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author:("Li, mianmin")
1.  NNK, a Tobacco-Specific Carcinogen, Inhibits the Expression of Lysyl Oxidase, a Tumor Suppressor 
A tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is believed to contribute to the cancer burden in cigarette smokers. To evaluate NNK effects on the expression of lysyl oxidase (LOX), a tumor suppressor, we examined this enzyme at various levels in NNK-treated rat fetal lung fibroblasts (RFL6). Exposure of cells to NNK reduced levels of steady-states LOX mRNA and new transcript synthesis. NNK inhibited all LOX protein species in a dose-dependent manner. Although 300 µM NNK markedly decreased the level in the 46 kDa preproenzyme, under same conditions, there was no detectable amounts of the 50 kDa proenzyme and the 32 kDa mature enzyme suggesting NNK perturbing the LOX protein processing to its mature form. Moreover, NNK also suppressed LOX activities in conditioned media of treated cells. At the promoter level, NNK enhanced methylation of CpG, but decreased acetylation of histone H3 at the core promoter region of the LOX gene. These results indicated that transcriptional and translational processes of LOX are major targets for NNK. Thus, inactivation of tumor suppressor gene LOX may play a critical role in NNK carcinogenesis.
PMCID: PMC4306850  PMID: 25546273
lysyl oxidase (LOX); 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK); CpG methylation; histone H3 acetylation
2.  CD271+ Osteosarcoma Cells Display Stem-Like Properties 
PLoS ONE  2014;9(6):e98549.
Cancer stem cell (CSC) theory has been proposed and verified in many cancers. The existence of osteosarcoma CSCs has been confirmed for many years and multiple surface markers have been employed to identify them. In this study, we identified CD271+ subpopulation of osteosarcoma displaying stem-like properties. CD271, known as the neural crest nerve growth factor receptor, is the marker of bone marrow mesenchymal stem cells (MSCs) and human melanoma-initiating cells. We discovered that CD271 was expressed differentially in diverse types of human osteosarcoma and stabilized cell lines. CD271+ osteosarcoma cells displayed most of the properties of CSC, such as self-renewal, differentiation, drug resistance and tumorigenicity in vivo. Nanog, Oct3/4, STAT3, DNA-PKcs, Bcl-2 and ABCG2 were more expressed in CD271+ cells compared with CD271− cells. Our study supported the osteosarcoma CSC hypothesis and, to a certain extent, revealed one of the possible mechanisms involved in maintaining CSCs properties.
PMCID: PMC4043643  PMID: 24893164
3.  The Epidemic of Non-Hodgkin Lymphoma in the United States: Disentangling the Effect of HIV, 1992–2009 
For decades, non-Hodgkin lymphoma (NHL) incidence has been increasing worldwide. NHL risk is strongly increased among HIV-infected people. Our understanding of trends in NHL incidence has been hampered by difficulties in separating HIV-infected NHL cases from general population rates.
Materials and Methods
NHL incidence data during 1992–2009 were derived from 10 U.S. SEER cancer registries with information on HIV status at NHL diagnosis. The CDC estimated the number of people living with HIV in the registry areas. The proportion of NHL cases with HIV and NHL rates in the total and the HIV-uninfected populations were estimated. Time trends were assessed with Joinpoint analyses.
Of 115,643 NHL cases diagnosed during 1992–2009, 5.9% were HIV-infected. The proportions of NHL cases with HIV were highest for diffuse large B-cell (DLBCL; 7.8%), Burkitt (26.9%), and peripheral T-cell lymphomas (3.2%) with low proportions (≤1.1%) in the other subtypes. NHL rates in the total population increased 0.3% per year during 1992–2009. However, rates of NHL in HIV-uninfected people increased 1.4% per year during 1992–2003, before becoming stable through 2009. Similar trends were observed for DLBCL and follicular lymphoma in HIV-uninfected people; rates increased 2.7% per year until 2003 and 1.7% per year until 2005, respectively, before stabilizing.
NHL incidence rates in the U.S. have plateaued over the last 5–10 years, independent of HIV infection.
Though the causes of the long-term increase in NHL incidence rates in the U.S. remain unknown, general population rates of NHL have stabilized since the early 2000s, independent of HIV.
PMCID: PMC3698875  PMID: 23595542
non-Hodgkin lymphoma; HIV; trends
4.  Regulation of extracellular signal-regulated kinase 1/2 influences hippocampal neuronal survival in a rat model of diabetic cerebral ischemia 
Neural Regeneration Research  2014;9(7):749-756.
Activation of extracellular signal-regulated kinase 1/2 has been demonstrated in acute brain ischemia. We hypothesized that activated extracellular signal-regulated kinase 1/2 can protect hippocampal neurons from injury in a diabetic model after cerebral ischemia/reperfusion. In this study, transient whole-brain ischemia was induced by four-vessel occlusion in normal and diabetic rats, and extracellular signal-regulated kinase 1/2 inhibitor (U0126) was administered into diabetic rats 30 minutes before ischemia as a pretreatment. Results showed that the number of surviving neurons in the hippocampal CA1 region was reduced, extracellular signal-regulated kinase 1/2 phosphorylation and Ku70 activity were decreased, and pro-apoptotic Bax expression was upregulated after intervention using U0126. These findings demonstrate that inhibition of extracellular signal-regulated kinase 1/2 activity aggravated neuronal loss in the hippocampus in a diabetic rat after cerebral ischemia/reperfusion, further decreased DNA repairing ability and accelerated apoptosis in hippocampal neurons. Extracellular signal-regulated kinase 1/2 activation plays a neuroprotective role in hippocampal neurons in a diabetic rat after cerebral ischemia/reperfusion.
