AIM:There is no consensus regarding the minimally invasive treatment method for concomitant cholecystolithiasis and choledocholithiasis. Therefore, this study aimed to develop a universal classification system for minimally invasive surgeries, thereby supporting development of consensus in guidelines for diagnosing choledocholithiasis. METHODS:This retrospective study included 1044 consecutive patients with concomitant cholecystolithiasis and choledocholithiasis who underwent different minimally invasive surgical treatments at the Zhongnan Hospital of Wuhan University, China, between January 2014 and April 2021. To identify the key factors influencing the choice of different minimally invasive surgical procedures, clinical data for all hospitalized patients were analyzed. The patients were followed up through outpatient visits or telephonic calls at 1 week, 6 weeks, 3 months, 6 months, and 1 year or immediately if symptoms developed following discharge from the hospital. This information was integrated in the form of a new disease classification model, and the optimal treatment approaches were screened. RESULTS:A significant correlation was observed between the choice of minimally invasive surgical procedures and the concomitant common bile duct (CBD) (p < 0.001), stone size (p < 0.001), or stone number (p < 0.001). A new clinical classification model was developed for patients with concomitant gallbladder (GB) and CBD stones based on the CBD diameter, stone sizes, and stone numbers, and the patients were sorted into Type I, II, III, and Ⅳ, respectively. Three invasive surgical methods were performed in patients with type I patients, revealing the laparoscopic cholecystectomy + Laparoscopic Transcystic Common Bile Duct Exploration (LC + LTCBDE) method as a preferred option for these patients. Furthermore, five surgical methods were performed on patients with type II CBD stones, demonstrating LC + LTCBDE as the viable option for these patients. Additionally, among the four minimally invasive surgical methods applied in patients with type III, the LC + laparoscopic choledochotomy for common bile duct exploration (LCCBDE) + Duodenoscope or LC + LCCBDE + primary closure demonstrated favorable results in this group of patients. Among the three methods applied in type IV patients, LC + laparoscopic choledocholithotomy and T-tube drainage (LCTD) were found to be more favorable. CONCLUSIONS:In summary, this novel and simple clinical classification system, which is based on CBD diameter, stone sizes, and stone numbers, can assist clinicians in selecting a minimally invasive treatment approach for managing concomitant GB and CBD stones.

Autophagy has been increasingly recognized as a critical regulatory mechanism in the maintenance of cellular homeostasis. A previous study showed that phospholipase C-like protein 1 (PLCL1) is associated with lipid metabolism in renal cell carcinoma (RCC). However, it is unclear whether PLCL1 regulates autophagy, thereby influencing the progression of RCC. Bioinformatics analysis of five microarray datasets revealed that expression of PLCL1 is decreased in tumours and is positively correlated with prognosis in RCC patients. Three independent public datasets, clinical RCC tissues and RCC cell lines, were validated using real-time qPCR, western blotting and immunohistochemistry. Using wound healing and transwell assays, we observed that elevated PLCL1 levels decreased the migratory distance and the invasive number of 786-O and ACHN cells, but PLCL1 knockdown reversed these changes in 769P cell lines compared to those in controls. The results of flow cytometry analysis indicated that PLCL1 promotes apoptosis. Moreover, transcriptional analysis based on stable overexpression of PLCL1 in 786-O cells revealed that PLCL1 is related to autophagy, and western blotting and autophagic experimental results further verified these findings. Mechanistic investigations confirmed that PLCL1 activates the AMPK/mTOR pathway and interacts with decidual protein induced by progesterone (DEPP). Collectively, our data suggest that PLCL1 functions as a suppressor of RCC progression by activating the AMPK/mTOR pathway, interacting with DEPP, initiating autophagy and inducing apoptosis. PLCL1 may be a promising therapeutic target for the diagnosis and treatment of ccRCC patients.

