Immune cell patterns before and after neoadjuvant immune checkpoint blockade combined with chemoradiotherapy in locally advanced esophageal squamous cell carcinoma.

BACKGROUND: Neoadjuvant immune checkpoint blockade (ICB) combined with chemoradiotherapy offers high pathologic complete response (pCR) rate for patients with locally advanced esophageal squamous cell carcinomas (ESCC). But the dynamic tumor immune microenvironment modulated by such neoadjuvant therapy remains unclear. PATIENTS AND METHODS: A total of 41 patients with locally advanced ESCC were recruited. All patients received neoadjuvant toripalimab combined with concurrent chemoradiotherapy. Matched pre- and post-treatment tissues were obtained for fluorescent multiplex immunohistochemistry (mIHC) and IHC analyses. The densities and spatial distributions of immune cells were determined by HALO modules. The differences of immune cell patterns before and after neoadjuvant treatment were investigated. RESULTS: In the pre-treatment tissues, more stromal CD3 + FoxP3 + Tregs and CD86+/CD163 + macrophages were observed in patients with residual tumor existed in the resected lymph nodes (pN1), compared with patients with pCR. The majority of macrophages were distributed in close proximity to tumor nest in pN1 patients. In the post-treatment tissues, pCR patients had less CD86 + cell infiltration, whereas higher CD86 + cell density was significantly associated with higher tumor regression grades (TRG) in non-pCR patients. When comparing the paired pre- and post-treatment samples, heterogeneous therapy-associated immune cell patterns were found. Upon to the treatment, CD3 + T lymphocytes were slightly increased in pCR patients, but markedly decreased in non-pCR patients. In contrast, a noticeable increase and a less obvious decrease of CD86 + cell infiltration were respectively depicted in non-pCR and pCR patients. Furthermore, opposite trends of the treatment-induced alterations of CD8 + and CD15 + cell infiltrations were observed between pN0 and pN1 patients. CONCLUSIONS: Collectively, our data demonstrate a comprehensive picture of tumor immune landscape before and after neoadjuvant ICB combined with chemoradiotherapy in ESCC. The infiltration of CD86 + macrophage may serve as an unfavorable indicator for neoadjuvant toripalimab combined with chemoradiotherapy.

Prevalence and Clustering of Cardiovascular Disease Risk Factors among Adults Along the Lancang-Mekong River: A Cross-Sectional Study from Low- and Middle-Income Countries.

Background: Progress in cardiovascular health is increasingly concentrated in high-income countries, while the burden of cardiovascular disease (CVD) is high in low- and middle-income countries, a clear health inequity that must be urgently addressed. Objective: This study aims to evaluate the prevalence and clustering of CVD risk factors in the three Lancang-Mekong regions. Methods: We conducted a population-based cross-sectional survey from January 2021 to March 2023 in China, Laos, and Cambodia. We compared the prevalence and clustering of CVD risk factors-including hypertension, dyslipidemia, diabetes mellitus, overweight/obesity, current smoking status, current drinking status, inadequate vegetable and fruit intake, and insufficient physical activity-across the three regions, further stratifying the data by gender and age. Multivariate logistic regression models were performed to explore factors influencing the aggregation of CVD risk factors (≥2, ≥3, ≥4). Results: A total of 11,005 adults were included in the study. Hypertension emerged as the primary metabolic risk factor in Laos (36.8%) and Cambodia (23.5%), whereas overweight/obesity was the primary risk factor in China (37.6%). In terms of behavioral risk factors, participants in all three regions showed insufficient vegetable and fruit intake. The prevalence of individuals without CVD risk factors was 10% in China, 1.9% in Laos, and 5.2% in Cambodia. Meanwhile, the prevalence of two or more risk factors was 64.6% in China, 79.2% in Laos, and 76.0% in Cambodia. Multivariate logistic regression models revealed that the propensity for CVD risk factors clustering was higher in men and increased with age in all three countries. Conclusions: CVD risk factors and multiple clustering are pressing health threats among adults in low- and middle-income areas along the Lancang-Mekong River Basin. This study highlights the urgent need for proactive tailored strategies to control CVD risk factors.