PMCID: PMC4146267  PMID: 25206883
nerve regeneration; brain injury; cerebral ischemia/reperfusion; DNA dependent protein kinase; extracellular signal-regulated kinase; Bax; apoptosis; hippocampus; neural regeneration
5.  The Effect of Resveratrol on Surgery-Induced Epidural Fibrosis in Laminectomy Rats 
Epidural fibrosis (EF) is a common complication for the patients who underwent laminectomy. Recently, EF is thought to cause recurrent postoperative pain after laminectomy. Resveratrol has been shown to exert its anti-inflammatory, antifibrotic, and antiproliferative multifaceted properties. The object of this study was to investigate the effects of resveratrol on the prevention of postlaminectomy EF formation in laminectomy rats. A controlled double-blinded study was performed on 60 healthy adult Sprague-Dawley rats that underwent lumbar laminectomy at the L1-L2 levels. They were divided randomly into 3 groups (1, 2, and 3) of 20 rats each—group 1: resveratrol treatment group; group 2: resveratrol dilution saline treatment group; group 3: sham group (rats underwent laminectomy without treatment). All rats were killed 4 weeks after operation. The Rydell score, hydroxyproline content, vimentin cells density, fibroblasts density, and inflammatory factors expressional levels all suggested better results in resveratrol group than the other two groups. Resveratrol is able to inhibit fibroblasts proliferation, and TGF-β1 and IL-6 expressions and prevent epidural fibrosis in postlaminectomy rat.
PMCID: PMC3982460  PMID: 24782910
6.  Apolipoprotein E mimetic peptide protects against diffuse brain injury 
Neural Regeneration Research  2014;9(5):463-473.
Apolipoprotein E plays a crucial role in inhibiting chronic neurodegenerative processes. However, its impact on neurological function following diffuse brain injury is still unclear. This study was designed to evaluate the therapeutic effects and mechanisms of action of apolipoprotein E mimetic peptide on diffuse brain injury. Apolipoprotein E mimetic peptide was administered into the caudal vein of rats with diffuse brain injury before and after injury. We found that apolipoprotein E mimetic peptide significantly decreased the number of apoptotic neurons, reduced extracellular signal-regulated kinase1/2 phosphorylation, down-regulated Bax and cytochrome c expression, decreased malondialdehyde content, and increased superoxide dismutase activity in a dose-dependent manner. These experimental findings demonstrate that apolipoprotein E mimetic peptide improves learning and memory function and protects against diffuse brain injury-induced apoptosis by inhibiting the extracellular signal-regulated kinase1/2-Bax mitochondrial apoptotic pathway.
PMCID: PMC4153503  PMID: 25206840
nerve regeneration; brain injury; apolipoprotein E; diffuse brain injury; learning and memory; extracellular signal-regulated kinase; Bax; mitochondria; reactive oxygen species; apoptosis; Scientific Research and Development Plan of Hebei Province in China; neural regeneration
7.  Proportions of Kaposi Sarcoma, Selected Non-Hodgkin Lymphomas, and Cervical Cancer in the United States Occurring in Persons With AIDS, 1980–2007 
Given the higher risk of AIDS-defining malignancies that include Kaposi sarcoma (KS), certain non-Hodgkin lymphomas (NHLs), and cervical cancer in persons with human immunodeficiency virus (HIV) infection, the HIV epidemic has likely contributed to the overall numbers of these cancers in the United States.
To quantify the proportions of KS, AIDS-defining NHLs, and cervical cancer in the United States that occurred among persons with AIDS from 1980 to 2007.
Design, Setting, and Participants
The HIV/AIDS Cancer Match Study (1980–2007) linked data from 16 US HIV/AIDS and cancer registries to identify cases with and without AIDS for KS, AIDS-defining NHLs (ie, diffuse large B-cell lymphoma [DLBCL], Burkitt lymphoma [BL], and central nervous system [CNS] lymphoma), and cervical cancer. Using linked data, we derived cancer rates for persons with and without AIDS. To estimate national counts, the rates were applied to national AIDS surveillance and US Census data.
Main Outcome Measure
Proportion of AIDS-defining malignancies in the United States occurring in persons with AIDS.
