Effective treatment of corticosteroid-induced facial erythema using fractional radiofrequency microneedling.

OBJECTIVES: To investigate the efficacy of Fractional Radiofrequency Microneedling (FRM) in treating corticosteroid-induced facial erythema. METHODS: A retrospective study was conducted involving eight patients diagnosed as corticosteroid-induced facial erythema. Each patient underwent a single session of FRM. Evaluative measures included Clinician's Erythema Assessment (CEA), Patient's Self-Assessment (PSA), assessment of telangiectasia severity, procedure-associated pain (10-point scale), patient satisfaction (3-point scale) and secondary outcomes. RESULTS: The study found a 75% success rate and 100% effectiveness rate in alleviating erythema symptoms. CEA and PSA scores decreased by 67.7% and 78.1%, respectively. No cases of erythema rebound were recorded during the 3-month follow-up period. CONCLUSIONS: FRM demonstrated effectiveness and safety in treating facial erythema, offering promising advancement in dermatologic therapeutics.

The transcription factor PbbHLH164 is destabilized by PbRAD23C/D.1 and mediates ethylene biosynthesis during pear fruit ripening.

The phytohormone ethylene plays an important role in climacteric fruit ripening. However, the knowledge on molecular regulation of ethylene biosynthesis remains limited in pear fruit. Herein, a new basic helix-loop-helix transcription factor, PbbHLH164, was identified based on the transcriptome analysis of different developing and ripening fruits of two pear cultivars 'Sucui No. 1' and 'Cuiguan'. PbbHLH164 was more highly expressed in ripening fruit than in developing fruit and positively correlated with ethylene production in both cultivars. PbbHLH164 could directly bind to the promoter of 1-aminocyclopropane-1-carboxylate synthase, PbACS1b, to enhance the expression, leading to the increase of ethylene production and the acceleration of fruit ripening. Interestingly, PbbHLH164 physically interacted with an ubiquitin-like/ubiquitin-associated protein PbRAD23C/D.1, and the interaction of PbbHLH164 with PbRAD23C/D.1 attenuated the function of PbbHLH164 in enhancing the activity of the PbACS1b promoter. Notably, PbRAD23C/D.1 was involved in the degradation of PbbHLH164, and this degradation was inhibited by an ubiquitin proteasome inhibitor MG132. Different from PbbHLH164, PbRAD23C/D.1 was more highly expressed in developing fruit than in ripening fruit of both cultivars. These results suggest that the increase of ethylene production during pear fruit ripening results from the up-regulated expression of PbbHLH164 and the down-regulated expression of PbRAD23C/D.1. This information provided new insights into the molecular regulation of ethylene biosynthesis during fruit ripening.

Human umbilical cord derived mesenchymal stem cells overexpressing HO-1 attenuate neural injury and enhance functional recovery by inhibiting inflammation in stroke mice.

AIMS: The current evidence demonstrates that mesenchymal stem cells (MSCs) hold therapeutic potential for ischemic stroke. However, it remains unclear how changes in the secretion of MSC cytokines following the overexpression of heme oxygenase-1 (HO-1) impact excessive inflammatory activation in a mouse ischemic stroke model. This study investigated this aspect and provided further insights. METHODS: The middle cerebral artery occlusion (MCAO) mouse model was established, and subsequent injections of MSC, MSCHO-1 , or PBS solutions of equal volume were administered via the mice's tail vein. Histopathological analysis was conducted on Days 3 and 28 post-MCAO to observe morphological changes in brain slices. mRNA expression levels of various factors, including IL-1ß, IL-6, IL-17, TNF-α, IL-1Ra, IL-4, IL-10, TGF-ß, were quantified. The effects of MSCHO-1 treatment on neurons, microglia, and astrocytes were observed using immunofluorescence after transplantation. The polarization direction of macrophages/microglia was also detected using flow cytometry. RESULTS: The results showed that the expression of anti-inflammatory factors in the MSCHO-1 group increased while that of pro-inflammatory factors decreased. Small animal fluorescence studies and immunofluorescence assays showed that the homing function of MSCsHO-1 was unaffected, leading to a substantial accumulation of MSCsHO-1 in the cerebral ischemic region within 24 h. Neurons were less damaged, activation and proliferation of microglia were reduced, and polarization of microglia to the M2 type increased after MSCHO-1 transplantation. Furthermore, after transplantation of MSCsHO-1 , the mortality of mice decreased, and motor function improved significantly. CONCLUSION: The findings indicate that MSCs overexpressing HO-1 exhibited significant therapeutic effects against hyper-inflammatory injury after stroke in mice, ultimately promoting recovery after ischemic stroke.

