Development and validation of a new prognostic immune-inflammatory-nutritional score for predicting outcomes after curative resection for intrahepatic cholangiocarcinoma: A multicenter study.

Background: Immune function, nutrition status, and inflammation influence tumor initiation and progression. This was a retrospective multicenter cohort study that investigated the prognostic value and clinical relevance of immune-, inflammatory-, and nutritional-related biomarkers to develop a novel prognostic immune-inflammatory-nutritional score (PIIN score) for patients with intrahepatic cholangiocarcinoma (ICC). Methods: The clinical data of 571 patients (406 in the training set and 165 in the validation set) were collected from four large hepato-pancreatico-biliary centers of patients with ICC who underwent surgical resection between January 2011 and September 2017. Twelve blood biomarkers were collected to develop the PIIN score using the LASSO Cox regression model. The predictive value was further assessed using validation datasets. Afterward, nomograms combining the PIIN score and other clinicopathological parameters were developed and validated based on the calibration curve, time-dependent AUC curves, and decision curve analysis (DCA). The primary outcomes evaluated were overall survival (OS) and recurrence-free survival (RFS) from the day of primary resection of ICC. Results: Based on the albumin-bilirubin (ALBI) grade, neutrophil- to- lymphocyte ratio (NLR), prognostic nutritional index (PNI), and systemic immune- inflammation index (SII) biomarkers, the PIIN score that classified patients into high-risk and low-risk groups could be calculated. Patients with high-risk scores had shorter OS (training set, p < 0.001; validation set, p = 0.003) and RFS (training set, p < 0.001; validation set, p = 0.002) than patients with low-risk scores. The high PIIN score was also associated with larger tumors (≥5 cm), lymph node metastasis (N1 stage), multiple tumors, and high tumor grade or TNM (tumor (T), nodes (N), and metastases (M)) stage. Furthermore, the high PIIN score was a significant independent prognostic factor of OS and RFS in both the training (p < 0.001) and validation (p = 0.003) cohorts, respectively. A PIIN-nomogram for individualized prognostic prediction was constructed by integrating the PIIN score with the clinicopathological variables that yielded better predictive performance than the TNM stage. Conclusion: The PIIN score, a novel immune-inflammatory-nutritional-related prognostic biomarker, predicts the prognosis in patients with resected ICC and can be a reliable tool for ICC prognosis prediction after surgery. Our study findings provide novel insights into the role of cancer-related immune disorders, inflammation, and malnutrition.

Efficacy of LR-5 and LR-4/5 by Liver Imaging Reporting and Data System (MRI) for hepatocellular carcinoma: A meta-analysis.

To comprehensive investigate the diagnostic efficacy of LR-5 and LR-4/5 by MRI LI-RADS of suspected liver nodules. A comprehensive search of authenticated international databases including PubMed/Medline, Ovid, Embase, Web of Science as well as a series of nation-level databases, including China National Knowledge Infrastructure was carried out to look for related studies with respect to the diagnostic performance of MRI LR-5 or LR-4/5 for HCC. Subsequently, main data including the basic information of the articles incorporated as well as main outcomes, including diagnostic sensitivity, specificity, accuracy, or original data like true positive, false positive, true negative and false negative values were extracted. Next, forest plots were generated to reveal the pooled diagnostic sensitivity, specificity. The diagnostic sensitivity, specificity of LR-5 and LR-4/5 by LI-RADS were comparatively satisfactory. The pooled diagnostic sensitivity and specificity of MRI LR-5 with respect to pathologically diagnosed HCC were 0.73 [95% CI 0.7-0.75] and 0.88 [95% CI 0.86-0.90] respectively. The pooled sensitivity and specificity of MRI LR-4/5 were 0.77 [95% CI 0.75-0.80] and 0.82 [95% CI 0.79-0.85] respectively. Through this systematic review and meta-analysis, we found a promisingly satisfactory diagnostic efficacy of LR-5 and LR-4/5 by MRI LI-RADS of suspected malignant liver nodules, manifested by optimal diagnostic sensitivity, specificity, and accuracy.

LncRNA CEBPA-DT promotes liver cancer metastasis through DDR2/ß-catenin activation via interacting with hnRNPC.

