Deciphering the Tumor Microenvironment of Colorectal Cancer and Guiding Clinical Treatment With Patient-Derived Organoid Technology: Progress and Challenges.

Colorectal cancer (CRC) is one of the most prevalent malignant tumors of the digestive tract worldwide. Despite notable advancements in CRC treatment, there is an urgent requirement for preclinical model systems capable of accurately predicting drug efficacy in CRC patients, to identify more effective therapeutic options. In recent years, substantial strides have been made in the field of organoid technology, patient-derived organoid models can phenotypically replicate the original intra-tumor and inter-tumor heterogeneity of CRC, reflecting cellular interactions of the tumor microenvironment. Patient-derived organoid models have become an indispensable tool for investigating the pathogenesis of CRC and facilitating translational research. This review focuses on the application of organoid technology in CRC modeling, tumor microenvironment, and guiding clinical treatment, particularly in drug screening and personalized medicine. It also examines the existing challenges encountered in clinical organoid research and provides a prospective outlook on the future development directions of clinical organoid research, encompassing the standardization of organoid culture technology and the application of tissue engineering technology.

Photo-crosslinked adhesive hydrogel loaded with extracellular vesicles promoting hemostasis and liver regeneration.

Hepatectomy is an effective surgical method for the treatment of liver diseases, but intraoperative bleeding and postoperative liver function recovery are still key issues. This study aims to develop a composite hydrogel dressing with excellent hemostatic properties, biocompatibility, and ability to promote liver cell regeneration. The modified gelatin matrix (GelMA, 10%) was mixed with equal volumes of sodium alginate-dopamine (Alg-DA) at concentrations of 0.5%, 1%, and 2%. Then a cross-linking agent (0.1%) was added to prepare different composite hydrogels under UV light, named GelMA/Alg-DA-0.5, GelMA/Alg-DA-1 and GelMA/Alg-DA-2, respectively. All the prepared hydrogel has a porous structure with a porosity greater than 65%, and could be stabilized in a gel state after being cross-linked by ultraviolet light. Physicochemical characterization showed that the elastic modulus, water absorption, adhesion, and compressibility of the composite hydrogels were improved with increasing Alg-DA content. Furthermore, the prepared hydrogel exhibits in vitro degradability, excellent biocompatibility, and good hemostatic function. Among all tested groups, the group of GelMA/Alg-DA-1 hydrogel performed the best. To further enhance its application potential in the field of liver regeneration, adipose-derived mesenchymal stem cell exosomes (AD-MSC-Exo) were loaded into GelMA/Alg-DA-1 hydrogel. Under the same conditions, GelMA/Alg-DA-1/Exo promoted cell proliferation and migration more effectively than hydrogels without extracellular vesicles. In conclusion, the prepared GelMA/Alg-DA-1 composite hydrogel loaded with AD-MSC-Exo has great application potential in liver wound hemostasis and liver regeneration.

Development and Validation of a Novel Mitochondrion and Ferroptosis-Related Long Non-Coding RNA Prognostic Signature in Hepatocellular Carcinoma.

Mitochondrion and ferroptosis are related to tumorigenesis and tumor progression of hepatocellular carcinoma (HCC). Therefore, this study focused on exploring the participation of lncRNAs in mitochondrial dysfunction and ferroptosis using public datasets from The Cancer Genome Atlas (TCGA) database. We identified the mitochondrion- and ferroptosis-related lncRNAs by Pearson's analysis and lasso-Cox regression. Moreover, real-time quantitative reverse transcription PCR (RT-qPCR) was utilized to further confirm the abnormal expression of these lncRNAs. Based on eight lncRNAs, the MF-related lncRNA prognostic signature (LPS) with outstanding stratification ability and prognostic prediction capability was constructed. In addition, functional enrichment analysis and immune cell infiltration analysis were performed to explore the possible functions of lncRNAs and their impact on the tumor microenvironment. The pathways related to G2M checkpoint and MYC were activated, and the infiltration ratio of regulatory T cells and M0 and M2 macrophages was higher in the high-risk group. In conclusion, these lncRNAs may affect mitochondria functions, ferroptosis, and immune cell infiltration in HCC through specific pathways, which may provide valuable insight into the progression and therapies of HCC.

