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Zheng, Hui

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Zheng

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Hui

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Zheng, Hui
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Now showing 1 - 10 of 17
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    Long-term reduction in hyperglycemia in advanced type 1 diabetes: the value of induced aerobic glycolysis with BCG vaccinations
    (Nature Publishing Group UK, 2018) Kuhtreiber, Willem; Tran, Lisa; Kim, Taesoo; Dybala, Michael; Nguyen, Brian; Plager, Sara; Huang, Daniel; Janes, Sophie; Defusco, Audrey; Baum, Danielle; Zheng, Hui; Faustman, Denise
    Mycobacterium are among the oldest co-evolutionary partners of humans. The attenuated Mycobacterium bovis Bacillus Calmette Guérin (BCG) strain has been administered globally for 100 years as a vaccine against tuberculosis. BCG also shows promise as treatment for numerous inflammatory and autoimmune diseases. Here, we report on a randomized 8-year long prospective examination of type 1 diabetic subjects with long-term disease who received two doses of the BCG vaccine. After year 3, BCG lowered hemoglobin A1c to near normal levels for the next 5 years. The BCG impact on blood sugars appeared to be driven by a novel systemic and blood sugar lowering mechanism in diabetes. We observe a systemic shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis, a state of high glucose utilization. Confirmation is gained by metabolomics, mRNAseq, and functional assays of cellular glucose uptake after BCG vaccinations. To prove BCG could induce a systemic change to promote accelerated glucose utilization and impact blood sugars, murine data demonstrated reduced blood sugars and aerobic induction in non-autoimmune mice made chemically diabetic. BCG via epigenetics also resets six central T-regulatory genes for genetic re-programming of tolerance. These findings set the stage for further testing of a known safe vaccine therapy for improved blood sugar control through changes in metabolism and durability with epigenetic changes even in advanced Type 1 diabetes.
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    Model for end‐stage liver disease Na Score predicts incident major cardiovascular events in patients with nonalcoholic fatty liver disease
    (John Wiley and Sons Inc., 2017) Simon, Tracey; Kartoun, Uri; Zheng, Hui; Chan, Andrew; Chung, Raymond; Shaw, Stanley; Corey, Kathleen
    Cardiovascular disease (CVD) is the leading cause of mortality among adults with nonalcoholic fatty liver disease (NAFLD); however, accurate tools for identifying NAFLD patients at highest CVD risk are lacking. Using a validated algorithm, we identified a retrospective cohort of 914 NAFLD patients without known CVD. Fibrosis severity was estimated using the fibrosis‐4 index. Patients were followed for 5 years for the development of a major adverse cardiovascular event (MACE); a composite of cardiovascular death, myocardial infarction, or unstable angina; urgent coronary revascularization; or stroke. Using an adjusted Cox proportional hazard regression model, NAFLD‐specific biomarkers of CVD risk were identified. Discrimination was compared to that of the Framingham Risk Score (FRS) using the area under the receiver operating characteristic curve. Among 914 patients, the mean age was 53.4 years and 60.6% were female. Over 5 years, 288 (31.5%) experienced MACE. After adjustment for traditional cardiometabolic risk factors and underlying FIB‐4 index score, each 1‐point increase in the model for end‐stage liver disease integrating sodium (MELD‐Na) was associated with a 4.2% increased risk of MACE (hazard ratio, 1.042; 95% confidence interval, 1.009‐1.075; P = 0.011). Compared to patients in the lowest MELD‐Na quartile (<7.5), those in the highest quartile (≥13.2) had a 2.2‐fold increased risk of MACE (adjusted hazard ratio, 2.21; 95% confidence interval, 1.11‐4.40; P = 0.024; P trend = 0.004). Incorporating MELD‐Na with the FRS significantly improved discrimination of future CVD risk (combined C‐statistic 0.703 versus 0.660 for the FRS alone; P = 0.040). Conclusion:: Among patients with NAFLD, the MELD‐Na score accurately stratifies the risk for patients according to future CVD event risk. The addition of the MELD‐Na score to the FRS may further improve discrimination of NAFLD‐related CVD risk. (Hepatology Communications 2017;1:429–438)
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    A Comparative Effectiveness Analysis of Three Continuous Glucose Monitors
    (American Diabetes Association, 2013) Damiano, Edward R.; El-Khatib, Firas H.; Zheng, Hui; Nathan, David; Russell, Steven
    OBJECTIVE To compare three continuous glucose monitoring (CGM) devices in subjects with type 1 diabetes under closed-loop blood glucose (BG) control. RESEARCH DESIGN AND METHODS Six subjects with type 1 diabetes (age 52 ± 14 years, diabetes duration 32 ± 14 years) each participated in two 51-h closed-loop BG control experiments in the hospital. Venous plasma glucose (PG) measurements (GlucoScout, International Biomedical) obtained every 15 min (2,360 values) were paired in time with corresponding CGM glucose (CGMG) measurements obtained from three CGM devices, the Navigator (Abbott Diabetes Care), the Seven Plus (DexCom), and the Guardian (Medtronic), worn simultaneously by each subject. Errors in paired PG–CGMG measurements and data reporting percentages were obtained for each CGM device. RESULTS The Navigator had the best overall accuracy, with an aggregate mean absolute relative difference (MARD) of all paired points of 11.8 ± 11.1% and an average MARD across all 12 experiments of 11.8 ± 3.8%. The Seven Plus and Guardian produced aggregate MARDs of all paired points of 16.5 ± 17.8% and 20.3 ± 18.0%, respectively, and average MARDs across all 12 experiments of 16.5 ± 6.7% and 20.2 ± 6.8%, respectively. Data reporting percentages, a measure of reliability, were 76% for the Seven Plus and nearly 100% for the Navigator and Guardian. CONCLUSIONS A comprehensive head-to-head-to-head comparison of three CGM devices for BG values from 36 to 563 mg/dL revealed marked differences in performance characteristics that include accuracy, precision, and reliability. The Navigator outperformed the other two in these areas.
