1.Clinical and pathological features and MYB detection in adenoid cystic carcinoma of the breast
Ping CHENG ; Honghai XU ; Wengeng WANG ; Zeyu CAI ; Lijuan HU ; Jun DU
Chinese Journal of Clinical and Experimental Pathology 2024;40(9):930-934
		                        		
		                        			
		                        			Purpose To investigate the clinical and patho-logical characteristics,molecular characteristics,treatments and prognosis of adenoid cystic carcinoma(AdCC)of the breast.Methods A retrospective analysis was conducted on the clini-cal pathology of 14 breast AdCC patients,and HE,immunohis-tochemistry,FISH testing,and follow-up were performed.Re-sults All cases were female,aged 43~70 years.10 cases of classic AdCC and 4 cases of solid-basal cell AdCC(SB-AdCC)were included.The tumor was composed of epithelial,myoepi-thelial and basal-like cells arranged in sieve,tubular and solid pattern with fibrous mucinous or glassy changes in the stroma.The tumor cells of SB-AdCC were moderately to severely atypical with frequent mitosis and necrosis,accompanied by ductal carci-noma in situ(DCIS).Expression of ER(1/14),PR(1/14),HER2(0/14),CK7(14/14),p63(12/14),CK5/6(14/14),CD117(13/14),MYB(9/14)was detected;Ki67 index was 13.2%and 46.1%in classic AdCC and SB-AdCC,respec-tively.The MYB rearrangement rates in classic AdCC and SB-AdCC were 55.6%(5/9)and 25%(1/4),respectively.All patients were underwent surgical resection and/or radiotherapy and chemotherapy.During the follow-up period(2-62 months),1 SB-AdCC patient died due to lung and liver metasta-sis,while the other 10 patients survived without tumors.Con-clusion SB-AdCC is more invasive than classical AdCC with lower frequency of MYB gene rearrangement,and immunohisto-chemical detection of MYB protein has potential value in assis-ting the diagnosis of SB-AdCC.
		                        		
		                        		
		                        		
		                        	
2.Application Regularity and Mechanism of Chinese Marine Drug Pair Haliotidis Concha-Oystreae Concha Based on Literature Mining Technology
Peijun ZHUANG ; Erwei HAO ; Zeyu LI ; Zhengcai DU ; Xiaotao HOU ; Jiagang DENG
Chinese Journal of Experimental Traditional Medical Formulae 2023;29(19):211-219
		                        		
		                        			
		                        			ObjectiveTo analyze the clinical application hotspots, development trends, compatibility characteristics, application rules, and formulation mechanisms of the Chinese marine drug pair Haliotidis Concha-Oystreae Concha in order to provide references for its clinical medication and further research. MethodBy means of various modern literature databases such as China National Knowledge Infrastructure (CNKI), modern clinical prescriptions containing Haliotidis Concha-Oystreae Concha, as well as the clinical application hotspots, were retrieved, followed by visualized analysis of hotspots and development trends of their clinical applications using Citespace. The drug composition, efficacy and indications, and drug dosages in the prescriptions were statistically analyzed. Additionally, various statistical software including SPSS Modeler 18.0 were employed to analyze the indications, syndromes, and formulation rules of Haliotidis Concha-Oystreae Concha. ResultThe visualized analysis included 90 articles, revealing a gradual decrease in publications in this field in recent years. Key clinical application keywords were identified as hypertension, collateral deficiency producing wind, insomnia, etc. Eighty clinical prescriptions were retrieved, involving 121 drugs. Frequency analysis of compatibility demonstrated that the top 10 drugs were Uncariae Ramulus cum Uncis, Gastrodiae Rhizoma, Os Draconis, Achyranthis Bidentatae Radix, Paeoniae Radix Alba, Chrysanthemi Flos, Scutellariae Radix, Gardeniae Frucuts, Glycyrrhizae Radix et Rhizoma, and Polygoni Multiflori Caulis. Association rule analysis showed that core combinations included "Uncariae Ramulus cum Uncis-Achyranthis Bidentatae Radix" and "Os Draconis-Pheretima-Chuanxiong Rhizoma". Through factor reliability analysis, new drug combinations were derived, such as "Gastrodiae Rhizoma-Polygoni Multiflori Caulis-Eucommiae Cortex-Taxilli Herba-Leonuri Herba", "Achyranthis Bidentatae Radix-Uncariae Ramulus cum Uncis", "Scutellariae Radix-Glycyrrhizae Radix et Rhizoma-Margarita-Prunellae Spica", "Os Draconis-Pheretima-Bombyx Batryticatus", "Chrysanthemi Flos-Chuanxiong Rhizoma", "Poria-Acori Tatarinowii Rhizoma", and "Paeoniae Radix Alba-Gardeniae Fructus-Sclerotium Poriae Pararadicis". The Haliotidis Concha-Oystreae Concha drug pair was mainly used to treat diseases with liver Yang hyperactivity syndrome, with hypertension accounting for 40.00%, migraines for 30.00%, and dizziness for 15.00%. In the treatment of liver Yang hyperactivity syndrome, the main categories of compatible drugs were liver-pacifying and wind-extinguishing ones (19.86%), blood-activating and stasis-resolving ones (12.13%), and spirit-calming ones (10.08%). High-frequency drugs in the prescriptions function to reduce blood pressure through multiple pathways, such as increasing nitric oxide (NO) levels, downregulating angiotensin Ⅱ (Ang Ⅱ), and inhibiting angiotensin-converting enzyme (ACE). ConclusionThrough comprehensive analysis of the results, the Haliotidis Concha-Oystreae Concha drug pair is commonly used for hypertension with liver Yang hyperactivity syndrome, and is often combined with deficiency-tonifying, liver-pacifying and wind-extinguishing, heat-clearing, and spirit-calming drugs, aiming to simultaneously extinguish wind, relieve spasms, and pacify the liver to subdue Yang, while also clearing heat to relax bowels, stabilizing the mind, and enhancing the liver-pacifying and Yang-subduing effects of this drug pair. 
		                        		
