Histone proteins constitute the core component of the nucleosome, the basic unit of chromatin. Chemical modifications of histone proteins affect their interaction with genomic DNA, the accessibility ...of recognized proteins, and the recruitment of enzymatic complexes to activate or diminish specific transcriptional programs to modulate cellular response to extracellular stimuli or insults. Methylation of histone proteins was demonstrated 50 years ago; however, the biological significance of each methylated residue and the integration between these histone markers are still under intensive investigation. Methylation of histone H3 on lysine 27 (H3K27) is frequently found in the heterochromatin and conceives a repressive marker that is linked with gene silencing. The identification of enzymes that add or erase the methyl group of H3K27 provides novel insights as to how this histone marker is dynamically controlled under different circumstances. Here we summarize the methyltransferases and demethylases involved in the methylation of H3K27 and show the new evidence by which the H3K27 methylation can be established via an alternative mechanism. Finally, the progress of drug development targeting H3K27 methylation-modifying enzymes and their potential application in cancer therapy are discussed.
Prospero homeobox 1 (PROX1) has been shown to function as a tumor suppressor in various types of cancer. However, it promotes colon cancer progression. The aim of this study is to clarify the ...underlying mechanism by which PROX1 regulates tumorigenicity of colon cancer.
Association of PROX1 and clinicopathological features was studied by immunohistochemical staining. Pri-miR-9-2 and miR-9 were detected by quantitative real-time PCR. Assays of cell invasion, adhesion, and matrix metalloproteinase activity were used to study PROX1-mediated epithelial-mesenchymal transition (EMT).
PROX1 was overexpressed in 43% (59/136) of colon cancer tissues and its expression was correlated with E-cadherin downregulation (P = 0.00005), advanced tumor staging (P = 0.005), and lymph node metastasis (P = 0.000009). Enforced expression of PROX1 in DLD-1 cells caused downregulation of E-cadherin and integrins and attenuated cell adhesion. These cells showed increase of matrix metalloproteinase activity and invasive ability. Conversely, knockdown of PROX1 in SW620 cells restored E-cadherin protein expression and reduced invasiveness. Unexpectedly, repression of E-cadherin by PROX1 was not mediated by transcriptional inhibition. We found that PROX1 bound to miR-9-2 promoter and triggered its expression to suppress E-cadherin 3'UTR reporter activity and protein expression. Anti-miR-9 restored E-cadherin in SW620 cells, whereas precursor miR-9 inhibited E-cadherin in PROX1-knockdown cells. The miR-9 level was higher in tumor tissues with high PROX1/low E-cadherin than that of tumor tissues with low PROX1/high E-cadherin.
Our results provide mechanistic insights by which PROX1 promotes EMT and colon cancer progression. Targeting of PROX1-mediated oncogenic activity may be helpful for the treatment of colon cancer.
This study was undertaken to investigate migraine glymphatic and meningeal lymphatic vessel (mLV) functions.
Migraine patients and healthy controls (HCs) were prospectively recruited between 2020 and ...2023. Diffusion tensor image analysis along the perivascular space (DTI-ALPS) index for glymphatics and dynamic contrast-enhanced magnetic resonance imaging parameters (time to peak TTP/enhancement integral EI/mean time to enhance MTE) for para-superior sagittal (paraSSS)-mLV or paratransverse sinus (paraTS)-mLV in episodic migraine (EM), chronic migraine (CM), and CM with and without medication-overuse headache (MOH) were analyzed. DTI-ALPS correlations with clinical parameters (migraine severity numeric rating scale/disability Migraine Disability Assessment (MIDAS)/bodily pain Widespread Pain Index/sleep quality Pittsburgh Sleep Quality Index (PSQI)) were examined.
In total, 175 subjects (112 migraine + 63 HCs) were investigated. DTI-ALPS values were lower in CM (median interquartile range = 0.64 0.12) than in EM (0.71 0.13, p = 0.005) and HCs (0.71 0.09, p = 0.004). CM with MOH (0.63 0.07) had lower DTI-ALPS values than CM without MOH (0.73 0.12, p < 0.001). Furthermore, CM had longer TTP (paraSSS-mLV: 55.8 12.9 vs 40.0 7.6, p < 0.001; paraTS-mLV: 51.2 8.1 vs 44.0 3.3, p = 0.002), EI (paraSSS-mLV: 45.5 42.0 vs 16.1 9.2, p < 0.001), and MTE (paraSSS-mLV: 253.7 6.7 vs 248.4 13.8, p < 0.001; paraTS-mLV: 252.0 6.2 vs 249.7 1.2, p < 0.001) than EM patients. The MIDAS (p = 0.002) and PSQI (p = 0.002) were negatively correlated with DTI-ALPS index after Bonferroni corrections (p < q = 0.01).