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    Pancreatic Ductal Adenocarcinoma: Long-Term Survival Does Not Equal Cure
    (Elsevier BV, 2012) Ferrone, Cristina; Pieretti-Vanmarcke, Rafael; Bloom, Jordan; Zheng, Hui; Szymonifka, Jackye; Wargo, Jennifer Ann; Thayer, Sarah P.; Lauwers, Gregory Y.; Deshpande, Vikram; Mino-Kenudson, Mari; Fernandez-Del Castillo, Carlos; Lillemoe, Keith; Warshaw, Andrew
    Background: Pancreatic ductal adenocarcinoma represents 90% of pancreatic cancers and is an important cause of cancer death in the United States. Operative resection remains as the only treatment providing prolonged survival, but even after a curative resection, 5-year survival rates are low. Our aim was to identify the prognostic factors for long-term survival after resection of pancreatic ductal adenocarcinoma related to patients, treatments, and tumor biology. Methods: Retrospective review identified 959 patients who underwent resection of their pancreatic adenocarcinoma between February 1985 and December 2010, of whom 499 were resected before November 2006 and represent the cohort we describe in this study. Patient, tumor, and treatment-related variables were assessed for their associations with 5- and 10-year overall survival. Results: Of the 499 patients, 49% were female and median age was 65 years. The majority of patients had stage IIb disease (60%). Actual 5-year survival after resection of pancreatic adenocarcinoma was 19% (95/499), and actual 10-year survival was 10% (33/329). Significant clinicopathologic factors predicting 5- and 10-year survival were negative margins and negative nodal status. Interestingly, 41% (39/95) of long-term survivors had positive nodes and 24% (23/95) had positive margins. Conclusion: Pancreatic ductal adenocarcinoma demonstrates a very heterogeneous biology, but patients with negative resection margins and node negative cancers are more likely to survive 5 years after resection. However, our series demonstrates that the biology of the cancer rather than simple pathologic factors determine a patient's prognosis.
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    Gastric Cancer in Individuals with Li-Fraumeni Syndrome
    (Nature Publishing Group, 2011) Masciari, Serena; Dewanwala, Akriti; Stoffel, Elena M.; Lauwers, Gregory Y.; Zheng, Hui; Achatz, Maria Isabel; Riegert-Johnson, Douglas; Foretova, Lenka; Silva, Edaise M.; Digianni, Lisa; Verselis, Sigitas J.; Schneider, Katherine; Li, Frederick Pei; Fraumeni, Joseph; Garber, Judy; Syngal, Sapna
    PURPOSE: Li-Fraumeni syndrome is a rare hereditary cancer syndrome associated with germline mutations in the TP53 gene. Although sarcomas, brain tumors, leukemias, breast and adrenal cortical carcinomas are typically recognized as Li-Fraumeni syndrome-associated tumors, the occurrence of gastrointestinal neoplasms has not been fully evaluated. In this analysis, we investigated the frequency and characteristics of gastric cancer in Li-Fraumeni syndrome. METHODS: Pedigrees and medical records of 62 TP53 mutation-positive families were retrospectively reviewed from the Dana-Farber/National Cancer Institute Li-Fraumeni syndrome registry. We identified subjects with gastric cancer documented either by pathology report or death certificate and performed pathology review of the available specimens. RESULTS: Among 62 TP53 mutation-positive families, there were 429 cancer-affected individuals. Gastric cancer was the diagnosis in the lineages of 21 (4.9%) subjects from 14 families (22.6%). The mean and median ages at gastric cancer diagnosis were 43 and 36 years, respectively (range: 24-74 years), significantly younger compared with the median age at diagnosis in the general population based on Surveillance Epidemiology and End Results data (71 years). Five (8.1%) families reported two or more cases of gastric cancer, and six (9.7%) families had cases of both colorectal and gastric cancers. No association was seen between phenotype and type/location of the TP53 mutations. Pathology review of the available tumors revealed both intestinal and diffuse histologies. CONCLUSIONS: Early-onset gastric cancer seems to be a component of Li-Fraumeni syndrome, suggesting the need for early and regular endoscopic screening in individuals with germline TP53 mutations, particularly among those with a family history of gastric cancer.
