Single-cell analysis of Crohn's disease: Unveiling heterogeneity and evaluating ustekinumab outcomes.

BACKGROUND: The present study aimed to dissect the cellular complexity of Crohn's disease (CD) using single-cell RNA sequencing, focusing on identifying key cell populations and their transcriptional profiles in inflamed tissue. METHODS: We applied scRNA-sequencing to compare the cellular composition of CD patients with healthy controls, utilizing Seurat for clustering and annotation. Differential gene expression analysis and protein-protein interaction networks were constructed to identify crucial genes and pathways. RESULTS: Our study identified eight distinct cell types in CD, highlighting crucial fibroblast and T cell interactions. The analysis revealed key cellular communications and identified significant genes and pathways involved in the disease's pathology. The role of fibroblasts was underscored by elevated expression in diseased samples, offering insights into disease mechanisms and potential therapeutic targets, including responses to ustekinumab treatment, thus enriching our understanding of CD at a molecular level. CONCLUSIONS: Our findings highlight the complex cellular and molecular interplay in CD, suggesting new biomarkers and therapeutic targets, offering insights into disease mechanisms and treatment implications.

Arginine methylation of ALKBH5 by PRMT6 promotes breast tumorigenesis via LDHA-mediated glycolysis.

ALKBH5 is a master regulator of N6-methyladenosine (m6A) modification, which plays a crucial role in many biological processes. Here, we show that ALKBH5 is required for breast tumor growth. Interestingly, PRMT6 directly methylates ALKBH5 at R283, which subsequently promotes breast tumor growth. Furthermore, arginine methylation of ALKBH5 by PRMT6 increases LDHA RNA stability via m6A demethylation, leading to increased aerobic glycolysis. Moreover, PRMT6-mediated ALKBH5 arginine methylation is confirmed in PRMT6-knockout mice. Collectively, these findings identify a PRMT6-ALKBH5-LDHA signaling axis as a novel target for the treatment of breast cancer.

Association of epicardial fat volume with subclinical myocardial damage in patients with type 2 diabetes mellitus.

Background: In type 2 diabetes mellitus (T2DM) patients, left ventricular systolic dyssynchrony (LVSD) with normal left ventricular ejection fraction (LVEF) and normal myocardial perfusion could referred to as subclinical myocardial damage, which is difficult to diagnose at an early stage. Epicardial adipose tissue, a distinctive heart-specific visceral fat, is closely related to various cardiovascular diseases. The objective of this study was to investigate the correlation between epicardial fat volume (EFV) and subclinical myocardial damage in T2DM patients. Methods: This retrospective cross-sectional study included 117 T2DM patients with normal myocardial perfusion by single photon emission computed tomography-computed tomography (SPECT-CT) and normal LVEF by echocardiography. The study was conducted from January 2018 to December 2022. Patient data were collected through electronic medical records including basic patient information, medical history, laboratory tests, and medication data. The EFV was quantified through a non-contrast CT scan. Quantitative indicators of LVSD including phase standard deviation (PSD) and phase histogram bandwidth (PBW) were obtained through phase analysis of the gated rest myocardial perfusion imaging (MPI). Additionally, 83 healthy individuals at the same time were selected to gain the reference threshold of LVSD indicators (13.1° for PSD and 37.6° for PBW). Univariate and multivariable logistic regression models were performed to analyze factors influencing LVSD. A generalized additive model (GAM) was applied to explore the relationship between EFV and LVSD. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of EFV for LVSD. Results: Among all patients, 32 (27.4%) patients had LVSD. Compared with the non-LVSD group, the body mass index (BMI) and EFV were higher in the LVSD group (25.83±2.66 vs. 23.94±3.13 kg/m2; 142.41±44.17 vs. 108.01±38.24 cm3, respectively, both P<0.05). Multivariate regression analysis revealed that EFV was independently associated with LVSD [odds ratio (OR) =1.19; 95% confidence interval (CI): 1.06-1.34; P=0.003]. Age, BMI, incidence of hypertension, and LVSD were increased with tertiles of EFV (all P<0.05). The GAM indicated a linear association between EFV and LVSD. The ROC curve analysis concluded that the area under the curve (AUC) of EFV for predicting subclinical myocardial damage in T2DM patients was 0.732 (95% CI: 0.633-0.831, P<0.001), with the optimal threshold of 122.26 cm3, sensitivity of 71.9%, and specificity of 69.4%. Conclusions: EFV is an independent risk factor for LVSD in T2DM patients with normal LVEF and normal MPI, which could potentially serve as a novel imaging marker and a potential therapeutic target for subclinical myocardial damage.