BACKGROUND: Hepatocellular carcinoma (HCC) is the world's third leading cause of cancer-related death; due to the fast growth and high prevalence of tumor recurrence, the prognosis of HCC patients remains dismal. Long non-coding RNA CEBPA-DT, a divergent transcript of the CCAAT Enhancer Binding Protein Alpha (CEBPA) gene, has been shown to participate in multiple tumor progression. However, no research has established its cancer-promoting mechanism in HCC yet. METHODS: CEBPA-DT was identified in human HCC tissues through RNA sequencing. The expression level of CEBPA-DT was assessed by quantitative real-time PCR. The biological effects of CEBPA-DT were evaluated in vitro and in vivo through gain or loss of function experiments. RNA fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down assays were applied to investigate the downstream target of CEBPA-DT. Immunofluorescence, subcellular protein fractionation, western blot, and co-immunoprecipitation were performed to analyze the subcellular location of ß-catenin and its interaction with Discoidin domain-containing receptor 2 (DDR2). RESULTS: CEBPA-DT was upregulated in human HCC tissues with postoperative distant metastasis and intimately related to the worse prognosis of HCC patients. Silencing of CEBPA-DT inhibited the growth, migration and invasion of hepatoma cells in vitro and in vivo, while enhancement of CEBPA-DT played a contrasting role. Mechanistic investigations demonstrated that CEBPA-DT could bind to heterogeneous nuclear ribonucleoprotein C (hnRNPC), which facilitated cytoplasmic translocation of hnRNPC, enhanced the interaction between hnRNPC and DDR2 mRNA, subsequently promoted the expression of DDR2. Meanwhile, CEBPA-DT induced epithelial-mesenchymal transition (EMT) process through upregulation of Snail1 via facilitating nuclear translocation of ß-catenin. Using DDR2 inhibitor, we revealed that the CEBPA-DT induced the interaction between DDR2 and ß-catenin, thus promoting the nuclear translocation of ß-catenin to activate transcription of Snail1, contributing to EMT and HCC metastasis. CONCLUSIONS: Our results suggested that CEBPA-DT promoted HCC metastasis through DDR2/ß-catenin mediated activation of Snail1 via interaction with hnRNPC, indicating that the CEBPA-DT-hnRNPC-DDR2/ß-catenin axis may be used as a potential therapeutic target for HCC treatment.

Case report: Adrenal myelolipoma resected by laparoscopic surgery.

Introduction: Adrenal myelolipomas are benign tumors composed mainly of lipomatous elements with myeloid cells. With the development of medical imaging technology, the detection rate has gradually increased. We report a case of adrenal myelolipoma successfully excised through the laparoscope and reviewed existing literature in recent ten years to summarize the feasibility of the laparoscopic approach for this tumor. Case presentation: Herein, we described a case of adrenal myelolipoma resected by laparoscope in a 63-year-old male patient. He did not have any other symptoms except the incidental finding of a left adrenal mass. An abdominal CT examination revealed a mixed-density lesion containing some amount of adipose tissue. In conjunction with the patient's willingness, we performed a laparoscopic operation to remove the lump. The definite diagnosis was confirmed as an adrenal myelolipoma according to the pathology. The patient recovered well postoperatively and without signs of recurrence at a 5-month follow-up. Conclusion: Adrenal myelolipoma is commonly benign, asymptomatic, and hormonal inactivity. A surgical strategy is suggested for high-complication-risk patients. The laparoscopic approach is safe and effective with an obvious advantage over open procedures.

Case report: A mesocolic lymphangioma in a 14-year-old child resected by laparoscopic surgery.

Introduction: Cystic lymphangioma is a benign malformation tumor of the lymphatic system. Its location is variable, and mesocolic localization remains extremely rare. Case presentation: We report a case of right mesocolon giant cystic lymphangioma in a previously healthy 14-year-old boy who was successfully managed through a minimally invasive laparoscopic excision. The patient presented with 8 months of dull abdominal pain, sporadic, located on the peri-umbilicus, exacerbated for a month. An abdominal computed tomography (CT) revealed a large, multiseptated cystic mass on the right mesocolon. Right mesocolic excision using a laparoscope was performed on this patient. He was discharged on the fifth day without complications. Recurrence was not detected in three months of follow-up. Conclusion: Cystic lymphangiomas in the mesocolon are rare benign neoplasms that pose diagnostic challenges. Complete resection is the optimal option for diagnostic confirmation and recurrence prevention. Laparoscopic surgery is feasible for children with mesocolic lymphangioma.

FLASH radiotherapy: A promising new method for radiotherapy.

