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Translocation of animals, especially for threatened and endangered species, is a currently popular but very challenging activity. We translocated 158 adult Agassiz’s desert tortoises (Gopherus agassizii), a threatened species, from the National Training Center, Fort Irwin, in the central Mojave Desert in California, USA, to 4 plots as part of a long-distance, hard-release, mitigation-driven translocation to prevent deaths from planned military maneuvers. We monitored demographic and behavioral variables of tortoises fitted with radio-transmitters from 2008 to 2018. By the end of the project, 17.72% of tortoises were alive, 65.82% were dead, 15.19% were missing, and 1.27% were removed from the study because they returned to Fort Irwin. Mortality was high during the first 3 years: >50% of the released animals died, primarily from predation. Thereafter, mortality declined but remained high. After 10.5 years, survival was highest, 37.50% (15/40), on the plot closest to original home sites, whereas from 2.56% to 23.68% remained alive on the other 3 release plots. Surviving tortoises settled early, repeatedly using locations where they constructed burrows, compared with tortoises that died or disappeared. Models of behavioral and other variables indicated that numbers of repeatedly used locations (burrows) were a driver of survival throughout the study, although plot location, size and sex of tortoises, and distance traveled were contributors, especially during early years. Because >50% mortality occurred, we considered this translocation unsuccessful. The study area appeared to be an ecological sink with historical and current anthropogenic uses contributing to habitat degradation and a decline in both the resident and released tortoises. Our findings will benefit design and selection of future translocation areas.

We evaluated the status of a population of Mojave Desert Tortoises (Gopherus agassizii), a threatened species, in the El Paso Mountains of the northwestern Mojave Desert in California, USA. The study area lies north of and adjacent to a designated critical habitat unit for the species, is adjacent to a state park, and is a short distance from the Desert Tortoise Research Natural Area. We randomly sampled 373 1-ha plots from a 239.1-km2 area in the mountain range to determine demographic attributes of the population, vegetation associations, predator presence, and human uses. Live and dead G. agassizii and sign (burrows, scats, tracks) occurred on 35.7% of plots. Densities of adults were higher than in adjacent critical habitat, and threats (traumatic injuries, infectious and other diseases) were similar to those reported elsewhere in the geographic range. Signs of human use were evident on 98.4% of plots. We used a multimodel approach to determine distribution of G. agassizii in relation to vegetation, anthropogenic, and predator variables. Vegetation, predators, trash, mining activity, and vehicles were important factors affecting the distribution and intensity of tortoise sign. We concluded that this population is in a downward trend, like other populations in the western Mojave Desert. The high death rate of adults, low population density, high human visitor use, and ongoing decline in the adjacent critical habitat unit indicate that a viable population is unlikely to persist in the study area. The future for the population found in the El Paso Mountains might depend on survival in the adjacent roadless El Paso Mountains Wilderness Area.

Worldwide, scientists have headstarted threatened and endangered reptiles to augment depleted populations. Not all efforts have been successful. For the threatened Agassiz's desert tortoise (Gopherus agassizii), one challenge to recovery is poor recruitment of juveniles into adult populations, and this is being addressed through headstart programs. We evaluated 8 cohorts of juvenile desert tortoises from 1 to 8 yrs old in a headstart program at Edwards Air Force Base, California, for health, behavior, and growth. We also examined capacities of the headstart pens. Of 148 juveniles evaluated for health, 99.3% were below a prime condition index; 14.9% were lethargic and unresponsive; 59.5% had protruding spinal columns and associated concave scutes; 29.1% had evidence of ant bites; and 14.2% had moderate to severe injuries to limbs or shell. Lifetime growth rates for juveniles 1–8 yrs of age were approximately two times less than growth rates reported for wild populations. Tortoises in older cohorts had higher growth rates, and models indicated that high density in pens and burrow sharing negatively affected growth rates. Densities of tortoises in pens (205–2042/ha) were 350–3500 times higher than the average density recorded in the wild (< 1/ha) for tortoises of similar sizes. The predominant forage species available to juveniles were alien annual grasses, which are nutritionally inadequate for growth. We conclude that the headstart pens were of inadequate size, likely contained too few shelters, and lacked the necessary biomass of preferred forbs to sustain the existing population. Additional factors to consider for future reptilian headstart pens include vegetative cover, food sources, soil seed banks, and soil composition.

Agassiz's Desert Tortoises (Gopherus agassizii) spend >95% of their lives underground in cover sites that serve as thermal buffers from temperatures, which can fluctuate >40°C on a daily and seasonal basis. We monitored temperatures at 30 active tortoise cover sites within the Soda Mountains, San Bernardino County, California, from February 2004 to September 2006. Cover sites varied in type and structural characteristics, including opening height and width, soil cover depth over the opening, aspect, tunnel length, and surficial geology. We focused our analyses on periods of extreme temperature: in summer, between July 1 and September 1, and winter, between November 1 and February 15. With the use of multivariate regression tree analyses, we found cover-site temperatures were influenced largely by tunnel length and subsequently opening width and soil cover. Linear regression models further showed that increasing tunnel length increased temperature stability and dampened seasonal temperature extremes. Climate change models predict increased warming for southwestern North America. Cover sites that buffer temperature extremes and fluctuations will become increasingly important for survival of tortoises. In planning future translocation projects and conservation efforts, decision makers should consider habitats with terrain and underlying substrate that sustain cover sites with long tunnels and expanded openings for tortoises living under temperature extremes similar to those described here or as projected in the future.