Effect of different chemotherapy schemes on early-stage breast cancer patients with Low HER-2 expression.

Objective: To explore the effect of different chemotherapy schemes on the prognosis, immune function and adverse reactions of breast cancer patients with low HER-2 expression after surgery. Methods: A retrospective analysis was carried out on the clinical data of 60 breast cancer patients with low HER-2 expression in Wuxi No.2 people's Hospital from January 2018 to December 2019. The enrolled patients were divided into two groups according to the different chemotherapy schemes. Patients in the DC group were treated with polyethylene glycol-coated liposome-encapsulated doxorubicin+cyclophosphamide, and those in the TC group were treated with TC (docetaxel+cyclophosphamide). Further comparison was performed on the difference in prognosis, immune function and adverse reaction between the two groups after different chemotherapy schemes. Results: After four courses of treatment, the IgG, CD4+ and CD4+/CD8+ values in the DC group after treatment were higher than those before treatment, while the IgG, CD3+ and CD4+values in the TC group after treatment were lower than those before treatment(P<0.05). Meanwhile, the IgG, CD4+ and CD4+/CD8+ values in the DC group were better than those in the TC group after treatment(P<0.05). During the treatment, the adverse reactions of leukopenia, alopecia, nausea and vomiting in the DC group were significantly lower than those in the TC group(P<0.05). Conclusion: The chemotherapy combination of liposome-encapsulated doxorubicin+cyclophosphamide can significantly improve immune function and greatly reduce the occurrence of adverse reactions in early-stage breast cancer patients with low HER-2 expression after surgery. It has the same effect as docetaxel+cyclophosphamide in improving the prognosis of patients.

MFAP2 promotes HSCs activation through FBN1/TGF-ß/Smad3 pathway.

Liver fibrosis is a chronic inflammatory process characterized by the accumulation of extracellular matrix (ECM), which contributes to cirrhosis and hepatocellular carcinoma. Increasing evidence suggests that the activation of hepatic stellate cells (HSCs) under an inflammatory state leads to the secretion of collagens, which can cause cirrhosis. In this study, we analysed data from the Gene Expression Omnibus (GEO) databases to identify differentially expressed genes (DEGs) between quiescent and fibrotic HSCs. We found that Microfibril Associated Protein 2 (MFAP2) was elevated in carbon tetrachloride (CCl4)-induced liver fibrosis and Transforming Growth Factor-Beta 1 (TGF-ß1)-activated HSCs. Knockdown of MFAP2 inhibited HSC proliferation and partially attenuated TGF-ß-stimulated fibrogenesis markers. Bioinformatics analysis revealed that Fibrillin-1 (FBN1) was correlated with MFAP2, and the expression of FBN1 was significantly upregulated after MFAP2 overexpression. Silencing MFAP2 partially attenuated the activation of HSCs by inhibiting HSC proliferation and decreasing collagen deposits. In vitro results showed that the inhibition of MFAP2 alleviated hepatic fibrosis by inhibiting the activation and inducing the apoptosis of active HSCs in a CCl4-induced mouse model. In conclusion, our results suggest that MFAP2 is a potential target for the clinical treatment of liver fibrosis.

[Retracted] TRIM16 suppresses the progression of prostate tumors by inhibiting the Snail signaling pathway.