Among the treatments for malignant tumors, radiotherapy is of great significance both as a main treatment and as an adjuvant treatment. Radiation therapy damages cancer cells with ionizing radiation, leading to their death. However, radiation-induced toxicity limits the dose delivered to the tumor, thereby constraining the control effect of radiotherapy on tumor growth. In addition, the delayed toxicity caused by radiotherapy significantly harms the physical and mental health of patients. FLASH-RT, an emerging class of radiotherapy, causes a phenomenon known as the 'FLASH effect', which delivers radiotherapy at an ultra-high dose rate with lower toxicity to normal tissue than conventional radiotherapy to achieve local tumor control. Although its mechanism remains to be fully elucidated, this modality constitutes a potential new approach to treating malignant tumors. In the present review, the current research progress of FLASH-RT and its various particular effects are described, including the status of research on FLASH-RT and its influencing factors. The hypothetic mechanism of action of FLASH-RT is also summarized, providing insight into future tumor treatments.

Long noncoding RNA TLNC1 promotes the growth and metastasis of liver cancer via inhibition of p53 signaling.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been demonstrated to play vital roles in cancer development and progression. However, their biological roles and function mechanisms in liver cancer remain largely unknown. METHODS: RNA-seq was performed with clinical hepatoma tissues and paired adjacent normal liver tissues to identify differentially expressed lncRNAs. qPCR was utilized to examine the expression levels of lncRNAs. We studied the function of TLNC1 in cell growth and metastasis of hepatoma with both cell and mouse models. RNA-seq, RNA pull-down coupled with mass spectrometry, RNA immunoprecipitation, dual luciferase reporter assay, and surface plasmon resonance analysis were used to analyze the functional mechanism of TLNC1. RESULTS: Based on the intersection of our own RNA-seq, TCGA RNA-seq, and TCGA survival analysis data, TLNC1 was identified as a potential tumorigenic lncRNA of liver cancer. TLNC1 significantly enhanced the growth and metastasis of hepatoma cells both in vitro and in vivo. TLNC1 exerted its tumorigenic function through interaction with TPR and inducing the TPR-mediated transportation of p53 from nucleus to cytoplasm, thus repressing the transcription of p53 target genes and finally contributing to the progression of liver cancer. CONCLUSIONS: TLNC1 is a promising prognostic factor of liver cancer, and the TLNC1-TPR-p53 axis can serve as a potential therapeutic target for hepatoma treatment.

CircNFIB inhibits tumor growth and metastasis through suppressing MEK1/ERK signaling in intrahepatic cholangiocarcinoma.

BACKGROUND: Considerable evidence shows that circular RNAs (circRNAs) play an important role in tumor development. However, their function in intrahepatic cholangiocarcinoma (ICC) metastasis and the underlying mechanisms are incompletely understood. METHODS: circNFIB (hsa_circ_0086376, termed as cNFIB hereafter) was identified in human ICC tissues through circRNAs sequencing. The biological role of cNFIB was determined in vitro and in vivo by gain or loss of functional experiments. Fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down assays were conducted to analyze the interaction of cNFIB with dual specificity mitogen-activated protein kinase kinase1 (MEK1). Duolink in situ proximity ligation assay (PLA) and coimmunoprecipitation (co-IP) assay were used to investigate the effects of cNFIB on the interaction between MEK1 and mitogen-activated protein kinase 2 (ERK2). Finally, a series of in vitro and in vivo experiments were performed to explore the influences of cNFIB on the anti-tumor activity of trametinib (a MEK inhibitor). RESULTS: cNFIB was significantly down-regulated in human ICC tissues with postoperative metastases. The loss of cNFIB was highly associated with aggressive characteristics and predicted unfavorable prognosis in ICC patients. Functional studies revealed that cNFIB inhibited the proliferation and metastasis of ICC cells in vitro and in vivo. Mechanistically, cNFIB competitively interacted with MEK1, which induced the dissociation between MEK1 and ERK2, thereby resulting in the suppression of ERK signaling and tumor metastasis. Moreover, we found that ICC cells with high levels of cNFIB held the potential to delay the trametinib resistance. Consistently, in vivo and in vitro studies demonstrated that cotreatment with trametinib and lentivirus vector encoding cNFIB showed greater inhibitory effect than isolated trametinib treatment. CONCLUSIONS: Our findings identified that cNFIB played a key role in ICC growth and metastasis by regulating MEK1/ERK signaling. Given the efficacy of cNFIB modulation on ICC suppression and trametinib sensitivity, cNFIB appears to be a potential therapeutic molecule for ICC treatment.

Robotic Versus Laparoscopic Distal Pancreatectomy for Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis.

