Single-cell immune profiling of mouse liver aging reveals Cxcl2+ macrophages recruit neutrophils to aggravate liver injury.

BACKGROUND AND AIMS: Immune cells play a crucial role in liver aging. However, the impact of dynamic changes in the local immune microenvironment on age-related liver injury remains poorly understood. We aimed to characterize intrahepatic immune cells at different ages to investigate key mechanisms associated with liver aging. APPROACH AND RESULTS: We carried out single-cell RNA sequencing on mouse liver tissues at 4 different ages, namely, the newborn, suckling, young, and aged stages. The transcriptomic landscape, cellular classification, and intercellular communication were analyzed. We confirmed the findings by multiplex immunofluorescence staining, flow cytometry, in vitro functional experiments, and chimeric animal models. Nine subsets of 89,542 immune cells with unique properties were identified, of which Cxcl2+ macrophages within the monocyte/macrophage subset were preferentially enriched in the aged liver. Cxcl2+ macrophages presented a senescence-associated secretory phenotype and recruited neutrophils to the aged liver through the CXCL2-CXCR2 axis. Through the secretion of IL-1ß and TNF-α, Cxcl2+ macrophages stimulated neutrophil extracellular traps formation. Targeting the CXCL2-CXCR2 axis limited the neutrophils migration toward the liver and attenuated age-related liver injury. Moreover, the relationship between Cxcl2+ macrophages and neutrophils in age-related liver injury was further validated by human liver transplantation samples. CONCLUSIONS: This in-depth study illustrates that the mechanism of Cxcl2+ macrophage-driven neutrophil activation involves the CXCL2-CXCR2 axis and provides a potential therapeutic strategy for age-related liver injury.

Identification of prognostic biomarkers for cholangiocarcinoma by combined analysis of molecular characteristics of clinical MVI subtypes and molecular subtypes.

Cholangiocarcinoma (CCA) is widely noted for its high degree of malignancy, rapid progression, and limited therapeutic options. This study was carried out on transcriptome data of 417 CCA samples from different anatomical locations. The effects of lipid metabolism related genes and immune related genes as CCA classifiers were compared. Key genes were derived from MVI subtypes and better molecular subtypes. Pathways such as epithelial mesenchymal transition (EMT) and cell cycle were significantly activated in MVI-positive group. CCA patients were classified into three (four) subtypes based on lipid metabolism (immune) related genes, with better prognosis observed in lipid metabolism-C1, immune-C2, and immune-C4. IPTW analysis found that the prognosis of lipid metabolism-C1 was significantly better than that of lipid metabolism-C2 + C3 before and after correction. KRT16 was finally selected as the key gene. And knockdown of KRT16 inhibited proliferation, migration and invasion of CCA cells.

Conversion therapy for advanced hepatocellular carcinoma in the era of precision medicine: Current status, challenges and opportunities.

Hepatocellular carcinoma (HCC), the most prevalent malignancy of the digestive tract, is characterized by a high mortality rate and poor prognosis, primarily due to its initial diagnosis at an advanced stage that precludes any surgical intervention. Recent advancements in systemic therapies have significantly improved oncological outcomes for intermediate and advanced-stage HCC, and the combination of locoregional and systemic therapies further facilitates tumor downstaging and increases the likelihood of surgical resectability for initially unresectable cases following conversion therapies. This shift toward high conversion rates with novel, multimodal treatment approaches has become a principal pathway for prolonged survival in patients with advanced HCC. However, the field of conversion therapy for HCC is marked by controversies, including the selection of potential surgical candidates, formulation of conversion therapy regimens, determination of optimal surgical timing, and application of adjuvant therapy post-surgery. Addressing these challenges and refining clinical protocols and research in HCC conversion therapy is essential for setting the groundwork for future advancements in treatment strategies and clinical research. This narrative review comprehensively summarizes the current strategies and clinical experiences in conversion therapy for advanced-stage HCC, emphasizing the unresolved issues and the path forward in the context of precision medicine. This work not only provides a comprehensive overview of the evolving landscape of treatment modalities for conversion therapy but also paves the way for future studies and innovations in this field.

