30 results on '"Lu AJ"'
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2. Reciprocal interactions between malignant cells and macrophages enhance cancer stemness and M2 polarization in HBV-associated hepatocellular carcinoma.
- Author
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Zhang Q, Tsui YM, Zhang VX, Lu AJ, Lee JM, Lee E, Cheung GC, Li PM, Cheung ET, Chia NH, Lo IL, Chan AC, Cheung TT, Ng IO, and Ho DW
- Subjects
- Humans, Animals, Mice, Hepatitis B virus, Macrophages metabolism, Coculture Techniques, Cell Line, Tumor, Tumor Microenvironment, Carcinoma, Hepatocellular pathology, Liver Neoplasms pathology
- Abstract
Background: The tumor microenvironment of cancers has emerged as a crucial component in regulating cancer stemness and plays a pivotal role in cell-cell communication. However, the specific mechanisms underlying these phenomena remain poorly understood. Methods: We performed the single-cell RNA sequencing (scRNA-seq) on nine HBV-associated hepatocellular carcinoma (HCC) patients. The heterogeneity of the malignant cells in pathway functions, transcription factors (TFs) regulation, overall survival, stemness, as well as ligand-receptor-based intercellular communication with macrophages were characterized. The aggressive and stemness feature for the target tumor subclone was validated by the conduction of in vitro assays including sphere formation, proliferation, Annexin V apoptosis, flow cytometry, siRNA library screening assays, and multiple in vivo preclinical mouse models including mouse hepatoma cell and human HCC cell xenograft models with subcutaneous or orthotopic injection. Results: Our analysis yielded a comprehensive atlas of 31,664 cells, revealing a diverse array of malignant cell subpopulations. Notably, we identified a stemness-related subclone of HCC cells with concurrent upregulation of CD24, CD47, and ICAM1 expression that correlated with poorer overall survival. Functional characterization both in vitro and in vivo validated S100A11 as one of the top downstream mediators for tumor initiation and stemness maintenance of this subclone. Further investigation of cell-cell communication within the tumor microenvironment revealed a propensity for bi-directional crosstalk between this stemness-related subclone and tumor-associated macrophages (TAMs). Co-culture study showed that this interaction resulted in the maintenance of the expression of cancer stem cell markers and driving M2-like TAM polarization towards a pro-tumorigenic niche. We also consolidated an inverse relationship between the proportions of TAMs and tumor-infiltrating T cells. Conclusions: Our study highlighted the critical role of stemness-related cancer cell populations in driving an immunosuppressive tumor microenvironment and identified the S100A11 gene as a key mediator for stemness maintenance in HCC. Moreover, our study provides support that the maintenance of cancer stemness is more attributed to M2 polarization than the recruitment of the TAMs., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)
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- 2024
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3. A cAMP Sensor Based on Ligand-Dependent Protein Stabilization.
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Sidoli M, Chen LC, Lu AJ, Wandless TJ, and Talbot WS
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- Animals, Cyclic AMP-Dependent Protein Kinases metabolism, Fluorescence Resonance Energy Transfer, Ligands, Zebrafish metabolism, Biosensing Techniques, Cyclic AMP metabolism
- Abstract
cAMP is a ubiquitous second messenger with many functions in diverse organisms. Current cAMP sensors, including Föster resonance energy transfer (FRET)-based and single-wavelength-based sensors, allow for real time visualization of this small molecule in cultured cells and in some cases in vivo. Nonetheless the observation of cAMP in living animals is still difficult, typically requiring specialized microscopes and ex vivo tissue processing. Here we used ligand-dependent protein stabilization to create a new cAMP sensor. This sensor allows specific and sensitive detection of cAMP in living zebrafish embryos, which may enable new understanding of the functions of cAMP in living vertebrates.
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- 2022
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4. Acute mitral valve regurgitation secondary to papillary muscle rupture due to infective endocarditis.
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Amirkhosravi F, Al Abri Q, Lu AJ, El Nihum LI, Eng RK, von Ballmoos MCW, and Ramchandani MK
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- Acute Disease, Humans, Male, Middle Aged, Papillary Muscles surgery, Endocarditis complications, Endocarditis, Bacterial complications, Endocarditis, Bacterial pathology, Endocarditis, Bacterial surgery, Heart Failure complications, Heart Rupture complications, Heart Rupture surgery, Mitral Valve Insufficiency diagnosis, Mitral Valve Insufficiency etiology, Mitral Valve Insufficiency surgery
- Abstract
Background: Papillary muscle rupture due to infective endocarditis is a rare event and proper management of this condition has not been described in the literature. Our case aims to shed light on treatment strategies for these patients using the current guidelines., Case Presentation: This case presents a 58-year-old male with acute heart failure secondary to papillary muscle rupture. He underwent an en bloc resection of his mitral valve with a bioprosthetic valve replacement. Specimen pathology later showed necrotic papillary muscle due to infective endocarditis. The patient was further treated with antibiotic therapy. He recovered well post-operatively and continued to do well after discharge., Conclusion: In patients who present with papillary muscle rupture secondary to infective endocarditis, clinical symptoms should drive the treatment strategy. Despite the etiology, early mitral valve surgery remains treatment of choice for patients who have papillary muscle rupture leading to acute heart failure. Culture-guided prolonged antibiotic treatment is vital in this category of patients, especially those who have a prosthetic valve implanted., (© 2022. The Author(s).)