Chromosomal Instability-Driven Cancer Progression: Interplay with the Tumour Microenvironment and Therapeutic Strategies.

Chromosomal instability (CIN) is a prevalent characteristic of solid tumours and haematological malignancies. CIN results in an increased frequency of chromosome mis-segregation events, thus yielding numerical and structural copy number alterations, a state also known as aneuploidy. CIN is associated with increased chances of tumour recurrence, metastasis, and acquisition of resistance to therapeutic interventions, and this is a dismal prognosis. In this review, we delve into the interplay between CIN and cancer, with a focus on its impact on the tumour microenvironment-a driving force behind metastasis. We discuss the potential therapeutic avenues that have resulted from these insights and underscore their crucial role in shaping innovative strategies for cancer treatment.

Correlation between conventional ultrasound features combined with contrast-enhanced ultrasound patterns and pathological prognostic factors in malignant non-mass breast lesions.

OBJECTIVE: To investigate the correlation between ultrasound performance and prognostic factors in malignant non-mass breast lesions (NMLs). MATERIALS AND METHODS: This study included 106 malignant NMLs in 104 patients. Different US features and contrast enhancement patterns were evaluated. Prognostic factors, including histological types and grades, axillary lymph node and peritumoral lymphovascular status, estrogen and progesterone receptor status and the expression of HER-2 and Ki-67 were determined. A chi-square test and logistic regression analysis were used to analyse possible associations. RESULTS: Lesion size (OR: 3.08, p = 0.033) and posterior echo attenuation (OR: 8.38, p < 0.001) were useful in reflecting malignant NMLs containing an invasive carcinoma component. Posterior echo attenuation (OR: 7.51, p = 0.003) and unclear enhancement margin (OR: 6.50, p = 0.018) were often found in tumors with axillary lymph node metastases. Peritumoural lymphovascular invasion mostly exhibited posterior echo attenuation (OR: 3.84, p = 0.049) and unclear enhancement margin (OR: 8.68, p = 0.042) on ultrasound images. Perfusion defect was a comparatively accurate enhancement indicator for negative ER (OR: 2.57, p = 0.041) and PR (OR: 3.04, p = 0.008) expression. Calcifications (OR: 3.03, p = 0.025) and enlarged enhancement area (OR: 5.36, p = 0.033) imply an increased risk of positive HER-2 expression. Similarly, Calcifications (OR: 4.13, p = 0.003) and enlarged enhancement area (OR: 11.05, p < 0.001) were valid predictors of high Ki-67 proliferation index. CONCLUSION: Ultrasound performance is valuable for non-invasive prediction of prognostic factors in malignant NMLs.

Transcriptome Analysis Revealed Potential Neuro-Immune Interaction in Papillary Thyroid Carcinoma Tissues.

BACKGROUND: A recent study reported that papillary thyroid carcinoma (PTC) was associated with increased adrenergic nerve density. Meanwhile, emerging evidence suggested that tumor-innervating nerves might play a role in shaping the tumor microenvironment. We aimed to explore the potential interaction between neuronal markers and tumor microenvironmental signatures through a transcriptomic approach. METHODS: mRNA sequencing was conducted using five pairs of PTC and adjacent normal tissues. The Gene Set Variation Analysis (GSVA) was performed to calculate enrichment scores of gene sets related to tumor-infiltrating immune cells and the tumor microenvironment. The potential interaction was tested using the expression levels of a series of neuronal markers and gene set enrichment scores. RESULTS: PTC tissues were associated with increased enrichment scores of CD8 T cells, cancer-associated fibroblasts, mast cells, and checkpoint molecules. The neuronal marker for cholinergic neurons was positively correlated with CD8 T cell activation, while markers for serotonergic and dopaminergic neurons showed an inverse correlation. CONCLUSION: Distinct neuronal markers exerted different correlations with tumor microenvironmental signatures. Tumor-innervating nerves might play a role in the formation of the PTC microenvironment.

