LPCAT2 inhibits colorectal cancer progression via the PRMT1/SLC7A11 axis.

Colorectal cancer (CRC) has a high degree of heterogeneity and identifying the genetic information of individual tumor cells could help enhance our understanding of tumor biology and uncover potential therapeutic targets for CRC. In this study, we identified LPCAT2+ tumor cell populations with less malignancy than LPCAT2- tumor cells in human and mouse CRC tissues using scRNA-seq. Combining in vitro and in vivo experiments, we found that LPCAT2 could inhibit the proliferation of CRC cells by inducing ferroptosis. Mechanistically, LPCAT2 arrested PRMT1 in cytoplasm of CRC cells via regulating acetylation of PRMT1 at the K145 site. In turn, PRMT1 enhanced SLC7A11 promoter activity. Thus, LPCAT2 attenuated the positive regulatory effect of PRMT1 on SLC7A11 promoter. Notably, SLC7A11 acts as a ferroptosis regulator. Furthermore, in LPCAT2 knockout mice (LPCAT2-/-) colon cancer model, we found that LPCAT2-/- mice exhibited more severe lesions, while PRMT1 or SLC7A11 inhibitors delayed the progression. Altogether, we elucidated that LPCAT2 suppresses SLC7A11 expression by inhibiting PRMT1 nuclear translocation, thereby inducing ferroptosis in CRC cells. Moreover, inhibitors of the PRMT1/SLC7A11 axis could delay tumor progression in CRC with low LPCAT2 expression, making it a potentially effective treatment for CRC.

High-Flow Nasal Oxygen versus Conventional Nasal Cannula in Preventing Hypoxemia in Elderly Patients Undergoing Gastroscopy with Sedation: A Randomized Controlled Trial.

Background: We aimed to compare the prevention of hypoxemia using High-flow nasal oxygen (HFNO) or regular nasal tubing (CNC) in elderly patients undergoing gastroscopy with sedation. Methods: This study was a prospective, randomized, controlled trial conducted at a single center. We included elective patients aged 65 and above who were undergoing gastroscopy with sedation. In the intervention group (HFNO), we set the oxygen flow rate to 60 liters per minute with an oxygen fraction (FiO2) of 0.6, while in the control group (CNC), it was 6 liters per minute. The primary outcome was the occurrence of hypoxemia (defined as Spo2 < 90%). Results: A total of 125 participants were enrolled (HFNO group: n = 63; CNC group: n = 62). The occurrence of hypoxemia was found to be significantly lower in the HFNO group compared to the CNC group (3.2% vs. 22.6%, p = 0.001). Additionally, a significantly shorter duration of low oxygen levels was observed in the HFNO group [0.0 seconds (0.0-13.0)] compared to the CNC group [0.0 seconds (0.0-124.0), p<0.001]. Moreover, a higher minimum Spo2 value was achieved in the HFNO group [99.0% (98.0-100.0) vs. 96.5% (91.0-99.0), p < 0.001], and a shorter recovery time was recorded [0.5 minutes (0.0-0.5) vs. 0.5 minutes (0.0-1.0), p = 0.016] in comparison to the CNC group. There were no differences in terms of comfort level [0 (0-4) vs. 0 (0-5), p = 0.268] between the two groups. Conclusions: The HFNO system was determined to be a safe and highly effective method for oxygen delivery, leading to a reduction in the occurrence of hypoxemia in elderly patients undergoing gastroscopy with sedation. It is recommended that HFNO be considered as the standard approach for management in this population.

Effect of Retrogression with Different Cooling Ways on the Microstructure and Properties of T'/η' Strengthened Al-Zn-Mg-Cu Alloys.

