Calcium polypeptide mitigates Cd toxicity in rice via reducing oxidative stress and regulating pectin modification.

KEY MESSAGE: Calcium polypeptide plays a key role during cadmium stress responses in rice, which is involved in increasing peroxidase activity, modulating pectin methylesterase activity, and regulating cell wall by reducing malondialdehyde content. Cadmium (Cd) contamination threatens agriculture and human health globally, emphasizing the need for sustainable methods to reduce cadmium toxicity in crops. Calcium polypeptide (CaP) is a highly water-soluble small molecular peptide acknowledged for its potential as an organic fertilizer in promoting plant growth. However, it is still unknown whether CaP has effects on mitigating Cd toxicity. Here, we investigated the effect of CaP application on the ability to tolerate toxic Cd in rice. We evaluated the impact of CaP on rice seedlings under varying Cd stress conditions and investigated the effect mechanism of CaP mitigating Cd toxicity by Fourier transform infrared spectroscopy (FTIR), fluorescent probe dye, immunofluorescent labeling, and biochemical analysis. We found a notable alleviation of Cd toxicity by reduced malondialdehyde content and increased peroxidase activity. In addition, our findings reveal that CaP induces structural alterations in the root cell wall by modulating pectin methylesterase activity. Altogether, our results confirm that CaP not only promoted biomass accumulation but also reduced Cd concentration in rice. This study contributes valuable insights to sustainable strategies for addressing Cd contamination in agricultural ecosystems.

Trajectories of α-fetoprotein and unresectable hepatocellular carcinoma outcomes receiving atezolizumab plus bevacizumab: a secondary analysis of IMbrave150 study.

BACKGROUND: α-fetoprotein (AFP) response has been demonstrated as a biomarker for unresectable hepatocellular carcinoma (uHCC) patients receiving immunotherapy, but its definition is still unclear. This exploratory study investigated the AFP trajectory and clinical outcomes of receiving atezolizumab plus bevacizumab (Atez/Bev) therapy. METHODS: This secondary analysis used the Atez/Bev arm data of phase III IMbrave150 study to distinguish potential AFP changing rate trajectories through latent class trajectory models. The multivariable Cox models were applied to calculate adjusted hazard ratios (HRs) and 95% CIs for clinical outcomes. RESULTS: Three distinct trajectories were identified among the uHCC patients with 7 times (range, 3 to 28) of AFP measurements: low-stable (50.0%, n = 132), sharp-falling (13.3%, n = 35), and high-rising (36.7%, n = 97). Compared with the high-rising class, HRs of disease progression were 0.52 (95% CI: 0.39, 0.70) and 0.26 (95% CI: 0.16, 0.43) for the low-stable class and sharp-falling class, respectively. In contrast, HRs of death were 0.59 (95% CI: 0.40, 0.81) and 0.30 (95% CI: 0.16, 0.57) for the two groups after propensity score adjustment. Besides, AFP trajectories had the highest relative importance of each covariate to survival. DISCUSSION: There are three distinct AFP trajectories in uHCC patients receiving Atez/Bev, and it is an independent biomarker for clinical outcomes.

The clinical application of arterialized venous flaps in repairing large area of soft tissue defects of extremities.

BACKGROUND: The reconstruction of microsurgery emphasizes the low morbidity of donor sites. The arterialized venous flaps (AVFs) are tissue flaps harvested without conventional vascular pedicles. However, reports of high necrosis rates and poor understanding of physiology hindered the application of many surgeons in clinical practice. Recently, experimental and clinical studies have demonstrated the feasibility and relative reliability of various AVF techniques. This study aims to report the clinical results of the arterialized venous free flaps in reconstructing soft tissue defects of limbs and propose methods to improve flap perfusion, extending the indications for using the flaps based on the authors' clinical experiences. METHODS: We retrospectively reviewed the records of 16 patients that underwent arterialized venous free flaps for limb wound reconstruction from January 2019 to June 2021. Following the venous network on the calf's tibial side, large venous flaps can be designed. RESULTS: Of the 16 cases, 14 (87.50%) cases (including 8 cases significantly congested with tension blisters) showed complete survival, and 2 (12.5%) cases, which had only one vein performed anastomosis of the efferent vein according to the vascularity of the recipient bed, showed partial necrosis. In all cases, no infection or other specific complications occurred in the donor areas. CONCLUSION: The rate of congestion and necrosis of arterialized venous flaps is still challenging, but it will be suitable for large soft tissue defects of limbs in the future.

