Differences in the rate of lymph node invasion in men with clinically localized prostate cancer might be related to the continent of origin

OBJECTIVETo test whether the rate of lymph node invasion (LNI) differs between patients treated with radical prostatectomy (RP) at a European or a North American centre.PATIENTS AND METHODSIn all, 1385 men had RP with bilateral lymphadenectomy for clinically localized prostate cancer (587 from Dallas, Texas and 798 from Milan, Italy). Univariate and multivariate analyses focused on the association between the continent of origin and the rate of LNI, after controlling for prostate‐specific antigen (PSA) level, clinical stage, biopsy Gleason sum and the number of examined and removed lymph nodes.RESULTSEuropean men had higher PSA levels (9.1 vs 7.8 ng/mL), a higher proportion of palpable cancers (44.5 vs 32.8%), more nodes removed (mean 14.9 vs 7.8) and a higher rate of LNI (9.0% vs 1.2%; all differences P < 0.001). In multivariate analyses that controlled for PSA level and clinical variables, European men had an 8.9‐fold higher risk of LNI (P < 0.001) than their counterparts from the USA. Among preoperative variables, the continent of origin was the third most informative predictor of LNI (67.5%), after biopsy Gleason sum (74.3%) and the number of examined lymph nodes (71.0%), and improved the ability to predict LNI by 4.7%.CONCLUSIONMen treated at a European centre had a 7.3–8.9‐fold higher rate of LNI, despite adjusting for all clinical and pathological variables. It remains to be shown what predisposes European men to a higher rate of LNI

Mechanisms behind temsirolimus resistance causing reactivated growth and invasive behavior of bladder cancer cells in vitro

Background: Although mechanistic target of rapamycin (mTOR) inhibitors, such as temsirolimus, show promise in treating bladder cancer, acquired resistance often hampers efficacy. This study evaluates mechanisms leading to resistance. Methods: Cell growth, proliferation, cell cycle phases, and cell cycle regulating proteins were compared in temsirolimus resistant (res) and sensitive (parental—par) RT112 and UMUC3 bladder cancer cells. To evaluate invasive behavior, adhesion to vascular endothelium or to immobilized extracellular matrix proteins and chemotactic activity were examined. Integrin α and β subtypes were analyzed and blocking was done to evaluate physiologic integrin relevance. Results: Growth of RT112res could no longer be restrained by temsirolimus and was even enhanced in UMUC3res, accompanied by accumulation in the S- and G2/M-phase. Proteins of the cdk-cyclin and Akt-mTOR axis increased, whereas p19, p27, p53, and p73 decreased in resistant cells treated with low-dosed temsirolimus. Chemotactic activity of RT112res/UMUC3res was elevated following temsirolimus re-exposure, along with significant integrin α2, α3, and β1 alterations. Blocking revealed a functional switch of the integrins, driving the resistant cells from being adhesive to being highly motile. Conclusion: Temsirolimus resistance is associated with reactivation of bladder cancer growth and invasive behavior. The α2, α3, and β1 integrins could be attractive treatment targets to hinder temsirolimus resistance

Radical prostatectomy improves survival in selected metastatic prostate cancer patients: A North American population-based study.

ObjectiveTo test whether radical prostatectomy might result in better survival than external beam radiation therapy in metastatic prostate cancer patients.MethodsNewly diagnosed metastatic prostate cancer patients with M1a/b substages, treated with radical prostatectomy or external beam radiation therapy were abstracted from the Surveillance, Epidemiology and End Results database (2004–2016). Temporal trend analyses, propensity score matching, cumulative incidence plots, multivariate competing risks regression models and landmark analyses were used.ResultsOf 4280 patients, 954 (22.3%) were treated with radical prostatectomy. After propensity score matching, 5‐year cancer‐specific mortality was 47.0 versus 53.0% in radical prostatectomy versus external beam radiation therapy patients (P = 0.003). In propensity score matched competing risks regression models, radical prostatectomy was associated with lower cancer‐specific mortality versus external beam radiation therapy (hazard ratio 0.79, 95% confidence interval 0.79–0.90; P = 0.001). Finally, landmark analyses rejected the bias favoring radical prostatectomy. Finally, in subgroup analyses, we relied on selection criteria that most closely resembled the STAMPEDE criteria and a similar hazard ratio of 0.8 (P < 0.001) was recorded.ConclusionIn metastatic prostate cancer, radical prostatectomy results in lower cancer‐specific mortality relative to external beam radiation therapy. Even after adjustment for age at diagnosis, prostate‐specific antigen and biopsy Gleason grade grouping, lower cancer‐specific mortality rates are recorded in radical prostatectomy patients than in external beam radiation therapy patients. As a result, radical prostatectomy should be considered as a treatment option in selected metastatic prostate cancer patients. However, further validation will be provided by ongoing clinical trials

