Antibody responses to galectin-8, TARP and TRAP1 in prostate cancer patients treated with a GM-CSF-secreting cellular immunotherapy

A critical factor in clinical development of cancer immunotherapies is the identification of tumor-associated antigens that may be related to immunotherapy potency. In this study, protein microarrays containing >8,000 human proteins were screened with serum from prostate cancer patients (N = 13) before and after treatment with a granulocyte–macrophage colony-stimulating factor (GM-CSF)-secreting whole cell immunotherapy. Thirty-three proteins were identified that displayed significantly elevated (P ≤ 0.05) signals in post-treatment samples, including three proteins that have previously been associated with prostate carcinogenesis, galectin-8, T-cell alternative reading frame protein (TARP) and TNF-receptor-associated protein 1 (TRAP1). Expanded analysis of antibody induction in metastatic, castration-resistant prostate cancer (mCRPC) patients (N = 92) from two phase 1/2 trials of prostate cancer immunotherapy, G-9803 and G-0010, indicated a significant (P = 0.03) association of TARP antibody induction and median survival time (MST). Antibody induction to TARP was also significantly correlated (P = 0.036) with an increase in prostate-specific antigen doubling time (PSADT) in patients with a biochemical (PSA) recurrence following prostatectomy or radiation therapy (N = 19) from in a previous phase 1/2 trial of prostate cancer immunotherapy, G-9802. RNA and protein encoding TARP and TRAP1 was up-regulated in prostate cancer tissue compared to matched normal controls. These preliminary findings suggest that antibody induction to TARP may represent a possible biomarker for treatment response to GM-CSF secreting cellular immunotherapy in prostate cancer patients and demonstrates the utility of using protein microarrays for the high-throughput screening of patient-derived antibody responses.     

The Empirical Analysis of Cigarette Tax Avoidance and Illicit Trade in Vietnam, 1998-2010

Illicit trade carries the potential to magnify existing tobacco-related health care costs through increased availability of untaxed and inexpensive cigarettes. What is known with respect to the magnitude of illicit trade for Vietnam is produced primarily by the industry, and methodologies are typically opaque. Independent assessment of the illicit cigarette trade in Vietnam is vital to tobacco control policy. This paper measures the magnitude of illicit cigarette trade for Vietnam between 1998 and 2010 using two methods, discrepancies between legitimate domestic cigarette sales and domestic tobacco consumption estimated from surveys, and trade discrepancies as recorded by Vietnam and trade partners. The results indicate that Vietnam likely experienced net smuggling in during the period studied. With the inclusion of adjustments for survey respondent under-reporting, inward illicit trade likely occurred in three of the four years for which surveys were available. Discrepancies in trade records indicate that the value of smuggled cigarettes into Vietnam ranges from $100 million to $300 million between 2000 and 2010 and that these cigarettes primarily originate in Singapore, Hong Kong, Macao, Malaysia, and Australia. Notable differences in trends over time exist between the two methods, but by comparison, the industry estimates consistently place the magnitude of illicit trade at the upper bounds of what this study shows. The unavailability of annual, survey-based estimates of consumption may obscure the true, annual trend over time. Second, as surveys changed over time, estimates relying on them may be inconsistent with one another. Finally, these two methods measure different components of illicit trade, specifically consumption of illicit cigarettes regardless of origin and smuggling of cigarettes into a particular market. However, absent a gold standard, comparisons of different approaches to illicit trade measurement serve efforts to refine and improve measurement approaches and estimates.     

COMPARISON OF ISOZYMES AMONG TYPHA SPECIES IN THE EASTERN UNITED STATES

Biochemical phenotsypes of four taxa of Typha from the eastern United States were determined by starch gel electrophoresis. The isozyme banding patterns of T. latifolia, T. angustifolia and T. domingensis are distinct and allow unambiguous species identification when morphological characters are inadequate or unsuitable. The fourth form, T. glauca, is not an F₁ hybrid, but it does appear to be intermediate between T. latifolia and T. angustifolia. The status of T. glauca and evolutionary relationships among the four forms may now be clarified by additional sampling because of the distinct and relatively invariant isozyme banding patterns which are described.     

Strength and physical fitness predict the perception of looming sounds

Listeners consistently perceive approaching sounds to be closer than they actually are and perceptually underestimate the time to arrival of looming sound sources. In a natural environment, this underestimation results in more time than expected to evade or engage the source and affords a “margin of safety” that may provide a selective advantage. However, a key component in the proposed evolutionary origins of the perceptual bias is the appropriate timing of anticipatory motor behaviors. Here we show that listeners with poorer physical fitness respond sooner to looming sounds and with a larger margin of safety than listeners with better physical fitness. The anticipatory perceptual bias for looming sounds is negatively correlated with physical strength and positively correlated with recovery heart rate (a measure of aerobic fitness). The results suggest that the auditory perception of looming sounds may be modulated by the response capacity of the motor system.     

