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1.  HIV Tat protein affects circadian rhythmicity by interfering with the circadian system 
Wang, T | Jiang, Z | Hou, W | Li, Z | Cheng, S | Green, LA | Wang, Y | Wen, X | Cai, L | Clauss, M | Wang, Z
HIV Medicine  2014;15(9):565-570.
Objectives
Sleep disorders are common in patients with HIV/AIDS, and can lead to poor quality of life. Although many studies have investigated the aetiology of these disorders, it is still unclear whether impaired sleep quality is associated with HIV itself, social problems, or side effects of antiretroviral therapy (ART). Moreover, despite its known neurological associations, little is known about the role of the trans-activator of transcription (Tat) protein in sleep disorders in patients with HIV/AIDS. The purpose of this study was to test the hypothesis that the sleep quality of patients with HIV/AIDS affected by an altered circadian rhythm correlates with cerebrospinal HIV Tat protein concentration.
Methods
Ninety-six patients with HIV/AIDS between 20 and 69 years old completed the Pittsburgh Sleep Quality Index. Their circadian rhythm parameters of blood pressure, Tat concentration in cerebrospinal fluid, melatonin concentration, CD4 cell count and HIV RNA viral load in serum were measured.
Results
The circadian amplitude of systolic blood pressure and the score for sleep quality (Pittsburgh Sleep Quality Index) were negatively correlated with HIV Tat protein concentration, while the melatonin value was positively correlated with Tat protein concentration.
Conclusions
The HIV Tat protein affects circadian rhythmicity by interfering with the circadian system in patients with HIV/AIDS and further increases the melatonin excretion value. A Tat protein-related high melatonin value may counteract HIV-related poor sleep quality during the progression of HIV infection. This study provides the first clinical evidence offering an explanation for why sleep quality did not show an association with progression of HIV infection in previous studies.
doi:10.1111/hiv.12154
PMCID: PMC4285855  PMID: 24750691
circadian rhythm; HIV/AIDS; sleep; Tat protein
2.  IFN-γ induces aberrant CD49b+ NK cell recruitment through regulating CX3CL1: a novel mechanism by which IFN-γ provokes pregnancy failure 
Cell Death & Disease  2014;5(11):e1512-.
Interferon-γ (IFN-γ), a pleiotropic lymphokine, has important regulatory effects on many cell types. Although IFN-γ is essential for the initiation of uterine vascular modifications and maintenance of decidual integrity, IFN-γ administration can also cause pregnancy failure in many species. However, little is known about the effector mechanisms involved. In this study, using an IFN-γ-induced abortion mouse model, we reported that no Dolichos biflorus agglutinin lectin-positive uterine natural killer (uNK) cells were observed in the uteri from IFN-γ-induced abortion mice. By contrast, the percentage of CD3−CD49b+ NK cells in the uterus and blood from a foetal resorption group was significantly higher than that of the control group. Similarly, significantly upregulated expression of CD49b (a pan-NK cell marker), CX3CL1 and CX3CR1 (CX3CL1 receptor) was detected in the uteri of IFN-γ-induced abortion mice. Using isolated uterine stromal cells, we showed that upregulated expression of CX3CL1 by IFN-γ was dependent on a Janus family kinase 2-signal transducers and activators of transcription 1 (JAK2-STAT1) pathway. We further demonstrated the chemotactic activity of CX3CL1 in uterine stromal cell conditioned medium on primary splenic NK cells. Finally, we observed increased recruitment of CD49b+ NK cells into the endometrium after exogenous CX3CL1 administration. Collectively, our findings indicate that IFN-γ can significantly increase uterine CX3CL1 expression via activation of the JAK2-STAT1 pathway, thus inducing CD49b+ NK cell uterine homing, and eventually provoke foetal loss. Thus, we provide a new line of evidence correlating the deleterious effects of IFN-γ on pregnancy with the aberrant regulation of CX3CL1 and CD49b+ NK cells.
doi:10.1038/cddis.2014.470
PMCID: PMC4260728  PMID: 25375377
3.  A morphometric study of the lumbar spinous process in the Chinese population 
Our goal was to analyze the anatomical parameters of the lumbar spine spinous process for an interspinous stabilization device designed for the Chinese population and to offer an anatomical basis for its clinical application. The posterior lumbar spines (T12-S1) of 52 adult cadavers were used for measuring the following: distance between two adjacent spinous processes (DB), distance across two adjacent spinous processes (DA), thickness of the central spinous processes (TC), thickness of the superior margin of the spinous processes (TS), thickness of the inferior margin of the spinous processes (TI), and height of the spinous processes (H). Variance and correlation analyses were conducted for these data, and the data met the normal distribution and homogeneity of variance. DB decreased gradually from L1-2 to L5-S1. DA increased from T12-L1 to L2-3 and then decreased from L2-3 to L4-5. The largest H in males was noted at L3 (25.45±5.96 mm), whereas for females the largest H was noted at L4 (18.71±4.50 mm). Usually, TS of the adjacent spinous process was lower than TI. Based on the anatomical parameters of the lumbar spinous processes obtained in this study, an “H”-shaped coronal plane (posterior view) was proposed as an interspinous stabilization device for the Chinese population. This study reports morphometric data of the lumbar spinous processes in the Chinese population, which provides an anatomical basis for future clinical applications.