A multi-hit therapeutic nanoplatform for hepatocellular carcinoma: Dual stimuli-responsive drug release, dual-modal imaging, and in situ oxygen supply to enhance synergistic therapy.

Nanomedicine has been widely studied for the diagnosis and treatment of hepatocellular carcinoma (HCC). How to synthesize a nanoplatform possessing a high synergistic therapeutic efficacy remains a challenge in this emerging research field. In this study, a convenient all-in-one therapeutic nanoplatform (FTY720@AM/T7-TL) is designed for HCC. This advanced nanoplatform consists of multiple functional elements, including gold-manganese dioxide nanoparticles (AM), tetraphenylethylene (T), fingolimod (FTY720), hybrid-liposome (L), and T7 peptides (T7). The nanoplatform is negatively charged at physiological pH and can transit to a positively charged state once moving to acidic pH environments. The specially designed pH-responsive charge-reversal nanocarrier prolongs the half-life of nanodrugs in blood and improves cellular uptake efficiency. The platform achieves a sustained and controllable drug release through dual stimulus-response, with pH as the endogenous stimulus and near-infrared as the exogenous stimulus. Furthermore, the nanoplatform realizes in situ O2 generation by catalyzing tumor over-expressed H2O2, which alleviates tumor microenvironment hypoxia and improves photodynamic therapy. Both in vitro and in vivo studies show the prepared nanoplatform has good photothermal conversion, cellular uptake efficiency, fluorescence/magnetic resonance imaging capabilities, and synergistic anti-tumor effects. These results suggest that the prepared all-in-one nanoplatform has great potential for dual-modal imaging-guided synergistic therapy of HCC.

Immune checkpoint inhibitor therapy for malignant tumors in liver transplantation recipients: A systematic review of the literature.

BACKGROUND: Treatment for de novo or recurrent tumors of liver transplantation (LT) recipients is challenging and immune checkpoint inhibitor (ICI) is recently well developed and could be a potentially effective option for this population. There remains limited evidence on the safety and efficacy of ICI therapy in LT recipients. METHODS: A systematic literature search was conducted on PubMed database through April 1, 2022, to identify publications reporting ICI treatment for malignant tumors in LT recipients. We summarized the allograft rejection, mortality, and tumor response of ICI treatment. RESULTS: 24 articles with 41 LT recipients were identified. The age of LT recipients ranged from 14 to 78, 76.2% were male, 56.1% had recurrent HCC, and 87.8% received anti-PD-1 therapy. Allograft rejection occurred in 31.7% of patients, death was reported in 46.3% and 6 cases died secondary to allograft rejection. Progressive disease rate of this population was 48.8% and 10 patients responded to immunotherapy. Half of recipients with positive PD-L1 staining (4/8) experienced allograft rejection. CONCLUSIONS: ICI therapy has potential therapeutic value on malignant tumors for LT recipients, accompanied by a high rate of allograft rejection and mortality. PD-L1 expression, type of ICI, and immunosuppression agent should be taken into consideration before initiation of immunotherapy. Further studies are needed to optimize this anticancer treatment approach in these patients.

Development of a novel prognostic nomogram for the early recurrence of liver cancer after curative hepatectomy.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant cancers worldwide. Curative resection is an effective treatment but HCC recurrence rates remain high. This study aimed to establish a novel prognostic nomogram to assess the risk of recurrence in patients following curative resection. METHODS: A total of 410 patients undergoing HCC curative resection were recruited from the Guangdong Provincial People's Hospital (GDPH). The cohort was divided into a training group (n=291) and a validation group (n=97). The risk factors for HCC early recurrence within 1 year of curative hepatectomy were identified. Finally, a multivariate prognostic nomogram was developed and validated. RESULTS: Age, tumor number, tumor capsule, portal vein tumor thrombi, pathological grade, vascular tumor emboli, activated partial thromboplastin time (APTT), and tumor size were identified as independent prognostic risk factors for HCC early recurrence within 1 year of curative hepatectomy. The area under the receiver operating characteristic (ROC) curve (AUC) was 0.806 [95% confidence interval (CI): 0.755 to 0.857; P<0.001], and no AUC/ROC statistical difference was detected between the training and validation sets. CONCLUSIONS: The nomogram effectively predicted postoperative HCC recurrence within 1 year after curative hepatectomy, which may be a useful tool for the postoperative treatment or follow up for HCC patients.

circRPS16 Promotes Proliferation and Invasion of Hepatocellular Carcinoma by Sponging miR-876-5p to Upregulate SPINK1.

