The time-to-surgery interval and its effect on pathological response after neoadjuvant chemoimmunotherapy in non-small cell lung cancer: a retrospective cohort study.

Background: The time to surgery (TTS) after the completion of the final cycle of neoadjuvant chemoimmunotherapy in patients with non-small cell lung cancer (NSCLC) is inconsistent. Pathological complete response (pCR) and major pathological response (MPR) are associated with enhanced survival in those with NSCLC. The optimal TTS interval remains to be determined, some studies indicated that TTS ≤6 weeks has a vital role in NSCLC prognosis. Therefore, this study aimed to determine whether TTS is correlated with pathological outcomes and to identify the factors associated with TTS. Methods: We retrospectively analyzed 82 individuals who had surgery after neoadjuvant chemoimmunotherapy for NSCLC between January 2020 and December 2023. Fifty participants were included in this study after inclusion and exclusion criteria. Participants were categorized into two groups: TTS ≤4 weeks and TTS >4 to 6 weeks. Univariate and multivariate regression analyses were employed to determine the impact of TTS on pathological response and to identify the variables associated with TTS. Variables that showed their P value <0.2 in univariate analyses were included in the multivariate analysis. Kaplan-Meier analysis was used to analyze disease-free survival (DFS). Results: Our study evaluating 50 patients revealed that patients in the TTS ≤4 weeks group achieved pCR or MPR compared to patients in the >4 to 6 weeks group (P=0.01). In univariate analyses, TTS ≤4 weeks was more correlated with achieving pCR or MPR than TTS >4 to 6 weeks [odds ratio (OR) =0.211; 95% confidence interval (CI): 0.062-0.711; P=0.01] The multivariate analysis showed that cT1 stage (compared to cT4), and cN1 stage (compared to cN0) showed statistical correlation with achieving pCR or MPR. cN1 stage was independent predictor of achieving pCR or MPR (OR =27.817; 95% CI: 1.536-503.88; P=0.02). Concerning to the DFS, TTS ≤4 weeks group and TTS >4 to 6 weeks group showed no statistical differences (2-year DFS rate were 70.6% and 72.6%, respectively). Regarding the tendency of being patients' TTS ≤4 weeks, patients with ventilatory impairment (OR =0.203; 95% CI: 0.04-0.98; P=0.047) were more tending to prolong the TTS to >4 to 6 weeks. Conclusions: TTS ≤4 weeks was associated with a significant improvement of pathological response. Therefore, patients with NSCLC should undergo surgery within 4 weeks after the last cycle of neoadjuvant chemoimmunotherapy.

Regulation of hippocampal miRNA expression by intestinal flora in anxiety-like mice.

This study investigated the possible interaction between gut flora and miRNAs and the effect of both on anxiety disorders. The model group was induced with chronic restraint stress (CRS) and each group was tested for anxiety-like behaviour by open field test and elevated plus maze test. Meanwhile, the gut flora was analysed by 16S rRNA high-throughput sequencing. The miRNAs in hippocampus were analysed by high-throughput sequencing, and the key miRNAs were obtained by using the method of bioinformatics analysis. PCR was used to verify the significantly related key miRNAs. Spearman correlation analysis was used to explore the correlation between behaviour, key miRNAs and differential gut microbiota. The 16S rRNA high-throughput sequencing result showed that the gut flora was dysregulated in the model group. In particular, Verrucomicrobia, Akkermansia, Anaerostipes, Ralstonia, Burkholderia and Anaeroplasma were correlated with behaviour. The results of miRNA high-throughput sequencing analysis and bioinformatics analysis showed that 7 key miRNAs influenced the pathogenesis of anxiety, and qRT-PCR results were consistent with the high-throughput sequencing results. Mmu-miR-543-3p and mmu-miR-26a-5p were positively correlated with Verrucomicrobia, Akkermansia and Anaerostipes. Therefore, we infer that chronic stress caused the decrease of Akkermansia abundance, which may aggravate the decrease of mmu-miR-543-3p and mmu-miR-26a-5p expression, leading to the increase of SLC1A2 expression. In conclusion, gut flora has played an important influence on anxiety with changes in miRNAs.

