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"Choi, Stephen"
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Molecular events in neuroendocrine prostate cancer development
Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer. NEPC arises de novo only rarely; the disease predominantly develops from adenocarcinoma in response to drug-induced androgen receptor signalling inhibition, although the mechanisms behind this transdifferentiation are a subject of debate. The survival of patients with NEPC is poor, and few effective treatment options are available. To improve clinical outcomes, understanding of the biology and molecular mechanisms regulating NEPC development is crucial. Various NEPC molecular drivers make temporal contributions during NEPC development, and despite the limited treatment options available, several novel targeted therapeutics are currently under research.Neuroendocrine prostate cancer predominantly develops from adenocarcinoma following a period of androgen suppressive treatment. Outcomes in patients with this disease are poor; the understanding of the molecular mechanisms behind its development will improve future targeted therapy options.
Journal Article
Lactic Acid and an Acidic Tumor Microenvironment suppress Anticancer Immunity
Immune evasion and altered metabolism, where glucose utilization is diverted to increased lactic acid production, are two fundamental hallmarks of cancer. Although lactic acid has long been considered a waste product of this alteration, it is now well accepted that increased lactic acid production and the resultant acidification of the tumor microenvironment (TME) promotes multiple critical oncogenic processes including angiogenesis, tissue invasion/metastasis, and drug resistance. We and others have hypothesized that excess lactic acid in the TME is responsible for suppressing anticancer immunity. Recent studies support this hypothesis and provide mechanistic evidence explaining how lactic acid and the acidic TME impede immune cell functions. In this review, we consider lactic acid’s role as a critical immunoregulatory molecule involved in suppressing immune effector cell proliferation and inducing immune cell de-differentiation. This results in the inhibition of antitumor immune responses and the activation of potent, negative regulators of innate and adaptive immune cells. We also consider the role of an acidic TME in suppressing anticancer immunity. Finally, we provide insights to help translate this new knowledge into impactful anticancer immune therapies.
Journal Article
Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer
There is an urgent need for exploring new actionable targets other than androgen receptor to improve outcome from lethal castration-resistant prostate cancer. Tumor metabolism has reemerged as a hallmark of cancer that drives and supports oncogenesis. In this regard, it is important to understand the relationship between distinctive metabolic features, androgen receptor signaling, genetic drivers in prostate cancer, and the tumor microenvironment (symbiotic and competitive metabolic interactions) to identify metabolic vulnerabilities. We explore the links between metabolism and gene regulation, and thus the unique metabolic signatures that define the malignant phenotypes at given stages of prostate tumor progression. We also provide an overview of current metabolism-based pharmacological strategies to be developed or repurposed for metabolism-based therapeutics for castration-resistant prostate cancer.
Journal Article
Do the Merits Matter Less After the Private Securities Litigation Reform Act?
This study provides evidence on the impact of the Private Securities Litigation Reform Act (PSLRA) of 1995. Others have furnished evidence that the PSLRA increased the significance of merit-related factors in determining the incidence and outcomes of securities fraud class actions. This increase is consistent with two hypotheses. First, the PSLRA may have reduced solely the incidence of nuisance litigation. Second, the PSLRA may have also reduced meritorious claims where the additional costs imposed by the PSLRA made such claims unprofitable from the perspective of plaintiffs' attorneys. The study provides evidence that pre-PSLRA nonnuisance claims lacking obvious \"hard evidence\" indicia of fraud (an accounting restatement or Securities and Exchange Commission action) would have faced (1) a lower probability of suit in the post-PSLRA period and (2) a greater likelihood of receiving a dismissal or low-value settlement in the post-PSLRA period.
Journal Article
What Can we Learn from Stock Prices?: Cash Flow, Risk, and Shareholder Welfare
»Vielmehr bietet [der Kommentar] auf höchstem Niveau eine substantielle Auseinandersetzung mit den Hintergründen, den Zusammenhängen, der Theorie und der Praxis des Grundgesetzes. Besseres lässt sich von einem Verfassungskommentar nicht sagen.“ Herbert Günther Staaatsanzeiger für das Land Hessen 2018 (50), 1494–1495
The 4th edition of the first volume of this work provides an update of the commentary on the preamble and articles 1 to 19 in case law and literature. The structure of the book has been retained and its content supplemented by more recent developments, such as the implications of Europeanisation and digitalisation as well as the Corona pandemic. As of the 4th edition, Frauke Brosius-Gersdorf has taken over the editorship of the commentary.