The Effect and Mechanism of Fructus lycii on Improvement of Exercise Fatigue Using a Network Pharmacological Approach with in vitro Experimental Verification.

Objective: This study aimed to investigate the effect and underlying mechanism of Fructus lycii in improving exercise fatigue. Methods: A network pharmacological approach was used to explore potential mechanisms of action of Fructus lycii. Skeletal muscle C2C12 cells and immunofluorescence were employed to verify the effect and mechanism of the representative components in Fructus lycii predicted by network pharmacological analysis. Results: Six potential active components, namely quercetin, ß-sitosterol, stigmasterol, 7-O-methylluteolin-6-C-beta-glucoside_qt, atropine, and glycitein, were identified to have potency in improving exercise fatigue via multiple pathways, such as the PI3K-Akt, neuroactive ligand-receptor interaction, IL-17, TNF, and MAPK signaling pathways. The immunofluorescence results indicated that quercetin, a significant active component in Fructus lycii, increased the mean staining area of 2-NBDG, TMRM, and MitoTracker, and decreased the area of CellRox compared to the control. Furthermore, the protein expression levels of p-38 MAPK, p-MAPK, p-JNK, p-PI3K, and p-AKT markedly increased after quercetin treatment. Conclusion: Fructus lycii might alleviate exercise fatigue through multiple components and pathways. Among these, quercetin appears to improve exercise fatigue by enhancing energy metabolism and reducing oxidative stress. The PI3K-AKT and MAPK signaling pathways also appear to play a role in this process.

Lnc-ANRIL modulates the immune response associated with NF-κB pathway in LPS-stimulated bovine mammary epithelial cells.

BACKGROUND: The antisense noncoding RNA in the INK4 locus (ANRIL) has been confirmed related to multiple disease progression, but the role and exact mechanisms of lnc-ANRIL in lipopolysaccharide (LPS)-induced inflammation of bovine mammary epithelial cells (MAC-T) remain unclear. AIMS: This manuscript focused on expounding the functional role of lnc-ANRIL through experiments performed in MAC-T. METHODS: At the in vitro level, we established a Bovine mammary epithelial cell (BMEC) cell model of mastitis by LPS treatment. Transfection of siRNA was examined by immunofluorescence localization and RT-qPCR. CCK8, clonogenic assay and EdU were used to detect the proliferation ability of the cells. Cell cycle and apoptosis were detected by flow cytometry and Western blot. The levels of inflammatory factors and oxidative stress markers were detected by ELISA kits. RESULTS: Cell Counting Kit-8, colony formation, and 5-ethynyl-20-deoxyuridine were adopted and the data illustrated that LPS could significantly suppress the cell proliferation, while knockdown of lnc-ANRIL expression obviously promoted MAC-T cell proliferation compared with LPS or LPS + si-NC group. Flow cytometry analysis demonstrated that lnc-ANRIL could induce MAC-T cell apoptosis. In addition, downregulation of lnc-ANRIL affected LPS-induced immune response by regulating inflammatory factor expressions and modulating the nuclear factor kappa B (NF-κB) axis in MAC-T cells. CONCLUSION: Our results suggest that lnc-ANRIL is involved in the regulation of cell proliferation, cell cycle, and cell apoptosis of MAC-T cells, and plays an important role in the inflammatory and immune response of MAC-T cells through the regulation of the NF-κB pathway, proposing new therapeutic strategies for the treatment of innate immune response-related disease such as bovine mastitis.

Regular gastroscopy and colonoscopy during the evaluation of urachal cancer: do we really need them?