Non-mass Breast Lesions: Could Multimodal Ultrasound Imaging Be Helpful for Their Diagnosis?

Objective: To develop a prediction model for discriminating malignant from benign breast non-mass-like lesions (NMLs) using conventional ultrasound (US), strain elastography (SE) of US elastography and contrast-enhanced ultrasound (CEUS). Methods: A total of 101 NMLs from 100 patients detected by conventional US were enrolled in this retrospective study. The characteristics of NMLs in conventional US, SE and CEUS were compared between malignant and benign NMLs. Histopathological results were used as the reference standard. Binary logistic regression analysis was performed to identify the independent risk factors. A multimodal method to evaluate NMLs based on logistic regression was developed. The diagnostic performance of conventional US, US + SE, US + CEUS and the combination of these modalities was evaluated and compared. Results: Among the 101 lesions, 50 (49.5%) were benign and 51 (50.5%) were malignant. Age ≥45 y, microcalcifications in the lesion, elasticity score >3, earlier enhancement time and hyper-enhancement were independent diagnostic indicators included to establish the multimodal prediction method. The area under the receiver operating characteristic curve (AUC) of US + SE + CEUS was significantly higher than that of US (p < 0.0001) and US + SE (p < 0.0001), but there was no significant difference between the AUC of US + SE + CEUS and the AUC of US + CEUS (p = 0.216). Conclusion: US + SE + CEUS and US + CEUS could significantly improve the diagnostic efficiency and accuracy of conventional US in the diagnosis of NMLs.

Predictive Values of sTREM-1, PCT and CRP for Multiple Trauma-Induced Acute Respiratory Distress Syndrome Complicated with Pulmonary Infection.

BACKGROUND: The aim is to investigate the predictive values of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), procalcitonin (PCT) and C-reactive protein (CRP) for multiple trauma-induced acute respiratory distress syndrome (ARDS) complicated with pulmonary infection. METHODS: One hundred and twelve patients with multiple trauma-induced ARDS admitted from April 2019 to April 2021 were selected and divided into infection group (n = 49) and non-infection group (n = 63). Their general data and laboratory test indicators were compared. Multivariate logistic regression analysis was utilized to identify the influencing factors for concurrent pulmonary infection. Pearson's analysis was employed to analyze the correlations of sTREM-1, PCT, and CRP with other influencing factors. The predictive values of sTREM-1, PCT, and CRP for pulmonary infection in ARDS patients were evaluated using receiver operating characteristic (ROC) curves. Based on the cutoff values, the patients were assigned to low-, medium-, and high-risk groups. Survival curves were plotted by Kaplan-Meier method to compare the 28-day survival. RESULTS: The infection group had significantly higher injury severity score (ISS), Acute Physiology and Chronic Health Evaluation II (APACHE II) score, sTREM-1, PCT, CRP, and macrophage inflammatory protein (MIP)-1α, longer tracheal intubation time and intensive care unit (ICU) stay time, and lower oxygenation index than those of the non-infection group (p < 0.05). Multivariate logistic regression analysis revealed that increased ISS, APACHE II score, as well as elevated blood concentrations of sTREM-1, PCT, CRP and MIP-1α were risk factors for concurrent pulmonary infection (p < 0.05). sTREM-1, PCT, and CRP were positively correlated with ISS, APACHE II score, and MIP-1α (p < 0.05). The areas under ROC curves of sTREM-1, PCT, CRP, and their combination were 0.795, 0.784, 0.756, and 0.860, respectively (p < 0.001), indicating high predictive values. The survival rate of the high-risk group (46.43%) was significantly lower than those of the low-risk group (89.58%) and medium-risk group (75.00%) (p < 0.05). CONCLUSIONS: sTREM-1, PCT, and CRP are highly expressed in serum of patients with multiple trauma-induced ARDS complicated with pulmonary infection. The combined detection of three markers is of high predictive value.

