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author:("Li, zhijin")
1.  Identification of a Diguanylate Cyclase and Its Role in Porphyromonas gingivalis Virulence 
Infection and Immunity  2014;82(7):2728-2735.
Porphyromonas gingivalis is a Gram-negative obligate anaerobic bacterium and is considered a keystone pathogen in the initiation of periodontitis, one of the most widespread infectious diseases. Bacterial bis-(3′-5′) cyclic GMP (cyclic di-GMP [c-di-GMP]) serves as a second messenger and is involved in modulating virulence factors in numerous bacteria. However, the role of this second messenger has not been investigated in P. gingivalis, mainly due to a lack of an annotation regarding diguanylate cyclases (DGCs) in this bacterium. Using bioinformatics tools, we found a protein, PGN_1932, containing a GGDEF domain. A deletion mutation in the pgn_1932 gene had a significant effect on the intracellular c-di-GMP level in P. gingivalis. Genetic analysis showed that expression of the fimA and rgpA genes, encoding the major protein subunit of fimbriae and an arginine-specific proteinase, respectively, was downregulated in the pgn_1932 mutant. Correspondingly, FimA protein production and the fimbrial display on the mutant were significantly reduced. Mutations in the pgn_1932 gene also had a significant impact on the adhesive and invasive capabilities of P. gingivalis, which are required for its pathogenicity. These findings provide evidence that the PGN_1932 protein is both responsible for synthesizing c-di-GMP and involved in biofilm formation and host cell invasion by P. gingivalis by controlling the expression and biosynthesis of FimA.
PMCID: PMC4097614  PMID: 24733094
2.  The Hypofunctional Effect of P335L Single Nucleotide Polymorphism on SSTR5 Function 
World journal of surgery  2011;35(8):1715-1724.
Somatostatin receptor subtype 5 (SSTR5) mediates the inhibitory effect of somatostatin on insulin expression/secretion and cell proliferation. A number of single nucleotide polymorphisms (SNPs) of SSTR5 have been identified, including P335L, a non-synonymous SNP located in the protein C-terminal region and encrypted by the codons CCG (proline) or CTG (leucine). In the present study, we sought to determine if the P335L SNP affected the cellular function of SSTR5 in human pancreatic cancer as has been reported previously for neuropsychiatric diseases and pituitary adenomas.
The P335L germline genotype of 246 patients with pancreatic cancer (213 Caucasians, 16 Hispanics and 17 African Americans), and 17 human pancreatic cell lines was determined with the TaqMan SNP Genotyping assay. Human SSTR5 leucine variant (L335) was generated by performing site-directed mutagenesis using SSTR5 proline variant (P335) as a template. Transient transfections were performed in HEK293, Mia PaCa-2 and β-TC-6 cells using Lipofectamine 2000. The expression of SSTR5 L335 was determined with a mouse monoclonal anti-SSTR5 L335 antibody generated in our laboratory. The cell proliferation rate was measured by performing MTS assays. Insulin concentration was measured by performing ELISA assays.
1. Genotyping of the patients' blood indicated that the frequency of the T allele (CT and TT genotypes) in codon 335 of SSTR5 in Caucasians, Hispanics and African Americans was 52%, 69% and 35%, respectively. Statistical analysis indicated no significant association existed between the frequency of the T allele and the existence of pancreatic cancer in each race. 2. Of the 17 tested human pancreatic cancer cell lines, 5 cell lines (CAPAN-2, HPAF-II, Panc03.27, Panc-1, and -3) had the homozygote TT genotype and 9 cell lines including Mia PaCa-2 were heterozygote (CT genotype). 3. Over-expression of SSTR5 L335 in Mia PaCa-2 cells enhanced cell proliferation compared to over-expression of SSTR5 P335; 4. Over-expression of SSTR5 P335 enhanced the inhibitory effect of SSTR5 agonist RPL-1980 on cell proliferation of Mia PaCa-2 cells and glucose-stimulated insulin secretion from mouse insulinoma cells, while over-expression of SSTR5 L335 blocked the inhibitory effect of RPL-1980. 5. Over-expression of SSTR5 L335 enhanced PDX-1 expression in Mia PaCa-2 cells.