		                        		
		                        		
		                        	
3.Syndrome Differentiation-based Treatment of Diarrhea-predominant Irritable Bowel Syndrome with Chinese Medicine via 5-HT Signaling Pathway: A Review
Qingrui YANG ; Zeyu HU ; Yuyu LEI ; Xinzhu LI ; Huan CHEN ; Wei CUI ; Haitao LIU ; Xiaoquan DU
Chinese Journal of Experimental Traditional Medical Formulae 2023;29(24):250-259
		                        		
		                        			
		                        			Diarrhea-predominant irritable bowel syndrome (IBS-D) is a chronic functional bowel disorder characterized by abdominal pain and diarrhea, with visceral hypersensitivity and abnormal gastrointestinal dynamics as the pathophysiological basis. The brain-gut interaction plays a role in pain-related functional gastrointestinal disorders, especially IBS-D. 5-Hydroxytryptamine (5-HT), as an important brain-gut peptide regulating gastrointestinal function, affects brain activity, gastrointestinal motility, pain perception, mucosal inflammation, and immune response through brain-gut interaction and is associated with the occurrence and development of IBS-D. In recent years, traditional Chinese medicine (TCM) has shown great potential to mitigate gastrointestinal symptoms and improve the quality of life with its holistic view and treatment based on syndrome differentiation. Studies have shown that TCM treats IBS-D by regulating the 5-HT signaling pathway. With a focus on syndrome differentiation in TCM, this paper systematically describes the efficacy and mechanism of TCM in treating different TCM syndromes of IBS-D via the 5-HT signaling pathway, aiming to provide a scientific basis for TCM treatment of this disease. 
		                        		
		                        		
		                        		
		                        	
4. Analysis on internal mechanism of zedoary turmeric in treatment of liver cancer based on pharmacodynamic substances and pharmacodynamic groups
Zeyu LI ; Erwei HAO ; Rui CAO ; Si LIN ; Linghui ZOU ; Tianyan HUANG ; Zhengcai DU ; Xiaotao HOU ; Jiagang DENG ; Zeyu LI ; Erwei HAO ; Rui CAO ; Si LIN ; Linghui ZOU ; Tianyan HUANG ; Zhengcai DU ; Xiaotao HOU ; Jiagang DENG ; Zeyu LI ; Erwei HAO ; Rui CAO ; Si LIN ; Linghui ZOU ; Tianyan HUANG ; Zhengcai DU ; Xiaotao HOU ; Jiagang DENG
Chinese Herbal Medicines 2022;14(4):479-493
		                        		