A synthetic lethal screen identifies HDAC4 as a potential target in MELK overexpressing cancers.

Maternal embryonic leucine zipper kinase (MELK) is frequently overexpressed in cancer, but the role of MELK in cancer is still poorly understood. MELK was shown to have roles in many cancer-associated processes including tumor growth, chemotherapy resistance, and tumor recurrence. To determine whether the frequent overexpression of MELK can be exploited in therapy, we performed a high-throughput screen using a library of Saccharomyces cerevisiae mutants to identify genes whose functions become essential when MELK is overexpressed. We identified two such genes: LAG2 and HDA3. LAG2 encodes an inhibitor of the Skp, Cullin, F-box containing (SCF) ubiquitin-ligase complex, while HDA3 encodes a subunit of the HDA1 histone deacetylase complex. We find that one of these synthetic lethal interactions is conserved in mammalian cells, as inhibition of a human homolog of HDA3 (Histone Deacetylase 4, HDAC4) is synthetically toxic in MELK overexpression cells. Altogether, our work identified a novel potential drug target for tumors that overexpress MELK.

CircPCMTD1 Acts as the Sponge of miR-224-5p to Promote Glioma Progression.

Glioma is the most common malignant tumor of the central nervous system with high morbidity and mortality. Circular RNAs (circRNAs) are abundant non-coding RNAs, which contribute to tumor progression by competing with other endogenous RNAs such as microRNA (miRNA). MiRNA are a class of small non-coding RNAs, which interrupt the translation of target mRNAs. CircPCMTD1 (hsa-circ-0001801) is a newly discovered circRNA that was found to be significantly upregulated in glioma. However, its function is unclear. In this study, circPCMTD1 upregulation promoted the cell viability, migration and invasion dramatically, while the inhibition of circPCMTD1 led to a significant reduction of tumor growth in vivo. MiRNAs microarray analyses on circPCMTD1 silencing models in U251 and U118MG cells were performed, and the results suggested that circPCMTD1 knockdown could upregulate the expression of miR-224-5p and downregulate the expression of mTOR, one of miR-224-5p targets, in both cell lines. According to the prediction from circular RNA interactome and Targetscan, there was a complementary sequence in circPCMTD1 for miR-224-5p. Dual-luciferase reporter assay demonstrated that circPCMTD1 were targets of miR-224-5p. RIP assay was also performed to further confirm their directly interaction. Overexpression of miR-224-5p inhibited the viability and proliferation, migration, and invasion of U251 and U118MG glioma cells. In conclusion, circPCMTD1 could contribute to the promotion of glioma progression, and it may serve as the sponge of miR-224-5p to exert its function.

Time-resolved protein activation by proximal decaging in living systems.

A universal gain-of-function approach for selective and temporal control of protein activity in living systems is crucial to understanding dynamic cellular processes. Here we report development of a computationally aided and genetically encoded proximal decaging (hereafter, CAGE-prox) strategy that enables time-resolved activation of a broad range of proteins in living cells and mice. Temporal blockage of protein activity was computationally designed and realized by genetic incorporation of a photo-caged amino acid in proximity to the functional site of the protein, which can be rapidly removed upon decaging, resulting in protein re-activation. We demonstrate the wide applicability of our method on diverse protein families, which enabled orthogonal tuning of cell signalling and immune responses, temporal profiling of proteolytic substrates upon caspase activation as well as the development of protein-based pro-drug therapy. We envision that CAGE-prox will open opportunities for the gain-of-function study of proteins and dynamic biological processes with high precision and temporal resolution.

Hepatoprotective effect of rhein against methotrexate-induced liver toxicity.

