Local failure events in prostate cancer treated with radiotherapy: A pooled analysis of 18 randomized trials from the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium (LEVIATHAN)

CONTEXT: The prognostic importance of local failure after definitive radiotherapy (RT) in National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa) patients remains unclear. OBJECTIVE: To evaluate the prognostic impact of local failure and the kinetics of distant metastasis following RT. EVIDENCE ACQUISITION: A pooled analysis was performed on individual patient data of 12 533 PCa (6288 high-risk and 6245 intermediate-risk) patients enrolled in 18 randomized trials (conducted between 1985 and 2015) within the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium. Multivariable Cox proportional hazard (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), distant metastasis-free survival (DMFS), and local failure as a time-dependent covariate. Markov PH models were developed to evaluate the impact of specific transition states. EVIDENCE SYNTHESIS: The median follow-up was 11 yr. There were 795 (13%) local failure events and 1288 (21%) distant metastases for high-risk patients and 449 (7.2%) and 451 (7.2%) for intermediate-risk patients, respectively. For both groups, 81% of distant metastases developed from a clinically relapse-free state (cRF state). Local failure was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06-1.30), PCSS (HR 2.02, 95% CI 1.75-2.33), and DMFS (HR 1.94, 95% CI 1.75-2.15, p \u3c 0.01 for all) in high-risk patients. Local failure was also significantly associated with DMFS (HR 1.57, 95% CI 1.36-1.81) but not with OS in intermediate-risk patients. Patients without local failure had a significantly lower HR of transitioning to a PCa-specific death state than those who had local failure (HR 0.32, 95% CI 0.21-0.50, p \u3c 0.001). At later time points, more distant metastases emerged after a local failure event for both groups. CONCLUSIONS: Local failure is an independent prognosticator of OS, PCSS, and DMFS in high-risk and of DMFS in intermediate-risk PCa. Distant metastasis predominantly developed from the cRF state, underscoring the importance of addressing occult microscopic disease. However a second wave of distant metastases occurs subsequent to local failure events, and optimization of local control may reduce the risk of distant metastasis. PATIENT SUMMARY: Among men receiving definitive radiation therapy for high- and intermediate-risk prostate cancer, about 10% experience local recurrence, and they are at significantly increased risks of further disease progression. About 80% of patients who develop distant metastasis do not have a detectable local recurrence preceding it

Effects of Environmental Gradients on the Abundance and Diversity of Helminths Across 7 Bison Herds in the Upper Midwest

Study Description: Data were collected from Wind Cave National Park and 6 satellite bison herds across the upper Midwest ranging across South Dakota, Indiana, and Kansas with a MAP gradient ranging from 34 to 82 mm and a MAT gradient ranging from 9 to 13°C. Fecal samples were collected non-invasively from 50 freshly voided bison dung patties at each herd. Helminth eggs were recovered and identified using sugar floatation; Trichostrongyle-type eggs were hatched by coproculture to identify to species. Preliminary findings indicate that general abundance of trichostrongyle-type helminths increases by 2.3 EPG per 1°C and by 0.2 EPG per mm, but Cooperia sp. decreases over MAT and MAP whereas Haemonchus sp. increases over MAT and MAP

Comparison of response to definitive radiotherapy for localized prostate cancer in black and white men: A meta-analysis