In the United States, an estimated 79.0% (95% confidence interval [CI], 78.6%–79.4%) of 85 922 KS cases, 5.5% (95% CI, 5.3%–5.6%) of 383 095 DLBCL cases, 19.4% (95% CI, 17.8%–21.1%) of 17 780 BL cases, 26.2% (95% CI, 25.2%–27.1%) of 28 259 CNS lymphoma cases, and 0.41% (95% CI, 0.36%–0.46%) of 386 166 cervical cancer cases occurred among persons with AIDS during 1980–2007. The proportion of KS and AIDS-defining NHLs in persons with AIDS peaked in the early 1990s (1990–1995: KS, 89.0% [95%CI, 88.6%–89.3%]; DLBCL, 9.5% [95%CI, 9.2%–9.8%]; BL, 27.4% [95% CI, 25.0%–29.7%]; and CNS lymphoma, 47.2% [95% CI, 45.7%–48.7%]; all P<.001 [compared with 1980–1989]) and then declined (2001–2007: KS, 67.0% [95% CI, 64.5%–69.4%]; DLBCL, 4.3% [95% CI, 3.9%–4.6%]; BL, 20.8% [95% CI, 17.2%–24.3%]; and CNS lymphoma, 12.3% [95% CI, 10.1%–14.4%]; all P<.001 [compared with 1990–1995]). The proportion of cervical cancers in persons with AIDS increased overtime (1980–1989: 0.11% [95% CI, 0.08%–0.13%]; 2001–2007: 0.69% [95% CI, 0.49%–0.89%]; P<.001).
In the United States, the estimated proportions of AIDS-defining malignancies that occurred among persons with AIDS were substantial, particularly for KS and some NHLs. Except for cervical cancer, the proportions of AIDS-defining malignancies occurring among persons with AIDS peaked in the mid-1990s and then declined.
PMCID: PMC3909038  PMID: 21486978
8.  Clinicopathological characteristics of vascular endothelial growth factor expression in uveal melanoma: A meta-analysis 
Molecular and Clinical Oncology  2014;2(3):363-368.
Angiogenesis is a potential prognostic factor that has been extensively investigated in patients with uveal melanoma (UM). Vascular endothelial growth factor (VEGF) expression is crucial in angiogenesis. However, there have been conflicting data regarding the clinicopathological data in UM. A meta-analysis was performed of all the germane literature to assess the clinicopathological characteristics of VEGF expression by combining separately estimated odds ratio (OR) values. Our combined results demonstrated that, according to the available studies, the expression of VEGF in UM was significantly higher compared to normal tissue [338 patients and 99 controls; OR=16.15, 95% confidence interval (CI): 8.65–30.12, P<0.00001]. When stratifying the studies by age (315 patients; OR=2.08, 95% CI: 1.19–3.62, P=0.01), cell type (423 patients; OR=0.54, 95% CI: 0.32–0.90, P=0.02), tumor size (222 patients; OR=0.30, 95% CI: 0.14–0.68, P=0.004) and scleral invasion (248 patients; OR=0.34, 95% CI: 0.15–0.78, P=0.01), significant clinicopathological information was provided. Our results indicated that VEGF expression in UM patients was significantly higher compared to that observed in controls. It was also significantly higher in patients who presented with scleral invasion and those who were aged <50 years. In addition, VEGF expression was higher in mixed-cell type and epithelioid-cell type UM and in patients with large-sized tumors.
PMCID: PMC3999140  PMID: 24772301
uveal melanoma; vascular endothelial growth factor expression; clinicopathological characteristics; angiogenesis
9.  Sparsity-Regularized HMAX for Visual Recognition 
PLoS ONE  2014;9(1):e81813.
About ten years ago, HMAX was proposed as a simple and biologically feasible model for object recognition, based on how the visual cortex processes information. However, the model does not encompass sparse firing, which is a hallmark of neurons at all stages of the visual pathway. The current paper presents an improved model, called sparse HMAX, which integrates sparse firing. This model is able to learn higher-level features of objects on unlabeled training images. Unlike most other deep learning models that explicitly address global structure of images in every layer, sparse HMAX addresses local to global structure gradually along the hierarchy by applying patch-based learning to the output of the previous layer. As a consequence, the learning method can be standard sparse coding (SSC) or independent component analysis (ICA), two techniques deeply rooted in neuroscience. What makes SSC and ICA applicable at higher levels is the introduction of linear higher-order statistical regularities by max pooling. After training, high-level units display sparse, invariant selectivity for particular individuals or for image categories like those observed in human inferior temporal cortex (ITC) and medial temporal lobe (MTL). Finally, on an image classification benchmark, sparse HMAX outperforms the original HMAX by a large margin, suggesting its great potential for computer vision.
PMCID: PMC3879257  PMID: 24392078
10.  PDL241, a novel humanized monoclonal antibody, reveals CD319 as a therapeutic target for rheumatoid arthritis 
Arthritis Research & Therapy  2013;15(6):R207.
Targeting the CD20 antigen has been a successful therapeutic intervention in the treatment of rheumatoid arthritis (RA). However, in some patients with an inadequate response to anti-CD20 therapy, a persistence of CD20- plasmablasts is noted. The strong expression of CD319 on CD20- plasmablast and plasma cell populations in RA synovium led to the investigation of the potential of CD319 as a therapeutic target.