Overexpression of SSR2 promotes proliferation of liver cancer cells and predicts prognosis of patients with hepatocellular carcinoma.

Signal Sequence Receptor Subunit 2 (SSR2) is a key endoplasmic reticulum gene involved in protein folding and processing. Previous studies found that it was upregulated in several cancers, but its precise role in hepatocellular carcinoma (HCC) remains unclear. To have a better understanding of this gene in HCC, we examined the expression of SSR2 in HCC tissues by analysing The Cancer Genome Atlas (TCGA) data and immunohistochemistry. We also assessed the association between SSR2 expression and clinicopathological characteristics of HCC patients and patient survival. Potential function of SSR2 was predicted through GSEA and protein-protein interaction analysis. MTT, flowcytometry, transwell and a nude mice xenograft model were employed to investigate the biological functions in vivo and in vitro. The results showed that the expression of SSR2 was significantly increased in HCC tissues, and SSR2 expression was associated with several clinical characteristics. In addition, patients with higher SSR2 expression had poorer survival. Enrichment analysis suggested that SSR2 was probably involved in biological process or signalling pathways related to G2/M checkpoint, passive transmembrane transporter activity, ATF2_S_UP. V1_UP and ncRNA metabolic process. Further experimental study showed that SSR2 knockdown inhibited cell proliferation, migration and invasion ability and promoted apoptosis and cell cycle arrest in vitro. Moreover, downregulation of SSR2 also repressed the growth of HepG2 cells in vivo. In conclusion, our study suggests that SSR2 may act as an oncogene in HCC.

Prevention of chronic diabetic complications in type 1 diabetes by co-transplantation of umbilical cord mesenchymal stromal cells and autologous bone marrow: a pilot randomized controlled open-label clinical study with 8-year follow-up.

BACKGROUND AIMS: To explore the long-term safety and benefit of umbilical cord mesenchymal stromal cell (MSCs) plus autologous bone marrow mononuclear cell (aBM-MNC) stem cell transplantation (SCT) without immunotherapy in established type 1 diabetes (T1D). METHODS: In the primary completion of this trial (ClinicalTrials.gov identifier: NCT01374854), the authors randomized patients (n = 21 per group) to either SCT or standard care (control) and previously reported effects on insulin secretion. The authors report about the incidence of chronic diabetes complications (primary endpoint) after 8 years of follow-up. The authors also report on secondary endpoints, safety, islet function and metabolic control. RESULTS: Data were obtained from 14 of 21 patients in the SCT group and 15 of 21 patients in the control group who completed follow-up. At 8 years, the incidence of peripheral neuropathy was 7.1% (one of 14) in the SCT group versus 46.7% (seven of 15) in the control group (P = 0.017). The incidence of diabetic nephropathy was 7.1% (one of 14) in the SCT group versus 40.0% (six of 15) in the control group (P = 0.039). The incidence of retinopathy was 7.1% (one of 14) in the SCT group versus 33.3% (five of 15) in the control group (P = 0.081). Two patients (two of 14, 14.3%) in the SCT group and 11 patients (11 of 15, 73.3%) in the control group developed at least one complication (P = 0.001). One and six patients in the SCT group and control group, respectively, had at least two complications (P = 0.039). No malignancies were reported in the treated group. CONCLUSIONS: Co-transplantation of umbilical cord MSCs and aBM-MNCs in patients with established T1D was associated with reduced incidence of chronic diabetes complications.

Overexpression of CENPL mRNA potentially regulated by miR-340-3p predicts the prognosis of pancreatic cancer patients.

