Oncogene addiction is a cellular property by which cancer cells become highly dependent on the expression of oncogenes for their survival. Oncogene addiction can be exploited to design molecularly ...targeted drugs that kill only cancer cells by inhibiting the specific oncogenes. Genes and cell lines exhibiting oncogene addiction, as well as the mechanisms by which cell death is induced when addicted oncogenes are suppressed, have been extensively studied. However, it is still not fully understood how oncogene addiction is acquired in cancer cells. Here, we take a synthetic biology approach to investigate whether oncogenic mutation or oncogene expression suffices to confer the property of oncogene addiction to cancer cells. We employed human mammary epithelium-derived MCF-10A cells expressing the oncogenic KRAS or BRAF. MCF-10A cells harboring an oncogenic mutation in a single-allele of KRAS or BRAF showed weak transformation activity, but no characteristics of oncogene addiction. MCF-10A cells overexpressing oncogenic KRAS demonstrated the transformation activity, but MCF-10A cells overexpressing oncogenic BRAF did not. Neither cell line exhibited any oncogene addiction properties. These results indicate that the introduction of oncogenic mutation or the overexpression of oncogenes is not sufficient for cells to acquire oncogene addiction, and that oncogene addiction is not associated with transformation activity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Generation of high pressure is a key to the investigation of the interior of the Earth. The Kawai-type multianvil apparatus (KMA) has been widely used in the fields of Earth science and material ...science. In conventional KMA, tungsten carbide (WC) has been used as the second stage anvil material. However, attainable pressure is limited to ∼70 GPa even if newly developed WC is used. Recently, on the other hand, second stage anvils of sintered diamond that is much harder than WC have enabled us to extend the pressure range of KMA up to 120 GPa, corresponding to the pressure of the D" layer in the Earth's mantle. It is evident that our development of pressure generation facilitates the investigation of the structure and dynamics of the deep mantle of the Earth.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Somatic mutation of RUNX1 is implicated in various hematological malignancies, including myelodysplastic syndrome and acute myeloid leukemia (AML), and previous studies using mouse models disclosed ...its critical roles in hematopoiesis. However, the role of RUNX1 in human hematopoiesis has never been tested in experimental settings. Familial platelet disorder (FPD)/AML is an autosomal dominant disorder caused by germline mutation of RUNX1, marked by thrombocytopenia and propensity to acute leukemia. To investigate the physiological function of RUNX1 in human hematopoiesis and pathophysiology of FPD/AML, we derived induced pluripotent stem cells (iPSCs) from three distinct FPD/AML pedigrees (FPD-iPSCs) and examined their defects in hematopoietic differentiation. By in vitro differentiation assays, FPD-iPSCs were clearly defective in the emergence of hematopoietic progenitors and differentiation of megakaryocytes, and overexpression of wild-type (WT)-RUNX1 reversed most of these phenotypes. We further demonstrated that overexpression of mutant-RUNX1 in WT-iPSCs did not recapitulate the phenotype of FPD-iPSCs, showing that the mutations were of loss-of-function type. Taken together, this study demonstrated that haploinsufficient RUNX1 allele imposed cell-intrinsic defects on hematopoietic differentiation in human experimental settings and revealed differential impacts of RUNX1 dosage on human and murine megakaryopoiesis. FPD-iPSCs will be a useful tool to investigate mutant RUNX1-mediated molecular processes in hematopoiesis and leukemogenesis.
Bulinus
are intermediate snail hosts of
Schistosoma haematobium
. Despite their vectorial role, the transmission dynamics and infectivity of these intermediate snail hosts remain understudied in the ...Ase River. This longitudinal study evaluated the geospatial and seasonal transmission patterns and infectivity of three
S. haematobium
vectors between November 2020 and October 2022 in the Ase River catchment, Delta State, Nigeria. Eleven (11) geospatial water contact coordinates were mapped for monthly spatiotemporal collection of
Bulinus
species along the Ase River and its catchment, for two years. Snail sampling was performed for 45 min at each study site using scooping/hand-picking techniques and subsequently counted, identified and recorded. Snails of the
Bulinus
genus were individually placed in a beaker containing distilled water and exposed to light to shed cercariae which were identified to be human schistosome type. The number of infected snails for each month and season was also documented to analyze the spatiotemporal and seasonal transmission dynamics of infectivity. Out of the 2345
Bulinus
snails collected, a total of 41.45% were found to be infected with
S. haematobium
. The monthly infectivity of
Bulinus
snails varied significantly (
P
< 0.05) throughout the study period (
P
= < 0.0001; F = 23.11; df = 11). Further analysis showed a strong significant association (χ
2
= 23.57; df = 11;
p
= 0.015) between the study years. The Principal Component Analysis (PCA) results suggest that
Bulinus
infectivity within the Ase River catchment area was primarily associated with the months of February and January.