CM patients, particularly those with MOH, have glymphatic and meningeal lymphatic dysfunctions, which are highly clinically relevant and may implicate pathogenesis for migraine chronification. ANN NEUROL 2024;95:583-595.
Cholesterol‐α‐glucosyltransferase (CGT) encoded by the type 1 capsular polysaccharide biosynthesis protein J (capJ) gene of Helicobacter pylori converts cellular cholesterol into cholesteryl ...glucosides. H. pylori infection induces autophagy that may increase bacterial survival in epithelial cells. However, the role of H. pylori CGT that exploits lipid rafts in interfering with autophagy for bacterial survival in macrophages has not been investigated. Here, we show that wild‐type H. pylori carrying CGT modulates cholesterol to trigger autophagy and restrain autophagosome fusion with lysosomes, permitting a significantly higher bacterial burden in macrophages than that in a capJ‐knockout (∆CapJ) mutant. Knockdown of autophagy‐related protein 12 impairs autophagosome maturation and decreases the survival of internalised H. pylori in macrophages. These results demonstrate that CGT plays a crucial role in the manipulation of the autophagy process to impair macrophage clearance of H. pylori.
The hemodialysis regimen is an inevitable and mandatory treatment for patients with end-stage renal disease (ESRD). During the dialysis journey, patients may experience maladaptation in terms of ...sleep disturbances, depressive symptoms, and reduced health-related quality of life (HRQOL). Psychosocial resources such as social support may have beneficial influences on health outcomes, but studies have rarely analyzed the integrated relationships among risk factors which include pain, sleep disturbances, duration since diagnosis and various health outcomes in Taiwan. This study aimed to bridge this gap by investigating the relationships among related risk factors, social support, sleep disturbances, depressive symptoms, and HRQOL, which is composed of physical quality of life (PQOL) and mental quality of life (MQOL), in ESRD patients.
A correlational design was used, and 178 patients aged 20 years or older were recruited via convenience sample. The relationships among the risk factors, the mediators, depressive symptoms, PQOL, and MQOL were analyzed using structural equation modeling.
The findings showed that more than 70% of the participants reported poor sleep quality, and 32% reported depressive symptoms. When participants had greater pain and more sleep disorders, they were more likely to be depressed. When participants had more appraisal support; they had better PQOL and fewer depressive symptoms. Overall, the structural equation model explained 31.8% of the variance in self-reported depressive symptoms, 29.4% of the variance in PQOL, and 5.7% of the variance in MQOL. Moreover, appraisal support enhanced PQOL and reduced depressive symptoms by exerting its two mediating effects on sleep disturbances.
Our findings indicate that patients with ESRD who have more social support have better PQOL and MQOL and fewer depressive symptoms than those with less social support.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Deep learning–based segmentation algorithms usually required large or multi‐institute data sets to improve the performance and ability of generalization. However, protecting patient ...privacy is a key concern in the multi‐institutional studies when conventional centralized learning (CL) is used.
Purpose
To explores the feasibility of a proposed lesion delineation for stereotactic radiosurgery (SRS) scheme for federated learning (FL), which can solve decentralization and privacy protection concerns.
Study Type
Retrospective.
Subjects
506 and 118 vestibular schwannoma patients aged 15–88 and 22–85 from two institutes, respectively; 1069 and 256 meningioma patients aged 12–91 and 23–85, respectively; 574 and 705 brain metastasis patients aged 26–92 and 28–89, respectively.
Field Strength/Sequence
1.5T, spin‐echo, and gradient‐echo Correction added after first online publication on 21 August 2023. Field Strength has been changed to “1.5T” from “5T” in this sentence..
Assessment
The proposed lesion delineation method was integrated into an FL framework, and CL models were established as the baseline. The effect of image standardization strategies was also explored. The dice coefficient was used to evaluate the segmentation between the predicted delineation and the ground truth, which was manual delineated by neurosurgeons and a neuroradiologist.