CXCL3: A key player in tumor microenvironment and inflammatory diseases.

CXCL3 (C-X-C Motif Chemokine 3), a member of the C-X-C chemokine subfamily, operates as a potent chemoattractant for neutrophils, thereby orchestrating the recruitment and migration of leukocytes alongside eliciting an inflammatory response. Recent inquiries have shed light on the pivotal roles of CXCL3 in the context of carcinogenesis. In the tumor microenvironment, CXCL3 emanating from both tumor and stromal cells intricately modulates cellular behaviors through autocrine and paracrine actions, primarily via interaction with its receptor CXCR2. Activation of signaling cascades such as ERK/MAPK, AKT, and JAK2/STAT3 underscores CXCL3's propensity to favor tumorigenic processes. However, CXCL3 exhibits dualistic behaviors, as evidenced by its capacity to exert anti-tumor effects under specific conditions. Additionally, the involvement of CXCL3 extends to inflammatory disorders like eclampsia, obesity, and asthma. This review encapsulates the structural attributes, biological functionalities, and molecular underpinnings of CXCL3 across both tumorigenesis and inflammatory diseases.

Intramuscular therapeutic doses of enrofloxacin affect microbial community structure but not the relative abundance of fluoroquinolones resistance genes in swine manure.

Livestock manure is a major source of veterinary antibiotics and antibiotic resistance genes (ARGs). Elucidation of the residual characteristics of ARGs in livestock manure following the administration of veterinary antibiotics is critical to assess their ecotoxicological effects and environmental contamination risks. Here, we investigated the effects of enrofloxacin (ENR), a fluoroquinolone antibiotic commonly used as a therapeutic drug in animal husbandry, on the characteristics of ARGs, mobile genetic elements, and microbial community structure in swine manure following its intramuscular administration for 3 days and a withdrawal period of 10 days. The results revealed the highest concentrations of ENR and ciprofloxacin (CIP) in swine manure at the end of the administration period, ENR concentrations in swine manure in groups L and H were 88.67 ± 45.46 and 219.75 ± 88.05 mg/kg DM, respectively. Approximately 15 fluoroquinolone resistance genes (FRGs) and 48 fluoroquinolone-related multidrug resistance genes (F-MRGs) were detected in swine manure; the relative abundance of the F-MRGs was considerably higher than that of the FRGs. On day 3, the relative abundance of qacA was significantly higher in group H than in group CK, and no significant differences in the relative abundance of other FRGs, F-MRGs, or MGEs were observed between the three groups on day 3 and day 13. The microbial community structure in swine manure was significantly altered on day 3, and the altered community structure was restored on day 13. The FRGs and F-MRGs with the highest relative abundance were qacA and adeF, respectively, and Clostridium and Lactobacillus were the dominant bacterial genera carrying these genes in swine manure. In summary, a single treatment of intramuscular ENR transiently increased antibiotic concentrations and altered the microbial community structure in swine manure; however, this treatment did not significantly affect the abundance of FRGs and F-MRGs.

An overview of the co-transcription factor NACC1: Beyond its pro-tumor effects.

Nucleus accumbens-associated protein 1 (NACC1) is a member of the broad complex, tramtrack, bric-a-brac/poxvirus and zinc finger (BTB/POZ) protein families, mainly exerting its biological functions as a transcription co-regulator. NACC1 forms homo- or hetero-dimers through the BTB/POZ or BANP, E5R, and NACC1 (BEN) domain with other transcriptional regulators to regulate downstream signals. Recently, the overexpression of NACC1 has been observed in various tumors and is positively associated with tumor progression, high recurrence rate, indicating poor prognosis. NACC1 also regulates biological processes such as embryonic development, stem cell pluripotency, innate immunity, and related diseases. Our review combines recent research to summarize advancements in the structure, biological functions, and relative molecular mechanisms of NACC1. The future development of NACC1 clinical appliances is also discussed.

Neoadjuvant immunotherapy combined with chemotherapy in the treatment of stage III lung squamous cell carcinoma: a retrospective cohort study.

