Potential role of LMP2 as an anti-oncogenic factor in human uterine leiomyosarcoma: Morphological significance of calponin h1

Uterine leiomyosarcoma (LMS) is a highly metastatic smooth muscle neoplasm for which calponin h1 is suspected to have a biological role as a tumor-suppressor. We earlier reported that LMP2-null mice spontaneously develop uterine LMS through malignant transformation of the myometrium, thus implicating this protein as an anti-tumorigenic candidate as well. In the present study, we show that LMP2 may negatively regulate LMS independently of its role in the proteasome. Moreover, several lines of evidence indicate that although calponin h1 does not directly influence tumorigenesis, it clearly affects LMP2-induced cellular morphological changes. Modulation of LMP2 may lead to new therapeutic approaches in human uterine LMS.ArticleFEBS LETTERS. 586(13):1824-1831 (2012)journal articl

Potential role of LMP2 as tumor-suppressor defines new targets for uterine leiomyosarcoma therapy

Although the majority of smooth muscle neoplasms found in the uterus are benign, uterine leiomyosarcoma (LMS) is extremely malignant, with high rates of recurrence and metastasis. We earlier reported that mice with a homozygous deficiency for LMP2, an interferon (IFN)-gamma-inducible factor, spontaneously develop uterine LMS. The IFN-gamma pathway is important for control of tumor growth and invasion and has been implicated in several cancers. In this study, experiments with human and mouse uterine tissues revealed a defective LMP2 expression in human uterine LMS that was traced to the IFN-gamma pathway and the specific effect of JAK-1 somatic mutations on the LMP2 transcriptional activation. Furthermore, analysis of a human uterine LMS cell line clarified the biological significance of LMP2 in malignant myometrium transformation and cell cycle, thus implicating LMP2 as an anti-tumorigenic candidate. This role of LMP2 as a tumor suppressor may lead to new therapeutic targets in human uterine LMS.ArticleSCIENTIFIC REPORTS. 1:180 (2011)journal articl

FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters

乳がんの再発を起こす原因細胞を解明. 京都大学プレスリリース. 2023-11-16.The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain–containing ion transport regulator 3 (FXYD3), a component of the Na⁺/K⁺ pump. Accordingly, FXYD3⁺ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3⁺ CSCs were persistent during neoadjuvant chemotherapy, hence linking them to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3⁺ CSCs were sensitive to senolytic Na⁺/K⁺ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3⁺ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targeting the Na⁺/K⁺ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis

Verification Firings of End-Burning Type Hybrid Rockets

The authors have previously proposed the concept of end-burning-type hybrid rockets, which would use cylindrical fuel grains consisting of an array of many small ports running in the axial direction, through which oxidizer gas would flow. Because of difficulty in manufacturing a fuel grain that satisfied requirements such as high volumetric filling rate (above 0.95) and microsized port intervals, the end-burning hybrid rocket had yet to be achieved. This paper reports the results of verification firing tests of a novel end-burning-type hybrid rocket made possible for the first time by recent progress in three-dimensional printing technology. The results clearly distinguish the initial transient and steady periods of the end-burning mode and prove that no oxidizer-to-fuel ratio shift occurs during firing. Because the initial transient is a period for the exit end face to attain a steady-state shape, an initial end-face shape being close to the steady-state shape can shorten this period. A firing test with fuel having tapered ports is shown to attain a steady-state shape in less than 1s, which is much shorter than the nontapered case of about 6 seconds

Functional alterations in neural substrates of geometric reasoning in adults with high-functioning autism.

Individuals with autism spectrum condition (ASC) are known to excel in some perceptual cognitive tasks, but such developed functions have been often regarded as "islets of abilities" that do not significantly contribute to broader intellectual capacities. However, recent behavioral studies have reported that individuals with ASC have advantages for performing Raven's (Standard) Progressive Matrices (RPM/RSPM), a standard neuropsychological test for general fluid intelligence, raising the possibility that ASC's cognitive strength can be utilized for more general purposes like novel problem solving. Here, the brain activity of 25 adults with high-functioning ASC and 26 matched normal controls (NC) was measured using functional magnetic resonance imaging (fMRI) to examine neural substrates of geometric reasoning during the engagement of a modified version of the RSPM test. Among the frontal and parietal brain regions involved in fluid intelligence, ASC showed larger activation in the left lateral occipitotemporal cortex (LOTC) during an analytic condition with moderate difficulty than NC. Activation in the left LOTC and ventrolateral prefrontal cortex (VLPFC) increased with task difficulty in NC, whereas such modulation of activity was absent in ASC. Furthermore, functional connectivity analysis revealed a significant reduction of activation coupling between the left inferior parietal cortex and the right anterior prefrontal cortex during both figural and analytic conditions in ASC. These results indicate altered pattern of functional specialization and integration in the neural system for geometric reasoning in ASC, which may explain its atypical cognitive pattern, including performance on the Raven's Matrices test