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Jian Huang,1,* Yun Yang,1,* Yong Xia,2,* Fu-Chen Liu,1,* Lei Liu,1 Peng Zhu,1 Sheng-Xian Yuan,1 Fang-Ming Gu,1 Si-Yuan Fu,1 Wei-Ping Zhou,1 Hui Liu,1 Bei-Ge Jiang,1 Ze-Ya Pan1 1The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 201805, People’s Republic of China; 2Department of Medical Oncology, Shanghai Mengchao Cancer Hospital, Shanghai, 201805, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ze-Ya Pan; Bei-Ge Jiang No. 700, MoYu North Road, Jiading, Shanghai, People’s Republic of ChinaTel +86-13391236437; +86-13764561303Email hjluffy@126.com; jiang_beige@aliyun.comPurpose: To predict patient survival in early-stage hepatocellular carcinoma (HCC) following hepatic resection. We evaluated the prognostic potential of the aspartate aminotransferase to platelet ratio index (APRI) in order to use it to model a nomogram.Patients and Methods: We randomized 901 early-stage HCC patients treated with hepatic resection at our center into training and validation cohorts that were followed from January 2009 to December 2012. X-tile software was used to establish the APRI cut-off threshold in the training cohort. The validation cohort was subsequently assessed to determine threshold value accuracy. Data generated from the multivariate analysis in the training cohort were used to design a prognostic nomogram. Decision curve analyses (DCA), concordance index values (C-index) and calibration curves were used to determine the performance of the nomogram.Results: X-tile software revealed that the optimal APRI cut-off threshold in the training cohort that distinguished between patients with different prognoses was 0.9. We, therefore, validated its prognostic value. Multivariate analyses showed that poor overall survival was associated with APRI above 0.9, blood loss of more than 400 mL, liver cirrhosis, multiple tumors, tumor size greater than 5 cm, microvascular invasion and satellite lesions. When the independent risk factors were integrated into the prognostic nomogram, it performed well with accurate predictions. Indeed, the performance was better than comparative prognosticators (P< 0.05 for all) with 0.752 as the C-index (95% CI: 0.706– 0.798). These results were verified by the validation cohort.Conclusion: APRI was a noninvasive and accurate predictive indicator for patients with early-stage HCC. Following hepatic resection to treat early-stage HCC, individualized patient survival predictions can be aided by the nomogram based on APRI.Keywords: hepatocellular carcinoma, hepatic resection, survival, nomogram, aspartate aminotransferase to platelet ratio index, APRI

The judicious construction of interfaces with swift charge communication to enhance the utilization efficiency of photogenerated carriers is a viable strategy for boosting the photocatalytic performance of heterojunctions. Herein, an in-situ partial conversion strategy is reported for decorating lead-free halide perovskite Cs 3 Bi 2 Br 9 nanocrystals onto BiOBr hollow nanotube, resulting in the formation of an S-scheme heterojunction Cs 3 Bi 2 Br 9 /BiOBr. This unique in-situ growth approach imparts a closely contacted interface to the Cs 3 Bi 2 Br 9 /BiOBr heterojunction, facilitating interfacial electron transfer and spatial charge separation compared to a counterpart (Cs 3 Bi 2 Br 9 :BiOBr) fabricated via traditional electrostatic self-assembly. Additionally, the establishment of an S-scheme charge transfer pathway preserves the robust redox capability of photogenerated carriers. Furthermore, the free electron transfer from Cs 3 Bi 2 Br 9 to BiOBr promotes the activation of the NN bond and diminishes the energy barrier associated with the rate-determining step in the N 2 reduction process. Consequently, the Cs 3 Bi 2 Br 9 /BiOBr heterojunction exhibits highly selective photocatalytic N 2 reduction to NH 3 (nearly 100 %) at a rate of 130 μmol g -1  h -1 under simulated sunlight (100 mW cm -2 ), surpassing BiOBr, Cs 3 Bi 2 Br 9 , and Cs 3 Bi 2 Br 9 :BiOBr by factors of 6, 4, and 2, respectively., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