PURPOSE: Urachal cancer is similar to gastrointestinal adenocarcinoma in histology, and gastroscopy/colonoscopy is often administered during perioperative evaluation. However, gastroscopy and colonoscopy have corresponding disadvantages. This study discusses whether gastroscopy/colonoscopy is truly necessary for patients with urachal cancer. PATIENTS AND METHODS: A total of 166 bladder adenocarcinoma cases diagnosed at Sun Yat-sen University Cancer Center were retrospectively reviewed and divided into two groups (urachal cancer and nonurachal cancer), and perioperative evaluations were retrieved. RESULTS: There were 78 patients with urachal cancer, the median age was 48 years, and 59 were male. Perioperative gastroscopy/colonoscopy revealed 5 intestinal polyps and 1 adenoma during these evaluations, and no primary gastrointestinal cancer was found. Meanwhile, preoperative imaging evaluation did not detect significant gastrointestinal lesions. For 88 patients with nonurachal cancer, including primary bladder adenocarcinoma and metastatic tumors from gastrointestinal cancer, the median age was 56 years, and 64 were male. Preoperative imaging evaluation demonstrated 36 cases of gastrointestinal lesions, and 32 were confirmed by gastroscopy/colonoscopy; the other 4 were negative. Another 4 cases of colon cancer were detected by regular colonoscopy for suspected primary bladder adenocarcinoma. In all, 35 cases of colon cancer and 1 case of gastric cancer were identified by endoscopic examination. The diagnostic consistency of imaging and gastrointestinal endoscopy was favorable (P < 0.001), and the negative predictive value and diagnostic efficiency of imaging were 96.9% and 94.6%, respectively. CONCLUSIONS: The vast majority of gastrointestinal cancer cases can be identified by assessment of the patient's clinical symptoms, meticulous physical examination, and imaging evaluation. We recommend that gastroscopy/colonoscopy only be applied to patients with urachal cancer when the above examinations are positive.

Optimal interval timing between transurethral resection of bladder tumors and Bacillus Calmette-Guerin perfusion.

OBJECTIVE: There is no consensus regarding the best interval time between transurethral resection of a bladder tumor and Bacillus Calmette-Guerin (BCG) perfusion. This study was to explore whether the interval time has an impact on the prognosis and adverse effects. METHODS: We retrospectively reviewed the clinical data of patients who received BCG intravesical perfusion at Sun Yat-sen University Cancer Center (SYSUCC) from September 2015 to October 2021. Recurrence-free survival (RFS) and progression-free survival were the primary endpoints. Cox regression was used to explore independent predictors. The association between interval time and adverse effect grade was detected by logistic regression. Propensity score matching (PSM) was performed. RESULTS: A total of 403 patients were enrolled, the median interval time was 24 days (6-163 days), and the follow-up was 28 months (7-82 months). Eighty-eight (20.9%) patients relapsed, and 40 patients (10.0%) suffered progression. The multivariate Cox regression analysis confirmed that interval time was an independent predictor of RFS (p = 0.017). Notably, when the interval time was less than or equal to 26 days, there was a trend toward better RFS, PSM resulted in 65 matched pairs in each group, and Kaplan-Meier analysis showed that there was a significant difference in RFS between groups (p = 0.009). The logistic regression analysis showed that there was no correlation between interval time and adverse effects and their grades (p > 0.05). CONCLUSIONS: We considered that the first BCG perfusion could be performed within 2-4 weeks after surgery.

Long-term evolution of LR-2, LR-3 and LR-4 observations in HBV-related cirrhosis based on LI-RADS v2018 using gadoxetic acid-enhanced MRI.