doi:10.1590/1414-431X20144164
PMCID: PMC4288498  PMID: 25493388
Lumbar spine; Morphometry; Spinal stenosis; Spinous process
4.  PMQR genes oqxAB and aac(6′)Ib-cr accelerate the development of fluoroquinolone resistance in Salmonella typhimurium 
Emergence of multidrug-resistant Salmonella typhimurium strains, especially the ACSSuT and nalidixic acid R types, has significantly compromised the effectiveness of current strategies to control Salmonella infections, resulting in increased morbidity and mortality. Clinical S. typhimurium isolates recovered in Hong Kong during the period of 2005–2011 were increasingly resistant to ciprofloxacin (CIP) and antibiotics of the ACSSuT group. Our data revealed that oqxAB and aac(6′)Ib-cr were encoded on plasmids of various sizes and the presence of these two elements together with a single gyrA mutation in S. typhimurium were sufficient to mediate resistance to CIP. Acquisition of the oqxAB and aac(6′)Ib-cr encoding plasmids by S. typhimurium caused a fourfold increase in CIP minimal inhibitory concentration. Furthermore, the presence of oqxAB and aac(6′)Ib-cr in Salmonella dramatically increased the mutation prevention concentration of CIP which may due to mutational changes in the drug target genes. In conclusion, possession of oqxAB and aac(6′)Ib-cr encoding plasmid facilitate the selection of CIP resistant S. typhimurium, thereby causing a remarkable increase of CIP resistance among clinical Salmonella strains in Hong Kong.
doi:10.3389/fmicb.2014.00521
PMCID: PMC4183184  PMID: 25324840
S. typhimurium; ciprofloxacin resistance; ACSSuT R type; oqxAB; aac(6′)Ib-cr
5.  Support vector machine-based nomogram predicts postoperative distant metastasis for patients with oesophageal squamous cell carcinoma 
British Journal of Cancer  2013;109(5):1109-1116.
Background:
We aim to develop effective models for predicting postoperative distant metastasis for oesophageal squamous cell carcinoma (OSCC) for the purpose of guiding tailored therapy.
Methods:
We used data from two centres to establish training (n=319) and validation (n=164) cohorts. All patients underwent curative surgical treatment. The clinicopathological features and 23 immunomarkers detected by immunohistochemistry were involved for variable selection. We constructed eight support vector machine (SVM)-based nomograms (SVM1–SVM4 and SVM1'–SVM4'). The nomogram constructed with the training cohort was tested further with the validation cohort.
Results:
The outcome of the SVM1 model in predicting postoperative distant metastasis was as follows: sensitivity, 44.7% specificity, 90.9% positive predictive value, 81.0% negative predictive value, 65.6% and overall accuracy, 69.5%. The corresponding outcome of the SVM2 model was as follows: 44.7%, 92.1%, 82.9%, 65.9%, and 70.1%, respectively. The corresponding outcome of the SVM3 model was as follows: 55.3%, 93.2%, 87.5%, 70.7%, and 75.6%, respectively. The SVM4 model was the most effective nomogram in prediction, and the corresponding outcome was as follows: 56.6%, 97.7%, 95.6%, 72.3%, and 78.7%, respectively.Similar results were observed in SVM1', SVM2', SVM3', and SVM4', respectively.
Conclusion:
The SVM-based models integrating clinicopathological features and molecular markers as variables are helpful in selecting the patients of OSCC with high risk of postoperative distant metastasis.
doi:10.1038/bjc.2013.379
PMCID: PMC3778272  PMID: 23942069
nomogram; oesophageal squamous cell carcinoma; surgery; metastasis
6.  A Critical Role for Immune System Response in Mediating Anti-influenza Drug Synergies Assessed by Mechanistic Modeling 
Influenza virus infections represent a serious public health problem worldwide, due to the rapid emergence of drug resistance. One strategy to improve treatment efficacy is to combine drugs that act synergistically. Potentially useful drug combinations are typically identified through empirical testing using in vitro and animal models, but the complexity of the clinical situation warrants the use of more careful analysis and sophisticated approaches. To explore new approaches, we constructed a mechanistic model representing the interaction of antiviral drugs with the viral replication pathway and human immune responses. Simulation of combination therapy using oseltamivir and amantadine predicted significant therapeutic synergy only when immune response was included, in agreement with previous in vitro and in vivo studies using amantadine-resistant strains. Our model can be used to predict the optimal doses for combination therapy, and also raises questions about current drug evaluation methods that do not account for immune system interactions.
doi:10.1038/psp.2014.32
PMCID: PMC4211263  PMID: 25207611
7.  Integrative epigenome analysis identifies a Polycomb-targeted differentiation program as a tumor-suppressor event epigenetically inactivated in colorectal cancer 
Tan, J | Yang, X | Jiang, X | Zhou, J | Li, Z | Lee, P L | Li, B | Robson, P | Yu, Q
Cell Death & Disease  2014;5(7):e1324-.