Retrogression and re-aging (RRA) treatment has been proven to effectively overcome the trade-off between strength and corrosion resistance. Current research focuses on the heating rate, temperature, and holding time of retrogression treatment while ignoring the retrogression cooling ways. In this paper, the effects of RRA treatment with different retrogression cooling ways on the microstructure and properties of newly developed T'/η' strengthened Al-Zn-Mg-Cu alloys were investigated by performing tests on mechanical properties, intergranular corrosion (IGC) resistance, and electrochemical corrosion behavior. The results show that the mechanical properties of samples subject to RRA treatment with water-quenching retrogression (ultimate tensile strength, yield strength, and elongation of 419.2 MPa, 370.2 MPa, and 15.9, respectively) are better than those of air-cooled and furnace-cooled samples. The corrosion resistance of water-quenching (IGC depth of 162.2 µm, corrosion current density of 0.833 × 10-5 A/cm2) and furnace-cooled samples (IGC depth of 123.7 µm, corrosion current density of 0.712 × 10-5 A/cm2) is better than that of air-cooled samples. Microstructure characterization reveals that the effect of the retrogression cooling rate on mechanical properties is related to the size of T'/η' precipitates with grains as well as the proportion of T' and η', while the difference in corrosion resistance depends on the continuity of grain boundary precipitates (GBPs). With mechanical properties, corrosion resistance, and time cost taken into consideration, it is appropriate to select water quenching for retrogression. These findings offer valuable insights for further design to achieve superior performance in various applications.

Study on performance of a relay-assisted UWOC system based on adaptive optics.

To improve the performance of underwater wireless optical communication (UWOC) systems, we propose a relay-assisted UWOC system model based on adaptive optics (AO). The closed expressions of the scintillation index, composite channel probability density function, and outage probability of the Gaussian beam before and after AO compensation are derived using the extended Rytov theory and Meijer G-function. The performance variation of an UWOC system with different parameters is analyzed by simulation. The results show that AO correction can compensate for the distorted wavefront and significantly reduce the intensity fluctuation at the receiving end. The proposed system can efficiently alleviate channel fading, improving the outage probability performance of the UWOC system.

Equalization equal gain combining for a single-input to multiple-output underwater wireless optical communication system under a Gaussian beam.

In this study, we examined the performance of an underwater wireless optical communication (UWOC) system employing a single-input to multiple-output (SIMO) scheme and proposed an equalization equal gain combining (EEGC) algorithm for it under Gaussian beam conditions. Furthermore, based on a Yue spectrum with the instability of oceanic water stratification and a finite outer scale, we derived the closed analytical formulas for the scintillation index and spatial coherence radius in weak oceanic turbulence for a Gaussian beam, from which we could obtain the threshold of the detector spacing and the strength of oceanic turbulence. We then derived the closed-form formula for the upper bound average bit error rate of the EEGC SIMO system with ON-OFF keying modulation by using the hyperbolic tangent distribution function. Our simulations demonstrate two issues if oceanic water stratification is treated as a steady state: the performance of the diversity receiver system will be significantly underestimated in salinity-dominated weak oceanic turbulence channels and will be significantly overestimated in temperature-dominated weak oceanic turbulence channels. Additionally, the SIMO system performance improvement using the proposed EEGC algorithm was more evident with increasing detector spacing, and the EEGC algorithm reduced the impact of the layout of the avalanche photodiode arrays on the UWOC system performance, in contrast to the equal gain combining algorithm.

Peripheral BDNF Regulates Somatosensory-Sympathetic Coupling in Brachial Plexus Avulsion-Induced Neuropathic Pain.

Brachial plexus avulsion (BPA) is a combined injury involving the central and peripheral nervous systems. Patients with BPA often experience severe neuropathic pain (NP) in the affected limb. NP is insensitive to the existing treatments, which makes it a challenge to researchers and clinicians. Accumulated evidence shows that a BPA-induced pain state is often accompanied by sympathetic nervous dysfunction, which suggests that the excitation state of the sympathetic nervous system is correlated with the existence of NP. However, the mechanism of how somatosensory neural crosstalk with the sympathetic nerve at the peripheral level remains unclear. In this study, through using a novel BPA C7 root avulsion mouse model, we found that the expression of BDNF and its receptor TrκB in the DRGs of the BPA mice increased, and the markers of sympathetic nervous system activity including α1 and α2 adrenergic receptors (α1-AR and α2-AR) also increased after BPA. The phenomenon of superexcitation of the sympathetic nervous system, including hypothermia and edema of the affected extremity, was also observed in BPA mice by using CatWalk gait analysis, an infrared thermometer, and an edema evaluation. Genetic knockdown of BDNF in DRGs not only reversed the mechanical allodynia but also alleviated the hypothermia and edema of the affected extremity in BPA mice. Further, intraperitoneal injection of adrenergic receptor inhibitors decreased neuronal excitability in patch clamp recording and reversed the mechanical allodynia of BPA mice. In another branch experiment, we also found the elevated expression of BDNF, TrκB, TH, α1-AR, and α2-AR in DRG tissues from BPA patients compared with normal human DRGs through western blot and immunohistochemistry. Our results revealed that peripheral BDNF is a key molecule in the regulation of somatosensory-sympathetic coupling in BPA-induced NP. This study also opens a novel analgesic target (BDNF) in the treatment of this pain with fewer complications, which has great potential for clinical transformation.