SSTR5 P335L SNP widely exists in the human population; in patients with pancreatic cancer, which are race-dependent; and in human pancreatic cancer cell lines. In contrast to SSTR5 P335, over-expression of SSTR5 L335 variant resulted in cellular proliferation and PDX-1 over-expression in human pancreas cancer cells and blocked the inhibitory effect of an SSTR5-specific analogue on human pancreas cancer cell proliferation and glucose-stimulated insulin secretion from mouse insulinoma cells. These data suggest that SSTR5 P335L is a hypofunctional protein with a potential harmful effect on function, as well as potential latent effect, and therefore could affect the clinical response to somatostatin analogue therapy for patients with pancreas cancer.
PMCID: PMC4137969  PMID: 21249361
3.  HIV and Syphilis Prevalence Among Men Who Have Sex With Men: A Cross-Sectional Survey of 61 Cities in China 
The prevalence of human immunodeficiency virus and syphilis among men who have sex with men in China is high, yet the 2 epidemics are largely geographically separate. Characteristics of the overall population surveyed as well as segments within this population are described.
Background. Human immunodeficiency virus (HIV) has rapidly spread among men who have sex with men (MSM) in China in recent years; the magnitude of the epidemic is unclear. We sought to test 3 hypotheses: (1) The prevalence of both HIV and syphilis among MSM in China is high, (2) the 2 epidemics each have unique geographical distributions, and (3) demographic and sexual behavior characteristics are different among segments of the MSM population in China.
Methods. A total of 47 231 MSM from 61 cities in China participated in a cross-sectional survey conducted from February 2008 to September 2009. Demographic and behavioral data were collected and analyzed and blood samples tested for HIV and syphilis. Three subgroups among the broader MSM sample were described. Main outcome measures were HIV and syphilis prevalence.
Results. An overall prevalence of 4.9% (2314/47 231; 95% confidence interval [CI], 4.7%–5.1%) for HIV and 11.8% (5552/47 231; 95% CI, 11.5%–12.0%) for syphilis was found. Syphilis-positive MSM had the highest HIV prevalence, 12.5% (693/5552; 95% CI, 11.6%–13.4%). However, correlations between HIV and syphilis prevalence were found in only 3 of 6 geographical regions (Northwest: r = 0.82, P = .0253; East: r = 0.78, P = .0004; and South-central: r = 0.63, P = .0276). Three subgroups—nonlocal MSM, Internet-using MSM, and female-partnering MSM—were found to have different profiles of characteristics and behaviors.
Conclusions. HIV and syphilis prevalences among MSM in China are high and the 2 epidemics are largely separate geographically. Three segments of the Chinese MSM population each have different demographic and sexual risk “profiles” that suggest high potential for bridging infection across geographies, generations, and sexes.
PMCID: PMC3689345  PMID: 23580732
HIV; syphilis; MSM; China
4.  Right axillary and femoral artery perfusion with mild hypothermia for aortic arch replacement 
Aortic arch replacement is associated with increased mortality and morbidity especially in acute type-A aortic dissection. Although hypothermic circulatory arrest with selective antegrade cerebral perfusion has been widely used because of its excellent cerebral protection, its optimal perfusion characteristics are unknown. The present study investigates clinical results obtained after perfusion method modification and temperature management during cardiopulmonary bypass (CPB).
Between July 2010 and August 2012, 16 consecutive adult patients (mean age 50.0 yr ± 14.1 yr, range 25 yr to 73 yr, 12 males, 4 females) who presented with acute Stanford type-A aortic dissection underwent aortic arch replacement (total arch, n = 11; hemiarch, n = 5) under mild hypothermia (31.1°C ± 1.5°C) with right axillary and femoral artery perfusion.
The mean CPB time was 201 min ± 53 min, and the mean myocardial ischemic time was 140 min ± 42 min. The mean selective cerebral perfusion time was 80 min ± 16 min, and the mean lower-body circulatory arrest time was 20 min ± 13 min. No patient death occurred within 30 post-operative days. The following details were observed: new post-operative permanent neurologic deficit in 1 patient (6.3%), temporary neurologic deficit in 2 patients (12.5%), acute renal dysfunction (creatinine level > 230 umol/L) in 3 patients (18.8%) and mechanical ventilation > 72 h in 5 patients (31.2%).
Aortic arch replacement for acute type-A aortic dissection under mild hypothermia with right axillary and femoral artery perfusion could be safely performed in the patient cohort.