Heart failure (HF) is the end stage of the progression of many cardiovascular diseases. Cardiac remodeling is the main pathophysiological process of cardiac function deterioration in HF patients. Inflammation is a key factor that stimulates cardiomyocyte hypertrophy, fibroblast proliferation, and transformation leading to myocardial remodeling, which severity is significantly related to the prognosis of patients. SAA1 (Serum amyloid A1) is a lipid-binding protein that was an important regulator involved in inflammation, whose biological functions in the heart remain rarely known. In this research, we intended to test the role of SAA1 in SAA1-deficient (SAA1(-/-)), and wild-type mice were exposed to transverse aortic banding surgery to establish the model of cardiac remodeling. Besides, we assessed the functional effects of SAA1 on cardiac hypertrophy and fibrosis. The expression of SAA1 was increased in the mice transverse aortic banding model induced by pressure overload. After 8 weeks of transverse aortic banding, SAA1(-/-) mice displayed a lower level of cardiac fibrosis than wild-type mice, but did not significantly influence the cardiomyocyte hypertrophy. In addition, there was also no significant difference in cardiac fibrosis severity between wild-type-sham and knockout-sham mice. These findings are the first to reveal SAA1 absence hinders cardiac fibrosis after 8 weeks of transverse aortic banding. Furthermore, SAA1 deficiency had no significant effect on cardiac fibrosis and hypertrophy in the sham group in this study.

HCC has remained one of the challenging cancers to treat, owing to the paucity of drugs targeting the critical survival pathways.Considering the cancer cells are deficient in DNase activity, the increase of an autonomous apoptisis endonuclease should be a reasonable choice for cancer treatment.In this study, we investigated whether DNASE1L3, an endonuclease implicated in apoptosis, could inhibit the progress of HCC.We found DNASE1L3 was down-regulated in HCC tissues, whereas its high expression was positively associated with the favorable prognosis of patients with HCC.Besides, serum DNASE1L3 levels were lower in HCC patients than in healthy individuals.Functionally, we found that DNASE1L3 inhibited the proliferation of tumor cells by inducing G0/G1 cell cycle arrest and cell apoptosis in vitro.Additionally, DNASE1L3 overexpression suppressed tumor growth in vivo.Furthermore, we found that DNASE1L3 overexpression weakened glycolysis in HCC cells and tissues via inactivating the rate-limiting enzymes involved in PTPN2-HK2 and CEBPβ-p53-PFK1 pathways.Finally, we identified the HBx to inhibit DNASE1L3 expression by up-regulating the expression of ZNF384.Collectively, our findings demonstrated that DNASE1L3 could inhibit the HCC progression through inducing cell apoptosis and weakening glycolysis.We believe DNASE1L3 could be considered as a promising prognostic biomarker and therapeutic target for HCC.

Emerging evidence has shown that aberrant expression of lncRNA-TP53TG1 plays important roles in various malignancies. However, the biological functions of lncRNA-TP53TG1 in hepatocarcinogenesis, as well as the underlying mechanisms, remain largely unknown. Here, we assessed whether lncRNA-TP53TG1 plays a key role in the progression of hepatocellular carcinoma (HCC). The expression of lncRNA-TP53TG1 was significantly decreased in HCC tissues and cells. Decreased expression of lncRNA-TP53TG1 was associated with aggressive clinical phenotypes and a poor prognosis. Ectopic expression of lncRNA-TP53TG1 inhibited hepatoma cell proliferation and migration in vitro and in vivo, whereas lncRNA-TP53TG1 knockdown exerted the opposite effects. Furthermore, lncRNA-TP53TG1 played an important role in slowing the epithelial-mesenchymal transition (EMT) process in HCC. Mechanistically, lncRNA-TP53TG1 physically interacted with PRDX4 and promoted its ubiquitin-mediated degradation, resulting in the inactivation of the WNT/β-catenin signaling pathway in hepatoma cells. Our findings demonstrate a novel mechanism by which lncRNA-TP53TG1 exerts its tumor-suppressive effects through the WNT/β-catenin signaling pathway in a PRDX4-mediated manner in HCC. Based on these results, lncRNA-TP53TG1 potentially represents a prognostic indicator and therapeutic target for patients with HCC.