		                        			
		                        			 Zedoary tumeric (Curcumae Rhizoma, Ezhu in Chinese) has a long history of application and has great potential in the treatment of liver cancer. The antiliver cancer effect of zedoary tumeric depends on the combined action of multiple pharmacodynamic substances. In order to clarify the specific mechanism of zedoary tumeric against liver cancer, this paper first analyzes the mechanism of its single pharmacodynamic substance against liver cancer, and then verifies the joint anti liver cancer mechanism of its “pharmacodynamic group”. By searching the research on the antihepatoma effect of active components of zedoary tumeric in recent years, we found that pharmacodynamic substances, including curcumol, zedoarondiol, curcumenol, curzerenone, curdione, curcumin, germacrone, β-elemene, can act on multi-target and multi-channel to play an antihepatoma role. For example, curcumin can regulate miR, GLO1, CD133, VEGF, YAP, LIN28B, GPR81, HCAR-1, P53 and PI3K/Akt/mTOR, HSP70/TLR4 and NF-κB. Wnt/TGF/EMT, Nrf2/Keap1, JAK/STAT and other pathways play an antihepatoma role. Network pharmacological analysis showed that the core targets of the “pharmacodynamic group” for anti-life cancer are AKT1, EGFR, MAPK8, etc, and the core pathways are neuroactive live receiver interaction, nitrogen metabolism, HIF-1 signaling pathway, etc. At the same time, by comparing and analyzing the relationship between the specific mechanisms of pharmacodynamic substance and “pharmacodynamic group”, it is found that they have great reference significance in target, pathway, biological function, determination of core pharmacodynamic components, formation of core target protein interaction, in-depth research of single pharmacodynamic substance, increasing curative effect and so on. By analyzing the internal mechanism of zedoary tumeric pharmacodynamic substance and “pharmacodynamic group” in the treatment of liver cancer, this paper intends to provide some ideas and references for the deeper pharmacological research of zedoary tumeric and the relationship between pharmacodynamic substance and “pharmacodynamic group”. 
		                        		
		                        		
		                        		
		                        	
5.Pharmacological Effect of Glycyrrizae Radix et Rhizoma Compatibility and Its Mechanism
Zeyu LI ; Erwei HAO ; Hui LI ; Jiayu WANG ; Xinxin LI ; Rui CAO ; Si LIN ; Huizhen QIN ; Jinling XIE ; Zhengcai DU ; Xiaotao HOU ; Jiagang DENG
Chinese Journal of Experimental Traditional Medical Formulae 2022;28(14):270-282
		                        		
		                        			
		                        			Glycyrrizae Radix et Rhizoma has high medicinal value and is widely used in compatibility. It is used most frequently in the compatibility of Chinese medicine prescriptions,and is known as ''Guolao''(national medicine) and "master of all medicines". The characteristic active ingredients are mainly liquitin,glycyrrizic acid,glycyrrizin,and licochalcone. In different compatibilities,based on traditional and modern pharmacological theories,the corresponding effect of Glycyrrizae Radix et Rhizoma are brought into play through different mechanisms. Based on the traditional pharmacology of Glycyrrizae Radix et Rhizoma for tonifying spleen,replenishing Qi,clearing heat,removing toxin,dispelling phlegm,relieving cough and pain,and harmonizing various medicines,this paper used herbal authentication to analyze its compatibility application and mechanism. It was found that Glycyrrizae Radix et Rhizoma played corresponding effect in compatibilities through "tonification","harmonization",and "regulation". For example,Glycyrrizae Radix et Rhizoma was combined with tonics including Ginseng Radix et Rhizoma and Atractylodis Macrocephalae Rhizoma to tonify the five Zang-organs through its strong tonifying effect,combined with Paeoniae Radix Alba and Aconiti Lateralis Radix Praeparata to relieve emergencies and pains through harmonizing medicine power and properties,and combined with Rhei Radix et Rhizoma and Natrii Sulfas to reduce medicine intensity through regulating medicine properties and body characteristics. The application law and mechanism of the modern pharmacological compatibility of Glycyrrizae Radix et Rhizoma were analyzed by data mining and network pharmacology. It was found that the modern clinical formula was often compatible with Glycyrrizae Radix et Rhizoma for anti-inflammation,cardiovascular and cerebrovascular protection,anti-virus,and anti-tumor,Ephedrae Herba and Scutellariae Radix for anti-inflammation,Bambusae Caulis in Taenias,Salviae Miltiorrhizae Radix et Rhizoma,and Aurantii Fructus Immaturus for cardiovascular and cerebrovascular protection,and Ophiopogonis Radix and Chuanxiong Rhizoma for nerves protection. Meanwhile,the important targets of the characteristic ingredients were protein kinase B1 (Akt1),interleukin-6 (IL-6),tumor necrosis factor (TNF),and epidermal growth factor receptor (EGFR). The important characteristic pathways such as tyrosine kinase inhibitor resistance pathway and cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) signal pathway played the role of cardiovascular and cerebrovascular protection,and proteoglycan pathway in cancer played a neuroprotective role. This study is expected to provide references for the rational compatibility and application of Glycyrrizae Radix et Rhizoma,as well as the compatibility application of Chinese medicine prescriptions. 
		                        		
