NOT-OD-02-069: FINDINGS OF SCIENTIFIC MISCONDUCT

Department of Health
and Human Services (HHS)
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FINDINGS OF SCIENTIFIC MISCONDUCT

Release Date:  September 10, 2002

NOTICE NUMBER: NOT-OD-02-069

Department of Health and Human Services

Notice is hereby given that the Office of Research Integrity (ORI) and 
the Assistant Secretary for Health have taken final action in the 
following case:

Zhenhai Yao, M.D., Ph.D., The University of North Carolina at Chapel 
Hill:  On August 20, 2002, the U.S. Public Health Service (PHS) entered 
into a Voluntary Exclusion Agreement with The University of North 
Carolina at Chapel Hill (UNC) and Zhenhai Yao, M.D., Ph.D., an 
Associate Professor of Anesthesiology, School of Medicine at UNC.  
Based on the UNC Report, the respondent"s admissions, and additional 
analysis conducted by ORI in its oversight review, PHS found that Dr. 
Yao engaged in scientific misconduct in research funded by the National 
Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health 
(NIH).

Specifically, PHS and UNC found that Dr. Yao:

(1)  Falsified two flourescent micrographs for figures presented in 
three NIH grant applications:

A.  Figure 5, p. 28, in a funded grant application in 1 R01 HL067416-
01, "Mechanism of Preconditioning and Cardiac Apoptosis," submitted to 
NIH on May 31, 2000,

B.  Figure 6, p. 33, in a funded grant application in 1 R01 HL68250-01, 
"Free Radicals, PKCd Signal Acetylcholine Preconditioning," submitted 
to NIH on September9, 2000, and

C.  Figure 7, p. 25, in an unfunded grant application in 1 R01 HL66230-
01A1, "Nitric Oxide and Opioid Preconditioning," Submitted to NIH on 
July 2, 2001.

Dr. Yao falsely claimed that two fluorescent micrographs in the figure 
represented neonatal rat cells transfected with an adenovirus-derived 
vector, when the cells actually were chick cells transfected with a 
cytomegalovirus-based vector, which he had taken from another scientist 
at the University of Chicago.

(2)  Falsified the same two fluorescence micrographs of CMV-transfected 
chick cells described in Issue 1, above, by misrepresenting their 
description as embryonic chick cells transfected with pcDNA, with and 
without green fluorescent protein, for Figure 13 on p. 30 in an 
unfunded NIH grant application, 1 R01 HL66230-01, "Molecular Mechanisms 
of Opioids in Myocardial Ischemia," submitted January 21, 2000.

(3)  Falsified a flow cytometry histogram in Figure 1B on p. 22 of NIH 
application R01 HL66230-01A1, by claiming the histogram represented 
results with rat myocardiocyte cultures treated with an opiate 
antagonist (staurosporine).

However, this histogram had been published by Liu, H., McPherson, B.C., 
& Yao, Z.  "Preconditioning Attentuates Apoptosis and Necrosis:  Role 
of Protein Kinase Ce and -d Isoforms."  Am. J. Physiology Heart Circ 
Physiol. 281:H404-H410, 2001, as Figure 1f showing the result from 
embryonic chick cells treated for 12 hours with deoxy-glucose in the 
absence of oxygen (simulated ischemia).

(4)  Falsified claims about research results in NIH grant application 
R01 HL66230-01A1, by claiming that data in Figure 3 on p. 23 
represented experiments on cultures of neonatal rat cardiomyocytes as 
an in vitro model of hypoxia-reoxygenation, shown as data from four 
separate experiments measuring apoptosis by different means.

The data in the four separate experiments portrayed in Figure 3 are 
identical to Figure 1, p. 2009, in the publication by Liu, H., Zhang, 
H.Y., McPherson, B.C., Baman, T., Roth, S., Shao, Z., Zhu, X., & Yao, 
Z.  "Role of Opioid d1 Receptors, Mitochondrial KATP Channels, and 
Protein Kinase C during Cardiocyte Apoptosis.  J. Mol. Cell. Cardio. 
33:2001-2014, 2001, which were reported as the results from experiments 
on cultures of embryonic chick cardiocytes.

(5)  Falsified the micrographs in panels a and d, Figure 1, p. 2009, in 
the publication by Liu, H. et al., J. Mol. Cell. Cardiol. 33:2001-2014, 
2001, by claiming they represented TUNEL data showing normal media and 
opioid antagonist (BTNX)-treated cultures of chick cardiocytes, 
respectively.

The same micrographs had been reported by Liu, H. et al., Am. J. 
Physiology Heart Circ Physiol. 281:H404-H410, 2001, in Figure 1 (panels 
a and e) and in Figure 2 (panels a and b), as representing cardiocyte 
cultures exposed for 24 hours to deoxy-glucose and no oxygen (simulated 
ischemia).