Rationale: Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies in the world. Apart from traditional surgical resection, radiotherapy, and chemotherapy, more recent techniques such as nano-photothermal therapy and biotherapy are gradually being adopted for the treatment of HCC. This project intends to combine the advantages of nanoscale drug delivery systems with the targeting ability of CAR-T cells. Method: Based on cell membrane-coated nanoparticles and cell membrane-targeting modifications, a novel nanomaterial was prepared by coating CAR-T cell membranes specifically recognizing GPC3+ HCC cells onto mesoporous silica containing IR780 nanoparticles. Subsequently, the physical properties were characterized, and the in vitro and in vivo targeting abilities of this nanoparticle were verified. Results: CAR-T cells were constructed which could recognize GPC3 expressed on the cell surface of HCC cells. Then the isolated CAR-T cell membrane was successfully coated on the IR780 loaded mesoporous silica materials, as verified by transmission electron microscopy. The superior targeting ability of CAR-T cell membrane coated nanoparticles compared to IR780 loaded mesoporous silica nanoparticles was verified, both in vitro and in vivo. Conclusion: This new nanomaterial exhibits photothermal antitumor abilities along with enhanced targeting abilities, suggesting a promising strategy for the treatment of HCC.

Hepatocellular carcinoma (HCC) remains hard to diagnose early and cure due to a lack of accurate biomarkers and effective treatments. Hence, it is necessary to explore the tumorigenesis and tumor progression of HCC to discover new biomarkers for clinical treatment. We performed weighted gene co-expression network analysis (WGCNA) to explore hub genes that have high correlation with clinical information. In this study, we found 13 hub genes (GTSE1, PLK1, NCAPH, SKA3, LMNB2, SPC25, HJURP, DEPDC1B, CDCA4, UBE2C, LMNB1, PRR11, and SNRPD2) that have high correlation with histologic grade in HCC by analyzing TCGA LIHC dataset. All of these 13 hub genes could be used to effectively distinguish high histologic grade from low histologic grade of HCC through analysis of the ROC curve. The overall survival and disease-free survival information showed that high expression of these 13 hub genes led to poor prognosis. Meanwhile, these 13 hub genes had significantly different expression in HCC tumor and non-tumor tissues. We downloaded GSE6764, which contains corresponding clinical information, to validate the expression of these 13 hub genes. At the same time, we performed quantitative real-time PCR to validate the differences in the expression tendencies of these 13 hub genes between HCC tumor tissues and non-tumor tissues and high histologic grade and low histologic grade. We also explored mutation and methylation information of these 13 hub genes for further study. In summary, 13 hub genes correlated with the progression and prognosis of HCC were discovered by WGCNA in our study, and these hub genes may contribute to the tumorigenesis and tumor progression of HCC.

Renal fibrosis acts as a clinical predictor in patients with chronic kidney disease and is characterized by excessive extracellular matrix (ECM) accumulation. Our previous study suggested that mindin can function as a mediator for liver steatosis pathogenesis. However, the role of mindin in renal fibrosis remains obscure. Here, tumour necrosis factor (TGF)‐β‐treated HK‐2 cells and global mindin knockout mouse were induced with renal ischaemia reperfusion injury (IRI) to test the relationship between mindin and renal fibrosis. In vitro, mindin overexpression promoted p65—the hub subunit of the NF‐κB signalling pathway—translocation from the cytoplasm into the nucleus, resulting in NF‐κB pathway activation in TGF‐β‐treated HK‐2 cells. Meanwhile, mindin activated the TGF‐β/Smad pathway, thereby causing fibrotic‐related protein expression in vitro. Mindin −/− mice exhibited less kidney lesions than controls, with small renal tubular expansion, inflammatory cell infiltration, as well as collagen accumulation, following renal IRI. Mechanistically, mindin −/− mice suppressed p65 translocation and deactivated NF‐κB pathway. Simultaneously, mindin disruption inhibited the TGF‐β/Smad pathway, alleviating the expression of ECM‐related proteins. Hence, mindin may be a novel target of renal IRI in the treatment of renal fibrogenesis.