Composite channel modeling for underwater optical wireless communication and analysis of multiple scattering characteristics.

In this study, we propose an innovative composite channel model that considers multi-size bubbles, absorption, and fading caused by scattering for investigating the effect of multiple scattering on the optical properties of a channel. The model is based on Mie theory, geometrical optics and the absorption-scattering model in the Monte-Carlo framework, and the performance of the optical communication system of the composite channel was analyzed for different positions, sizes, and number densities of bubbles. A comparison with the corresponding optical properties of conventional particle scattering indicated that a larger number of bubbles corresponded to greater attenuation of the composite channel, which was manifested by a low power at the receiver, an increased channel impulse response, and the observance of a prominent peak in the volume scattering function or critical scattering angles. Additionally, the effects of the position of large bubbles on the scattering property of the channel were investigated. The proposed composite channel model can provide reference data for designing a more reliable and comprehensive underwater optical wireless communication link.

Brachial plexus avulsion induced changes in gut microbiota promotes pain related anxiety-like behavior in mice.

Introduction: Brachial plexus avulsion (BPA) injury develops frequent and intense neuropathic pain, involving in both peripheral and central nervous systems. The incidence of anxiety or depression caused by BPA-induced neuropathic pain is high, but the underlying mechanism remains unclear. Methods: We established a BPA mice model and assessed its negative emotions through behavioral tests. To further explore the role of the microbiota-gut-brain axis in the unique emotional behavior after BPA, we performed intestinal fecal 16s and metabolomics assays. Psychobiotics (PB) supplementation was administered to BPA mice to check the probiotics effects on BPA-induced anxiety behaviors. Results: Pain related anxiety-like behavior was observed at the early stage after BPA (7 days), while no depression-like behavior was detected. Intriguingly, gut microbiota diversity was increased in BPA mice, and the most abundant probiotics, Lactobacillus, showed obvious changes. Lactobacillus_reuteri was significantly decreased in BPA mice. Metabolomics analysis showed that Lactobacillus_reuteri-related bile acid pathway and some neurotransmitter amino acids were significantly altered. Further PB (dominated by Lactobacillus_reuteri) supplementation could significantly relieve BPA-induced anxiety-like behaviors in mice. Conclusion: Our study suggests that pathological neuralgia after BPA could alter intestinal microbiota diversity, especially Lactobacillus, and the changes in neurotransmitter amino acid metabolites may be the key reason for the onset of anxiety-like behaviors in BPA mice.

XBP1-elicited environment by chemotherapy potentiates repopulation of tongue cancer cells by enhancing miR-22/lncRNA/KAT6B-dependent NF-κB signalling.

BACKGROUND: Tumour repopulation initiated by residual tumour cells in response to cytotoxic therapy has been described clinically and biologically, but the mechanisms are unclear. Here, we aimed to investigate the mechanisms for the tumour-promoting effect in dying cells and for tumour repopulation in surviving tongue cancer cells. METHODS: Tumour repopulation in vitro and in vivo was represented by luciferase activities. The differentially expressed cytokines in the conditioned medium (CM) were identified using a cytokine array. Gain or loss of function was investigated using inhibitors, neutralising antibodies, shRNAs and ectopic overexpression strategies. RESULTS: We found that dying tumour cells undergoing cytotoxic therapy increase the growth of living tongue cancer cells in vitro and in vivo. Dying tumour cells create amphiregulin (AREG)- and basic fibroblast growth factor (bFGF)-based extracellular environments via cytotoxic treatment-induced endoplasmic reticulum stress. This environment stimulates growth by activating lysine acetyltransferase 6B (KAT6B)-dependent nuclear factor-kappa B (NF-κB) signalling in living tumour cells. As direct targets of NF-κB, miR-22 targets KAT6B to repress its expression, but long noncoding RNAs (lncRNAs) (XLOC_003973 and XLOC_010383) counter the effect of miR-22 to enhance KAT6B expression. Moreover, we detected increased AREG and bFGF protein levels in the blood of tongue cancer patients with X-box binding protein-1 (XBP1) activation in tumours under cytotoxic therapy and found that XBP1 activation is associated with poor prognosis of patients. We also detected activation of miR-22/lncRNA/KAT6B/NF-κB signalling in recurrent cancers compared to paired primary tongue cancers. CONCLUSIONS: We identified the molecular mechanisms of cell death-induced tumour repopulation in tongue cancer. Such insights provide new avenues to identify predictive biomarkers and effective strategies to address cancer progression.

