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Predictive factors associated with carcinoid syndrome in patients with gastrointestinal neuroendocrine tumors

World Journal of Gastroenterology 2017年第40期23卷 7283-7291页

作者： Beilei Cai Michael S Broder eunice chang Tingjian Yan David C Metz Novartis Pharmaceuticals Corporation One Health Plaza Partnership for Health Analytic Research LLC 280 S. Beverly Dr. Division of Gastroenterology University of Pennsylvania Health System 3400 Civic Center Boulevard Perelman Center for Advanced Medicine

AIM To discover unknown factors associated with carcinoid syndrome(CS) with the goal of earlier diagnosis of *** In this retrospective case-control study using United States administrative claims, patients(≥ 18 years) newly-diagnosed with gastrointestinal neuroendocrine tumors(GI NETs) without CS(controls) were exactly matched to patients with CS(cases) based on NET diagnosis date at a 3-to-1 ratio. Study index date was first CS diagnosis(controls: same distance from NET diagnosis as cases). The most observed conditions, excluding CS-associated symptoms/diagnoses, during the year before index date were assessed. Forwardstepwise logistic regression models were used to derive predictors, and were validation within another claims database. RESULTS In the development database, 1004 patients with GI NETs were identified; 251(25%) had CS and 753(75%) were controls. In the validation database, 724 patients with GI NETs were identified; 181(25%) had CS and 543(75%) were controls. A total of 33 common diagnoses(excluding conditions already known to be associated with CS) in the development database were entered in forward step-wise logistic regression models. In the final, validated logistic regression model, three factors prior to CS diagnosis were found consistently associated with higher risks for CS, including liver disorder [odds ratio(95%CI): 3.38(2.07-5.51)], enlargement of lymph nodes [2.13(1.10-4.11)], and abdominal mass [3.79(1.87-7.69)].CONCLUSION GI NET patients with CS were 2-4 times as likely to have preexisting diagnoses(i.e., liver disorder, enlarged lymph nodes, abdominal mass) than non-CS patients.

关键词： Carcinoid syndrome Gastrointestinal neuroendocrine tumors Predictive factors Data mining

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Healthcare and economic impact of diarrhea in patientswith carcinoid syndrome

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World Journal of Gastroenterology 2016年第6期22卷 2118-2125页

作者： Michael S Broder eunice chang Dorothy Romanus Dasha Cherepanov Maureen P Neary Partnership for Health Analytic Research LLCBeverly HillsCA 90212United States Novartis Pharmaceuticals Corporation East HanoverNJ 07936United States

AIM To examine healthcare resource utilizationpatterns and costs accrued by carcinoid syndrome （CS）patients with and without ***： We conducted a retrospective cohort studyusing MarketScan data from 1/1/2002-12/31/*** diagnosed CS patients had 1 medical claim forCS （ICD-9-CM code 259.2） plus either ≥ 1 additionalclaim for CS or for carcinoid tumors （ICD-9-CM 209.x）, and had no evidence of CS for 1 year prior to index CS diagnosis, in commercially-insured patients 〈 65years old. Patients were required to have continuousenrollment one year prior and after index date （firstclaim with CS diagnosis in the ID period）. We identifiedpatients with evidence of non-infectious diarrhea （ICD-9-CM codes 564.5 and 787.91） within one year from theindex date. Overall and CS-related healthcare resourceutilization and costs were compared between patientswith and without non-infectious diarrhea during theone year period after the index ***： There were 2822 newly diagnosed CSpatients; 534 （18.9%） had evidence of non-infectiousdiarrhea. Compared to patients without non-infectiousdiarrhea, non-infectious diarrhea patients morecommonly had at ≥ 1 CS-related hospitalization（13.7% vs 7.2%）, ≥ 1 CS-related ED visit （11.0% vs4.4%）, and CS-related office visits in one year （6.9 vs4.1; all p 〈 0.001）. After adjusting for demographics,region, number of chronic conditions and the CharlsonComorbidity Index, the proportions of patients withany and with CS-related hospitalizations were 9.7%and 6.8% higher, respectively, among non-infectiousdiarrhea patients compared to those with without noninfectiousdiarrhea （p 〈 0.001）. Unadjusted costs weresignificantly higher among non-infectious diarrheapatients vs those without non-infectious diarrhea. Thenon-infectious diarrhea group was also more costly,with adjusted mean annual costs of $81610, comparedto $51719 in the group without non-infectious diarrhea（p 〈 0.001）.CONCLUSION： Diarrhea is burdensome and costlyin CS patients. Red

关键词： Carcinoid Neuroendocrine tumor Diarrhea Cost Healthcare resource utilization

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Real-world treatment patterns of gastrointestinal neuroendocrine tumors: A claims database analysis

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World Journal of Gastroenterology 2017年第33期23卷 6128-6136页

作者： Al B Benson III Michael S Broder Beilei Cai eunice chang Maureen P Neary Elya Papoyan Northwestern University Partnership for Health Analytic Research Novartis Pharmaceuticals

AIM To describe real-world treatment patterns of gastrointestinal neuroendocrine tumors(GI NET).METHODS In this retrospective cohort study,we used 2009-2014 data from 2 United States commercial claims databases to examine newly pharmacologically treated patients using tabular and graphical techniques. Treatments included somatostatin analogues(SSA),cytotoxic chemotherapy(CC),targeted therapy(TT),interferon(IF) and combinations. We identified patients at least 18 years of age,with ≥ 1 inpatient or ≥ 2 outpatient claims for GI NET who initiated pharmacologic treatment from 7/1/09-6/30/14. A 6 mo clean period prior to first treatment ensured patients were newly treated. Patients were followed until end of enrollment or the study end date,whichever was *** We identified 2258 newly treated GI NET patients: mean(SD) age was 55.6 years(SD = 9.7),47.2% of the patients were between 55 and 64 years,and 48.8% were female. All regions of the United States were represented. 59.6% started first-line therapy with SSA monotherapy(964 with octreotide LAR,380 with octreotide SA,and 1 with lanreotide),33.3% CC,3.6% TT,and 0.5% IF. The remainder received combinations. Mean follow up was 576 d. Overall mean first-line therapy duration was 361 d(449 d for SSA,215 for CC,267 for TT). 58.9% of patients had no pharmacological treatment beyond first line. The most common secondline was combination therapy with SSA. In graphical pattern analysis,there was no clear pattern visible after first line *** In this study,60% of patients initiated treatment with SSA alone or in combination. The relatively long time to discontinuation suggests possible sustained effectiveness and tolerability.

关键词： Gastrointestinal neuroendocrine tumors Treatment patterns Insurance claims Somatostatin analogue Targeted therapy Chemotherapy

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The interplay of aging,genetics and environmental factors in the pathogenesis of Parkinson’s disease

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Translational Neurodegeneration 2019年第1期8卷 279-289页

作者： Shirley Yin-Yu Pang Philip Wing-Lok Ho Hui-Fang Liu Chi-Ting Leung Lingfei Li eunice Eun Seo chang David Boyer Ramsden Shu-Leong Ho Division of Neurology Department of MedicineQueen Mary HospitalUniversity of Hong KongHong KongPeople’s Republic of China Institute of Metabolism and Systems Research University of BirminghamBirminghamUK

Background:Parkinson’s disease(PD)is characterized by dopaminergic neuronal loss in the substantia nigra pars compacta and intracellular inclusions called Lewy bodies(LB).During the course of disease,misfoldedα-synuclein,the major constituent of LB,spreads to different regions of the brain in a prion-like fashion,giving rise to successive non-motor and motor *** is likely multifactorial,and involves interplay among aging,genetic susceptibility and environmental *** body:The prevalence of PD rises exponentially with age,and aging is associated with impairment of cellular pathways which increases susceptibility of dopaminergic neurons to cell ***,the majority of those over the age of 80 do not have PD,thus other factors in addition to aging are needed to cause *** of neurotoxins which can result in parkinsonism led to efforts in identifying environmental factors which may influence PD ***,the causality of most environmental factors is not conclusively established,and alternative explanations such as reverse causality and recall bias cannot be *** lack of geographic clusters and conjugal cases also go against environmental toxins as a major cause of *** mutations as well as common variants in genes such as SNCA,LRRK2 and GBA are associated with risk of PD,but Mendelian causes collectively only account for 5%of PD and common polymorphisms are associated with small increase in PD *** of PD has been estimated to be around 30%.Thus,aging,genetics and environmental factors each alone is rarely sufficient to cause PD for most ***:PD is a multifactorial disorder involving interplay of aging,genetics and environmental *** has implications on the development of appropriate animal models of PD which take all these factors into *** converging pathways likely include mitochondrial dysfunction,impaired autophagy,oxidative stress and neuroinflammation,which are