Following the publication of this paper, it was drawn to the Editor's attention by concerned readers that the western blotting data shown in Figs. 4C and 7B and D, the scratch­wound assay images shown in Figs. 5A and 6A, and certain of the cell migration and invasion assay data shown in Figs. 5B and 6B were strikingly similar to data that had previously appeared in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to International Journal of Molecular Medicine, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 38: 1734­1742, 2016; DOI: 10.3892/ijmm.2016.2774].

Vitamin B ameliorates PM2.5-induced kidney damage by reducing endoplasmic reticulum stress and oxidative stress in pregnant mice and HK-2.

As an air pollutant, particulate matters 2.5 (PM2.5) poses a severe risk to kidney and the mechanism involves oxidative stress and endoplasmic reticulum (ER) stress. As an essential nutrient for human health, Vitamin B performs anti-inflammatory and antioxidant functions. In order to study the effect of Vitamin B on PM2.5-induced kidney damage during pregnancy, the pregnant mice were divided into the four experimental groups randomly: control group, model group, treatment group and VB group. PM2.5 was sprayed on the trachea of pregnant mice once each three days for six times from pregnancy until delivery. The model group was given 30 µL PM2.5 suspension of 3.456 µg/µL and 10 mL/(kg·d) PBS. The treatment group was given 30 µL PM2.5 suspension of 3.456 µg/µL and 10 mL/(kg·d) Vitamin B. The VB group was given 10 mL/(kg·d) Vitamin B and the control group was given the same dose of PBS. Vitamin B was composed of Vitamin B6, Vitamin B12 and folic acid, with final concentrations are 1.14, 0.02 and 0.06 mg/mL, respectively. The results showed Vitamin B ameliorated PM2.5-induced kidney damage such as improving histopathological change, decreasing expressions of Bip and Chop, increasing expressions of Nrf2, HO-1 and Nqo1. In addition, HK-2 cells were used for cell experiments and were divided into the four groups, in which the dosage of PM2.5 was 75 µg/mL for 24 h and Vitamin B was 5 µL/100 µL. The results showed Vitamin B ameliorated PM2.5-induced HK-2 damage, such as decreasing expressions of Bip, Chop, P47phox and ROS, increasing expressions of Nrf2, HO-1, Nqo1 and NO. Our findings showed Vitamin B ameliorated PM2.5-induced kidney damage by reducing ER stress and oxidative stress in pregnant mice and in HK-2.

Maternal tamoxifen exposure leads to abnormal primordial follicle assembly.

Tamoxifen (TAM) is an accredited drug used for treatment and prevention of breast cancer. Due to the long-term taking and the trend for women to delay childbearing, inadvertent conception occasionally occurs during TAM treatment. To explore the effects of TAM on a fetus, pregnant mice at gestation day 16.5 were orally administrated with different concentrations of TAM. Molecular biology techniques were used to analyze the effects of TAM on primordial follicle assembly of female offspring and the mechanism. It was found that maternal TAM exposure affected primordial follicle assembly and damaged the ovarian reserve in 3 dpp offspring. Up to 21 dpp, the follicular development had not recovered, with significantly decreased antral follicles and decreased total follicle number after maternal TAM exposure. Cell proliferation was significantly inhibited; however, the cell apoptosis was induced by maternal TAM exposure. Epigenetic regulation was also involved in the process of TAM induced abnormal primordial follicle assembly. The changed levels of H3K4me3, H3K9me3, and H3K27me3 presented the function of histone methylation in the regulation of the effects of maternal TAM exposure on the reproduction of female offspring. Moreover, the changed level of RNA m6A modification and the changed expression of genes related to transmethylation and demethylation proved the role of m6A in the process. Maternal TAM exposure led to abnormal primordial follicle assembly and follicular development by affecting cell proliferation, cell apoptosis, and epigenetics.

FDX1 enhances endometriosis cell cuproptosis via G6PD-mediated redox homeostasis.