HCC is globally recognized as a major health threat. Despite significant progress in the development of treatment strategies for liver cancer, recurrence, metastasis, and drug resistance remain key factors leading to a poor prognosis for the majority of liver cancer patients. Thus, there is an urgent need to develop effective biomarkers and therapeutic targets for HCC. Collagen, the most abundant and diverse protein in the tumor microenvironment, is highly expressed in various solid tumors and plays a crucial role in the initiation and progression of tumors. Recent studies have shown that abnormal expression of collagen in the tumor microenvironment is closely related to the occurrence, development, invasion, metastasis, drug resistance, and treatment of liver cancer, making it a potential therapeutic target and a possible diagnostic and prognostic biomarker for HCC. This article provides a comprehensive review of the structure, classification, and origin of collagen, as well as its role in the progression and treatment of HCC and its potential clinical value, offering new insights into the diagnosis, treatment, and prognosis assessment of liver cancer., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

It is unclear whether cognitive impairment and the longitudinal change in cognition are associated with the risk of fatal stroke in aging populations. Based on the Guangzhou Biobank Cohort Study data a sum of 26,064 participants at baseline and all deaths caused by stroke in a mean follow-up of 14.3 years (standard deviation = 3.2) were included, and the Cox proportional hazard regression was used in this prospective cohort study. Cognitive impairment was respectively associated with an increased risk of fatal strokes (the adjusted hazard ratio (aHR) = 1.38, 95% CI1.16-1.64, P  < 0.001) and fatal ischaemic stroke (aHR = 1.39, 95% CI1.10-1.77, P  = 0.007), compared to median cognition; the Delayed Word Recall Test (DWRT) score was associated with a decreasing trend for the risk of fatal strokes in a restricted cubic spline analysis; the longitudinal DWRT score decline was associated with the increased risks of fatal strokes (aHR = 1.42, 95% CI 1.11-1.82, P  = 0.006) and fatal haemorrhagic stroke (aHR = 1.75, 95% CI 1.10-2.78, P  = 0.02), compared to the longitudinal DWRT score rise. In summary, cognitive impairment and the longitudinal decline in DWRT scores were associated with the increased risk of fatal strokes; early screening of cognitive function should be conducive to predictive intervention in fatal stroke among relatively healthy middle-aged to older populations., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Purpose: Laparoscopic isolated caudate lobectomy is still a challenging operation for surgeons. The access route of the operation plays a vital role during laparoscopic caudate lobectomy. There are few references regarding this technique. Here, we introduce a preferred inferior vena cava (IVC) approach in laparoscopic caudate lobectomy., Methods: Twenty-one consecutive patients with caudate hepatic tumours between June 2016 and December 2021 were included in this study. All of them received laparoscopic caudate lobectomy involving an IVC priority approach. The IVC priority approach refers to prioritizing the dissection of the IVC from the liver parenchyma before proceeding with the conventional left or right approach. It emphasizes the importance of the IVC dissection during process. Clinical data, intraoperative parameters and postoperative results were evaluated. Sixteen patients were performed pure IVC priority approach, while 5 patients underwent a combined approach. We subsequently compared the intraoperative and postoperative between the two groups., Results: All 21 patients were treated with laparoscopic technology. The operative time was 190.95 ± 92.65 min. The average estimated blood loss was 251.43 ± 247.45 ml, and four patients needed blood transfusions during the perioperative period. The average duration of hospital stay was 8.43 ± 2.64 (range from 6.0 to 16.0) days. Patients who underwent the pure inferior vena cava (IVC) approach required a shorter hepatic pedicle clamping time (26 vs. 55 min, respectively; P < 0.001) and operation time (150 vs. 380 min, respectively; P = 0.002) than those who underwent the combined approach. Hospitalization (7.0 vs. 9.0 days, respectively; P = 0.006) was shorter in the pure IVC group than in the combined group., Conclusions: Laparoscopic caudate lobectomy with an IVC priority approach is safe and feasible for patients with caudate hepatic tumours., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The pathogenesis of glioma has remained unclear. In this study, it was found that high expression of the outer dense fibers of sperm tail 3B (ODF3B) in gliomas was positively correlated with the grade of glioma. The higher the grade, the worse the prognosis. ODF3B is closely related to the growth and apoptosis of glioma. In terms of mechanism, ODF3B was found to affect the proliferation and apoptosis of glioma through the JAK1 and JAK2/STAT3 pathways. ODF3B was also found to affect the growth and apoptosis of glioma in vivo . We conclude that ODF3B affects glioma proliferation and apoptosis via the JAK/STAT pathway and is a potential therapeutic target., Competing Interests: None., (AJCR Copyright © 2024.)