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- 2022
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5. Opposite trends of glycosides and alkaloids in Dendrobium nobile of different age based on UPLC-Q/TOF-MS combined with multivariate statistical analyses.
- Author
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Lu AJ, Jiang Y, Wu J, Tan DP, Qin L, Lu YL, Qian Y, Bai CJ, Yang JY, Ling H, Shi JS, Yang Z, and He YQ
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- Chromatography, High Pressure Liquid methods, Gas Chromatography-Mass Spectrometry, Glycosides, Tandem Mass Spectrometry methods, Alkaloids analysis, Dendrobium chemistry, Drugs, Chinese Herbal chemistry
- Abstract
Introduction: Alkaloids and glycosides are the active ingredients of the herb Dendrobium nobile, which is used in traditional Chinese medicine. The pharmacological effects of alkaloids include neuroprotective effects and regulatory effects on glucose and lipid metabolism, while glycosides improve the immune system. The pharmacological activities of the above chemical components are significantly different. In practice, the stems of 3-year-old D. nobile are usually used as the main source of Dendrobii Caulis. However, it has not been reported whether this harvesting time is appropriate., Objective: The aim of this study was to compare the chemical characteristics of D. nobile in different growth years (1-3 years)., Methods: In this study, ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q/TOF-MS) was employed to analyze the constituents of D. nobile. The relative abundance of each constituent was analyzed with multivariate statistical analyses to screen the characteristic constituents that contributed to the characterization and classification of D. nobile. Dendrobine, a component of D. nobile that is used for quality control according to the Chinese Pharmacopoeia, was assayed by gas chromatography., Results: As a result, 34 characteristic constituents (VIP > 2) were identified or tentatively identified as alkaloids and glycosides based on MS/MS data. Moreover, the content of alkaloids decreased over time, whereas the content of glycosides showed the opposite trend. The absolute quantification of dendrobine was consistent with the metabolomics results., Conclusion: Our findings provide valuable information to optimize the harvest period and a reference for the clinical application of D. nobile., (© 2022 The Authors. Phytochemical Analysis published by John Wiley & Sons Ltd.)
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- 2022
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6. Surgical salvage of left internal mammary artery graft ostial stenosis.
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Lu AJ, Al Abri Q, Amirkhosravi F, and Ramchandani MK
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- 2022
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7. Diffuse Cerebral Edema and Impending Herniation Complicating Hepatic Encephalopathy in Hereditary Hemorrhagic Telangiectasia.
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Mylavarapu C, Lu AJ, Burns EA, Samorajski J, Gotur D, and Baker K
- Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disease characterized by the formation of cutaneous and visceral telangiectasias and arteriovenous malformations (AVM). Multiple organs may be affected, including the nasal mucosa, skin, lungs, gastrointestinal tract, and brain. The following case highlights a unique manifestation of HHT in a patient with a gastrointestinal hemorrhage and epistaxis, resulting in hyperammonemia and diffuse cerebral edema and herniation. Clinicians should be aware of this potential complication in such patients and initiate ammonia-reducing agents early to avoid this devastating consequence., Competing Interests: This case report was written under the employment of Houston Methodist Hospital. COI for Dr. Deepa Gotur: advisory committee for GlaxoSmithKline receives research funding from Chest Foundation, ROCHE, Gilead, IMAB Biopharma, NIAID. The remaining authors have no conflicts of interest to declare., (Copyright © 2022 Charisma Mylavarapu et al.)
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- 2022
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8. Identification of Pyrrolizidine Alkaloids in Senecio Plants by Liquid Chromatography-Mass Spectrometry.
- Author
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Lu AJ, Lu YL, Tan DP, Qin L, Ling H, Wang CH, and He YQ
- Abstract
Pyrrolizidine alkaloids (PAs) are considered as the major constituents that cause hepatoxicity in Senecio plants. PAs can be found in about 3%-5% of the world's flowering plants. Nowadays, the identification method of PAs by separation and preparation was too slow and lacked effective power. A rapid method to identify PAs in plants must be developed. Based on the fragmentation regularity, the hepatoxic PAs and nonhepatoxic PAs were characterized by liquid chromatography-mass spectrometry (LC-MS). The detailed structures of PAs in five Senecio plants were identified based on tandem mass spectrometry (MS/MS) spectrum and chemical research information. In the present study, some new fragmentation regularities of PAs have been found, such as product ions at m/z 122, m/z 140 and m/z 124, m/z 142, which have been discovered as the characteristic fragments of lactone and mono-esterase type of saturated PAs, respectively. Moreover, two product ions at m/z 120 and m/z 138 have been reported as the characteristic fragments of unsaturated PAs. Some of them were found in Senecio species for the first time, and some of them may be new nature product or even new compound. Finally, we classified these plants into five categories based on PAs which were identified in the present study; the result corresponded with the classification by morphology. In addition, we have found some constituents that have odd molecular weight number only in Senecio species but not in Ligularia species; the detailed structures of these non-PAs constituents need penetrating study. LC-MS was rapid and sensitive method for detecting and identifying PAs in plants. Pyrrolizidine alkaloids were the toxiferous constituent of Senecio plants. In this study, we found that PAs can be used as the characteristic constituent of Senecio species., Competing Interests: The authors declare that they have no conflicts of interest regarding the publication of this paper., (Copyright © 2021 An-Jing Lu et al.)