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    Trends in Presentation and Survival for Gallbladder Cancer During a Period of More Than 4 Decades
    (American Medical Association (AMA), 2009) Konstantinidis, Ioannis T; Deshpande, Vikram; Genevay, Muriel; Berger, David; Fernandez-Del Castillo, Carlos; Tanabe, Kenneth; Zheng, Hui; Lauwers, Gregory Y.; Ferrone, Cristina
    Objectives: To determine the prevalence of incidentally found cases of gallbladder cancer, the incidence of residual disease at reexploration, and the changes in the mode of presentation, treatment, and survival of patients with gallbladder cancer during a period of more than 4 decades. Design: Retrospective case series. Setting: University-affiliated tertiary care center. Patients: Between January 1, 1962, and March 1, 2008, 402 patients with gallbladder cancer were identified and their clinicopathologic data were analyzed. Interventions: Surgical treatment, radiotherapy, and chemotherapy. Main Outcome Measures: Incidentally discovered gallbladder cancer, incidence of residual disease, and differences in presentation, treatment, and survival. Results: Surgical exploration was performed in 260 patients (64.7%), of whom 151 (58.1%) underwent resection. The median age of the patients was 72 years, and 72.3% were female. Between January 1, 1994, and March 1, 2008, 6881 laparoscopic cholecystectomies were performed, and there were 17 incidentally discovered cases of gallbladder cancer (0.25%). Residual disease on reexploration was identified in 0 of 2 patients with T1 tumor, 3 of 13 patients with T2 tumor, and 8 of 10 patients with T3 tumor (P = .01). Patients with stage IV disease (34 [13.1%] diagnosed from 1962-1979; 34 [13.1%] diagnosed from 1980-1997; and 22 [8.5%] diagnosed from 1998-2008) had a median survival of 4 months (range, 0-37 months). Concomitant liver resections increased in the third study period (11.1%, 10.1%, and 54.3%; P < .001), with an increase in negative margins (33.3%, 42.0%, and 63.0%; P = .01). Cox regression analysis identified T stage and surgical margin status as significant prognostic factors. Conclusions: Gallbladder cancer is incidentally found during 0.25% of laparoscopic cholecystectomies. As T stage increases, the likelihood of residual disease on reexploration increases. Although many patients with gallbladder cancer present with incurable disease and have very poor survival, the overall prognosis is improving, likely because of more extensive operations.
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    Gallbladder Lesions Identified on Ultrasound. Lessons from the Last 10 Years
    (Springer Nature, 2011) Konstantinidis, Ioannis T; Bajpai, Surabhi; Kambadakone, Avinash R.; Tanabe, Kenneth; Berger, David; Zheng, Hui; Sahani, Dushyant; Lauwers, Gregory Y.; Fernandez-Del Castillo, Carlos; Warshaw, Andrew; Ferrone, Cristina
    Background: Possible mass lesions identified on ultrasound (US) of the gallbladder may prompt an aggressive surgical intervention due to the possibility of a malignant neoplasm. Aim: This study aims to utilize a large modern series of patients with gallbladder lesions identified on US to evaluate imaging characteristics consistent with malignancy. Methods: A retrospective review was conducted of gallbladder ultrasound reports and clinicopathologic data of patients with a mass identified on US. Results: Approximately 59,271 abdominal ultrasounds and 9,117 cholecystectomies were performed between February 2000 and February 2010. We identified 213 patients with a questionable gallbladder neoplasm on ultrasonography who underwent surgical exploration. Median age was 52 years (range = 11–87 years) and 147 (69%) were females. Final pathology demonstrated no neoplasm in 130 patients (61%), while 32 patients (15%) had a wall adenomyoma, 36 (17%) had a polyp (five of which were malignant), 14 (7%) had an adenocarcinoma not arising from a polyp, and one patient had a cystic papillary neoplasm. The smaller the lesion, the more likely it was to be a pseudo-mass. For lesions measuring <5 mm on US, 83% had no lesion found on final pathology. Significant predictors of malignancy were age >52 years (p < 0.001), presence of gallstones on US (p = 0.004), size >9 mm (p < 0.001), evidence of invasion at the liver interface (p < 0.001), and wall thickening >5 mm (p < 0.001). Shape (sessile or penduculated), echogenicity (echogenic or isoechoic), or presence of flow on Doppler were not predictors of malignancy. An US size of ≤9 mm had a negative predictive value of 100% for malignancy. Conclusions: Despite improvements in imaging, most apparent lesions measuring <5 mm on US are not identified in the surgical specimen. US size >9 mm, age >52 years, US suggestion of invasion at the liver interface, and wall thickening >5 mm, especially in the presence of gallstones, should raise the suspicion of malignancy.