PURPOSE: To investigate the long-term evolution of LR-2, LR-3 and LR-4 observations in patients with hepatitis B virus (HBV)-related cirrhosis based on LI-RADS v2018 and identify predictors of progression to a malignant category on serial gadoxetic acid-enhanced magnetic resonance imaging (Gd-EOB-MRI). METHODS: This retrospective study included 179 cirrhosis patients with untreated indeterminate observations who underwent Gd-EOB-MRI exams at baseline and during the follow-up period between June 2016 and December 2021. Two radiologists independently assessed the major features, ancillary features, and LI-RADS category of each observation at baseline and follow-up. In cases of disagreement, a third radiologist was consulted for consensus. Cumulative incidences for progression to a malignant category (LR-5 or LR-M) and to LR-4 or higher were analyzed for each index category using Kaplan‒Meier methods and compared using log-rank tests. The risk factors for malignant progression were evaluated using a Cox proportional hazard model. RESULTS: A total of 213 observations, including 74 (34.7%) LR-2, 95 (44.6%) LR-3, and 44 (20.7%) LR-4, were evaluated. The overall cumulative incidence of progression to a malignant category was significantly higher for LR-4 observations than for LR-3 or LR-2 observations (each P < 0.001), and significantly higher for LR-3 observations than for LR-2 observations (P < 0.001); at 3-, 6-, and 12-month follow-ups, the cumulative incidence of progression to a malignant category was 11.4%, 29.5%, and 39.3% for LR-4 observations, 0.0%, 8.5%, and 19.6% for LR-3 observations, and 0.0%, 0.0%, and 0.0% for LR-2 observations, respectively. The cumulative incidence of progression to LR-4 or higher was higher for LR-3 observations than for LR-2 observations (P < 0.001); at 3-, 6-, and 12-month follow-ups, the cumulative incidence of progression to LR-4 or higher was 0.0%, 8.5%, and 24.6% for LR-3 observations, and 0.0%, 0.0%, and 0.0% for LR-2 observations, respectively. In multivariable analysis, nonrim arterial phase hyperenhancement (APHE) [hazard ratio (HR) = 2.13, 95% CI 1.04-4.36; P = 0.038], threshold growth (HR = 6.50, 95% CI 2.88-14.65; P <0.001), and HBP hypointensity (HR = 16.83, 95% CI 3.97-71.34; P <0.001) were significant independent predictors of malignant progression. CONCLUSION: The higher LI-RADS v2018 categories had an increasing risk of progression to a malignant category during long-term evolution. Nonrim APHE, threshold growth, and HBP hypointensity were the imaging features that were significantly predictive of malignant progression.

Identification of tumor immunophenotypes associated with immunotherapy response in bladder cancer.

OBJECTIVES: This study aims to reveal immunophenotypes associated with immunotherapy response in bladder cancer, identify the signature genes of immune subtypes, and provide new molecular targets for improving immunotherapy response. METHODS: Bladder cancer immunophenotypes were characterized in the bulk RNA sequencing dataset GSE32894 and Imvigor210, and gene expression signatures were established to identify the immunophenotypes. Expression of gene signatures were validated in single-cell RNA sequencing dataset GSE145140 and human proteins expression data source. Investigation of Immunotherapy Response was performed in IMvigor210 dataset. Prognosis of tumor immunophenotypes was further analyzed. RESULTS: Inflamed and immune-excluded immunophenotypes were characterized based on the tumor immune cell scores. Risk score models that were established rely on RNA sequencing profiles and overall survival of bladder cancer cohorts. The inflamed tumors had lower risk scores, and the low-risk tumors were more likely to respond to atezolizumab, receiving complete response/partial response (CR/PR). Patients who responded to atezolizumab had higher SRRM4 and lower NPHS1 and TMEM72 expression than the non-responders. SRRM4 expression was a protective factor for bladder cancer prognosis, while the NPHS1 and TMEM72 showed the opposite pattern. CONCLUSION: This study provided a novel classification method for tumor immunophenotypes. Bladder cancer immunophenotypes can predict the response to immune checkpoint blockade. The immunophenotypes can be identified by the expression of signature genes.

CD8+ tissue-resident memory T cells induce oral lichen planus erosion via cytokine network.