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- 2021
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9. Chronic Thromboembolic Pulmonary Hypertension: A Comprehensive Review and Multidisciplinary Approach to Surgical Treatment.
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Al Abri Q, Lu AJ, and Ramchandani MK
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- Chronic Disease, Endarterectomy adverse effects, Humans, Pulmonary Artery diagnostic imaging, Pulmonary Artery surgery, Hypertension, Pulmonary diagnosis, Hypertension, Pulmonary etiology, Hypertension, Pulmonary surgery, Pulmonary Embolism diagnostic imaging, Pulmonary Embolism surgery
- Abstract
Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed and undertreated sequelae of acute pulmonary embolism. In this comprehensive review, we provide an introductory overview of CTEPH, highlight recent advances in its diagnostic imaging, and describe the surgical technique for pulmonary thromboendarterectomy (PTE), the only established curative treatment for CTEPH. We also discuss the emerging role of balloon pulmonary angioplasty, both independently and combined with PTE, for patients with inoperable, residual, or refractory pulmonary hypertension post PTE. Finally, we stress the importance of a specialized multidisciplinary team approach to CTEPH patient care and share our approach to optimizing care for these patients., (Copyright: © 2021 The Author(s).)
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- 2021
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10. [A clinical and pathological report of delayed encephalopathy after heat stroke].
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Lu AJ, Cheng M, Dong CX, Guo HW, Cao BZ, and Hu HQ
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- Adult, Brain, Humans, Magnetic Resonance Imaging, Male, Retrospective Studies, Brain Diseases, Heat Stroke
- Abstract
Objective: To explore the clinical manifestations, dynamic neuroimaging changes and brain histopathologic characteristics of a patient with delayed encephalopathy after heat stroke. Methods: In October 2019, the clinical manifestations, electroencephalogram, cerebrospinal fluid, imaging changes and brain histopathological characteristics of a patient with brain damage caused by heat stroke were retrospectively analyzed. Results: The patient was a 40-year-old male who suddenly appeared dizziness, unconscious, high fever when working in the high temperature environment. The EEG showed diffuse slow wave activity. Early CT was normal, and abnormal signals gradually appeared in the basal ganglia region of the thalamus after a few days. In the late, the MRI found a large area of abnormal signals under the cerebral cortex, and white matter was involved. Pathological examination of brain biopsy showed that cortical neuron loss, loose white matter changes, and significant demyelination changes, while no inflammatory cell infiltration was observed in subarachnoid space, meninges, and dermal white matter. Conclusion: Imaging examination dynamic changes of the delayed encephalopathy is important in the heat stroke, and the main pathological manifestation is demyelination.
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- 2021
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11. Price transparency implementation: Accessibility of hospital chargemasters and variation in hospital pricing after CMS mandate.
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Lu AJ, Chen EM, Vutam E, Brandt J, and Sadda P
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- Centers for Medicare and Medicaid Services, U.S. legislation & jurisprudence, Centers for Medicare and Medicaid Services, U.S. organization & administration, Centers for Medicare and Medicaid Services, U.S. statistics & numerical data, Fuzzy Logic, Health Care Costs trends, Hospitals standards, Hospitals statistics & numerical data, Humans, Reimbursement, Disproportionate Share statistics & numerical data, United States, Costs and Cost Analysis standards, Health Care Costs legislation & jurisprudence
- Abstract
Background: National regulations have increasingly focused on transparency in hospital billing and pricing practices. A January 2019 federal mandate required hospitals to publicize lists of billable procedures and items known as chargemasters., Methods: We identified the 500 top self-pay/uninsured revenue grossing hospitals nationally and searched each hospital's website for a chargemaster. Corresponding items were matched across chargemasters. Intrahospital and interhospital price variation were calculated. To investigate variation in item naming, a name variant and fuzzy matching search was conducted for fifteen common chargemaster items., Results: Of 500 hospitals in this study, 69 (13.8%) had chargemasters that were inaccessible and 30 (6.0%) had chargemasters that did not meet mandated requirements. Among the remaining 431 hospitals, the mean interhospital and intrahospital variation in pricing for identical items was 18% (SD 28%) and 28% (SD 29%), respectively. 388 hospitals listed multiple prices for the same item, with a mean of 687.3 duplicated items (SD 1157.7). Among fifteen common chargemaster items, each item was associated with an average of 275 (SD 213) unique name variants. Interhospital price variation of these items ranged from 53% (transthoracic echocardiogram) to 243% (furosemide 40 mg)., Conclusions: Many chargemasters have barriers to access, and item naming is inconsistent across chargemasters. There is significant interhospital price variation for similar items., Implications: Chargemasters are uninterpretable for the purpose of patient price comparison in their current form. Further regulatory efforts are necessary to increase price transparency and enhance the ability of patients to compare hospital prices., (Copyright © 2020 Elsevier Inc. All rights reserved.)
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- 2020
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12. Detecting substance-related problems in narrative investigation summaries of child abuse and neglect using text mining and machine learning.