Misrepresentation of group contributions undermines conditional cooperation in a human decision making experiment.

Cooperative behaviour can evolve through conditional strategies that direct cooperation towards interaction partners who have themselves been cooperative in the past. Such strategies are common in human cooperation, but they can be vulnerable to manipulation: individuals may try to exaggerate their past cooperation to elicit reciprocal contributions or improve their reputation for future gains. Little is known about the prevalence and the ramifications of misrepresentation in human cooperation, neither in general nor about its cultural facets (self-sacrifice for the group is valued differently across cultures). Here, we present a large-scale interactive decision making experiment (N = 870), performed in China and the USA, in which individuals had repeated cooperative interactions in groups. Our results show that (1) most individuals from both cultures overstate their contributions to the group if given the opportunity, (2) misrepresentation of cooperation is detrimental to cooperation in future interactions, and (3) the possibility to build up a personal reputation amplifies the effects of misrepresentation on cooperation in China, but not in the USA. Our results suggest that misrepresentation of cooperation is likely to be an important factor in (the evolution of) human social behaviour, with, depending on culture, diverging impacts on cooperation outcomes.

Smoke-induced SAV1 Gene Promoter Hypermethylation Disrupts YAP Negative Feedback and Promotes Malignant Progression of Non-small Cell Lung Cancer.

YAP (gene symbol YAP1) as a potential oncoprotein, is positively correlated with the malignancy of various tumors. However, overexpression of YAP alone in multiple normal tissue cells has failed to induce tumor formation and the underlying mechanism is poorly understood. Herein, we show that YAP activation directly induces transcription of its negative regulator, SAV1, to constitute a negative feedback loop, which plays a vital role in maintaining lung epithelial cell homeostasis and was dysregulated in non-small cell lung cancer (NSCLC). Notably, smoking promotes the hypermethylation of the SAV1 promoter region, which disrupts YAP negative feedback by inactivating the Hippo pathway. Besides, exogenous overexpression of SAV1 can act as a traffic protein, activating the Hippo signaling and concurrently inhibiting the WNT pathway to decrease cancer cell growth. Furthermore, using the lung cancer organoids, we found that lentivirus-mediated SAV1 gene transfer combined with methylation inhibitor and YAP-TEAD inhibitor is a potential feasible clinical medication regimen for the lung cancer patient, especially among the smoking population. Thus, this SAV1 mediated feedback loop provides an efficient mechanism to establish the robustness and homeostasis of YAP regulation and as a potential target of gene therapy for the smoking NSCLC population.

Construction and validation of an immune-related LncRNA prognostic model for hepatocellular carcinoma.

Herein, based on mRNA data from TCGA database, hepatocellular carcinoma (HCC) samples were subjected to a single-sample Gene Set Enrichment Analysis (ssGSEA). Then, HCC samples were finally classified into high-, middle-, and low-immunity groups using K-means consensus clustering (K = 3) according to ssGSEA scores. After the tumor microenvironment of HCC patients was further analyzed using ESTIMATE algorithm, the results indicated high immune score, stromal score, ESTIMATE score and low tumor purity in high-immunity group. HLA family genes and PD-L1(CD274) were remarkably highly expressed in high-immunity group. Immune-related lncRNAs were required by analyzing differentially expressed genes in high- and low-immunity groups. Differential expression analysis was undertaken on HCC samples, with normal samples as the control. After immune-related lncRNAs and differentially expressed lncRNAs were intersected, 321 differentially expressed immune-related lncRNAs were acquired. Later, the prognostic model based on immune-related lncRNAs was obtained following the Cox regression analysis of previous samples. According to the riskScore, the samples in TCGA-LIHC were divided into high- and low-risk groups. Kaplan-Meier survival analysis, ROC curve, and independence analysis confirmed that the immune-related lncRNAs prognostic model was an important factor independent from clinical characteristics. We further analyzed the difference in immune microenvironment and mutational landscapes in both risk groups. Prominent differences were shown in multiple immunity-related gene sets and immune cells in both groups. The mutation rate of TP53 in high-risk group was much higher than the low-risk one. All these conclusions offered references to prognostic evaluations and personalized treatments for patients with HCC.