(6)  Falsified the physiological effects of gene transduction into 
hearts, by copying and re-using the same pressure tracing for untreated 
rates as he did for rats purportedly treated by intracardial injection 
with adenovirus (AdEGFP) in:

A.  Figure 11, p. 26, in unfunded NIH grant application R01 HL66230-
01Al,
B.  Figure 9, p. 30, in funded NIH grant application R01 HL67416-01,
C.  Figure 9, p. 34, in funded NIH grant application R01 HL68250-01, 
and
D.  Figure 8, p. 30, in funded NIH grant application 1 K08 HL03881-01.

(7)  Falsified data in panels c and d in Figure 13, p. 26, in NIH grant 
application R01 HL66230-01A1.  Dr. Yao claimed that panel c represented 
a TUNEL assay on histological sections of myocardium from a rat 
transfected with Ad. gal and subjected to ischemia-reperfusion and that 
panel d represented a tissue section from a rat transfected with 
Ad.PKCd-FL.

Panel c is a horizontally compressed copy of panel b, purported to be a 
non-transfected rat subjected to ischemia-reperfusion, and panel d is a 
horizontally expanded version of panel a, purported to be a sham-
operated, non-transfected control.

(8)  Falsified the claims about the micrograph of ischemic data ("panel 
b" in issue 7, above) reported as:

A.  Figure 11, p. 31, in R01 HL67416-01 (submitted May 31, 2000), and
B.  Figure 12, p. 35, in R01 HL68250-01 (submitted September 29, 2000).

In both examples, the figures, which are identical, consist of two 
panels purported to be TUNEL data showing sham operated controls (panel 
a) and the effect of transient ischemia for 30 minutes (panel b).  
However, these data are identical to Figure 10, p. 32, in NIH 
application K08 HL03881-01, reported a control and the effect of 
nontransient ischemia, i.e., 20 hours of ischemia followed by 24 hours 
of reperfusion.

(9)Falsified data in Figure 14 on p. 27 in NIH grant application R01 
HL66230-01A1, as representing a gel electophoresis data from an in vivo 
experiment on rat myocardial ischemia.

However, the same data was represented as Figure 3, p. 23, of the 
application (and also as in Figure 1, J. Cell. Mol. Cardiol. 33:2007-
2014, 2001), as results from a study of embryonic chick heart cell 
cultures for the effect of preconditioning on opioid receptors.  
Furthermore, Dr. Yao falsified the stated size of the fragments in the 
DNA marker ladder by altering the position of the molecular weight 
markers in Figure 14.

(10)  Falsified Figure 3, p. 27, in 1 R01 HL67416-01, a DNA-laddering 
gel electrophoresis experiment, showing that apoptosis in cardiocyte 
cultures is significantly increased by staurosporin and by 12 hours of 
simulated ischemia.

The same data was shown in Figure 1, p. 26, in application HL03881-07 
showing that apoptosis is significantly increased by 10 ?M NE and by 15 
nM TNF-a.

The research misconduct was significant because Dr. Yao"s research 
involved the fundamental mechanisms for cardiac cell injury and 
pathogenesis after a heart attack.  The falsified data were significant 
to reviewers" opinions on funding because they were advanced as 
preliminary results showing successful new experiments extending his 
experimental model to adult rat hearts.

Dr. Yao has entered into a Voluntary Exclusion Agreement in which he 
has voluntarily agreed:

(1)  to exclude himself from any contracting or subcontracting with any 
agency of the United States Government and from eligibility for, or 
involvement in, nonprocurement transactions (e.g., grants and 
cooperative agreements) of the United States Government as defined in 
45 C.F.R. Part 76 (Debarment Regulations) for a period of five (5) 
years, beginning on August 20, 2002,

(2)  to exclude himself from serving in any advisory capacity to PHS, 
including but not limited to service on any PHS advisory committee, 
board, and/or peer review committee, or as a consultant for a period of 
five (5) years, beginning on August 20, 2002, and

(3)  to submit a letter to the Journal of Molecular and Cellular 
Cardiology requesting retraction of Figure 1 in the article by Hui Liu, 
et al., J. Mol. Cell. Cardiol. 33:2001-2014, 2001, within 30 days of 
notification of this action.  This requirement will be noted on the 
ALERT System until Dr. Yao sends a copy of the retraction letter to 
ORI.

INQUIRIES

For further information contact:

Director
Division of Investigative Oversight
Office of Research Integrity
5515 Security Lane, Suite 700
Rockville, MD  20852
Telephone:  301-443-5330
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