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    Battery of behavioral tests in mice to study postoperative delirium
    (Nature Publishing Group, 2016) Peng, Mian; Zhang, Ce; Dong, Yuanlin; Zhang, Yiying; Nakazawa, Harumasa; Kaneki, Masao; Zheng, Hui; Shen, Yuan; Marcantonio, Edward; Xie, Zhongcong
    Postoperative delirium is associated with increased morbidity, mortality and cost. However, its neuropathogenesis remains largely unknown, partially owing to lack of animal model(s). We therefore set out to employ a battery of behavior tests, including natural and learned behavior, in mice to determine the effects of laparotomy under isoflurane anesthesia (Anesthesia/Surgery) on these behaviors. The mice were tested at 24 hours before and at 6, 9 and 24 hours after the Anesthesia/Surgery. Composite Z scores were calculated. Cyclosporine A, an inhibitor of mitochondria permeability transient pore, was used to determine potential mitochondria-associated mechanisms of these behavioral changes. Anesthesia/Surgery selectively impaired behaviors, including latency to eat food in buried food test, freezing time and time spent in the center in open field test, and entries and duration in the novel arm of Y maze test, with acute onset and various timecourse. The composite Z scores quantitatively demonstrated the Anesthesia/Surgery-induced behavior impairment in mice. Cyclosporine A selectively ameliorated the Anesthesia/Surgery-induced reduction in ATP levels, the increases in latency to eat food, and the decreases in entries in the novel arm. These findings suggest that we could use a battery of behavior tests to establish a mouse model to study postoperative delirium.
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    Treg activation defect in type 1 diabetes: correction with TNFR2 agonism
    (Nature Publishing Group, 2016) Okubo, Yoshiaki; Topley, Heather; Butterworth, John; Zheng, Hui; Faustman, Denise
    Activated T-regulatory cells (aTregs) prevent or halt various forms of autoimmunity. We show that type 1 diabetics (T1D) have a Treg activation defect through an increase in resting Tregs (rTregs, CD4+CD25+Foxp3+CD45RA) and decrease in aTregs (CD4+CD25+Foxp3+CD45RO) (n= 55 T1D, n=45 controls, P=0.01). The activation defect persists life long in T1D subjects (T1D=45, controls=45, P=0.01, P=0.04). Lower numbers of aTregs had clinical significance because they were associated with a trend for less residual C-peptide secretion from the pancreas (P=0.08), and poorer HbA1C control (P=0.03). In humans, the tumor necrosis factor receptor 2 (TNFR2) is obligatory for Treg induction, maintenance and expansion of aTregs. TNFR2 agonism is a method for stimulating Treg conversion from resting to activated. Using two separate in vitro expansion protocols, TNFR2 agonism corrected the T1D activation defect by triggering conversion of rTregs into aTregs (n=54 T1D, P<0.001). TNFR2 agonism was superior to standard protocols and TNF in proliferating Tregs. In T1D, TNFR2 agonist-expanded Tregs were homogeneous and functionally potent by virtue of suppressing autologous cytotoxic T cells in a dose-dependent manner comparable to controls. Targeting the TNFR2 receptor for Treg expansion in vitro demonstrates a means to correct the activation defect in T1D.
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    Circulating Soluble CD163 is Associated with Steatohepatitis and Advanced Fibrosis in Nonalcoholic Fatty Liver Disease
    (Nature Publishing Group, 2015) Mueller, Jessica L; Feeney, Eoin R; Zheng, Hui; Misdraji, Joseph; Kruger, Annie; Alatrakchi, Nadia; King, Lindsay Y; Gelrud, Louis; Corey, Kathleen; Chung, Raymond
    OBJECTIVES: Soluble CD163 (sCD163), a marker of Kupffer cell activation detectable in serum, correlates with inflammation and fibrosis in chronic viral hepatitis, but its role in nonalcoholic fatty liver disease is unknown. We hypothesized that sCD163 would correlate with nonalcoholic fatty liver disease activity and fibrosis. METHODS: Liver biopsies and serum were obtained from 145 obese subjects undergoing gastric bypass surgery. Subjects were divided into four groups based on fibrosis stage and nonalcoholic fatty liver disease activity score (NAS); Group 1: F0, NAS=0; Group 2: F<2, 0