PMCID: PMC4068358  PMID: 24885031
Aortic arch surgery; Cardiopulmonary bypass; Mild hypothermia; Brain protection; Selective antegrade cerebral perfusion
5.  Chinese SLE Treatment and Research Group Registry: III. Association of Autoantibodies with Clinical Manifestations in Chinese Patients with Systemic Lupus Erythematosus 
Journal of Immunology Research  2014;2014:809389.
We investigated the characteristics of Chinese SLE patients by analyzing the association between specific autoantibodies and clinical manifestations of 2104 SLE patients from registry data of CSTAR cohort. Significant (P < 0.05) associations were found between anti-Sm antibody, anti-rRNP antibody, and malar rash; between anti-RNP antibody, anti-SSA antibody, and pulmonary arterial hypertension (PAH); between anti-SSB antibody and hematologic involvement; and between anti-dsDNA antibody and nephropathy. APL antibody was associated with hematologic involvement, interstitial lung disease, and a lower prevalence of oral ulcerations (P < 0.05). Associations were also found between anti-dsDNA antibody and a lower prevalence of photosensitivity, and between anti-SSA antibody and a lower prevalence of nephropathy (P < 0.05). Most of these findings were consistent with other studies in the literature but this study is the first report on the association between anti-SSA and a lower prevalence of nephropathy. The correlations of specific autoantibodies and clinical manifestations could provide clues for physicians to predict organ damages in SLE patients. We suggest that a thorough screening of autoantibodies should be carried out when the diagnosis of SLE is established, and repeated echocardiography annually in SLE patients with anti-RNP or anti-SSA antibody should be performed.
PMCID: PMC4017718  PMID: 24864270
6.  MiR-124 Radiosensitizes Human Colorectal Cancer Cells by Targeting PRRX1 
PLoS ONE  2014;9(4):e93917.
One of the challenges in the treatment of colorectal cancer patients is that these tumors show resistance to radiation. MicroRNAs (miRNAs) are involved in essential biological activities, including chemoresistance and radioresistance. Several research studies have indicated that miRNA played an important role in sensitizing cellular response to ionizing radiation (IR). In this study, we found that miR-124 was significantly down-regulated both in CRC-derived cell lines and clinical CRC samples compared with adjacent non-tumor colorectal tissues, MiR-124 could sensitize human colorectal cancer cells to IR in vitro and in vivo. We identified PRRX1, a new EMT inducer and stemness regulator as a novel direct target of miR-124 by using target prediction algorithms and luciferase assay. PRRX1 knockdown could sensitize CRC cells to IR similar to the effects caused by miR-124. Overexpression of PRRX1 in stably overexpressed-miR-124 cell lines could rescue the effects of radiosensitivity enhancement brought by miR-124. Taking these observations into consideration, we illustrated that miR-124 could increase the radiosensitivity of CRC cells by blocking the expression of PRRX1, which indicated miR-124 could act as a great therapeutic target for CRC patients.
PMCID: PMC3976353  PMID: 24705396
7.  Path-Following Control of Wheeled Planetary Exploration Robots Moving on Deformable Rough Terrain 
The Scientific World Journal  2014;2014:793526.
The control of planetary rovers, which are high performance mobile robots that move on deformable rough terrain, is a challenging problem. Taking lateral skid into account, this paper presents a rough terrain model and nonholonomic kinematics model for planetary rovers. An approach is proposed in which the reference path is generated according to the planned path by combining look-ahead distance and path updating distance on the basis of the carrot following method. A path-following strategy for wheeled planetary exploration robots incorporating slip compensation is designed. Simulation results of a four-wheeled robot on deformable rough terrain verify that it can be controlled to follow a planned path with good precision, despite the fact that the wheels will obviously skid and slip.
PMCID: PMC3984778  PMID: 24790582
8.  The Lack of Standard Definitions in the Supportive and Palliative Oncology Literature 
Journal of pain and symptom management  2011;43(3):10.1016/j.jpainsymman.2011.04.016.
Multiple organizations have raised concerns about the lack of standard definitions for terminology in the supportive and palliative oncology literature.
We aimed to determine: 1) the frequency of 10 commonly used terms in the supportive and palliative oncology literature; 2) the proportion of articles that provided definitions for each term; and 3) how each term was defined.