The identification of viability-associated long noncoding RNAs (lncRNAs) is a means of uncovering therapeutic approaches for hepatocellular carcinoma (HCC). In addition, aberrant genome-wide hypomethylation has been implicated in HCC initiation and progression. However, the relationship between lncRNA dysregulation and genome-wide hypomethylation in hepatocarcinogenesis has not been fully elucidated. A novel lncRNA named LINC00662 was previously demonstrated to play a role in gastrointestinal cancer. In this study, we demonstrated that this lncRNA was correlated with survival and exhibited oncogenic properties, both in vitro and in vivo. Moreover, we determined that LINC00662 could lead to genome-wide hypomethylation and alter the genomic methylation profile by synchronously reducing the S-adenosylmethionine (SAM) level and enhancing the S-adenosylhomocysteine (SAH) level. Mechanistically, LINC00662 was determined to regulate the key enzymes influencing SAM and SAH levels, namely, methionine adenosyltransferase 1A (MAT1A) and S-adenosylhomocysteine hydrolase (AHCY), by RNA–RNA and RNA–protein interactions. In addition, we demonstrated that some SAM-dependent HCC-promoting genes could be regulated by LINC00662 by altering the methylation status of their promoters via the LINC00662-coupled axes of MAT1A/SAM and AHCY/SAH. Taken together, the results of this this study indicate that LINC00662 could be a potential biomarker for HCC therapy. More importantly, we proposed a new role of lncRNA in regulating genomic methylation to promote oncogene activation.

BACKGROUND:Postoperative gastrointestinal dysfunction remains a major determinant of the duration of stay after complex abdominal surgery. This study was performed to evaluate the effectiveness of heated fennel therapy in accelerating the recovery of gastrointestinal function.METHODS:This surgeon-blinded, prospective randomized controlled study included 381 patients with hepatobiliary, pancreatic, and gastric tumors who were divided into 2 groups. The patients in the experimental groups received heated fennel therapy, and those in the control groups received heated rice husk therapy. We compared the baseline characteristics, time to first postoperative flatus and defecation, fasting time, duration of postoperative hospital stay, grading of abdominal pain, classification of abdominal distension, inflammatory markers, and nutritional status indicators.RESULTS:The time to first flatus and first defecation and the fasting time were statistically significantly less in the heated fennel therapy group than those in the control groups (P < .05 each); and abdominal distension was also relieved in the experimental groups (P < .001). Heated fennel therapy had no obvious beneficial effect on inflammatory markers but improved the serum albumin (ALB) level of the patients at postop day 9 (P < .001). Among the patients with alimentary tract reconstruction, those in the heated fennel therapy group had a clinically important, lesser hospital stay than those in the control group (9.2 5 ± 5.1 versus 11.1 ± 6.4; P < .023).CONCLUSION:Heated fennel therapy facilitated the gastrointestinal motility function of patients early postoperatively.

Developing new drugs for cancer treatment remains a challenging task. Herein, cancer cell membrane biomimetic ferrous ion-doped metal-organic framework nanoparticles (ZIF-8 nanoparticles) combined with dihydroartemisinin (DHA) have been designed for targeted cancer treatment with low toxicity and side effects. The biomimetic nanomaterials (CDZs) have excellent homologous targeting ability and can accumulate in tumor tissues. In an acid tumor microenvironment, ferrous ions and DHA could be released with the degradation of materials. DHA, an ancient Chinese medicine, combines with ferrous ions to produce a powerful anti-tumor effect. In human liver cancer models, about 90.8% of tumor growth was suppressed. In addition, the nanomaterial has no obvious toxic and side effects in vivo and is a highly effective and low-toxicity anti-tumor drug with a strong clinical application value.

