EPISTEMIC MODALITY, EVIDENTIALITY AND (INTER) SUBJECTIVITY: A CHANGING PARADIGM

The paper is a reflection on the debate concerning the relation between (epistemic) modality and evidentiality. It cuts across different views and approaches to epistemic modality and evidentiality, bringing in, as a differentiating agent, the criterion of (inter)subjectivity. Starting from Lyons’ (1977) and Palmer’s (1986, 2001) concept of subjectivity as “the locutionary agent’s expression of himself and his own attitudes and beliefs” that is inherent in epistemic modality, the paper looks into Traugott’s use of the term (Traugott 1989, 2001) that understands and sees subjectivity as the way in which a speaker’s psychological or emotional perspective is incorporated into the description of a situation or event, and moves on to Nuyts (2001a, 2001b) for whom (inter)subjectivity indicates that the speaker has access to the situation-relevant evidence. The difference in approaches to the notion of subjectivity is inextricably related to the changed views on the status of evidentiality within (or, rather without) epistemic modality.

CD1d expression in glioblastoma is a promising target for NKT cell-based cancer immunotherapy

Glioblastoma is the most common and aggressive type of brain tumor with high recurrence and fatality rates. Although various therapeutic strategies have been explored, there is currently no effective treatment for glioblastoma. Recently, the number of immunotherapeutic strategies has been tested for malignant brain tumors. Invariant natural killer T (iNKT) cells play an important role in anti-tumor immunity. To address if iNKT cells can target glioblastoma to exert anti-tumor activity, we assessed the expression of CD1d, an antigen-presenting molecule for iNKT cells, on glioblastoma cells. Glioblastoma cells from 10 of 15 patients expressed CD1d, and CD1d-positive glioblastoma cells pulsed with glycolipid ligand induced iNKT cell-mediated cytotoxicity in vitro. Although CD1d expression was low on glioblastoma stem-like cells, retinoic acid, which is the most common differentiating agent, upregulated CD1d expression in these cells and induced iNKT cell-mediated cytotoxicity. Moreover, intracranial administration of human iNKT cells induced tumor regression of CD1d-positive glioblastoma in orthotopic xenografts in NOD/Shi-scid IL-2RγKO (NOG) mice. Thus, CD1d expression represents a novel target for NKT cell-based immunotherapy for glioblastoma patients.

The Analysis of The Written Test at The End Semester in History Lesson Class X SMA 2 Banda Maluku Tengah Regency

The purpose of this study is to determine: (1) the quality of repetition of the semester subjects History class X SMA Negeri 2 Banda viewed from the aspects of materials, construction and language, (2) the distribution of the level of cognitive sphere of Bloom taxonomy measured in repetition of the end of the semester of the eye lesson of class X history of SMA Negeri 2 Banda, (3) quality of repetition of semester subjects of class X history of SMA Negeri 2 Banda viewed from Validity, Reliability, Distinguishing Power, Level of Difficultness, Key Effectiveness and Effectiveness. This research is descriptive quantitative. Data collection techniques are primary data and secondary data. The results showed that these problems have a relatively high (un-reliable) reliability aspect, which is coefficient - 0.1762. From the logical (logical validity) aspect there is one problem that has not been validated yet. From the problem level aspect, 66.67% of the problems are included in the easy criteria, 30% of the questions including medium criteria and 3.33% of the questions including difficult criteria. From the aspect of the differentiating agent, the grains show 7 or 23.33% have bad distinguishing power, 8 grains or 26,67% have weak distinguishing power, 7 grain or about 23,33% have medium distinguishing power, 6 grain or about 20% classified as having both distinguishing power and 2 grains or 6.67% classified as having excellent distinguishing power.

Autophagy: New Insights into Mechanisms of Action and Resistance of Treatment in Acute Promyelocytic leukemia

Autophagy is one of the main cellular catabolic pathways controlling a variety of physiological processes, including those involved in self-renewal, differentiation and death. While acute promyelocytic leukemia (APL) cells manifest low levels of expression of autophagy genes associated with reduced autophagy activity, the introduction of all-trans retinoid acid (ATRA)—a differentiating agent currently used in clinical settings—restores autophagy in these cells. ATRA-induced autophagy is involved in granulocytes differentiation through a mechanism that involves among others the degradation of the PML-RARα oncoprotein. Arsenic trioxide (ATO) is another anti-cancer agent that promotes autophagy-dependent clearance of promyelocytic leukemia retinoic acid receptor alpha gene (PML-RARα) in APL cells. Hence, enhancing autophagy may have therapeutic benefits in maturation-resistant APL cells. However, the role of autophagy in response to APL therapy is not so simple, because some autophagy proteins have been shown to play a pro-survival role upon ATRA and ATO treatment, and both agents can activate ETosis, a type of cell death mediated by the release of neutrophil extracellular traps (ETs). This review highlights recent findings on the impact of autophagy on the mechanisms of action of ATRA and ATO in APL cells. We also discuss the potential role of autophagy in the development of resistance to treatment, and of differentiation syndrome in APL.

Transient Downregulation of Nanog and Oct4 Induced by DETA/NO Exposure in Mouse Embryonic Stem Cells Leads to Mesodermal/Endodermal Lineage Differentiation

The function of pluripotency genes in differentiation is a matter of investigation. We report here that Nanog and Oct4 are reexpressed in two mouse embryonic stem cell (mESC) lines following exposure to the differentiating agent DETA/NO. Both cell lines express a battery of both endoderm and mesoderm markers following induction of differentiation with DETA/NO-based protocols. Confocal analysis of cells undergoing directed differentiation shows that the majority of cells expressing Nanog express also endoderm genes such as Gata4 and FoxA2 (75.4% and 96.2%, resp.). Simultaneously, mRNA of mesodermal markers Flk1 and Mef2c are also regulated by the treatment. Acetylated histone H3 occupancy at the promoter of Nanog is involved in the process of reexpression. Furthermore, Nanog binding to the promoter of Brachyury leads to repression of this gene, thus disrupting mesendoderm transition.