PDL241, a novel humanized IgG1 monoclonal antibody (mAb) to CD319, was generated and examined for its ability to inhibit immunoglobulin production from plasmablasts and plasma cells generated from peripheral blood mononuclear cells (PBMC) in the presence and absence of RA synovial fibroblasts (RA-SF). The in vivo activity of PDL241 was determined in a human PBMC transfer into NOD scid IL-2 gamma chain knockout (NSG) mouse model. Finally, the ability of PDL241 to ameliorate experimental arthritis was evaluated in a collagen-induced arthritis (CIA) model in rhesus monkeys.
PDL241 bound to plasmablasts and plasma cells but not naïve B cells. Consistent with the binding profile, PDL241 inhibited the production of IgM from in vitro PBMC cultures by the depletion of CD319+ plasmablasts and plasma cells but not B cells. The activity of PDL241 was dependent on an intact Fc portion of the IgG1 and mediated predominantly by natural killer cells. Inhibition of IgM production was also observed in the human PBMC transfer to NSG mouse model. Treatment of rhesus monkeys in a CIA model with PDL241 led to a significant inhibition of anti-collagen IgG and IgM antibodies. A beneficial effect on joint related parameters, including bone remodeling, histopathology, and joint swelling was also observed.
The activity of PDL241 in both in vitro and in vivo models highlights the potential of CD319 as a therapeutic target in RA.
PMCID: PMC3978732  PMID: 24299175
11.  Meta-analysis of the association of HLA-DRB1 with rheumatoid arthritis in Chinese populations 
Individual studies have reported different results regarding the association of HLA alleles with RA in Chinese populations. This study was performed to systematically summarize results on the association of HLA-DRB1 with rheumatoid arthritis (RA) in China.
We examined the case–control studies concerned about the relationship between HLA-DRB1and RA and differences of clinical and laboratory parameters between the HLA-DR4 (DR4)+ and DR4- in RA patients in Chinese populations. Odds ratios (ORs) and weighted mean difference (WMD) with corresponding 95% confidence intervals (CI) was used to describe the relationship.
22 studies with 1690 cases and 1793 controls were included. Chinese populations with RA had significantly higher frequencies of HLA-DRB1*04, *0401, *0404, *0405 and *0410 than controls (ORDRB1*04 =4.19, 95% CI =3.44–5.11, p<0.00001; ORDRB1*0401 =2.53, 95% CI =1.54–4.16, p=0.0003; ORDRB1*0404 =2.28, 95% CI =1.28–4.06, p=0.005; ORDRB1*0405=3.71, 95% CI =2.52–5.45, p<0.00001; ORDRB1*0410 =2.99, 95% CI =1.25–7.14, p=0.01respectively). As to laboratory parameters, Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Rheumatoid factor (RF), Anti-cyclic citrullinated peptide antibodies (Anti-CCP ) in patients with DR4+ were higher than patients with DR4- (WMD=0.26, 95% CI =0.15–0.37, p<0.00001; WMD = 0.26, 95% CI =0.12–0.41, p=0.0005; WMD = 0.44, 95% CI =0.23–0.65, p<0.00001; WMD = 0.58, 95% CI =0.24–0.91, p=0.0007 respectively). As to clinical features, there was no difference in duration of morning stiffness, number of swollen joints, number of joint tenderness, X-ray phases and joint function between the DR4+ and DR4- in RA patients.
It was found that HLA-DRB1*04, *0401, *0404, *0405 and *0410 are risk factors for RA in Chinese populations. ESR, CRP, RF, Anti-CCP are different between the DR4+ and DR4- in RA patients in Chinese populations, while there’s no difference for indexes of clinical features.
PMCID: PMC4231398  PMID: 24161032
Rheumatoid arthritis; HLA-DRB1; Laboratory parameters; Meta-analysis
12.  Protective effects of dl-3n-butylphthalide against diffuse brain injury 
Neural Regeneration Research  2013;8(28):2615-2624.
Dl-3n-butylphthalide can effectively treat cerebral ischemia; however, the mechanisms underlying the effects of dl-3n-butylphthalide on microcirculation disorders following diffuse brain injury remain unclear. In this study, models of diffuse brain injury were established in Sprague-Dawley rats with the vertical impact method. Dl-3n-butylphthalide at 80 and 160 mg/kg was given via intraperitoneal injection immediately after diffuse brain injury. Ultrastructural changes in the cerebral cortex were observed using electron microscopy. Cerebral blood flow was measured by laser Doppler flowmetry, vascular density was marked by tannic acid-ferric chloride staining, vascular permeability was es-timated by the Evans blue method, brain water content was measured using the dry-wet method, and rat behavior was measured by motor function and sensory function tests. At 6, 24, 48, and 72 hours after administration of dl-3n-butylphthalide, reduced cerebral ultrastructure damage, creased vascular density and cerebral blood flow, and improved motor and sensory functions were observed. Our findings demonstrate that dl-3n-butylphthalide may have protective effects against diffuse brain injury by ameliorating microcirculation disorder and reducing blood-brain barrier age and cerebral edema.
PMCID: PMC4146025  PMID: 25206572
neural regeneration; brain injury; diffuse brain injury; blood-brain barrier; brain edema; vascular density; cerebral blood flow; vascular permeability; brain water content; grants-supported paper; neuroregeneration
13.  Parameters of lengthened sacroiliac screw fixation: a radiological anatomy study 
European Spine Journal  2012;21(9):1807-1814.