The roles of serine protease inhibitor Kazal type 1 (SPINK1) in multiple types of cancers have been significantly documented. However, its specific roles in hepatocellular carcinoma (HCC) remain to be investigated. This study found that SPINK1 is upregulated in HCC and its upregulation correlates with poor prognosis. Besides, functional assays revealed that SPINK1 promotes cell proliferation, cell cycle, and invasion in vitro. Through bioinformatics analysis, we speculate that circRPS16 regulates SPINK1 expression by sponging miR-876-5p. This was further verified by the dual-luciferase reporter and fluorescent in situ hybridization (FISH) assays. Subsequently, rescue assays verified that circRPS16 promotes cell proliferation, cell cycle, and invasion through miR-876-5p. Importantly, silencing circRPS16 inhibited tumor growth by downregulating SPINK1 expression in vivo. Collectively, our results confirm that SPINK1 is a downstream target of circRPS16. Besides, circRPS16 and SPINK1 are oncogenic factors in HCC progression; they provide novel diagnostic and therapeutic targets for HCC patients.

Real-Time Elastography: A Web-Based Nomogram Improves the Preoperative Prediction of Central Lymph Node Metastasis in cN0 PTC.

BACKGROUND: Given the difficulty of accurately determining the central lymph node metastasis (CLNM) status of patients with clinically node-negative (cN0) papillary thyroid carcinoma (PTC) before surgery, this study aims to combine real-time elastography (RTE) and conventional ultrasound (US) features with clinical features. The information is combined to construct and verify the nomogram to foresee the risk of CLNM in patients with cN0 PTC and to develop a network-based nomogram. METHODS: From January 2018 to February 2020, 1,157 consecutive cases of cN0 PTC after thyroidectomy and central compartment neck dissection were retrospectively analyzed. The patients were indiscriminately allocated (2:1) to a training cohort (771 patients) and validation cohort (386 patients). Multivariate logistic regression analysis of US characteristics and clinical information in the training cohort was performed to screen for CLNM risk predictors. RTE data were included to construct prediction model 1 but were excluded when constructing model 2. DeLong's test was used to select a forecast model with better receiver operator characteristic curve performance to establish a web-based nomogram. The clinical applicability, discrimination, and calibration of the preferable prediction model were assessed. RESULTS: Multivariate regression analysis showed that age, sex, tumor size, bilateral tumors, the number of tumor contacting surfaces, chronic lymphocytic thyroiditis, and RTE were risk predictors of CLNM in cN0 PTC patients, which constituted prediction model 1. Model 2 included the first six risk predictors. Comparison of the areas under the curves of the two models showed that model 1 had better prediction performance (training set 0.798 vs. 0.733, validation set 0.792 vs. 0.715, p < 0.001) and good discrimination and calibration. RTE contributed significantly to the performance of the prediction model. Decision curve analysis showed that patients could obtain good net benefits with the application of model 1. CONCLUSION: A noninvasive web-based nomogram combining US characteristics and clinical risk factors was developed in the research. RTE could improve the prediction accuracy of the model. The dynamic nomogram has good performance in predicting the probability of CLNM in cN0 PTC patients.

Correction to: LncMAPK6 drives MAPK6 expression and liver TIC self-renewal.

In the original publication of this article [1], the author found an error in Fig. 2f. lncGPR107 should be changed to lncMAPK6, and the corrected Fig. 2 is shown below.

A Predictive Risk Scoring System for Clinically Relevant Pancreatic Fistula After Pancreaticoduodenectomy.