BACKGROUND: In our previous study it was found that CENPL was overexpressed in hepatocellular carcinoma and significantly predicted patient's prognosis. However, the expression and prognostic value of CENPL in other gastrointestinal tumors remain unknown. Therefore, we investigated the expression and prognostic value of CENPL in esophageal carcinoma (ESCA), stomach adenocarcinoma (STAD), pancreatic adenocarcinoma (PAAD), colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ). METHODS: In this study, Oncomine, GEPIA, OncoLnc, TIMER, cBioPortal, miRWalk and ENCORI databases were used to analyze the level of CENPL mRNA, prognostic value and potential regulatory mechanism of CENPL mRNA in tumors. The CENPL expression and clinicopathological data regarding PAAD were from the UCSC Xena database and univariate and multivariate Cox regression analyses were performed using R (Version 3.6.3). Immunohistochemical staining was used to verify the expression of CENPL protein in clinical specimens. Cytoscape (Version: 3.7.2) was used to visualize microRNA (miRNA) that potentially regulates CENPL. RESULTS: Gene differential expression analysis showed that CENPL mRNA was significantly overexpressed in ESCA, STAD, PAAD, COAD and READ (p < 0.01). The overexpression of CENPL mRNA was significantly correlated with the poor prognosis of PAAD patients (p < 0.05). However, there was no significant correlation between the level of CENPL mRNA and the prognosis of ESCA, STAD, COAD and READ patients (p > 0.05). Univariate and multivariate Cox regression analyses suggested that CENPL was a prognostic risk factor for PAAD. The mutation rate of CENPL in PAAD was 2.2% (17/850). There was no significant correlation between the CENPL expression and the infiltration levels of immune cells in PAAD (|Cor|< 0.5). Immunohistochemical staining showed that CENPL was overexpressed in 42% (11/26) of PAAD specimens, which was significantly higher compared with that in the normal tissues. The expression of miR-340-3p and miR-484 in PAAD were significantly lower than in the normal tissues (p < 0.05) and PAAD patients with lower expression of miR-340-3p had poorer prognosis (p < 0.05). CONCLUSION: CENPL potentially regulated by miR-340-3p, is overexpressed in PAAD and predicts patient's prognosis, suggestive of a diagnostic and prognostic value in PAAD patients.

The blooming intersection of subfatin and metabolic syndrome.

Metabolic Syndrome (MS) remains the leading cause of mortality and morbidity globally. Adipose tissue releases adipokines that play key roles in metabolic and cardio-cerebro-vascular homeostasis. Subfatin, induced after exercise or upon cold exposure in adipose tissue, is a novel secreted protein homologous to Metrn, a neutrophic factor with angiogenic properties. The protein was proved to be of great significance in the browning of white adipose tissue (BWT) and insulin resistance (IR). It affected insulin sensitivity at least via its local autocrine/paracrine action through AMP-activated protein kinase (AMPK) or peroxisome proliferator-activated receptor δ (PPAR-δ) dependent signaling. Subfatin blocked the release of inflammatory mediators, improved intracellular insulin signal transduction and reversed IR. It also improved glucose tolerance and played a key role in metabolism and cardiovascular and cerebrovascular homeostasis. It was reported that the level of serum subfatin was significantly correlated with the occurrence and severity of coronary heart disease, which might be a new target for the treatment of coronary heart disease. In addition, exercise increased the level of subfatin in circulation and adipose tissue, promoted energy consumption, improved glucose and lipid metabolism, increased the heat production of brown fat, and strengthened the anti-inflammatory mechanism. Given its role in metabolic disorders, subfatin is considered as a candidate biomarker of MS. However, the clinical significance of subfatin remains largely unclear. The purpose of this article is to review the research on the effect of subfatin on MS in recent years.

Molecular determinants of microvascular dysfunction in hypertensive pregnancy and preeclampsia.