Background: Neoadjuvant immunochemotherapy has been proven to be a successful therapeutic strategy for patients with locally advanced non-small cell lung cancer (NSCLC). Nevertheless, there is a paucity of information regarding surgical feasibility and safety as well as tumor response. The present study aimed to investigate the therapeutic and surgical outcomes for patients with stage III lung squamous cell carcinoma (LSCC). Methods: Patients with stage III potentially resectable LSCC treated with neoadjuvant immunochemotherapy at The First Affiliated Hospital of Ningbo University between March 2020 and June 2022 were retrospectively included. Oncologic outcomes and intraoperative and postoperative variables were assessed. Results: A total of 17 locally advanced LSCC patients were included in the study. Patients in stages IIIA and IIIB were represented by 10 (58.8%) and 7 (41.2%) cases, respectively. A minimally invasive procedure was successfully completed in 12 out of 17 cases (70.6%). A total of 10 patients (58.8%) had standard lobectomies performed, 1 (5.9%) had a bilobectomy, 3 (17.6%) had pneumonectomies, and 1 (5.9%) had a wedge resection. A total of 7 patients (41.2%) experienced postoperative complications, and there were no 30- or 90-day mortalities. The 2-year disease-free survival (DFS) and overall survival (OS) rates were 76.6% and 82.5%, respectively. The rate of major pathological response (MPR) was 70.6%. Conclusions: Lung resection after immunochemotherapy for potentially resectable stage III LSCC is feasible and safe. This treatment strategy results in a significant pathologic response and promising rates of OS at 2 years.

[Locking loop stitch with suture-bridge technique in repair of acute closed distal Achilles tendon rupture by using suture anchors].

OBJECTIVE: To explore clinical efficacy of Locking loop stitch with suture-bridge technique in repair of acute closed distal Achilles tendon rupture by using suture anchors. METHODS: From July 2019 to March 2021, 20 patients with acute closed distal Achilles tendon rupture were treated by minimally invasive suture anchor locking suture bridging repair technique. Among them, including 18 males and 2 females, aged from 19 to 52 years old with an average of(40.0±9.0) years old. Complications were observed, and recovery of ankle function was evaluated by American Orthopaedic Foot & Ankle Society(AOFAS) ankle and hindfoot function scoring system before operation and 1 year after operation. RESULTS: All patients followed up from 6 to 18 months with an average of (12.0±3.2) months. The incisions were healed at stageⅠwithout infection and skin necrosis occurred;no gastrocnemius nerve injury and deep vein thrombosis of the lower extremities occurred;and no heel pain and Achilles tendon re-rupture occurred. AOFAS scores of ankle and hindfoot increased from(59.0±4.3) before opertaion to(95.1±2.6) at 1 year after operation (t=-32.1, P<0.05). CONCLUSION: The effect of locking suture bridging with suture anchor nails to repair acute distal Achilles tendon rupture is definite, and it could reduce incidence of complications such as Achilles tendon re-rupture, nerve injury, and skin necrosis, which has advantages of small surgical trauma, reliable anastomosis method and good functional recovery, and is an ideal method for treating acute closed distal Achilles tendon rupture.

Deletion of osteopontin in non-small cell lung cancer cells affects bone metabolism by regulating miR-34c/Notch1 axis: a clue to bone metastasis.

Lung cancer is prone to bone metastasis, and osteopontin (OPN) has an important significance in maintaining bone homeostasis. The goal of this study was to explore the impact of OPN level on bone metabolism and the molecular mechanism of inhibiting bone metastasis in non-small cell lung cancer (NSCLC). The expression of OPN in NSCLC was ascertained by Western blot and immunohistochemistry, and the correlation between the expression level of OPN and survival of patients was analyzed. Then the shRNA technology was applied to reduce the expression of OPN in NSCLC cells, and CCK-8 assay was carried out to investigate the effect of low expression of OPN on the proliferation of NSCLC cells. In addition, the effects of low expression of OPN on osteoclast differentiation, osteoblast generation and mineralization were studied using osteoclast precursor RAW264.7 and human osteoblast SaOS-2 cells, and whether OPN could regulate miR-34c/ Notch pathway to affect bone metabolism was further explored. The findings showed that the high level of OPN in NSCLC was closely related to the poor prognosis of patients and the abnormal proliferation of NSCLC cell lines. The suppression of OPN was beneficial to inhibit the differentiation of osteoclasts and promote the mineralization of osteoblasts. Besides, this study confirmed that the deletion of OPN can regulate bone metabolism through the regulation of miR-34c/Notch1 pathway, which will contribute to inhibiting the occurrence of osteolytic bone metastasis in NSCLC.