Chitosan-coated organosilica nanoparticles as a dual responsive delivery system of natural fragrance for axillary odor problem.

Citronellol (CI)-loaded, chitosan (CS)-enclosed dendritic mesoporous organosilica nanoparticles (CI@D-MONs@CS) are successfully fabricated. The synthesized CI@D-MONs@CS present spherical shape with the particle size of 424±24 nm in diameter and dendritic mesopores. CI loading ratio of CI@D-MONs@CS is about 12.42% from TGA analysis. CI release from CI@D-MONs@CS exhibits pH-redox dual responsiveness. More interesting, the axillary deodorant effect is investigated with Staphylococcus haemolyticus in an artificial sweat model. The results show that CI@D-MONs@CS present an excellent bacteria-killing effect and the smell of artificial sweat is greatly improved, avoiding the formation of undesirable odorant compounds from the bacteria. The obtained CI@D-MONs@CS is a potential carrier of natural fragrance or actives with dual responsive release. The application of CI@D-MONs@CS is a new and effective strategy to the axillary odor problem.

Integrative Analysis of DNA Methylation and Transcriptome Identifies a Predictive Epigenetic Signature Associated With Immune Infiltration in Gliomas.

Glioma is the most common primary brain tumor with poor prognosis and high mortality. The purpose of this study was to use the epigenetic signature to predict prognosis and evaluate the degree of immune infiltration in gliomas. We integrated gene expression profiles and DNA methylation data of lower-grade glioma and glioblastoma to explore epigenetic differences and associated differences in biological function. Cox regression and lasso analysis were used to develop an epigenetic signature based on eight DNA methylation sites to predict prognosis of glioma patients. Kaplan-Meier analysis showed that the overall survival time of high- and low-risk groups was significantly separated, and ROC analysis verified that the model had great predictive ability. In addition, we constructed a nomogram based on age, sex, 1p/19q status, glioma type, and risk score. The epigenetic signature was obviously associated with tumor purity, immune checkpoints, and tumor-immune infiltrating cells (CD8+ T cells, gamma delta T cells, M0 macrophages, M1 macrophages, M2 macrophages, activated NK cells, monocytes, and activated mast cells) and thus, it may find application as a guide for the evaluation of immune infiltration or in treatment decisions in immunotherapy.

Genomic insights into evolution of pathogenicity and resistance of multidrug-resistant Raoultella ornithinolytica WM1.

Raoultella ornithinolytica is a poorly understood opportunistic pathogen, and the underlying mechanisms of its multidrug resistance and pathogenicity have not yet been comprehensively investigated. The multidrug-resistant (MDR) strain WM1 was isolated from the blood of a male patient in Tianjin, China, in 2018. Here, we describe the complete genome and provide a genomic analysis of R. ornithinolytica WM1. The isolate was resistant to all tested antimicrobials except amikacin, tobramycin, and tigecycline. Two plasmids, pWM1-1 (IncHI5) and pWM1-2 (IncR), carried multidrug-resistance regions. A large antimicrobial resistance island region resided on pWM1-1 and exhibited mosaic structures resulting from the acquisition of complex integrations of variable regions, including genes conferring resistance to multiple classes of antimicrobials. Moreover, WM1 possessed virulence-related elements that encode several virulence factors, including type I fimbriae, Escherichia coli common pilus, type II and VI secretion systems, yersiniabactin, enterobactin, and surface polysaccharide, indicating pathogenic potential. Furthermore, the core genome phylogeny and pan-genome analyses revealed extensive genetic diversity. Our analysis indicates the need for stringent infection control, antimicrobial stewardship, periodic resistance monitoring, and rational medication to address potential threats posed by MDR R. ornithinolytica strains.

lncRNA LINC01057 promotes mesenchymal differentiation by activating NF-κB signaling in glioblastoma.