Preeclampsia is a pregnancy-related disorder characterized by hypertension and often fetal intrauterine growth restriction, but the underlying mechanisms are unclear. Defective placentation and apoptosis of invasive cytotrophoblasts cause inadequate remodeling of spiral arteries, placental ischemia, and reduced uterine perfusion pressure (RUPP). RUPP causes imbalance between the anti-angiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin and the pro-angiogenic vascular endothelial growth factor and placental growth factor, and stimulates the release of proinflammatory cytokines, hypoxia-inducible factor, reactive oxygen species, and angiotensin AT1 receptor agonistic autoantibodies. These circulating factors target the vascular endothelium, smooth muscle and various components of the extracellular matrix. Generalized endotheliosis in systemic, renal, cerebral, and hepatic vessels causes decreases in endothelium-derived vasodilators such as nitric oxide, prostacyclin and hyperpolarization factor, and increases in vasoconstrictors such as endothelin-1 and thromboxane A2. Enhanced mechanisms of vascular smooth muscle contraction, such as intracellular Ca2+ , protein kinase C, and Rho-kinase cause further increases in vasoconstriction. Changes in matrix metalloproteinases and extracellular matrix cause inadequate vascular remodeling and increased arterial stiffening, leading to further increases in vascular resistance and hypertension. Therapeutic options are currently limited, but understanding the molecular determinants of microvascular dysfunction could help in the design of new approaches for the prediction and management of preeclampsia.

Preoperative exercise facilitates abundant bone marrow collection in patients with type 2 diabetes for mononuclear cell therapy.

BACKGROUND AIMS: Traditional bone marrow (BM) collection is inadequate for separation of abundant mononuclear cells (MNCs). We aimed to investigate the effects of preoperative exercise on BM collection in patients with type 2 diabetes mellitus (T2DM). METHODS: Sixty patients with T2DM were randomly assigned to either a control group or an exercise group (n = 30 each). The patients in the exercise group exercised before the collection. All patients underwent routine surgical care. The collected BM volume, operation duration, collecting speed, puncture times and pain scores were recorded. BM samples were tested before and after MNCs separation for CD34+ flow cytometry and whole blood cell count. RESULTS: The collected BM volumes were significantly larger and collection speed was faster in the exercise group (379.77 ± 4.93 mL and 1.40 ± 0.14 mL/s) than those in the control group (356.67 ± 15.36 mL and 0.89 ± 0.16 mL/s, P = 0.00 for both). Puncture times were significantly less and pain scores were lower in the exercise group (2.07 ± 0.25 and 2.67 ± 1.56) than those in the control group (2.50 ± 0.63 and 3.43 ± 1.76, P = 0.00 and 0.02, respectively). CD34+ cells and whole blood cell count variables were comparable in the 2 groups. CONCLUSIONS: Preoperative exercise facilitates BM collection by increasing collected volume, improving collecting speed, relieving patients' pains and ensuring MNC quality.

Autologous bone marrow mononuclear cell infusion and hyperbaric oxygen therapy in type 2 diabetes mellitus: an open-label, randomized controlled clinical trial.

BACKGROUND AIMS: The use of bone marrow mononuclear cells (BM-MNCs) has achieved great outcomes in clinical practice. We aim to evaluate the efficacy and safety of autologous BM-MNC infusion and hyperbaric oxygen therapy (HOT) in type 2 diabetes mellitus. METHODS: This single-center, randomized, open-label, controlled clinical trial with a factorial design included two phases. The patients received standard medical therapy in the run-in phase; in the treatment phase, patients with glycated hemoglobin of 7.5-9.5% were randomly assigned into four groups and underwent BM-MNC infusion along with HOT (BM-MNC+HOT group), BM-MNC infusion (BM-MNC group), HOT (HOT group) and standard medical therapy (control group), respectively. The area under the curve of C-peptide was recorded as a primary end point. Our research is registered at ClinicalTrials.gov (NCT00767260). RESULTS: A total of 80 patients completed the follow-up. At 12 months after treatment, the area under the curve of C-peptide (ng/mL per 180 min) of the BM-MNC+HOT group and the BM-MNC group were significantly improved (34.0% and 43.8% from the baseline, respectively). The changes were both significant compared with that in the control group, but no remarkable change was observed in the HOT group. Treatment-related adverse events were mild, including transient abdominal pain (n = 5) and punctual hemorrhage (n = 3). CONCLUSIONS: BM-MNC infusion for type 2 diabetes mellitus improves islet function and metabolic control, with mild adverse effects. HOT does not synergize with BM-MNC infusion.