Die 4. Auflage bringt zunächst die Kommentierung der Präambel und der Art. 1 bis 19 auf den aktuellen Stand von Judikatur und Literatur. Die grundlegende Struktur des Kommentares wurde beibehalten und um neuere Entwicklungen wie die Implikationen der Europäisierung und Digitalisierung sowie der Corona-Pandemie ergänzt.Die Herausgeberschaft des Kommentares hat ab der 4. Auflage Frauke Brosius-Gersdorf übernommen. Auch im Autorenkreis sind personelle Veränderungen zu verzeichnen: Mit Ausnahme von Frauke Brosius-Gersdorf, Alexander Thiele und Ferdinand Wollenschläger, die bereits an der 3. Auflage mitgewirkt haben, liegen die Kommentierungen in den Händen neuer Autorinnen und Autoren.Der Kommentar erscheint in drei Bänden und wird nur geschlossen abgegeben.Der Grundgesetz-Kommentar ist Bestandteil des Moduls Verfassungsrecht PREMIUM, das bei beck-online.de erhältlich ist.
Journal Article
Tranexamic acid for the prevention of postpartum haemorrhage: the TAPPH-1 pilot randomized trial and lessons learned for trials in Canadian obstetrics
Postpartum haemorrhage (PPH) is a leading cause of maternal morbidity and mortality. While tranexamic acid (TXA) reduces bleeding and transfusion requirements in established PPH, we sought to determine the feasibility of conducting a fully powered trial assessing the effect of prophylactic tranexamic acid, prior to PPH onset, in a Canadian Obstetric setting. With institutional and Health Canada approval, consenting, eligible parturients (singleton, > 32 weeks gestation, vaginal or caesarian delivery) were randomly assigned to receive TXA (1 g intravenously) or placebo (0.9% saline) prior to delivery. Participants, investigators, data collectors/adjudicators, and analysis was blinded. The primary outcome was administration of study intervention to > 85% of randomized individuals. Secondary outcomes included recruitment rate (feasibility) and safety outcomes. Over 8 months, 611 were approached, 35 consented, and 27 randomized (14 TXA, 13 placebo). 89% of randomized participants received the assigned intervention. Recruitment fell below feasibility (23% target). No serious adverse outcomes occurred. Our pilot trial in a Canadian Obstetric setting was unable to demonstrate feasibility to conduct a large, multicentre trial to examine prophylactic use of tranexamic for PPH secondary to the complex regulatory requirements associated with a trial for an off-label, but commonly utilized intervention. These challenges should inform stakeholders on the resources and challenges of conducting future trials using off-label interventions.
Trial registration:
www.clinicaltrials.gov
, NCT03069859 (03/03/2017).
Journal Article
Production of aqueous spherical gold nanoparticles using conventional ultrasonic bath
A conventional ultrasonic bath was used to examine the feasibility of forming aqueous spherical gold nanoparticles (GNPs) under atmospheric conditions. The effects of ultrasonic energy on the size and morphology of GNPs were also investigated. Highly monodispersed spherical GNPs were successfully synthesised by sodium citrate reduction in a conventional ultrasonic bath, without an additional heater or magnetic stirrer, as evidenced by ultraviolet–visible spectra and transmission electron microscopy. Ultrasonic energy was shown to be a key parameter for producing spherical GNPs of tunable sizes (20 to 50 nm). A proposed scheme for understanding the role of ultrasonic energy in the formation and growth of GNPs was discussed. The simple single-step method using just a conventional ultrasonic bath as demonstrated in this study offers new opportunities in the production of aqueous suspensions of monodispersed spherical GNPs.
Journal Article
Contractual Landmines
Conventional wisdom is that the standardized boilerplate terms used in large commercial markets survive unchanged because they are an optimal solution to the contracting problems facing parties in these markets. As Smith and Warner explained, \"harmful heuristics, like harmful mutations, will die out.\" But an examination of a sample of current sovereign bond contracts reveals numerous instances of harmful landmines-some are deliberate changes to standard language that increase a creditor's nonpayment risk, others are blatant drafting errors, and yet others are inapt terms that have been carelessly imported from corporate transactions. Moreover, these landmines differ from each other in important respects: deliberate changes to the standard form reflect strategic lawyering on behalf of sovereign clients, while errors that only benefit subsequent activists reflect haste in adapting precedents to new transactions. Using both quantitative data and interviews with market participants, we find that the conventional view fails to recognize the unique and distorting role that lawyers play in the drafting of standard form contracts. Systematic asymmetries in the market for the lawyers who negotiate and draft these contracts explain why real-world contracts depart from the efficient contract paradigm.
Journal Article