle mushroom-like micro/nanostructures at the 1,3-dibutylimidazolium bis(trifluoromethylsulfonyl)imide ([C4bim][Tf2N]) - water interface and ambient conditions. The as-obtained gold needle mushrooms (AuNMs) have been characterized and analyzed systemically by scanning electron microscopy, X-ray powder diffraction, energy-dispersive X-ray spectroscopy, and transmission electron microscopy. It is shown that the as-prepared AuNMs can be used as substrates to perform surface enhanced Raman scattering (SERS) investigation with striking SERS sensitivity. By employing ILs with different alkyl chain lengths of the imidazolium cations and/or different nature of anions, Au nanomaterials with diverse morphologies can be easily prepared at different ILs-H2O interfaces. Based on the analysis of the control experiments, the growth and formation of AuNMs at the [C4bim][Tf2N]-H2O interface have been discussed.

Clinical trials and experimental studies have highlighted the importance of epigenetic processes in the development of diabetic complications. One of the earliest features of diabetic nephropathy is renal enlargement. The epidermal growth factor (EGF) has a pivotal role in the development of diabetic nephromegaly and transactivation of its receptor has been implicated in the pathogenesis of later-stage disease. As EGF signaling is altered by the acetylation status of histone proteins, we measured the effects of the histone deacetylase (HDAC) inhibitor, vorinostat, in mediating renal enlargement in diabetes focusing on the EGF-EGF receptor (EGFR) axis. In cultured proximal tubule (normal rat kidney) cells, vorinostat treatment reduced EGFR protein and mRNA, and attenuated cellular proliferation. Within 72 h of diabetes induction with streptozotocin, urinary EGF excretion was increased approximately threefold and was unaffected by vorinostat, even though the kidneys of vorinostat-treated diabetic rats had reduced tubular epithelial cell proliferation. Daily treatment of diabetic rats with vorinostat for 4 weeks blunted renal growth and glomerular hypertrophy. Thus, early renal changes in diabetes are amenable to epigenetic intervention. Attenuating effects of HDAC inhibition, although multifactorial, are likely to be mediated in part through downregulation of the EGFR.