Aberrant DNA hypermethylation in human cancer has been associated with Polycomb target genes in embryonic stem (ES) cells, but a functional link of the Polycomb-targeted differentiation program to tumorigenesis remains to be established. Here, through epigenome analysis correlating DNA hypermethylation in colon cancer with ES cell pluripotency and differentiation, we identified a set of DNA hypermethylated genes in cancer cells that are Polycomb targets strongly associated with ES cell differentiation, including HAND1, a developmental regulator. Intriguingly, HAND1 is silenced in over 90% of human primary colorectal tumors, and re-expression of HAND1 in colon cancer cells induces terminal differentiation, inhibits proliferation and prevents xenograft tumor formation. Moreover, hypermethylated HAND1 has a minimum enrichment of EZH2-H3K27me3 in cancer cells, but becomes EZH2 bound and bivalent upon the loss of DNA methylation, suggesting a sequential gene silencing event during oncogenesis. These findings established a functional role of Polycomb-targeted differentiation program as a tumor-suppressor event epigenetically inactivated in human cancer.
doi:10.1038/cddis.2014.283
PMCID: PMC4123077  PMID: 25032847
8.  The transient expression of miR-203 and its inhibiting effects on skeletal muscle cell proliferation and differentiation 
Luo, W | Wu, H | Ye, Y | Li, Z | Hao, S | Kong, L | Zheng, X | Lin, S | Nie, Q | Zhang, X
Cell Death & Disease  2014;5(7):e1347-.
Previous studies have shown that miR-203 is a skin-specific microRNA (miRNA) with a profound role in skin cell differentiation. However, emerging microarray and deep sequencing data revealed that miR-203 is also expressed in embryonic skeletal muscle and myoblasts. In this study, we found that miR-203 was transiently upregulated in chicken embryos on days 10 to 16 (E10–E16) and was sharply downregulated and even not expressed after E16 in chicken embryonic skeletal muscle. Histological profiles and weight variations of embryo skeletal muscle revealed that miR-203 expression is correlated with muscle development. In vitro experiments showed that miR-203 exhibited downregulated expression during myoblast differentiation into myotubes. miR-203 overexpression inhibited myoblast proliferation and differentiation, whereas its loss-of-function increased myoblast proliferation and differentiation. During myogenesis, miR-203 can target and inhibit the expression of c-JUN and MEF2C, which were important for cell proliferation and muscle development, respectively. The overexpression of c-JUN significantly promoted myoblast proliferation. Conversely, knockdown of c-JUN by siRNA suppressed myoblast proliferation. In addition, the knockdown of MEF2C by siRNA significantly inhibited myoblast differentiation. Altogether, these data not only suggested that the expression of miR-203 is transitory during chicken skeletal muscle development but also showed a novel role of miR-203 in inhibiting skeletal muscle cell proliferation and differentiation by repressing c-JUN and MEF2C, respectively.
doi:10.1038/cddis.2014.289
PMCID: PMC4123083  PMID: 25032870
9.  Zebrafish Noxa promotes mitosis in early embryonic development and regulates apoptosis in subsequent embryogenesis 
Cell Death and Differentiation  2014;21(6):1013-1024.
Noxa functions in apoptosis and immune system of vertebrates, but its activities in embryo development remain unclear. In this study, we have studied the role of zebrafish Noxa (zNoxa) by using zNoxa-specifc morpholino knockdown and overexpression approaches in developing zebrafish embryos. Expression pattern analysis indicates that zNoxa transcript is of maternal origin, which displays a uniform distribution in early embryonic development until shield stage, and the zygote zNoxa transcription is initiated from this stage and mainly localized in YSL of the embryos. The zNoxa expression alterations result in strong embryonic development defects, demonstrating that zNoxa regulates apoptosis from 75% epiboly stage of development onward, in which zNoxa firstly induces the expression of zBik, and then cooperates with zBik to regulate apoptosis. Moreover, zNoxa knockdown also causes a reduction in number of mitotic cells before 8 h.p.f., suggesting that zNoxa also promotes mitosis before 75% epiboly stage. The effect of zNoxa on mitosis is mediated by zWnt4b in early embryos, whereas zMcl1a and zMcl1b suppress the ability of zNoxa to regulate mitosis and apoptosis at different developmental stages. In addition, mammalian mouse Noxa (mNoxa) mRNA was demonstrated to rescue the arrest of mitosis when zNoxa was knocked down, suggesting that mouse and zebrafish Noxa might have similar dual functions. Therefore, the current findings indicate that Noxa is a novel regulator of early mitosis before 75% epiboly stage when it translates into a key mediator of apoptosis in subsequent embryogenesis.
doi:10.1038/cdd.2014.22
PMCID: PMC4013518  PMID: 24608793
Noxa; Bik; Wnt4b; Mcl1; mitosis; apoptosis
10.  IRF4 is a novel mediator for neuronal survival in ischaemic stroke 
Cell Death and Differentiation  2014;21(6):888-903.
