Naresuan University Journal
Not a member yet
39887 research outputs found
Sort by
Stromal cell-mediated mitochondrial redox adaptation regulates drug resistance in childhood acute lymphoblastic leukemia.
No full textDespite the high cure rates in childhood acute lymphoblastic leukemia (ALL), relapsed ALL remains a significant clinical problem. Genetic heterogeneity does not adequately explain variations in response to therapy. The chemoprotective tumor microenvironment may additionally contribute to disease recurrence. This study identifies metabolic reprogramming of leukemic cells by bone marrow stromal cells (BMSC) as a putative mechanism of drug resistance. In a BMSC-extracellular matrix culture model, BMSC produced chemoprotective soluble factors and facilitated the emergence of a reversible multidrug resistant phenotype in ALL cells. BMSC environment induced a mitochondrial calcium influx leading to increased reactive oxygen species (ROS) levels in ALL cells. In response to this oxidative stress, drug resistant cells underwent a redox adaptation process, characterized by a decrease in ROS levels and mitochondrial membrane potential with an upregulation of antioxidant production and MCL-1 expression. Similar expanded subpopulations of low ROS expressing and drug resistant cells were identified in pre-treatment bone marrow samples from ALL patients with slower response to therapy. This suggests that the bone marrow microenvironment induces a redox adaptation in ALL subclones that protects against cytotoxic stress and potentially gives rise to minimal residual disease. Targeting metabolic remodeling by inhibiting antioxidant production and antiapoptosis was able to overcome drug resistance. Thus metabolic plasticity in leukemic cell response to environmental factors contributes to chemoresistance and disease recurrence. Adjunctive strategies targeting such processes have the potential to overcome therapeutic failure in ALL
Lynch syndrome caused by MLH1 mutations is associated with an increased risk of breast cancer: a cohort study.
No full textINTRODUCTION: Lynch syndrome is known to cause an increased risk of malignancies, including bowel and endometrial cancers. However, the risk of breast cancer associated with mutations in the mismatch repair (MMR) genes that cause Lynch syndrome is still unclear. MATERIALS AND METHODS: This study assesses the cumulative risk of breast cancer in 106 MLH1 and 118 MSH2 families. Families were referred on the basis of clinical criteria. Pedigree information was obtained, and tumour immunohistochemistry and microsatellite testing performed. Appropriate patients underwent sequencing and multiple ligation dependent probe amplification of all relevant exons of the MMR genes. Kaplan-Meier analysis of cumulative lifetime risk of breast cancer was made combining proven mutation carriers and their first-degree female relatives. RESULTS: After allocation of mutation status, the cumulative risk of breast cancer to 70 years in MLH1 carriers was 18.6% (95% CI 11.3 to 25.9)). This is significantly higher than the cumulative risk for MSH2 which was 11.2% (95% CI 1.4 to 21.0) to age 70 years (p=0.014). The UK population risk is 7.5%-8% at the age of 70 years. Prospective analysis identified six breast cancers in 1120 years of follow-up with an OR of 3.41 (95% CI 1.53 to 7.59). DISCUSSIONS: Female MLH1 carriers would appear to be at moderate risk of breast cancer and should be considered for breast screening at ages earlier than national screening programmes
GFI1 proteins orchestrate the emergence of haematopoietic stem cells through recruitment of LSD1.
No full textIn vertebrates, the first haematopoietic stem cells (HSCs) with multi-lineage and long-term repopulating potential arise in the AGM (aorta-gonad-mesonephros) region. These HSCs are generated from a rare and transient subset of endothelial cells, called haemogenic endothelium (HE), through an endothelial-to-haematopoietic transition (EHT). Here, we establish the absolute requirement of the transcriptional repressors GFI1 and GFI1B (growth factor independence 1 and 1B) in this unique trans-differentiation process. We first demonstrate that Gfi1 expression specifically defines the rare population of HE that generates emerging HSCs. We further establish that in the absence of GFI1 proteins, HSCs and haematopoietic progenitor cells are not produced in the AGM, revealing the critical requirement for GFI1 proteins in intra-embryonic EHT. Finally, we demonstrate that GFI1 proteins recruit the chromatin-modifying protein LSD1, a member of the CoREST repressive complex, to epigenetically silence the endothelial program in HE and allow the emergence of blood cells
Towards a Fictionalist Philosophy of Mathematics
No full textIn this thesis, I aim to motivate a particular philosophy of mathematics characterised by the following three claims. First, mathematical sentences are generally speaking false because mathematical objects do not exist. Second, people typically use mathematical sentences to communicate content that does not imply the existence of mathematical objects. Finally, in using mathematical language in this way, speakers are not doing anything out of the ordinary: they are performing straightforward assertions. In Part I, I argue that the role played by mathematics in our scientific explanations is a purely expressive one, merely allowing us to say more about the physical world than we would otherwise be able to. Mathematical objects do not need to exist for mathematics to play this role. This proposal puts a normative constraint on our use of mathematical language: we ought to use mathematically presented theories to express belief only in the consequences they have for non-mathematical things. In Part II, I will argue that what the normative proposal recommends is in fact what people generally do in both pure and applied mathematical contexts. I motivate this claim by showing that it is predicted by our best general means of analysing natural language. I provide a semantic theory of applied arithmetical sentences that reveals they do not purport to refer to numbers, as well as a pragmatic theory for pure mathematical language use which reveals that pure mathematical utterances do not typically communicate content that implies the existence of mathematical objects. In conclusion, I show that the emerging hermeneutic fictionalist position is preferable to any alternative interpretation of mathematical discourse as aimed at describing a domain of independently existing abstract mathematical objects
Resistance to BRAF inhibitors induces glutamine dependency in melanoma cells
