On the co-existence of chemically peculiar Bp stars, slowly pulsating B stars and constant B stars in the same part of the H-R diagram

Aims. In order to better model massive B-type stars, we need to understand the physical processes taking place in slowly pulsating B (SPB) stars, chemically peculiar Bp stars, and non-pulsating normal B stars co-existing in the same part of the H-R diagram. Methods. We carry out a comparative study between samples of confirmed and well-studied SPB stars and a sample of well-studied Bp stars with known periods and magnetic field strengths. We determine their evolutionary state using accurate HIPPARCOS parallaxes and Geneva photometry. We discuss the occurrence and strengths of magnetic fields as well as the occurrence of stellar pulsation among both groups. Further, we make a comparison of Geneva photometric variability for both kinds of stars. Results. The group of Bp stars is significantly younger than the group of SPB stars. Longitudinal magnetic fields in SPB stars are weaker than those of Bp stars, suggesting that the magnetic field strength is an important factor for B type stars to become chemically peculiar. The strongest magnetic fields appear in young Bp stars, indicating a magnetic field decay in stars at advanced ages. Rotation periods of Bp and pulsation periods of SPB stars are of the same order and the behaviour of Geneva photometric variability of some Bp stars cannot be distinguished from the variability of SPB stars, illustrating the difficulty to interpret the observed variability of the order of days for B-type stars. We consider the possibility that pulsation could be responsible for the variability among chemically peculiar stars. In particular, we show that a non-linear pulsation model is not excluded by photometry for the Bp star HD175362.Comment: Accepted for publication in Astronomy & Astrophysics on 29/01/2007, 8 pages, 9 figure

Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity.

The majority of chimeric antigen receptor (CAR) T-cell research has focused on attacking cancer cells. Here, we show that targeting the tumor-promoting, nontransformed stromal cells using CAR T cells may offer several advantages. We developed a retroviral CAR construct specific for the mouse fibroblast activation protein (FAP), comprising a single-chain Fv FAP [monoclonal antibody (mAb) 73.3] with the CD8α hinge and transmembrane regions, and the human CD3ζ and 4-1BB activation domains. The transduced muFAP-CAR mouse T cells secreted IFN-γ and killed FAP-expressing 3T3 target cells specifically. Adoptively transferred 73.3-FAP-CAR mouse T cells selectively reduced FAP(hi) stromal cells and inhibited the growth of multiple types of subcutaneously transplanted tumors in wild-type, but not FAP-null immune-competent syngeneic mice. The antitumor effects could be augmented by multiple injections of the CAR T cells, by using CAR T cells with a deficiency in diacylglycerol kinase, or by combination with a vaccine. A major mechanism of action of the muFAP-CAR T cells was the augmentation of the endogenous CD8(+) T-cell antitumor responses. Off-tumor toxicity in our models was minimal following muFAP-CAR T-cell therapy. In summary, inhibiting tumor growth by targeting tumor stroma with adoptively transferred CAR T cells directed to FAP can be safe and effective, suggesting that further clinical development of anti-human FAP-CAR is warranted

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

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Trumpler 16-26: A New Centrifugal Magnetosphere Discovered via SDSS/APOGEE H-band Spectroscopy

We report the discovery of a new example of the rare class of highly magnetized, rapidly rotating, helium enhanced, early B stars that produce anomalously wide hydrogen emission due to a centrifugal magnetosphere (CM). The star is Trumpler 16-26, a B1.5 V member of the Trumpler 16 open cluster. A CM was initially suspected based on hydrogen Brackett series emission observed in SDSS/APOGEE $H$-band spectra. Similar to the other stars of this type, the emission was highly variable and at all times remarkable due to the extreme velocity separations of the double peaks (up to 1300 km s$^{-1}$.) Another clue lay in the TESS lightcurve, which shows two irregular eclipses per cycle when phased with the likely 0.9718115 day rotation period, similar to the behavior of the well known CM host star $\sigma$ Ori E. To confirm a strong magnetic field and rotation-phase-locked variability, we initiated a follow-up campaign consisting of optical spectropolarimetry and spectroscopy. The associated data revealed a longitudinal magnetic field varying between $-3.1$ and $+1.6$ kG with the period found from photometry. The optical spectra confirmed rapid rotation ($v \sin i=195$ km s$^{-1}$), surface helium enhancement, and wide, variable hydrogen emission. Tr16-26 is thus confirmed as the 20$^{\rm th}$ known, the fourth most rapidly rotating, and the faintest CM host star yet discovered. With a projected dipole magnetic field strength of $B_{\rm d}>11$ kG, Tr16-26 is also among the most magnetic CM stars

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

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

B fields in OB stars (BOB): on the detection of weak magnetic fields in the two early B-type stars beta CMa and epsilon CMa