Cuproptosis is a new form of programmed cell death, which is associated with the mitochondrial TCA (tricarboxylic acid) cycle. But the functions of cuproptosis in endometriosis progression are still unknown. Here, we find that cuproptosis suppresses the growth of endometriosis cells and the growth of ectopic endometrial tissues in a mouse model. FDX1 as a key regulator in cuproptosis pathway could promote cuproptosis in endometriosis cells. Interestingly, FDX1 interacts with G6PD, and reduces its protein stability, which predominantly affects the cellular redox-regulating systems. Then, the reduced G6PD activity enhances cuproptosis via down-regulating NADPH and GSH levels. Collectively, our study demonstrates that FDX1 mediates cuproptosis in endometriosis via G6PD pathway, resulting in repression of endometriosis cell proliferation and metastasis.

The Expression of HPV E6/E7 mRNA In Situ Hybridization in HPV Typing-negative Cervical Cancer.

High-risk human papillomavirus (HPV) persistent infection is the major tumorigenesis factor for cervical cancer (CC). However, the incidence of HPV-negative CC is 5% to 30% with different HPV detection methods. High-risk HPV E6/E7 mRNA in situ hybridization (RISH) can detect HPV-driven tumors. Our study aimed to explore whether HPV typing-negative CC was caused by HPV infection. The tissues of CC patients with HPV typing results, collected from cervical biopsies, conization, or hysterectomies, were submitted to RISH using RNAscope chromogenicin. Immunohistochemistry was performed to evaluate the expression of p16INK4a and Ki-67. A total of 308 women with HPV typing results were enrolled, and 30 (9.74%) cases of HPV typing were negative. In HPV typing-negative CCs, 28/30 (93.3%) were positive for RISH, which contained 22/22 (100%) squamous cell carcinomas and 6/8 (75%) adenocarcinomas. RISH was positive in 278/278 (100%) HPV typing-positive CCs, which included 232/232 (100%) squamous cell carcinomas and 46/46 (100%) adenocarcinomas. Positive RISH in HPV typing-negative CC was significantly lower than in the HPV typing-positive group ( P =0.002, 95% confidence interval: 0.848-1.027). However, this significant difference only existed in adenocarcinoma. No significant differences were seen in the expression of p16INK4a and Ki-67 (all P >0.05). HPV typing may cause misdiagnosis in 9.74% of CC patients, and HPV E6/E7 mRNA can detect HPV in CC with HPV typing-negative patients. This approach could provide a novel option to accurately detect high-risk HPVs in cervical tumors and help to eliminate the percentage of misdiagnosed HPV-related cases.

Safety of AS04-HPV-16/18 vaccine in Chinese women aged 26 years and older and long-term protective effect in women vaccinated at age 18-25 years: A 10-year follow-up study.

INTRODUCTION: The pivotal efficacy study assessed efficacy and safety of GSK's AS04-HPV-16/18 vaccine in Chinese women aged 18-25 years up to 6 years. The present extension study, performed 4 years later, offered AS04-HPV-16/18 vaccination to placebo recipients. Vaccine safety and its long-term protective effect were assessed at Year 10. METHODS: All 6051 women who received AS04-HPV-16/18 or the placebo during the initial study (NCT00779766) were invited to phase III/IV, open-label, partially controlled extension Year 10 study (NCT03629886). Placebo recipients were offered three-dose AS04-HPV-16/18 vaccination and followed up over 12 months to assess the safety. Cervical samples from all women were examined. Vaccine efficacy (VE) against incident infections and cytological lesions associated with HPV-16/18 and other oncogenic types was assessed as exploratory objective. RESULTS: Among 3537 women (out of 6051) enrolled in the extension study, 1791 women (mean age 32.7 years; standard deviation 1.8 years) received AS04-HPV-16/18 and reported no serious adverse events, potential immune-mediated diseases, or adverse pregnancy outcomes related to vaccination. Among 6051 women, VE against incident HPV-16, -18, and -16/18 infections up to Year 10 was 82.8% (95% confidence interval: 72.5-89.7), 79.8% (64.5-89.2), and 80.8% (72.4-87.0), respectively. VE against HPV-16/18 ASC-US+, CIN1+, and CIN2+ was 92.7% (82.2-97.7), 94.8% (67.4-99.9), and 90.5% (34.6-99.8), respectively. CONCLUSION: AS04-HPV-16/18 vaccine showed an acceptable safety profile in Chinese women vaccinated at age 26 years or above, and a long-term protection similar to other efficacy trials worldwide.