Protective effects of mesenchymal stromal cells on adriamycin-induced minimal change nephrotic syndrome in rats and possible mechanisms.

BACKGROUND AIMS: Minimal change nephrotic syndrome is the most frequent cause of nephrotic syndrome in childhood. Current treatment regimes, which include glucocorticoid hormones and immunosuppressive therapy, are effective and have fast response. However, because of the side effects, long treatment course, poor patient compliance and relapse, novel approaches for the disease are highly desired. METHODS: The adriamycin-induced nephrotic rat model was established. Rats were allocated to a model group, a prednisone group or mesenchymal stromal cell (MSC) group. Clinical parameters in each treatment group were determined at 2 weeks, 4 weeks and 8 weeks. The messenger RNA (mRNA) levels of synaptopodin, p21 and monocyte chemoattractant protein-1 were determined through the use of quantitative real-time-polymerase chain reaction. Protein levels were determined by means of Western blot or enzyme-linked immunosorbent assay. Podocytes were isolated and apoptotic rate after adriamycin with or without MSC treatment was analyzed by means of flow cytometry. RESULTS: MSC intervention improved renal function as assessed by urinary protein, blood creatinine and triglyceride levels. MSC intervention reduced adriamycin-induced renal tissue damage visualized by immunohistochemistry and light and electron microscopic analysis and reduced adriamycin-induced podocyte apoptosis. After MSC intervention, mRNA and protein levels of synaptopodin and p21 in renal cortex were significantly increased. MSCs also restored synaptopodin mRNA and protein expression in isolated podocytes. In addition, monocyte chemoattractant protein-1 mRNA in renal cortex and protein level in serum of the MSC treatment group were significantly decreased compared with that in the adriamycin-induced nephropathy model group. CONCLUSIONS: Our data indicate that MSCs could protect rats from adriamycin-induced minimal change nephrotic syndrome, and the protective effects of MSCs are mediated through multiple actions.

Titanium catalyzed [2σ + 2π] cycloaddition of bicyclo[1.1.0]-butanes with 1,3-dienes for efficient synthesis of stilbene bioisosteres.

Natural stilbenes have shown significant potential in the prevention and treatment of diseases due to their diverse pharmacological activities. Here we present a mild and effective Ti-catalyzed intermolecular radical-relay [2σ + 2π] cycloaddition of bicyclo[1.1.0]-butanes and 1,3-dienes. This transformation enables the synthesis of bicyclo[2.1.1]hexane (BCH) scaffolds containing aryl vinyl groups with excellent regio- and trans-selectivity and broad functional group tolerance, thus offering rapid access to structurally diverse stilbene bioisosteres.

BMSCs reduce rat granulosa cell apoptosis induced by cisplatin and perimenopause.

BACKGROUND: The objective of this study was to evaluate the effect of bone marrow mesenchymal stem cells (BMSCs) on the apoptosis of granulosa cells (GCs) in rats. RESULTS: Cisplatin increased GC apoptosis from 0.59% to 13.04% in the control and cisplatin treatment groups, respectively, which was significantly reduced upon co-culture with BMSCs to 4.84%. Cisplatin treatment increased p21 and bax and decreased c-myc mRNA expression, which was reversed upon co-culture with BMSCs. As compared to young rats, increased apoptosis was observed in the perimenopausal rats (P < 0.001). After 3 months, the apoptosis rate in the BMSC group was significantly lower than that of the control group (P = 0.007). CONCLUSIONS: BMSC therapy may protect against GC apoptosis induced by cisplatin and perimenopause. Further studies are necessary to evaluate therapeutic efficacy of BMSCs.