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Perron BE, Victor BG, Bushman G, Moore A, Ryan JP, Lu AJ, and Piellusch EK
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- Algorithms, Child, Child Protective Services, Child Welfare, Computer Simulation, Feasibility Studies, Humans, Mental Disorders, Child Abuse diagnosis, Data Mining, Machine Learning, Narration
- Abstract
Background: State child welfare agencies collect, store, and manage vast amounts of data. However, they often do not have the right data, or the data is problematic or difficult to inform strategies to improve services and system processes. Considerable resources are required to read and code these text data. Data science and text mining offer potentially efficient and cost-effective strategies for maximizing the value of these data., Objective: The current study tests the feasibility of using text mining for extracting information from unstructured text to better understand substance-related problems among families investigated for abuse or neglect., Method: A state child welfare agency provided written summaries from investigations of child abuse and neglect. Expert human reviewers coded 2956 investigation summaries based on whether the caseworker observed a substance-related problem. These coded documents were used to develop, train, and validate computer models that could perform the coding on an automated basis., Results: A set of computer models achieved greater than 90% accuracy when judged against expert human reviewers. Fleiss kappa estimates among computer models and expert human reviewers exceeded .80, indicating that expert human reviewer ratings are exchangeable with the computer models., Conclusion: These results provide compelling evidence that text mining procedures can be a cost-effective and efficient solution for extracting meaningful insights from unstructured text data. Additional research is necessary to understand how to extract the actionable insights from these under-utilized stores of data in child welfare., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
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- 2019
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13. Panretinal Photocoagulation along the Long Ciliary Nerve in Diabetic Retinopathy.
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Lu AJ, Freedman IG, Shakir O, Adelman RA, and Del Priore LV
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- Choroid pathology, Diabetic Retinopathy surgery, Female, Fundus Oculi, Humans, Male, Middle Aged, Ophthalmic Nerve, Retina surgery, Ciliary Body innervation, Fluorescein Angiography methods, Laser Coagulation methods, Ophthalmoscopy methods, Retina pathology, Visual Acuity
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- 2019
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14. Role of Core Number and Location in Targeted Magnetic Resonance Imaging-Ultrasound Fusion Prostate Biopsy.
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Lu AJ, Syed JS, Ghabili K, Hsiang WR, Nguyen KA, Leapman MS, and Sprenkle PC
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- Humans, Male, Multimodal Imaging, Multiparametric Magnetic Resonance Imaging, Neoplasm Grading, Prostate diagnostic imaging, Retrospective Studies, Ultrasonography, Image-Guided Biopsy methods, Prostate pathology, Prostatic Neoplasms diagnosis, Prostatic Neoplasms pathology
- Abstract
The optimal method of magnetic resonance imaging (MRI)-ultrasound (US) fusion biopsy to adequately sample regions of interest (ROIs) remains unknown. We sought to determine the number and location of cores needed to adequately detect clinically significant prostate cancer (PCa). We identified patients undergoing MRI-US fusion prostate biopsy at our institution for known history or clinical suspicion of PCa. Multiparametric MRI studies were reviewed using Likert and Prostate Imaging Reporting and Data System (PI-RADS) v2 schema. Multiple targeted cores were taken from each ROI followed by 12-core systematic biopsy. In a distinct cohort of patients, lesions were targeted using a predetermined five-core template. We estimated cancers detected through sampling of five or fewer cores, assessed by core number and core location. We identified 744 patients with 581 lesions with PCa. Seventy-seven percent (279/361) of Gleason (G) ≥3+4 tumors and 72% (137/189) of G >3+4 tumors were detected on two-core sampling. Relative to all targeted cores, a two-core approach missed 16% of clinically significant cancers at first biopsy, 27% in prior negative, and 32% in active surveillance patients. Detection of G ≥3+4 cancers did not differ by core location. Sampling of two cores of ROIs misses nearly one-quarter of clinically significant PCa detected on additional sampling. PATIENT SUMMARY: We aimed to understand how the number of cores obtained from a suspicious area during prostate magnetic resonance imaging-ultrasound fusion biopsy affects cancer detection. We found that sampling of five cores missed substantially fewer cancers compared to two cores., (Published by Elsevier B.V.)
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- 2019
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15. Chondrosarcoma Metastasis to the Choroid.
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Kim JM, Wong AJ, Lu AJ, and Pointdujour-Lim R
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We report a rare case of chondrosarcoma metastatic to the choroid. A 64-year-old male with a history of chondrosarcoma metastatic to the lungs and to the spine presented with blurred vision. A choroidal tumor was found. Fine-needle biopsy confirmed the histologic identity of the tumor as chondrosarcoma. Metastatic spread of chondrosarcoma to the eye is extremely rare. When present, lesions may grow rapidly, and systemic prognosis is poor. Co-management with medical oncology is of utmost importance. This is the third case of chondrosarcoma metastatic to the choroid in the literature and the first with bilateral involvement., Competing Interests: The authors have no conflicts of interest to declare.
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- 2019
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16. Analysis of Patient-Reported Barriers to Diabetic Retinopathy Follow-Up.
