Oncological Outcomes of Patients with High-Volume mCRPC. Results from a Longitudinal Real-Life Multicenter Cohort

Simple Summary Metastatic prostate cancer (PCa) may occur as progression after local therapy with curative intent or may be metastatic as newly onset. Approximately 5% of PCa present with metastatic stage at the time of diagnosis. Therapeutic management differs widely according to the site of metastases, the sensitivity to hormonal treatments and the volume of disease. We reported survival outcomes of patients with high-volume metastatic castration-resistant PCa (mCRPC) treated with ARTA in a chemo-naive setting compared to patients treated with chemotherapy as first-line from a longitudinal real-life multicenter series. In our population of 88 high-volume-disease mCRPC patients, we showed that survival probabilities are comparable between first-line ARTA and upfront chemotherapy-treated cohorts. Therefore, regardless tumor burden, novel antiandrogens can be useful treatment options and could be considered as first-line in order to postpone the use of more toxic treatments such as chemotherapy, in the case of significant disease progression.Abstract Registrative trials recommended the use of upfront chemotherapy in high-volume metastatic prostate cancer. We reported survival outcomes of patients with high-volume mCRPC treated with ARTA in a chemo-naive setting compared to patients treated with chemotherapy as first-line from a longitudinal real-life multicenter series. We retrospectively collected data on mCRPC patients treated at six centers. The dataset was queried for high-volume disease (defined as more than 6 bone lesions or bulky nodes >= 5 cm). We compared the main clinical features of chemo-naive versus chemo-treated patients. The Mann-Whitney U test and Chi-squared test were used to compare continuous and categorial variables, respectively. The Kaplan-Meier method was used to compare differences in terms of progression-free survival (PFS), cancer specific survival (CSS) and overall survival (OS) in an upfront ARTA or chemo-treated setting. Survival probabilities were computed at 12, 24, 48, and 60 months. Out of 216 patients, 88 cases with high-volume disease were selected. Sixty-nine patients (78.4%) received upfront ARTA, while 19 patients received chemotherapy as the first-line treatment option. Forty-eight patients received Abiraterone (AA), 21 patients received Enzalutamide (EZ) as the first-line treatment. The ARTA population was older (p = 0.007) and less likely to receive further lines of treatment (p = 0.001) than the chemo-treated cohort. The five-year PFS, CSS and OS were 60%, 73.3%, and 72.9%, respectively. Overall, 28 patients (31.8%) shifted after their first-line therapy to a second-line therapy: EZ was prescribed in 17 cases, AA in seven cases and radiometabolic therapy in four patients. Sixteen cases (18.2%) developed significant progression and were treated with chemotherapy. At Kaplan-Meyer analysis PFS, CSS and OS were comparable for upfront ARTA vs chemo-treated patients (log rank p = 0.10, p = 0.64 and p = 0.36, respectively). We reported comparable survival probabilities in a real-life series of high-volume mCRPC patients who either received upfront ARTA or chemotherapy. Patients primarily treated with chemotherapy were younger and more likely to receive further treatment lines than the upfront ARTA cohort. Our data support the use of novel antiandrogens as first line treatment regardless tumor burden, delaying the beginning of a more toxic chemotherapy in case of significant disease progression

International Coercion, Emulation and Policy Diffusion: Market-Oriented Infrastructure Reforms, 1977-1999

Why do some countries adopt market-oriented reforms such as deregulation, privatization and liberalization of competition in their infrastructure industries while others do not? Why did the pace of adoption accelerate in the 1990s? Building on neo-institutional theory in sociology, we argue that the domestic adoption of market-oriented reforms is strongly influenced by international pressures of coercion and emulation. We find robust support for these arguments with an event-history analysis of the determinants of reform in the telecommunications and electricity sectors of as many as 205 countries and territories between 1977 and 1999. Our results also suggest that the coercive effect of multilateral lending from the IMF, the World Bank or Regional Development Banks is increasing over time, a finding that is consistent with anecdotal evidence that multilateral organizations have broadened the scope of the “conditionality” terms specifying market-oriented reforms imposed on borrowing countries. We discuss the possibility that, by pressuring countries into policy reform, cross-national coercion and emulation may not produce ideal outcomes.http://deepblue.lib.umich.edu/bitstream/2027.42/40099/3/wp713.pd