Renal fibrosis, which is characterized by excessive extracellular matrix (ECM) accumulation in the renal tubulointerstitium, can lead to chronic kidney disease (CKD). The role of microfiber-associated protein 4 (MFAP4), which is an ECM protein that interacts with elastin and collagen, in renal fibrosis has not been investigated. The aim of this study was to examine the role of MFAP4 in the pathogenesis of renal fibrosis and the underlying mechanism using in vivo and in vitro models. The MFAP4(-/-)mice were subjected to unilateral ureteral obstruction (UUO) to elucidate the role of MFAP4 in renal fibrosis in vivo. Compared to the wild-type mice, the MFAP4(-/-)mice exhibited decreased protein expression of p-p65 and p-IKB alpha and ECM deposition after UUO. The MFAP4(-/-)mice exhibited attenuated nuclear translocation of p65 (the hub subunit of nuclear factor (NF)-kappa B signaling pathway), suppressed activation of transforming growth factor (TGF)-beta/Smad pathways, and downregulated expression of fibronectin, collagen I, and plasminogen activator inhibitor-1. The knockdown of MFAP4 mitigated the TGF-beta-induced upregulated expression of fibronectin, collagen I, and plasminogen activator inhibitor-1 in the human proximal tubular epithelial cells (HK-2). Compared to the HK-2 cells transfected with sh-MFAP4, the HK-2 cells co-transfected with sh-MFAP4 and Ad-MFAP4 exhibited severe inflammatory response and increased fibrosis-related proteins expression. Mechanistically, the knockdown of MFAP4 inhibited the activation of NF-kappa B and TGF-beta/Smad signaling pathways and downregulated the expression of fibrosis-related proteins. The findings of this study indicate that MFAP4 is involved in UUO-induced renal fibrosis through regulation of NF-kappa B and TGF-beta/Smad pathways.

BACKGROUND:Hepatocellular carcinoma (HCC) still remains a dominating medical challenge in early diagnosis and clinical therapy. Centromere protein M (CENPM) has been proved to be over-expressed in HCC tissues, but carcinogenic mechanism of CENPM contributing to liver cancer is poorly understood.METHODS:In this study, we first explored mRNA and protein levels of CENPM in HCC samples, matching adjacent non-tumor tissues and six hepatoma cell lines by polymerase chain reaction (PCR), western blotting and immunohistochemistry (IHC). Clinical data of HCC patients downloaded from The Cancer Genome Atlas (TCGA) were also analyzed. The character of CENPM concerned with HCC progression through several functional experimentations in vitro and in vivo was researched. Bioinformatics was carried out to further discover biological functions of CENPM.RESULTS:CENPM was positively up-regulated in HCC and connected with a poor prognosis. Silencing CENPM repressed cell proliferation in vivo and in vitro, and knock-down CENPM inhibited cell migration and invasion. Additionally, depletion of CENPM can promote cell apoptosis and arrested cell cycle. Furthermore, single-gene gene set enrichment analysis (GSEA) analysis indicated that CENPM was linked to the P53 signaling pathway and cell cycle pathway, and our research supported this prediction. Finally, we also found that miR-1270 was a negative regulator and participated in post-transcriptional regulation of CENPM, and hepatitis B virus X protein (HBx) can promote hepatocellular carcinoma by suppressing miR1270.CONCLUSION:CENPM was closely associated with HCC progression and it could be considered as a new possible biomarker along with a therapeutic target for HCC.