CD8+ tissue-resident memory T (CD8+ Trm) cells play key roles in many immune-inflammation-related diseases. However, their characteristics in the pathological process of oral lichen planus (OLP) remains unclear. Therefore, we investigated the function of CD8+ Trm cells in the process of OLP. By using single-cell RNA sequencing profiling and spatial transcriptomics, we revealed that CD8+ Trm cells were predominantly located in the lamina propria adjacent to the basement membrane and were significantly increased in patients with erosive oral lichen planus (EOLP) compared to those with non-erosive oral lichen planus (NEOLP). Furthermore, these cells displayed enhanced cytokine production, including IFN-γ (Interferon-gamma, a pro-inflammatory signaling molecule), TNF-α (Tumor Necrosis Factor-alpha, a cytokine regulating inflammation), and IL-17 (Interleukin-17, a cytokine involved in immune response modulation), in patients with EOLP. And our clinical cohort of 1-year follow-up was also supported the above results in RNA level and protein level. In conclusion, our study provided a novel molecular mechanism for triggering OLP erosion by CD8+ Trm cells to secrete multiple cytokines, and new insight into the pathological development of OLP.

Clinical Analysis of Laparoscopic Common Bile Duct Primary Suture and T-Tube Drainage in the Treatment of Common Bile Duct Stones.

Background: At present, T-tube drainage or primary suture for common bile duct stones is common management. Methods: The clinical data of 100 patients who underwent laparoscopic common bile duct exploration and T-tube drainage or primary suture for common bile duct stones from 2019 to 2021 were analyzed retrospectively, including 50 cases of primary suture and 50 cases of T-tube drainage. Results: The operation time and postoperative hospital stay of patients with primary suture were lower than those in T-tube drainage group (P < .05). There was no significant difference in the incidence of postoperative complications and hospitalization expenses between the two groups (P > .05). Conclusions: It has been suggested that the therapeutic effect of laparoscopic primary suture is better than that of T-tube drainage; although they have different indications, they should be selected according to the specific individual situation of patients.

Kinase Inhibitor VvBKI1 Interacts with Ascorbate Peroxidase VvAPX1 Promoting Plant Resistance to Oomycetes.

Downy mildew caused by oomycete pathogen Plasmopara viticola is a devastating disease of grapevine. P. viticola secretes an array of RXLR effectors to enhance virulence. One of these effectors, PvRXLR131, has been reported to interact with grape (Vitis vinifera) BRI1 kinase inhibitor (VvBKI1). BKI1 is conserved in Nicotiana benthamiana and Arabidopsis thaliana. However, the role of VvBKI1 in plant immunity is unknown. Here, we found transient expression of VvBKI1 in grapevine and N. benthamiana increased its resistance to P. viticola and Phytophthora capsici, respectively. Furthermore, ectopic expression of VvBKI1 in Arabidopsis can increase its resistance to downy mildew caused by Hyaloperonospora arabidopsidis. Further experiments revealed that VvBKI1 interacts with a cytoplasmic ascorbate peroxidase, VvAPX1, an ROS-scavenging protein. Transient expression of VvAPX1 in grape and N. benthamiana promoted its resistance against P. viticola, and P. capsici. Moreover, VvAPX1 transgenic Arabidopsis is more resistant to H. arabidopsidis. Furthermore, both VvBKI1 and VvAPX1 transgenic Arabidopsis showed an elevated ascorbate peroxidase activity and enhanced disease resistance. In summary, our findings suggest a positive correlation between APX activity and resistance to oomycetes and that this regulatory network is conserved in V. vinifera, N. benthamiana, and A. thaliana.

Necroptosis signaling and mitochondrial dysfunction cross-talking facilitate cell death mediated by chelerythrine in glioma.