Cross-species metabolomic profiling reveals phosphocholine-mediated liver protection from cold and ischemia/reperfusion.

Cold and ischemia/reperfusion (IR)-associated injuries are seemingly inevitable during liver transplantation and hepatectomy. As Syrian hamsters demonstrate intrinsic tolerance to transplantation-like stimuli, cross-species comparative metabolomic analyses were conducted with hamster, rat and donor liver samples to seek hepatic cold and IR-adaptive mechanisms. Lower hepatic phosphocholine contents were found in early graft-dysfunctioned recipients with virus-caused cirrhosis or high MELD scores (≥30). Choline/phosphocholine deficiency in cultured human THLE-2 hepatocytes and animal models weakened hepatocellular cold tolerance and recovery of glutathione and ATP production, which was rescued by phosphocholine supplements. Among the biological processes impacted by choline/phosphocholine deficiency, three lipid-related metabolic processes were downregulated, whilst phosphocholine elevated the expression of genes in methylation processes. Consistently, in THLE-2, phosphocholine enhanced the overall RNA m6A methylation, among which the transcript stability of Fatty acid desaturase 6 (FADS6) was improved. FADS6 functioned as a key phosphocholine effector in the production of polyunsaturated fatty acids, which may facilitate the hepatocellular recovery of energy and redox homeostasis. Thus, our study reveals the choline-phosphocholine metabolism and its downstream FADS6 functions in hepatic adaptation to cold and IR, which may inspire new strategies to monitor donor liver quality and improve recipient recovery from the LT process.

Pseudouridine synthase 1 promotes hepatocellular carcinoma through mRNA pseudouridylation to enhance the translation of oncogenic mRNAs.

BACKGROUND AND AIMS: Pseudouridine is a prevalent RNA modification and is highly present in the serum and urine of patients with HCC. However, the role of pseudouridylation and its modifiers in HCC remains unknown. We investigated the function and underlying mechanism of pseudouridine synthase 1 (PUS1) in HCC. APPROACH AND RESULTS: By analyzing the TCGA data set, PUS1 was found to be significantly upregulated in human HCC specimens and positively correlated with tumor grade and poor prognosis of HCC. Knockdown of PUS1 inhibited cell proliferation and the growth of tumors in a subcutaneous xenograft mouse model. Accordingly, increased cell proliferation and tumor growth were observed in PUS1-overexpressing cells. Furthermore, overexpression of PUS1 significantly accelerates tumor formation in a mouse HCC model established by hydrodynamic tail vein injection, while knockout of PUS1 decreases it. Additionally, PUS1 catalytic activity is required for HCC tumorigenesis. Mechanistically, we profiled the mRNA targets of PUS1 by utilizing surveying targets by apolipoprotein B mRNA-editing enzyme 1 (APOBEC1)-mediated profiling and found that PUS1 incorporated pseudouridine into mRNAs of a set of oncogenes, thereby endowing them with greater translation capacity. CONCLUSIONS: Our study highlights the critical role of PUS1 and pseudouridylation in HCC development, and provides new insight that PUS1 enhances the protein levels of a set of oncogenes, including insulin receptor substrate 1 (IRS1) and c-MYC, by means of pseudouridylation-mediated mRNA translation.

Prognostic Value of Serum α-Fetoprotein Level as an Important Characteristic of Tumor Biology for Patients Undergoing Liver Resection of Early-Stage Hepatocellular Carcinoma (BCLC Stage 0/A): A Large Multicenter Analysis.