B. truncatus
consistently had the highest transmission potential, followed by
B. globosus
and
B. senegalensis
. ANOVA confirms that the monthly/study site infectivity and transmission potential in
B. truncates
,
B. globosus
and
S. senegalensis
were statistically, significant (
P
< 0.05). These results demonstrated a clear distinction in the patterns and relationships between the different months in terms of snail infectivity and seasonal transmission potential. This understanding will help in the continuous monitoring and targeted interventions to control schistosomiasis transmission in Ase River.
The cubic perovskite BaRuO₃ has been synthesized under 18 GPa at 1,000°C. Rietveld refinement indicates that the new compound has a stretched Ru-O bond. The cubic perovskite BaRuO₃ remains metallic ...to 4 K and exhibits a ferromagnetic transition at $T_{c}=60\ {\rm K}$, which is significantly lower than the $T_{c}\approx 160\ {\rm K}$ for SrRuO₃. The availability of cubic perovskite BaRuO₃ not only makes it possible to map out the evolution of magnetism in the whole series of ARuO₃ (A = Ca, Sr, Ba) as a function of the ionic size of the A-site $r_{{\rm A}}$, but also completes the polytypes of BaRuO₃. Extension of the plot of $T_{c}$ versus $r_{{\rm A}}$ in perovskites ARuO₃ (A = Ca, Sr, Ba) shows that $T_{c}$ does not increase as the cubic structure is approached, but has a maximum for orthorhombic SrRuO₃. Suppressing $T_{c}$ by Ca and Ba doping in SrRuO₃ is distinguished by sharply different magnetic susceptibilities χ(T) of the paramagnetic phase. This distinction has been interpreted in the context of a Griffiths' phase on the (Ca Sr)RuO₃ side and bandwidth broadening on the (Sr,Ba)RuO₃ side.
There is increasing evidence supporting the role of members of the polycomb group (PcG) gene family in tumor development and progression. However, their precise role in tumorigenesis and mechanisms ...of their regulation remain to be elucidated. Using nasopharyngeal carcinoma (NPC) as a disease model, a comprehensive analysis was undertaken on the clinical significance of EZH2 expression, identification of the cellular processes regulated by EZH2, and the mechanisms of its deregulated expression. Herein, we report EZH2 as being associated with a higher risk of relapse in NPC patients (P = 0.002). Genome-wide microarray and bioinformatics identified several vital cellular processes (such as differentiation, development, and apoptosis) to be regulated by EZH2, corroborated by in vitro lethality, and delayed tumor formation in vivo upon EZH2 depletion. The combination of global microRNA (miR) profiling in primary NPC specimens, and in silico analyses provided several candidate miRs that could regulate EZH2. Using a luciferase-based assay, miR-26a, miR-101, and miR-98 were validated as bona fide regulators of EZH2 expression. In particular, miR-98 was underexpressed in relapsed patient samples, strongly suggesting an important role for the miR-98 and EZH2 axis in NPC biology.
The neural circuitry comprising the central pattern generator (CPG) that drives feeding behavior in the great pond snail (Lymnaea stagnalis (L., 1758)) has been worked out. Because the feeding ...behavior undergoes associative learning and long-term memory (LTM) formation, it provides an excellent opportunity to study the causal neuronal mechanisms of these two processes. In this review, we explore some of the possible causal neuronal mechanisms of associative learning of conditioned taste aversion (CTA) and its subsequent consolidation processes into LTM in L. stagnalis. In the CTA training procedure, a sucrose solution, which evokes a feeding response, is used as the conditioned stimulus (CS) and a potassium chloride solution, which causes a withdrawal response, is used as the unconditioned stimulus (US). The pairing of the CS-US alters both the feeding response of the snail and the function of a pair of higher order interneurons in the cerebral ganglia. Following the acquisition of CTA, the polysynaptic inhibitory synaptic input from the higher order interneurons onto the feeding CPG neurons is enhanced, resulting in suppression of the feeding response. These changes in synaptic efficacy are thought to constitute a "memory trace" for CTA in L. stagnalis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Extramammary Paget's disease (EMPD) is a relatively rare malignancy, and there are few reports related to radiation therapy. In the present study, we investigated the outcome of radiation therapy for ...EMPD.