		                        		
		                        		
		                        	
6.The impact of obstructive sleep apnea on cardiac structure and function in elderly patients with type 2 diabetes mellitus
Sha SHA ; Zeyu SHU ; Tingting DU ; Jin TAN ; Qiang ZHANG
Chinese Journal of Geriatrics 2021;40(6):695-700
		                        		
		                        			
		                        			Objective:To investigate the impact of obstructive sleep apnea(OSA)on cardiac structure and function in elderly patients with type 2 diabetes mellitus(T2DM).Methods:This was a case-control study.Elderly patients with T2DM aged 65 years and above at the Department of Geriatrics of Tianjin Medical University General Hospital were consecutively enrolled in this study, and eventually 61 patients with complete general information were included.All patients were examined with polysomnography(PSG). They were divided into the T2DM group and the T2DM+ OSA group based on whether there was concurrent OSA.Differences in cardiac structure and function were compared between the two groups and between patients with mild OSA and those with moderate-severe OSA.The correlation of OSA with cardiac structure and function in T2DM patients was analyzed by using Pearson correlation and multiple linear regression analysis.Results:The left ventricular ejection fraction(LVEF)was lower in the T2DM+ OSA group than in the T2DM group(52.38±4.70 % vs.56.34±5.92%, t=2.892, P=0.005). The anteroposterior diameter of the right ventricle, inter-ventricular septum thickness and left ventricular posterior wall thickness increased in the T2DM+ OSA group compared with the T2DM group(21.50±1.49 mm vs.20.55±1.05 mm, 10.21±0.88 mm vs.9.52±1.04 mm, 10.42±0.83 mm vs.9.83±0.83 mm, t=-2.670, -2.770 and -2.716, P=0.010, 0.007 and 0.009). LVEF was lower in patients with moderate-severe OSA than in those with mild OSA group(50.58±3.55% vs.55.83±4.83%, t=3.813, P=0.001). The anteroposterior diameter of the right ventricle, inter-ventricular septum thickness and left ventricular posterior wall thickness were greater in patients with moderate-severe OSA than in those with mild OSA(21.86±1.39 mm vs.20.79±1.46 mm, 10.48±0.82 mm vs.9.69±0.75 mm, 10.68±0.80 mm vs.9.92±0.64 mm, t=-2.231, -2.871 and -2.943, P=0.032, 0.007 and 0.006). Pearson correlation analysis showed that the Apnea Hypopnea Index(AHI)was correlated with LVEF, the anteroposterior diameter of the right ventricle, inter-ventricular septum thickness and left ventricular posterior wall thickness( r=-0.425, 0.340, 0.458 and 0.473, P=0.001, 0.007, <0.001 and <0.001). After adjusting for age, body mass index, systolic blood pressure and triglycerides, multiple linear regression analysis showed that AHI was also correlated with LVEF, the anteroposterior diameter of the right ventricle, inter-ventricular septum thickness and left ventricular posterior wall thickness( β=-0.385, 0.520, 0.604 and 0.388, P=0.036, 0.011, 0.001 and 0.039). Conclusions:OSA aggravates cardiac remodeling and systolic insufficiency in T2DM patients and may be related to the severity of intermittent hypoxia.
		                        		