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Lu AJ, Chen AJ, Hwang V, Law PY, Stewart JM, and Chao DL
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- Adult, Aged, Comorbidity, Employment, Female, Follow-Up Studies, Health Knowledge, Attitudes, Practice, Hospitals, Urban statistics & numerical data, Humans, Logistic Models, Macular Edema therapy, Male, Middle Aged, Prospective Studies, Waiting Lists, Diabetic Retinopathy therapy, Health Services Accessibility standards
- Abstract
Background and Objectives: Close follow-up of diabetic retinopathy (DR) has been linked to improved visual outcomes. This study elucidates patient-identified barriers to DR follow-up in a diverse urban clinic population., Patients and Methods: Patients 18 years of age or older with DR or macular edema were interviewed using a 21-question survey on attitudes and barriers toward care. Univariate and multivariate logistic analysis identified barriers associated with non-compliance to follow-up., Results: Two hundred nine patients participated with mean age of 58.2 years and hemoglobin A1c of 8.5%. The most common barriers cited were long waiting times (46.4%), other medical conditions (35.9%), forgetting (28.2%), and inability to leave work (9.1%). In a multivariate analysis, forgetting (odds ratio [OR]: 4.35) and other medical conditions (OR: 1.91) were barriers independently associated with non-compliance. Having proliferative DR was associated with other medical conditions in univariate (OR: 4.60) and multivariate analysis (OR: 4.35)., Conclusion: Patients with DR who report other medical conditions or forgetting have a higher risk of non-compliance to follow-up. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:99-105.]., (Copyright 2019, SLACK Incorporated.)
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- 2019
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17. Determinants of Active Surveillance in Patients With Small Renal Masses.
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Nguyen KA, Nolte AC, Alimi O, Hsiang W, Lu AJ, Ghabili K, Syed JS, Suarez-Sarmiento A, Perecman AJ, Shuch B, and Leapman MS
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- Aged, Aged, 80 and over, Female, Humans, Kidney Neoplasms pathology, Male, Middle Aged, Neoplasm Staging, Tumor Burden, Kidney Neoplasms therapy, Watchful Waiting statistics & numerical data
- Abstract
Objective: To evaluate trends in the utilization of active surveillance (AS) in a nationally representative cancer database. AS has been increasingly recognized as an effective strategy for patients with small renal masses but little is known about national usage patterns., Methods: We identified patients with clinical T1a renal masses within the National Cancer Database in 2010 through 2014. Patients were classified according to initial management strategy received including AS, surgery, ablation, or other treatment. We characterized time trends in the use of AS vs definitive therapy and examined clinical and socio-demographic determinants of AS among patients with small renal masses using multivariable logistic regression models., Results: We identified 59,189 patients who satisfied the inclusion criteria. Of the total cohort, 1733 (2.9%) individuals received initial management with AS, while 57,456 (97.1%) received definitive treatment. Surveillance rates remained below 5% in all years. On multivariate analysis, patient age (OR: 1.08, 95% CI 1.08-1.09), smaller tumor size of <2 cm vs ≥2 cm (OR: 2.43, 95% CI: 2.20-2.7, P < .0001), management at an academic center vs community center (OR: 2.05, 95% CI: 1.83-2.29), and African American vs Caucasian race (OR: 1.56, 95% CI:1.35-1.80) were independently associated with use of AS as initial management., Conclusion: In a representative national cohort of patients with small renal masses, we observed clinical and facility-level differences in the utilization of active surveillance in patients with T1a renal masses. Further investigation is warranted to better understand the forces underlying initial management decisions for patients with small renal masses., (Copyright © 2019. Published by Elsevier Inc.)
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- 2019
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18. Proptosis and Double Vision in a Child.
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Lu AJ, Kim JM, and Fisayo A
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- Brain pathology, Child, Humans, Male, Brain diagnostic imaging, Cavernous Sinus diagnostic imaging, Cavernous Sinus pathology, Diplopia etiology, Exophthalmos etiology
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- 2018
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19. Discovery of a Potent (4 R,5 S)-4-Fluoro-5-methylproline Sulfonamide Transient Receptor Potential Ankyrin 1 Antagonist and Its Methylene Phosphate Prodrug Guided by Molecular Modeling.
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Chen H, Volgraf M, Do S, Kolesnikov A, Shore DG, Verma VA, Villemure E, Wang L, Chen Y, Hu B, Lu AJ, Wu G, Xu X, Yuen PW, Zhang Y, Erickson SD, Dahl M, Brotherton-Pleiss C, Tay S, Ly JQ, Murray LJ, Chen J, Amm D, Lange W, Hackos DH, Reese RM, Shields SD, Lyssikatos JP, Safina BS, and Estrada AA
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- Animals, Dogs, Drug Discovery, Drug Stability, Humans, Ligands, Madin Darby Canine Kidney Cells, Microsomes, Liver metabolism, Models, Molecular, Molecular Conformation, Prodrugs chemical synthesis, Prodrugs chemistry, Prodrugs pharmacokinetics, Proline chemical synthesis, Proline pharmacokinetics, Rats, Solubility, Structure-Activity Relationship, Sulfonamides chemical synthesis, Sulfonamides chemistry, Sulfonamides pharmacokinetics, TRPA1 Cation Channel chemistry, Prodrugs pharmacology, Proline analogs & derivatives, Proline pharmacology, Sulfonamides pharmacology, TRPA1 Cation Channel antagonists & inhibitors
- Abstract
Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel expressed in sensory neurons where it functions as an irritant sensor for a plethora of electrophilic compounds and is implicated in pain, itch, and respiratory disease. To study its function in various disease contexts, we sought to identify novel, potent, and selective small-molecule TRPA1 antagonists. Herein we describe the evolution of an N-isopropylglycine sulfonamide lead (1) to a novel and potent (4 R,5 S)-4-fluoro-5-methylproline sulfonamide series of inhibitors. Molecular modeling was utilized to derive low-energy three-dimensional conformations to guide ligand design. This effort led to compound 20, which possessed a balanced combination of potency and metabolic stability but poor solubility that ultimately limited in vivo exposure. To improve solubility and in vivo exposure, we developed methylene phosphate prodrug 22, which demonstrated superior oral exposure and robust in vivo target engagement in a rat model of AITC-induced pain.