Quantification of human spermatogenesis: germ cell degeneration during spermatocytogenesis and meiosis in testes from younger and older adult men

Germ cell degeneration during spermatocytogenesis and meiosis was investigated to explain the age-related decline in daily sperm production (DSP). Numbers of Types A-dark, A-pale, and B-spermatogonia, potential daily sperm production per g parenchyma (PDSP) based on type B-spermatogonia, early primary spermatocytes, and late primary spermatocytes, and DSP per g based on early spermatids were determined in 15 men aged 20 to 48 yr (mean +/- SEM, 33 +/- 2 yr) and 15 men aged 52 to 90 yr (65 +/- 3 yr). Testes obtained within 15 h of death (largely due to trauma or heart failure) were perfused vascularly with glutaraldehyde. The number of each cell type per g parenchyma was calculated as the product of the percentage of nuclei in the parenchyma times a correction factor for section thickness and nuclear diameter divided by the volume of a single nucleus of that cell type. Paired testicular weight was lower (p less than 0.01) in older men (33 +/- 3 g) than in the younger men (49 +/- 3 g). Younger and older men had similar numbers of A-dark, A-pale, and B-spermatogonia per g parenchyma. PDSP based on late primary spermatocytes and DSP based on early spermatids were lower (p less than 0.01) in older men than in younger men. In younger men, PDSP was similar (p greater than 0.05) between B-spermatogonia and late primary spermatocytes, whereas DSP measured at the spermatid level was abruptly lower than that estimated from younger cell types. Older men showed reduction in PDSP between early and late primary spermatocytes, with further reduction occurring in DSP at the spermatid level.(ABSTRACT TRUNCATED AT 250 WORDS)     

The cost of mutualism in a fly-fungus interaction

The movement ability of individuals has become increasingly important to a variety of ecological questions. In this study, I investigate how plant structure and changes in body size through development affect the movement ability of a predaceous stinkbug, Podisus maculiventris, on three species of goldenrod (Solidago spp.) representing a wide range of surface complexities. I adapt existing techniques for quantifying movement in two dimensions to the study of movement on natural plant structures in three dimensions. These experiments indicate that plant structure and insect size are significant factors affecting the movement ability of P. maculiventris. Changes in movement ability due to factors of ontogeny and different habitat structures suggest that the scale of an individual’s ambit or ecological sphere of influence may vary within its lifespan. Considering the influence of ontogeny and habitat structure on movement ability may be useful to investigations of population dynamics, foraging behavior, and pest management. Received: 14 July 1999 / Accepted: 23 March 2000     

Endless forms most stupid,icky, and small: The preponderance of noncharismatic invertebrates as integral to a biologically sound view of life

Big, beautiful organisms are useful for biological education, increasing evolution literacy, and biodiversity conservation. But if educators gloss over the ubiquity of streamlined and miniaturized organisms, they unwittingly leave students and the public vulnerable to the idea that the primary evolutionary plot of every metazoan lineage is “progressive” and "favors" complexity. We show that simple, small, and intriguingly repulsive invertebrate animals provide a counterpoint to misconceptions about evolution. Our examples can be immediately deployed in biology courses and outreach. This context emphasizes that chordates are not the pinnacle of evolution. Rather, in the evolution of animals, miniaturization, trait loss, and lack of perfection are at least as frequent as their opposites. Teaching about invertebrate animals in a “tree thinking” context uproots evolution misconceptions (for students and the public alike), provides a mental scaffold for understanding all animals, and helps to cultivate future ambassadors and experts on these little‐known, weird, and fascinating taxa.     

Multipotent Cancer Stem Cells Derived from Human Malignant Peritoneal Mesothelioma Promote Tumorigenesis

During the progression of malignant peritoneal mesothelioma (MPeM), tumor nodules propagate diffusely within the abdomen and tumors are characterized by distinct phenotypic sub-types. Recent studies in solid organ cancers have shown that cancer stem cells (CSCs) play a pivotal role in the initiation and progression of tumors. However, it is not known whether tumorigenic stem cells exist and whether they promote tumor growth in MPeM. In this study, we developed and characterized a CSC model for MPeM using stably expandable tumorigenic stem cells derived from patient tumors. We found morphologically distinct populations of CSCs that divide asymmetrically or symmetrically in MPeM in vitro cell culture. The MPeM stem cells (MPeMSCs) express stem cell markers c-MYC, NES and VEGFR2 and in the presence of matrix components cells form colony spheres. MPeMSCs are multipotent, differentiate into neuronal, vascular and adipose progeny upon defined induction and the differentiating cells express lineage-specific markers such as TUBB3, an early neuronal marker; vWF, VEGFA, VEGFC and IL-8, endothelial markers; and PPARγ and FABP4, adipose markers. Xenotransplantation experiments using MPeMSCs demonstrated early tumor growth compared with parental cells. Limiting dilution experiments using MPeMSCs and endothelial lineage-induced cells derived from a single MPeMSC resulted in early tumor growth in the latter group indicating that endothelial differentiation of MPeMSCs is important for MPeM tumor initiation. Our observation that the MPeM tumors contain stem cells with tumorigenic potential has important implications for understanding the cells of origin and tumor progression in MPeM and hence targeting CSCs may be a useful strategy to inhibit malignant progression.