The Supernova Gamma-Ray Burst Connection

The chief distinction between ordinary supernovae and long-soft gamma-ray bursts (GRBs) is the degree of differential rotation in the inner several solar masses when a massive star dies, and GRBs are rare mainly because of the difficulty achieving the necessary high rotation rate. Models that do provide the necessary angular momentum are discussed, with emphasis on a new single star model whose rapid rotation leads to complete mixing on the main sequence and avoids red giant formation. This channel of progenitor evolution also gives a broader range of masses than previous models, and allows the copious production of bursts outside of binaries and at high redshifts. However, even the production of a bare helium core rotating nearly at break up is not, by itself, a sufficient condition to make a gamma-ray burst. Wolf-Rayet mass loss must be low, and will be low in regions of low metallicity. This suggests that bursts at high redshift (low metallicity) will, on the average, be more energetic, have more time structure, and last longer than bursts nearby. Every burst consists of three components: a polar jet (~0.1 radian), high energy, subrelativistic mass ejection (~1 radian), and low velocity equatorial mass that can fall back after the initial explosion. The relative proportions of these three components can give a diverse assortment of supernovae and high energy transients whose properties may vary with redshift.Comment: 10 pages, to appear in AIP Conf. Proc. "Gamma Ray Bursts in the Swift Era", Eds. S. S. Holt, N. Gehrels, J. Nouse

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

Discovery of the peculiar supernova 1998bw in the error box of GRB980425

The discovery of X-ray, optical and radio afterglows of gamma-ray bursts (GRBs) and the measurements of the distances to some of them have established that these events come from Gpc distances and are the most powerful photon emitters known in the Universe, with peak luminosities up to 10^52 erg/s. We here report the discovery of an optical transient, in the BeppoSAX Wide Field Camera error box of GRB980425, which occurred within about a day of the gamma-ray burst. Its optical light curve, spectrum and location in a spiral arm of the galaxy ESO 184-G82, at a redshift z = 0.0085, show that the transient is a very luminous type Ic supernova, SN1998bw. The peculiar nature of SN1998bw is emphasized by its extraordinary radio properties which require that the radio emitter expand at relativistical speed. Since SN1998bw is very different from all previously observed afterglows of GRBs, our discovery raises the possibility that very different mechanisms may give rise to GRBs, which differ little in their gamma-ray properties.Comment: Under press embargo at Nature (submitted June 10, 1998

Analogue peptides for the immunotherapy of human acute myeloid leukemia

Accepted manuscript. The final publication is available at: http://link.springer.com/article/10.1007%2Fs00262-015-1762-9The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies

Lower Use of Hospice by Cancer Patients who Live in Minority Versus White Areas

BACKGROUND: Although hospice care can alleviate suffering at the end of life for patients with cancer, it remains underutilized, particularly by African Americans and Hispanics. OBJECTIVE: To examine whether the racial composition of the census tract where an individual resides is associated with hospice use. DESIGN: Retrospective analysis of the Surveillance, Epidemiology, and End Results–Medicare file for individuals dying from breast, colorectal, lung, or prostate cancer (n = 70,669). MEASUREMENTS: Hospice use during the 12 months before death. RESULTS: Hospice was most commonly used by individuals who lived in areas with fewer African-American and Hispanic residents (47%), and was least commonly used by individuals who lived in areas with a high percentage of African-American and Hispanic residents (35%). Hispanics (odds ratio 0.51, 95% confidence interval 0.29–0.91) and African Americans (0.56, 0.44–0.71) were less likely to use hospice if they lived in a census tract with a high percentage of both African Americans and Hispanics than if they lived in a low minority tract. African Americans and whites were less likely to receive hospice care if they lived in a census tract with a high percentage of Hispanics than if they lived in a low minority area. CONCLUSIONS: Increasing hospice use may require interventions to improve the delivery of hospice care in minority communities