Background: Low physical activity (LPA) is linked to the risk of stroke, but the disease burden of stroke attributable to LPA needs to be understood to develop effective preventive strategies. We aim to assess spatiotemporal trends in the global burden of stroke attributable to LPA from 1990 to 2019., Methods: Based on the Global Burden of Disease, Injuries, and Risk Factors Study, our research examined deaths, the Disability-Adjusted Life Years (DALYs), the Age-Standardized Mortality Rate (ASMR), the Age-Standardized DALY Rate (ASDR), and the Estimated Annual Percentage Change (EAPC) for stroke attributable to LPA., Results: Deaths and DALYs were on the rise worldwide from 1990 to 2019, with increases of 72.72% for the former and 67.41% for the latter; ASMR and ASDR decreased, with the ASMR-related EAPC of -1.61 (95% CI:-1.71--1.5) and ASDR-related EAPC of -1.35 (95% CI:-1.43--1.27); females had more numbers of deaths and DALYs, and the majorities of deaths and DALYs were shared by those aged ≥ 70. The highest burden rates were shared by North Africa, the Middle East, and Tropical Latin America; the ASMR-related EAPC was associated with the ASMR in 1990 (R = -0.26, P < 0.001) and the Socio-Demographic Index (SDI) across different countries in 2019 (R = -0.61, P < 0.001), respectively, and such patterns were similar to what ASDR and the ASDR-related EAPC had; the Human Development Index (HDI) in 2019 was associated with the ASMR-related EAPC (R = 0.63, P < 0.001) and the ASDR-related EAPC across different countries (R = -0.62, P < 0.001), respectively., Conclusions: Globally, deaths and DALYs of stroke attributable to LPA were on the rise, although their age-standardized rates presented downward over the past three decades; the burden of stroke attributable to LPA showed upward trends especially in those aged ≥ 70 and females in the regions of East Asia, North Africa, and the Middle East, which need more attention to the effects of physical activity on health interventions., (© 2023. The Author(s).)

Hepatitis B protein x (HBx) has been reported to promote tumorigenesis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), but the mechanism awaits further investigation. In this study, we found that cFAM210A (a circular RNA derived from the third exon of transcript NM&#95;001098801 of the FAM210A gene; CircBase ID: hsa&#95;circ&#95;0003979) can be silenced by HBx. cFAM210A expression was downregulated and negatively correlated with tumorigenesis in patients with HBV-related HCC. Furthermore, cFAM210A reduced the proliferation, stemness, and tumorigenicity of HCC cells. Mechanistically, HBx increased the N6-methyladenosine (m6A) level of cFAM210A by promoting the expression of RBM15 (an m6A methyltransferase), thus inducing the degradation of cFAM210A via the YTHDF2-HRSP12-RNase P/MRP pathway. cFAM210A bound to YBX1 and inhibited its phosphorylation, suppressing its transactivation function toward MET. These findings suggest the important role of circular RNAs in HBx-induced hepatocarcinogenesis and identify cFAM210A a potential target in the prevention and treatment of HBV-related HCC., (© 2023. The Author(s).)

Artificial photosynthesis for CO 2 reduction coupled with water oxidation currently suffers from low efficiency due to inadequate interfacial charge separation of conventional Z-scheme heterojunctions. Herein, an unprecedented nanoscale Janus Z-scheme heterojunction of CsPbBr 3 /TiO x is constructed for photocatalytic CO 2 reduction. Benefitting from the short carrier transport distance and direct contact interface, CsPbBr 3 /TiO x exhibits significantly accelerated interfacial charge transfer between CsPbBr 3 and TiO x (8.90 × 10 8 s -1 ) compared with CsPbBr 3 :TiO x counterpart (4.87 × 10 7 s- 1 ) prepared by traditional electrostatic self-assembling. The electron consumption rate of cobalt doped CsPbBr 3 /TiO x can reach as high as 405.2 ± 5.6 µmol g -1 h -1 for photocatalytic CO 2 reduction to CO coupled with H 2 O oxidation to O 2 under AM1.5 sunlight (100 mW cm -2 ), over 11-fold higher than that of CsPbBr 3 :TiO x , and surpassing the reported halide-perovskite-based photocatalysts under similar conditions. This work provides a novel strategy to boost charge transfer of photocatalysts for enhancing the performance of artificial photosynthesis., (© 2023 Wiley-VCH GmbH.)