Forty-one patients with EMPD in the genitalia underwent radiation therapy with curative intent. Fifteen patients had regional lymph node metastases before radiation therapy, but none had distant metastasis. Total doses of 45–80.2 Gy (median, 60 Gy) were delivered to tumor sites in 23–43 fractions (median, 33 fractions).
At a median follow-up period of 41 months, 16 patients had developed recurrences, including 5 with local progression within the radiation field and 12 with lymph node or/and distant metastases outside the radiation field. The local progression-free and disease-free rates were 88% and 55% at 3 years, and 82% and 46% at 5 years, respectively. Nine patients died at 6–73 months after irradiation; the causes of death were tumor progression in five patients, infectious pneumonia in two, renal failure in one and old age in one. The overall and cause-specific survival rates were 93% and 96% at 3 years, and 68% and 84% at 5 years, respectively. Tumor invasion into the dermis and regional lymph node metastasis were significant prognostic factors for both distant metastasis and survival. No therapy-related toxicities of grade ≥3 were observed.
Radiation therapy is safe and effective for patients with EMPD. It appeared to contribute to prolonged survival owing to good tumor control, and to be a promising curative treatment option.
Cyprideis torosa is a species of ostracode that inhabits a wide range of aquatic habitats in which its low Alk/Ca requirement is met. Its fossil remains are widely used in palaeoecological studies of ...coastal environments and inland salt lakes. We collected C. torosa from 20 water bodies near Valencia, Spain. Temperature, chlorophyll a concentration, electrical conductivity, and the concentration of major ions and oxygen isotopes were measured at each site. Between 2 and 20 live individuals of C. torosa were collected per site, their instar stage and sex determined and their shell chemistry (Mg/Ca, Sr/Ca and carbon and oxygen isotope composition) analyzed. Three of these sites were sampled monthly for one year, and ostracode population structure and shell chemistry (20–40 shells) were analyzed. The water chemistry varied widely between sites. TDS (total dissolved solids) ranged from 0.5 to 71.8g/L but chloride was always the dominant anion.
There is a significant positive relationship between ostracode and water δ18O except at high TDS (>20g/L) when shell δ18O values are lower than expected. No effect of either temperature or water Mg/Ca is observed on the Mg/Ca in the ostracode calcite in waters with Mg/Ca<6 (molar ratio). Ostracode shell Sr/Ca is strongly and significantly related to water Sr/Ca. δ13C values in C. torosa shells are ∼2‰ lower than observed δ13CDIC. These results provide new and more accurate quantification tools to reconstruct past hydrochemistry from C. torosa shells.
Insulin is well known as a hormone regulating glucose homeostasis across phyla. Although there are insulin-independent mechanisms for glucose uptake in the mammalian brain, which had contributed to a ...perception of the brain as an insulin-insensitive organ for decades, the finding of insulin and its receptors in the brain revolutionized the concept of insulin signaling in the brain. However, insulin’s role in brain functions, such as cognition, attention, and memory, remains unknown. Studies using invertebrates with their open blood-vascular system have the promise of promoting a better understanding of the role played by insulin in mediating/modulating cognitive functions. In this review, the relationship between insulin and its impact on long-term memory (LTM) is discussed particularly in snails. The pond snail
Lymnaea stagnalis
has the ability to undergo conditioned taste aversion (CTA), that is, it associatively learns and forms LTM not to respond with a feeding response to a food that normally elicits a robust feeding response. We show that molluscan insulin-related peptides are up-regulated in snails exhibiting CTA–LTM and play a key role in the causal neural basis of CTA–LTM. We also survey the relevant literature of the roles played by insulin in learning and memory in other phyla.
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