Importance: Black men have a 2-fold increased risk of dying from prostate cancer compared with White men. However, race-specific differences in response to initial treatment remain unknown. Objective: To compare overall and treatment-specific outcomes of Black and White men with localized prostate cancer receiving definitive radiotherapy (RT). Data Sources: A systematic search was performed of relevant published randomized clinical trials conducted by the NRG Oncology/Radiation Therapy Oncology Group between January 1, 1990, and December 31, 2010. This meta-analysis was performed from July 1, 2019, to July 1, 2021. Study Selection: Randomized clinical trials of definitive RT for patients with localized prostate cancer comprising a substantial number of Black men (self-identified race) enrolled that reported on treatment-specific and overall outcomes. Data Extraction and Synthesis: Individual patient data were obtained from 7 NRG Oncology/Radiation Therapy Oncology Group randomized clinical trials evaluating definitive RT with or without short- or long-term androgen deprivation therapy. Unadjusted Fine-Gray competing risk models, with death as a competing risk, were developed to evaluate the cumulative incidences of end points. Cox proportional hazards models were used to evaluate differences in all-cause mortality and the composite outcome of distant metastasis (DM) or death. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed. Main Outcomes and Measures: Subdistribution hazard ratios (sHRs) of biochemical recurrence (BCR), DM, and prostate cancer-specific mortality (PCSM). Results: A total of 8814 patients (1630 [18.5%] Black and 7184 [81.5%] White) were included; mean (SD) age was 69.1 (6.8) years. Median follow-up was 10.6 (IQR, 8.0-17.8) years for surviving patients. At enrollment, Black men were more likely to have high-risk disease features. However, even without adjustment, Black men were less likely to experience BCR (sHR, 0.88; 95% CI, 0.58-0.91), DM (sHR, 0.72; 95% CI, 0.58-0.91), or PCSM (sHR, 0.72; 95% CI, 0.54-0.97). No significant differences in all-cause mortality were identified (HR, 0.99; 95% CI, 0.92-1.07). Upon adjustment, Black race remained significantly associated with improved BCR (adjusted sHR, 0.79; 95% CI, 0.72-0.88; P \u3c .001), DM (adjusted sHR, 0.69; 95% CI, 0.55-0.87; P = .002), and PCSM (adjusted sHR, 0.68; 95% CI, 0.50-0.93; P = .01). Conclusions and Relevance: The findings of this meta-analysis suggest that Black men enrolled in randomized clinical trials present with more aggressive disease but have better BCR, DM, and PCSM with definitive RT compared with White men, suggesting that other determinants of outcome, such as access to care, are important factors of achieving racial equity

Causal explanations for the evolution of ‘low gear’ locomotion in insular ruminants

Aim: Mammals on islands often undergo remarkable evolutionary changes. The acquisition of ‘low gear’ locomotion, namely short and robust limb elements, has been typically associated with the island syndrome in large mammals and, especially, ruminants. Here we provide an investigative framework to examine biotic and abiotic selective factors hypothesized to influence evolution of this peculiar type of gait. Location: Islands worldwide. Taxon: Bovidae. Methods: We calculated response variables associated with ‘low gear’ locomotion in 21 extinct and extant insular bovids. We assembled data on the physiography of 11 islands and on life history and ecological traits of the focal taxa. We estimated 10 predictors (island area and four topographic indices, body mass, body size divergence, number of predators and competitors, large mammal richness) and used multiple regressions, regression trees, and random forests to assess their contextual importance. Results: The acquisition of ‘low gear’ locomotion generally happens on islands with a small number of competitors. However, the roughness of the island terrain appears to be also important, without being a main driver. Finally, although the most extreme cases of ‘low gear’ locomotion occurred on islands with no mammalian predators, our models show a non-significant relationship with this factor. Main conclusions: The evolution of ‘low gear’ locomotion in insular ruminants does not simply result from phyletic dwarfing and predatory release. Variation in morphological responses within Bovidae to ecological and topographic traits suggests, instead, a complex interplay of biotic and abiotic factors. Current understanding on the main drivers of species evolutionary pathways and biogeographic patterns are disproportionally based on few taxa, mainly vertebrates, and in some extreme cases (like this one) even on few species. Here we show how adding more data, even within the same taxonomic group, can challenge historically accepted macroevolutionary and macroecological concepts

The influence of floral traits on specialisation and modularity of plant-pollinator networks in a biodiversity hotspot in the Peruvian Andes