To provide the anatomical basis for the feasibility and clinical practice of lengthened sacroiliac screw fixation, by measuring various related indicators of the safe insertion regions of S1 and S2 lengthened sacroiliac screws.
A total of 66 healthy pelvises of adults were scanned by 64-slice spiral CT and the length, width and height of the safe insertion regions for S1 and S2 lengthened sacroiliac screw were measured. The safe screw entrance point locations were described with a quantitative method. The indicators were recorded by descriptive statistics and the statistics of left and right sides, segments of S1 and S2, and different layers (including top, middle and bottom parts) of S1 and S2 were compared.
The lengths of ilium within the safe insertion regions for lengthened screws are more than 16 mm. The width and height of the safe insertion region of S1 and S2 are almost all more than 7.3 mm. Generally, the width and height of S1 are larger than those of S2. The reference ranges of the best/safest entrance point locations of lengthened sacroiliac screws are as follows—S1: 42.21–63.69 mm in front of posterior superior iliac spine, 32.77–53.75 mm above the highest point of the greater sciatic notch; S2: 22.68–54.28 mm in front of posterior superior iliac spine, 14.06–33.70 mm above the highest point of the greater sciatic notch.
(1) There is anatomical feasibility for the placements of S1 and S2 lengthened sacroiliac screws. (2) φ 7.3-mm partial thread cannulated screw (thread length 16 mm) and φ 6.5-mm partial thread cancellous screw(thread length 16 mm) can be used as lengthened sacroiliac lag screw. (3) The safe insertion space of S1 is larger than that of S2. (4) There is safe space for placement of at least one piece of lengthened sacroiliac screw in both S1 and S2. (5) The best/safest entrance points of S1 and S2 can be approximately located with anatomical landmarks.
PMCID: PMC3459111  PMID: 22610442
Sacroiliac screw; Pelvis; Anatomy; CT
14.  Biomimetic enzyme nanocomplexes and their use as antidotes and preventive measures for alcohol intoxication 
Nature nanotechnology  2013;8(3):187-192.
Organisms have sophisticated subcellular compartments containing enzymes that function in tandem. These confined compartments ensure effective chemical transformation and transport of molecules, and the elimination of toxic metabolic wastes1,2. Creating functional enzyme complexes that are confined in a similar way remains challenging. Here we show that two or more enzymes with complementary functions can be assembled and encapsulated within a thin polymer shell to form enzyme nanocomplexes. These nanocomplexes exhibit improved catalytic efficiency and enhanced stability when compared with free enzymes. Furthermore, the co-localized enzymes display complementary functions, whereby toxic intermediates generated by one enzyme can be promptly eliminated by another enzyme. We show that nanocomplexes containing alcohol oxidase and catalase could reduce blood alcohol levels in intoxicated mice, offering an alternative antidote and prophylactic for alcohol intoxication.
PMCID: PMC3670615  PMID: 23416793
15.  Osteopontin genetic variants are associated with overall survival in advanced non-small-cell lung cancer patients and bone metastasis 
Osteopontin (OPN) plays important roles in the modulation of apoptosis, angiogenesis, immune response, and tumor invasion. Elevated osteopontin expression has been reported in the lung cancer tissues compared to counterpart normal tissues. This study examined whether genetic variations in the osteopontin gene are associated with survival of lung cancer patients and occurrence rate of bone metastasis.
Experimental design
Three hundred and sixty patients with stages I to IV between 2003 and 2007 were recruited in this study and same number of healthy persons were used as control. Three promoter osteopontin polymorphisms, OPN-66 T/G, -156G/GG, and -443C/T variants were genotyped using DNA from blood lymphocytes. Chi-square test and a Fisher’s exact test were used to analyze the genotype distribution among TNM stages and incidence of bone metastasis and lymph mode metastasis. Kaplan-Meier method and log-rank test were used to compare survival by different genotypes.
For the variant at nt −443 (CC), there was a significant difference between the number of patients with stage IV and those with all other stages of lung cancer (p < 0.01). Patients with −443 (CC) variant had significant higher incidence of bone metastasis development compared to other genotypes. For the variant at nt −443 (CT), there was a significant difference between the number of lung cancer patients with stage III + IV and those with stage I + II (P < 0.01). The survival rates for patients with the C/C genotype were significantly lower than for patients with the other two genotypes (C/T, T/T).
OSTEOPONTIN −443C/T polymorphism is a potential predictive marker of survival in lung cancer patients, it is correlated with bone metastasis significantly.
PMCID: PMC3728114  PMID: 23883434
Osteopontin; Non-small-cell lung cancer; Genetic variants; Bone metastasis
16.  Cancer Burden in the HIV-Infected Population in the United States 
Effective antiretroviral therapy has reduced the risk of AIDS and dramatically prolonged the survival of HIV-infected people in the United States. Consequently, an increasing number of HIV-infected people are at risk of non-AIDS-defining cancers that typically occur at older ages. We estimated the annual number of cancers in the HIV-infected population, both with and without AIDS, in the United States.
