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author:("Li, zhijin")
1.  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.
doi:10.1371/journal.pone.0093917
PMCID: PMC3976353  PMID: 24705396
2.  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.
Context
Multiple organizations have raised concerns about the lack of standard definitions for terminology in the supportive and palliative oncology literature.
Objectives
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1016/j.jpainsymman.2011.04.016
PMCID: PMC3818788  PMID: 22104619
Palliative care; supportive care; neoplasms; literature; terminology; definitions
3.  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.
doi:10.1371/journal.pone.0077325
PMCID: PMC3805593  PMID: 24167569
4.  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.
doi:10.1007/s10822-012-9556-z
PMCID: PMC3322274  PMID: 22395902
membrane proteins; structure quality; inter-residue interactions; frequency score; average number of interactions
5.  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
6.  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.
doi:10.1155/2012/239210
PMCID: PMC3346979  PMID: 22577470
7.  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.
doi:10.1158/0008-5472.CAN-10-4300
PMCID: PMC3088989  PMID: 21487039
CUL9; p53; apoptosis; tumor suppression
8.  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.
doi:10.3201/eid1803.110760
PMCID: PMC3309572  PMID: 22377167
isoniazid; rifampicin; multidrug-resistant tuberculosis; MDR TB; tuberculosis and other mycobacteria; bacteria; cross-sectional survey; prevalence; China
9.  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.
doi:10.1002/bip.21528
PMCID: PMC2966529  PMID: 20672377
seven-helix membrane protein; GPCR; binding site; comparison analysis; cluster analysis
10.  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.
Purpose.
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.
Results.
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).
Conclusion.
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.
doi:10.1634/theoncologist.2010-0161
PMCID: PMC3228056  PMID: 21212438
Supportive care; Palliative care; Cancer; Symptom management; End-of-life care
11.  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.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSION
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.
doi:10.1002/cncr.24942
PMCID: PMC2854875  PMID: 20162701
neoplasms; therapeutics; antineoplastic agents; targeted agents; palliative care
12.  METHADONE INITIATION AND ROTATION IN THE OUTPATIENT SETTING FOR PATIENTS WITH CANCER PAIN 
Cancer  2010;116(2):520-528.
Background
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.
Methods
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.
Results
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.
Conclusions
Outpatient methadone initiation and rotation for cancer pain treatment were safe, with high success rate and low side effect profile.
doi:10.1002/cncr.24754
PMCID: PMC2811764  PMID: 19924788
methadone; pain; neoplasms; outpatients; palliative care
13.  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.
Abstract
Background
Acute palliative care units (APCUs) are new programs aimed at integrating palliative and oncology care. Few outcome studies from APCUs are available.
Objectives
We examined the frequency, survival, and predictors associated with home discharge and death in our APCU.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1089/jpm.2009.0166
PMCID: PMC2883821  PMID: 19824813
14.  The calcimimetic R-568 induces apoptotic cell death in prostate cancer cells 
Background
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.
Methods
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.
Results
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,.
Conclusion
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.
doi:10.1186/1756-9966-28-100
PMCID: PMC2716307  PMID: 19602280
15.  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.
doi:10.1128/AAC.00737-07
PMCID: PMC2223896  PMID: 17954689

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