Neuroprotection following ischaemic stroke is driven by the interplay between regulatory transcription factors and endogenous protective factors. IRF4, a member of the interferon regulatory factor (IRF) family, is implicated in the survival of tumour cells. However, its role in the survival of normal cells including neurons remains elusive. Using genetic approaches, we established a central role for IRF4 in protection against ischaemia/reperfusion (I/R)-induced neuronal death. IRF4 was expressed in neurons, and induced by ischaemic stroke. Neuron-specific IRF4 transgenic (IRF4-TG) mice exhibited reduced infarct lesions, and this effect was reversed in IRF4-knockout mice. Notably, we revealed that IRF4 rescues neurons from I/R-induced death both in vivo and in vitro. Integrative transcriptional and cell survival analyses showed that IRF4 functions mechanistically as a transcription activator of serum response factor (SRF) crucial to salvage neurons during stroke. Indeed, the expression of SRF and SRF-dependent molecules was significantly upregulated upon IRF4 overexpression and conversely inhibited upon IRF4 ablation. Similar results were observed in oxygen glucose deprivation (OGD)-treated primary cortical neurons. Furthermore, we identified the IRF4-binding site in the promoter region of the SRF gene essential for its transcription. To verify the IRF4–SRF axis in vivo, we generated neuron-specific SRF knockout mice, in which SRF exerted profound cerebroprotective effects similar to those of IRF4. More importantly, the phenotype observed in IRF4-TG mice was completely reversed by SRF ablation. Thus, we have shown that the IRF4–SRF axis is a novel signalling pathway critical for neuronal survival in the setting of ischaemic stroke.
doi:10.1038/cdd.2014.9
PMCID: PMC4013523  PMID: 24510125
IRF4; SRF; ischaemic stroke; neuronal survival
11.  High-Precision Distribution of Highly Stable Optical Pulse Trains with 8.8 × 10−19 instability 
Scientific Reports  2014;4:5109.
The high-precision distribution of optical pulse trains via fibre links has had a considerable impact in many fields. In most published work, the accuracy is still fundamentally limited by unavoidable noise sources, such as thermal and shot noise from conventional photodiodes and thermal noise from mixers. Here, we demonstrate a new high-precision timing distribution system that uses a highly precise phase detector to obviously reduce the effect of these limitations. Instead of using photodiodes and microwave mixers, we use several fibre Sagnac-loop-based optical-microwave phase detectors (OM-PDs) to achieve optical-electrical conversion and phase measurements, thereby suppressing the sources of noise and achieving ultra-high accuracy. The results of a distribution experiment using a 10-km fibre link indicate that our system exhibits a residual instability of 2.0 × 10−15 at1 s and8.8 × 10−19 at 40,000 s and an integrated timing jitter as low as 3.8 fs in a bandwidth of 1 Hz to 100 kHz. This low instability and timing jitter make it possible for our system to be used in the distribution of optical-clock signals or in applications that require extremely accurate frequency/time synchronisation.
doi:10.1038/srep05109
PMCID: PMC4037707  PMID: 24870442
12.  Attentional bias modulation by reappraisal in patients with generalized anxiety disorder: an event-related potential study 
Affective states influence subsequent attention allocation. We evaluated emotional negativity bias modulation by reappraisal in patients with generalized anxiety disorder (GAD) relative to normal controls. Event-related potential (ERP) recordings were obtained, and changes in P200 and P300 amplitudes in response to negative or neutral words were noted after decreasing negative emotion or establishing a neutral condition. We found that in GAD patients only, the mean P200 amplitude after negative word presentation was much higher than after the presentation of neutral words. In normal controls, after downregulation of negative emotion, the mean P300 amplitude in response to negative words was much lower than after neutral words, and this was significant in both the left and right regions. In GAD patients, the negative bias remained prominent and was not affected by reappraisal at the early stage. Reappraisal was observed to have a lateralized effect at the late stage.
doi:10.1590/1414-431X20143622
PMCID: PMC4123837  PMID: 24863650
Reappraisal; Generalized anxiety disorder; Event-related potential; P200; P300
13.  An antiapoptotic Bcl-2 family protein index predicts the response of leukaemic cells to the pan-Bcl-2 inhibitor S1 
Zhang, Z | Liu, Y | Song, T | Xue, Z | Shen, X | Liang, F | Zhao, Y | Li, Z | Sheng, H
British Journal of Cancer  2013;108(9):1870-1878.