Long non-coding RNAs (lncRNAs) have been potentially identified as new diagnostic markers, prognostic factors and therapeutic targets in cancer. The acquisition of a mesenchymal (MES) phenotype in glioblastomas (GBMs) results into therapeutic resistance and poor clinical outcomes. The correlation between lncRNAs and MES differentiation remains elusive. Here, we report that LINC01057 as a lncRNA is overexpressed in GBMs, especially in MES subtype. LINC01057 knockdown suppresses proliferation, invasion and radioresistance of GBM cells in vitro, and tumor growth in vivo. LINC01057 knockdown leads to loss of MES signature in MES subpopulation of GBM cells, but LINC01057 overexpression promotes MES differentiation in proneural (PN) subpopulation. LINC01057 interacts with IKKα and maintains IKKα nucleus localization, leading to effective chromatin accessibility at NF-κB responsive promoters via histone modification and final NF-κB activation. IKKα knockdown disrupts the effect of LINC01057 overexpression on PN to MES transition (PMT). LINC01057 level is negatively correlated with patient prognosis in MES-subtype GBM. Collectively, our findings uncover LINC01057 as a regulator of NF-κB signaling to promote MES differentiation and a potential target for therapeutic intervention for MES-subtype GBM.

A prognostic 11-DNA methylation signature for lung squamous cell carcinoma.

BACKGROUND: Lung squamous cell carcinoma (LUSC), as the second frequent subtype of lung cancer, causes lots of mortalities primarily due to a lack of precise prognostic markers and timely treatment intervention. Previous studies have constructed several risk prognostic models based on DNA methylation sites in multiple tumors, whereas, DNA methylation signature of LUSC remains to be built, and its predictive value need to be evaluated. METHODS: The genome-wide DNA methylation data of LUSC samples was obtained from The Cancer Genome Atlas dataset. Univariate Cox analysis and the least absolute shrinkage and selection operator (LASSO) were implemented to identify DNA methylation sites related to overall survival of LUSC patients. Thus, we performed multivariate Cox regression to establish a DNA methylation signature. The Kaplan-Meier (K-M) survival curves and time-dependent receiver operating characteristic (ROC) curves were plotted to estimate the prognostic power of the signature. Comparison with other known prognostic biomarkers, our DNA methylation signature showed higher predictive specificity and sensitivity. In addition, multivariate Cox regression screened out independent prognostic factors and constructed a nomogram. RESULTS: Several statistical methods were performed to construct an 11-DNA methylation signature. LUSC patients were divided into low- and high-risk group based on risk score, and high-risk group had a shorter survival time. According to the results of K-M and ROC analyses, the 11-DNA methylation signature showed significant sensitivity and specificity in predicting the LUSC patients' overall survival. Finally, we integrated some independent prognostic factors (risk score, metastasis stage, and tobacco smoking history) to construct a nomogram, which has excellent prognostic power and may provide guidance for the therapeutic strategies. CONCLUSIONS: We constructed the first risk prognosis model based on DNA methylation site in LUSC, which showed better predictive ability. In addition, a nomogram integrating the DNA methylation signature, metastasis stage, and tobacco smoking history was developed.

LncRNA SNORD3A specifically sensitizes breast cancer cells to 5-FU by sponging miR-185-5p to enhance UMPS expression.

Breast cancer is the most common cancer type in women. Long non-coding RNAs (lncRNAs) have been reported as potential new diagnostic markers, prognostic factors, and therapeutic targets in cancer. However, the specific roles and mechanisms of lncRNAs in breast cancer remain to be elucidated. Here we demonstrated the downregulation of lncRNA SNORD3A in breast cancer cells and tissues and verified its non-protein-coding property. SNORD3A overexpression had no effect on cell proliferation but specifically sensitized breast cancer cells to 5-fluorouracil (5-FU) in vitro and in vivo. Mechanistically, SNORD3A exerts its effect via enhancing uridine monophosphate synthetase (UMPS) protein expression. SNORD3A acts as a competing endogenous RNA for miR-185-5p, leading to UMPS protein upregulation. miR-185-5p overexpression disrupted the effect of SNORD3A on chemosensitization to 5-FU in vitro and in vivo. Moreover, Meis1 overexpression transcriptionally promotes SNORD3A expression, and Meis1 is downregulated in breast cancer cells and tissues. In breast cancer tissues, SNORD3A level positively correlates with Meis1 and UMPS protein levels, whereas miR-185-5p level negatively correlates with UMPS protein level. High SNORD3A transcript and Meis1 and UMPS protein levels predicts a better outcome, but high miR-185-5p level predicts a worse outcome in breast cancer patients receiving 5-FU-based chemotherapy. Our findings indicate that Meis1-regulated SNORD3A specifically sensitizes breast cancer cells to 5-FU via enhancing UMPS expression. The SNORD3A-UMPS axis may serve as a potential biomarker and therapeutic target to improve the efficacy of 5-FU-based chemotherapy for breast cancer patients.

