Certain puzzling cases have been discussed in the literature recently which appear to support the thought that knowledge can be obtained by way of deduction from a falsehood; moreover, these cases ...put pressure, prima facie, on the thesis of counter closure for knowledge. We argue that the cases do not involve knowledge from falsehood; despite appearances, the false beliefs in the cases in question are causally, and therefore epistemologically, incidental, and knowledge is achieved despite falsehood. We also show that the principle of counter closure, and the concomitant denial of knowledge from falsehood, is well motivated by considerations in epistemological theory—in particular, by the view that knowledge is first in the epistemological order of things.
Cyclin-dependent kinases (CDK) regulate cell cycle and transcriptional activity. Pan-CDK inhibitors demonstrated early efficacy in lymphoid malignancies, but also have been associated with narrow ...therapeutic index. Among transcriptional CDKs, CDK7 and CDK9 emerged as promising targets. CDK9 serves as a component of P-TEFb elongation complex and thus is indispensable in mRNA transcription. Selective CDK9 inhibitors demonstrated pre-clinical efficacy in
and
models of B-cell non-Hodgkin lymphoma. CDK9 inhibition results in transcriptional pausing with rapid downmodulation of short-lived oncogenic proteins, e.g. Myc and Mcl-1, followed by cell apoptosis. Early phase clinical trials established safety of CDK9 inhibitors, with manageable neutropenia, infections and gastrointestinal toxicities. In this review, we summarize the rationale of targeting CDK9 in lymphoid malignancies, as well as pre-clinical and early clinical data with pan-CDK and selective CDK9 inhibitors.
The hypomethylating agents (HMA) azacitidine and decitabine are both approved by the FDA for the treatment of myelodysplastic syndromes (MDS). Although heralded as a significant advancement, HMA lead ...to responses in less than half of patients and for those that respond most will relapse. As such, there is a crucial need to improve frontline therapy approaches. One promising strategy involves combining azacitidine or decitabine with investigational or existing therapies with the goal of achieving synergistic activity and better patient outcomes. The purpose of this paper is to critically review the efficacy and safety of reported HMA-based combination regimens in patients with higher-risk MDS.
In this paper I compare Timothy Williamson's knowledge rule of assertion with Ishani Maitra and Brian Weatherson's action rule. The paper is in two parts. In the first part I present and respond to ...Maitra and Weatherson's master argument against the knowledge rule. I argue that while its second premise, to the effect that an action X can be the thing to do though one is in no position to know that it is, is true, its first premise is not: the data do not support the claim that whenever X is the thing for one to do, one is in a position to assert that it is. In the second part I consider Maitra and Weatherson's alternative hypotheses, arguing that they do not provide a better explanation of the linguistic data. I conclude, in particular, that the knowledge rule is preferable to the action rule.
Abstract 947
Large hemizygous chromosomal deletions are among the most common molecular abnormalities in cancer, but the identification of critical haploinsufficiency disease genes within the deleted ...regions has been difficult. The 5q- syndrome, a subtype of myelodysplastic syndrome (MDS), is a well-studied chromosomal deletion syndrome characterized by a consistent clinical phenotype with macrocytic anemia and thrombocytosis. We have previously shown that while hemizygous loss of RPS14 recapitulates the failed erythroid differentiation seen in 5q- syndrome, it does not account for the thrombocytosis. Evaluation of the effects of all protein coding genes in the CDR on hematopoietic differentiation showed no genes other than RPS14 altered the ratio of megakaryocytic to erythroid cells, either alone or in combination with RPS14. We therefore examined the 5q- syndrome CDR for non-coding RNAs and identified a microRNA, miR-145, which targets Fli-1, a transcriptional factor that regulates megakaryocyte development. Patients with del(5q) MDS have decreased expression of miR-145 and increased expression of Fli-1. Overexpression of miR-145 or inhibition of Fli-1 in CD34+ cells decreases megakaryocyte production, while inhibition of miR-145 or overexpression of Fli-1 has the reciprocal effect. These findings have been validated in vivo using transgenic mice. Moreover, the combined loss of miR-145 and RPS14 cooperate to alter erythroid-megakaryocytic differentiation in a manner similar to the 5q- syndrome. Taken together, these findings demonstrate for the first time that coordinate deletion of a microRNA and a protein-coding gene contributes to the phenotype of a human malignancy, the 5q- syndrome.
No relevant conflicts of interest to declare.
Relapsed or refractory (R/R) acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3) mutations remains a difficult and hard to treat entity. Gilteritinib is a potent oral FLT-3 inhibitor ...that improves overall survival in R/R AML, but studies are limited in combining gilteritinib with a hypomethylating agent and venetoclax treatment backbone (HMA-VEN-GILT). Here we report our experience with HMA-VEN-GILT for 22 R/R FLT3 AML patients. HMA-VEN-GILT yielded an ORR of 77.3% (17/22), CR 4.5% (1/22), CRi 13.6% (3/22), MLFS 59.1% (13/22). Median follow-up was 10.4 months with a relapse rate of 29.4% (5/17), median time to relapse of 69 days (range 35-298 days), 6-month overall survival of 84%, and median OS of 10.1 months. Additionally, 36.4% (8/22) of patients proceeded to hematopoietic stem cell transplant. In conclusion, HMA-VEN-GILT for the treatment of R/R FLT3 AML is feasible and can be used as a bridge to allogeneic transplantation.
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