Maternal ochratoxin A exposure impairs meiosis progression and primordial follicle formation of F1 offspring.

Ochratoxin A (OTA), a mycotoxin produced by Aspergillus and Penicillium fungi, widely contaminates feed, food and their raw materials. OTA has been proved to have hepatotoxicity and nephrotoxicity. Its reproductive toxicity needs to be further explored. We found that OTA inhibited the progression of meiosis, keeping more germ cells at leptotene and zygotene. Furthermore, OTA impaired primordial follicle formation, keeping more germ cells in cysts. Increased γH2AX suggested that DNA damage occurred both at the stages of meiosis and primordial follicle formation. The expression of RAD51 increased with the concentration of OTA at the stage of meiosis, while decreased later, suggesting the activated DNA repair induced by DNA damage then inhibited by persistent and excessive stress of DNA damage, which further induced apoptosis. DEGs caused by OTA were also mainly enriched in DNA damage and repair through RNA-seq analysis. Higher level of reactive oxygen species (ROS) and increased degree of oxidative damage marker 8-OHdG were both found in the ovaries exposed to OTA. We concluded that maternal OTA exposure affected meiosis progression and primordial follicle formation via oxidative damage and DNA repair. Clarification of the mechanism of OTA will contribute to the development of more effective detoxification strategies.

Ubiquitination of NF-κB p65 by FBXW2 suppresses breast cancer stemness, tumorigenesis, and paclitaxel resistance.

The F-box and WD-repeat-containing protein 2 (FBXW2) plays a crucial role as an E3 ligase in regulating tumorigenesis. However, the functions of FBXW2 in breast cancer are still unknown. Here, we find that nuclear factor-kB (NF-κB) p65 is a new substrate of FBXW2. FBXW2 directly binds to p65, leading to its ubiquitination and degradation. Interestingly, p300 acetylation of p65 blocks FBXW2 induced p65 ubiquitination. FBXW2-p65 axis is a crucial regulator of SOX2-induced stemness in breast cancer. Moreover, FBXW2 inhibits breast tumor growth by regulating p65 degradation in vitro and in vivo. FBXW2 overexpression abrogates the effects of p65 on paclitaxel resistance in vitro and in vivo. Furthermore, FBXW2 induced p65 degradation is also confirmed in FBXW2-knockout mice. Our results identify FBXW2 as an important E3 ligase for p65 degradation, which provide insights into the tumor suppressor functions of FBXW2 in breast cancer.

Functional roles of the SHCBP1 and KIF23 interaction in modulating the cell-cycle and cisplatin resistance of head and neck squamous cell carcinoma.

BACKGROUND: This study aimed to explore the functional roles of Shc SH2-domain-binding protein 1 (SHCBP1) and Kinesin Family Member 23 (KIF23) in HPV-negative head and neck squamous cell carcinoma (HNSCC). METHODS: Bioinformatic analysis was conducted using data from The Cancer Genome Atlas (TCGA) and GSE103322. HNSCC cell lines were used for in vitro and in vivo analysis. RESULTS: SHCBP1 upregulation was associated with unfavorable survival. SHCBP1 knockdown reduced cell proliferation and increased the cisplatin sensitivity of SCC9/SCC25 cells. SHCBP1 interacted with KIF23 via its Nesd homology domain (NHD) domain, which was important for its nucleus localization. SHCBP1 positively modulated KIF23 expression and activated phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), extracellular signal regulated kinase (ERK)1/2, nuclear factor kappa B (NF/κB)-p65, and Wnt/ß-catenin signaling. KIF23 knockdown abrogated cisplatin resistance induced by SHCBP1 overexpression. CONCLUSION: SHCBP1 interacts with KIF23 and cooperatively regulates cell-cycle progression and cisplatin resistance of HNSCC tumor cells.

[Research Progress of FAM60A in the Regulation of Cellular Function].

