Targeting TAG-72 in cutaneous T cell lymphoma.

Purpose: Current monoclonal antibody-based treatment approaches for cutaneous T cell lymphoma (CTCL) rely heavily on the ability to identify a tumor specific target that is essentially absent on normal cells. Herein, we propose tumor associated glycoprotein-72 (TAG-72) as one such target. TAG-72 is a mucin-associated, truncated O-glycan that has been identified as a chimeric antigen receptor (CAR)-T cell target in solid tumor indications.

Engineering T cell receptor fusion proteins using nonviral CRISPR/Cas9 genome editing for cancer immunotherapy.

Manufacture of chimeric antigen receptor (CAR)-T cells usually involves the use of viral delivery systems to achieve high transgene expression. However, it can be costly and may result in random integration of the CAR into the genome, creating several disadvantages including variation in transgene expression, functional gene silencing and potential oncogenic transformation. Here, we optimized the method of nonviral, CRISPR/Cas9 genome editing using large donor DNA delivery, knocked-in an anti-tumor single chain variable fragment (scFv) into the N-terminus of CD3ε and efficiently generated fusion protein (FP) T cells.

Mitoribosome sensitivity to HSP70 inhibition uncovers metabolic liabilities of castration-resistant prostate cancer.

The androgen receptor is a key regulator of prostate cancer and the principal target of current prostate cancer therapies collectively termed androgen deprivation therapies. Insensitivity to these drugs is a hallmark of progression to a terminal disease state termed castration-resistant prostate cancer. Therefore, novel therapeutic options that slow progression of castration-resistant prostate cancer and combine effectively with existing agents are in urgent need.

Variation and correlation in the timing of breeding of North Atlantic seabirds across multiple scales.

Timing of breeding, an important driver of fitness in many populations, is widely studied in the context of global change, yet despite considerable efforts to identify environmental drivers of seabird nesting phenology, for most populations we lack evidence of strong drivers. Here we adopt an alternative approach, examining the degree to which different populations positively covary in their annual phenology to infer whether phenological responses to environmental drivers are likely to be (a) shared across species at a range of spatial scales, (b) shared across populations of a species or (c) idiosyncratic to populations. We combined 51 long-term datasets on breeding phenology spanning 50 years from nine seabird species across 29 North Atlantic sites and examined the extent to which different populations share early versus late breeding seasons depending on a hierarchy of spatial scales comprising breeding site, small-scale region, large-scale region and the whole North Atlantic.

The rate of telomere loss is related to maximum lifespan in birds.

Telomeres are highly conserved regions of DNA that protect the ends of linear chromosomes. The loss of telomeres can signal an irreversible change to a cell's state, including cellular senescence. Senescent cells no longer divide and can damage nearby healthy cells, thus potentially placing them at the crossroads of cancer and ageing.

Integrating Monitoring and Genetic Methods To Infer Historical Risks of PCBs and DDE to Common and Roseate Terns Nesting Near the New Bedford Harbor Superfund Site (Massachusetts, USA).

Common and roseate terns are migratory piscivorous seabirds with major breeding colonies within feeding range of the polychlorinated biphenyl (PCB)-contaminated New Bedford Harbor (NBH, MA, USA) Superfund site. Our longitudinal study shows that before PCB discharges into NBH ceased (late 1970s), tern eggs had very high but variable PCB concentrations. However, egg concentrations of PCBs as well as DDE (1,1-bis(p-chlorophenyl)-2,2-dichloroethene), the degradation product of the ubiquitous global contaminant DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane), have since declined.

Energetic constraint of non-monotonic mass change during offspring growth: a general hypothesis and application of a new tool.

Post-natal growth is an important life-history trait and can be a sensitive indicator of ecological stress. For over 50 years, monotonic (never-decreasing) growth has been viewed as the predominant trajectory of post-natal mass change in most animal species, notably among birds. However, prevailing analytical approaches and energetic constraints may limit detection of non-monotonic (or multiphasic), determinate growth patterns, such as mass recession in birds (weight loss prior to fledging, preceded by overshooting adult mass), which is currently believed to be restricted to few taxa.

Archiving Primary Data: Solutions for Long-Term Studies.

The recent trend for journals to require open access to primary data included in publications has been embraced by many biologists, but has caused apprehension amongst researchers engaged in long-term ecological and evolutionary studies. A worldwide survey of 73 principal investigators (Pls) with long-term studies revealed positive attitudes towards sharing data with the agreement or involvement of the PI, and 93% of PIs have historically shared data. Only 8% were in favor of uncontrolled, open access to primary data while 63% expressed serious concern.

Netupitant PET imaging and ADME studies in humans.

Netupitant is a new, selective NK1 receptor antagonist under development for the prevention of chemotherapy-induced nausea and vomiting. Two studies were conducted to evaluate the brain receptor occupancy (RO) and disposition (ADME) of netupitant in humans. Positron emission tomography (PET) imaging with the NK1 receptor-binding-selective tracer [(11) C]-GR205171 was used to evaluate the brain penetration of different doses of netupitant (100, 300, and 450 mg) and to determine the NK1 -RO duration.

Changes in adrenal capacity contribute to a decline in the stress response with age in a long-lived seabird.