CSF2 upregulates CXCL3 expression in adipocytes to promote metastasis of breast cancer via the FAK signaling pathway.

Recent studies have demonstrated that cancer-associated adipocytes (CAAs) in the tumor microenvironment are involved in the malignant progression of breast cancer. However, the underlying mechanism of CAA formation and its effects on the development of breast cancer are still unknown. Here, we show that CSF2 is highly expressed in both CAAs and breast cancer cells. CSF2 promotes inflammatory phenotypic changes of adipocytes through the Stat3 signaling pathway, leading to the secretion of multiple cytokines and proteases, particularly C-X-C motif chemokine ligand 3 (CXCL3). Adipocyte-derived CXCL3 binds to its specific receptor CXCR2 on breast cancer cells and activates the FAK pathway, enhancing the mesenchymal phenotype, migration, and invasion of breast cancer cells. In addition, a combination treatment targeting CSF2 and CXCR2 shows a synergistic inhibitory effect on adipocyte-induced lung metastasis of mouse 4T1 cells in vivo. These findings elucidate a novel mechanism of breast cancer metastasis and provide a potential therapeutic strategy for breast cancer metastasis.

Identification of immune-related ferroptosis prognostic marker and in-depth bioinformatics exploration of multi-omics mechanisms in thyroid cancer.

Background: Factors such as variations in thyroid carcinoma (THCA) gene characteristics could influence the clinical outcome. Ferroptosis and immunity have been verified to play an essential role in various cancers, and could affect the cancer patients' prognosis. However, their relationship to the progression and prognosis of many types of THCA remains unclear. Methods: First, we extracted prognosis-related immune-related genes and ferroptosis-related genes from 2 databases for co-expression analysis to obtain prognosis-related differentially expressed immune-related ferroptosis genes (PR-DE-IRFeGs), and screened BID and CDKN2A for building a prognostic model. Subsequently, multiple validation methods were used to test the model's performance and compare its performance with other 4 external models. Then, we explored the mechanism of immunity and ferroptosis in the occurrence, development and prognosis of THCA from the perspectives of anti-tumor immunity, CDKN2A-related competitive endogenous RNA regulatory, copy number variations and high frequency gene mutation. Finally, we evaluated this model's clinical practice value. Results: BID and CDKN2A were identified as prognostic risk and protective factors, respectively. External data and qRT-PCR experiment also validated their differential expression. The model's excellent performance has been repeatedly verified and outperformed other models. Risk scores were significantly associated with most immune cells/functions. Risk score/2 PR-DE-IRFeGs expression was strongly associated with BRAF/NRAS/HRAS mutation. Single copy number deletion of CDKN2A is associated with upregulation of CDKN2A expression and worse prognosis. The predicted regulatory network consisting of CYTOR, hsa-miRNA-873-5p and CDKN2A was shown to significantly affect prognosis. The model and corresponding nomogram have been shown to have excellent clinical practice value. Conclusion: The model can effectively predict the THCA patients' prognosis and guide clinical treatment. Ferroptosis and immunity may be involved in the THCA's progression through antitumor immunity and BRAF/NRAS/HRAS mutation. CYTOR-hsa-miRNA-873-5p-CDKN2A regulatory networks and single copy number deletion of CDKN2A may also affect THCA' progression and prognosis.

Development and Comparison of Predictive Models Based on Different Types of Influencing Factors to Select the Best One for the Prediction of OSAHS Prevalence.