关键词： Parkinson’s disease Genetics Aging Environmental toxins

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LRRK2 mutant knock-in mouse models: therapeutic relevance in Parkinson’s disease

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Translational Neurodegeneration 2022年第1期11卷 790-808页

作者： eunice Eun Seo chang Philip Wing-Lok Ho Hui-Fang Liu Shirley Yin-Yu Pang Chi-Ting Leung Yasine Malki Zoe Yuen-Kiu Choi David Boyer Ramsden Shu-Leong Ho Division of Neurology Department of MedicineQueen Mary HospitalUniversity of Hong KongPok Fu LamHong KongChina Institute of Metabolism and Systems Research University of BirminghamBirminghamUK.

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are one of the most frequent genetic causes of both familial and sporadic Parkinson’s disease (PD). Mounting evidence has demonstrated pathological similarities between LRRK2-associated PD (LRRK2-PD) and sporadic PD, suggesting that LRRK2 is a potential disease modulator and a thera-peutic target in PD. LRRK2 mutant knock-in (KI) mouse models display subtle alterations in pathological aspects that mirror early-stage PD, including increased susceptibility of nigrostriatal neurotransmission, development of motor and non-motor symptoms, mitochondrial and autophagy-lysosomal defects and synucleinopathies. This review provides a rationale for the use of LRRK2 KI mice to investigate the LRRK2-mediated pathogenesis of PD and implications from current findings from different LRRK2 KI mouse models, and ultimately discusses the therapeutic potentials against LRRK2-associated pathologies in PD.

关键词： Parkinson’s disease LRRK2 Knock-in mouse model Neurotransmission Motor dysfunction Autophagy Lysosome Mitochondrial dysfunction Synucleinopathy Hyperkinase activity LRRK2 inhibitor

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LRRK2, GBA and their interaction in the regulation of autophagy: implications on therapeutics in Parkinson’s disease

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Translational Neurodegeneration 2022年第1期11卷 869-882页

作者： Shirley Yin-Yu Pang Rachel Cheuk Nam Lo Philip Wing-Lok Ho Hui-Fang Liu eunice Eun Seo chang Chi-Ting Leung Yasine Malki Zoe Yuen-Kiu Choi Wing Yan Wong Michelle Hiu-Wai Kung David Boyer Ramsden Shu-Leong Ho Division of Neurology Department of MedicineQueen Mary HospitalUniversity of Hong KongHong KongChina School of Biomedical Sciences Li Ka Shing Faculty of MedicineUniversity of Hong KongHong KongChina Institute of Metabolism and Systems Research University of BirminghamBirminghamUK.