BACKGROUND AND OBJECTIVE: According to the Barcelona Clinic Liver Cancer (BCLC) algorithm, tumor burden and liver function, but not tumor biology, are the key factors in determining tumor staging and treatment modality, and evaluating treatment prognosis. The serum α-fetoprotein (AFP) level is an important characteristic of hepatocellular carcinoma (HCC) biology, and we aimed to evaluate its prognostic value for patients undergoing liver resection of early-stage HCC. METHODS: Patients who underwent curative liver resection for early-stage HCC were identified from a multi-institutional database. Patients were divided into three groups according to preoperative AFP levels: low (< 400 ng/mL), high (400-999 ng/mL), and extremely-high (≥ 1000 ng/mL) AFP groups. Overall survival (OS) and recurrence rates were compared among these three groups. RESULTS: Among 1284 patients, 720 (56.1%), 262 (20.4%), and 302 (23.5%) patients had preoperative low, high, and extremely-high AFP levels, respectively. The cumulative 5-year OS and recurrence rates were 71.3 and 38.9% among patients in the low AFP group, 66.3 and 48.5% in the high AFP group, and 45.7 and 67.2% in the extremely-high AFP group, respectively (both p < 0.001). Multivariate Cox regression analysis identified both high and extremely-high AFP levels to be independent risk factors of OS (hazard ratio [HR] 1.275 and 1.978, 95% confidence interval [CI] 1.004-1.620 and 1.588-2.464, respectively; p = 0.047 and p < 0.001, respectively) and recurrence (HR 1.290 and 2.050, 95% CI 1.047-1.588 and 1.692-2.484, respectively; p = 0.017 and p < 0.001, respectively). CONCLUSIONS: This study demonstrated the important prognostic value of preoperative AFP levels among patients undergoing resection for early-stage HCC. Incorporating AFP to prognostic estimation of the BCLC algorithm can help guide individualized risk stratification and identify neoadjuvant/adjuvant treatment necessity.

Combined inhibition of surface CD51 and γ-secretase-mediated CD51 cleavage improves therapeutic efficacy in experimental metastatic hepatocellular carcinoma.

BACKGROUND & AIMS: Integrin αv (ITGAV, CD51) is regarded as a key component in multiple stages of tumor progression. However, the clinical failure of cilengitide, a specific inhibitor targeting surface CD51, suggests the importance of yet-unknown mechanisms by which CD51 promotes tumor progression. METHODS: In this study, we used several hepatocellular carcinoma (HCC) cell lines and murine hepatoma cell lines. To investigate the role of CD51 on HCC progression, we used a 3D invasion assay and in vivo bioluminescence imaging. We used periostin-knockout transgenic mice to uncover the role of the tumor microenvironment on CD51 cleavage. Moreover, we used several clinically relevant HCC models, including patient-derived organoids and patient-derived xenografts, to evaluate the therapeutic efficacy of cilengitide in combination with the γ-secretase inhibitor LY3039478. RESULTS: We found that CD51 could undergo transmembrane cleavage by γ-secretase to produce a functional intracellular domain (CD51-ICD). The cleaved CD51-ICD facilitated HCC invasion and metastasis by promoting the transcription of oxidative phosphorylation-related genes. Furthermore, we identified cancer-associated fibroblast-derived periostin as the major driver of CD51 cleavage. Lastly, we showed that cilengitide-based therapy led to a dramatic therapeutic effect when supplemented with LY3039478 in both patient-derived organoid and xenograft models. CONCLUSIONS: In summary, we revealed previously unrecognized mechanisms by which CD51 is involved in HCC progression and uncovered the underlying cause of cilengitide treatment failure, as well as providing evidence supporting the translational prospects of combined CD51-targeted therapy in the clinic. IMPACT AND IMPLICATIONS: Integrin αv (CD51) is a widely recognized pro-tumoral molecule that plays a crucial role in various stages of tumor progression, making it a promising therapeutic target. However, despite early promising results, cilengitide, a specific antagonist of CD51, failed in a phase III clinical trial. This prompted further investigation into the underlying mechanisms of CD51's effects. This study reveals that the γ-secretase complex directly cleaves CD51 to produce an intracellular domain (CD51-ICD), which functions as a pro-tumoral transcriptional regulator and can bypass the inhibitory effects of cilengitide by entering the nucleus. Furthermore, the localization of CD51 in the nucleus is significantly associated with the prognosis of patients with HCC. These findings provide a theoretical basis for re-evaluating cilengitide in clinical settings and highlight the importance of identifying a more precise patient subpopulation for future clinical trials targeting CD51.