We explored variables likely to affect health of Agassiz's desert tortoises (Gopherus agassizii) in a 1,183-km² study area in the central Mojave Desert of California between 2005 and 2008. We evaluated 1,004 tortoises for prevalence and spatial distribution of 2 pathogens, Mycoplasma agassizii and M. testudineum, that cause upper respiratory tract disease. We defined tortoises as test-positive if they were positive by culture and/or DNA identification or positive or suspect for specific antibody for either of the two pathogens. We used covariates of habitat (vegetation, elevation, slope, and aspect), tortoise size and sex, distance from another test-positive tortoise, and anthropogenic variables (distances to roads, agricultural areas, playas, urban areas, and centroids of human-populated census blocks). We used both logistic regression models and regression trees to evaluate the 2 species of Mycoplasma separately. The prevalence of test-positive tortoises was low: 1.49% (15/1,004) for M. agassizii and 2.89% (29/1,004) for M. testudineum. The spatial distributions of testpositive tortoises for the 2 Mycoplasma species showed little overlap; only 2 tortoises were test-positive for both diseases. However, the spatial distributions did not differ statistically between the 2 species. We consistently found higher prevalence of test-positive tortoises with shorter distances to centroids of humanpopulated census blocks. The relationship between distance to human-populated census blocks and tortoises that are test-positive for M. agassizii and potentially M. testudineum may be related to release or escape of captive tortoises because the prevalence of M. agassizii in captive tortoises is high. Our findings have application to other species of chelonians where both domestic captive and wild populations exist. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

The Venus flytrap, Dionaea muscipula , is perhaps the world’s best-known botanical carnivore. The act of prey capture and digestion along with its rapidly closing, charismatic traps make this species a compelling model for studying the evolution and fundamental biology of carnivorous plants. There is a growing body of research on the genome, transcriptome, and digestome of Dionaea muscipula , but surprisingly limited information on changes in trap transcript abundance over time since feeding. Here we present the results of a comparative transcriptomics project exploring the transcriptomic changes across seven timepoints in a 72-hour time series of prey digestion and three timepoints directly comparing triggered traps with and without prey items. We document a dynamic response to prey capture including changes in abundance of transcripts with Gene Ontology (GO) annotations related to digestion and nutrient uptake. Comparisons of traps with and without prey documented 174 significantly differentially expressed genes at 1 hour after triggering and 151 genes with significantly different abundances at 24 hours. Approximately 50% of annotated protein-coding genes in Venus flytrap genome exhibit change (10041 of 21135) in transcript abundance following prey capture. Whereas peak abundance for most of these genes was observed within 3 hours, an expression cluster of 3009 genes exhibited continuously increasing abundance over the 72-hour sampling period, and transcript for these genes with GO annotation terms including both catabolism and nutrient transport may continue to accumulate beyond 72 hours.

