Use of cancer-specific yeast-secreted in vivo biotinylated recombinant antibodies for serum biomarker discovery

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Characterization of Gravitational Microlensing Planetary Host Stars

The gravitational microlensing light curves that reveal the presence of extrasolar planets generally yield the planet-star mass ratio and separation in units of the Einstein ring radius. The microlensing method does not require the detection of light from the planetary host star. This allows the detection of planets orbiting very faint stars, but it also makes it difficult to convert the planet-star mass ratio to a value for the planet mass. We show that in many cases, the lens stars are readily detectable with high resolution space-based follow-up observations in a single passband. When the lens star is detected, the lens-source relative proper motion can also be measured, and this allows the masses of the planet and its host star to be determined and the star-planet separation can be converted to physical units. Observations in multiple passbands provide redundant information, which can be used to confirm this interpretation. For the recently detected super-Earth planet, OGLE-2005-BLG-169Lb, we show that the lens star will definitely be detectable with observations by the Hubble Space Telescope (HST) unless it is a stellar remnant. Finally, we show that most planets detected by a space-based microlensing survey are likely to orbit host stars that will be detected and characterized by the same survey.Comment: accepted for publication in ApJ, May 10, 200

Systematic Evaluation of Candidate Blood Markers for Detecting Ovarian Cancer

Epithelial ovarian cancer is a significant cause of mortality both in the United States and worldwide, due largely to the high proportion of cases that present at a late stage, when survival is extremely poor. Early detection of epithelial ovarian cancer, and of the serous subtype in particular, is a promising strategy for saving lives. The low prevalence of ovarian cancer makes the development of an adequately sensitive and specific test based on blood markers very challenging. We evaluated the performance of a set of candidate blood markers and combinations of these markers in detecting serous ovarian cancer.We selected 14 candidate blood markers of serous ovarian cancer for which assays were available to measure their levels in serum or plasma, based on our analysis of global gene expression data and on literature searches. We evaluated the performance of these candidate markers individually and in combination by measuring them in overlapping sets of serum (or plasma) samples from women with clinically detectable ovarian cancer and women without ovarian cancer. Based on sensitivity at high specificity, we determined that 4 of the 14 candidate markers--MUC16, WFDC2, MSLN and MMP7--warrant further evaluation in precious serum specimens collected months to years prior to clinical diagnosis to assess their utility in early detection. We also reported differences in the performance of these candidate blood markers across histological types of epithelial ovarian cancer.By systematically analyzing the performance of candidate blood markers of ovarian cancer in distinguishing women with clinically apparent ovarian cancer from women without ovarian cancer, we identified a set of serum markers with adequate performance to warrant testing for their ability to identify ovarian cancer months to years prior to clinical diagnosis. We argued for the importance of sensitivity at high specificity and of magnitude of difference in marker levels between cases and controls as performance metrics and demonstrated the importance of stratifying analyses by histological type of ovarian cancer. Also, we discussed the limitations of studies (like this one) that use samples obtained from symptomatic women to assess potential utility in detection of disease months to years prior to clinical detection

Chemical dissociation of human awareness: focus on non-competitive NMDA receptor antagonists

Since the mid-1950s the pharmaceutical industry has developed a number of chemicals, including phencyclidine, ketamine and related arylcyclohexylamines (PCE and TCP), dizocilpine (MK-801), N-allylnormetazocine [ NANM, (±)SKF-10,047], etoxadrol, dioxadrol and its enantiomers dexoxadrol and levoxadrol, which produce a constellation of unusual behavioral effects in animals and man. The compounds best studied in humans are phencyclidine and ketamine. They produce a remarkable dose-dependent dissociation of awareness. All of these substances are now known to be non-competitive antagonists of NMDA receptors of glutamic acid. They act in the NMDA receptor ion channel. One can conclude, on the basis of the effects observed with these agents, that glutamic acid and related excitatory amino acids are extremely important in the maintenance of human awareness.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68872/2/10.1177_026988119200600312.pd

Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

BackgroundT cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.MethodsPatients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.ResultsFourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.ConclusionThese findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity

The Role of Innate APOBEC3G and Adaptive AID Immune Responses in HLA-HIV/SIV Immunized SHIV Infected Macaques

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Deployable Laboratory Response to Influenza Pandemic; PCR Assay Field Trials and Comparison with Reference Methods

Background: The influenza A/H1N1/09 pandemic spread quickly during the Southern Hemisphere winter in 2009 and reached epidemic proportions within weeks of the official WHO alert. Vulnerable population groups included indigenous Australians and remote northern population centres visited by international travellers. At the height of the Australian epidemic a large number of troops converged on a training area in northern Australia for an international exercise, raising concerns about their potential exposure to the emerging influenza threat before, during and immediately after their arrival in the area. Influenza A/H1N1/09 became the dominant seasonal variant and returned to Australia during the Southern winter the following year. Methods: A duplex nucleic acid amplification assay was developed within weeks of the first WHO influenza pandemic alert, demonstrated in northwestern Australia shortly afterwards and deployed as part of the pathology support for a field hospital during a military exercise during the initial epidemic surge in June 2009. Results: The nucleic acid amplification assay was twice as sensitive as a point of care influenza immunoassay, as specific but a little less sensitive than the reference laboratory nucleic acid amplification assay. Repetition of the field assay with blinded clinical samples obtained during the 2010 winter influenza season demonstrated a 91.7% congruence with the reference laboratory method. Conclusions: Rapid in-house development of a deployable epidemic influenza assay allowed a flexible laboratory response, effective targeting of limited disease control resources in an austere military environment, and provided the public health laboratory service with a set of verification tools for resource-limited settings. The assay method was suitable for rapid deployment in time for the 2010 Northern winter

Reliability and validity of the ESRD Symptom Checklist – Transplantation Module in Norwegian kidney transplant recipients

BACKGROUND: The aim of the study was to validate the Norwegian version of a self-administered 43-item questionnaire designed to assess quality of life in kidney transplant recipients, the End-Stage Renal Disease Symptom Checklist – Transplantation Module (ESRD-SCL). METHODS: In total, 53 kidney transplant recipients from one university-affiliated hospital responded to a questionnaire including the ESRD-SCL and the Short Form 36 (SF-36). We assessed internal consistency reliability and test-retest reliability with 2 weeks between assessments. Construct validity was assessed by correlations of the ESRD-SCL subscales with related and unrelated SF-36 scales, demographic, and clinical characteristics. RESULTS: Subscales of the ESRD-SCL showed good internal consistency reliability (Cronbach's = 0.72–0.81) and for the aggregate total scale α was 0.94. Test-retest reliability median 14 days apart was excellent with intraclass coefficients ranging from 0.87 to 0.95. The pattern of correlations of the ESRD-SCL scales with related and unrelated scales SF-36 scales and demographic and clinical characteristics gave support to the construct validity of the ESRD-SCL. CONCLUSION: The Norwegian translation of the ESRD-SCL showed satisfactory internal consistency reliability, test-retest reliability and construct validity, at the level of the original German version