Predicting the outcomes of hepatocellular carcinoma downstaging with the use of clinical and radiomics features.

BACKGROUND: Downstaging of hepatocellular carcinoma (HCC) makes it possible for patients beyond the criteria to have the chance of liver transplantation (LT) and improved outcomes. Thus, a procedure to predict the prognosis of the treatment is an urgent requisite. The present study aimed to construct a comprehensive framework with clinical information and radiomics features to accurately predict the prognosis of downstaging treatment. METHODS: Specifically, three-dimensional (3D) tumor segmentation from contrast-enhanced computed tomography (CT) is employed to extract spatial information of the lesions. Then, the radiomics features within the segmented region are calculated. Combining radiomics features and clinical data prompts the development of feature selection to enhance the robustness and generalizability of the model. Finally, we adopt the support vector machine (SVM) algorithm to establish a classification model for predicting HCC downstaging outcomes. RESULTS: Herein, a comparative study was conducted on three different models: a radiomics features-based model (R model), a clinical features-based model (C model), and a joint radiomics clinical features-based model (R-C model). The average accuracy of the three models was 0.712, 0.792, and 0.844, and the average area under the receiver-operating characteristic (AUROC) of the three models was 0.775, 0.804, and 0.877, respectively. CONCLUSIONS: The novel and practical R-C model accurately predicted the downstaging outcomes, which could be utilized to guide the HCC downstaging toward LT treatment.

Ca2+ Regulates Autophagy Through CaMKKß/AMPK/mTOR Signaling Pathway in Mechanical Spinal cord Injury: An in vitro Study.

Spinal cord injury (SCI), resulting in damage of the normal structure and function of the spinal cord, would do great harm to patients, physically and psychologically. The mechanism of SCI is very complex. At present, lots of studies have reported that autophagy was involved in the secondary injury process of SCI, and several researchers also found that calcium ions (Ca2+) played an important role in SCI by regulating necrosis, autophagy, or apoptosis. However, to our best of knowledge, no studies have linked the spinal cord mechanical injury, intracellular Ca2+, and autophagy in series. In this study, we have established an in vitro model of SCI using neural cells from fetal rats to explore the relationship among them, and found that mechanical injury could promote the intracellular Ca2+ concentration, and the increased Ca2+ level activated autophagy through the CaMKKß/AMPK/mTOR pathway. Additionally, we found that apoptosis was also involved in this pathway. Thus, our study provides new insights into the specific mechanisms of SCI and may open up new avenues for the treatment of SCI.

Pharmacological agents for defatting livers by normothermic machine perfusion.

BACKGROUND: Ex-vivo normothermic machine perfusion (NMP) preserves the liver metabolism at 37°C and has rapidly developed as a promising approach for assessing the viability and improving the performance of organs from expanded criteria donors, including fatty liver grafts. NMP is an effective method for defatting fatty livers when combined with pharmaceutical therapies. Pharmacological agents have been shown to facilitate liver defatting by NMP. OBSERVATIONS: This systematic review summarizes available pharmacological therapies for liver defatting, with a particular emphasis on defatting agents that can be employed clinically as defatting components during liver NMP as an ex vivo translational paradigm. CONCLUSION: NMP provides an opportunity for organ treatment and can be used as a defatting platform in the future with defatting agents. Nagrath's cocktail is the most commonly used defatting cocktail in NMP; however, its carcinogenic components may limit its clinical application. Thus, the combination of a defatting cocktail with a new clinically applicable component, for example, a polyphenolic natural compound, may be a novel pharmacological option.

Conversion therapy in liver transplantation for hepatocellular carcinoma: What's new in the era of molecular and immune therapy?