Background and Aims: Modularity is a ubiquitous and important structural property of ecological networks which describes the relative strengths of sets of interacting species and gives insights into the dynamics of ecological communities. However, this has rarely been studied in species-rich, tropical plant–pollinator networks. Working in a biodiversity hotspot in the Peruvian Andes we assessed the structure of quantitative plant–pollinator networks in nine valleys, quantifying modularity among networks, defining the topological roles of species and the influence of floral traits on specialization. Methods: A total of 90 transects were surveyed for plants and pollinators at different altitudes and across different life zones. Quantitative modularity (QuanBiMo) was used to detect modularity and six indices were used to quantify specialization. Key Results: All networks were highly structured, moderately specialized and significantly modular regardless of size. The strongest hubs were Baccharis plants, Apis mellifera, Bombus funebris and Diptera spp., which were the most ubiquitous and abundant species with the longest phenologies. Species strength showed a strong association with the modular structure of plant–pollinator networks. Hubs and connectors were the most centralized participants in the networks and were ranked highest (high generalization) when quantifying specialization with most indices. However, complementary specialization d' quantified hubs and connectors as moderately specialized. Specialization and topological roles of species were remarkably constant across some sites, but highly variable in others. Networks were dominated by ecologically and functionally generalist plant species with open access flowers which are closely related taxonomically with similar morphology and rewards. Plants associated with hummingbirds had the highest level of complementary specialization and exclusivity in modules (functional specialists) and the longest corollas. Conclusions: We have demonstrated that the topology of networks in this tropical montane environment was non-random and highly organized. Our findings underline that specialization indices convey different concepts of specialization and hence quantify different aspects, and that measuring specialization requires careful consideration of what defines a specialist

Complementarity of a Low Energy Photon Collider and LHC Physics

We discuss the complementarity between the LHC and a low energy photon collider. We mostly consider the scenario, where the first linear collider is a photon collider based on dual beam technology like CLIC.Comment: 29 pages, 37 figure, LP-200

Methodology for Microscopic Traffic Simulation Modelling of Land Port of Entries along the U.S.-Mexican Border: Ysleta – Zaragoza Land Port of Entry Case Study

AbstractLand Ports of Entry (LPOEs) are facilities that control access into the U.S., as well as departures of persons and freight. While traffic simulation modeling techniques are not typically used to evaluate LPOE operational processes, they should be considered more often, because LPOEs have a significant impact on surrounding traffic conditions and vice versa. This paper proposes a methodology for developing microscopic traffic simulation models of LPOEs along the U.S.-Mexico border. The methodology consists of seven steps: (i) collect data; (ii) develop traffic or roadway network; (iii) model inspection and toll booths; (iv) develop traffic management strategies; (v) set up traffic demand; (vi) calibrate model; and (vii) validate model. The paper also presents a case study in which this methodology was followed to develop the Ysleta – Zaragoza LPOE traffic simulation model, which can be controlled from a web-based interface to help LPOE personnel without previous transportation modeling experience

Identification of key structural elements for neuronal calcium sensor-1 function in the regulation of the temperature-dependency of locomotion in C. elegans

BACKGROUND: Intracellular Ca(2+) regulates many aspects of neuronal function through Ca(2+) binding to EF hand-containing Ca(2+) sensors that in turn bind target proteins to regulate their function. Amongst the sensors are the neuronal calcium sensor (NCS) family of proteins that are involved in multiple neuronal signalling pathways. Each NCS protein has specific and overlapping targets and physiological functions and specificity is likely to be determined by structural features within the proteins. Common to the NCS proteins is the exposure of a hydrophobic groove, allowing target binding in the Ca(2+)-loaded form. Structural analysis of NCS protein complexes with target peptides has indicated common and distinct aspects of target protein interaction. Two key differences between NCS proteins are the size of the hydrophobic groove that is exposed for interaction and the role of their non-conserved C-terminal tails. RESULTS: We characterised the role of NCS-1 in a temperature-dependent locomotion assay in C. elegans and identified a distinct phenotype in the ncs-1 null in which the worms do not show reduced locomotion at actually elevated temperature. Using rescue of this phenotype we showed that NCS-1 functions in AIY neurons. Structure/function analysis introducing single or double mutations within the hydrophobic groove based on information from characterised target complexes established that both N- and C-terminal pockets of the groove are functionally important and that deletion of the C-terminal tail of NCS-1 did not impair its ability to rescue. CONCLUSIONS: The current work has allowed physiological assessment of suggestions from structural studies on the key structural features that underlie the interaction of NCS-1 with its target proteins. The results are consistent with the notion that full length of the hydrophobic groove is required for the regulatory interactions underlying NCS-1 function whereas the C-terminal tail of NCS-1 is not essential. This has allowed discrimination between two potential modes of interaction of NCS-1 with its targets