We systematically searched MEDLINE, PubMed, PsycINFO, the Cochrane Library, Embase, ISI Web of Science, and CINAHL for original studies, review articles and systematic reviews related to palliative care and cancer in the first six months of 2004 and 2009. We counted the number of occurrences for “palliative care,” “supportive care,” “best supportive care,” “hospice care,” “terminal care,” “end-of-life,” “terminally ill,” “goals of care,” “actively dying,” and “transition of care” in each article, reviewed them for the presence of definitions, and documented the journal characteristics.
Among the 1213 articles found, 678 (56%) were from 2009. “Palliative care” and “end-of-life” were the most frequently used terms. “Palliative care,” “end-of-life” and “terminally ill” appeared more frequently in palliative care journals, while “supportive care” and “best supportive care” were used more often in oncology journals (P<0.001). Among 35 of 601 (6%) articles with a definition for “palliative care,” there were 16 different variations (21 of 35 articles used the World Health Organization definition). “Hospice care” had 13 definitions among 13 of 151 (9%) articles. “Supportive care” and other terms were rarely defined (less than 5% of articles that used the term).
Our findings highlight the lack of definitional clarity for many important terms in the supportive and palliative oncology literature. Standard definitions are needed to improve administrative, clinical and research operations.
PMCID: PMC3818788  PMID: 22104619
Palliative care; supportive care; neoplasms; literature; terminology; definitions
9.  Motor Imagery Cognitive Network after Left Ischemic Stroke: Study of the Patients during Mental Rotation Task 
PLoS ONE  2013;8(10):e77325.
Although motor imagery could improve motor rehabilitation, the detailed neural mechanisms of motor imagery cognitive process of stroke patients, particularly from functional network perspective, remain unclear. This study investigated functional brain network properties in each cognitive sub-stage of motor imagery of stroke patients with ischemic lesion in left hemisphere to reveal the impact of stroke on the cognition of motor imagery. Both stroke patients and control subjects participated in mental rotation task, which includes three cognitive sub-stages: visual stimulus perception, mental rotation and response cognitive process. Event-related electroencephalograph was recorded and interdependence between two different cortical areas was assessed by phase synchronization. Both global and nodal properties of functional networks in three sub-stages were statistically analyzed. Phase synchronization of stroke patients significantly reduced in mental rotation sub-stage. Longer characteristic path length and smaller global clustering coefficient of functional network were observed in patients in mental rotation sub-stage which implied the impaired segregation and integration. Larger nodal clustering coefficient and betweenness in contralesional occipitoparietal and frontal area respectively were observed in patients in all sub-stages. In addition, patients also showed smaller betweenness in ipsilesional central-parietal area in response sub-stage. The compensatory effects on local connectedness and centrality indicated the neuroplasticity in contralesional hemisphere. The functional brain networks of stroke patients demonstrated significant alterations and compensatory effects during motor imagery.
PMCID: PMC3805593  PMID: 24167569
10.  Developing a High-Quality Scoring Function for Membrane Protein Structures Based on Specific Inter-Residue Interactions 
Membrane proteins are of particular biological and pharmaceutical importance, and computational modeling and structure prediction approaches play an important role in studies of membrane proteins. Developing an accurate model quality assessment program is of significance to the structure prediction of membrane proteins. Few such programs are proposed that can be applied to a broad range of membrane protein classes and perform with high accuracy. We developed a new model scoring function IQ, based on the analysis of four types of inter-residue interactions within the transmembrane domains of helical membrane proteins. This function was tested using three high-quality model sets: all 206 models of GPCR Dock 2008, all 284 models of GPCR Dock 2010, and all 92 helical membrane protein models of the HOMEP set. For all three sets, the scoring function can select the native structures among all of the models with the success rates of 93%, 85%, and 100% respectively. For comparison, these three model sets were also adopted for a recently published model assessment program for membrane protein structures, ProQM, which gave the success rates of 85%, 79%, and 92% separately. These results suggested that IQ outperforms ProQM when only the transmembrane regions of the models are considered. This scoring function should be useful for the computational modeling of membrane proteins.
PMCID: PMC3322274  PMID: 22395902
membrane proteins; structure quality; inter-residue interactions; frequency score; average number of interactions
11.  A novel porcine reproductive and respiratory syndrome virus vector system that stably expresses enhanced green fluorescent protein as a separate transcription unit 
Veterinary Research  2013;44(1):104.