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common cancer globally, with limited therapies and unsatisfactory prognosis once in the advanced stages. With promising advances in locoregional and systematic treatments, fast development of targeted drugs, the success of immunotherapy, as well as the emergence of the therapeutic alliance, conversion therapy has recently become more well developed and an effective therapeutic strategy. This article aimed to review recent developments in conversion therapy in liver transplantation (LT) for HCC. DATA SOURCES: We searched for relevant publications on PubMed before September 2022, using the terms "HCC", "liver transplantation", "downstaging", "bridging treatment" and "conversion therapy." RESULTS: Conversion therapy was frequently represented as a combination of multiple treatment modalities to downstage HCC and make patients eligible for LT. Although combining various local and systematic treatments in conversion therapy is still controversial, growing evidence has suggested that multimodal combined treatment strategies downstage HCC in a shorter time, which ultimately increases the opportunities for LT. Moreover, the recent breakthrough of immunotherapy and targeted therapy for HCC also benefit patients with advanced-stage tumors. CONCLUSIONS: In the era of targeted therapy and immunotherapy, applying the thinking of transplant oncology to benefit HCC patients receiving LT is a new topic that has shed light on advanced-stage patients. With the expansion of conversion therapy concepts, further investigation and research is required to realize the full potential of conversion treatment strategies, including accurately selecting candidates, determining the timing of surgery, improving the conversion rate, and guaranteeing the safety and long-term efficacy of treatment.

Comparison between models for detecting hepatocellular carcinoma in patients with chronic liver diseases of various etiologies: ASAP score versus GALAD score.

BACKGROUND: Diagnostic panels based on multiple biomarkers and clinical characteristics are considered more favorable than individual biomarker to diagnose hepatocellular carcinoma (HCC). Based on age, sex, alpha-fetoprotein (AFP), and protein induced by vitamin K absence II (PIVKA-II) with/without AFP-L3, ASAP and GALAD models are potential diagnostic panels. The diagnostic performances of these two panels were compared relative to HCC detection among patients with various etiologies of chronic liver diseases (CLDs). METHODS: A multicenter case-control study recruited CLDs patients with and without HCC from 14 Chinese hospitals. The etiologies of CLDs included hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic liver disease (ALD), and nonalcoholic fatty liver disease (NAFLD). Using area under the receiver operating characteristic curve (AUC) values, the diagnostic performances of ASAP and GALAD models were compared to detect HCC among patients with various etiologies of CLDs. RESULTS: Among 248 HCC patients and 722 CLD controls, the ASAP model demonstrated the highest AUC (0.886) to detect HCC at any stage, outperforming the GALAD model (0.853, P = 0.001), as well as any individual biomarker (0.687-0.799, all P < 0.001). In the subgroup analysis of various CLDs etiologies, the ASAP model outperformed the GALAD model to HCC independent of CLDs etiology. In addition, the ASAP model performed better in detecting early-stage (BCLC stage 0/A) HCC versus the GALAD model. CONCLUSIONS: Despite using one less laboratory variable (AFP-L3), the ASAP model demonstrated better diagnostic performance than the GALAD model to detect all-stage HCC among patients with various etiologies of CLDs-related HCC.

Effect Of Urinary Kidney Injury Molecule-1 Levels On Short-Term Prognosis Of Chronic Heart Failure.