In response to stressors, most vertebrates elevate secretion of glucocorticoids (CORT) to produce a 'stress response' that enhances survival, but simultaneously inhibits reproduction. Circumstances in which the value of current reproduction is high relative to the value of future reproduction and survival, often lead to suppression of the stress response thus ensuring that critical resources are not diverted away from reproduction. Consistent with this expectation, we have previously reported that the magnitude of the stress response (maximum levels of CORT) declines with age in breeding adults of a long-lived seabird, the common tern (Sterna hirundo).

Telomerase activity is maintained throughout the lifespan of long-lived birds.

Telomerase is an enzyme capable of elongating telomeres, the caps at the ends of chromosomes associated with aging, lifespan and survival. We investigated tissue-level variation in telomerase across different ages in four bird species that vary widely in their life history. Telomerase activity in bone marrow may be associated with the rate of erythrocyte telomere shortening; birds with lower rates of telomere shortening and longer lifespans have higher bone marrow telomerase activity throughout life.

Older parents are less responsive to a stressor in a long-lived seabird: a mechanism for increased reproductive performance with age?

In many taxa, reproductive performance increases throughout the lifespan and this may occur in part because older adults invest more in reproduction. The mechanisms that facilitate an increase in reproductive performance with age, however, are poorly understood. In response to stressors, vertebrates release glucocorticoids, which enhance survival but concurrently shift investment away from reproduction.

Age-related differences in nest defense in common terns: Relationship to other life-history parameters.

The Common Tern (Sterno hirundo) is a long-lived colonial nesting seabird. Previous studies have shown that chick growth and fledging success vary with age of the parental pair and with laying date, with older parents and those nesting earlier being more successful. This study investigated the dependence of breeding performance and one aspect of behavior, defense against conspecifics, on age and laying date.

Serum immunoglobulin G levels are positively related to reproductive performance in a long-lived seabird, the common tern (Sterna hirundo).

The evolution of longevity requires a low risk of mortality from extrinsic factors, relative to intrinsic factors, so that individuals that differentially invest in physiological self-maintenance and minimize their annual reproductive costs will maximize lifetime fitness through a prolonged reproductive lifespan. The trade-off between reproductive effort and self-maintenance, as measured by immune function, has been well documented in short-lived birds, but is difficult to demonstrate in long-lived birds. To assess self-maintenance in a long-lived seabird, we measured serum protein levels, including immunoglobulin G (IgG = IgY), in 30 breeding pairs of common terns (Sterna hirundo) and their first-hatched (A) chicks.

A prospective longitudinal study of sexual recidivism among adolescent sex offenders.

This paper reports on a follow-up of a sample of 303 adolescent male sex offenders from New South Wales, Australia. Adult rearrest and reconviction data were obtained for 292 of these individuals. The mean observation period between their adjudication as adolescents and their follow-up as adults was 7.

Telomerase expression is differentially regulated in birds of differing life span.

Cellular senescence caused by telomere shortening has been suggested as one potential causal agent of aging. In some tissues, telomeres are maintained by telomerase; however, telomerase promotes tumor formation, suggesting a trade-off between aging and cancer. We predicted that telomerase activity should vary directly with life span.

Telomeres shorten more slowly in long-lived birds and mammals than in short-lived ones.

We know very little about physiological constraints on the evolution of life-history traits in general, and, in particular, about physiological and molecular adjustments that accompany the evolution of variation in lifespan. Identifying mechanisms that underlie adaptive variation in lifespan should provide insight into the evolution of trade-offs between lifespan and other life-history traits. Telomeres, the DNA caps at the ends of linear chromosomes, usually shorten as animals age, but whether telomere rate of change is associated with lifespan is unknown.

Calibrating the telomere clock in common terns, Sterna hirundo.

Field biologists often work with animals for which there are no prior history. A marker of an animal's age would offer insight into how age and experience affect reproductive success and other life history parameters. We previously reported that length of telomere restriction fragments shorten predictably with age in the captive zebra finch (Taeniopygia guttata).

Serum immunoglobulin G levels in very old common terns Sterna hirundo.

The evolutionary theory of aging predicts that self-maintenance functions, such as immunity, will be selectively maintained in old age when extrinsic sources of mortality are low relative to intrinsic sources. Long-lived seabirds may provide an animal model for testing this prediction. We measured serum immunoglobulin G (IgG) levels across the lifespan, especially the oldest individuals, of a wild breeding population of the common tern (Sterna hirundo) in 1999 and 2002.

Gonadal feminization and halogenated environmental contaminants in common terns (Sterna hirundo): evidence that ovotestes in male embryos do not persist to the prefledgling stage.

Common terns (Sterna hirundo) and roseate terns (Sterna dougallii) breed on Bird Island, Massachusetts, USA, near a Superfund site highly contaminated with polychlorinated biphenyls (PCBs). Observations of skewed sex ratios and female-female pairings among endangered roseate terns (Nisbet and Hatch (1999) Ibis 141, 307) suggested the possibility of contaminant-related endocrine disruption in these birds and prompted investigation of common terns as a surrogate species. In 1993 and 1994, 60-90% of pipping male common tern embryos sampled exhibited ovarian cortical tissue in their testes (ovotestes) (Nisbet et al.

Detecting and measuring senescence in wild birds: experience with long-lived seabirds.

This paper points out and discusses several practical and methodological problems that arise in attempts to detect and measure senescent declines in survival or breeding performance of wild animals, with specific emphasis on long-lived seabirds. Birds have no anatomical markers of age, so studies of age-related biology require marking individuals at the time of hatching and following them throughout their lives. Seabirds live longer than the working lifespan of biologists, and longer than the turnover times of study techniques or theories of senescence.