Here we report the rescue of a recombinant porcine reproductive and respiratory syndrome virus (PRRSV) carrying an enhanced green fluorescent protein (EGFP) reporter gene as a separate transcription unit. A copy of the transcription regulatory sequence for ORF6 (TRS6) was inserted between the N protein and 3′-UTR to drive the transcription of the EGFP gene and yield a general purpose expression vector. Successful recovery of PRRSV was obtained using an RNA polymerase II promoter to drive transcription of the full-length virus genome, which was assembled in a bacterial artificial chromosome (BAC). The recombinant virus showed growth replication characteristics similar to those of the wild-type virus in the infected cells. In addition, the recombinant virus stably expressed EGFP for at least 10 passages. EGFP expression was detected at approximately 10 h post infection by live-cell imaging to follow the virus spread in real time and the infection of neighbouring cells occurred predominantly through cell-to-cell-contact. Finally, the recombinant virus generated was found to be an excellent tool for neutralising antibodies and antiviral compound screening. The newly established reverse genetics system for PRRSV could be a useful tool not only to monitor virus spread and screen for neutralising antibodies and antiviral compounds, but also for fundamental research on the biology of the virus.
PMCID: PMC4176086  PMID: 24176053
12.  Polymorphisms of CHRNA5-CHRNA3-CHRNB4 Gene Cluster and NSCLC Risk in Chinese Population1 
Translational Oncology  2012;5(6):448-452.
AIM: To explore the potential association between single-nucleotide polymorphisms (SNPs) and haplotypes of the CHRNA5-CHRNA3-CHRNB4 gene cluster and the non-small cell lung cancer (NSCLC) susceptibility in never-smoking Chinese. METHODS: A case-control study was conducted with 200 NSCLC patients and 200 healthy controls, matched on age and sex. Five SNPs distributed in CHRNA5-CHRNA3-CHRNB4 gene cluster were selected for genotyping. The association between genotype and lung cancer risk was evaluated by computing the odds ratio (OR) and 95% confidence interval (CI) from multivariate unconditional logistic regression analyses with adjustment for gender and age. RESULTS: For CHRNA3 rs578776 status, data were available in 199 NSCLC patients and 199 controls. The G/G homozygote in CHRNB4 rs7178270 had a reduced risk of developing NSCLC (OR = 0.553; 95% CI = 0.309–0.989; P = .0437), especially squamous cell carcinoma (SQC) (OR = 0.344; 95% CI = 0.161–0.732; P = .0043), compared with those who carry at least one C allele (C/C and C/G). The polymorphisms of rs578776, rs938682, rs17486278, and rs11637635 were not significantly different between controls and cases or between controls and histologic subgroups, adenocarcinoma and SQC, respectively. CONCLUSIONS: In our study, we found that the SNP of CHRNB4 rs7178270 is significantly associated with reduced risk of NSCLC, especially with reduced risk of SQC in never-smoking Chinese population.
PMCID: PMC3567724  PMID: 23397474
13.  Inferring Functional Neural Connectivity with Phase Synchronization Analysis: A Review of Methodology 
Functional neural connectivity is drawing increasing attention in neuroscience research. To infer functional connectivity from observed neural signals, various methods have been proposed. Among them, phase synchronization analysis is an important and effective one which examines the relationship of instantaneous phase between neural signals but neglecting the influence of their amplitudes. In this paper, we review the advances in methodologies of phase synchronization analysis. In particular, we discuss the definitions of instantaneous phase, the indexes of phase synchronization and their significance test, the issues that may affect the detection of phase synchronization and the extensions of phase synchronization analysis. In practice, phase synchronization analysis may be affected by observational noise, insufficient samples of the signals, volume conduction, and reference in recording neural signals. We make comments and suggestions on these issues so as to better apply phase synchronization analysis to inferring functional connectivity from neural signals.
PMCID: PMC3346979  PMID: 22577470
14.  Cytoplasmic CUL9/PARC ubiquitin ligase is a tumor suppressor and promotes p53-dependent apoptosis 
Cancer research  2011;71(8):2969-2977.
A wide range of cell stresses, including DNA damage, signal to p53 through post-translational modification of p53. The cytoplasmic functions of p53 are emerging as an important constituent of p53’s role in tumor suppression. Here we report that deletion of the Cul9 (formerly Parc) gene, which encodes an E3 ubiquitin ligase that binds to p53 and localizes in the cytoplasm, resulted in spontaneous tumor development, accelerated Eμ-Myc-induced lymphomagenesis and rendered mice susceptible to carcinogenesis. Cul9-p53 double mutant mice exhibited indistinguishable tumor phenotypes as p53 single mutant mice, indicating that the function of Cul9 in tumor suppression is largely mediated by p53. Deletion of Cul9 had no significant effect on cell cycle progression, but attenuated DNA damage-induced apoptosis. Ectopic expression of wild-type CUL9, but not a point mutant CUL9 deficient in p53 binding, promotes apoptosis. These results demonstrate CUL9 as a potential p53 activating E3 ligase in the cytoplasm.