Glioma is the most common primary malignant brain tumor with poor survival and limited therapeutic options. Chelerythrine (CHE), a natural benzophenanthridine alkaloid, has been reported to exhibit the anti-tumor effects in a variety of cancer cells. However, the molecular target and the signaling process of CHE in glioma remain elusive. Here we investigated the underlying mechanisms of CHE in glioma cell lines and glioma xenograft mice model. Our results found that CHE-induced cell death is associated with RIP1/RIP3-dependent necroptosis rather than apoptotic cell death in glioma cells at the early time. Mechanism investigation revealed the cross-talking between necroptosis and mitochondria dysfunction that CHE triggered generation of mitochondrial ROS, mitochondrial depolarization, reduction of ATP level and mitochondrial fragmentation, which was the important trigger for RIP1-dependent necroptosis activation. Meanwhile, PINK1 and parkin-dependent mitophagy promoted clearance of impaired mitochondria in CHE-incubated glioma cells, and inhibition of mitophagy with CQ selectively enhanced CHE-induced necroptosis. Furthermore, early cytosolic calcium from the influx of extracellular Ca2+ induced by CHE acted as important "priming signals" for impairment of mitochondrial dysfunction and necroptosis. Suppression of mitochondrial ROS contributed to interrupting positive feedback between mitochondrial damage and RIPK1/RIPK3 necrosome. Lastly, subcutaneous tumor growth in U87 xenograft was suppressed by CHE without significant body weight loss and multi-organ toxicities. In summary, the present study helped to elucidate necroptosis was induced by CHE via mtROS-mediated formation of the RIP1-RIP3-Drp1 complex that promoted Drp1 mitochondrial translocation to enhance necroptosis. Our findings indicated that CHE could potentially be further developed as a novel therapeutic strategy for treatment of glioma.

Grapevine VaRPP13 protein enhances oomycetes resistance by activating SA signal pathway.

KEY MESSAGE: Expression of the VaRPP13 in Arabidopsis and tobacco enhanced resistance to oomycete pathogens, and this enhancement is closely related to the activation of salicylic acid (SA) signaling pathway. Resistance (R) genes, which usually contain a nucleotide-binding site and a leucine-rich repeat (NBS-LRR) domain, play crucial roles in disease resistance. In this study, we cloned a CC-NBS-LRR gene VaRPP13 from Vitis amurensis 'Shuang Hong' grapevine, and investigated its function on disease resistance. VaRPP13 expression was induced by Plasmopara viticola, an oomycetes pathogen causing downy mildew disease in grapevine. Heterologous expression VaRPP13 could also enhance resistance to Hyaloperonospora arabidopsidis in Arabidopsis thaliana and Phytophthora capsici in Nicotiana benthamiana, both oomycete pathogens. Further study indicated that VaRPP13 could enhance the expression of genes in SA signal pathway, while exogenous SA could also induce the expression of VaRPP13. In conclusion, our studies demonstrated that VaRPP13 contributes to a broad-spectrum resistance to oomycetes via activating SA signaling pathway.

Dietary supplementation with low and high polymerization inulin ameliorates adipose tissue inflammation via the TLR4/NF-κB pathway mediated by gut microbiota disturbance in obese dogs.

Inflammation induced by gut microbiota disorder plays an important role in promoting obesity. Inulin has beneficial effects on gut microflora and metabolic endotoxaemia. However, the chain length of inulin determines its different physiological effects. This study aimed to investigate the effect of low polymerization inulin (LPI) and high polymerization inulin (HPI) on inflammation in dogs with obesity induced by a high-fat diet and its potential mechanism. HPI, relative to LPI, significantly reduced the concentrations of LPS, IL-6 and TNF-α in serum and downregulated both the mRNA and protein expression of TLR4, NF-κB, TNF-α and IL-6 in adipose tissue. HPI and LPI intervention reduced adipose tissue fatty accumulation, which improved obesity. Supplementation with LPI and HPI increased gut microbiota diversity and altered specific bacterial populations at both the phylum and genus levels. The relative abundances of Prevotella, Fusobacterium and Enterobacter, which were positively correlated with the serum concentrations of LPS, IL-6 and TNF-α, were reduced. Our results demonstrate that both LPI and HPI can be used as an effective strategy for reducing inflammation and regulating gut microbiota, which can ameliorate obesity in dogs. Moreover, HPI exerts more positive regulation of the inflammatory response and gut microbiota dysfunction than LPI.

Cortisol Stimulates Local Progesterone Withdrawal Through Induction of AKR1C1 in Human Amnion Fibroblasts at Parturition.