Objective: This study aims to retrospectively analyze numerous related clinical data to identify three types of potential influencing factors of obstructive sleep apnea-hypopnea syndrome (OSAHS) for establishing three predictive nomograms, respectively. The best performing one was screened to guide further clinical decision-making. Methods: Correlation, difference and univariate logistic regression analysis were used to identify the influencing factors of OSAHS. Then these factors are divided into three different types according to the characteristics of the data. Lasso regression was used to filter out three types of factors to construct three nomograms, respectively. Compare the performance of the three nomograms evaluated by C-index, ROC curve and Decision Curve Analysis to select the best one. Two queues were obtained by randomly splitting the whole queue, and similar methods are used to verify the performance of the best nomogram. Results: In total, 8 influencing factors of OSAHS have been identified and divided into three types. Lasso regression finally determined 6, 3 and 4 factors to construct mixed factors nomogram (MFN), baseline factors nomogram (BAFN) and blood factors nomogram (BLFN), respectively. MFN performed best among the three and also performed well in multiple queues. Conclusion: Compared with BAFN and BLFN constructed by single-type factors, MFN constructed by six mixed-type factors shows better performance in predicting the risk of OSAHS.

Treatment paradigms and survival outcomes in esophageal adenocarcinoma with liver metastasis: a retrospective cohort study using the SEER database.

Background: Esophageal adenocarcinoma with liver metastasis (EACLM) at the time of diagnosis has a poor prognosis and few therapeutic options. The best treatment options and prognostic factors for EACLM patients are unclear. The present study sought to explore the optimal treatment modalities for and the prognosis of these patients. Methods: Patients diagnosed with EACLM at the time of diagnosis were identified from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2015. The last follow-up date was December 31, 2018. Treatment patterns were divided into four groups: local therapy (surgery/radiation), systemic therapy [chemotherapy (CT)], combination therapy (surgery/radiation + CT), and no treatment. The Kaplan-Meier (K-M) method and log-rank test were used for overall survival (OS) and disease-specific survival (DSS). Univariable and multivariable Cox regression were performed to identify the prognostic factors. Propensity score-matching (PSM) analyses were performed for sensitive analyses. Results: A total of 925 patients diagnosed with EACLM were included in the study. The median OS was 12, 10, 3, and 2 months for combination therapy, systemic therapy, local therapy, and no treatment, respectively (P<0.001). After PSM, the patients who received systemic treatment had a better OS (median 9 vs. 2 months; P<0.001) and DSS (median 9 vs. 3 months; P<0.001) than those who received no treatment. Compared to systemic therapy, combination therapy did not increase patients' OS (median 13 vs. 12 months, P=0.069) but did improve their DSS (median 19 vs. 13 months, P=0.048). Conclusions: EACLM patients might benefit the most from systemic therapy and combination therapy. For patients who are well-tolerated, combination therapy should be considered as a preferable option.

The Molecular Basis and Therapeutic Potential of Leukemia Inhibitory Factor in Cancer Cachexia.

Cachexia is a chronic metabolic syndrome that is characterized by sustained weight and muscle mass loss and anorexia. Cachexia can be secondary to a variety of diseases and affects the prognosis of patients significantly. The increase in inflammatory cytokines in plasma is deeply related to the occurrence of cachexia. As a member of the IL-6 cytokine family, leukemia inhibitory factor (LIF) exerts multiple biological functions. LIF is over-expressed in the cancer cells and stromal cells of various tumors, promoting the malignant development of tumors via the autocrine and paracrine systems. Intriguingly, increasing studies have confirmed that LIF contributes to the progression of cachexia, especially in patients with metastatic tumors. This review combines all of the evidence to summarize the mechanism of LIF-induced cachexia from the following four aspects: (i) LIF and cancer-associated cachexia, (ii) LIF and alterations of adipose tissue in cachexia, (iii) LIF and anorexia nervosa in cachexia, and (iv) LIF and muscle atrophy in cachexia. Considering the complex mechanisms in cachexia, we also focus on the interactions between LIF and other key cytokines in cachexia and existing therapeutics targeting LIF.

HIF-1α-mediated augmentation of miRNA-18b-5p facilitates proliferation and metastasis in osteosarcoma through attenuation PHF2.

Extensive evidence has explored the involvement of microRNAs (miRNAs) in osteosarcoma (OS). Limitedly, the concrete function of microRNA-18b-5p (miR-18b-5p) in OS remains unexplored and largely elusive. Here, we validated that miR-18b-5p significantly elevated in OS via analyzing the data from GEO database. The results showed that miR-18b-5p was overexpressed in human OS tissues and cell lines. The clinical evidence suggested that high level of miR-18b-5p was negatively correlated with the poor prognosis of OS. Meanwhile, miR-18b-5p upregulation facilitated the proliferation and metastasis of OS cells in vitro and in vivo. The mechanism exploration demonstrated that miR-18b-5p acted as a potential inhibitor of PHF2, a tumor suppressor gene, at post-transcriptional level. Moreover, hypoxia induced gene expression of miR-18b-5p was clarified to be transcriptionally mediated by HIF-1α. The clinicopathological analysis in samples of OS patients further supported that miR-18b-5p had a positive correlation with HIF-1α expression, and negative correlation with PHF2. Collectively, the present study uncovered a new molecular mechanism of OS tumorigenesis and development and miR-18b-5p might be a prognostic biomarker and potential therapeutic target for OS treatment.

[Effect and Mechanism of Cxcr4 Gene-Modified BMSC-Derived Exosomes on Aplastic Anemia].

OBJECTIVE: To explore the improvement effect of CXC chemokine receptor 4 (Cxcr4) gene-modified bone marrow mesenchymal stem cell (BMSC)-derived exosomes on aplastic anemia (AA), and make a preliminary exploration of the mechanism. METHODS: Mouse BMSCs were isolated and cultured, then infected by recombinant lentivirus carrying Cxcr4 gene. The expression of green fluorescence was observed through fluorescence microscope, the expression of Cxcr4 mRNA was detected by real-time fluorescence quantitative PCR, and the BMSC-derived exosomes modified with Cxcr4 gene were extracted. Mouse models of AA were constructed, and control group, model group (AA), AA+BMSC group, AA+NC-BMSC group, AA+Cxcr4-BMSC group were set up. Except control group and model group, the other three groups of mice were injected 400 µl exosomes from different sources via the tail vein, after 2 weeks, the routine blood indices and the number of bone marrow nucleated cells were detected, the pathological changes of bone marrow were observed by HE staining, and the expression level of Treg cells was detected by flow cytometry. RESULTS: Mouse BMSCs were successfully isolated, and BMSCs with high expression of Cxcr4 and their exosomes were obtained. Compared with the control group, the number of red blood cell (RBC), white blood cell (WBC), and platelet (PLT), the hemoglobin (Hb) content and proportion of Treg cells in the peripheral blood of mice in the model group significantly decreased (P<0.01), as well as the number of bone marrow nucleated cells (P<0.01). The proliferation level of nucleated cells was low, and the medullary cavity was filled with a large number of fat cells. Compared with the model group, the number of RBC, WBC, PLT, the Hb content and proportion of Treg cells in the peripheral blood of mice in the AA+BMSC group, AA+NC-BMSC group, and AA+Cxcr4-BMSC group significantly increased (P<0.01), as well as the number of bone marrow nucleated cells (P<0.01), and pathological changes of bone marrow were improved. In addition, the number of RBC, WBC, PLT, the Hb content and proportion of Treg cells in the peripheral blood of mice in the AA+Cxcr4-BMSC group were significantly higher than those in the AA+BMSC group (P<0.01), as well as the number of bone marrow nucleated cells (P<0.01). CONCLUSION: Injection of Cxcr4 gene-modified BMSC-derived exosomes has a certain improvement effect on AA mice, and the mechanism may be related to an increase of the proportion of Treg cells.

C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C motif chemokine receptor 7(CXCR7) regulates epithelial-mesenchymal transition process and promotes the metastasis of esophageal cancer by activating signal transducer and activator of transcription 3 (STAT3) pathway.

Esophageal cancer is a malignant tumor of the digestive system that is prone to metastasis. Chemokines and their receptors act an essential role in the occurrence and development of tumors. Here, we investigated the regulatory mechanism of CXCL12/CXCR7 in the growth and metastasis of esophageal cancer. CXCR7 was found highly expressed in clinical tissues and cells of esophageal cancer. Knockdown of CXCR7 inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) process of esophageal cancer cells. The knockdown of chemokine CXCL12 also inhibited the expression of EMT-related proteins and the mesenchymal morphology changes of esophageal cancer cells, but the knockdown of C-X-C motif chemokine receptor 4 (CXCR4) had no such effect. Furthermore, the knockdown of CXCR7 attenuated the enhanced EMT process induced by CXCL12 overexpression, while the knockdown of CXCR4 cannot inhibit this process. In addition, overexpressed CXCL12/CXCR7 activated the downstream STAT3 pathway, but had little effect on the extracellular regulated protein kinase (ERK) or serine-threonine kinase (AKT) pathways. Inhibition of the STAT3 pathway using AZD9150 weakened the accelerated effects of CXCL12/CXCR7 on the growth and metastasis of esophageal cancer in vitro and in vivo. In conclusion, our research revealed that CXCL12/CXCR7 regulates EMT and other malignant processes by activating the STAT3 pathway to accelerate the growth and metastasis of esophageal cancer.

Cancer-associated adipocytes promote the invasion and metastasis in breast cancer through LIF/CXCLs positive feedback loop.

Cancer-associated adipocytes (CAAs), which are adipocytes transformed by cancer cells, are of great importance in promoting the progression of breast cancer. However, the underlying mechanisms involved in the crosstalk between cancer cells and adipocytes are still unknown. Here we report that CAAs and breast cancer cells communicate with each other by secreting the cytokines leukemia inhibitory factor (LIF) and C-X-C subfamily chemokines (CXCLs), respectively. LIF is a pro-inflammatory cytokine secreted by CAAs, which promotes migration and invasion of breast cancer cells via the Stat3 signaling pathway. The activation of Stat3 induced the secretion of glutamic acid-leucine-arginine (ELR) motif CXCLs (CXCL1, CXCL2, CXCL3 and CXCL8) in tumor cells. Interestingly, CXCLs in turn activated the ERK1/2/NF-κB/Stat3 signaling cascade to promote the expression of LIF in CAAs. In clinical breast cancer pathology samples, the up-regulation of LIF in paracancerous adipose tissue was positively correlated with the activation of Stat3 in breast cancer. Furthermore, we verified that adipocytes enhanced lung metastasis of breast cancer cells, and the combination of EC330 (targeting LIF) and SB225002 (targeting C-X-C motility chemokine receptor 2 (CXCR2)) significantly reduced lung metastasis of breast cancer cells in vivo. Our findings reveal that the interaction of adipocytes with breast cancer cells depends on a positive feedback loop between the cytokines LIF and CXCLs, which promotes breast cancer invasion and metastasis.

[Clinical Study on Calcitriol Combined with Sirolimus in the Treatment of Chronic Primary Immune Thrombocytopenia Patients].