Background: Reports on Lenvatinib-based therapies show promising treatment outcomes for patients with unresectable hepatocellular carcinoma (uHCC). However, the effect and safety of Lenvatinib-based therapies still need to be further studies., Methods: This was a retrospective, single-center study on the safety and treatment efficacy of Lenvatinib-based combination therapies for uHCC Patients. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were progressive disease (PD), stable disease (SD), partial response (PR), and complete response (CR)., Results: Of 91 patients, there were 16 females and 75 males with uHCC who received systemic therapies based on Lenvatinib in our center. Forty-six patients (50.5%) received Lenvatinib combined with PD-1 antibody treatment. All these patients also received local therapy with the exception of 2 patients. The remaining 36 patinets received Lenvatinib combined with transcatheter arterial chemoembolization (TACE), 1 patient treated Lenvatinib combined with radiotherapy, 8 patients received Lenvatinib alone. At a median treatment time of 8 months, the objective response rate (ORR) of the entire cohort was 58.2% (53 patients), including 7 patients with CR and 46 patients with PR. 21 patients (23.1%) had SD. The disease control rate (DCR) of all patients was 81.3% (74 patients). However, 17 patients (18.7%) developed PD. The 1- and 2-year cumulative OS rates for the entire cohort were 66.8% and 39.3%, while the corresponding PFS rates were 38.0% and 17.1%, respectively. Univariate and multivariate Cox regression analysis revealed multiple tumor sites to be an independent OS risk factor for uHCC patients (HR=2.204, 95% CI=1.104-4.399, P =0.025). The most frequently reported adverse events in all patients were AST elevation (51.6%), followed by hypertension (33.0%), ALT elevation (26.4%), and decreased appetite (25.3%). After a combination treatment of Lenvatinib-based therapies, 15 patients met the criteria for salvage liver resection and underwent down-staging hepatectomy with a curative intent. The combination of PD-1 treatment was not very effective in improving the prognosis of uHCC patients treated with Lenvatinib combined with TACE., Conclusion: Our study demonstrated that a proportive of patients benefited from Lenvatinib-based combination therapies with manageable safety profiles, allowing these patients to undergo downstaging surgery with curative intent., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Huang, Wang, Tao, Yang, Yuan, Gu, Liu, Pan, Jiang, Lau and Zhou.)

Background: The differences in short- and long-term outcome between laparoscopic liver resection (LLR) and open liver resection (OLR) for BCLC stage A large hepatocellular carcinoma (HCC) in difficult segments (I, IVa, VII, VIII) remain unclear. This PSM two-centre study aimed to compare perioperative and long-term survival outcomes of LLR with OLR for this HCC., Methods: HCC patients with BCLC stage A who underwent OLR or LLR in two medical centres were enrolled in the study. PSM analysis was performed to match patients between the LLR cohort and OLR cohort. Survival was analysed based on the Kaplan-Meier method. Independent risk factors were identified by Cox regression., Results: After PSM, 35 patients remained in the LLR cohort, and 84 remained in the OLR cohort. Patients in the LLR cohort had more intraoperative blood loss (p=0.036) and shorter hospital stays after surgery (p<0.001). The LLR cohort and OLR cohort had no difference in intraoperative blood transfusion, surgical margin or postoperative short-term outcomes. The OS and RFS were not significantly different between the two cohorts. The OS and RFS of these two cohorts were not different in the subgroup analysis. Surgical margin was identified as an independent risk factor for tumour recurrence., Conclusion: For BCLC stage A large HCC patients with lesions in difficult segments, LLR was feasible and had shorter hospital stay than OLR. In addition, a surgical margin ≥1 cm could significantly decrease the recurrence probability for large HCC located in different segments without compromising short-term outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ding, Liu, Lin, Gan, Guo, Ding, Sun, Li, Tao, Gu, Guo, Zeng, Zhou and Yuan.)