Patients with large B-cell lymphoma (LBCL) primary refractory to or relapsed within 12 months of first-line therapy are at high risk for poor outcomes with current standard of care, platinum-based salvage immunochemotherapy and autologous haematopoietic stem cell transplantation (HSCT). Lisocabtagene maraleucel (liso-cel), an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has previously demonstrated efficacy and manageable safety in third-line or later LBCL. In this Article, we report a prespecified interim analysis of liso-cel versus standard of care as second-line treatment for primary refractory or early relapsed (within 12 months after response to initial therapy) LBCL. TRANSFORM is a global, phase 3 study, conducted in 47 sites in the USA, Europe, and Japan, comparing liso-cel with standard of care as second-line therapy in patients with primary refractory or early (≤12 months) relapsed LBCL. Adults aged 18–75 years, Eastern Cooperative Oncology Group performance status score of 1 or less, adequate organ function, PET–positive disease per Lugano 2014 criteria, and candidates for autologous HSCT were randomly assigned (1:1), by use of interactive response technology, to liso-cel (100 × 106 CAR+ T cells intravenously) or standard of care. Standard of care consisted of three cycles of salvage immunochemotherapy delivered intravenously—R-DHAP (rituximab 375 mg/m2 on day 1, dexamethasone 40 mg on days 1–4, two infusions of cytarabine 2000 mg/m2 on day 2, and cisplatin 100 mg/m2 on day 1), R-ICE (rituximab 375 mg/m2 on day 1, ifosfamide 5000 mg/m2 on day 2, etoposide 100 mg/m2 on days 1–3, and carboplatin area under the curve 5 [maximum dose of 800 mg] on day 2), or R-GDP (rituximab 375 mg/m2 on day 1, dexamethasone 40 mg on days 1–4, gemcitabine 1000 mg/m2 on days 1 and 8, and cisplatin 75 mg/m2 on day 1)—followed by high-dose chemotherapy and autologous HSCT in responders. Primary endpoint was event-free survival, with response assessments by an independent review committee per Lugano 2014 criteria. Efficacy was assessed per intention-to-treat (ie, all randomly assigned patients) and safety in patients who received any treatment. This trial is registered with ClinicalTrials.gov, NCT03575351, and is ongoing. Between Oct 23, 2018, and Dec 8, 2020, 232 patients were screened and 184 were assigned to the liso-cel (n=92) or standard of care (n=92) groups. At the data cutoff for this interim analysis, March 8, 2021, the median follow-up was 6·2 months (IQR 4·4–11·5). Median event-free survival was significantly improved in the liso-cel group (10·1 months [95% CI 6·1–not reached]) compared with the standard-of-care group (2·3 months [2·2–4·3]; stratified hazard ratio 0·35; 95% CI 0·23–0·53; stratified Cox proportional hazards model one-sided p<0·0001). The most common grade 3 or worse adverse events were neutropenia (74 [80%] of 92 patients in the liso-cel group vs 46 [51%] of 91 patients in the standard-of-care group), anaemia (45 [49%] vs 45 [49%]), thrombocytopenia (45 [49%] vs 58 [64%]), and prolonged cytopenia (40 [43%] vs three [3%]). Grade 3 cytokine release syndrome and neurological events, which are associated with CAR T-cell therapy, occurred in one (1%) and four (4%) of 92 patients in the liso-cel group, respectively (no grade 4 or 5 events). Serious treatment-emergent adverse events were reported in 44 (48%) patients in the liso-cel group and 44 (48%) in the standard-of-care group. No new liso-cel safety concerns were identified in the second-line setting. There were no treatment-related deaths in the liso-cel group and one treatment-related death due to sepsis in the standard-of-care group. These results support liso-cel as a new second-line treatment recommendation in patients with early relapsed or refractory LBCL. Celgene, a Bristol-Myers Squibb Company.

Brain tumor initiating cells (BTICs) utilize high-affinity glucose uptake, which is normally active in neurons to maintain energy demands and self-renew. Leveraging metabolomic and genomic analyses, Wang et al . report that de novo purine biosynthesis reprograms BTIC metabolism, revealing a potential point of fragility amenable to targeted cancer therapy. Brain tumor initiating cells (BTICs), also known as cancer stem cells, hijack high-affinity glucose uptake active normally in neurons to maintain energy demands. Here we link metabolic dysregulation in human BTICs to a nexus between MYC and de novo purine synthesis, mediating glucose-sustained anabolic metabolism. Inhibiting purine synthesis abrogated BTIC growth, self-renewal and in vivo tumor formation by depleting intracellular pools of purine nucleotides, supporting purine synthesis as a potential therapeutic point of fragility. In contrast, differentiated glioma cells were unaffected by the targeting of purine biosynthetic enzymes, suggesting selective dependence of BTICs. MYC coordinated the control of purine synthetic enzymes, supporting its role in metabolic reprogramming. Elevated expression of purine synthetic enzymes correlated with poor prognosis in glioblastoma patients. Collectively, our results suggest that stem-like glioma cells reprogram their metabolism to self-renew and fuel the tumor hierarchy, revealing potential BTIC cancer dependencies amenable to targeted therapy.

Microenvironmental pressures in glioblastoma select for glioma stem cells (GSCs) subpopulations that are maintained through preferential activation of BMI1 and EZH2 in different niches. Given the high degree of intratumor heterogeneity, combined pharmacological inhibition of Polycomb repressive complexes targets proneural and mesenchynmal GSCs and expands lifespan in mice, warranting the therapeutic evaluation of this approach in patients with glioblastoma. Glioblastomas are lethal cancers defined by angiogenesis and pseudopalisading necrosis. Here, we demonstrate that these histological features are associated with distinct transcriptional programs, with vascular regions showing a proneural profile, and hypoxic regions showing a mesenchymal pattern. As these regions harbor glioma stem cells (GSCs), we investigated the epigenetic regulation of these two niches. Proneural, perivascular GSCs activated EZH2, whereas mesenchymal GSCs in hypoxic regions expressed BMI1 protein, which promoted cellular survival under stress due to downregulation of the E3 ligase RNF144A. Using both genetic and pharmacologic inhibition, we found that proneural GSCs are preferentially sensitive to EZH2 disruption, whereas mesenchymal GSCs are more sensitive to BMI1 inhibition. Given that glioblastomas contain both proneural and mesenchymal GSCs, combined EZH2 and BMI1 targeting proved more effective than either agent alone both in culture and in vivo , suggesting that strategies that simultaneously target multiple epigenetic regulators within glioblastomas may be effective in overcoming therapy resistance caused by intratumoral heterogeneity.