Objectives: To explore the influential elements of urinary kidney injury molecule-1 levels in chronic heart failure, and to judge its ability to predict 90-day rehospitalisation. METHODS: The cross-sectional case-control study was conducted from November 2020 to April 2021, at Hanzhong Central Hospital, China, and comprised adult patients having chronic heart failure with normal renal function in group A and healthy subjects in control group B. Patients in group A received anti-heart failure therapy for 1 week in hospital and were followed up for 90 days after discharge. Blood pressure (BP), kidney injury molecule-1, creatinine and serum pro- B-type natriuretic peptide levels were evaluated at baseline and 1 week after treatment in group A, while the samples were collected only at baseline in the control group B. Data was analysed using SPSS 22. RESULTS: Of the 102 subjects, 68(66.6%) were in group A; 44(64.7%) males and 24 (35.3%) females with mean age 62.38±9.51 years. The remaining 34(33.3%) subjects were in group B; 21(61.7%) males and 13(38.2%) females with mean age vs. 58.82±8.11 years. The urinary kidney injury molecule-1 level in group A was essentially on the increase compared to group B (p<0.05). After 1 week of treatment, the kidney injury molecule-1 level decreased compared to the baseline value in group A (p<0.05). Diastolic blood pressure and pro-B-type natriuretic peptide were the determinants of urinary kidney injury molecule-1 level, and urinary kidney injury molecule-1 level before discharge was significantly associated with rehospitalisation within 90 days (p<0.05). CONCLUSIONS: Urinary kidney injury molecule-1 level before discharge was a significant predictor of rehospitalisation within 90 days, and diastolic blood pressure and pro-B-type natriuretic peptide levels were the influencing factors of urinary kidney injury molecule-1. Also, urinary kidney injury molecule-1 levels were significantly raised in chronic heart failure.

Combination of high-frequency ultrasound and virtual touch tissue imaging and quantification improve the diagnostic efficiency for mild carpal tunnel syndrome.

BACKGROUND: Carpal tunnel syndrome (CTS) is the most common entrapment symptom in the peripheral nerves. High-frequency ultrasound (HFUS) is widely used in the diagnosis of CTS. Virtual Touch Tissue Imaging and Quantification (VTIQ), which provides more information about the hardness of organization, is used to diagnose CTS. However, the data of diagnostic value of them in various degrees of CTS are limited. Whether the combination of HFUS and VTIQ can improve the diagnostic efficiency also remains unknown. The study aimed to explore the diagnostic value of HFUS and VTIQ in various degrees of CTS and whether combination of HFUS and VTIQ could improve the diagnostic efficiency of CTS. METHODS: A collection and analysis of 133 CTS patients and 35 volunteers from January 2016 to January 2019 were performed. We compared the clinical characteristics, cross-sectional area (CSA) value and shear wave velocity SWVmean value of CTS group with volunteer group. RESULTS: The CSA value and SWVmean value of CTS cohort were significantly higher than volunteer group (10.79 ± 2.88 vs. 8.06 ± 1.39, p < 0.001, 4.36 ± 0.95 vs. 3.38 ± 1.09, p < 0.001, respectively). The area under the curve (AUC) of receiver operating characteristic (ROC) curve of CSA value and SWVmean value were 0.794 and 0.757, respectively. Hierarchical analysis of CSA value and SWVmean value showed that the AUC in the moderate and severe CTS group were higher than in mild CTS group. Furthermore, the CSA value combined with SWVmean value used to diagnose mild CTS was 0.758, which was higher than that of single CSA value or single SWVmean value. CONCLUSIONS: Both HFUS and VTIQ technology were feasible to evaluate CTS. HFUS was suitable for use in diagnosis of moderate and severe CTS. For mild CTS, combination of HFUS and VTIQ was relevant to improve the diagnostic efficiency of CTS.

Raman spectroscopic study of cervical precancerous lesions and cervical cancer.

Early detection of cervical lesions, accurate diagnosis of cervical lesions, and timely and effective therapy can effectively avoid the occurrence of cervical cancer or improve the survival rate of patients. In this paper, the spectra of tissue sections of cervical inflammation (n = 60), CIN (cervical intraepithelial neoplasia) I (n = 30), CIN II (n = 30), CIN III (n = 30), cervical squamous cell carcinoma (n = 30), and cervical adenocarcinoma (n = 30) were collected by a confocal Raman micro-spectrometer (LabRAM HR Evolution, Horiba France SAS, Villeneuve d'Ascq, France). The Raman spectra of six kinds of cervical tissues were analyzed, the dominant Raman peaks of different kinds of tissues were summarized, and the differences in chemical composition between the six tissue samples were compared. An independent sample t test (p ≤ 0.05) was used to analyze the difference of average relative intensity of Raman spectra of six types of cervical tissues. The difference of relative intensity of Raman spectra of six kinds of tissues can reflect the difference of biochemical components in six kinds of tissues and the characteristic of biochemical components in different kinds of tissues. The classification models of cervical inflammation, CIN I, CIN II, CIN III, cervical squamous cell carcinoma, and cervical adenocarcinoma were established by using a support vector machine (SVM) algorithm. Six types of cervical tissues were classified and identified with an overall diagnostic accuracy of 85.7%. This study laid a foundation for the application of Raman spectroscopy in the clinical diagnosis of cervical precancerous lesions and cervical cancer.