		                        		
		                        		
		                        	
7.Efficacy and safety of transvaginal anterior pelvic reconstruction with mesh in treatment of cystocele with lower urinary tract symptoms
Zeyu CHEN ; Junqi WANG ; Raorao ZHOU ; Renfu CHEN ; Xiaolei SUN ; Wensheng DU ; Haitao ZHU
Chinese Journal of Urology 2020;41(8):613-618
		                        		
		                        			
		                        			Objective:To explore the efficacy and safety of transvaginal anterior pelvic floor reconstruction with mesh in treatment of patients with cystocele and lower urinary tract symptoms.Methods:A retrospective analysis of 32 patients who underwent transvaginal anterior pelvic reconstruction with mesh from June 2015 to February 2019 was performed. The age of the patients was 57-86 years old, with an average of (67.8±7.6) years; body mass index(BMI) (22.6±3.0) kg/m 2; mean duration of disease (2.9±2.3) years; delivery 1-7 times, mean(3.0±1.5) times. All patients underwent transvaginal anterior pelvic reconstruction. The anterior wall of the vagina was incised, and the space between the pelvic floor and the bladder was bluntly separated. The mesh was placed under the guidance of the puncture needle after locating marks of body surface. Patients underwent the American Urological Association Symptom Scoring (AUASS) with (14.2±3.5) points, the residual urine (71.3±53.0) ml and the maximum urine flow rate (16.9 ± 3.8) ml/s were measured preoperative. The Pelvic Organ Prolapse Distress Inventory(POPDI-6), Urogenital Distress Inventory(UDI-6) and Pelvic Floor Impact Questionnaire(PFIQ-7) were recorded as the value of (48.0±7.3) points, (41.7 ± 8.2) points and (62.5 ± 16.4) points, respectively. Thirty-two patients were divided into 2 groups as the group of urinary storage symptom (22 patients) and the group of voiding symptom (10 patients) according to the preoperative lower urinary tract symptoms. The operative time, intraoperative bleeding volume and average hospital stay were recorded. The patients were followed up with AUASS, maximum urine flow rate, residual urine, POPDI-6, UDI-6, PFIQ-7 and complications during and after operations. Results:All the operations of 32 cases were successfull. The average operation time was (61.1±18.6) min, the average intraoperative blood loss was (41.5±12.3)ml, and the average hospital day was (9.1±1.8)d. There were no major organ injuries such as bladder, ureter, iliac vessels and rectum. 27 patients were followed up for 3 to 36 months, with an average of (24.7±10.8) months. There significant improvement of LUTS. At the last follow-up, the AUASS storage phase score (3.4±1.9) points in the urinary storage symptom group(19 patients) and the AUASS urinating phase score (3.9±1.7) points in the voiding symptom group(8 patients) were compared with the preoperative AUASS scores (11.6±1.9) points and (13.9±1.2) points which were significantly reduced. By the last follow up of all the 27 patients, residual urine (23.4±11.0)ml, POPDI-6(3.1±5.4) points, UDI-6 (3.2±5.1) points and PFIQ-7 (12.4±1.7) points were significantly lower than preoperative data. The maximum urinary flow rate(22.4±4.1)ml/s, was significantly higher than that before the operation. All the differences were statistically significant ( P<0.05). All patients had no recurrence of cystocele. One patient had anterior vaginal wall mesh exposure 3 months after surgery. After removing excess mesh in the outpatient clinic, she was cured by smearing with estrogen ointment. One patient experienced frequent urination and urgency who was cured by oral tolterodine tartrate. One patient with de novo mild SUI during the 1-year follow-up. The symptoms were improved in the outpatient clinic after pelvic floor muscle exercise. At 2-year follow-up, one patient was observed de novo mild posterior wall prolapse with no clinical manifestations and no treatment was carried out. Conclusions:Transvaginal anterior pelvic reconstruction with mesh could be effective in treating cystocele with lower urinary tract symptoms with less surgical trauma, fewer complications and lower recurrence rate. It could effectively improve lower urinary tract symptoms such as frequent urination, urgency and difficulty urinating.However, safety issues such as the incidence of long-term de novo SUI and mesh exposure still require further long-term follow-up.
		                        		