BACKGROUND Postoperative pancreatic fistula remains a challenge after pancreaticoduodenectomy (PD). This study aimed to establish a scoring system to predict clinically relevant postoperative pancreatic fistula (CR-POPF) after PD. MATERIAL AND METHODS The clinical records of 361 consecutive patients who underwent PD between 2009 and 2017 were reviewed retrospectively. Patients were divided into a study group (225 patients) and a validation group (136 patients). CR-POPF was defined and classified based on the 2016 ISGPS definition and classification system. Univariate and multivariate logistic regression analyses were performed and we thus developed a scoring system based on the regression coefficient of the multivariate logistic regression model. The predictive value was determined using the receiver operating characteristic (ROC) curve. RESULTS A predictive scoring system with a maximum of 6 points for CR-POPF was established using the following 4 factors: 1 point for soft pancreatic texture (OR 2.09, 95%CI 1.10-3.98, P=0.025), 1.5 points for main pancreatic duct diameter ≤2.5 mm (OR 2.72, 95%CI 1.23-5.99, P=0.013), 0.5 points for extended lymphadenectomy (OR 1.57, 95%CI 1.13-2.18, P=0.007), 0.5 points for a 25-30 g/L postoperative day 1 serum albumin (OR 1.43, 95%CI 1.02-2.00, P=0.037), and 3 points for postoperative day 1 serum albumin ≤25 g/L (OR 5.12, 95%CI 1.82-14.41, P=0.002). The ROC curve showed that this scoring system was highly predictive for CR-POPF in the validation group (AUC=0.806, 95%CI: 0.735-0.878). CONCLUSIONS This 6-point risk scoring system will be useful for perioperative risk management of CR-POPF.

LncGPR107 drives the self-renewal of liver tumor initiating cells and liver tumorigenesis through GPR107-dependent manner.

BACKGROUND: With self-renewal and differentiation properties, liver tumor initiating cells (TICs) are the reasons for tumor initiation, metastasis and drug resistance. G protein coupled receptors (GPCR) are critical modulators in many physiological and pathological processes. While, their roles in liver TICs are unknown. METHODS: An unbiased screening was performed using online-available data dataset. Liver TICs were sorted by FACS with surface marker CD133, or enriched by oncosphere formation. TIC self-renewal was examined by oncosphere formation and tumor initiation assay. Loss of function and gain of function assays were performed to examine the role of lncRNA. RNA pulldown, RNA immunoprecipitation, ChIP, western blot and double FISH were used explore the molecular mechanism of lncRNA. RESULTS: We performed an unbiased screening for GPCR expression in liver cancers, and found GPR107 was the most highly expressed GPCR in liver cancer and liver TICs. GPR107 was essential for the self-renewal of liver TICs. The expression of GPR107 was regulated by a long noncoding RNA lncGPR107. LncGPR107 was also highly expressed in liver cancers and liver TICs. LncGPR107 drove the self-renewal of liver TICs through GPR107. Moreover, lncGPR107 recruited SRCAP complex to GPR107 promoter to drive its transcriptional activation. LncGPR107 depletion inhibited the binding of SRCAP complex and GPR107 promoter and subsequent GPR107 expression. Moreover, LncGPR107-SRCAP-GPR107 can be targeted for liver TIC elimination. CONCLUSION: GPR107 was the most highly expressed GPCR in liver cancer and liver TICs. LncGPR107 participated in the transcriptional regulation of GPR107 in cis, through recruiting SRCAP remodeling complex to GPR107 promoter. This work revealed the important role of GPCR signaling in liver TIC self-renewal and added a new layer for liver TIC and GPCR regulation.

LncMAPK6 drives MAPK6 expression and liver TIC self-renewal.