Dual-view integral imaging display using a polarizer.

We propose a dual-view integral imaging display using a polarizer. It consists of a display panel, a polarizer, a microlens array, and two pairs of polarizer glasses. The polarizer comprises the left and right subpolarizers whose polarization directions are orthogonal. Two kinds of elemental images are captured from different three-dimensional scenes and located on the left and right half of the display panel. The lights emitting from two kinds of elemental images are polarized by the left and right subpolarizers. The polarization directions of the two pairs of polarizer glasses used in the left and right viewing zones are the same as those of the right and left subpolarizers, respectively. Two different three-dimensional images are simultaneously viewed in the left and right viewing directions by wearing two pairs of polarizer glasses. A prototype of the proposed dual-view integral imaging display is developed, and the experimental results verify the hypothesis.

Albumin-fibrinogen ratio and fibrinogen-prealbumin ratio as promising prognostic markers for cancers: an updated meta-analysis.

OBJECTIVE: Provide an updated and comprehensive evaluation of the prognostic value of the albumin-fibrinogen ratio (AFR) and the fibrinogen-prealbumin ratio (FPR) for patients with cancer. MATERIALS AND METHODS: Four databases (PubMed, Web of Science, Cochrane Library, and WanFang) were searched. The primary endpoints were overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS). Pooled data were synthesized using StataMP 14 and expressed as hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: This update examined 19 studies (7282 cases) that assessed the correlation of AFR with cancer prognosis. Pooled univariate and multivariate analyses indicated significant correlations of low AFR with poor OS (HR 2.18, 95%CI 1.87-2.55 and HR 1.75, 95%CI 1.54-2.00, respectively), poor DFS (HR 1.89, 95%CI 1.54-2.32 and HR 1.51, 95%CI 1.29-1.76, respectively), and poor PFS (HR 1.68, 95%CI 1.42-1.99 and HR 1.48, 95%CI 1.16-1.88, respectively). Pooled univariate and multivariate analyses of 6 studies (2232 cases) indicated high FPR significantly correlated with poor OS (HR 2.37, 95%CI 2.03-2.77 and HR 1.97, 95%CI 1.41-2.77, respectively). One study reported that high FPR correlated with poor DFS (univariate analysis: HR 2.20, 95%CI 1.35-3.57; multivariate analysis: HR 1.77, 95%CI 1.04-2.99) and one study reported a correlation of high FPR with poor PFS in univariate analysis alone (HR 1.79, 95%CI 1.11-2.88). CONCLUSION: A low AFR and a high FPR correlated with increased risk of cancer mortality and recurrence. AFR and FPR may be promising prognostic markers for cancers.

Epithelial-mesenchymal transition in the formation of hypertrophic scars and keloids.

Abnormal wound healing is likely to induce the formation of hypertrophic scars and keloids, which leads to dysfunction, deformity, and mental problem in the patients. Despite the advances in prevention and management of hypertrophic scar and keloids, the mechanism underlying scar and keloid formation has not been fully elucidated. Recent insights into the role of the epithelial-mesenchymal transition (EMT) in development, wound healing, stem cell regulation, fibrosis, and tumorigenesis have increased our understanding of the pathophysiology of hypertrophic scarring and keloids and suggested new therapeutic targets. This review summarizes recent progress in the elucidation of the role of EMT in physiologic wound healing and pathologic scar formation. This knowledge will facilitate an understanding of EMT roles in scar formation and shed new light on the modulation and potential treatment of hypertrophic scars and keloids.