PMCID: PMC3088989  PMID: 21487039
CUL9; p53; apoptosis; tumor suppression
15.  Drug-Resistant Tuberculosis in Zhejiang Province, China, 1999–2008 
Emerging Infectious Diseases  2012;18(3):496-498.
To evaluate levels and trends in drug-resistant tuberculosis (TB) in Zhejiang Province, China, we conducted 1 survey in each of 3 years (1999, 2004, and 2008). We found that <5% of new cases were multidrug-resistant TB. The prevalence of multidrug-resistant TB has not increased in new or re-treated cases in this province.
PMCID: PMC3309572  PMID: 22377167
isoniazid; rifampicin; multidrug-resistant tuberculosis; MDR TB; tuberculosis and other mycobacteria; bacteria; cross-sectional survey; prevalence; China
16.  Comparison Analysis of Primary Ligand Binding Sites in Seven-Helix Membrane Proteins 
Biopolymers  2011;95(1):31-38.
Seven-helix transmembrane proteins, including the G-protein coupled receptors, mediate a broad range of fundamental cellular activities through binding to a wide range of ligands. Understanding the structural basis for the ligand-binding selectivity of these proteins is of significance to their structure-based drug design. Comparison analysis of proteins’ ligand binding sites provides a useful way to study their structure-activity relationships. Various computational methods have been developed for the binding site comparison of soluble proteins. In this work, we applied this approach to the analysis of the primary ligand-binding sites of 92 seven-helix transmembrane proteins. Results of the studies confirmed that the binding site of bacterial rhodopsins is indeed different from all G-protein coupled receptors. In the latter group, further comparison of the binding sites indicated a group of residues that could be responsible for ligand-binding selectivity and important for structure-based drug design. Further, unexpected binding site dissimilarities were observed among adrenergic and adenosine receptors, suggesting that the percentage of the overall sequence identity between a target protein and a template protein alone is not sufficient for selecting the best template for homology modeling of seven-helix membrane proteins. These results provided novel insight into the structural basis of ligand-binding selectivity of seven-helix membrane proteins and are of practical use to the computational modeling of these proteins.
PMCID: PMC2966529  PMID: 20672377
seven-helix membrane protein; GPCR; binding site; comparison analysis; cluster analysis
17.  Association Between a Name Change from Palliative to Supportive Care and the Timing of Patient Referrals at a Comprehensive Cancer Center 
The Oncologist  2011;16(1):105-111.
The impact of a name change from palliative care to supportive care was examined in a comprehensive cancer center. The name change was associated with more inpatient referrals and earlier referrals in the outpatient setting.
Palliative care consultation services are now available in the majority of cancer centers, yet most referrals to palliative care occur late. We previously found that the term “palliative care” was perceived by oncology professionals as a barrier to early patient referral. We aimed to determine whether a service name change to supportive care was associated with earlier referrals.
Patients and Methods.
Records of 4,701 consecutive patients with a first palliative care consultation before (January 2006 to August 2007) and after (January 2008 to August 2009) the name change were analyzed, including demographics and dates of first registration to hospital, advanced cancer diagnosis, palliative care consultation, and death. One-sample proportions tests, median tests, χ2 tests, and log-rank tests were used to identify group differences.
The median age was 59 years, 50% were male, and 90% had solid tumors. After the name change, we found: (a) a 41% greater number of palliative care consultations (1,950 versus 2,751 patients; p < .001), mainly as a result of a rise in inpatient referrals (733 versus 1,451 patients; p < .001), and (b) in the outpatient setting, a shorter duration from hospital registration to palliative care consultation (median, 9.2 months versus 13.2 months; hazard ratio [HR], 0.85; p < .001) and from advanced cancer diagnosis to palliative care consultation (5.2 months versus 6.9 months; HR, 0.82; p < .001), and a longer overall survival duration from palliative care consultation (median 6.2 months versus 4.7 months; HR, 1.21; p < .001).