Scents of Adolescence: The Maturation of the Olfactory Phenotype in a Free-Ranging Mammal

Olfaction is an important sensory modality for mate recognition in many mammal species. Odorants provide information about the health status, genotype, dominance status and/or reproductive status. How and when odor profiles change during sexual maturation is, however often unclear, particularly in free-ranging mammals. Here, we investigated whether the wing sac odorant of male greater sac-winged bats (Saccopteryx bilineata, Emballonuridae) differs between young and adults, and thus offers information about sexual maturity to potential mating partners. Using gas chromatography – mass spectrometry, we found differences in the odorants of young and adult males prior and during, but not after the mating period. The wing sac odorant of adult males consists of several substances, such as Pyrocoll, 2,6,10-trimethyl-3-oxo-6,10-dodecadienolide, and a so far unidentified substance; all being absent in the odor profiles of juveniles prior to the mating season. During the mating season, these substances are present in most of the juvenile odorants, but still at lower quantities compared to the wing sac odorants of adults. These results suggest that the wing sac odorant of males encodes information about age and/or sexual maturity. Although female S. bilineata start to reproduce at the age of half a year, most males of the same age postpone the sexual maturation of their olfactory phenotype until after the first mating season

Occupational correlates of smoking among urban transit operators: A prospective study

<p>Abstract</p> <p>Background</p> <p>Workers in blue-collar and service occupations smoke at higher rates than workers in white-collar and professional occupations. Occupational stress may explain some of the occupational class differences in smoking and quitting behavior. The purpose of this study is to investigate the contribution of occupational factors to smoking behavior over a ten year period among a multiethnic cohort of urban transit operators, while accounting for demographic factors and alcohol.</p> <p>Methods</p> <p>The sample consists of 654 San Francisco Municipal Railway (MUNI) transit operators who participated in two occupational health studies and biennial medical examinations during 1983–85 and 1993–95. Workers who had initiated, increased, or maintained their smoking over the ten year period were compared to workers who remained non-smokers. Occupational factors included self-rated frequency of job problems (e.g., difficulties with equipment, passengers, traffic), job burnout (i.e., the emotional exhaustion subscale of the Maslach Burnout Inventory), time needed to unwind after work, and years employed as a transit operator. A series of logistic regression models were developed to estimate the contribution of occupational factors to smoking behavior over time.</p> <p>Results</p> <p>Approximately 35% of the workers increased, initiated, or maintained their smoking over the ten-year period. Frequency of job problems was significantly associated with likelihood of smoking increase, initiation, or maintenance (OR = 1.30; 95% CI 1.09, 1.55). Black operators were significantly more likely to have smoked over the ten-year period compared to operators in other racial/ethnic groups.</p> <p>Conclusion</p> <p>Understanding the role of work-related stress vis-à-vis smoking behavior is of critical importance for crafting workplace smoking prevention and cessation interventions that are applicable to blue-collar work settings, and for developing policies that mitigate occupational stress.</p

Extending basic principles of measurement models to the design and validation of Patient Reported Outcomes

A recently published article by the Scientific Advisory Committee of the Medical Outcomes Trust presents guidelines for selecting and evaluating health status and health-related quality of life measures used in health outcomes research. In their article, they propose a number of validation and performance criteria with which to evaluate such self-report measures. We provide an alternate, yet complementary, perspective by extending the types of measurement models which are available to the instrument designer. During psychometric development or selection of a Patient Reported Outcome measure it is necessary to determine which, of the five types of measurement models, the measure is based on; 1) a Multiple Effect Indicator model, 2) a Multiple Cause Indicator model, 3) a Single Item Effect Indicator model, 4) a Single Item Cause Indicator model, or 5) a Mixed Multiple Indicator model. Specification of the measurement model has a major influence on decisions about item and scale design, the appropriate application of statistical validation methods, and the suitability of the resulting measure for a particular use in clinical and population-based outcomes research activities