FAM60A,a cell cycle protein,is a subunit of the SIN3 transcription regulator family member A/histone deacetylase(SIN3-HDAC)complex and plays an important role in cell cycle regulation,cell morphology change,cell proliferation,differentiation and migration,early embryogenesis and so on.Studies in recent years have shown that FAM60A plays a role in the occurrence and development of tumors including human osteosarcoma,esophageal cancer,gastric cancer,lung cancer and liver cancer,providing a new research direction for tumor diagnosis and treatment.Based on the research results in recent years at home and abroad,this paper discussed the effects of FAM60A on cellular functions.

Positive regulation of PFKFB3 by PIM2 promotes glycolysis and paclitaxel resistance in breast cancer.

BACKGROUND: Breast cancer (BC) is one of the most common female malignancies in the world. Chemotherapeutic resistance is the major cause of BC therapy failure, leading to tumor recurrence and metastasis. Studies have illustrated the close relationship between glycolysis and BC progression and drug resistance. The key glycolysis regulator, PFKFB3 makes a difference during BC progression and drug resistance. However, the mechanism remains to be unknown. METHODS: Mass spectrometry analyses were used to found that PIM2 was a potential new binding protein of PFKFB3. Co-immunoprecipitated and western blot were used to verify the interaction between PIM2 and PFKFB3 in BC and the molecular mechanism by which PIM2 phosphorylates PFKFB3 in regulating the protein function. PFKFB3 mutant forms were used to demonstrate the need for PFKFB3 in BC drug resistance. RESULTS: We identified that PIM2 is a new binding protein of PFKFB3. We used biochemical methods to determine that PIM2 can directly bind and change the phosphorylation of PFKFB3 at Ser478 to enhance PFKFB3 protein stability through the ubiquitin-proteasome pathway. Importantly, phosphorylation of PFKFB3 at Ser478 promoted glycolysis, BC cell growth, and paclitaxel resistance together with PIM2 in vitro and in vivo. CONCLUSION: Our study demonstrates that PIM2 mediates PFKFB3 phosphorylation thus regulates glycolysis and paclitaxel resistance to promote tumor progression in BC and provides preclinical evidence for targeting PFKFB3 as a new strategy in BC treatment to battle paclitaxel resistance.

Efficacy and safety of endoscopic submucosal dissection versus endoscopic mucosal resection for superficial esophageal carcinoma: a systematic review and meta-analysis.

Endoscopic submucosal dissection (ESD) has been developed to overcome the limitations of endoscopic mucosal resection (EMR). Yet, the potential for EMR should not be ignored. This study aimed to compare the efficacy and safety of ESD and EMR in the treatment of superficial esophageal carcinoma (SEC). All relevant articles were retrieved from electronic databases. The primary outcomes included en bloc resection, curative resection, R0 resection, and local recurrence rates. Secondary outcomes included procedure time, rates of perforation, bleeding, and postoperative stricture. Subgroup analyses based on histologic types and lesion sizes were conducted. Twenty-two studies were enrolled. Overall results showed higher en bloc, curative, and R0 resection rate, and lower recurrence rate in ESD compared with EMR. ESD was significantly more time-consuming and induced more perforations than EMR procedure. In subgroup analyses of squamous cell carcinoma (SCC) and Barrett's esophagus (BE)-associated neoplasia and esophageal adenocarcinoma (EAC) subtypes, ESD also excelled in en bloc, curative, R0 resection and local recurrence rates. However, in subgroup analysis stratifying outcomes according to lesion sizes, the superior effect of ESD in en bloc resection, curative resection, and local recurrence rate only manifested when lesion size >20 mm. Overall, ESD seemed to have superior efficacy and similar safety profiles compared to EMR in treating SCC, BE-associated neoplasia and EAC. Nevertheless, the selection of ESD or EMR should take lesion size into consideration. EMR is appropriate when lesion size ≤10 mm, EMR and ESD are both applicable for lesion between 11 and 20 mm, and ESD is preferable for lesions >20 mm. More evidences are needed to confirm the current findings.