Measurement of αΩ in Ω− → ΛΚ− Decays

The HyperCP experiment (E871) at Fermilab has collected the largest sample of hyperon decays in the world. With a data set of over a million Ω− → ΛΚ− decays we have measured the product of αΩαΛ from which we have extracted αΩ. This preliminary result indicates that αΩ is small, but non‐zero. Prospects for a test of CP symmetry by comparing the α parameters in Ω− and Ω̄+ decays will be discussed. © 2003 American Institute of PhysicsPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87682/2/251_1.pd

Prognostic significance of pathologic lymph node invasion in metastatic renal cell carcinoma in the immunotherapy era

Background This study aimed to test the prognostic significance of pathologically confirmed lymph node invasion in metastatic renal cell carcinoma (mRCC) patients in this immunotherapy era. Methods Surgically treated mRCC patients were identified in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2018. Kaplan-Meier plots and multivariable Cox-regression models were fitted to test for differences in cancer-specific mortality (CSM) and overall mortality (OM) according to N stage (pN0 vs pN1 vs. pNx). Subgroup analyses addressing pN1 patients tested for CSM and OM differences according to postoperative systemic therapy status. Results Overall, 3149 surgically treated mRCC patients were identified. Of these patients, 443 (14%) were labeled as pN1, 812 (26%) as pN0, and 1894 (60%) as pNx. In Kaplan-Meier analyses, the median CSM-free survival was 15 months for pN1 versus 40 months for pN0 versus 35 months for pNx (P < 0.001). In multivariable Cox regression analyses, pN1 independently predicted higher CSM (hazard ratio [HR], 1.88; P < 0.01) and OM (HR, 1.95; P < 0.01) relative to pN0. In sensitivity analyses addressing pN1 patients, postoperative systemic therapy use independently predicted lower CSM (HR, 0.73; P < 0.01) and OM (HR, 0.71; P < 0.01). Conclusion Pathologically confirmed lymph node invasion independently predicted higher CSM and OM for surgically treated mRCC patients. For pN1 mRCC patients, use of postoperative systemic therapy was associated with lower CSM and OM. Consequently, N stage should be considered for individual patient counseling and clinical decision-making

Regional differences in clear cell metastatic renal cell carcinoma patients across the USA

Purpose To test for regional differences in clear cell metastatic renal cell carcinoma (ccmRCC) patients across the USA. Methods The Surveillance, Epidemiology, and End Results (SEER) database (2000–2018) was used to tabulate patient (age at diagnosis, sex, race/ethnicity), tumor (N stage, sites of metastasis) and treatment characteristics (proportions of nephrectomy and systemic therapy), according to 12 SEER registries. Multinomial regression models, as well as multivariable Cox regression models, tested the overall mortality (OM) adjusting for those patient, tumor and treatment characteristics. Results In 9882 ccmRCC patients, registry-specific patient counts ranged from 4025 (41%) to 189 (2%). Differences across registries existed for sex (24–36% female), race/ethnicity (1–75% non-Caucasian), N stage (N1 25–35%, NX 3–13%), proportions of nephrectomy (44–63%) and systemic therapy (41–56%). Significant inter-registry differences remained after adjustment for proportions of nephrectomy (46–63%) and systemic therapy (35–56%). Unadjusted 5-year OM ranged from 73 to 85%. In multivariable analyses, three registries exhibited significantly higher OM (SEER registry 5: hazard ratio (HR) 1.20, p = 0.0001; SEER registry 7:HR 1.15, p = 0.008M SEER registry 10: HR 1.15, p = 0.04), relative to the largest reference registry (n = 4025). Conclusion Important regional differences including patient, tumor and treatment characteristics exist, when ccmRCC patients included in the SEER database are studied. Even after adjustment for these characteristics, important OM differences persisted, which may require more detailed analyses to further investigate these unexpected differences