		                        		
		                        		
		                        	
8.Magnetic nanoparticles for specifically capturing endothelial progenitor cells and evaluation of its cellular compatibility.
Journal of Biomedical Engineering 2018;35(6):900-904
		                        		
		                        			
		                        			Immobilization of CD34 antibody on ferroferric oxide magnetic nanoparticles was achieved by the traditional carboxyl-amine conjugation reaction. Fourier transform infrared spectroscopy (FT-IR), nanoparticle size analysis (dynamic light scattering and transmission electron microscope), and other testing methods were used to detect the surface modified magnetic nanoparticles. The endothelial progenitor cells (EPCs) were cultured with the surface modified magnetic nanoparticles to evaluate cell compatibility and the combination effect of nanoparticles on EPCs in a short period of time. Directional guide of the surface modified magnetic nanoparticles to EPCs was evaluated under applied magnetic field and simulated dynamic flow condition. The results showed that the magnetic nanoparticles were successfully modified with CD34 antibody, which had good cell compatibility within a certain range of the nanoparticle concentrations. The surface modified nanoparticles can combine with EPCs effectively in a short time, and those nanoparticles combined EPCs can be directional guided under the magnetic field in the dynamic flow environment.
		                        		
		                        		
		                        		
		                        	
9.Reflection on Disorder Phenomenon in Medical Dispute Handling
Zeyu DU ; Jun LIU ; Yingyu YUAN ; Jianyu ZHOU
Chinese Medical Ethics 2018;31(7):855-858
		                        		
		                        			
		                        			In the process of medical dispute handling,violent injury medical incident,medical disturbance,mediation confusion and other disorder phenomena have serious harms,and the lack of faith in rule of law and idea of rule of law,loss of government supervision responsibility,poor access to the rule of law and insufficient solutions and the lagging of related legal construction are the main causes of disorder phenomena.It should start from estab-lishing the awareness in the rule of law and idea of the rule of law,through strictly implementing government re-sponsibility,building diversified disputes resolution approaches and perfecting the relevant legal construction,pro-mote the medical disputes handling return to order and return to the rule of law channels.
		                        		
		                        		
		                        		
		                        	
10.Value of 3.0T magnetic resonance multi-b value diffusion-weighted imaging in efficacy evaluation of chemotherapy for central lung cancer with atelectasis
Lina HOU ; Jianxin ZHANG ; Xiaosong DU ; Zhikai ZHAO ; Lei XIN ; Zeyu BIAN ; Fang ZHENG ; Xiuyun WANG ; Xiaotang YANG
Cancer Research and Clinic 2017;29(5):308-312
		                        		
		                        			
		                        			Objective To evaluate the value of 3.0T magnetic resonance multi-b value diffusion-weighted imaging (DWI) in evaluating the efficacy of chemotherapy for patients with central lung squamous cell carcinoma and atelectasis. Methods Twenty patients with lung squamous cell carcinoma were examined by magnetic resonance imaging (MRI) (including T1WI, T2WI and multi-b value DWI) before chemotherapy, 2 cycles of chemotherapy and 4 cycles of chemotherapy. The images, the tumor volume and changes of apparent diffusion coefficient (ADC) were analyzed. Results In the patients with central lung cancer and atelectasis, the tumor and atelectasis could be distinguished on MRI examination before radiotherapy. It was more easily identified on T2WI images after radiotherapy. In the 20 patients, the ADC values in the effective group (partial remission or complete remission) and the invalid group were increased, but the differences of ADC values in the effective group before chemotherapy, 2 cycles and 4 cycles of chemotherapy were statistically significant [b=800 s/mm2:(1.09 ± 0.52) × 10-6 mm2/s, (1.22 ± 0.59) × 10-6 mm2/s, (1.24 ± 0.52) × 10-6 mm2/s, F = 31.19, P < 0.001]. There was no significant difference in ADC values between before and after chemotherapy (b = 800 s/mm2: (1.10 ± 0.49) × 10-6 mm2/s, (1.16 ± 0.60) × 10-6 mm2/s, (1.20 ± 0.72) × 10-6 mm2/s, F=2.86, P=0.089]. When b=800 s/mm2, the ADC curve slope in the effective group was more stable, better linearity. Conclusions The MRI technique can accurately distinguish the tumor from atelectasis before and after chemotherapy. The change of ADC value after chemotherapy is earlier than that of morphological change. The change rate of b value can better evaluate the curative effect of chemotherapy.
		                        		
		                        		
		                        		
		                        	
            
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