Background: At present, the first-line treatment for advanced intrahepatic cholangiocarcinoma (ICC) is gemcitabine combined with cisplatin, but a considerable portion of ICC patients exhibit resistance to gemcitabine. Therefore, finding sensitisers for gemcitabine chemotherapy in ICC patients and predicting molecular markers for chemotherapy efficacy have become urgent needs., Methods: In this study, PDX models were established to conduct gemcitabine susceptibility tests. The selected PDX tissues of the chemotherapy-sensitive group and drug-resistant group were subjected to transcriptome sequencing and protein chip technology to identify the key genes. Sixty-one ICC patients treated with gemcitabine chemotherapy were recruited for clinical follow-up validation., Results: We found that thrombospondin-1 (TSP1) can predict gemcitabine chemosensitivity in ICC patients. The expression level of TSP1 could reflect the sensitivity of ICC patients to gemcitabine chemotherapy. Functional experiments further confirmed that TSP1 can increase the efficacy of gemcitabine chemotherapy for ICC. A mechanism study showed that TSP1 may affect the intake of oleic acid by binding to the CD36 receptor., Conclusions: In summary, we found a key molecule-TSP1-that can predict and improve the sensitivity of ICC patients to gemcitabine chemotherapy, which is of great significance for the treatment of advanced cholangiocarcinoma., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: To explore the carrier rate, genotype and phenotype of α-thalassemia fusion gene in Huadu district of Guangzhou, Guangdong province of China, and provide data reference for the prevention and control of thalassemia., Methods: A total of 10 769 samples who were screened for thalassemia in Maternal and Child Health Hospital of Huadu District from July 2019 to November 2020 were analyzed retrospectively. Blood cell analysis and hemoglobin (Hb) electrophoresis were performed. Thalassemia genes were analyzed by gap-PCR and PCR-reverse dot blot hybridization (PCR-RDB)., Results: A total of 9 cases with α-thalassemia fusion gene were detected in 10 769 samples (0.08%). There were 7 cases with fusion gene heterozygote, 1 case with compound of α-thalassemia fusion gene and Hb G-Honolulu, 1 case with compound of α-thalassemia fusion gene and Hb QS. The MCV results of 4 samples of blood cell analysis were within the reference range, the Hb A2 value of 1 case was decreased, and there were no other abnormalities found., Conclusion: The α-thalassemia fusion gene is common in Huadu district of Guangzhou, and heterozygotes are more common, and current screening methods easily lead to misdiagnosis.

Background: Early singular nodular hepatocellular carcinoma (HCC) is an ideal surgical indication in clinical practice. However, almost half of the patients have tumor recurrence, and there is no reliable prognostic prediction tool. Besides, it is unclear whether preoperative neoadjuvant therapy is necessary for patients with early singular nodular HCC and which patient needs it. It is critical to identify the patients with high risk of recurrence and to treat these patients preoperatively with neoadjuvant therapy and thus, to improve the outcomes of these patients. The present study aimed to develop two prognostic models to preoperatively predict the recurrence-free survival (RFS) and overall survival (OS) in patients with singular nodular HCC by integrating the clinical data and radiological features., Methods: We retrospective recruited 211 patients with singular nodular HCC from December 2009 to January 2019 at Eastern Hepatobiliary Surgery Hospital (EHBH). They all met the surgical indications and underwent radical resection. We randomly divided the patients into the training cohort (n =132) and the validation cohort (n = 79). We established and validated multivariate Cox proportional hazard models by the preoperative clinicopathologic factors and radiological features for association with RFS and OS. By analyzing the receiver operating characteristic (ROC) curve, the discrimination accuracy of the models was compared with that of the traditional predictive models., Results: Our RFS model was based on HBV-DNA score, cirrhosis, tumor diameter and tumor capsule in imaging. RFS nomogram had fine calibration and discrimination capabilities, with a C-index of 0.74 (95% CI: 0.68-0.80). The OS nomogram, based on cirrhosis, tumor diameter and tumor capsule in imaging, had fine calibration and discrimination capabilities, with a C-index of 0.81 (95% CI: 0.74-0.87). The area under the receiver operating characteristic curve (AUC) of our model was larger than that of traditional liver cancer staging system, Korea model and Nomograms in Hepatectomy Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma, indicating better discrimination capability. According to the models, we fitted the linear prediction equations. These results were validated in the validation cohort., Conclusions: Compared with previous radiography model, the new-developed predictive model was concise and applicable to predict the postoperative survival of patients with singular nodular HCC. Our models may preoperatively identify patients with high risk of recurrence. These patients may benefit from neoadjuvant therapy which may improve the patients' outcomes., Competing Interests: Competing interest No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article., (Copyright © 2022 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Bones are categorized as the second most prevalent location of extra-hepatic metastasis in Hepatocellular Carcinoma (HCC), which is linked to an extremely poor prognosis due to limited therapeutic options. N 6 -methyladenosine (m 6 A) is a prominent modification involved in HCC, but the exact mechanisms on how m 6 A modifications induce HCC bone metastases (BM) remain unclear. The key modulators responsible for the abundant m 6 A RNA modification-induced HCC BM was found to be the METTL3 and YTHDF1 . The expression of Anillin actin-binding protein ( ANLN ) was dramatically higher in HCC with BM tissues, and its messenger RNA (mRNA) stability was enhanced via m 6 A epitranscriptomic regulation by METTL3 and YTHDF1 . High METTL3 and YTHDF1 expression along with nuclear ANLN protein was clinically correlated with BM in HCC patients. Furthermore, HCC BM was attributed to over-expression of nuclear ANLN forming a transcriptional complex with SP1 which enhanced KIF2C transcriptional activity to activate the mTORC1 pathway, therefore increased the expression of RANKL and disproportionated RANKL-OPG expression in bone microenvironment leading to malignant neoplasms invade bone tissue. In addition, inhibition of ANLN m 6 A modification by DZNeP attenuated HCC BM. This data provides meaningful understanding of the modulation and association of m 6 A epitranscriptomic-regulated BM in HCC, and moreover, defines potentially valuable therapeutic targets., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Rationale: Hepatocellular carcinoma (HCC) is a highly heterogeneous and malignant disease with the complex immune microenvironment, which ultimately influence clinic outcomes of patients. However, the spatial expression patterns of diverse immune cells among tumor microenvironment remain to be further deciphered. Methods: Spatial transcriptomics sequencing (ST) was implemented on two portions of HCC specimens. Differentially expressed genes, cell cycle phases, epithelial-mesenchymal features, pseudo-time and immune infiltration analysis were applied to demonstrate the intratumor heterogeneity and define the specific immune-related regions, and the results were further validated by a second analysis on another ST study. In vitro and in vivo experiments were conducted to confirm the functional mechanisms of key molecules such as CCL15, CCL19 and CCL21. Clinical tissue samples were used to assess their potential prognostic and therapeutic values. Results: Totally, 7553 spots were categorized into 15 subsets by hierarchical clustering, and malignant subsets with intratumor heterogeneity phenotypes were identified. Spatial heterogeneity from distinct sectors highlights specific chemokines: CCL15 is remarkable in the core region of the carcinoma sector and facilitates the immunosuppressive microenvironment by recruiting and polarizing M2-like macrophages in vitro and in vivo ; High expression of CCL15 and CD163 respectively predicts poor prognosis of HCC patients, and the combined application of them has better predictive value. CCL19 and CCL21, sharing similar spatial expression patterns, are highly-correlated and prominent in the immune infiltration enrichment and recruit CD3 + T cells and CD20 + B cells to inhibit the growth of HCC, indicating a good prognosis of HCC patients. Conclusions: Taken together, our studies preliminarily reveal intratumor heterogeneity of HCC based on ST techniques and unravel the previously unexplored spatial expression patterns in the immune microenvironment. We also highlight the clinical significance and spatial discrepancy of key molecules, providing novel insight for further developing therapeutic strategies in HCC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