SWI/SNF Complex Genomic Alterations as a Predictive Biomarker for Response to Immune Checkpoint Inhibitors in Multiple Cancers.

Whether there is an association between SWI/SNF genomic alterations in tumors and response to immune checkpoint inhibitors (ICI) remains unclear because prior studies have focused on either an individual gene or a predefined set of genes. Herein, using mutational and clinical data from 832 ICI-treated patients who underwent whole-exome sequencing, including sequencing of all 31 genes of the SWI/SNF complex, we found that SWI/SNF complex alterations were associated with significantly improved overall survival (OS) in melanoma, clear-cell renal cell carcinoma, and gastrointestinal cancer, as well as improved progression-free survival (PFS) in non-small cell lung cancer. Including tumor mutational burden as a variable, the multivariate Cox regression analysis showed SWI/SNF genomic alterations had prognostic value in melanoma [HR, 0.63 (95% confidence interval, CI, 0.47-0.85), P = 0.003], clear-cell renal cell carcinoma [HR, 0.62 (95% CI, 0.46-0.85), P = 0.003], and gastrointestinal cancer [HR, 0.42 (95% CI, 0.18-1.01), P = 0.053]. Furthermore, we used the random forest method for variable screening, identifying 14 genes as a SWI/SNF signature for potential clinical application. Significant correlations were observed between SWI/SNF signature alterations and improved OS and PFS in all cohorts. This suggests that SWI/SNF gene alterations are associated with better clinical outcomes in ICI-treated patients and may serve as a predictive marker for ICI therapy in multiple cancers.

Proximal coil occlusion preceding distal sclerotherapy in patients with pelvic congestion syndrome: A multicenter, retrospective study.

OBJECTIVE: We investigated the efficacy, feasibility, and safety of proximal coil occlusion preceding distal sclerotherapy (PCODS) for patients with pelvic congestion syndrome (PCS). METHODS: We performed a multicenter, retrospective cohort study of 94 patients with PCS who had undergone PCODS and 53 patients who had undergone standard endovascular embolization (control group) between June 2014 and April 2020. The primary end point was the clinical remission rate and the secondary end points were the operative time, total fluoroscopy time, radiation dose, overall length of coils used per case, and adverse events. The patients were followed up at 1, 3, 6, and 12 months. RESULTS: PCODS was successfully performed in 94 patients (100%). The clinical remission rates were significantly higher in the PCODS group than in the control group at 1, 6, and 12 months (P = .036, P = .032, and P = .032). The operative time and total fluoroscopy time were shorter for the PCODS group than for the control group (48.3 ± 5.2 minutes and 37.7 ± 4.4 minutes vs 53.9 ± 4.8 minutes and 42.6 ± 4.1 minutes, respectively; P < .001 for both). The radiation dose was significantly lower in the PCODS group than in the control group (362,634.69 ± 41,533.13 mGy·cm2 vs 421,578.30 ± 49,517.93 mGy·cm2; P < .001). The overall length of coils used per case was 19.8 ± 6.0 cm in the PCODS group and 31.7 ± 8.5 cm in the control group (P < .001). Migration of n-butyl cyanoacrylate to the renal vein occurred in two patients in the control group. CONCLUSIONS: We found PCODS was feasible with a higher clinical remission rate and mild adverse effects in patients with PCS.

Fas/FasL and Complement Activation are Associated with Chronic Active Epstein-Barr Virus Hepatitis.