Photodynamic Therapy Using HMME for Port-Wine Stains: Clinical Effectiveness and Sonographic Appearance.

This study aims at exploring the clinical efficacy and sonographic changes of photodynamic therapy (PDT) using Hematoporphyrin Monomethyl Ether (HMME) for the treatment of port-wine stains (PWS). Forty-five patients with PWS were recruited between March 2017 and June 2018 from the Department of Dermatology of The Third Affiliated Hospital of Soochow University. Five cases were of the pink type, thirty-nine cases were of the purple-red type, and one case was of the thickened type. All patients received three treatment sessions of PDT. After covering normal skin outside the treated area, patients received an intravenous injection of 5 mg/kg HMME within 20 minutes. The affected areas were exposed to a 532 nm LED light and were kept vertically at a distance of 10 cm. The irradiation energy density was set between 80 and 110 J/cm2 in 15-minute sessions. Intermittent power density adjustment was performed at a rate of 5 mW/cm2, and the treatment was withheld when the endpoint reaction appeared. Three follow-ups were performed before and after treatment, respectively, and the efficacy, thickness, and density of skin before and after treatment were evaluated with high-frequency ultrasound. The overall efficacy rate was 97.78% in forty-five cases after treatment for three sessions. Efficacy was related to age (P = 0.029) and lesion severity (P < 0.001). There were significant differences in the efficacy between the groups of <18 years old, 18-29 years old, and >29 years old (P = 0.029). A marked decrease in the numbers of distorted enlarged blood vessels per unit of the lesion was observed under high-frequency ultrasound. There were significant differences in skin thickness and skin density before and after treatment (F = 14.528, 5.428, P < 0.001). The swelling was reported to varying degrees in the treated areas in 23 patients with cheek lesion and in 6 frontal lesions. Hyperpigmentation after inflammation was observed in four patients that faded spontaneously after two months. In conclusion, photodynamic therapy for the treatment of PWS using HMME is effective and safe with few adverse reactions. Moreover, monitoring the changes in skin thickness and density of lesion tissue using high-frequency ultrasound can objectively evaluate the clinical efficacy of HMME photodynamic therapy and provide the basis for the formulation of individualized photodynamic therapy.

Fructose-1, 6-bisphosphatase 1 interacts with NF-κB p65 to regulate breast tumorigenesis via PIM2 induced phosphorylation.

Rationale: Fructose-1, 6-bisphosphatase 1 (FBP1), a rate-limiting enzyme in gluconeogenesis, was recently shown to be a tumor suppressor and could mediate the activities of multiple transcriptional factors via its non-canonical functions. However, the underlying mechanism of posttranscriptional modification on the non-canonical functions of FBP1 remains elusive. Methods: We employed immunoaffinity purification to identify binding partner(s) and used co-immunoprecipitation to verify their interactions. Kinase reaction was used to confirm PIM2 could phosphorylate FBP1. Overexpression or knockdown proteins were used to assess the role in modulating p65 protein stability. Mechanistic analysis was involved in protein degradation and polyubiquitination assays. Nude mice and PIM2-knockout mice was used to study protein functions in vitro and in vivo. Results: Here, we identified Proviral Insertion in Murine Lymphomas 2 (PIM2) as a new binding partner of FBP1, which could phosphorylate FBP1 on Ser144. Surprisingly, phosphorylated FBP1 Ser144 abrogated its interaction with NF-κB p65, promoting its protein stability through the CHIP-mediated proteasome pathway. Furthermore, phosphorylation of FBP1 on Ser144 increased p65 regulated PD-L1 expression. As a result, phosphorylation of FBP1 on Ser144 promoted breast tumor growth in vitro and in vivo. Moreover, the levels of PIM2 and pSer144-FBP1 proteins were positively correlated with each other in human breast cancer and PIM2 knockout mice. Conclusions: Our findings revealed that phosphorylation noncanonical FBP1 by PIM2 was a novel regulator of NF-κB pathway, and highlights PIM2 inhibitors as breast cancer therapeutics.