BACKGROUND: Robotic distal pancreatectomy (RDP) and laparoscopic distal pancreatectomy (LDP) are the two principal minimally invasive surgical approaches for patients with pancreatic body and tail adenocarcinoma. The use of RDP and LDP for pancreatic ductal adenocarcinoma (PDAC) remains controversial, and which one can provide a better R0 rate is not clear. METHODS: A comprehensive search for studies that compared robotic versus laparoscopic distal pancreatectomy for PDAC published until July 31, 2021, was conducted. Data on perioperative outcomes and oncologic outcomes (R0-resection and lymph node dissection) were subjected to meta-analysis. PubMed, Cochrane Central Register, Web of Science, and EMBASE were searched based on a defined search strategy to identify eligible studies before July 2021. RESULTS: Six retrospective studies comprising 572 patients (152 and 420 patients underwent RDP and LDP) were included. The present meta-analysis showed that there were no significant differences in operative time, tumor size, and lymph node dissection between RDP and LDP group. Nevertheless, compared with the LDP group, RDP results seem to demonstrate a possibility in higher R0 resection rate (p<0.0001). CONCLUSIONS: This systematic review and meta-analysis suggest that RDP is a technically and oncologically safe and feasible approach for selected PDAC patients. Large randomized and controlled prospective studies are needed to confirm this data. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier [CRD42021269353].

Accurate Detection and Evaluation of the Gene-Editing Frequency in Plants Using Droplet Digital PCR.

Gene-editing techniques are becoming powerful tools for modifying target genes in organisms. Although several methods have been reported that detect mutations at targeted loci induced by the CRISPR/Cas system in different organisms, they are semiquantitative and have difficulty in the detection of mutants in processed food samples containing low initial concentrations of DNA and may not accurately quantify editing frequency, especially at very low frequencies in a complex polyploid plant genome. In this study, we developed a duplexed dPCR-based method for the detection and evaluation of gene-editing frequencies in plants. We described the design, performance, accurate quantification, and comparison with other detection systems. The results show that the dPCR-based method is sensitive to different kinds of gene-editing mutations induced by gene-editing. Moreover, the method is applicable to polyploid plants and processed food samples containing low initial concentrations of DNA. Compared with qPCR and NGS-based methods, the dPCR method has a lower limit of detection (LOD) of the editing frequency and a better relationship with the expected editing frequency in detecting the edited region of gene-edited rice samples. Taken together, the duplexed dPCR assay is accurate and precise, and it will be a powerful tool for the detection and evaluation of gene-editing frequencies in plants in gene-editing technology.

CPX Targeting DJ-1 Triggers ROS-induced Cell Death and Protective Autophagy in Colorectal Cancer.

Rationale: Colorectal cancer (CRC) is one of the most common cancers worldwide. Ciclopirox olamine (CPX) has recently been identified to be a promising anticancer candidate; however, novel activities and detailed mechanisms remain to be uncovered. Methods: The cytotoxic potential of CPX towards CRC cells was examined in vitro and in vivo. The global gene expression pattern, ROS levels, mitochondrial function, autophagy, apoptosis, etc. were determined between control and CPX-treated CRC cells. Results: We found that CPX inhibited CRC growth by inhibiting proliferation and inducing apoptosis both in vitro and in vivo. The anti-cancer effects of CPX involved the downregulation of DJ-1, and overexpression of DJ-1 could reverse the cytotoxic effect of CPX on CRC cells. The loss of DJ-1 resulted in mitochondrial dysfunction and ROS accumulation, thus leading to CRC growth inhibition. The cytoprotective autophagy was provoked simultaneously, and blocking autophagy pharmacologically or genetically could further enhance the anti-cancer efficacy of CPX. Conclusion: Our study demonstrates that DJ-1 loss-induced ROS accumulation plays a pivotal role in CPX-mediated CRC inhibition, providing a further understanding for CRC treatment via modulating compensatory protective autophagy.

Rapid detection of cadmium and its distribution in Miscanthus sacchariflorus based on visible and near-infrared hyperspectral imaging.

