Search results for: French colonial America

Authors: Nathan Garcia

Abstract:

The polarizing dialogue of contemporary political America results from core philosophical differences. But these differences are beyond ideological and reach metaphysical distinction. Good intellectual historians have theorized that fundamental concepts such as freedom, God, and nature have been sterilized of their intellectual vigor. They are partially correct. 19th-century pragmatist Charles Sanders Peirce offers a penetrating philosophy which can yield greater insight into the contemporary political divide. Peirce argues that metaphysical and ethical issues are derivative of operational logic. His triadic logical structure and ensuing metaphysical principles constructed therefrom is contemporaneously applicable for three reasons. First, Peirce’s logic aptly scrutinizes the logical processes of liberal and conservative mindsets. Each group arrives at a cosmological root metaphor (abduction), resulting in a contemporary assessment (deduction), ultimately prompting attempts to verify the original abduction (induction). Peirce’s system demonstrates that liberal citizens develop a cosmological root metaphor in the concept of fairness (abduction), resulting in a contemporary assessment of, for example, underrepresented communities being unfairly preyed upon (deduction), thereby inciting anger toward traditional socio-political structures suspected of purposefully destabilizing minority communities (induction). Similarly, conservative citizens develop a cosmological root metaphor in the concept of freedom (abduction), resulting in a contemporary assessment of, for example, liberal citizens advocating an expansion of governmental powers (deduction), thereby inciting anger towards liberal communities suspected of attacking freedoms of ordinary Americans in a bid to empower their interests through the government (induction). The value of this triadic assessment is the categorization of distinct types of inferential logic by their purpose and boundaries. Only deductive claims can be concretely proven, while abductive claims are merely preliminary hypotheses, and inductive claims are accountable to interdisciplinary oversight. Liberals and conservative logical processes preclude constructive dialogue because of (a) an unshared abductive framework, and (b) misunderstanding the rules and responsibilities of their types of claims. Second, Peircean metaphysical principles offer a greater summary of the contemporaneously divisive political climate. His insights can weed through the partisan theorizing to unravel the underlying philosophical problems. Corrosive nominalistic and essentialistic presuppositions weaken the ability to share experiences and communicate effectively, both requisite for any promising constructive dialogue. Peirce’s pragmatist system can expose and evade fallacious thinking in pursuit of a refreshing alternative framework. Finally, Peirce’s metaphysical foundation enables a logically coherent, scientifically informed orthopraxis well-suited for American dialogue. His logical structure necessitates radically different anthropology conducive to shared experiences and dialogue within a dynamic, cultural continuum. Pierce’s fallibilism and sensitivity to religious sentiment successfully navigate between liberal and conservative values. In sum, he provides a normative paradigm for intranational dialogue that privileges individual experience and values morally defensible notions of freedom, God, and nature. Utilizing Peirce’s thought will yield fruitful analysis and offers a promising philosophical alternative for framing and engaging in contemporary American political discourse.

Keywords: Charles s. Peirce, american politics, logic, pragmatism

Procedia PDF Downloads 117

Authors: Claire Harrison, Raajit K. Rampal, Vikas Gupta, Srdan Verstovsek, Moshe Talpaz, Jean-Jacques Kiladjian, Ruben Mesa, Andrew Kuykendall, Alessandro Vannucchi, Francesca Palandri, Sebastian Grosicki, Timothy Devos, Eric Jourdan, Marielle J. Wondergem, Haifa Kathrin Al-Ali, Veronika Buxhofer-Ausch, Alberto Alvarez-Larrán, Sanjay Akhani, Rafael Muñoz-Carerras, Yury Sheykin, Gozde Colak, Morgan Harris, John Mascarenhas

Abstract:

Myelofibrosis (MF) is characterized by bone marrow fibrosis, anemia, splenomegaly and constitutional symptoms. Progressive bone marrow fibrosis results from aberrant megakaryopoeisis and expression of proinflammatory cytokines, both of which are heavily influenced by bromodomain and extraterminal domain (BET)-mediated gene regulation and lead to myeloproliferation and cytopenias. Pelabresib (CPI-0610) is an oral small-molecule investigational inhibitor of BET protein bromodomains currently being developed for the treatment of patients with MF. It is designed to downregulate BET target genes and modify nuclear factor kappa B (NF-κB) signaling. MANIFEST-2 was initiated based on data from Arm 3 of the ongoing Phase 2 MANIFEST study (NCT02158858), which is evaluating the combination of pelabresib and ruxolitinib in Janus kinase inhibitor (JAKi) treatment-naïve patients with MF. Primary endpoint analyses showed splenic and symptom responses in 68% and 56% of 84 enrolled patients, respectively. MANIFEST-2 (NCT04603495) is a global, Phase 3, randomized, double-blind, active-control study of pelabresib and ruxolitinib versus placebo and ruxolitinib in JAKi treatment-naïve patients with primary MF, post-polycythemia vera MF or post-essential thrombocythemia MF. The aim of this study is to evaluate the efficacy and safety of pelabresib in combination with ruxolitinib. Here we report updates from a recent protocol amendment. The MANIFEST-2 study schema is shown in Figure 1. Key eligibility criteria include a Dynamic International Prognostic Scoring System (DIPSS) score of Intermediate-1 or higher, platelet count ≥100 × 10^9/L, spleen volume ≥450 cc by computerized tomography or magnetic resonance imaging, ≥2 symptoms with an average score ≥3 or a Total Symptom Score (TSS) of ≥10 using the Myelofibrosis Symptom Assessment Form v4.0, peripheral blast count <5% and Eastern Cooperative Oncology Group performance status ≤2. Patient randomization will be stratified by DIPSS risk category (Intermediate-1 vs Intermediate-2 vs High), platelet count (>200 × 10^9/L vs 100–200 × 10^9/L) and spleen volume (≥1800 cm^3 vs <1800 cm^3). Double-blind treatment (pelabresib or matching placebo) will be administered once daily for 14 consecutive days, followed by a 7 day break, which is considered one cycle of treatment. Ruxolitinib will be administered twice daily for all 21 days of the cycle. The primary endpoint is SVR35 response (≥35% reduction in spleen volume from baseline) at Week 24, and the key secondary endpoint is TSS50 response (≥50% reduction in TSS from baseline) at Week 24. Other secondary endpoints include safety, pharmacokinetics, changes in bone marrow fibrosis, duration of SVR35 response, duration of TSS50 response, progression-free survival, overall survival, conversion from transfusion dependence to independence and rate of red blood cell transfusion for the first 24 weeks. Study recruitment is ongoing; 400 patients (200 per arm) from North America, Europe, Asia and Australia will be enrolled. The study opened for enrollment in November 2020. MANIFEST-2 was initiated based on data from the ongoing Phase 2 MANIFEST study with the aim of assessing the efficacy and safety of pelabresib and ruxolitinib in JAKi treatment-naïve patients with MF. MANIFEST-2 is currently open for enrollment.

Keywords: CPI-0610, JAKi treatment-naïve, MANIFEST-2, myelofibrosis, pelabresib

Procedia PDF Downloads 201