Mutations in leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA) represent two most common genetic causes of Parkinson’s disease (PD). Both genes are important in the autophagic-lysosomal pathway (ALP), defects of which are associated with α-synuclein (α-syn) accumulation. LRRK2 regulates macroautophagy via activation of the mitogen activated protein kinase/extracellular signal regulated protein kinase (MAPK/ERK) kinase (MEK) and the calcium-dependent adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathways. Phosphorylation of Rab GTPases by LRRK2 regulates lysosomal homeostasis and endosomal trafficking. Mutant LRRK2 impairs chaperone-mediated autophagy, resulting in α-syn binding and oligomerization on lysosomal membranes. Mutations in GBA reduce glucocerebrosidase (GCase) activity, leading to glucosylceramide accumulation, α-syn aggregation and broad autophagic abnormalities. LRRK2 and GBA influence each other: GCase activity is reduced in LRRK2 mutant cells, and LRRK2 kinase inhibition can alter GCase activity in GBA mutant cells. Clinically, LRRK2 G2019S mutation seems to modify the effects of GBA mutation, resulting in milder symptoms than those resulting from GBA mutation alone. However, dual mutation carriers have an increased risk of PD and earlier age of onset compared with single mutation carriers, suggesting an additive deleterious effect on the initiation of PD pathogenic processes. Crosstalk between LRRK2 and GBA in PD exists, but its exact mechanism is unclear. Drugs that inhibit LRRK2 kinase or activate GCase are showing efficacy in pre-clinical models. Since LRRK2 kinase and GCase activities are also altered in idiopathic PD (iPD), it remains to be seen if these drugs will be useful in disease modification of iPD.

关键词： Parkinson’s disease Interaction LRRK2 GBA GCase Mutation Autophagy α-Synuclein

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Development of a Consolidated Anaerobic Digester and Microbial Fuel Cell to Produce Biomethane and Electricity from Cellulosic Biomass Using Bovine Rumen Microorganisms

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Journal of Sustainable Bioenergy Systems 2019年第2期9卷 17-28页

作者： Rebecca Chung eunice Yujin Kang Yun Jae Shin Justin Jong Park Peter Sang Park chang Hyun Han Byungjun Kim Seog In Moon Jooheon Park Paul Sung Chung Centreville High School Clifton VA USA West Springfield High School Springfield VA USA Department of Biological Science University of Southern California Los Angeles CA USA Biology College of Arts & Science Cornell University Ithaca NY USA Biological Science Mellon College of Science Carnegie Mellon University Pittsburgh PA USA Department of Biology Amherst College Amherst MA USA Biology Science Program University of Alberta Edmonton Canada Fuzbien Technology Institute (FTI) Rockville USA

Microbial fuel cells (MFCs) are bioelectrochemical systems that convert chemical energy contained in organic matter into electrical energy by using the catalytic (metabolic) activity of living microorganisms. Mediator-less two chamber H-type MFCs were constructed in the current study, using dairy digester microbial population as anode inocula to convert finely ground pine tree (Avicel) at 2% (w/v) to electricity. MFCs were placed at 37°C and after the circuit voltage was stabilized on d9, bovine rumen microorganisms cultured anaerobically for 48 hrs in cellulose broth media were added to treatment group of MFC at 1% v/v dosage. MFC power and current across an external resistor were measured daily for 10 d. At the end of incubation on d19 head space gas and anode chamber liquid solutions were collected and analyzed for total gas volume and composition, and volatile fatty acids, respectively. Addition of enriched rumen microorganisms to anaerobic anode chamber increased cellulose digestibility and increased both CO2 and methane production;however, it decreased the methane to CO2 ratio. Over the experimental period, electricity generation was increased with rumen microorganism addition, and power density normalized to anode surface area was 17.6 to 67.2 mW/m2 with average of 36.0 mW/m2 in treatment, while control group had 3.6 to 21.6 (AVE 12.0) mW/m2. These observations imply that biocatalysis in MFCs requires additional cellulolytic activities to utilize structural biomass in bioenergy production.

关键词： Microbial Fuel Cells (MFCs) Bovine Rumen Bacteria Bioenergy

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Calcium/calcimimetic via calcium-sensing receptor ameliorates cholera toxin-induced secretory diarrhea in mice

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World Journal of Gastroenterology 2024年第3期30卷 268-279页

作者： Lie-Qi Tang Johnathan Fraebel Shi Jin Steven P Winesett Jane Harrell Wen-Han chang Sam Xianjun Cheng Department of Pediatrics University of FloridaGainesvilleFL 32610United States College of Medicine University of FloridaGainesvilleFL 32610United States Applied Physiology and Kinesiology University of FloridaGainesvilleFL 32610United States Brain Rehabilitation Research Center Malcom Randall VA Medical CenterGainesvilleFL 32610United States Department of Medicine Endocrine Research UnitVeterans Affairs Medical CenterUniversity of CaliforniaSan FranciscoSan FranciscoCA 94121United States Department of Pediatric Gastroenterology Hepatologyand NutritionUniversity of Florida Shands Children’s HospitalGainesvilleFL 32608United States