Background and Aims: Chronic active Epstein-Barr virus hepatitis (CAEBVH) is a rare and highly lethal disease characterized by hepatitis and hepatomegaly. This study aimed to investigate the clinicopathological features and pathogenic mechanisms of CAEBVH. Methods: Ten patients with confirmed Epstein-Barr virus hepatitis infection were enrolled. The clinicopathological characteristics of these patients were summarized and analyzed. Flow cytometry was utilized to detect peripheral blood immune cell phenotypes and whole exome sequencing was used to explore pathogenic genetic mechanisms. Lastly, immunohistochemical staining was employed to verify pathogenic mechanisms. Results: Clinical features observed in all Epstein-Barr virus hepatitis patients included fever (7/10), splenomegaly (10/10), hepatomegaly (9/10), abnormal liver function (8/10), and CD8+ T cell lymphopenia (6/7). Hematoxylin and eosin staining revealed lymphocytic infiltration in the liver. Positive Epstein-Barr virus-encoded small RNA in-situ hybridization (EBER-ISH) of lymphocytes of liver tissues was noted. Whole exome sequencing indicated that cytotoxic T lymphocytes and the complement system were involved. The expression of CD8, Fas, FasL, and Caspase-8 expression as well as apoptotic markers was enhanced in the Epstein-Barr virus hepatitis group relative to the controls (p<0.05). Lastly, Complement 1q and complement 3d expression, were higher in CAEBVH patients relative to controls (p<0.05). Conclusions: CAEBVH patients developed fever, hepatosplenomegaly, and lymphadenopathy. Histopathological changes were a diffuse lymphocytic sinusoidal infiltrate with EBER-ISH positivity. Fas/FasL and complement activation were involved in CAEBVH patients.

Trajectories of serum α-fetoprotein and intermediate-stage hepatocellular carcinoma outcomes after transarterial chemoembolization: A longitudinal, retrospective, multicentre, cohort study.

Background: α-fetoprotein (AFP) response has been proven a key tumor marker for hepatocellular carcinoma (HCC), but its definition remains controversial. This study aims to characterize AFP trajectories after transarterial chemoembolization (TACE) and examine its impact on clinical outcomes. Methods: This longitudinal, multicenter, retrospective, cohort study examined data from the electronic medical record system of four hospitals in China between January 1, 2007 to December 31, 2016. A latent class growth mixed model was applied to distinguish potential AFP dynamic changing trajectories. The multivariable Cox models were used to calculate adjusted hazard ratios (aHRs) and 95% CIs for overall survival. Inverse-probability-of-treatment weighted analyses were performed to eliminate unmeasured confounders through marginal structural models. Findings: A total of 881 patients, who had intermediate-stage HCC with AFP repeatedly measured 3 to 10 times, were included in the study. Three distinct trajectories were identified using the latent class growth mixture model: high-rising (25.7%; n = 226), low-stable (58.7%; n = 517), and sharp-falling (AFP serological response, 15.6%; n = 138). Compared with the low-stable class, the aHRs for death were 5.13 (3.71, 7.10) and 0.52 (0.33, 0.81) for the high-rising and sharp-falling class, adjusted by gender, baseline major tumor size, intrahepatic lesions number, and logAFP(smooth). Furthermore, high-rising class had a significantly higher HR in the subgroup of female patients (10.60, 95%CI: 6.29, 17.86), age<55 (6.78, 95%CI: 4.79, 9.59) and Child-Pugh class B (23.01, 95%CI:8.07, 65.63) (P = 0.014, 0.046 and 0.033 for interaction, respectively). Trajectories of AFP had the highest relative importance of each parameter to survival, including largest tumor size, intrahepatic lesions number, Child-Pugh class, and baseline AFP. Interpretation: AFP trajectories were associated with overall survival for intermediate-stage HCC after TACE. Funding: The Natural Science Foundation of Fujian Province (Nos. 2018J01352, 2016J01576 and 2016J01586); the Science and Technology Innovation Joint Foundation of Fujian Province (Nos. 2017Y9125).

Orthotopic liver transplantation improves postoperative quality of life, survival rate and reduces recurrence rate in patients with liver cancer.

