Large chromosomal deletions are among the most common molecular abnormalities in cancer, yet the identification of relevant genes has proven difficult. The 5q− syndrome, a subtype of myelodysplastic ...syndrome (MDS), is a chromosomal deletion syndrome characterized by anemia and thrombocytosis. Although we have previously shown that hemizygous loss of RPS14 recapitulates the failed erythroid differentiation seen in 5q− syndrome, it does not affect thrombocytosis. Here we show that a microRNA located in the common deletion region of 5q− syndrome, miR-145, affects megakaryocyte and erythroid differentiation. We find that miR-145 functions through repression of Fli-1, a megakaryocyte and erythroid regulatory transcription factor. 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 decreases the production of megakaryocytic cells relative to erythroid cells, whereas inhibition of miR-145 or overexpression of Fli-1 has a reciprocal effect. Moreover, combined loss of miR-145 and RPS14 cooperates to alter erythroid-megakaryocytic differentiation in a manner similar to the 5q− syndrome. Taken together, these findings demonstrate that coordinate deletion of a miRNA and a protein-coding gene contributes to the phenotype of a human malignancy, the 5q− syndrome.
The central thesis of this paper is that fake news and related phenomena serve as defeaters for knowledge transmission via journalistic channels. This explains how they pose a threat to democracy; ...and it points the way to determining how to address this threat. Democracy is both intrinsically and instrumentally good provided the electorate has knowledge (however partial and distributed) of the common good and the means of achieving it. Since journalism provides such knowledge, those who value democracy have a reason to protect it. Hostile agents, however, can undermine both the effectiveness of democratic decision-making and faith in democracy itself, by deliberately promulgating fake news and hyper-partisan views; moreover, these effects can come about unintentionally on social media. I conclude that we may need to change, not just the way we process information online, but also the informational environment in which we operate.
What role, if any, should centered possible worlds play in characterizing the attitudes? Lewis (Philos Rev 88(4):513-543, 1979) argued (in effect) that, in order to account for the phenomena of ...self-location (Perry in Philos Rev 86(4):474-497, 1977, Noûs 13(1):3-21, 1979), the contents of the attitudes should be taken to be centered propositions (i.e. sets of centered worlds). Stalnaker (Our knowledge of the internal world, Oxford University Press, Oxford, 2008, in: Brown, Cappelen (eds) Assertion: New philosophical essays, Oxford University Press, Oxford, 2011, Context, Oxford University Press, Oxford, 2014), however, has argued that while centered worlds are needed to characterize e.g. belief states, the contents of such states should be understood as ordinary, uncentered propositions (cf. Hintikka in Knowledge and belief, Cornell University Press, Ithaca, NY, 1962). But Stalnaker does not, as is common, provide a semantics of attitude ascriptions based on the models he develops of the attitudinal states themselves. This paper begins to explore the prospects for doing so. It argues that a simple but wellmotivated approach does not yield the principles of knowledge and belief Stalnaker endorses; and that a modification which does brings with it worries of its own surrounding communication and learnability. A technical appendix contains novel and pertinent results in doxastic/epistemic logic.
The three main approaches to the metaphysics of intentionality can arguably be subjected to analysis in terms of grammatical point of view: the approach of the (internalist) phenomenal intentionality ...programme (plus productivism about linguistic content) may be regarded as first-personal; interpretationism, perhaps, as second-personal; and (reductive externalist) causal information theories (including teleosemantics) as third-personal. After making this plausible, the current paper focusses on the role of the interpreter (if any) in interpretationism. It argues that, despite some considerations from the publicity of meaning potentially suggesting the contrary, radical interpretation is not subject to epistemic constraint; nor should the interpretationist appeal to the idiosyncratic interests of actual interpreters, thereby rendering the approach irremediably relativistic. Instead, an appeal to the pure form of interestedness is all that is involved; this supports a methodologically non-reductive outlook on intentionality.
●Ontogeny assignment from the database registry lacks sensitivity and specificity.●Ontogeny stratifies the outcome of AML with myelodysplasia-related gene mutations.
Accurate classification and risk ...stratification is critical for clinical decision making in AML patients. In the newly proposed World Health Organization (WHO) and International Consensus classifications (ICC) of hematolymphoid neoplasms, the presence of myelodysplasia-related (MR) gene mutations is included as one of the diagnostic criteria of AML, myelodysplasia-related (AML-MR), largely based on the assumption that these mutations are specific for AML with an antecedent myelodysplastic syndrome. ICC also prioritizes MR gene mutations over ontogeny (as defined by clinical history). Furthermore, European LeukemiaNet (ELN) 2022 stratifies these MR gene mutations to the adverse-risk group. By thoroughly annotating a cohort of 344 newly diagnosed AML patients treated at Memorial Sloan Kettering Cancer Center (MSKCC), we show that ontogeny assignment based on database registry lacks accuracy. MR gene mutations are frequently seen in de novo AML. Among MR gene mutations, only EZH2 and SF3B1 were associated with an inferior outcome in a univariate analysis. In a multivariate analysis, AML ontogeny had independent prognostic values even after adjusting for age, treatment, allo-transplant and genomic classes or ELN risks. Ontogeny also stratified the outcome of AML with MR gene mutations. Finally, de novo AML with MR gene mutations did not show an adverse outcome. In summary, our study emphasizes the importance of accurate ontogeny designation in clinical studies, demonstrates the independent prognostic value of AML ontogeny and questions the current classification and risk stratification of AML with MR gene mutations.