Fetal membrane activation is seen as being one of the crucial triggering components of human parturition. Increased prostaglandin E2 (PGE2) production, a common mediator of labor onset in virtually all species, is recognized as one of the landmark events of membrane activation. Fetal membranes are also equipped with a high capacity of cortisol regeneration by 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1), and the cortisol regenerated potently induces PGE2 synthesis, an effect normally suppressed by progesterone during gestation. There is no precipitous decline of progesterone synthesis in human parturition. It is intriguing how this suppression is lifted in parturition. Here, we investigated this issue by using human amnion tissue and primary amnion fibroblasts which synthesize the most PGE2 in the fetal membranes. Results showed that the expression of 11ß-HSD1 and aldo-keto reductase family 1 member C1 (AKR1C1), a progesterone-inactivating enzyme, increased in parallel in human amnion tissue with gestational age toward the end of gestation and at parturition. Cortisol induced AKR1C1 expression via the transcription factor CCAAT enhancer binding protein δ (C/EBPδ) in amnion fibroblasts. Inhibition of AKR1C1 not only blocked progesterone catabolism induced by cortisol, but also enhanced the suppression of cortisol-induced cyclooxygenase-2 (COX-2) expression by progesterone in amnion fibroblasts. In conclusion, our results indicate that cortisol regenerated in the fetal membranes triggers local progesterone withdrawal through enhancement of AKR1C1-mediated progesterone catabolism in amnion fibroblasts, so that the suppression of progesterone on the induction of COX-2 expression and PGE2 synthesis by cortisol can be lifted for parturition.

Inflammatory myofibroblastic tumor after breast prosthesis: A case report and literature review.

BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are defined as tumors composed of differentiated myofibroblastic spindle cells, usually accompanied by numerous plasma cells and lymphocytes, and classified as intermediate (occasionally metastatic) by the World Health Organization. Its pathogenesis and biological behavior have not yet been elucidated. Breast IMT is extremely rare, and prosthesis implantation combined with IMT has not been reported. This study reports a case of IMT following resection of a malignant phyllodes tumor of the left breast and implantation of a prosthesis. CASE SUMMARY: A 41-year-old female presented to our hospital with a mass in the left breast for 3 mo. The patient had undergone resection of a large mass in her left breast pathologically diagnosed as a malignant phyllodes tumor and implantation of a prosthesis five years prior. Ultrasonic examination revealed an oval mass in the left breast, and the patient underwent left breast mass resection and prosthesis removal. Light microscopy revealed the spindle cells to be diffusely proliferated, with a large number of neutrophils, lymphocytes, and plasma cell infiltration. Immunohistochemical staining revealed that the spindle cells were partially positive for smooth muscle actin, which is positive for BCL-2 and cluster of differentiation (CD) 99 but were negative for anaplastic lymphoma kinase, cytokeratin, S-100 protein, desmin, and CD34. The final diagnosis was IMT. No recurrence or metastasis was observed during the 5-year postoperative follow-up. CONCLUSION: Prosthesis implantation may be one of the causes of IMT, but further investigation is necessary to prove it.

ACT001 inhibits pituitary tumor growth by inducing autophagic cell death via MEK4/MAPK pathway.

ACT001, derived from traditional herbal medicine, is a novel compound with effective anticancer activity in clinical trials. However, little is known regarding its role in pituitary adenomas. Here, we demonstrated that ACT001 suppressed cell proliferation and induced cell death of pituitary tumor cells in vitro and in vivo. ACT001 was also effective in suppressing the growth of different subtypes of human pituitary adenomas. The cytotoxic mechanism ACT001 employed was mainly related to autophagic cell death (ACD), indicated by autophagosome formation and LC3-II accumulation. In addition, ACT001-mediated inhibitory effect decreased when either ATG7 was downregulated or cells were cotreated with autophagy inhibitor 3-methyladenine (3-MA). RNA-seq analysis showed that mitogen-activated protein kinase (MAPK) pathway was a putative target of ACT001. Specifically, ACT001 treatment promoted the phosphorylation of JNK and P38 by binding to mitogen-activated protein kinase kinase 4 (MEK4). Our study indicated that ACT001-induced ACD of pituitary tumor cells via activating JNK and P38 phosphorylation by binding with MEK4, and it might be a novel and effective anticancer drug for pituitary adenomas.