Background:
Bcl-2-like members have been found to be inherently overexpressed in many types of haematologic malignancies. The small-molecule S1 is a BH3 mimetic and a triple inhibitor of Bcl-2, Mcl-1 and Bcl-XL.
Methods:
The lethal dose 50 (LD50) values of S1 in five leukaemic cell lines and 41 newly diagnosed leukaemia samples were tested. The levels of Bcl-2 family members and phosphorylated Bcl-2 were semiquantitatively measured by western blotting. The interactions between Bcl-2 family members were tested by co-immunoprecipitation. The correlation between the LD50 and expression levels of Bcl-2 family members, alone or in combination, was analysed.
Results:
S1 exhibited variable sensitivity with LD50 values ranging >2 logs in both established and primary leukaemic cells. The ratio of pBcl-2/(Bcl-2+Mcl-1) could predict the S1 response. Furthermore, we demonstrated that pBcl-2 antagonised S1 by sequestering the Bak and Bim proteins that were released from Mcl-1, andpBcl-2/Bak, pBcl-2/Bax and pBcl-2/Bim complexes cannot be disrupted by S1.
Conclusion:
A predictive index was obtained for the novel BH3 mimetic S1. The shift of proapoptotic proteins from being complexed with Mcl-1 to being complexed with pBcl-2 was revealed for the first time, which is the mechanism underlying the index value described herein.
doi:10.1038/bjc.2013.152
PMCID: PMC3658527  PMID: 23558901
Bcl-2 phosphorylation; S1; BH3 mimetics; antileukaemic
14.  Variation in access to sugar-sweetened beverages in vending machines across rural, town and urban high schools 
Public health  2013;127(5):485-491.
SUMMARY
Objectives
The 2010 Dietary Guidelines for Americans include reducing consumption of sugar-sweetened beverages. Among the many possible routes of access for youth, school vending machines provide ready availability of sugar-sweetened beverages. The purpose of this study was to determine variation in high school student access to sugar-sweetened beverages through vending machines by geographic location – urban, town or rural – and to offer an approach for analysing school vending machine content.
Study design
Cross-sectional observational study.
Methods
Between October 2007 and May 2008, trained coders recorded beverage vending machine content and machine-front advertising in 113 machines across 26 schools in New Hampshire and Vermont, USA.
Results
Compared with town schools, urban schools were significantly less likely to offer sugar-sweetened beverages (P=0.002). Rural schools also offered more sugar-sweetened beverages than urban schools, but this difference was not significant. Advertisements for sugar-sweetened beverages were highly prevalent in town schools.
Conclusions
High school students have ready access to sugar-sweetened beverages through their school vending machines. Town schools offer the highest risk of exposure; school vending machines located in towns offer up to twice as much access to sugar-sweetened beverages in both content and advertising compared with urban locations. Variation by geographic region suggests that healthier environments are possible and some schools can lead as inspirational role models.
doi:10.1016/j.puhe.2013.01.024
PMCID: PMC3749240  PMID: 23498924
Adolescent; Sugar-sweetened beverage; School nutrition; Obesity; Policy
15.  CTC1 increases the radioresistance of human melanoma cells by inhibiting telomere shortening and apoptosis 
Melanoma has traditionally been viewed as a radioresistant cancer. However, recent studies suggest that under certain clinical circumstances, radiotherapy may play a significant role in the treatment of melanoma. Previous studies have demonstrated that telomere length is a hallmark of radiosensitivity. The newly discovered mammalian CTC1-STN1-TEN1 (CST) complex has been demonstrated to be an important telomere maintenance factor. In this study, by establishing a radiosensitive/radioresistant human melanoma cell model, MDA-MB-435/MDA-MB-435R, we aimed to investigate the association of CTC1 expression with radiosensitivity in human melanoma cell lines, and to elucidate the possible underlying mechanisms. We found that CTC1 mRNA and protein levels were markedly increased in the MDA-MB-435R cells compared with the MDA-MB-435 cells. Moreover, the downregulation of CTC1 enhanced radiosensitivity, induced DNA damage and promoted telomere shortening and apoptosis in both cell lines. Taken together, our findings suggest that CTC1 increases the radioresistance of human melanoma cells by inhibiting telomere shortening and apoptosis. Thus, CTC1 may be an attractive target gene for the treatment of human melanoma.
doi:10.3892/ijmm.2014.1721
PMCID: PMC4055431  PMID: 24718655
telomere-binding protein; conserved telomere maintenance component 1; radioresistance
16.  Longikaurin A, a natural ent-kaurane, induces G2/M phase arrest via downregulation of Skp2 and apoptosis induction through ROS/JNK/c-Jun pathway in hepatocellular carcinoma cells 
Cell Death & Disease  2014;5(3):e1137-.