BACKGROUND: Liver tumor initiating cells (TICs) have self-renewal and differentiate capacities, and largely contribute to tumor initiation, metastasis and drug resistance. MAPK signaling is a critical pathway in many biological processes, while its role in liver TICs hasn't been explored. METHODS: Online-available dataset was used for unbiased screening. Liver TICs were examined CD133 FACS or oncosphere formation. TIC self-renewal was detected by oncosphere formation and tumor initiation assay. LncRNA function was detected by loss of function or gain of function assays. The molecular mechanism of lncRNA was explored by RNA pulldown, RNA immunoprecipitation, ChIP, western blot and double FISH. RESULTS: Here, we examined the expression profiles of MAPK components (MAPKs, MAP2Ks, MAP3Ks, MAP4Ks), and found MAPK6 is most highly expressed in liver cancer samples. Moreover, a divergent lncRNA (long noncoding RNA) of MAPK6, termed lncMAPK6 here, is also overexpressed along with liver tumorigenesis. LncMAPK6 promotes liver tumor propagation and TIC self-renewal through MAPK6. LncMAPK6 interacts with and recruits RNA polymerase II to MAPK6 promoter, and finally activates the transcription of MAPK6. Through MAPK6 transcriptional regulation, lncMAPK6 drives MARK signaling activation. LncMAPK6-MAPK6 pathway can be used for liver TIC targeting. Altogether, lncMAPK6 promotes MARK signaling and the self-renewal of liver TICs through MAPK6 expression. CONCLUSION: MAPK6 was the most highly expressed MAPK component in liver cancer and liver TICs and lncMAPK6 participated in the transcriptional regulation of MAPK6in cis. This work revealed the importance role of MAPK signaling in liver TIC self-renewal and added a new layer for liver TIC and MAPK6 expression regulation.

Quantification of liver fibrosis via second harmonic imaging of the Glisson's capsule from liver surface.

Liver surface is covered by a collagenous layer called the Glisson's capsule. The structure of the Glisson's capsule is barely seen in the biopsy samples for histology assessment, thus the changes of the collagen network from the Glisson's capsule during the liver disease progression are not well studied. In this report, we investigated whether non-linear optical imaging of the Glisson's capsule at liver surface would yield sufficient information to allow quantitative staging of liver fibrosis. In contrast to conventional tissue sections whereby tissues are cut perpendicular to the liver surface and interior information from the liver biopsy samples were used, we have established a capsule index based on significant parameters extracted from the second harmonic generation (SHG) microscopy images of capsule collagen from anterior surface of rat livers. Thioacetamide (TAA) induced liver fibrosis animal models was used in this study. The capsule index is capable of differentiating different fibrosis stages, with area under receiver operating characteristics curve (AUC) up to 0.91, making it possible to quantitatively stage liver fibrosis via liver surface imaging potentially with endomicroscopy.

[Artificial and bioartificial liver support systems for acute and acute-on-chronic liver failure: a meta-analysis].

OBJECTIVE: To evaluate the effect of artificial and bioartificial liver support systems for management of acute and acute-on-chronic liver failure. METHODS: Articles documenting randomized clinical trials concerning any liver support systems vs standard conservative therapy, published between January, 1970 and June, 2008, were retrieved by database searching. Of the 1134 articles retrieved, 12 randomized trials involving 479 patients were included. The data were extracted and the trial quality was assessed by 2 independent reviewers. The primary outcome measure was all-cause mortality, and the results were combined on the risk ratio (RR) scale. RESULTS: Of the 12 trials included, 10 assessed artificial liver support systems for acute or acute-on-chronic liver failure, and 2 assessed bioartificial systems for acute liver failure. Overall, the liver support systems had moderate effect on mortality compared with standard conservative therapy (RR=0.80; 95% CI 0.664-0.969, P=0.022). Meta-regression indicated that the effect of the support systems depended on the type of liver failure (P=0.00). In stratified meta-analyses, the support systems appeared to reduce the mortality by 43% in acute-on-chronic liver failure (RR=0.57; 95% CI 0.39-0.84, P=0.004), but not in acute liver failure (RR=0.899; 95% CI 0.72-1.12, P=0.361). CONCLUSION: Artificial liver support systems reduce the mortality of acute-on-chronic liver failure as compared with standard conservative therapy, but have no significant effect on the mortality of acute liver failure. Bioartificial liver support systems lower the mortality rates in both acute and acute-on-chronic liver failure, and should be the future focus of development.