CP Violation in Hyperon and Charged Kaon Decays

The primary purpose of the HyperCP experiment at Fermilab is to test CP in hyperon decays by comparing the decay distributions for Ξ− (“cascade”) decays in the decay sequence: Ξ− → π− + Λ0, Λ0 → π− + p, with those for the antiparticle Ξ̄+. In addition, we can test CP in charged kaon decays by comparing the slopes of the Dalitz plot for Κ+ and Κ− decays. We are also looking at rare decay modes of charged kaons and hyperons, particularly those involving muons. In two runs in 1997 and 1999, we collected approx. 500 millon charged kaon decays, 2.5 billion Ξ− and Ξ̄+ decays, and 19 million Ω− and Ω̄+ decays. This is the largest sample of fully reconstructed particle decays ever collected. © 2002 American Institute of PhysicsPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87464/2/298_1.pd

Isolation and Characterization of Novel Murine Epiphysis Derived Mesenchymal Stem Cells

BACKGROUND: While bone marrow (BM) is a rich source of mesenchymal stem cells (MSCs), previous studies have shown that MSCs derived from mouse BM (BMMSCs) were difficult to manipulate as compared to MSCs derived from other species. The objective of this study was to find an alternative murine MSCs source that could provide sufficient MSCs. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we described a novel type of MSCs that migrates directly from the mouse epiphysis in culture. Epiphysis-derived MSCs (EMSCs) could be extensively expanded in plastic adherent culture, and they had a greater ability for clonogenic formation and cell proliferation than BMMSCs. Under specific induction conditions, EMSCs demonstrated multipotency through their ability to differentiate into adipocytes, osteocytes and chondrocytes. Immunophenotypic analysis demonstrated that EMSCs were positive for CD29, CD44, CD73, CD105, CD166, Sca-1 and SSEA-4, while negative for CD11b, CD31, CD34 and CD45. Notably, EMSCs did not express major histocompatibility complex class I (MHC I) or MHC II under our culture system. EMSCs also successfully suppressed the proliferation of splenocytes triggered by concanavalin A (Con A) or allogeneic splenocytes, and decreased the expression of IL-1, IL-6 and TNF-α in Con A-stimulated splenocytes suggesting their anti-inflammatory properties. Moreover, EMSCs enhanced fracture repair, ameliorated necrosis in ischemic skin flap, and improved blood perfusion in hindlimb ischemia in the in vivo experiments. CONCLUSIONS/SIGNIFICANCES: These results indicate that EMSCs, a new type of MSCs established by our simple isolation method, are a preferable alternative for mice MSCs due to their better growth and differentiation potentialities

Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950-2019 : a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Background: Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods: 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10–14 and 50–54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings: The global TFR decreased from 2·72 (95% uncertainty interval [UI] 2·66–2·79) in 2000 to 2·31 (2·17–2·46) in 2019. Global annual livebirths increased from 134·5 million (131·5–137·8) in 2000 to a peak of 139·6 million (133·0–146·9) in 2016. Global livebirths then declined to 135·3 million (127·2–144·1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2·1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27·1% (95% UI 26·4–27·8) of global livebirths. Global life expectancy at birth increased from 67·2 years (95% UI 66·8–67·6) in 2000 to 73·5 years (72·8–74·3) in 2019. The total number of deaths increased from 50·7 million (49·5–51·9) in 2000 to 56·5 million (53·7–59·2) in 2019. Under-5 deaths declined from 9·6 million (9·1–10·3) in 2000 to 5·0 million (4·3–6·0) in 2019. Global population increased by 25·7%, from 6·2 billion (6·0–6·3) in 2000 to 7·7 billion (7·5–8·0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58·6 years (56·1–60·8) in 2000 to 63·5 years (60·8–66·1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens