Malignant Gastrointestinal Neuroectodermal Tumor (GNET) Mimicking Small Bowel Lymphoma: A Case Report.

A malignant gastrointestinal neuroectodermal tumor (GNET) is a rare entity, characterized as a malignant mesenchymal neoplasm occurring exclusively near the gastrointestinal tract, prone to frequent local recurrence and metastasis. Here, we report a case of a 49-year-old male presented with abdominal pain and weight loss. The patient had a remote history of thymic B-cell lymphoma. An abdominal computed tomography (CT) scan revealed a focal wall thickening of the terminal ileum with mesenteric lymphadenopathy, suggestive of lymphoma. A core needle biopsy of the mesenteric node was inconclusive. A right hemicolectomy was subsequently performed. Histologically, abundant multinucleated osteoclast-like giant cells are present. The tumor cells show diffuse strong positivity for S100 and SOX10. EWSR1-ATF1 gene fusion was identified by fluorescence in situ hybridization (FISH), consistent with a diagnosis of GNET. This case emphasizes a diagnostic challenge of a rare malignancy.

Nerve-tumor crosstalk in tumor microenvironment: From tumor initiation and progression to clinical implications.

The autonomic nerve system (ANS) innervates organs and tissues throughout the body and maintains functional balance among various systems. Further investigations have shown that excessive activation of ANS not only causes disruption of homeostasis, but also may promote tumor formation. In addition, the dynamic interaction between nerve and tumor cells in the tumor microenvironment also regulate tumor progression. On the one hand, nerves are passively invaded by tumor cells, that is, perineural invasion (PNI). On the other hand, compared with normal tissues, tumor tissues are subject to more abundant innervation, and nerves can influence tumor progression through regulating tumor proliferation, metastasis and drug resistance. A large number of studies have shown that nerve-tumor crosstalk, including PNI and innervation, is closely related to the prognosis of patients, and contributes to the formation of cancer pain, which significantly deteriorates the quality of life for patients. These findings suggest that nerve-tumor crosstalk represents a potential target for anti-tumor therapies and the management of cancer pain in the future. In this review, we systematically describe the mechanism by which nerve-tumor crosstalk regulates tumorigenesis and progression.

IRE1α regulates macrophage polarization in type 2 diabetic periodontitis through promoting endoplasmic reticulum stress.

OBJECTIVES: The aim of this study was to investigate the effect of 4µ8c, an inhibitor targeting the endoplasmic reticulum stress-associated factor IRE1α, on macrophage polarization in an experimental model of diabetic periodontitis through ex vivo experiments. MATERIALS AND METHODS: Local alveolar bone parameters were evaluated using Micro-CT following intraperitoneal administration of 4µ8c in mice with experimental diabetic periodontitis. Surface markers indicating macrophage polarization were identified using immunofluorescence. In vitro experiments were performed employing bone marrow-derived macrophages and gingival fibroblasts. Macrophage polarization was determined using flow cytometry. Principal impacted signaling pathways were identified through Western blot analysis. RESULTS: Results from both in vitro and in vivo experiments demonstrated that 4µ8c mitigated alveolar bone resorption and inflammation in mice with diabetic periodontitis. Furthermore, it modulated macrophage polarization towards the M2 phenotype and augmented M2 macrophage polarization through the MAPK signaling pathway. CONCLUSIONS: These findings suggest that inhibiting IRE1α can modulate macrophage polarization and alleviate ligature-induced diabetic periodontitis via the MAPK signaling pathway. This unveils a novel mechanism, offering a scientific foundation for the treatment of experimental diabetic periodontitis.

A Humeral Osteosarcoma Mimicking Osseous Leiomyosarcoma: A Case Report.

Osteosarcoma stands as one of the primary mesenchymal bone neoplasms commonly encountered in clinical practice. This malignancy often presents with a wide range of distinctive imaging characteristics. Here, we present a unique case wherein a delayed diagnosis of high-grade osteosarcoma occurred due to the absence of an osteoid matrix in the initial imaging studies. A 61-year-old female, initially presented with a left humeral fracture. As the healing of the fractured bone was delayed and the possibility of a pathologic fracture was considered, a CT-guided biopsy was performed. Histological examination of the biopsy sample initially suggested an osseous leiomyosarcoma. The lack of osteoid matrix on radiographs including aggressive intra-medullary mass seen on MRI, combined with the patient's age, appeared consistent with a diagnosis of leiomyosarcoma of bone. As a result, the initial diagnosis was not called into question. Due to neurovascular involvement, this led to a forequarter amputation. However, upon microscopic examination of the amputation specimen, certain areas exhibited features indicative of malignant osteoid deposition, ultimately supporting a revised diagnosis of high-grade osteosarcoma. This case underscores the critical importance of considering the limitations of core biopsy samples, especially when dealing with suspected limb masses associated with pathological fractures. Radiographs and CT scans can prove invaluable in ruling out subtle adjacent osteoid, and ultimately a multidisciplinary approach to the diagnosis of osteosarcoma is imperative to ensure accurate identification.

Tibial osteochondroma with thick cartilage which mimicked a chondrosarcoma: A case report.

We report a case of tibial osteochondroma in a 25-year-old female who presented with a palpable calf mass. This mass was associated with a thick cartilaginous cap on cross-sectional imaging, suggesting chondrosarcoma. A CT-guided biopsy was performed, and histology, however, was consistent with osteochondroma. Orthopedic oncology recommended surgical excision due to the potential high sampling error with chondroid lesions. The patient underwent surgical resection, resulting in a final diagnosis of osteochondroma. No post-surgical complications occurred, and a 12-month follow-up showed no evidence of local recurrence. This case highlights the atypical imaging feature of a thick cartilaginous cap in a benign etiology without malignant transformation.

Predictive value of machine learning models for lymph node metastasis in gastric cancer: A two-center study.

BACKGROUND: Gastric cancer is one of the most common malignant tumors in the digestive system, ranking sixth in incidence and fourth in mortality worldwide. Since 42.5% of metastatic lymph nodes in gastric cancer belong to nodule type and peripheral type, the application of imaging diagnosis is restricted. AIM: To establish models for predicting the risk of lymph node metastasis in gastric cancer patients using machine learning (ML) algorithms and to evaluate their predictive performance in clinical practice. METHODS: Data of a total of 369 patients who underwent radical gastrectomy at the Department of General Surgery of Affiliated Hospital of Xuzhou Medical University (Xuzhou, China) from March 2016 to November 2019 were collected and retrospectively analyzed as the training group. In addition, data of 123 patients who underwent radical gastrectomy at the Department of General Surgery of Jining First People's Hospital (Jining, China) were collected and analyzed as the verification group. Seven ML models, including decision tree, random forest, support vector machine (SVM), gradient boosting machine, naive Bayes, neural network, and logistic regression, were developed to evaluate the occurrence of lymph node metastasis in patients with gastric cancer. The ML models were established following ten cross-validation iterations using the training dataset, and subsequently, each model was assessed using the test dataset. The models' performance was evaluated by comparing the area under the receiver operating characteristic curve of each model. RESULTS: Among the seven ML models, except for SVM, the other ones exhibited higher accuracy and reliability, and the influences of various risk factors on the models are intuitive. CONCLUSION: The ML models developed exhibit strong predictive capabilities for lymph node metastasis in gastric cancer, which can aid in personalized clinical diagnosis and treatment.

Comparison of Machine Learning and Logic Regression Algorithms for Predicting Lymph Node Metastasis in Patients with Gastric Cancer: A two-Center Study.

OBJECTIVES: This two-center study aimed to establish a model for predicting the risk of lymph node metastasis in gastric cancer patients using machine learning (ML) and logistic regression (LR) algorithms, and to evaluate its predictive performance in clinical practice. METHODS: Data of a total of 369 patients who underwent radical gastrectomy in the Department of General Surgery of Affiliated Hospital of Xuzhou Medical University (Xuzhou, China) from March 2016 to November 2019 were collected and retrospectively analyzed as the training group. In addition, data of 123 patients who underwent radical gastrectomy in the Department of General Surgery of Jining First People's Hospital (Jining, China) were collected and analyzed as the verification group. Besides, 7 ML and logistic models were developed, including decision tree, random forest, support vector machine (SVM), gradient boosting machine (GBM), naive Bayes, neural network, and LR, in order to evaluate the occurrence of lymph node metastasis in patients with gastric cancer. The ML model was established following 10 cross-validation iterations within the training dataset, and subsequently, each model was assessed using the test dataset. The model's performance was evaluated by comparing the area under the receiver operating characteristic curve of each model. RESULTS: Compared with the traditional logistic model, among the 7 ML algorithms, except for SVM, the other models exhibited higher accuracy and reliability, and the influences of various risk factors on the model were more intuitive. CONCLUSION: For the prediction of lymph node metastasis in gastric cancer patients, the ML algorithm outperformed traditional LR, and the GBM algorithm exhibited the most robust predictive capability.

Crohn's disease as the intestinal manifestation of pan-lymphatic dysfunction: An exploratory proposal based on basic and clinical data.

Crohn's disease (CD) is caused by immune, environmental, and genetic factors. It can involve the entire gastrointestinal tract, and although its prevalence is rapidly increasing its etiology remains unclear. Emerging biological and small-molecule drugs have advanced the treatment of CD; however, a considerable proportion of patients are non-responsive to all known drugs. To achieve a breakthrough in this field, innovations that could guide the further development of effective therapies are of utmost urgency. In this review, we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases, and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data. The supporting evidence is fully summarized, including the existence of lymphatic system dysfunction, recognition of the inside-out model, disorders of immune cells, changes in cell plasticity, partial overlap of the underlying mechanisms, and common gut-derived fatty and bile acid metabolism. Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases, especially CD, as this model is good at presenting and mimicking lymphatic dysfunction. More importantly, the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.

Identification of a pyroptosis-related long non-coding RNA Signature for prognosis and its related ceRNA regulatory network of ovarian cancer.

Aim: To identify the pyroptosis-related long non-coding RNAs (lncRNAs) in ovarian cancer and construct a prognostic signature based on them. Methods: Expression data from TCGA was used to explore differentially expressed pyroptosis-related lncRNAs in ovarian cancer. A risk signature was established by LASSO and cox regression analysis and then validated. Databases such as ESTIMATE, CIBERSORT, TIMER, XCELL were used to identify the relation between this signature and the immune microenvironment of ovarian cancer. Gene Set Enrichment Analysis was introduced to identify the pathways and functions that the signature may participate in. Based on miRcode and starBase databases, microRNAs related to the lncRNAs in our signature and the positively co-expressed pyroptosis- related genes were screened and a competing endogenous RNA (ceRNA) network was then constructed. Quantitative reverse transcription PCR was conducted to validate the expression levels of two lncRNAs in this ceRNA network. Results: A 13 pyroptosis-related lncRNA prognostic signature (MYCNOS, AL161772.1, USP30-AS1, ZNF32-AS2, AC068733.3, AC012236.1, AC015802.5, KIAA1671-AS1, AC013403.2, MIR223HG, KRT7-AS, PTPRD-AS1 and LINC01094) was constructed. Patients in high-risk group had a significantly worse prognosis than that of low-risk (P<0.0001). Immune infiltration analysis found that patients identified as high-risk had a higher infiltration of macrophages and tumor-associated fibroblasts. Further pathway analysis revealed that the signature may be involved in epithelial mesenchymal transition, extracellular matrix receptor interaction, and focal adhesion. Finally, a competitive endogenous inhibition relationship was discovered between LINC01094, KRT7-AS, MYCNOS, ZNF32-AS2, AC012236.1 and pyroptosis- related genes such as IRF1, NOD1, GSDMC, NLRP1, PLCG1, GSDME and GZMB, in which LINC01094 and KRT7-AS were found to be overexpressed in three ovarian cancer cell lines. Conclusion: We constructed a pyroptosis-related lncRNA signature and correlate it to the immune microenvironment. A ceRNA regulatory network related to pyroptosis was also constructed, which provides novel insights useful for the study of pyroptosis in ovarian cancer.

Coordination of Single-cell and Bulk RNA Sequencing to Construct a Cuproptosis-related Gene Prognostic Index for Endometrial Cancer Prognosis, Immune Microenvironment Infiltration, and Immunotherapy Treatment Options.

Background: This study aims to identify molecular subtypes and develop a cuproptosis-related gene prognostic index (CRGPI) for endometrial cancer (EC), in addition to outlining the immune features and the efficacy of immune checkpoint inhibitor (ICI) therapy in CRGPI-defined groups of EC. Methods: Between malignant and normal cells distinguished from single-cell RNA sequencing data GSE154763 dataset, the difference in KEGG pathways and cuproptosis-related gene (CRG) scores was intensively investigated. On the basis of TCGA dataset (n=492), CRGs were used to identify two distinct molecular subtypes. Using the Cox regression method, a CRGPI was constructed and externally validated with the IMvigor210 dataset (n=348) and GSE78220. Then, the molecular and immune characteristics and the efficacy of ICI therapy in subgroups defined by CRGPI were investigated. Results: Compared to normal cells, the expression of the TCA cycle and CRGs genes was significantly higher in malignant cells. The CRGPI was established on the premise of ATF5, FBXO46, P2RX4, SMARCD3, DAPK3, and C1orf53. Comprehensive results demonstrated a correlation between a low CRGPI score and better overall survival, younger age, early stage, immune cells and functions activation, high tumor mutation burden and high microsatellite instability, as well as better benefit from ICI therapy, and its significance for forecasting immunotherapeutic effects was verified as well (IMvigor210 cohort: HR, 1.358; 95% CI, 1.047, 1.761; p=0.02; GSE78220 cohort: HR, HR = 3.857, 95% CI, 1.009, 14.74; p=0.034). CRGPI anticipated the immunotherapy medication. Conclusions: CRGPI is a prospective biomarker to estimate the prognosis, immune and molecular characteristics, and treatment benefit of immunotherapy in EC.

Establishment of a prognostic model for gastric cancer patients who underwent radical gastrectomy using machine learning: a two-center study.

Objective: Gastric cancer is a prevalent gastrointestinal malignancy worldwide. In this study, a prognostic model was developed for gastric cancer patients who underwent radical gastrectomy using machine learning, employing advanced computational techniques to investigate postoperative mortality risk factors in such patients. Methods: Data of 295 patients with gastric cancer who underwent radical gastrectomy at the Department of General Surgery of Affiliated Hospital of Xuzhou Medical University (Xuzhou, China) between March 2016 and November 2019 were retrospectively analyzed as the training group. Additionally, 109 patients who underwent radical gastrectomy at the Department of General Surgery Affiliated to Jining First People's Hospital (Jining, China) were included for external validation. Four machine learning models, including logistic regression (LR), decision tree (DT), random forest (RF), and gradient boosting machine (GBM), were utilized. Model performance was assessed by comparing the area under the curve (AUC) for each model. An LR-based nomogram model was constructed to assess patients' clinical prognosis. Results: Lasso regression identified eight associated factors: age, sex, maximum tumor diameter, nerve or vascular invasion, TNM stage, gastrectomy type, lymphocyte count, and carcinoembryonic antigen (CEA) level. The performance of these models was evaluated using the AUC. In the training group, the AUC values were 0.795, 0.759, 0.873, and 0.853 for LR, DT, RF, and GBM, respectively. In the validation group, the AUC values were 0.734, 0.708, 0.746, and 0.707 for LR, DT, RF, and GBM, respectively. The nomogram model, constructed based on LR, demonstrated excellent clinical prognostic evaluation capabilities. Conclusion: Machine learning algorithms are robust performance assessment tools for evaluating the prognosis of gastric cancer patients who have undergone radical gastrectomy. The LR-based nomogram model can aid clinicians in making more reliable clinical decisions.

Molecular subtypes based on cuproptosis-related genes and tumor microenvironment infiltration characterization in ovarian cancer.

BACKGROUND: Cuproptosis (copper death) is a recently found cell death type produced by copper iron; nonetheless, the properties of cuproptosis molecular subtypes and possible involvement of cuproptosis-related genes (CRGs) in the tumor microenvironment (TME) in ovarian cancer (OC) remain unknown. METHODS: CRG changes were characterized at the genomic and transcriptional levels in 656 OC samples, and their expression patterns were investigated using three different datasets. RESULTS: We identified three distinct molecular subtypes, and discovered that variations in molecular subtypes were linked to patient prognosis, TME cell infiltration characteristics, malignancy, and immune-related pathways. Then, in order to predict overall survival (OS), we created a risk score and tested its predictive potential in OC patients. As a result, we created a very accurate nomogram to increase risk score clinical applicability. Better OS, younger age, early stage, and immune activity were all associated with a low risk score. The hallmarks of a high-risk score are older age, advanced stage, immunosuppression, and a bad prognosis. Furthermore, risk score was linked to immune checkpoint expression (including PD-L1, CTLA4), targeted therapy gene expression (PARP, PDGFRA), cancer stem cell (CSC), chemotherapy and targeted medication sensitivity. CONCLUSIONS: Our comprehensive analysis of CRGs in OC showed their potential role in TME, clinicopathological characteristics, chemotherapy and targeted drug screening and prognosis. These discoveries could help us better understand CRGs in OC, as well as pave the path for novel ways to assess prognosis and design more effective immunotherapy strategies.

High-fat diet aggravates colitis via mesenteric adipose tissue derived exosome metastasis-associated lung adenocarcinoma transcript 1.

BACKGROUND: Obesity is associated with an increased risk of developing Crohn's disease (CD), higher disease activity, and comparatively worse clinical outcomes. AIM: To investigate the role of mesenteric adipose tissue-derived exosomes in the pathogenesis of CD aggravation in obese individuals. METHODS: First, we induced colitis in mice initiated on high-fat and normal diets and compared the severity of colitis. We then extracted and identified exosomes from mesenteric adipose tissue and determined the levels of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in mesenteric adipose tissue-derived exosomes and the colon. Next, we demonstrated an interaction between MALAT1 and the miR-15a-5p/activating transcription factor 6 (ATF6) axis. Finally, we explored the effects of mesenteric adipose tissue-derived exosomes extracted from mice fed a high-fat or normal diet on the severity of 2,4,6-trinitrobe-nzenesulfonic acid (TNBS)-induced colitis and ATF6-related endoplasmic reticulum stress pathways. RESULTS: High-fat diet was found to aggravate TNBS-induced colitis in mice. The expression of MALAT1 in mesenteric adipose tissue-derived exosomes of high-fat diet-fed mice increased. The increased expression of MALAT1 in colon tissue exacerbated TNBS-induced colitis and activated the ATF6 endoplasmic reticulum stress pathway. This effect was partially reversed by the reduced expression of MALAT1 and overexpression of miR-15a-5p. CONCLUSION: Mesenteric adipose tissue-derived exosome-encapsulated long noncoding RNAs MALAT1 targets the colon and aggravates TNBS-induced colitis in obese mice, which may potentially act on the miR-15a-5p/ATF6 axis and activate endoplasmic reticulum stress.

Reduction of SIRT1 Mediates Monosodium Iodoacetate-Induced Osteoarthritic Pain by Upregulating p53 Expression in Rats.

BACKGROUND: Clinically, chronic pain is the most common and disabling symptom of osteoarthritis (OA). OA pain is associated with OA lesion of the knee and the plastic changes in the peripheral and central nervous systems. However, the central mechanisms involved at the spinal cord level are not fully understood. OBJECTIVES: The aim of this study was to identify the mechanism underlying the role of spinal cord Sirtuin 1 (SIRT1) in OA pain induced by intraarticular injection of monosodium iodoacetate (MIA) in rats. STUDY DESIGN: Controlled animal study. METHODS: MIA was injected intraarticularly into the rat knee joint for the induction of OA. The OA lesion of the knee was assessed by histopathological examination. The mechanical allodynia were measured over 21 days post-injection by von Frey filaments. The messenger RNA and protein levels of SIRT1 and p53 were determined by real-time quantitative polymerase chain reaction and western blotting, respectively. Involvement of SIRT1-mediated p53 expression in the development of MIA-persistent pain was studied using intrathecal (i.t.) injection of the SIRT1-activating molecule resveratrol and intraperitoneal (i.p.) injection of the p53 inhibitor pifithrin-mu (PTF-µ). RESULTS: MIA induced mechanical allodynia, decreased the expression of SIRT1, and upregulated the expression of p53 in the spinal dorsal horn. Consecutive i.t. injection of resveratrol or i.p. injection of PTF-µ alleviated the MIA-induced mechanical allodynia. Upregulation of dorsal horn SIRT1 expression by i.t. injection of resveratrol also inhibited the increase of dorsal horn p53 induced by MIA. Moreover, silencing of dorsal horn SIRT1 expression by i.t. administration of small interfering RNA SIRT1 into normal rats induced the mechanical allodynia and upregulation of p53 expression in the dorsal horn. LIMITATIONS: More underlying mechanism(s) of the role of p53 signaling pathway in OA pain need to be explored in future research. CONCLUSIONS: These findings suggest that the reduction of dorsal horn SIRT1 mediated upregulation of p53 expression, which plays a critical role in persistent pain induced by OA. The i.t. drug delivery treatments targeting the spinal cord SIRT1/p53 pathway might be novel therapeutic options for OA-induced persistent pain.

Paraganglioma with highly malignant potential involving the rib - Case report and review of the literature.

Paragangliomas are rare neuroendocrine tumors arising from paraganglion cells in sympathetic or parasympathetic chains, which may develop in the abdomen, chest, skull base, and neck. As paragangliomas have a wide range of imaging features, the diagnosis often requires tissue sampling. We present a unique case of a paraganglioma which originally presented as a rib tumor. A 64-year-old male with right flank pain for 2 months' was referred for a noncontrast renal colic CT. He was found to have a 3.7 × 3.5 cm soft tissue mass invading the left posterior 9th rib and paraspinal muscle. This was fluorodeoxyglucose F 18, (18F-FDG) avid, with no other distant metabolic activity. He underwent ultrasound-guided core biopsy which revealed a diagnosis of paraganglioma. A right thoracotomy with chest wall resection of 8, 9, and 10 ribs were subsequently performed. The tumor was removed along with a small portion of adherent lung. The tumor was positive for CD56, synaptophysin and chromogranin. S-100 highlighted occasional sustentacular cells, consistent with a pathologic diagnosis of a paraganglioma. The patient remains symptom free for 6 months' after the operation. Our case highlights that, when paragangliomas occur within the chest wall, they may present as a rib tumor and can mimic metastasis, myeloma or other primary neoplastic etiologies originating from ribs. Both imaging and pathologic diagnosis can be challenging.

Palmitoylation in Crohn's disease: Current status and future directions.

S-palmitoylation is one of the most common post-translational modifications in nature; however, its importance has been overlooked for decades. Crohn's disease (CD), a subtype of inflammatory bowel disease (IBD), is an autoimmune disease characterized by chronic inflammation involving the entire gastrointestinal tract. Bowel damage and subsequent disabilities caused by CD are a growing global health issue. Well-acknowledged risk factors for CD include genetic susceptibility, environmental factors, such as a westernized lifestyle, and altered gut microbiota. However, the pathophysiological mechanisms of this disorder are not yet comprehensively understood. With the rapidly increasing global prevalence of CD and the evident role of S-palmitoylation in CD, as recently reported, there is a need to investigate the relationship between CD and S-palmitoylation. In this review, we summarize the concept, detection, and function of S-palmitoylation as well as its potential effects on CD, and provide novel insights into the pathogenesis and treatment of CD.

Endoscopic rhizotomy for chronic lumbar zygapophysial joint pain.

BACKGROUND: Chronic lumbar zygapophysial joint pain is a common cause of chronic low back pain. Percutaneous radiofrequency ablation (RFA) is one of the effective management options; however, the results from the traditional RFA need to be improved in certain cases. The aim of this study is to investigate the effect of percutaneous radiofrequency ablation under endoscopic guidance (ERFA) for chronic low back pain secondary to facet joint arthritis. METHODS: This is a prospective study enrolled 60 patients. The cases were randomized into two groups: 30 patients in the control group underwent traditional percutaneous radiofrequency ablation, others underwent ERFA. The lumbar visual analog scale (VAS), MacNab score, and postoperative complications were used to evaluate the outcomes. All outcome assessments were performed at postoperative 1 day, 1 month, 3 months, 6 months, and 12 months. RESULTS: There was no difference between the two groups in preoperative VAS (P > 0.05). VAS scores, except the postoperative first day, in all other postoperative time points were significantly lower than preoperative values each in both groups (P < 0.05). There was no significant difference between the two groups in VAS at 1 day, 1 month, and 3 months after surgery (P > 0.05). However, the EFRA demonstrated significant benefits at the time points of 3 months and 6 months (P > 0.05). The MacNab scores of 1-year follow-up in the ERFA group were higher than that in the control group (P < 0.05). The incidence of complications in the ERFA group was significantly less than that in the control group (P < 0.05). CONCLUSIONS: ERFA may achieve more accurate and definite denervation on the nerves, which leads to longer lasting pain relief.