The name change to supportive care was associated with more inpatient referrals and earlier referrals in the outpatient setting. The outpatient setting facilitates earlier access to supportive/palliative care and should be established in more centers.
PMCID: PMC3228056  PMID: 21212438
Supportive care; Palliative care; Cancer; Symptom management; End-of-life care
18.  Anti-Neoplastic Therapy Use in Advanced Cancer Patients Admitted to an Acute Palliative Care Unit at a Comprehensive Cancer Center: A Simultaneous Care Model 
Cancer  2010;116(8):2036-2043.
Cancer patients admitted to a palliative care unit generally have a poor prognosis. The role of antineoplastic therapy (ANT) in these patients is controversial. We examined the frequency and predictors associated with ANT use in hospitalized patients who required an acute palliative care unit (APCU) stay.
We included all 2604 patients admitted over a five-year period to a 12-bed APCU located within a National Cancer Institute comprehensive cancer center, where patients can access both palliative care and ANT. We retrospectively retrieved from institutional databases patient demographics, cancer diagnosis, ANT use, length of hospital stay, and survival from time of admission.
The median hospital stay was 11 days and the median survival was 22 days. During hospitalization, 435 patients (17%) received ANT, including chemotherapy (N=297, 11%), hormonal agents (N=54, 2%) and targeted therapy (N=155, 6%). No significant change in frequency of ANT use was detected over the 5 year period. Multivariate logistic regression analysis revealed that younger age, specific cancer diagnoses and longer admissions were independently associated with ANT use.
The use of ANT during hospitalization that included an APCU stay was limited to a small percentage of patients, and did not increase over time. ANT use was associated with younger age, specific cancer diagnoses and longer admissions. The APCU facilitates simultaneous care where patients access palliative care while on ANT.
PMCID: PMC2854875  PMID: 20162701
neoplasms; therapeutics; antineoplastic agents; targeted agents; palliative care
Cancer  2010;116(2):520-528.
Methadone is an effective and inexpensive opioid for cancer pain treatment. It has been reported as difficult to use in the outpatient setting due to its variable relative potency and long half-life. The purpose of this study was to determine the outcome of methadone initiation or rotation for cancer pain treatment in outpatient settings.
Chart review of 189 consecutive patients who underwent methadone initiation or rotation in our palliative care outpatient center. Data were collected regarding demographic and clinical characteristics, symptoms, and opioid side effects at baseline and for 2 follow up visits(F1,F2). Failure was defined as methadone discontinuation by the palliative care physician or patient's hospitalization for uncontrolled pain or methadone-related side effects at F1.
100(53%) initiations and 89(47%) rotations were conducted. Success rates for methadone initiation and rotation were 82/89(92%) and 85/100(84%) respectively. Mean(standard deviation) age was 60(11) years. 100(53%) patients were female, 138(73%) white, 182(96%) had solid cancers. The main reason for rotation was pain (65/89 patients, 47%). Median(interquartile range, IR) pain scores (Edmonton Symptom Assessment System/0–10) were 6(5–8), 4(3–6), and 3(2–5) at baseline, F1, and F2, respectively(p<0.0001). Median(IR) daily methadone dose for initiation and rotation was 10(5–15)mg and 15(10–30)mg at F1(p<0.0001) and 10(8–15)mg and 18(10–30)mg at F2(p<0.0001), respectively. Constipation and nausea improved (p<0.005) after initiation/rotation to methadone. Frequency of sedation, hallucinations, myoclonus, and delirium did not increase after initiation/rotation to methadone.
Outpatient methadone initiation and rotation for cancer pain treatment were safe, with high success rate and low side effect profile.
PMCID: PMC2811764  PMID: 19924788
methadone; pain; neoplasms; outpatients; palliative care
20.  Discharge Outcomes and Survival of Patients with Advanced Cancer Admitted to an Acute Palliative Care Unit at a Comprehensive Cancer Center 
Journal of Palliative Medicine  2010;13(1):49-57.
Acute palliative care units (APCUs) are new programs aimed at integrating palliative and oncology care. Few outcome studies from APCUs are available.
We examined the frequency, survival, and predictors associated with home discharge and death in our APCU.
All patients discharged from the APCU between September 1, 2003 and August 31, 2008 were included. Demographics, cancer diagnosis, discharge outcomes, and overall survival from discharge were retrieved retrospectively.
