Risk factors for renal failure among 72 consecutive patients with rhabdomyolysis related to illicit drug use.
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Acute Kidney Injury↗
Biomedical subjects
Lin Zhang
Publications and source records attributed to Lin Zhang.
Bend sensors with direction recognition based on long-period gratings written in D-shaped fiber.
The curvature- or bend-sensing response of long-period gratings (LPGs) UV inscribed in D-shaped fiber has been investigated experimentally. Strong fiber-orientation dependence of the spectral response when such LPGs are subjected to bending at different directions has been observed and is shown to form the basis for a new class of single-device sensor with vector-sensing capability. Potential applications utilizing the linear response and unique bend-orientation characteristics of the devices are discussed.
Journal Article↗
Differential birefringence in Bragg gratings in multicore fiber under transverse stress.
We present experimental measurements of the peak splitting of the reflection spectra of fiber Bragg gratings as a result of birefringence induced by transverse loading of a multicore fiber. Measurements show that the splitting is a function of the applied load and the direction of the load relative to the azimuth of the fiber. A model for calculating the stress in the fiber that is due to an applied load is in good agreement with our experimental observations.
Journal Article↗
Co-administration of a DNA vaccine encoding the prostate specific membrane antigen and CpG oligodeoxynucleotides suppresses tumor growth.
BACKGROUND: Prostate-specific membrane antigen (PSMA) is a well characterized prostate-specific tumor associated antigen. Its expression is elevated in prostate carcinoma, particularly in metastatic and recurrent lesions. These observations suggest that PSMA can be used as immune target to induce tumor cell-specific recognition by the host and, consequently tumor rejection. We utilized a DNA-based vaccine to specifically enhance PSMA expression. An immune modulator, such as CpG oligodeoxynucleotides which promote Th1-type immune responses was combined to increase the efficacy of tumor recognition and elimination. METHODS: A eukaryotic expression plasmid pCDNA3.1-PSMA encoding full-length PSMA was constructed. C57BL/6 mice were immunized with endotoxin-free pCDNA3.1-PSMA alone or in combination with CpG oligodeoxynucleotides by intramuscular injection. After 4 immunizations, PSMA specific antibodies and cytotoxic T lymphocyte reactivity were measured. Immunized C57BL/6 mice were also challenged subcutaneously with B16 cells transfected with PSMA to evaluate suppression of tumor growth. RESULTS: Vaccine-specific cytotoxic T lymphocytes reactive with B16 cells expressing PSMA could be induced with this treatment schedule. Immune protection was observed in vaccinated mice as indicated by increased tumor growth in the control group (100%) compared with the groups vaccinated with DNA alone (66.7%) or DNA plus CpG oligodeoxynucleotides (50%) respectively. Average tumor volume was smaller in vaccinated groups and tumor-free survival time was prolonged by the vaccination. CONCLUSION: The current findings suggest that specific anti-tumor immune response can be induced by DNA vaccines expressing PSMA. In addition, the suppression of in vivo growth of tumor cells expressing PSMA was augmented by CpG oligodeoxynucleotides. This strategy may provide a new venue for the treatment of carcinoma of prostate after failure of standard therapy.
Journal Article↗
Tumor-infiltrating dendritic cell precursors recruited by a beta-defensin contribute to vasculogenesis under the influence of Vegf-A.
The involvement of immune mechanisms in tumor angiogenesis is unclear. Here we describe a new mechanism of tumor vasculogenesis mediated by dendritic cell (DC) precursors through the cooperation of beta-defensins and vascular endothelial growth factor-A (Vegf-A). Expression of mouse beta-defensin-29 recruited DC precursors to tumors and enhanced tumor vascularization and growth in the presence of increased Vegf-A expression. A new leukocyte population expressing DC and endothelial markers was uncovered in mouse and human ovarian carcinomas coexpressing Vegf-A and beta-defensins. Tumor-infiltrating DCs migrated to tumor vessels and independently assembled neovasculature in vivo. Bone marrow-derived DCs underwent endothelial-like differentiation ex vivo, migrated to blood vessels and promoted the growth of tumors expressing high levels of Vegf-A. We show that beta-defensins and Vegf-A cooperate to promote tumor vasculogenesis by carrying out distinct tasks: beta-defensins chemoattract DC precursors through CCR6, whereas Vegf-A primarily induces their endothelial-like specialization and migration to vessels, which is mediated by Vegf receptor-2.