Statistical Tests
The paired t‐test was applied to compare the mean for the evaluated dice scores (p < 0.05).
Results
FL performed the comparable mean dice coefficient to CL for the testing set of Taipei Veterans General Hospital regardless of standardization and parameter; for the Taichung Veterans General Hospital data, CL significantly (p < 0.05) outperformed FL while using bi‐parameter, but comparable results while using single‐parameter. For the non‐SRS data, FL achieved the comparable applicability to CL with mean dice 0.78 versus 0.78 (without standardization), and outperformed to the baseline models of two institutes.
Data Conclusion
The proposed lesion delineation successfully implemented into an FL framework. The FL models were applicable on SRS data of each participating institute, and the FL exhibited comparable mean dice coefficient to CL on non‐SRS dataset. Standardization strategies would be recommended when FL is used.
Level of Evidence
4
Technical Efficacy
Stage 1
Triple negative breast cancer (TNBC) displays higher risk of recurrence and distant metastasis. Due to absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor ...receptor 2 (HER2), TNBC lacks clinically established targeted therapies. Therefore, understanding of the mechanism underlying the aggressive behaviors of TNBC is required for the design of individualized strategies and the elongation of overall survival duration. Here, we supported a positive correlation between β1 integrin and malignant behaviors such as cell migration, invasion, and drug resistance. We found that silencing of β1 integrin inhibited cell migration, invasion, and increased the sensitivity to anti-cancer drug. In contrast, activation of β1 integrin increased cell migration, invasion, and decreased the sensitivity to anti-cancer drug. Furthermore, we found that silencing of β1 integrin abolished Focal adhesion kinese (FAK) mediated cell survival. Overexpression of FAK could restore cisplatin-induced apoptosis in β1 integrin-depleted cells. Consistent to in vitro data, β1 integrin expression was also positively correlated with FAK (p = 0.031) in clinical tissue. More importantly, β1 integrin expression was significantly correlated with patient outcome. In summary, our study indicated that β1 integrin could regulate TNBC cells migration, invasion, drug sensitivity, and be a potential prognostic biomarker in TNBC patient survival.
Vascular endothelial growth factor receptor 3 (VEGFR3) has been known for its involvement in tumor-associated lymphangiogenesis and lymphatic metastasis. The VEGFR3 signaling is stimulated by its ...main cognate ligand, vascular endothelial growth factor C (VEGF-C), which in turn promotes tumor progression. Activation of VEGF-C/VEGFR3 signaling in lymphatic endothelial cells (LECs) was shown to enhance the proliferation of LECs and the formation of lymphatic vessels, leading to increased lymphatic metastasis of tumor cells. In the past decade, the expression and pathological roles of VEGFR3 in tumor cells have been described. Moreover, the VEGF-C/VEGFR3 axis has been implicated in regulating immune tolerance and suppression. Therefore, the inhibition of the VEGF-C/VEGFR3 axis has emerged as an important therapeutic strategy for the treatment of cancer. In this review, we discuss the current findings related to VEGF-C/VEGFR3 signaling in cancer progression and recent advances in the development of therapeutic drugs targeting VEGF-C/VEGFR3.
Human ribonuclease 1 (hRNase 1) is critical to extracellular RNA clearance and innate immunity to achieve homeostasis and host defense; however, whether it plays a role in cancer remains elusive. ...Here, we demonstrate that hRNase 1, independently of its ribonucleolytic activity, enriches the stem-like cell population and enhances the tumor-initiating ability of breast cancer cells. Specifically, secretory hRNase 1 binds to and activates the tyrosine kinase receptor ephrin A4 (EphA4) signaling to promote breast tumor initiation in an autocrine/paracrine manner, which is distinct from the classical EphA4-ephrin juxtacrine signaling through contact-dependent cell-cell communication. In addition, analysis of human breast tumor tissue microarrays reveals a positive correlation between hRNase 1, EphA4 activation, and stem cell marker CD133. Notably, high hRNase 1 level in plasma samples is positively associated with EphA4 activation in tumor tissues from breast cancer patients, highlighting the pathological relevance of the hRNase 1-EphA4 axis in breast cancer. The discovery of hRNase 1 as a secretory ligand of EphA4 that enhances breast cancer stemness suggests a potential treatment strategy by inactivating the hRNase 1-EphA4 axis.
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