No full textBRAF inhibitors can extend progression-free and overall survival in melanoma patients whose tumors harbor mutations in BRAF. However, the majority of patients eventually develop resistance to these drugs. Here we show that BRAF mutant melanoma cells that have developed acquired resistance to BRAF inhibitors display increased oxidative metabolism and increased dependency on mitochondria for survival. Intriguingly, the increased oxidative metabolism is associated with a switch from glucose to glutamine metabolism and an increased dependence on glutamine over glucose for proliferation. We show that the resistant cells are more sensitive to mitochondrial poisons and to inhibitors of glutaminolysis, suggesting that targeting specific metabolic pathways may offer exciting therapeutic opportunities to treat resistant tumors, or to delay emergence of resistance in the first-line setting
Application of PIM-1 for solvent swing adsorption and solvent recovery by nanofiltration
No full textA concept is demonstrated for the separation of two organic solutes from a common solvent by solvent swing adsorption (SSA), coupled with organic solvent nanofiltration (OSN) for solvent recycling. The polymer of intrinsic microporosity PIM-1 was utilized both for the adsorbent and for the nanofiltration membrane. For adsorption from solution in ethanol or water–ethanol (30/70) mixture, PIM-1 showed high affinity for a neutral solute (Oil Red O) with negligible uptake of an anionic solute (Remazol Brilliant Blue R). The obtained equilibrium values of distribution coefficient K revealed that Oil Red O can be concentrated in PIM-1 by 4300 times from its ethanol solution, and this value can be significantly improved up to 53,000 times in the case of water/ethanol (30/70) binary mixture. Such difference in the affinity of neutral solute to PIM-1 was explained by means of competitive sorption between solute and solvent molecules, and a clear relationship between distribution coefficient K and solvent solubility parameter was observed. The adsorbent could be regenerated by washing with a less polar solvent (toluene), which gave almost quantitative desorption of the neutral solute (K = 6). PIM-1 membranes as cast and after cross-linking were also successfully utilized for solvent recovery. It was demonstrated that PIM-1 membranes can possess either solvent-selective transport or solute-selective transport in OSN, depending on the nature of the solvent
Integration of computational modeling with membrane transport studies reveals new insights into amino acid exchange transport mechanisms.
No full textUptake of system L amino acid substrates into isolated placental plasma membrane vesicles in the absence of opposing side amino acid (zero-trans uptake) is incompatible with the concept of obligatory exchange, where influx of amino acid is coupled to efflux. We therefore hypothesized that system L amino acid exchange transporters are not fully obligatory and/or that amino acids are initially present inside the vesicles. To address this, we combined computational modeling with vesicle transport assays and transporter localization studies to investigate the mechanisms mediating [(14)C]L-serine (a system L substrate) transport into human placental microvillous plasma membrane (MVM) vesicles. The carrier model provided a quantitative framework to test the 2 hypotheses that l-serine transport occurs by either obligate exchange or nonobligate exchange coupled with facilitated transport (mixed transport model). The computational model could only account for experimental [(14)C]L-serine uptake data when the transporter was not exclusively in exchange mode, best described by the mixed transport model. MVM vesicle isolates contained endogenous amino acids allowing for potential contribution to zero-trans uptake. Both L-type amino acid transporter (LAT)1 and LAT2 subtypes of system L were distributed to MVM, with L-serine transport attributed to LAT2. These findings suggest that exchange transporters do not function exclusively as obligate exchangers
Inter-country exploration of factors associated with admission to long-term institutional dementia care: Evidence from the RightTimePlaceCare study
No full textAimTo explore inter-country variation of factors associated with institutionalization of people with dementia.BackgroundThere is an urgent need for evidence on whether factors associated with admission to institutional dementia care are applicable across healthcare systems, as increasing evidence suggests that these factors could be country-specific.DesignA prospective cohort study.MethodPrimary data were collected in eight European countries, at baseline and after 3 months follow-up (November 2010–April 2012). The sample included 2014 dyads of people with dementia and their informal caregivers; 791 patients were recently institutionalized, 1223 patients lived at home and were at risk of institutionalization. Associations between care setting (institution vs. home) and factors shown to influence institutionalization (e.g. cognition, independence in activities of daily life, behaviour) were studied.ResultsConsiderable differences were found between the eight countries in characteristics of people with dementia who had been recently admitted to ILTC. However, caregiver burden appeared the most consistent factor associated with institutionalization in all analyses. Indications for the importance of independence in activities of daily life were found as well, although country differences may be more prominent for this factor.ConclusionEvidence was found for two common factors, crucial in the process of institutionalization across countries: caregiver burden and independency in activities of daily life. However, this study also suggests that admission to institutional dementia care is context-specific, as wide variation exists in factors associated with institutionalization across countries. Tailored best-practice strategies are needed to reflect variations in response to these needs
Call Me Back: exploring the anthropological understanding of an uncertain future through creative practice
No full text16 July 2014, 18 year old James enters a phone booth in Shipley, North England, to start a dialogue with his future self, posing pressing questions about the future of his life and world. One year later, 19 year old James walks into the same phone booth responding to his past self, revealing changed outlooks and perspectives. During the year, a shopping centre is being built in the background of the phone booth, putting the change of time and immediate environment of James' home, on display. The ethnographic film Call Me Back is in postproduction and part of an on-going research project on ‘ethno science fiction’ as a method in Visual Anthropology. The research presentation will draw on the film project to explore how projective improvisation in ethnographic film could contribute to the anthropological understanding of how the participants of the fieldwork and filmmaking relate to the future, especially with regards to scientific predictions about environmental and climate change