SRGN crosstalks with YAP to maintain chemoresistance and stemness in breast cancer cells by modulating HDAC2 expression.

Background: Chemoresistance is a significant obstacle to the effective treatment of breast cancer (BC), resulting in more aggressive behavior and worse clinical outcome. The molecular mechanisms underlying breast cancer chemoresistance remain unclear. Our microarray analysis had identified the overexpression of a small molecular glycoprotein serglycin (SRGN) in multidrug-resistant BC cells. Here, we aimed to investigate the role of SRGN in chemoresistance of breast cancer and elucidate the underlying mechanisms. Methods: SRNG overexpression was identified using microarray analysis and its clinical relevance was analyzed. To investigate the role of SRGN, we performed various in vitro and in vivo studies, as well as characterization of serum and tissue samples from BC patients. Chemosensitivity measurement, gene expression interference, immunofluorescence staining, mammosphere assay, flow cytometry analysis, luciferase reporter assay, ChIP-qPCR, coimmunoprecipitation, and immunohistochemistry were performed to explore the potential functions and mechanisms of SRGN. Results: We confirmed overexpression of SRGN in chemoresistant BC cells and in serum and tissue samples from BC patients with poor response to chemotherapy. SRGN specifically predicted poor prognosis in BC patients receiving chemotherapy. Mechanistically, SRGN promoted chemoresistance both in vitro and in vivo by cross-talking with the transcriptional coactivator YES-associated protein (YAP) to maintain stemness in BC cells. Ectopic YAP expression restored the effects of SRGN knockdown. Inversely, YAP knockdown rescued the effects of SRGN overexpression. The secreted SRGN triggered ITGA5/FAK/CREB signaling to enhance YAP transcription. Reciprocally, YAP promoted SRGN transcription in a TEAD1-dependent manner to form a feed-forward circuit. Moreover, the YAP/RUNX1 complex promoted HDAC2 transcription to induce chemoresistance and stemness in BC cells. Importantly, the SRGN levels were positively correlated with the YAP and HDAC2 levels in chemoresistant BC tissues. YAP and HDAC2 acted downstream of SRNG and correlated with poor outcomes of BC patients receiving chemotherapy. Conclusions: Our findings clarify the roles and mechanisms of SRGN in mediating chemoresistance in breast cancer and suggest its use a potential biomarker for chemotherapeutic response. We believe that novel therapeutic strategies for breast cancer can be designed by targeting the signaling mediated by the crosstalk between SRGN and YAP.

Identification of Key Candidate Genes and Pathways of Candida albicans-Infected Human Umbilical Vein Endothelial Cells and Drug Screening.

Candida albicans is a common opportunistic pathogen that can cause serious infection by blood transmission. C. albicans enters the blood circulation and adheres to the endothelial cells of the vascular wall. However, the detailed mechanism of the effect of C. albicans on the endothelial cells remains unclear. In this study, the microarray expression profile of human umbilical vein endothelial cells exposed to C. albicans was analyzed. The 191 up-regulated genes were enriched in TNF, T cell receptor, and NF-kappa B signaling pathways. The 71 down-regulated genes were enriched in pyruvate metabolic, purine nucleotide metabolic, purine nucleotide biosynthetic, and humoral immune response processes. Gene set enrichment analysis showed that apoptosis, oxidative phosphorylation, IL6/JAK/STAT3 signaling pathways were enriched. Moreover, two hub genes with a high degree of connectivity, namely, MYC and IL6, were selected. Molecular screening of traditional Chinese medicine libraries was performed on the basis of the structure of MYC protein. The okanin had the highest docking score. MYC might be used as molecular targets for treatment. In addition, okanin may inhibit the infection of C. albicans. Thus, MYC can be subjected to further research.