Identification of key structural elements for neuronal calcium sensor-1 function in the regulation of the temperature-dependency of locomotion in C. elegans

BACKGROUND: Intracellular Ca2+ regulates many aspects of neuronal function through Ca2+ binding to EF hand-containing Ca2+ sensors that in turn bind target proteins to regulate their function. Amongst the sensors are the neuronal calcium sensor (NCS) family of proteins that are involved in multiple neuronal signalling pathways. Each NCS protein has specific and overlapping targets and physiological functions and specificity is likely to be determined by structural features within the proteins. Common to the NCS proteins is the exposure of a hydrophobic groove, allowing target binding in the Ca2+-loaded form. Structural analysis of NCS protein complexes with target peptides has indicated common and distinct aspects of target protein interaction. Two key differences between NCS proteins are the size of the hydrophobic groove that is exposed for interaction and the role of their non-conserved C-terminal tails. RESULTS: We characterised the role of NCS-1 in a temperature-dependent locomotion assay in C. elegans and identified a distinct phenotype in the ncs-1 null in which the worms do not show reduced locomotion at actually elevated temperature. Using rescue of this phenotype we showed that NCS-1 functions in AIY neurons. Structure/function analysis introducing single or double mutations within the hydrophobic groove based on information from characterised target complexes established that both N- and C-terminal pockets of the groove are functionally important and that deletion of the C-terminal tail of NCS-1 did not impair its ability to rescue. CONCLUSIONS: The current work has allowed physiological assessment of suggestions from structural studies on the key structural features that underlie the interaction of NCS-1 with its target proteins. The results are consistent with the notion that full length of the hydrophobic groove is required for the regulatory interactions underlying NCS-1 function whereas the C-terminal tail of NCS-1 is not essential. This has allowed discrimination between two potential modes of interaction of NCS-1 with its targets

Rapid Oscillations in Cataclysmic Variables. XVI. DW Cancri

We report photometry and spectroscopy of the novalike variable DW Cancri. The spectra show the usual broad H and He emission lines, with an excitation and continuum slope characteristic of a moderately high accretion rate. A radial-velocity search yields strong detections at two periods, 86.1015(3) min and 38.58377(6) min. We interpret these as respectively the orbital period P_orb of the binary, and the spin period P_spin of a magnetic white dwarf. The light curve also shows the spin period, plus an additional strong signal at 69.9133(10) min, which coincides with the difference frequency 1/P_spin-1/P_orb. These periods are stable over the 1 year baseline of measurement. This triply-periodic structure mimics the behavior of several well-credentialed members of the "DQ Herculis" (intermediate polar) class of cataclysmic variables. DQ Her membership is also suggested by the mysteriously strong sideband signal (at nu_spin-nu_orb), attesting to a strong pulsed flux at X-ray/EUV/UV wavelengths. DW Cnc is a new member of this class, and would be an excellent target for extended observation at these wavelengths.Comment: PDF, 28 pages, 6 tables, 9 figures; accepted, in press, to appear June 2004, PASP; more info at http://cba.phys.columbia.edu