The purpose of this study was to investigate the protective effect of rhein, a major metabolite of diacerein, on methotrexate (MTX)-induced hepatotoxicity and clarify the pharmacological mechanism. Rhein significantly reduced the elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) caused by MTX in rat serum and improved liver morphological damage induced by MTX. Moreover, rhein increased the cell survival rate and reduced the number of apoptosis cells in MTX-treated normal human hepatocyte (L02 cells). Rhein treatment in rats up-regulated nuclear factor erythroid 2-related factor 2 (Nrf2), B-cell lymphoma-2 (Bcl-2), heme oxygenase 1 (HO-1) and glutamate-cysteine ligase catalytic subunit (GCLC), and down-regulated Bcl-2 associated x (Bax) in mRNA and protein levels. Furthermore, rhein treatment further decreased protein expression of nuclear factor-kappa B (NF-κB), tumor necrosis factor alpha (TNF-α) and cysteine aspartic acid specific protease 3 (Caspase-3), increased protein expression of B-cell lymphoma-extra large (Bcl-xl), and reduced mRNA expression of Bcl-2 homologous antagonist/killer (Bak) in MTX-treated rat liver in vivo. However, the protein expression changes of Nrf2, HO-1, GCLC, Bcl-2, Bcl-xl and Bax could be abrogated by Nrf2 antagonist brusatol. In addition, protective effect of rhein against MTX-mediated liver damage could also be suppressed by Nrf2 siRNA in L02 cells. Taken together, these findings suggested that rhein ameliorated liver damage mediated by MTX through acting on Nrf2-HO-1 pathway. NF-κB, TNF-α, Caspase-3 and Bcl-2 family were also participated in the protection. As effectively hepatoprotective ability of rhein, it would raise an important issue for patients orally receiving MTX treatment together with diacerein/rhein.

MicroRNA-644a promotes apoptosis of hepatocellular carcinoma cells by downregulating the expression of heat shock factor 1.

In this study, we investigated the role of microRNA-644a (miR-644a) in the growth and survival of hepatocellular carcinoma (HCC) cells. MiR-644a levels were lower in HCC tissues than in adjacent peri-cancerous tissues (n = 135). MiR-644a expression was inversely correlated with heat shock factor 1 (HSF1) expression, tumour diameter and TNM stage. Moreover, HepG2 and SMMC-7721 cell lines showed lower miR-644a expression than normal L-O2 hepatocytes. MiR-644a overexpression in HepG2 and SMMC-7721 cells increased apoptosis by downregulating HSF1. Dual luciferase reporter assays confirmed the presence of a miR-644a binding site in the 3'-untranslated region (3'-UTR) of HSF1. Xenograft tumours derived from SMMC-7721 cells transfected with a miR-664a mimic showed less growth than tumours derived from untransfected controls. Protein chip analysis revealed that miR-644a-overexpressing SMMC-7721 and HepG2 cells strongly expressed pro-apoptotic BH3-only proteins, such as BID, BAD, BIM, SMAC, Apaf-1 and cleaved caspases-3 and -9. These findings suggest miR-644a promotes apoptosis in HCC cells by inhibiting HSF1.

Targeting Bacillus anthracis toxicity with a genetically selected inhibitor of the PA/CMG2 protein-protein interaction.

The protein-protein interaction between the human CMG2 receptor and the Bacillus anthracis protective antigen (PA) is essential for the transport of anthrax lethal and edema toxins into human cells. We used a genetically encoded high throughput screening platform to screen a SICLOPPS library of 3.2 million cyclic hexapeptides for inhibitors of this protein-protein interaction. Unusually, the top 3 hits all contained stop codons in the randomized region of the library, resulting in linear rather than cyclic peptides. These peptides disrupted the targeted interaction in vitro; two act by binding to CMG2 while one binds PA. The efficacy of the most potent CMG2-binding inhibitor was improved through the incorporation of non-natural phenylalanine analogues. Cell based assays demonstrated that the optimized inhibitor protects macrophages from the toxicity of lethal factor.