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- 2018
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20. Negative Multiparametric Magnetic Resonance Imaging of the Prostate Predicts Absence of Clinically Significant Prostate Cancer on 12-Core Template Prostate Biopsy.
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Lu AJ, Syed JS, Nguyen KA, Nawaf CB, Rosoff J, Spektor M, Levi A, Humphrey PA, Weinreb JC, Schulam PG, and Sprenkle PC
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- Aged, Cohort Studies, Contrast Media, Diffusion Magnetic Resonance Imaging, Humans, Male, Middle Aged, Neoplasm Grading, Predictive Value of Tests, Prostate-Specific Antigen, Ultrasonography, Interventional, Carcinoma diagnostic imaging, Carcinoma pathology, Image-Guided Biopsy, Magnetic Resonance Imaging, Interventional, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms pathology
- Abstract
Objective: To determine the negative predictive value of multiparametric magnetic resonance imaging (mpMRI), we evaluated the frequency of prostate cancer detection by 12-core template mapping biopsy in men whose mpMRI showed no suspicious regions., Methods: Six hundred seventy patients underwent mpMRI followed by transrectal ultrasound (TRUS)-guided systematic prostate biopsy from December 2012 to June 2016. Of this cohort, 100 patients had a negative mpMRI. mpMRI imaging sequences included T2-weighted and diffusion-weighted imaging, and dynamic contrast enhancement sequences., Results: The mean age, prostate-specific antigen, and prostate volume of the 100 men included were 64.3 years, 7.2 ng/mL, and 71 mL, respectively. Overall cancer detection was 27% (27 of 100). Prostate cancer was detected in 26.3% (10 of 38) of patients who were biopsy-naïve, 12.1% (4 of 33) of patients who had a prior negative biopsy, and in 44.8% (13 of 29) of patients previously on active surveillance; Gleason grade ≥7 was detected in 3% of patients overall (3 of 100). The negative predictive value of a negative mpMRI was 73% for all prostate cancer and 97% for Gleason ≥7 prostate cancer., Conclusion: There is an approximately 3% chance of detecting clinically significant prostate cancer with systematic TRUS-guided biopsy in patients with no suspicious findings on mpMRI. This information should help guide recommendations to patients about undergoing systematic TRUS-guided biopsy when mpMRI is negative., (Published by Elsevier Inc.)
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- 2017
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21. Identification of rare variants in Alzheimer's disease.
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Lord J, Lu AJ, and Cruchaga C
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Much progress has been made in recent years in identifying genes involved in the risk of developing Alzheimer's disease (AD), the most common form of dementia. Yet despite the identification of over 20 disease associated loci, mainly through genome wide association studies (GWAS), a large proportion of the genetic component of the disorder remains unexplained. Recent evidence from the AD field, as with other complex diseases, suggests a large proportion of this "missing heritability" may be due to rare variants of moderate to large effect size, but the methodologies to detect such variants are still in their infancy. The latest studies in the field have been focused on the identification of coding variation associated with AD risk, through whole-exome or whole-genome sequencing. Such variants are expected to have larger effect sizes than GWAS loci, and are easier to functionally characterize, and develop cellular and animal models for. This review explores the issues involved in detecting rare variant associations in the context of AD, highlighting some successful approaches utilized to date.
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- 2014
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22. Multi-substituted N-phenyl-2, 2-dichloroacetamide analogues as anti-cancer drugs: design, synthesis and biological evaluation.
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Li TW, Yang YC, Cheng CM, Wang DC, Lu AJ, and Zhao YF
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- Acetamides chemistry, Acetamides pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Apoptosis drug effects, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Humans, Inhibitory Concentration 50, Molecular Structure, Structure-Activity Relationship, Acetamides chemical synthesis, Antineoplastic Agents chemical synthesis, Drug Design
- Abstract
Our earlier research has shown that mono-substituted N-phenyl-2, 2-dichloroacetamide exhibited much higher anti-cancer activity than the lead compound sodium dichloroacetate (DCA). In this paper, a variety of multi-substituted N-phenyl-2, 2-dichloroacetamides were synthesized and biologically evaluated. The results showed that 3, 5-disubstituted N-phenyl-2, 2-dichloroacetamide analogues had satisfactory potency. Among them, N-(3, 5-diiodophenyl)-2, 2-dichloroacetamide had an IC50 of 2.84 micromol x L(-1) against non-small cell lung cancer cell line A549 and could induce cancer cell apoptosis.