Oncogenic Akt-FOXO3 loop favors tumor-promoting modes and enhances oxidative damage-associated hepatocellular carcinogenesis.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, accounting for 80-90% of cases. Mutations are commonly found in the signaling regulating the PI3K/Akt pathway, leading to oncogenic cell proliferation and survival. Key transcription factors that are negatively regulated downstream of PI3K/Akt are members of the forkhead box O family (FOXO). FOXOs were initially considered as tumor suppressors by inducing cell cycle arrest and apoptosis. However, there is increasing evidence showing that FOXOs, especially FOXO3, can support tumorigenesis. METHODS: To understand the roles of FOXO3 in liver tumorigenesis and hepatocarcinogenesis, we analyzed HCC patient specimens and also established a doxycycline-regulated transgenic mouse model with hepatocyte-specific FOXO3 expression in a constitutively active form. RESULTS: We found that FOXO3 protein is significantly overexpressed and activated in livers of HCC patients. Hepatic activation of FOXO3 induced extensive hepatic damage and elevated gene expression of several HCC-associated factors. Furthermore, FOXO3 expression enhanced hepatotoxicin-induced tumorigenesis. Mechanistically, FOXO3 activation caused oxidative stress and DNA damage and triggered positive feedback-loop for Akt activation as well as mTORC2 activation. Interestingly, FOXO3 activated not only reactive oxygen species (ROS)-promoting pathways, but also ROS-eliminating systems, which can be associated with the activation of the pentose phosphate pathway. CONCLUSIONS: FOXO3 is a master regulator of ROS in a 'carrot and stick' manner; on one side avoiding cellular crisis while also supporting hepatocellular carcinogenesis. Clinically, we suggest analyzing FOXO3 activation status in patients with liver diseases, in addition to PI3K/Akt signaling. Personalized therapy of FOXO3 inhibition may be a reasonable, depending on the activation status of FOXO3.

c-Myc maintains the self-renewal and chemoresistance properties of colon cancer stem cells.

Cancer stem cells (CSCs) are responsible for cancer formation, recurrence and drug resistance. c-Myc, one of the core markers for stem cells, has recently been considered to serve as a link between malignancy and 'stemness'. However, the precise function of c-Myc in colon CSCs is still unclear. In the present study, a subpopulation of colon CSCs expressing a CD133 surface phenotype was isolated from the human HT-29 cell line, which possess greater tumor sphere-forming efficiency and have higher expression of 'stemness'-associated genes compared with CD133-negative cells. Furthermore, it was demonstrated that c-Myc was highly expressed in CD133+ colon CSCs. Knockdown of c-Myc expression with small interfering RNA in colon CSCs can significantly inhibit tumor sphere formation, reduce the invasive and migratory capacity of CD133+ cells in vitro, and suppress the tumorigenicity of colon CSCs in vivo. In addition, it was suggested that c-Myc silencing may sensitize colon CSCs to chemotherapy-induced cytotoxicity via the downregulation of ABCG2 and ABCB5. These findings support a central role for c-Myc in maintaining the self-renewing and chemoresistant properties of colon CSCs.

Brg1 promotes liver regeneration after partial hepatectomy via regulation of cell cycle.

Brahma-related gene 1 (Brg1), a catalytic subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, is known to be involved in proliferative cell processes. Liver regeneration is initiated spontaneously after injury and leads to a strong proliferative response. In this study, a hepatocyte-specific Brg1 gene knockout mouse model was used to analyse the role of Brg1 in liver regeneration by performing a 70% partial hepatectomy (PH). After PH, Brg1 was significantly upregulated in wildtype mice. Mice with hepatocyte-specific Brg1 gene knockout showed a significantly lower liver to body weight ratio 48 h post-PH concomitant with a lower hepatocellular proliferation rate compared to wildtype mice. RNA sequencing demonstrated that Brg1 controlled hepatocyte proliferation through the regulation of the p53 pathway and several cell cycle genes. The data of this study reveal a crucial role of Brg1 for liver regeneration by promoting hepatocellular proliferation through modulation of cell cycle genes and, thus, identify Brg1 as potential target for therapeutic approaches.