OBJECTIVE: To evaluate the impact of orthotopic liver transplantation (OLT) on postoperative quality of life (QoL), survival rate and recurrence rate of patients with liver cancer (LC). METHODS: One hundred and twenty-seven patients with LC treated in our hospital from December 2016 to January 2018 were divided into two groups according to different treatment schemes. Patients in the research group (n=67) were given OLT and those in the control group (n=60 cases) were given hepatectomy. The incidence of postoperative complications, hospitalization expenses, the time to liver function recovery, surgical wound healing, pain resolution and hospitalization were compared between the two groups. The overall survival rate (OSR), disease-free survival rate (DFSR), and average survival time of patients were recorded and compared. The Visual Analogue Scale (VAS) score one day and three days after surgery, alpha-fetoprotein (AFP) level, and adverse emotion before and after operation were compared. QoL scores at six months after surgery, one-year recurrence and metastasis rates, and treatment satisfaction one year after surgery were also compared. The expression of Ki-67 and Topo IIαin the tumor-bearing group (n=5) was detected. RESULTS: The research group presented markedly lower incidence of postoperative complications, and evidently shorter time to liver function recovery, surgical wound healing, pain resolution and hospitalization, while with noticeably higher hospitalization expenses. The one-year and five-year OSRs and DFSRs were noticeably higher, and the average survival time was remarkably longer in the research group as compared to the control group. Patients in the research group scored remarkably lower in VAS scores on the first and third day after surgery than patients in the control group. In comparison with the control group, the one-year recurrence and metastasis rates were evidently lower in the research group, and the scores of SF-36 were remarkably higher. The AFP level at one month after surgery was obviously lower in the research group, and the treatment satisfaction was greatly higher. Ki-67 in the tumor-bearing group was mainly located in the nucleus, and Topo IIα was mainly nucleus positive; the positive Ki-67 and Topo IIα expression rates in the tumor-bearing group was 66.7% and 69.8%, respectively. CONCLUSIONS: OLT can improve the postoperative QoL, survival rate and reduce the recurrence rate of LC patients.

The upregulation of CLGN in hepatocellular carcinoma is potentially regulated by hsa-miR-194-3p and associated with patient progression.

Background: Patients with hepatocellular carcinoma (HCC) have poor prognosis, especially in advanced stages. Targeted therapy is the main treatment for advanced HCC patients, but the optimal targets for HCC remain poorly understood. The main purpose of this study was to identify potential novel prognostic markers and therapeutic targets. Methods: Firstly, differentially expressed genes (DEGs) in HCC were identified from the Gene Expression Omnibus (GEO) database. The expression, significance in prognosis, and potential mechanisms of DEGs were analyzed using GEPIA, TIMER, HPA, Kaplan Meier Plotter, CBioPortal, miRWalk, TargetScan, and ENCORI databases. Immunohistochemical staining was used to determine the protein expression levels of potential candidate genes. Results: The mRNA levels of MND1, STXBP6, and CLGN were significantly increased in HCC (p< 0.01). HCC patients with elevated CLGN mRNA levels had poorer overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and disease-specific survival (DSS) (p < 0.05). Higher MND1 mRNA levels significantly correlated with poorer DFS in HCC patients (p< 0.05). However, there was no significant correlation between STXBP6 expression and prognosis of HCC (p> 0.05). Further analysis revealed that patients with elevated CLGN mRNA expression in advanced pathology stages had poorer prognosis (p< 0.01). In addition, CLGN protein levels were elevated in HCC compared to their levels in normal tissues. The mRNA levels of CLGN had no significant correlation with the abundance of six common tumor infiltrating lymphocytes in HCC (COR < 0.5). Moreover, the mutation rate of CLGN was less than 1% in HCC patients (10/1089). Finally, the expression level of hsa-miR-194-3p in HCC was significantly lower than that in normal tissues (p < 0.05), and prognosis of HCC with low expression of hsa-miR-194 was poor (p < 0.05). Conclusion: The upregulation of CLGN in HCC is significantly associated with poor patient prognosis, especially in the advanced stages, and may be regulated by hsa-miR-194-3p. These findings suggest that CLGN may be closely related to the progression of HCC, and is a potential therapeutic target and prognostic indicator for patients with advanced HCC.