There is a deluge of AI-assisted decision-making systems, where our data serve as proxy to our actions, suggested by AI. The closer we investigate our data (raw input, or their learned ...representations, or the suggested actions), we begin to discover “bugs”. Outside of their test, controlled environments, AI systems may encounter situations investigated primarily by those in other disciplines, but experts in those fields are typically excluded from the design process and are only invited to attest to the ethical features of the resulting system or to comment on demonstrations of intelligence and aspects of craftmanship after the fact. This communicative impasse must be overcome. Our idea is that philosophical and engineering considerations interact and can be fruitfully combined in the AI design process from the very beginning. We embody this idea in the role of a philosopher engineer. We discuss the role of philosopher engineers in the three main design stages of an AI system:
deployment management
(what is the system’s intended use, in what environment?);
objective setting
(what should the system be trained to do, and how?); and
training
(what model should be used, and why?). We then exemplify the need for philosopher engineers with an illustrative example, investigating how the future decisions of an AI-based hiring system can be fairer than those contained in the biased input data on which it is trained; and we briefly sketch the kind of interdisciplinary education that we envision will help to bring about better AI.
Carey has argued that there is a system of core numerical cognition - the analog magnitude (AM) system - in which (approximate) cardinal numbers are explicitly represented in iconic format. While the ...existence of this system is beyond doubt, this paper aims to show that its representations cannot have the combination of features attributed to them by Carey. According to the argument from abstractness, the representation of the (approximate) cardinal number of a collection of individuals as such requires the representation of individuals as such, and this in turn requires non-iconic format, from which it is concluded that the explicit representation of the (approximate) cardinal number of some individuals requires non-iconic representational format. In support of the first premise, an account is given of what approximate cardinal numbers might be (namely, quantifiers), and in support of the second, a direct argument is articulated and defended. Finally, in response to an objection, a second argument (from parts) for the central thesis is provided. While the discussion is couched in the terms of Carey's work, the considerations it adduces are perfectly general, and the conclusion should therefore be taken into consideration by all those aiming to characterize the AM system.
Hematopoietic cell transplantation (HCT) and chimeric antigen receptor (CAR)-T cell patients are immunocompromised, remain at high risk following SARS-CoV-2 infection, and are less likely than ...immunocompetent individuals to respond to vaccination. As part of the safety lead-in portion of a phase 2 clinical trial in patients post HCT/CAR-T for hematological malignancies (HM), we tested the immunogenicity of the synthetic modified vaccinia Ankara-based COVID-19 vaccine COH04S1 co-expressing spike (S) and nucleocapsid (N) antigens. Thirteen patients were vaccinated 3–12 months post HCT/CAR-T with two to four doses of COH04S1. SARS-CoV-2 antigen-specific humoral and cellular immune responses, including neutralizing antibodies to ancestral virus and variants of concern (VOC), were measured up to six months post vaccination and compared to immune responses in historical cohorts of naïve healthy volunteers (HV) vaccinated with COH04S1 and naïve healthcare workers (HCW) vaccinated with the FDA-approved mRNA vaccine Comirnaty® (Pfizer, New York, NY, USA). After one or two COH04S1 vaccine doses, HCT/CAR-T recipients showed a significant increase in S- and N-specific binding antibody titers and neutralizing antibodies with potent activity against SARS-CoV-2 ancestral virus and VOC, including the highly immune evasive Omicron XBB.1.5 variant. Furthermore, vaccination with COH04S1 resulted in a significant increase in S- and N-specific T cells, predominantly CD4+ T lymphocytes. Elevated S- and N-specific immune responses continued to persist at six months post vaccination. Furthermore, both humoral and cellular immune responses in COH04S1-vaccinated HCT/CAR-T patients were superior or comparable to those measured in COH04S1-vaccinated HV or Comirnaty®-vaccinated HCW. These results demonstrate robust stimulation of SARS-CoV-2 S- and N-specific immune responses including cross-reactive neutralizing antibodies by COH04S1 in HM patients post HCT/CAR-T, supporting further testing of COH04S1 in immunocompromised populations.
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