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, and is also highly resistant to conventional chemotherapy treatments. In this study, we report that Longikaurin A (LK-A), an ent-kaurane diterpenoid isolated from the plant Isodon ternifolius, induced cell cycle arrest and apoptosis in human HCC cell lines. LK-A also suppressed tumor growth in SMMC-7721 xenograft models, without inducing any notable major organ-related toxicity. LK-A treatment led to reduced expression of the proto-oncogene S phase kinase-associated protein 2 (Skp2) in SMMC-7721 cells. Lower Skp2 levels correlated with increased expression of p21 and p-cdc2 (Try15), and a corresponding decrease in protein levels of Cyclin B1 and cdc2. Overexpression of Skp2 significantly inhibited LK-A-induced cell cycle arrest in SMMC-7721 cells, suggesting that LK-A may target Skp2 to arrest cells at the G2/M phase. LK-A also induced reactive oxygen species (ROS) production and apoptosis in SMMC-7721 cells. LK-A induced phosphorylation of c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinase and P38 MAP kinase. Treatment with, the JNK inhibitor SP600125 prevented LK-A-induced apoptosis in SMMC-7721 cells. Moreover, the antioxidant N-acetylcysteine prevented phosphorylation of both JNK and c-Jun. Taken together, these data indicate that LK-A induces cell cycle arrest and apoptosis in cancer cells by dampening Skp2 expression, and thereby activating the ROS/JNK/c-Jun signaling pathways. LK-A is therefore a potential lead compound for development of antitumor drugs targeting HCC.
doi:10.1038/cddis.2014.66
PMCID: PMC3973226  PMID: 24651440
Longikaurin A; hepatocellular carcinoma; cell cycle arrest; apoptosis; Skp2
17.  The role of plasma membrane STIM1 and Ca2 +entry in platelet aggregation. STIM1 binds to novel proteins in human platelets 
Cellular Signalling  2014;26(3):502-511.
Ca2 + elevation is essential to platelet activation. STIM1 senses Ca2 + in the endoplasmic reticulum and activates Orai channels allowing store-operated Ca2 + entry (SOCE). STIM1 has also been reported to be present in the plasma membrane (PM) with its N-terminal region exposed to the outside medium but its role is not fully understood. We have examined the effects of the antibody GOK/STIM1, which recognises the N-terminal region of STIM1, on SOCE, agonist-stimulated Ca2 + entry, surface exposure, in vitro thrombus formation and aggregation in human platelets. We also determined novel binding partners of STIM1 using proteomics. The dialysed GOK/STIM1 antibody failed to reduced thapsigargin- and agonist-mediated Ca2 + entry in Fura2-labelled cells. Using flow cytometry we detect a portion of STIM1 to be surface-exposed. The dialysed GOK/STIM1 antibody reduced thrombus formation by whole blood on collagen-coated capillaries under flow and platelet aggregation induced by collagen. In immunoprecipitation experiments followed by proteomic analysis, STIM1 was found to extract a number of proteins including myosin, DOCK10, thrombospondin-1 and actin. These studies suggest that PM STIM1 may facilitate platelet activation by collagen through novel interactions at the plasma membrane while the essential Ca2 +-sensing role of STIM1 is served by the protein in the ER.
Highlights
•STIM1 promotes collagen induced platelet aggregation and thrombus formation.•In human platelets SOCE activates but is not essential for platelet aggregation.•Plasma membrane STIM1 may facilitate platelet activation independent of SOCE.
doi:10.1016/j.cellsig.2013.11.025
PMCID: PMC4062937  PMID: 24308967
STIM1, stromal interaction molecule 1; SOCE, store operated Ca2 + entry; DAG, 1,2-diacyl-sn-glycerol; PM, plasma membrane; TG, thapsigargin; OAG, 1-Oleoyl-2-acetyl-sn-glycerol; TRPC, transient receptor potential canonical; Aggregation; Ca2 + entry; Collagen; STIM1; Thrombospondin-1
18.  Oncogenic K-Ras requires activation for enhanced activity 
Oncogene  2013;33(4):532-535.
Oncogenic Ras mutations are widely considered to be locked in a permanent ‘On’ state and ‘constitutively active’. Yet, many healthy people have cells possessing mutant Ras without apparent harm, and in animal models mutant Ras causes transformation only after upregulation of Ras activity. Here, we demonstrate that oncogenic K-Ras is not constitutively active but can be readily activated by upstream stimulants to lead to prolonged strong Ras activity. These data indicate that in addition to targeting K-Ras downstream effectors, interventions to reduce K-Ras activation may have important cancer-preventive value, especially in patients with oncogenic Ras mutations. As other small G proteins are regulated in a similar manner, this concept is likely to apply broadly to the entire Ras family of molecules.
doi:10.1038/onc.2012.619
PMCID: PMC3923400  PMID: 23334325
cancer; Ras-GTP
19.  Clinical efficacy of a medically supervised outpatient high-protein, low-calorie diet program is equivalent in prediabetic, diabetic and normoglycemic obese patients 
Nutrition & Diabetes  2014;4(2):e105-.