Incidence rates for individual cancer types were obtained from the HIV/AIDS Cancer Match Study by linking 15 HIV and cancer registries in the United States. Estimated counts of the US HIV-infected and AIDS populations were obtained from Centers for Disease Control and Prevention surveillance data. We obtained estimated counts of AIDS-defining (ie, Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer) and non-AIDS-defining cancers in the US AIDS population during 1991–2005 by multiplying cancer incidence rates and AIDS population counts, stratified by year, age, sex, race and ethnicity, transmission category, and AIDS-relative time. We tested trends in counts and standardized incidence rates using linear regression models. We multiplied overall cancer rates and HIV-only (HIV infected, without AIDS) population counts, available from 34 US states during 2004–2007, to estimate cancers in the HIV-only population. All statistical tests were two-sided.
The US AIDS population expanded fourfold from 1991 to 2005 (96 179 to 413 080) largely because of an increase in the number of people aged 40 years or older. During 1991–2005, an estimated 79 656 cancers occurred in the AIDS population. From 1991–1995 to 2001–2005, the estimated number of AIDS-defining cancers decreased by greater than threefold (34 587 to 10 325 cancers; Ptrend < .001), whereas non-AIDS-defining cancers increased by approximately threefold (3193 to 10 059 cancers; Ptrend < .001). From 1991–1995 to 2001–2005, estimated counts increased for anal (206 to 1564 cancers), liver (116 to 583 cancers), prostate (87 to 759 cancers), and lung cancers (875 to 1882 cancers), and Hodgkin lymphoma (426 to 897 cancers). In the HIV-only population in 34 US states, an estimated 2191 non-AIDS-defining cancers occurred during 2004–2007, including 454 lung, 166 breast, and 154 anal cancers.
Over a 15-year period (1991–2005), increases in non-AIDS-defining cancers were mainly driven by growth and aging of the AIDS population. This growing burden requires targeted cancer prevention and treatment strategies.
PMCID: PMC3086877  PMID: 21483021
17.  Crosslinking Characteristics and Mechanical Properties of an Injectable Biomaterial Composed of Polypropylene fumarate and Polycaprolactone Copolymer 
In this work, a series of copolymers of polypropylene fumarate-co-polycaprolactone (PPF-co-PCL) were synthesized via a three-step polycondensation reaction of oligomeric polypropylene fumarate (PPF) with polycaprolactone (PCL). The effects of PPF precursor molecular weight, PCL precursor molecular weight, and PCL fraction in the copolymer (PCL feed ratio) on the maximum crosslinking temperature, gelation time, and mechanical properties of the crosslinked copolymers were investigated. The maximum crosslinking temperature fell between 38.2±0.3 and 47.2±0.4 °C, which increased with increasing PCL precursor molecular weight. The gelation time was between 4.2±0.2 and 8.5±0.7 min, and decreased with increasing PCL precursor molecular weight. The compressive moduli ranged from 44±1.8 to 142±7.4 MPa, with enhanced moduli at higher PPF precursor molecular weight and lower PCL feed ratio. The compressive toughness was in the range of 4.1±0.3 and 17.1±1.3 KJ/m3. Our data suggest that the crosslinking and mechanical properties of PPF-co-PCL can be modulated by varying the composition. Therefore the PPF-co-PCL copolymers may offer increased versatility as an injectable, in situ polymerizable biomaterial than the individual polymers of PPF and PCL.
PMCID: PMC3062160  PMID: 20566042
Polypropylene fumarate; polycaprolactone; injectable biomaterials; in situ polymerizable
18.  RNAi-mediated knockdown of ERK1/2 inhibits cell proliferation and invasion and increases chemosensitivity to cisplatin in human osteosarcoma U2-OS cells in vitro 
International Journal of Oncology  2011;40(4):1291-1297.
Osteosarcoma is the most common primary malignancy of the bone. There have been some advances in surgical and chemotherapeutic strategies, but it is still a tumor with a high mortality rate in children and young adults. Mitogen-activated protein kinase/extracellular signal regulated kinase (ERK) pathway plays an essential role in the development and progression of various tumors. ERK1/2 is a key component of this pathway and hyperactivated in different tumors including osteosarcoma. This study aimed to investigate whether downregulation of ERK1/2 by siRNA (small interfering RNA) could inhibit cell proliferation and invasion and increase chemosensitivity to cisplatin in human osteosarcoma U2-OS cells in vitro. Results showed that the downregulation of ERK1/2 expression by siRNA in human osteosarcoma cells significantly inhibited cell proliferation and invasion in vitro. Furthermore, ERK1/2 knockdown led to cell arrest in the G1/G0 phase of the cell cycle, and eventual apoptosis and chemosensitivity enhancement in tumor cells. Our data reveal that RNAi-mediated downregulation of ERK1/2 expression can lead to potent antitumor activity and chemosensitizing effects in human osteosarcoma.