Data report: evaluation of shipboard magnetostratigraphy by alternating field demagnetization of discrete samples, Expedition 361, Site U1475

The paleomagnetic shipboard data of International Ocean Discovery Program Site U1475, with a record reaching back to approximately 7 Ma, allowed for the identification of major magnetic polarity chrons and subchrons back to ~3.5 Ma. However, the natural remanent magnetization (NRM) was very weak, and transitional intervals with unclear polarity were as thick as several meters. The midpoints of these transitional intervals were reported in the shipboard results without decimal places because of the poor data quality. To evaluate and possibly refine the shipboard magnetostratigraphy, subsampling was performed across the polarity transitions. Detailed alternating field (AF) demagnetization experiments were conducted on these discrete samples and were complemented by anhysteretic remanent magnetization acquisition measurements and subsequent demagnetization. AF demagnetization data of NRM were analyzed using anchored principal component analysis (PCA) to obtain the characteristic remanent magnetization. These PCA results generally confirm the smoothed signal across polarity transitions at Site U1475. However, the midpoint depths of the top of the Keana Subchron, the Gauss-Matuyama and Matuyama-Brunhes boundaries, and the base of the Olduvai Subchron were adjusted

p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8(+) T cells

T cell senescence is thought to contribute to immune function decline, but the pathways that mediate senescence in these cells are not clear. Here, we evaluated T cell populations from healthy volunteers and determined that human CD8+ effector memory T cells that reexpress the naive T cell marker CD45RA have many characteristics of cellular senescence, including decreased proliferation, defective mitochondrial function, and elevated levels of both ROS and p38 MAPK. Despite their apparent senescent state, we determined that these cells secreted high levels of both TNF-α and IFN-γ and showed potent cytotoxic activity. We found that the senescent CD45RA-expressing population engaged anaerobic glycolysis to generate energy for effector functions. Furthermore, inhibition of p38 MAPK signaling in senescent CD8+ T cells increased their proliferation, telomerase activity, mitochondrial biogenesis, and fitness; however, the extra energy required for these processes did not arise from increased glucose uptake or oxidative phosphorylation. Instead, p38 MAPK blockade in these senescent cells induced an increase in autophagy through enhanced interactions between p38 interacting protein (p38IP) and autophagy protein 9 (ATG9) in an mTOR-independent manner. Together, our findings describe fundamental metabolic requirements of senescent primary human CD8+ T cells and demonstrate that p38 MAPK blockade reverses senescence via an mTOR-independent pathway

Complementarity and Institutional Change: How Useful a Concept?

The concept of institutional complementarity – i.e. the idea that the co-existence of two or more institutions enhances the functioning of each – is increasingly used to explain why institutions are resistant to change and why introducing new institutions into a system often leads to unintended consequences or failure to achieve the intended objective. While the concept is appealing and intuitive, in reality its utility for explaining change is less than straightforward. This paper utilizes examples from comparative political economy to, first, unpack and delineate the concept and address the issue of how to measure the strength or ‘binding force’ of complementarities. Second, it assesses the utility of the concept for explaining institutional change. It is suggested that one’s view of the methods and utility of measuring complementarity will hinge importantly on one’s general theory of institutions and institutional change. In the end, while institutional complementarities are significant, assessing their causal effect on institutional change is difficult and ambiguous in most instances. A better understanding requires that we embed complementarities within a more general theory of institutional change which takes a broader view of the ways in which institutions interconnect and change.Das Konzept der institutionellen Komplementarität – d.h. die Idee, dass zwei oder mehr Institutionen sich gegenseitig stützen und ihre Funktionsfähigkeit erhöhen – gilt mehr und mehr als Erklärung dafür, dass Institutionen gegen Veränderungen resistent sind und das Einführen neuer Institutionen in ein bestehendes System oft unerwartete Konsequenzen oder nicht darin erfolgreich sind, das gewünschte Ziel zu erreichen. Obwohl das Konzept attraktiv und intuitiv ist, ist sein Erklärungsnutzen nicht offensichtlich. In diesem Aufsatz werden Beispiele aus der vergleichenden politischen Ökonomie verwendet, um zunächst den Inhalt des Konzeptes zu umschreiben und die Frage zu stellen, wie die Stärke bzw. „Bindungskraft“ von Komplementaritäten zu messen sind. Dann bewertet er den Nutzen des Konzeptes zur Erklärung von institutionellem Wandel. Dabei ist darauf hinzuweisen, dass es stark vom Hintergrund des Betrachters, seiner allgemeinen Theorie von Institutionen und institutionellem Wandel, abhängt, welchen Blickwinkel er in Bezug auf die Einschätzung der Methoden und des Nutzen der Komplementaritätsmessung einnimmt. Abschließend stellt sich heraus, dass institutionelle Komplementaritäten wichtig sind, es aber in den meisten Fällen schwierig und unklar bleibt, ihren kausalen Effekt auf institutionellen Wandel zu bewerten. Zum besseren Verständnis ist es notwendig, dass das Konzept der Komplementaritäten in eine allgemeine Theorie des institutionellen Wandels eingebettet wird, die eine breitere Sicht über die Art und Weise zulässt, wie Institutionen untereinander verbunden sind und sich verändern