Objective:
Type 2 diabetes mellitus (T2DM) affects approximately 10% of Americans, while 79 million Americans are estimated to have glucose intolerance or prediabetes (pre-DM). The present study was designed to determine whether obese patients with pre-DM or T2DM would lose weight as effectively as obese normoglycemic patients, in a medically supervised high-protein, low-calorie-weight management program.
Method:
Patients enrolled in a self-paid, university-based, outpatient weight loss program using prescribed very-low-calorie diet (VLCD) (500–800 cal per day) or LCD diet (800–1200 cal per day), recommended exercise and group behavioral counseling were studied retrospectively. Patients entering the program for the first time and attending weekly clinic visits for more than 4 weeks were included in the analysis.
Results:
A total of 2093 obese patients, of whom 583 patients with pre-DM (fasting glucose ⩾100 and <126 mg dl−1), 367 patients with T2DM and 1143 normoglycemic patients entered the program from 1991 to 2010, who met all the inclusion criteria were included in the analysis. The body weight at baseline was 104.0±20.0 kg for DM, 101.4±18.4 for pre-DM and 99.0±18.8 kg for non-DM. Weight loss and percent of weight loss within 12 months were analyzed using a linear mixed-effects model. There was no significant difference in weight loss between DM vs non-DM (P=0.4597) and pre-DM vs non-DM (P=0.6006) in 12 months. The length of enrollment in the program was positively correlated to weight loss rates in all patients (P<0.001).
Conclusion:
This study demonstrates that obese, pre-DM and DM patients all lost weight as effectively with VLCD or LCD over 12 months. Given the impact of weight loss on the progression of comorbid conditions, these data support the hypothesis that medically supervised diets, including VLCD and LCD, should be more widely used in the prevention and treatment of obese patients with pre-DM or T2DM.
doi:10.1038/nutd.2014.1
PMCID: PMC3940825  PMID: 24513578
VLCD; diabetes mellitus; weight loss; obesity; prediabetes
20.  Diagnostic evaluation of t(4;14) in multiple myeloma and evidence for clonal evolution 
Leukemia  2007;21(11):10.1038/sj.leu.2404800.
doi:10.1038/sj.leu.2404800
PMCID: PMC3882151  PMID: 17568814
21.  Kinetic quantification of protein polymer nanoparticles using non-invasive imaging 
Protein polymers are repetitive amino acid sequences that can assemble monodisperse nanoparticles with potential applications as cancer nanomedicines. Of the currently available molecular imaging methods, positron emission tomography (PET) is the most sensitive and quantitative; therefore, this work explores microPET imaging to track protein polymer nanoparticles over several days. To achieve reliable imaging, the polypeptides were modified by site-specific conjugation using a heterobifunctional sarcophagine chelator, AmBaSar, which was subsequently complexed with 64Cu. AmBaSar/64Cu was selected because it can label particles in vivo over periods of days, which is consistent with the timescales required to follow long-circulating nanotherapeutics. Using an orthotopic model of breast cancer, we observed four elastin-like polypeptides (ELPs)-based protein polymers of varying molecular weight, amino acid sequence, and nanostructure. To analyze this data, we developed a six-compartment image-driven pharmacokinetic model capable of describing their distribution within individual subjects. Surprisingly, the assembly of an ELP block copolymer (78 kD) into nanoparticles (Rh = 37.5 nm) minimally influences pharmacokinetics or tumor accumulation compared to a free ELP of similar length (74 kD). Instead, ELP molecular weight is the most important factor controlling the fate of these polymers, whereby long ELPs (74 kD) have a heart activity half-life of 8.7 hours and short ELPs (37 kD) have a half-life of 2.1 hrs. These results suggest that ELP-based protein polymers may be a viable platform for the development of multifunctional therapeutic nanoparticles that can be imaged using clinical PET scanners.
doi:10.1039/c2ib20169k
PMCID: PMC3762326  PMID: 23093022
22.  Galectin-1 overexpression promotes progression and chemoresistance to cisplatin in epithelial ovarian cancer 
Zhang, P | Zhang, P | Shi, B | Zhou, M | Jiang, H | Zhang, H | Pan, X | Gao, H | Sun, H | Li, Z
Cell Death & Disease  2014;5(1):e991-.
This study was performed to investigate the role of galectin-1 (Gal-1) in epithelial ovarian cancer (EOC) progression and chemoresistance. Tissue samples from patients with EOC were used to examine the correlation between Gal-1 expression and clinical stage of EOC. The role of Gal-1 in EOC progression and chemoresistance was evaluated in vitro by siRNA-mediated knockdown of Gal-1 or lentivirus-mediated overexpression of Gal-1 in EOC cell lines. To elucidate the molecular mechanisms underlying Gal-1-mediated tumor progression and chemoresistance, the expression and activities of some signaling molecules associated with Gal-1 were analyzed. We found overexpression of Gal-1 in advanced stages of EOC. Knockdown of endogenous Gal-1 in EOC cells resulted in the reduction in cell growth, migration, and invasion in vitro, which may be caused by Gal-1's interaction with H-Ras and activation of the Raf/extracellular signal-regulated kinase (ERK) pathway. Additionally, matrix metalloproteinase-9 (MMP-9) and c-Jun were downregulated in Gal-1-knockdown cells. Notably, Gal-1 overexpression could significantly decrease the sensitivities of EOC cells to cisplatin, which might be ascribed to Gal-1-induced activation of the H-Ras/Raf/ERK pathway and upregulation of p21 and Bcl-2. Taken together, the results suggest that Gal-1 contributes to both tumorigenesis and cisplatin resistance in EOC. Thus, Gal-1 is a potential therapeutic target for EOC.
doi:10.1038/cddis.2013.526
PMCID: PMC4040687  PMID: 24407244
galectin-1; epithelial ovarian cancer; progression; chemoresistance
23.  A Selective Blocking Method To Control the Overgrowth of Pt on Au Nanorods 
A method for the preparation of smooth deposits of Pt on Au nanorods is described, involving sequential deposition steps with selective blocking of surface sites that reduces Pt-on-Pt deposition. The Au–Pt nanorods prepared by this method have higher long-term stability than those prepared by standard Pt deposition. Electrochemical data show that the resulting structure has more extended regions of Pt surface and enhanced activity toward the carbon monoxide oxidation and oxygen reduction reactions.
doi:10.1021/ja4003475
PMCID: PMC3842091  PMID: 23594230
24.  Clinical Utility of Magnetic Resonance Thermal Imaging (MRTI) For Realtime Guidance of Deep Hyperthermia 
Proceedings of SPIE  2009;7181:10.1117/12.812188.
A critical need has emerged for volumetric thermometry to visualize 3D temperature distributions in real time during deep hyperthermia treatments used as an adjuvant to radiation or chemotherapy for cancer. For the current effort, magnetic resonance thermal imaging (MRTI) is used to measure 2D temperature rise distributions in four cross sections of large extremity soft tissue sarcomas during hyperthermia treatments. Novel hardware and software techniques are described which improve the signal to noise ratio of MR images, minimize motion artifact from circulating coupling fluids, and provide accurate high resolution volumetric thermal dosimetry. For the first 10 extremity sarcoma patients, the mean difference between MRTI region of interest and adjacent interstitial point measurements during the period of steady state temperature was 0.85°C. With 1min temporal resolution of measurements in four image planes, this non-invasive MRTI approach has demonstrated its utility for accurate monitoring and realtime steering of heat into tumors at depth in the body.
doi:10.1117/12.812188
PMCID: PMC3820377  PMID: 24224074
Non-Invasive Thermometry; Magnetic Resonance Temperature Imaging; Deep Hyperthermia; Radiofrequency Phased Array Heating
25.  Expression of cyclin D1a and D1b as predictive factors for treatment response in colorectal cancer 
British Journal of Cancer  2012;107(10):1684-1691.
Background:
The aim of this study was to investigate the value of the cyclin D1 isoforms D1a and D1b as prognostic factors and their relevance as predictors of response to adjuvant chemotherapy with 5-fluorouracil and levamisole (5-FU/LEV) in colorectal cancer (CRC).
Methods:
Protein expression of nuclear cyclin D1a and D1b was assessed by immunohistochemistry in 335 CRC patients treated with surgery alone or with adjuvant therapy using 5-FU/LEV. The prognostic and predictive value of these two molecular markers and clinicopathological factors were evaluated statistically in univariate and multivariate survival analyses.
Results:
Neither cyclin D1a nor D1b showed any prognostic value in CRC or colon cancer patients. However, high cyclin D1a predicted benefit from adjuvant therapy measured in 5-year relapse-free survival (RFS) and CRC-specific survival (CSS) compared to surgery alone in colon cancer (P=0.012 and P=0.038, respectively) and especially in colon cancer stage III patients (P=0.005 and P=0.019, respectively) in univariate analyses. An interaction between treatment group and cyclin D1a could be shown for RFS (P=0.004) and CSS (P=0.025) in multivariate analysis.
Conclusion:
Our study identifies high cyclin D1a protein expression as a positive predictive factor for the benefit of adjuvant 5-FU/LEV treatment in colon cancer, particularly in stage III colon cancer.
doi:10.1038/bjc.2012.463
PMCID: PMC3493874  PMID: 23099809
cyclin D1a; cyclin D1b; colorectal cancer; treatment response; IHC

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