- Published
- 2012
23. Protolimonoids from Melia toosendan.
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Sang YS, Zhou CY, Lu AJ, Yin XJ, Min ZD, and Tan RX
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- Antineoplastic Agents, Phytogenic chemistry, Antineoplastic Agents, Phytogenic pharmacology, Drug Screening Assays, Antitumor, Drugs, Chinese Herbal chemistry, Drugs, Chinese Herbal pharmacology, HL-60 Cells, HT29 Cells, Humans, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Triterpenes chemistry, Triterpenes pharmacology, Antineoplastic Agents, Phytogenic isolation & purification, Drugs, Chinese Herbal isolation & purification, Melia chemistry, Triterpenes isolation & purification
- Abstract
Toosendanone A (1), a new euphane (tirucallane)-type triterpene bearing a five-membered ring in the side chain and the first cyclopentanyl protolimonoid, was isolated from the bark of Melia toosendan, along with two new tirucallanes, toosendanic acids A (2) and B (3). The structure and absolute configuration of compound 1 was elucidated by spectroscopic data interpretation and X-ray diffraction analysis. Compounds 1-3 were evaluated for cytotoxicity against a small panel of cancer cell lines.
- Published
- 2009
- Full Text
- View/download PDF
24. 3D-QSAR studies of boron-containing dipeptides as proteasome inhibitors with CoMFA and CoMSIA methods.
- Author
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Zhu YQ, Lei M, Lu AJ, Zhao X, Yin XJ, and Gao QZ
- Subjects
- Computer Simulation, Drug Design, Ligands, Molecular Conformation, Boron chemistry, Dipeptides chemistry, Dipeptides pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Models, Molecular, Proteasome Inhibitors, Quantitative Structure-Activity Relationship
- Abstract
Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed for a series of dipeptide boronate proteasome inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. A training set containing 46 molecules served to establish the models. The optimum CoMFA and CoMSIA models obtained for the training set were all statistically significant with cross-validated coefficients (q(2)) of 0.676 and 0.630 and conventional coefficients (r(2)) of 0.989 and 0.956, respectively. The predictive capacities of both models were successfully validated by calculating a test set of 13 molecules that were not included in the training set. The predicted correlation coefficients (r(2)(pred)) of CoMFA and CoMSIA are 0.963 and 0.919, respectively. The CoMFA and CoMSIA field contour maps agree well with the structural characteristics of the binding pocket of beta5 subunit of 20S proteasome, which suggests that the 3D-QSAR models constructed in this paper can be used to guide the development of novel dipeptide boronate inhibitors of 20S proteasome.
- Published
- 2009
- Full Text
- View/download PDF
25. Unique electronic band structures of hydrogen-terminated [Formula: see text] silicon nanowires.
- Author
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Lu AJ, Zhang RQ, and Lee ST
- Abstract
Band structure mutation from an indirect to a direct gap is a well-known character of small hydrogen-terminated [Formula: see text] and [Formula: see text] silicon nanowires (SiNWs), and suggests the possible emission of silicon. In contrast, we show that hydrogen-terminated [Formula: see text] SiNWs consistently present indirect band gaps even at an extremely small size, according to our calculations using density functional theory. Interestingly, the band gap of [Formula: see text] SiNWs shows a quasi-direct feature as the wire size increases, suggesting the possibility of using medium SiNWs in optoelectronic devices. This result also indicates that the electronic structures of SiNWs are strongly orientation dependent.
- Published
- 2008
- Full Text
- View/download PDF
26. [Clinical observation on point implantation of slowly-releasing medication for treatment of functional ventricular premature].
- Author
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Lu AJ, Pang AJ, Xiu WF, Wang ZG, and Ma XS
- Subjects
- Acupuncture Points, Adult, Aged, Delayed-Action Preparations, Female, Humans, Male, Middle Aged, Ventricular Premature Complexes physiopathology, Acupuncture Therapy methods, Medicine, Chinese Traditional, Ventricular Premature Complexes therapy
- Abstract
Objective: To probe into a safe and effective method for treatment of functional ventricular premature, and develop a new preparation of Chinese herbs with high science and technique contents., Methods: Two hundred and thirty-eight cases were randomly divided into a slowly-releasing medication group (n = 118) and a western medicine group (n = 120). The slowly-control needle group were treated with intramuscular injection of slowly-releasing medication new type preparation made by proved recipe of Chinese herbs with replenishing and strengthening pectoral qi, and nourishing yin and tranquillization into Tanzhong (CV 17), Neiguan (PC 6), Xinshu (BL 15), Pishu (BL 20) and Feishu (BL 13) by a trocar to slowly release and control releasing of the medicine so as to maintain lasting stimulation; the western medicine group with oral administration of Rythmol, thrice daily, 150 mg each time., Results: The cured rate and the cured and markedly effective rate for the ventricular premature was 51.7% and 71.2% in the slowly-releasing medication group, which were significantly higher than 28.3% and 50.8% in the western medicine group (P < 0.001)., Conclusion: The slowly-releasing medication new type preparation has a better therapeutic effect on functional ventricular premature, with high safety.
- Published
- 2007
27. Molecular characterisation and inductive expression of a fish protein arginine methyltransferase 1 gene in response to virus infection.