The 2568 patients admitted to APCU had the following characteristics: median age, 59 years (range, 18–101); male, 51%; median hospital stay, 11 days; median APCU stay, 7 days; and median survival 21 days (95% confidence interval [CI] 19–23 days). Five hundred ninety-two (20%), 89 (3%), and 1259 (43%) patients were discharged to home, health care facilities, and hospice, respectively, with a median survival of 60, 29, and 14 days, respectively (p < 0.001). Nine hundred fifty-eight (33%) patients died during admission (median stay, 11 days). Compared to hospice transfers, home discharge (hazard ratio = 0.35, 95% CI 0.30–0.41, p < 0.001) was associated with longer survival in multivariate analysis, with a 6-month survival of 22%. Multivariate logistic regression revealed that male gender, specific cancer primaries, and admissions from oncology units were associated with death in the APCU, while younger age and direct admissions to the APCU were associated with home discharge.
Our APCU serves patients with advanced cancer with diverse clinical characteristics and survival, and discharged home a significant proportion with survival greater than 6 months. Results from this simultaneous care program suggest a pattern of care different from that of traditional hospice and palliative care services.
PMCID: PMC2883821  PMID: 19824813
21.  The calcimimetic R-568 induces apoptotic cell death in prostate cancer cells 
Increased serum level of parathyroid hormone (PTH) was found in metastatic prostate cancers. Calcimimetic R-568 was reported to reduce PTH expression, to suppress cell proliferation and to induce apoptosis in parathyroid cells. In this study, we investigated the effect of R-568 on cellular survival of prostate cancer cells.
Prostate cancer cell lines LNCaP and PC-3 were used in this study. Cellular survival was determined with MTT, trypan blue exclusion and fluorescent Live/Death assays. Western blot assay was utilized to assess apoptotic events induced by R-568 treatment. JC-1 staining was used to evaluate mitochondrial membrane potential.
In cultured prostate cancer LNCaP and PC-3 cells, R-568 treatment significantly reduced cellular survival in a dose- and time-dependent manner. R-568-induced cell death was an apoptotic event, as evidenced by caspase-3 processing and PARP cleavage, as well as JC-1 color change in mitochondria. Knocking down calcium sensing receptor (CaSR) significantly reduced R-568-induced cytotoxicity. Enforced expression of Bcl-xL gene abolished R-568-induced cell death, while loss of Bcl-xL expression led to increased cell death in R-568-treated LNCaP cells,.
Taken together, our data demonstrated that calcimimetic R-568 triggers an intrinsic mitochondria-related apoptotic pathway, which is dependent on the CaSR and is modulated by Bcl-xL anti-apoptotic pathway.
PMCID: PMC2716307  PMID: 19602280
22.  Betulinic Acid Derivatives That Target gp120 and Inhibit Multiple Genetic Subtypes of Human Immunodeficiency Virus Type 1▿  
Betulinic acid (BA) derivatives can inhibit human immunodeficiency virus type 1 (HIV-1) entry or maturation depending on side chain modifications. While BA derivatives with antimaturation activity have attracted considerable interest, the anti-HIV-1 profile and molecular mechanism of BA derivatives with anti-HIV-1 entry activity (termed BA entry inhibitors) have not been well defined. In this study, we have found that two BA entry inhibitors, IC9564 and A43D, exhibited a broad spectrum of anti-HIV-1 activity. Both compounds inhibited multiple strains of HIV-1 from clades A, B, and C at submicromolar concentrations. Clade C viruses were more sensitive to the compounds than clade A and B viruses. Interestingly, IC9564 at subinhibitory concentrations could alter the antifusion activities of other entry inhibitors. IC9564 was especially potent in increasing the sensitivity of HIV-1YU2 Env-mediated membrane fusion to the CCR5 inhibitor TAK-779. Results from this study suggest that the V3 loop of gp120 is a critical determinant for the anti-HIV-1 activity of IC9564. IC9564 escape viruses contained mutations near the tip of the V3 loop. Moreover, IC9564 could compete with the binding of V3 monoclonal antibodies 447-52D and 39F. IC9564 also competed with the binding of gp120/CD4 complexes to chemokine receptors. In summary, these results suggest that BA entry inhibitors can potently inhibit a broad spectrum of primary HIV-1 isolates by targeting the V3 loop of gp120.
PMCID: PMC2223896  PMID: 17954689

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