BACKGROUND Enterotoxins produce diarrhea through direct epithelial action and indirectly by activating the enteric nervous ***-sensing receptor(CaSR)inhibits both *** latter has been well documented in vitro but not in *** hypothesis to be tested was that activating CaSR inhibits diarrhea in *** To determine whether CaSR agonists ameliorate secretory diarrhea evoked by cholera toxin(CTX)in *** CTX was given orally to C57BL/6 mice to induce *** and calci-mimetic R568 were used to activate *** maximize their local intestinal actions,calcium was administered luminally via oral rehydration solution(ORS),whereas R568 was applied serosally using an intraperitoneal *** verify that their actions resulted from the intestine,effects were also examined on Cre-lox intestine-specific CaSR *** outcome was measured biochemically by monitoring changes in fecal Cl-or clinically by assessing stool consistency and weight *** CTX induced secretory diarrhea,as evidenced by increases in fecal Cl-,stool consistency,and weight loss following CTX exposure,but did not alter CaSR,neither in content nor in ***,calcium and R568 were each able to ameliorate diarrhea when applied to diseased *** CaSR involvement is suggested by gene knockout experiments where the anti-diarrheal actions of R568 were lost in intestinal epithelial CaSR knockouts(villinCre/Casrflox/flox)and neuronal CaSR knockouts(nestinCre/Casrflox/flox).CONCLUSION Treatment of acute secretory diarrheas remains a global *** advances in diarrhea research,few have been made in the realm of diarrhea *** therapy has remained the standard of care,although it does not halt the losses of intestinal fluid and ions caused by *** is no cost-effective therapeutic for *** and other studies suggest that adding calcium to ORS or using calcimimetics to activate intestinal CaSR might

关键词： Cholera Enteric nervous system Secretory diarrhea Oral rehydration solution Calcium-sensing receptor Gene knockout

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DIETARY PATTERNS IN 10 GROUPS AND THE RELATIONSHIP WITH BLOOD PRESSURE

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中华医学杂志(英文版) 1989年第4期102卷 261-261页

作者： Zhou Bei-fang Wu Xi-gui Tao Shou-qi Yang Jun Cao Tian-xiu Zheng Run-ping Tian Xiu-zhen Lu chang-qing Miao Huai-yi Ye Feng-ming Zhu Li-guang Zhu Cun Jiang Jie-ping He Hou-qi Ma Fu Du Fu-chang Wan Bin Department of Epidemiology Cardiovascular Institute CHinese Academy of Medica Sciences Cardiovascular Institute of Capital Iron and Steel Complex Department of Biostatistics Institute of Basic Medicine Chinese Academy of Medical Sciences Institute of Cardiovascular Diseases Shijingshan Disctrict Beijing Yu County Hospital Shanxi Cardiovascular Institute Hanzhong Shaanxi Guangxi Medical College Zhoushan City Bureau of Health Zhejiang Qian-an Mine Hospital Harbin University of Medical Sciences Harbin Pingfang District Hospital First Hospital Nanjing Medical College Jintan County Health Station Jiangsu

An epidemiological comparative study on dietary patterns and poWlation means of blood pressure was undertaken in 10 groups (3 of workers, 6 of farmers, 1 of fishermen) of adult males and females of northeast, north, south, middle and east China. Standardized methods and record forms were used for blood pressure measurements and 24-hr dietary recall interviews. Simple correlation and linear regression, multiple regression (adjusted for age, sex and body mass index) and ridge regression were used to analyze the relationship of dietary electrolytes and animal protein to blood pressure. The results show a significant negative association of mean daily intake of Ca and animal protein with population mean blood pressure. Excluding the fishermen’s group, mean daily intake of Na showed significant positive association with both systolic and diastolic blood pressure. The Chinese diet should probably be improved, increasing Ca and animal protein and cutting salt to a much lower level.

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