Within the context of the "B fields in OB stars (BOB)" collaboration, we used the HARPSpol spectropolarimeter to observe the early B-type stars beta CMa (HD44743; B1 II/III) and epsilon CMa (HD52089; B1.5 II). For both stars, we consistently detected the signature of a weak (<30 G in absolute value) longitudinal magnetic field. We determined the physical parameters of both stars and characterise their X-ray spectrum. For beta CMa, our mode identification analysis led to determining a rotation period of 13.6+/-1.2 days and of an inclination angle of the rotation axis of 57.6+/-1.7 degrees, with respect to the line of sight. On the basis of these measurements and assuming a dipolar field geometry, we derived a best fitting obliquity of ~22 degrees and a dipolar magnetic field strength (Bd) of ~100 G (60<Bd<230 G within 1 sigma), below what is typically found for other magnetic massive stars. For epsilon CMa we could only determine a lower limit on the dipolar magnetic field strength of 13 G. For this star, we determine that the rotation period ranges between 1.3 and 24 days. Both stars are expected to have a dynamical magnetosphere. We also conclude that both stars are most likely core hydrogen burning and that they have spent more than 2/3 of their main sequence lifetime. A histogram of the distribution of the dipolar magnetic field strength for the magnetic massive stars known to date does not show the magnetic field "desert" observed instead for intermediate-mass stars. The biases involved in the detection of (weak) magnetic fields in massive stars with the currently available instrumentation and techniques imply that weak fields might be more common than currently observed. Our results show that, if present, even relatively weak magnetic fields are detectable in massive stars and that more observational effort is probably still needed to properly access the magnetic field incidence.Comment: Accepted for publication on A&A. The astroph abstract has been shortened compared to that of the pdf fil

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

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Proteomic-based identification of haptoglobin-1 precursor as a novel circulating biomarker of ovarian cancer

Screening for specific biomarkers of early-stage detection of ovarian cancer is a major health priority due to the asymptomatic nature and poor survival characteristic of the disease. We utilised two-dimensional gel electrophoresis (2DE) to identify differentially expressed proteins in the serum of ovarian cancer patients that may be useful as biomarkers of this disease. In this study, 38 ovarian cancer patients at different pathological grades (grade 1 (n=6), grade 2 (n=8) and grade 3 (n=24)) were compared to a control group of eight healthy women. Serum samples were treated with a mixture of Affigel-Blue and protein A (5 : 1) for 1 h to remove high abundance protein (e.g. immunoglobulin and albumin) and were displayed using 11 cm, pH 4-7 isoelectric focusing strips for the first dimension and 10% acrylamide gel electrophoresis for the second dimension. Protein spots were visualised by SYPRO-Ruby staining, imaged by FX-imager and compared and analysed by PDQuest software. A total of 24 serum proteins were differentially expressed in grade 1 (P<0.05), 31 in grade 2 (P<0.05) and 25 in grade 3 (P<0.05) ovarian cancer patients. Six of the protein spots that were significantly upregulated in all groups of ovarian cancer patients were identified by nano-electrospray quadrupole quadrupole time-of-flight mass spectrometry (n-ESIQ(q)TOFMS) and matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOFMS) as isoforms of haptoglobin-1 precursor (HAP1), a liver glycoprotein present in human serum. Further identification of the spots at different pathological grades was confirmed by Western blotting using monoclonal antibody against a haptoglobin epitope contained within HAP1. Immunohistochemical localisation of HAP1-like activity was present in malignant ovarian epithelium and stroma but strong immunostaining was present in blood vessels, areas with myxomatous stroma and vascular spaces. No tissue localisation of HAP1-like immunoreactivity was observed in normal ovarian surface epithelium. These data highlight the need to assess circulating concentration of HAP1 in the serum of ovarian cancer patients and evaluate its potential as a biomarker in the early diagnosis of ovarian cancer.N Ahmed, G Barker, KT Oliva, P Hoffmann, C Riley, S Reeve, AI Smith, BE Kemp, MA Quinn and GE Ric

A Mouse to Human Search for Plasma Proteome Changes Associated with Pancreatic Tumor Development

Background: The complexity and heterogeneity of the human plasma proteome have presented significant challenges in the identification of protein changes associated with tumor development. Refined genetically engineered mouse (GEM) models of human cancer have been shown to faithfully recapitulate the molecular, biological, and clinical features of human disease. Here, we sought to exploit the merits of a well-characterized GEM model of pancreatic cancer to determine whether proteomics technologies allow identification of protein changes associated with tumor development and whether such changes are relevant to human pancreatic cancer. Methods and Findings: Plasma was sampled from mice at early and advanced stages of tumor development and from matched controls. Using a proteomic approach based on extensive protein fractionation, we confidently identified 1,442 proteins that were distributed across seven orders of magnitude of abundance in plasma. Analysis of proteins chosen on the basis of increased levels in plasma from tumor-bearing mice and corroborating protein or RNA expression in tissue documented concordance in the blood from 30 newly diagnosed patients with pancreatic cancer relative to 30 control specimens. A panel of five proteins selected on the basis of their increased level at an early stage of tumor development in the mouse was tested in a blinded study in 26 humans from the CARET (Carotene and Retinol Efficacy Trial) cohort. The panel discriminated pancreatic cancer cases from matched controls in blood specimens obtained between 7 and 13 mo prior to the development of symptoms and clinical diagnosis of pancreatic cancer. Conclusions: Our findings indicate that GEM models of cancer, in combination with in-depth proteomic analysis, provide a useful strategy to identify candidate markers applicable to human cancer with potential utility for early detection