A new cyclic peptide from the fibrous root of Pseudostellaria heterophylla.

A new cyclic peptide, Pseudostellarin K (1), together with thirteen known compounds, including two cyclic peptides (2 and 3), one ß-carboline alkaloid (4), two amides (5 and 6), three phenylpropanoids (7-9) and other compounds (10-14), were isolated from the fibrous root of Pseudostellaria heterophylla. Their structures were elucidated by extensive spectroscopic analysis. Compounds 1, 4-6, 10 were isolated from the genus pseudostellaria for the first time. All compounds were evaluated for cytotoxic activities against MCF-7, A549, HCT-116 and SGC-7901 cell lines by MTT assay. Unfortunately, all these compounds displayed weak cytotoxic activities.

The EGFR Polymorphism Increased the Risk of Hepatocellular Carcinoma Through the miR-3196-Dependent Approach in Chinese Han Population.

BACKGROUND: Previous studies have shown that epidermal growth factor receptor (EGFR) promotes cell proliferation through the PI3K-Akt-mTOR signaling pathway and participates in the occurrence and development of hepatocellular carcinoma (HCC). Here, we focused on the functional polymorphism of EGFR in the 3'-untranslated region (UTR), aiming to reveal the potential mechanisms by which functional polymorphism is associated with the risk and development of HCC in the Han Chinese population. METHODS: This study was a hospital-based case-control study. A total of 600 patients were enrolled, and another 600 healthy volunteers served as controls. The miR-associated SNPs in EGFR were screened, and genotyping was performed by TaqMan allele differential analysis. In this study, genotyping, real-time PCR, cell transfection and double luciferase reporter gene were used for subsequent analysis. RESULTS: HBV/HCV infection instead of alcohol exposure, smoking exposure, hypertension or diabetes mellitus was associated with an increased risk of HCC. Compared with TT genotypes, TG and GG genotypes of EGFR rs884225 were significantly associated with reduced HCC risk. The stratified analysis of association between rs884225 and HCC subgroup feature reveal a highly correlation with tumor size. Furthermore, qRT-PCR confirmed that EGFR rs884225, TG and GG genotypes were more likely to bind to miR-3196 and down-regulate EGFR level in cells, thereby inhibiting cell proliferation. CONCLUSION: This study suggested that EGFR rs884225 is associated with a reduced risk of liver cancer and may be a developing biomarker.

Efficacy and safety of scleral crosslinking using poly(ethylene glycol)ether tetrasuccinimidyl glutarate for form-deprivation myopia progression in rabbits.

Myopia is becoming increasingly prevalent worldwide at an alarming rate. However, no effective treatment is available for inhibiting myopia progression. Materials chemistry advancements have made it possible to regulate mechanical properties and rate of degradation with good compatibility by developing newly crosslinking systems such as the branched polyethylene glycol (PEG) systems. Herein, we presented a PEG molecule with N-hydroxysuccinimide (NHS) ester functional groups at the chain ends as a macromolecular crosslinking agent for the treatment of myopia. We found that the scleral collagen crosslinked with the four-armed star-shaped PEG molecule with NHS ester functional group (4S-PEG) showed better biomechanical properties, increased thermal stability and higher resistance to degradation. 4S-PEG exhibited relatively low cytotoxicity for human fetal scleral fibroblasts. The retrobulbar injection of 4S-PEG at a relatively low concentration (2.5 mM) showed good effective control of the progression of form-deprivation myopia in rabbits. There were no signs of adverse effect or damage by repeated injections with 4S-PEG in rabbits. The results of this work demonstrate that 4S-PEG can serve as a robust macromolecular crosslinking agent and is expected to have promise for application in the treatment of the progression of myopia.