- Author
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Dong CW, Zhang YB, Lu AJ, Zhu R, Zhang FT, Zhang QY, and Gui JF
- Subjects
- Amino Acid Sequence, Animals, Base Sequence, Cell Line, DNA Primers chemistry, Embryo, Nonmammalian cytology, Fish Diseases enzymology, Fish Diseases virology, Flounder genetics, Flounder virology, Molecular Sequence Data, Phylogeny, Protein-Arginine N-Methyltransferases biosynthesis, Protein-Arginine N-Methyltransferases chemistry, Protein-Arginine N-Methyltransferases immunology, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction veterinary, Rhabdoviridae immunology, Rhabdoviridae Infections enzymology, Rhabdoviridae Infections immunology, Sequence Alignment veterinary, Sequence Homology, Amino Acid, Up-Regulation, Fish Diseases immunology, Flounder immunology, Gene Expression Regulation, Enzymologic immunology, Protein-Arginine N-Methyltransferases genetics, Rhabdoviridae Infections veterinary
- Abstract
Protein arginine methyltransferase 1 (PRMT1) is currently thought as an effector to regulate interferon (IFN) signalling. Here Paralichthys olivaceus PRMT1 (PoPRMT1) gene was identified as a virally induced gene from UV-inactivated Scophthalmus maximus Rhabdovirus (SMRV)-infected flounder embryonic cells (FEC). PoPMRT1 encodes a 341-amino-acid protein that shares the conserved domains including post-I, motif I, II and III. Homology comparisons show that the putative PoPMRT1 protein is the closest to zebrafish PMRT1 and belongs to type I PRMT family (including PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, PRMT8). Expression analyses revealed an extensive distribution of PoPMRT1 in all tested tissues of flounder. In vitro induction of PoPRMT1 was determined in UV-inactivated SMRV-infected FEC cells, and under the same conditions, flounder Mx was also transcriptionally up-regulated, indicating that an IFN response might be triggered. Additionally, live SMRV infection of flounders induced an increased expression of PoPRMT1 mRNA and protein significantly in spleen, and to a lesser extent in head kidney and intestine. Immunofluorescence analysis revealed a major cyptoplasmic distribution of PoPRMT1 in normal FEC but an obvious increase occurred in nucleus in response to UV-inactivated SMRV. This is the first report on in vitro and in vivo expression of fish PRMT1 by virus infection, suggesting that PoPRMT1 might be implicated in flounder antiviral immune response.
- Published
- 2007
- Full Text
- View/download PDF
28. 3D-QSAR study of 20 (S)-camptothecin analogs.
- Author
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Lu AJ, Zhang ZS, Zheng MY, Zou HJ, Luo XM, and Jiang HL
- Subjects
- Least-Squares Analysis, Camptothecin analogs & derivatives, Camptothecin chemistry, Quantitative Structure-Activity Relationship
- Abstract
Aim: To build up a quantitative structure-activity relationship (QSAR) model of 20 (S)-camptothecin (CPT) analogs for the prediction of the activity of new CPT analogs for drug design., Methods: A training set of 43 structurally diverse CPT analogs which were inhibitors of topoisomerase I were used to construct a quantitative structure-activity relationship model with a comparative molecular field analysis (CoMFA). The QSAR model was optimized using partial least squares (PLS) analysis. A test set of 10 compounds was evaluated using the model., Results: The CoMFA model was constructed successfully, and a good cross-validated correlation was obtained in which q(2) was 0.495. Then, the analysis of the non-cross-validated PLS model in which r(2) was 0.935 was built and permitted demonstrations of high predictability for the activities of the 10 CPT analogs in the test set selected in random., Conclusion: The CoMFA model indicated that bulky negative-charged group at position 9, 10 and 11 of CPT would increase activity, but excessively increasing bulky group at position 10 is adverse to inhibitory activity; substituents that occupy position 7 with the bulky positive group will enhance the inhibitive activity. The model can be used to design new CPT analogs and understand the mechanism of action.
- Published
- 2007
- Full Text
- View/download PDF
29. [Exploring relationship between traditional effects of traditional Chinese medicine and modern pharmacological activities by "co-effect compounds"].
- Author
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Liu HB, Lu AJ, Liu B, and Zhou JJ
- Subjects
- Anthraquinones isolation & purification, Drugs, Chinese Herbal isolation & purification, Flavonoids isolation & purification, Flavonoids pharmacology, Plants, Medicinal chemistry, Anthraquinones pharmacology, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Cathartics pharmacology, Drugs, Chinese Herbal pharmacology, Medicine, Chinese Traditional
- Abstract
The compound that distributes in the herbs with one common effect was named as "co-effect compound" (CEC). The CECs of three traditional Chinese medicine(TCM) effects, purgative, relieving pain and clearing heat, had been found and studied. A strong corresponding relationship was found between the pharmacological activities of CECs and the TCM effect they belong to. The study shows that it may be a feasible method to connect traditional effect of TCM with modem pharmacological activity.
- Published
- 2005
30. Nature of single vacancy in achiral carbon nanotubes.
- Author
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Lu AJ and Pan BC
- Abstract
We have performed systematic calculations for single vacancies and their related point defects in achiral carbon nanotubes using a tight-binding model. Our calculations clarify that the local structures around single vacancies in such tubes do reconstruct with no constraint. We find that the structural configuration and formation energy of the resulting point defect are dependent on the radius and chirality, as well as the electric properties of a tube. The electronic structures of the single vacancies also depend strongly upon the chirality of the carbon nanotubes.
- Published
- 2004
- Full Text
- View/download PDF
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