Hepatocellular carcinoma(HCC) is a malignant tumor with high mortality due to lack of early diagnostic methods and effective treatments, and the molecular mechanisms are intricate and remain unclear. In the present study, the role of macrophage receptor with collagenous structure (MARCO) in tumor advancement of HCC was investigated. We examined expression level of MARCO in HCC samples, corresponding adjacent nontumor tissues and six hepatoma cell lines by polymerase chain reaction and immunohistochemistry (IHC). Clinical information of HCC patients was also analyzed. The role of MARCO involved in HCC progression via multiple functional experiments in vitro and in vivo was investigated. Bioinformatics analysis was conducted to further explore biological functions of MARCO. We found MARCO was suggestively down-regulated in HCC and associated with favorable prognosis, and MARCO upregulation oppressed tumor cell migration and invasion. Besides, overexpression of MARCO not only promoted apoptosis of hepatoma cells but also suppressed proliferation in vivo and in vitro. Furthermore, gene set enrichment analysis (GSEA) analysis suggested that MARCO may be related to the P53 signaling pathway, and this prediction was confirmed in this study as well. In sum, our study indicated that MARCO was involved in HCC progression and it can be defined as a novel probable biomarker as well as treatment target for HCC.

Patients with renal cell carcinoma (RCC) usually develop drug resistance and have poor prognosis owing to its insensitive property. However, the underlying mechanisms of RCC are still unclear. We implemented an integrative analysis of The Cancer Genome Atlas and Gene Expression Omnibus datasets. Three genes (CRHBP, RAB25 and PSAT1) were found to be potential biomarkers in ccRCC and validated by four independent cohorts. Then, ccRCC patients with a decreased expression of CRHBP in tumor tissues had significantly poor survival by TCGA ccRCC datasets and verified by clinical samples as well as RCC cell lines. Overexpression of CRHBP suppressed cell proliferation, migration, invasion as well as apoptosis in vitro and in vivo. Moreover, the results of western blot analysis showed the effects of CRHBP via upregulating NF-κB and p53-mediated mitochondria apoptotic pathway. Our results suggested that CRHBP may be an effective target to treat ccRCC patients.

This study determines whether cullin 4B (CUL4B) promotes pancreatic cancer (PC) metastasis by inducing epithelial-mesenchymal transition (EMT) via the Wnt/β-catenin signaling pathway. A total of 64 PC patients were enrolled in this study. Human PC cell lines were distributed into blank, negative control, shCUL4B, PLOC, PLOC-CUL4B, and PLOC-CUL4B + siRNA-β-catenin groups. The expressions of CUL4B, Wnt/β-catenin signaling pathway-related proteins, and EMT-related proteins were determined using RT-qPCR and Western blotting. The positive expressions of CUL4B and β-catenin protein in tissues were detected by immunohistochemistry. MTT assay and flow cytometry was performed for cell proliferation and cell cycle, scratch test, and transwell assay for cell migration and invasion ability. CUL4B and β-catenin were expressed at a higher level in PC tissues than in paracancerous tissues though paracancerous tissues had higher expressions of CUL4B and β-catenin than normal tissues. The PLOC-CUL4B group showed increased CUL4B, Wnt, β-catenin, LEF-1, c-Jun, Cyclin D1, N-cadherin, Vimentin, Snail, and ZEB1 expression; decreased E-cadherin expression; accelerated cell proliferation; increased S-phase cell percentages; increased cell migration ability; more liver metastases; and enlarged tumor than the PLOC and PLOC-CUL4B + siRNA-β-catenin groups. The shCUL4B group showed decreased CUL4B, Wnt, β-catenin, LEF-1, c-Jun, Cyclin D1, N-cadherin, Vimentin, Snail, and ZEB1 expression; increased E-cadherin expression; decelerated cell proliferation; decreased S-phase cell percentages; reduced cell migration ability; less liver metastases; and decreased tumor weight than the blank and negative control groups. We demonstrate that CUL4B promotes PC metastasis by inducing EMT via the Wnt/β-catenin signaling pathway. Therefore, CUL4B might be the clinical target for treating PC.