PMCID: PMC3584577  PMID: 22179790
ERK1/2; osteosarcoma; siRNA; chemosensitivity
19.  Effects of early administration of a novel anticholinergic drug on acute respiratory distress syndrome induced by sepsis 
Acute respiratory distress syndrome (ARDS) is the inflammatory disorder of the lung most commonly caused by sepsis. It was hypothesized that treating the lung with penehyclidine hydrochloride (PHC), a new type of hyoscyamus drug, early in the development of sepsis could diminish the lung dysfunction.
Sprague-Dawley rats were divided into 4 groups: 1) a control group; 2) a sham-operated group; 3) a cecal ligation and puncture (CLP) group; 4) a PHC-treated group. One hour after CLP surgery, rats were either untreated or treated with PHC via intraperitoneal injection. Lung wet/dry weight ratio, bronchoalveolar lavage fluid (BALF), serum tumor necrosis factor (TNF-α), interleukin 6 (IL-6), interleukin 10 (IL-10), total nitrite/nitrate (NOx), superoxide dismutase (SOD), malondialdehyde (MDA) in lung tissues, and pulmonary functions were examined 24 hour after surgery. Another 60 rats were randomly assigned to 4 equal groups to observe survival status 96 hours after surgery.
Treatment of PHC markedly decreased TNF-α, IL-6, NOx, SOD, MDA content, protein concentration in BALF, and lung wet/dry weight ratio and enhanced SOD activity (p<0.05), which are indicative of PHC-induced suppression in the pathogenesis of ARDS caused by sepsis. In comparison to group CLP/saline, plasma IL-10 level markedly increased in group CLP/PHC. In PHC-treated groups, the administered PHC had a significant protective effect on the lung dysfunction induced by sepsis.
We conclude that administration of PHC at the time of a systemic insult can protect the lung from the damaging effects of sepsis.
PMCID: PMC3539499  PMID: 22037734
acute respiratory distress syndrome; penehyclidine hydrochloride; sepsis; inflammatory responses; intervention
20.  Quantum-Dot-Decorated Robust Transductable Bioluminescent Nanocapsules 
Journal of the American Chemical Society  2010;132(37):12780-12781.
Bioluminescence, due to its high sensitivity, has been exploited in various analytical and imaging applications. In this work, we report a highly stable, cell-transductable and wavelength-tunable bioluminescence system achieved with an elegant and simple design. Using aqueous in-situ polymerization on bioluminescent enzyme anchored with polymerizable vinyl groups, we obtained nano-sized core-shell nanocapsules with enzyme as the core and crosslinked thin polymer net as the shell. These nanocapusles possess greatly enhanced stability, retained bioactivity, and readily engineered surface. In particular, by incorporating polymerizable amines in the polymerization, we endowed the nanocapsules with efficient cell-transduction and sufficient conjugation sites for follow-up modification. Following in-situ polymerization, decorating the polymer shell with fluorescent quantum dots allowed us to access continuous tunable wavelength, which extends the application of such bioluminescent nanocapsules, especially in deep tissue. In addition, the unique core-shell structure and adequate conjugation sites on surface enabled us to maximize the BRET efficiency by adjusting the QD/enzyme conjugation ratio.
PMCID: PMC2976844  PMID: 20795619
21.  Deficiency of Rac1 Blocks NADPH Oxidase Activation, Inhibits Endoplasmic Reticulum Stress, and Reduces Myocardial Remodeling in a Mouse Model of Type 1 Diabetes 
Diabetes  2010;59(8):2033-2042.
Our recent study demonstrated that Rac1 and NADPH oxidase activation contributes to cardiomyocyte apoptosis in short-term diabetes. This study was undertaken to investigate if disruption of Rac1 and inhibition of NADPH oxidase would prevent myocardial remodeling in chronic diabetes.
Diabetes was induced by injection of streptozotocin in mice with cardiomyocyte-specific Rac1 knockout and their wild-type littermates. In a separate experiment, wild-type diabetic mice were treated with vehicle or apocynin in drinking water. Myocardial hypertrophy, fibrosis, endoplasmic reticulum (ER) stress, inflammatory response, and myocardial function were investigated after 2 months of diabetes. Isolated adult rat cardiomyocytes were cultured and stimulated with high glucose.
In diabetic hearts, NADPH oxidase activation, its subunits' expression, and reactive oxygen species production were inhibited by Rac1 knockout or apocynin treatment. Myocardial collagen deposition and cardiomyocyte cross-sectional areas were significantly increased in diabetic mice, which were accompanied by elevated expression of pro-fibrotic genes and hypertrophic genes. Deficiency of Rac1 or apocynin administration reduced myocardial fibrosis and hypertrophy, resulting in improved myocardial function. These effects were associated with a normalization of ER stress markers' expression and inflammatory response in diabetic hearts. In cultured cardiomyocytes, high glucose–induced ER stress was inhibited by blocking Rac1 or NADPH oxidase.
Rac1 via NADPH oxidase activation induces myocardial remodeling and dysfunction in diabetic mice. The role of Rac1 signaling may be associated with ER stress and inflammation. Thus, targeting inhibition of Rac1 and NADPH oxidase may be a therapeutic approach for diabetic cardiomyopathy.