Nutraceutical therapies for atherosclerosis

Atherosclerosis is a chronic inflammatory disease affecting large and medium arteries and is considered to be a major underlying cause of cardiovascular disease (CVD). Although the development of pharmacotherapies to treat CVD has contributed to a decline in cardiac mortality in the past few decades, CVD is estimated to be the cause of one-third of deaths globally. Nutraceuticals are natural nutritional compounds that are beneficial for the prevention or treatment of disease and, therefore, are a possible therapeutic avenue for the treatment of atherosclerosis. The purpose of this Review is to highlight potential nutraceuticals for use as antiatherogenic therapies with evidence from in vitro and in vivo studies. Furthermore, the current evidence from observational and randomized clinical studies into the role of nutraceuticals in preventing atherosclerosis in humans will also be discussed

Characterization of barefoot and shod running

Barefoot (BF) and shod (SD) running mark relevant mechanical boundary conditions for affecting running biomechanics. This thesis studies the variation in foot-strike strategy (FSS), and whilst accounting for this variation provides a description of BF and SD running at different aerobic training velocities in uninjured, highly trained competitive (1500 m personal best: mean (standard deviation) = 3:59.8 (10.0)) male distance runners (n = 19). At one velocity, BF running for nine uninjured competitive female runners is also studied. Three dimensional (3D) gait analysis was used to measure lower-limb joint angles during treadmill running, and surface electromyography (EMG) was used to measure lower-leg muscle activity. Generalized linear mixed models (GLMMs) were used to account for and quantify between-subject variation and stride-specific foot-strike angle (FSA). This thesis provides evidence to discourage the general practice of classifying runners in the present population within a FSS group for BF running. Also, a subset of individuals exhibited high FSA variability for BF running, possibly because of discomfort. The hypothesis that FSA correlates with changes in running kinematics was supported. A larger hip width to femur length ratio found in females was associated with more hip adduction, corroborating previous research. More plantarflexed FSA was hypothesized for higher velocities, and flatter foot placement was anticipated for BF versus SD running. Flatter foot placement was observed for BF running, but FSA was independent of velocity for BF running and more foot dorsiflexion at foot-strike (FS) was observed for fast velocity for SD running. These adjustments may be motivated by maximal or sub-maximal deformation of the heel pad and the novelty of BF running. Coupled with the observed increase in gastrocnemius muscle activity for BF versus SD running, these observations may be cause for caution for the novice BF runner. A different coordinative structure for tibia and rearfoot coupling emerged as velocity increased, possibly in response to an increased functional demand of the talocrural and subtalar joints for BF running as velocity increases. The hypothesis that coordinative variability changes with FSA during impact phase, to reflect the underlying elevated injury risk for rearfoot-strike runners, was not supported. Coordinative variability was independent of FSA. In addition, coordination was more robust to changes in velocity and differences in FSA for SD running, possibly reflecting habituation. Running BF may have potential as a diagnostic tool for studying injury etiology, because the limit of no external cushioning may place mechanical demands on the runner sufficient to elicit anomalous running kinematics, which may manifest as high kinematic variability.</p