Angiogenesis Inducing Agents↗
Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.
Regulatory T (T(reg)) cells mediate homeostatic peripheral tolerance by suppressing autoreactive T cells. Failure of host antitumor immunity may be caused by exaggerated suppression of tumor-associated antigen-reactive lymphocytes mediated by T(reg) cells; however, definitive evidence that T(reg) cells have an immunopathological role in human cancer is lacking. Here we show, in detailed studies of CD4(+)CD25(+)FOXP3(+) T(reg) cells in 104 individuals affected with ovarian carcinoma, that human tumor T(reg) cells suppress tumor-specific T cell immunity and contribute to growth of human tumors in vivo. We also show that tumor T(reg) cells are associated with a high death hazard and reduced survival. Human T(reg) cells preferentially move to and accumulate in tumors and ascites, but rarely enter draining lymph nodes in later cancer stages. Tumor cells and microenvironmental macrophages produce the chemokine CCL22, which mediates trafficking of T(reg) cells to the tumor. This specific recruitment of T(reg) cells represents a mechanism by which tumors may foster immune privilege. Thus, blocking T(reg) cell migration or function may help to defeat human cancer.
Animals↗
RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR).
The cardiac ryanodine receptor (RyR2) governs the release of Ca2+ from the sarcoplasmic reticulum, which initiates muscle contraction. Mutations in RyR2 have been linked to ventricular tachycardia (VT) and sudden death, but the precise molecular mechanism is unclear. It is known that when the sarcoplasmic reticulum store Ca2+ content reaches a critical level, spontaneous Ca2+ release occurs, a process we refer to as store-overload-induced Ca2+ release (SOICR). In view of the well documented arrhythmogenic nature of SOICR, we characterized the effects of disease-causing RyR2 mutations on SOICR in human embryonic kidney (HEK)293 cells and found that, at elevated extracellular Ca2+ levels, HEK293 cells expressing RyR2 displayed SOICR in a manner virtually identical to that observed in cardiac cells. Using this cell model, we demonstrated that the RyR2 mutations linked to VT and sudden death, N4104K, R4496C, and N4895D, markedly increased the occurrence of SOICR. At the molecular level, we showed that these RyR2 mutations increased the sensitivity of single RyR2 channels to activation by luminal Ca2+ and enhanced the basal level of [3H]ryanodine binding. We conclude that disease-causing RyR2 mutations, by enhancing RyR2 luminal Ca2+ activation, reduce the threshold for SOICR, which in turn increases the propensity for triggered arrhythmia. Abnormal RyR2 luminal Ca2+ activation likely contributes to the enhanced SOICR commonly observed in various cardiac conditions, including heart failure, and may represent a unifying mechanism for Ca2+ overload-associated VT.
Animals↗
Synthesis and biological evaluation of a new class of geldanamycin derivatives as potent inhibitors of Hsp90.
The heat shock protein Hsp90 has increasingly become an important therapeutic target especially for treatment of cancers. Inhibition of the ATPase activity of Hsp90 by natural products (e.g., 17-allylaminogeldanamycin or radicicol) leads to the ubiquitination of oncogenic client proteins such as Her-2, Raf-1, and p-Akt followed by their proteasomal degradation. Hsp90 inhibitors simultaneously target multiple oncogenic proteins and provide an advantage for cancer therapy due to the potential for increased efficacy and overcoming drug resistance. In an effort to convert geldanamycin into a druglike compound with better pharmacokinetic properties and efficacy in human tumor xenograft models, geldanamycin was derivatized on the 17-position to prepare new analogues such as 17-geldanamycin amides, carbamates, and ureas and 17-arylgeldanamycins. All the compounds were first evaluated ex vivo using a cell-based Her-2 degradation assay and in vitro using biochemical assays that measure recombinant Hsp90 (rHsp90) competitive binding and changes in rHsp90 conformation. In addition, we confirmed the selectivity of geldanamycin analogues for Hsp90 derived from tumor cells using a novel cell lysate binding assay.
Animals↗
[The function of the level of serum carcinoembryonic antigen on early recurrence of non-small cell lung cancer].
OBJECTIVE: To explore clinical and pathological factors correlating with early recurrence of resected non small cell lung cancer (NSCLC), and to further understand the function of serum carcinoembryonic antigen (CEA) on NSCLC. METHODS: 93 patients of NSCLC were selected. All of them received resection and were followed up for more than one year. The first time of recurrence was recorded. Logistic univariate and multivariable analysis were used to find the factors that affect the early recurrence of NSLSC, including age, sex, serum CEA level, tumor size, tumor location, tumor differentiation, histological type and clinical staging, and the ability of factors predicting the recurrence were compared by receiver operating characteristic (ROC) curve. RESULTS: Of all the clinical and pathological factors that are correlated with early recurrence of NSCLC, the serum carcinoembryonic antigen (CEA) value, clinical staging, and tumor difference are of statistical significance. The preoperative serum CEA value is the most valuable factor to predict early recurrence of NSCLC (ROC area: 0.843, 95% CI: 0.723 approximately 0.963, P = 0.000). When preoperative serum CEA value > 10 micro g/L, patients of NSCLC will have an early recurrence rate of 88%; and when preoperative serum CEA value </= 10 micro g/L, the probability of no early recurrence is 92%. CONCLUSION: For the patients with respectable NSCLC, it is very important to know the precise clinical stage and pathological difference, and so is the preoperative serum CEA value. When preoperative serum CEA value > 10 micro g/L, even if the lesion is of early stage and well differenced, the general situation of patients should be carefully examined for the prompt and accurate treatment to them and close follow up is needed to treat these patients.
Biomarkers, Tumor↗
Separation of acidic and basic compounds in capillary electrochromatography with polymethacrylate-based monolithic columns.
Methacrylate-based monolithic columns with electroosmotic flow (EOF) or very weak EOF are prepared by in situ copolymerization in the presence of a porogen in fused-silica capillaries pretreated with a bifunctional reagent. Satisfactory separations of acidic and basic compounds on the column with EOF at either low or high pH are achieved, respectively. With sulfonic groups as dissociation functionalities, sufficient EOF mobility still remains as high as 1.74 x 10(-4) cm2 s(-1) V(-1) at low pH. Under this condition, seven acidic compounds are readily separated within 5.7 min. Moreover, at high pH, the peak shape of basic compounds is satisfactory without addition of any masking amines into running mobile phase since the secondary interaction between the basic compounds and the monolithic stationary phase are minimized at high pH. Reversed-phase mechanism for both acidic and basic compounds is observed under investigated separation conditions. In addition, possibilities of acidic and basic compound separations on a monolithic column with extremely low EOF are discussed.
Chromatography, Micellar Electrokinetic Capillary↗
Polysomnography performed in the unattended home versus the attended laboratory setting--Sleep Heart Health Study methodology.
STUDY OBJECTIVE: To compare polysomnographic recordings obtained in the home and laboratory setting. DESIGN AND SETTING: Multicenter study comparing unsupervised polysomnography performed in the participant's home with polysomnography supervised at an academic sleep disorders center, using a randomized sequence of study setting. Sleep Heart Health Study (SHHS) standardized polysomnographic recording and scoring techniques were used for both settings. PARTICIPANTS: 64 of 76 non-SHHS participants recruited from 7 SHHS field sites who had both a laboratory and home polysomnogram meeting acceptable quality criteria. MEASUREMENTS AND RESULTS: Median sleep duration was greater in the home than in the laboratory (375 vs 318 minutes, respectively, P < .0001) as was sleep efficiency (86% vs 82%, respectively, P < .0024). Very small, but significant increases in percentage of rapid eye movement sleep and decreases in stage 1 sleep were noted in the laboratory. Employing multiple definitions of respiratory disturbance index (RDI), median RDI was similar in both settings (for example, RDI with 3% desaturation: home 12.4, range 0.6-67; laboratory 9.5, range 0.1-93.4, P = .41). Quartile analysis of laboratory RDI showed moderate agreement with home RDI measurements. Based on the mean of laboratory and home RDI and using a cutpoint of 20, there was a biphasic distribution, with the RDI 3% above 20 being more common in the recordings performed in the laboratory than in the home and below 20 being more common in the recordings performed in the home than in the laboratory. These differences could not be attributed to quality of recording, age, sex, or body mass index. CONCLUSIONS: Using SHHS methodology, median RDI was similar in the unattended home and attended laboratory setting with differences of small magnitude in some sleep parameters. Differences in RDI between settings resulted in a rate of disease misclassification that is similar to repeated studies in the same setting.
Adult↗
Quadratic behavior of fiber Bragg grating temperature coefficients.
We describe the characterization of the temperature and strain responses of fiber Bragg grating sensors by use of an interferometric interrogation technique to provide an absolute measurement of the grating wavelength. The fiber Bragg grating temperature response was found to be nonlinear over the temperature range -70 degrees C to 80 degrees C. The nonlinearity was observed to be a quadratic function of temperature, arising from the linear dependence on temperature of the thermo-optic coefficient of silica glass over this range, and is in good agreement with a theoretical model.
Journal Article↗
Sulforaphane-induced G2/M phase cell cycle arrest involves checkpoint kinase 2-mediated phosphorylation of cell division cycle 25C.
Previously, we showed that sulforaphane (SFN), a naturally occurring cancer chemopreventive agent, effectively inhibits proliferation of PC-3 human prostate cancer cells by causing caspase-9- and caspase-8-mediated apoptosis. Here, we demonstrate that SFN treatment causes an irreversible arrest in the G(2)/M phase of the cell cycle. Cell cycle arrest induced by SFN was associated with a significant decrease in protein levels of cyclin B1, cell division cycle (Cdc) 25B, and Cdc25C, leading to accumulation of Tyr-15-phosphorylated (inactive) cyclin-dependent kinase 1. The SFN-induced decline in Cdc25C protein level was blocked in the presence of proteasome inhibitor lactacystin, but lactacystin did not confer protection against cell cycle arrest. Interestingly, SFN treatment also resulted in a rapid and sustained phosphorylation of Cdc25C at Ser-216, leading to its translocation from the nucleus to the cytoplasm because of increased binding with 14-3-3beta. Increased Ser-216 phosphorylation of Cdc25C upon treatment with SFN was the result of activation of checkpoint kinase 2 (Chk2), which was associated with Ser-1981 phosphorylation of ataxia telangiectasia-mutated, generation of reactive oxygen species, and Ser-139 phosphorylation of histone H2A.X, a sensitive marker for the presence of DNA double-strand breaks. Transient transfection of PC-3 cells with Chk2-specific small interfering RNA duplexes significantly attenuated SFN-induced G(2)/M arrest. HCT116 human colon cancer-derived Chk2(-/-) cells were significantly more resistant to G(2)/M arrest by SFN compared with the wild type HCT116 cells. These findings indicate that Chk2-mediated phosphorylation of Cdc25C plays a major role in irreversible G(2)/M arrest by SFN. Activation of Chk2 in response to DNA damage is well documented, but the present study is the first published report to link Chk2 activation to cell cycle arrest by an isothiocyanate.
Active Transport, Cell Nucleus↗
Use of dual-grating sensors formed by different types of fiber Bragg gratings for simultaneous temperature and strain measurements.
We report on a systematic investigation of the dependence of both temperature and strain sensitivities on the fiber Bragg grating type, including the well-known Type I, Type IIA, and a new type that we have designated Type IA, using both hydrogen-free and hydrogenated B/Ge codoped fibres. We have identified distinct sensitivity characteristics for each grating type, and we have used them to implement a novel dual-grating, dual-parameter sensor device. Three dual-grating sensing schemes with different combinations of grating type have been constructed and compared, and that of a Type IA-Type IIA combination exhibits the best performance, which is also superior to that of previously reported grating-based structures. The characteristics of the measurement errors in such dual-grating sensor systems is also presented in detail.
Journal Article↗
Ovarian carcinoma expresses the NKG2D ligand Letal and promotes the survival and expansion of CD28- antitumor T cells.
The role of the NKG2D immunoreceptor and its ligands in antitumor immune response is incompletely understood. Here, we report that effector immune cells infiltrating ovarian carcinoma are mostly CD8+ lymphocytes lacking CD28 but expressing the NKG2D costimulatory receptor. Human ovarian carcinoma expresses the novel NKG2D ligand lymphocyte effector cell toxicity-activating ligand (Letal). Letal was found to be an independent prognosticator of improved survival in advanced ovarian cancer. Higher levels of tumor-derived Letal were associated with stronger lymphocyte infiltration. Letal exerted marked costimulatory effects and induced type-1 polarization in CD8+CD28- tumor-infiltrating lymphocytes ex vivo. Letal engagement increased the expression of the glucose transporter Glut-1, enhanced glucose up-take, and protected CD8+ lymphocytes from cisplatin-induced killing. Letal also down-regulated the expression of Fas in CD8+ cells and rendered them resistant to Fas ligand-induced apoptosis. Our results indicate that Letal promotes tumor immune surveillance by promoting the survival and intratumoral expansion of antitumor cytotoxic lymphocytes. We propose that Letal could be used for the ex vivo expansion of apoptosis-resistant tumor-reactive cytotoxic lymphocytes for adoptive transfer.
Adenocarcinoma, Mucinous↗
Location of auxilin within a clathrin cage.
The Dna J homologue, auxilin, acts as a co-chaperone for Hsc70 in the uncoating of clathrin-coated vesicles during endocytosis. Biochemical studies have aided understanding of the uncoating mechanism but until now there was no structural information on how auxilin interacts with the clathrin cage. Here we have determined the three-dimensional structure of a complex of auxilin with clathrin cages by cryo-electron microscopy and single particle analysis. We show that auxilin forms a discrete shell of density on the inside of the clathrin cage. Peptide competition assays confirm that a candidate clathrin box motif in auxilin, LLGLE, can bind to a clathrin construct containing the beta-propeller domain and also displace the well-characterised LLNLD clathrin box motif derived from the beta-adaptin hinge region. The means by which auxilin could both aid clathrin coat assembly and displace clathrin from AP2 during uncoating is discussed.
Amino Acid Motifs↗
Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population.
CONTEXT: Premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene are frequent in the general population, with estimated prevalences of 1 per 259 females and 1 per 813 males. Several articles have recently described the presence of late-onset neurological symptoms in male carriers of premutation (FMR1) alleles. The main clinical features described in this newly identified syndrome are cerebellar ataxia and intention tremor. Additional documented symptoms include short-term memory loss, executive functional deficits, cognitive decline, parkinsonism, peripheral neuropathy, lower-limb proximal muscle weakness, and autonomic dysfunction. OBJECTIVE: To study the penetrance of the fragile X-associated tremor/ataxia syndrome (FXTAS) among premutation carriers. DESIGN, SETTING, AND PARTICIPANTS: Family-based study of 192 individuals (premutation carriers and controls) whose families belong to the Northern or Southern California Fragile X Associations. Data were collected (March 2002-April 2003) through a survey and a standardized neurological examination, which was videotaped and subsequently scored in a blinded fashion. MAIN OUTCOME MEASURES: Penetrance of intention tremor and ataxia among adult carriers (aged > or =50 years) of premutation expansions of the FMR1 gene. RESULTS: Data from the survey of 192 individuals demonstrated an age-related penetrance of the combination of reported intention tremor and gait ataxia in male carriers (17%, 38%, 47%, and 75% [lower-bound estimates] for participants aged 50-59, 60-69, 70-79, and > or =80 years, respectively). The male carrier group had an age-adjusted 13-fold increased risk (95% confidence interval, 3.9-25.4; P =.003) of combined intention tremor and gait ataxia when compared with male controls. The clinical examination data from 93 individuals demonstrated that male carriers experienced more difficulties on each of 3 standardized neurological rating scales compared with controls (P<.05). Female carrier scores were also higher than those of female controls (P<.05) on 2 of the 3 neurological rating scales, but no participant was identified with probable or definite FXTAS. CONCLUSIONS: The study demonstrates that older male carriers of premutation alleles of the FMR1 gene are at high risk of developing FXTAS. Since male premutation carriers are relatively common in the general population, older men with ataxia and intention tremor should be screened for the FMR1 mutation, especially if these signs are accompanied by parkinsonism, autonomic dysfunction, or cognitive decline, regardless of family history.
Aged↗
Optical sensor interrogation with a blazed fiber Bragg grating and a charge-coupled device linear array.
We present what is to our knowledge the first comprehensive investigation of the use of blazed fiber Bragg gratings (BFBGs) to interrogate wavelength division multiplexed (WDM) in-fiber optical sensor arrays. We show that the light outcoupled from the core of these BFBGs is radiated with sufficient optical power that it may be detected with a low-cost charge-coupled device (CCD) array. We present thorough system performance analysis that shows sufficient spectral-spatial resolution to decode sensors with a WDM separation of 75 rhom, signal-to-noise ratio greater than 45-dB bandwidth of 70 nm, and drift of only 0.1 rhom. We show the system to be polarization-state insensitive, making the BFBG-CCD spectral analysis technique a practical, extremely low-cost, alternative to traditional tunable filter approaches.
Journal Article↗