PMCID: PMC2911061  PMID: 20522592
22.  Limb sparing surgery for bone tumours of the shoulder girdle: the oncological and functional results 
International Orthopaedics  2009;34(6):869-875.
It is a great challenge to spare the upper limb with a malignant or invasive benign bone tumour of the shoulder girdle. We retrospectively analysed 35 patients with bone tumours of the shoulder girdle treated with various limb salvage procedures. The tumours included 25 primary malignancies, three metastases and seven giant cell tumours which involved the proximal humerus in 21 patients, scapula in 12 and clavicle in two. The reconstruction procedures included eight prosthetic replacements, four devitalised tumorous bone grafts, three osteoarticular allografts, two autogenous fibular grafts, one intramedullary cemented nail, three Tikhoff-Linberg procedures, two replantation of shortened arms, and four humeral head suspensions. Six partial scapulectomies and two lateral clavicectomies needed no bone reconstruction. With an average follow-up of 71 months, local recurrences occurred in four cases and systemic metastases in six. Nine patients died and 23 remained disease free. The five year Kaplan-Meier survival rate of 28 patients with malignancies was 69.5%. The average Musculoskeletal Tumour Society (MSTS) functional score was 77% (range 40–100%) in all patients.
PMCID: PMC2989017  PMID: 19701633
23.  Mineralocorticoid Receptor Blockade Reverses Obesity-Related Changes in Expression of Adiponectin, PPARγ and Pro-inflammatory Adipokines 
Circulation  2008;117(17):2253-2261.
In obesity, decreases in adiponectin and increases in pro-inflammatory adipokines are associated with heart disease. Since adipocytes express mineralocorticoid receptor (MR) and MR blockade reduces cardiovascular inflammation and injury, we tested the hypothesis that MR blockade reduces inflammation and expression of pro-inflammatory cytokines in adipose tissue and increases adiponectin expression in adipose tissue and hearts of obese mice.
Methods and Results
We determined the effect of MR blockade (eplerenone, 100 mg/kg/day for 16 weeks) on gene expression in retroperitoneal adipose and heart tissue from obese, diabetic db/db mice (n=8) as compared with untreated obese, diabetic db/db mice (n=10) and lean, non-diabetic db/+ littermates (n=11). There was increased expression of tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor type-1 (PAI-1) and macrophage protein CD68 and decreased expression of adiponectin and peroxisome proliferator-activated receptor-γ (PPARγ) in retroperitoneal adipose tissue from obese versus lean mice. Also, adiponectin expression in heart was reduced in obese versus lean mice. MR blockade prevented these obesity-related changes in gene expression. Further, treatment of undifferentiated preadipocytes with aldosterone (10−8 M for 24 h) increased mRNA levels of TNF-α and MCP-1, and reduced mRNA and protein levels of PPARγ and adiponectin, supporting a direct aldosterone effect on gene expression.
MR blockade reduced expression of pro-inflammatory and pro-thrombotic factors in adipose tissue and increased expression of adiponectin in heart and adipose tissue of obese, diabetic mice. These effects on adiponectin and adipokine gene expression may represent a novel mechanism for the cardioprotective effects of MR blockade.
PMCID: PMC2746647  PMID: 18427128
Obesity; Inflammation; aldosterone antagonist; adipose tissue; mineralocorticoid receptor
24.  Date of first positive HIV test: reliability of information collected for HIV/AIDS surveillance in the United States. 
Public Health Reports  2005;120(1):89-95.
OBJECTIVES: This study examined the reliability of the first positive HIV test date reported in the U.S. HIV/AIDS Reporting System (HARS). This date is essential to determine case counts for resource allocation for HIV treatment and prevention efforts. METHODS: The dates of first positive HIV tests reported by individuals with HIV in an interview survey conducted in 16 states (n=16,394, interviewed 1995-2002) were compared with the dates of HIV diagnosis reported to HARS. The percentage of agreement for the year of diagnosis and the weighed kappa (k) with 95% confidence intervals (CIs) was calculated. RESULTS: Self-reported year of diagnosis agreed with the year of diagnosis in HARS for 56% of date pairs (k=0.69; 95% CI 0.68, 0.70); 30% reported an earlier diagnosis year. Agreement differed by sex, age, race, exposure, and reason or place of testing (p<.01). Lower agreement was found when the self-reported diagnostic test was anonymous (k=0.57; 95% CI 0.52, 0.62) compared with confidential tests (k=0.66; 95% CI 0.64, 0.68). Lower agreement was also found for cases first reported with AIDS (k=0.58; 95% CI 0.55, 0.62) compared with cases first reported with HIV not AIDS (k=0.71; 95% CI 0.70, 0.73) as well as for participants interviewed three years or more after their HARS diagnosis date (k=0.55; 95% CI 0.52, 0.57) compared with those interviewed within one year (k=0.62; 95% CI 0.61, 0.63). More than 20% of participants in almost all groups, however, reported earlier diagnosis years than those recorded in HARS. CONCLUSION: As many as 30% of HIV diagnoses may have occurred earlier than recorded in HARS. Additional studies need to determine mechanisms to adequately capture diagnosis dates in HARS.
PMCID: PMC1497688  PMID: 15736337

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