Monitoring the effectiveness of Miscanthus sacchariflorus to meet the basic requirements for environmental remediation projects is an important step in determining its use as a productive bioenergy crop for phytoremediation. Conventional chemical methods for the determination of cadmium (Cd) contents involve time-consuming, monotonous and destructive procedures and are not suitable for high-throughput screening. In the present study, visible and near-infrared hyperspectral imaging technology combined with chemometric methods was used to assess the Cd concentrations in M. sacchariflorus. The total Cd concentrations in different plant tissues were measured using an inductively coupled plasma-mass spectrometer. Partial least-squares regression and least-squares support vector machine were implemented to estimate Cd contents from spectral reflectance. Successive projections algorithm and competitive adaptive reweighted sampling (CARS) methodology were used for selecting optimal wavelength. The CARS-partial least-squares regression model resulted in the most accurate predictions of Cd contents in M. sacchariflorus leaves, with a determination coefficient (R2) of 0.87 and a root mean square error (RMSE) value of 97.78 for the calibration set, and an R2 value of 0.91 and a RMSE value of 75.95 for the prediction set. The CARS-least-squares support vector machine model resulted in the most satisfactory predictions of Cd contents in roots, with R2 values of 0.95 (RMSE, 0.92 × 103) for the calibration set and 0.90 (RMSE, 1.64 × 103) for the prediction set. Finally, the Cd concentrations in different plant tissues were visualized on the prediction maps by predicted spectral features on each hyperspectral image pixel. Thus, visible and near-infrared imaging combined with chemometric methods produces a promising technique to evaluate M. sacchariflorus' Cd phytoremediation capability in high-throughput metal-contaminated field applications.

Cell-surface translocation of annexin A2 contributes to bleomycin-induced pulmonary fibrosis by mediating inflammatory response in mice.

Bleomycin, a widely used anti-cancer drug, may give rise to pulmonary fibrosis, a serious side effect which is associated with significant morbidity and mortality. Despite the intensive efforts, the precise pathogenic mechanisms of pulmonary fibrosis still remain to be clarified. Our previous study showed that bleomycin bound directly to annexin A2 (ANXA2, or p36), leading to development of pulmonary fibrosis by impeding transcription factor EB (TFEB)-induced autophagic flux. Here, we demonstrated that ANXA2 also played a critical role in bleomycin-induced inflammation, which represents another major cause of bleomycin-induced pulmonary fibrosis. We found that bleomycin could induce the cell surface translocation of ANXA2 in lung epithelial cells through exosomal secretion, associated with enhanced interaction between ANXA2 and p11. Knockdown of ANXA2 or blocking membrane ANXA2 mitigated bleomycin-induced activation of nuclear factor (NF)-κB pathway and production of pro-inflammatory cytokine IL-6 in lung epithelial cells. ANXA2-deficient (ANXA2-/-) mice treated with bleomycin exhibit reduced pulmonary fibrosis along with decreased cytokine production compared with bleomycin-challenged wild-type mice. Further, the surface ANXA2 inhibitor TM601 could ameliorate fibrotic and inflammatory response in bleomycin-treated mice. Taken together, our results indicated that, in addition to disturbing autophagic flux, ANXA2 can contribute to bleomycin-induced pulmonary fibrosis by mediating inflammatory response.

Tubeimoside I induces accumulation of impaired autophagolysosome against cervical cancer cells by both initiating autophagy and inhibiting lysosomal function.

Cervical cancer is one of the most aggressive human cancers with poor prognosis due to constant chemoresistance and repeated relapse. Tubeimoside I (TBM) has been identified as a potent antitumor agent that inhibits cancer cell proliferation by triggering apoptosis and inducing cell cycle arrest. Nevertheless, the detailed mechanism remains unclear and needs to be further elucidated, especially in cervical cancer. In this study, we found that TBM could induce proliferation inhibition and cell death in cervical cancer cells both in vitro and in vivo. Further results demonstrated that treatment with TBM could induce autophagosome accumulation, which was important to TBM against cervical cancer cells. Mechanism studies showed that TBM increased autophagosome by two pathways: First, TBM could initiate autophagy by activating AMPK that would lead to stabilization of the Beclin1-Vps34 complex via dissociating Bcl-2 from Beclin1; Second, TBM could impair lysosomal cathepsin activity and block autophagic flux, leading to accumulation of impaired autophagolysosomes. In line with this, inhibition of autophagy initiation attenuated TBM-induced cell death, whereas autophagic flux inhibition could exacerbated the cytotoxic activity of TBM in cervical cancer cells. Strikingly, as a novel lethal impaired autophagolysosome inducer, TBM might enhance the therapeutic effects of chemotherapeutic drugs towards cervical cancer, such as cisplatin and paclitaxel. Together, our study provides new insights into the molecular mechanisms of TBM in the antitumor therapy, and establishes potential applications of TBM for cervical cancer treatment in clinic.