OBJECTIVE: To investigate the clinical efficacy of calcitriol combined with sirolimus in the treatment of chronic primary immune thrombocytopenia (cITP) patients. METHODS: A total of 146 adult cITP patients reated in the First Affiliated Hospital of Hebei North University from March 2017 to March 2020 were randomly divided into observation group (73 cases) and control group (73 cases) according to random number table. The control group was treated with oral sirolimus capsule, the observation group was treated with oral calcitriol capsule combined with sirolimus capsule, and the curative effect of the 2 groups was evaluated after continuous treatment for 6 weeks. The changes of World Health Organization (WHO) bleeding grade, laboratory related index, including peripheral blood regulatory T cell (Treg), serum 1,25-dihydroxy-vitamin D3 [1,25(OH)2D3], and serum level of vitamin D receptor (VDR), in the 2 groups before and after treatment were observed, and the scores of functional assessment of chronic illness therapy-figure (FACIT-F), ITP quality of life scale (ITP-PAQ) in the 2 groups were recorded and analyzed. Finally, the occurrence of side effects between the 2 groups was compared. RESULTS: The total effective rate of the observation group was 79.5% (58/73), which was significantly higher than 64.4% (47/73) of the control group (P<0.05). The revised WHO bleeding grades after treatment were significantly better than those before treatment in the 2 groups (P<0.05), but the observation group was improved more significantly than the control group (P<0.05). After treatment, platelet count (PLT), peripheral blood Treg cell ratio, and serum 1,25(OH)2D3 concentration in both the 2 groups significantly increased (P<0.05), while peripheral blood lymphocyte VDR significantly decreased (P<0.05). In addition, the ratio of PLT and Treg cells in peripheral blood and the level of 1,25(OH)2D3 in serum in the observation group were significantly higher than those in the control group (P<0.05) at the same period, while the content of VDR in peripheral blood was significantly lower (P<0.05). The scores of FACIT-F and ITP-PAQ after treatment in the two groups were significantly higher than those before treatment (P<0.05), but the scores in the observation group were increased more significantly than the control group (P<0.05). The side reaction rate of the observation group [11.0% (8/73)] had no significant difference compared with the control group [13.7% (10/73)] (P>0.05). CONCLUSION: The overall efficacy of calcitriol combined with sirolimus in the treatment of cITP in adults is satisfactory, which can effectively alleviate patient's condition, improve the quality of life, further increase the platelet level and decrease the expression of VDR in peripheral blood lymphocyte, the mechanism may be related to increasing the level of serum 1,25(OH)2D3 and up-regulating the expression of Treg cells in peripheral blood.

LncRNA RUSC1-AS1 promotes osteosarcoma progression through regulating the miR-340-5p and PI3K/AKT pathway.

Dysregulation of long noncoding RNA (lncRNA) is frequently involved in the progression and development of osteosarcoma. LncRNA RUSC1-AS1 is reported to be upregulated and acts as an oncogene in hepatocellular carcinoma, cervical cancer and breast cancer. However, its role in osteosarcoma has not been studied yet. In the present study, we investigated the role of RUSC1-AS1 in osteosarcoma both in vitro and in vivo. The results showed that the expression of RUSC1-AS1 was significantly upregulated in osteosarcoma cell line U2OS and HOS compared to that in human osteoblast cell line hFOB1.19. Similar results were found in human samples. Silencing RUSC1-AS1 by siRNA significantly inhibited U2OS and HOS cell proliferation and invasion, measured by CCK-8 and transwell assay. Besides, knockdown of RUSC1-AS1 increased cell apoptosis in osteosarcoma cell lines. In addition, RUSC1-AS1 promoted the epithelial-mesenchymal transition (EMT) process of osteosarcoma cells. In vivo experiments confirmed that RUSC1-AS1 knockdown had an inhibitory effect on osteosarcoma tumor growth. Mechanically, we showed that RUSC1-AS1 directly binds to and inhibits miR-340-5p and activates the PI3K/AKT signaling pathway. In conclusion, our study demonstrated that RUSC1-AS1 promoted osteosarcoma development both in vitro and in vivo through sponging to miR-340-5p and activating the PI3K/AKT signaling pathway. Therefore, RUSC1-AS1 becomes a potential therapeutic target for osteosarcoma.

ERG1 plays an essential role in rat cardiomyocyte fate decision by mediating AKT signaling.

ERG1, a potassium ion channel, is essential for cardiac action potential repolarization phase. However, the role of ERG1 for normal development of the heart is poorly understood. Using the rat embryonic stem cells (rESCs) model, we show that ERG1 is crucial in cardiomyocyte lineage commitment via interactions with Integrin ß1. In the mesoderm phase of rESCs, the interaction of ERG1 with Integrin ß1 can activate the AKT pathway by recruiting and phosphorylating PI3K p85 and focal adhesion kinase (FAK) to further phosphorylate AKT. Activation of AKT pathway promotes cardiomyocyte differentiation through two different mechanisms, (a) through phosphorylation of GSK3ß to upregulate the expression levels of ß-catenin and Gata4; (b) through promotion of nuclear translocation of nuclear factor-κB by phosphorylating IKKß to inhibit cell apoptosis, which occurs due to increased Bcl2 expression. Our study provides solid evidence for a novel role of ERG1 on differentiation of rESCs into cardiomyocytes.