In order to understand the effects of different patterns of prefabricated fractures and grain size compositions on the fracture characteristics, acoustic emission characteristics and mechanical properties of the rock masses. We conducted compression shear experiments on square rock masses with different modes of prefabricated fractures and different grain size compositions. The experimental results showed that five fracture patterns were produced in specimens with different fracture patterns. The first fracture specimen, the fourth fracture specimen and the fifth fracture specimen were all brittle fractures. The other four specimens were not brittle fractures. The fracture patterns, fracture processes and mechanical characteristics of the different fracture pattern rock masses were revealed. The lowest peak shear stresses were found in specimens consisting of two grain size ranges and the highest peak shear stresses were found in specimens consisting of three grain size ranges. The highest shear displacements corresponding to the peak shear stresses were found in the specimens consisting of three particle size ranges. The effect of different grain size compositions on the peak shear stress and its corresponding shear displacement of the rock mass was revealed. Specimens consisting of one grain size range produced significant fracture and acoustic emission prior to the peak shear stress. The acoustic emission was jumped after the main fracture was formed. The specimen consisting of two grain size ranges produced fractures and strong acoustic emission characteristics after the peak shear stress. Thereafter, fracture reappeared and the acoustic emission signature increased again. As the specimen entered the residual strength phase, the acoustic emission was jumpy. Specimens consisting of three grain size ranges were brittle fractures with weak acoustic emission characteristics after the main fracture has formed. The cumulative energy of shear acoustic emission was the highest for a rock mass consisting of three grain size ranges. The rock mass consisting of three grain size ranges was also the strongest and most difficult to fracture because the grains were more fully embedded in each other., (© 2022. The Author(s).)

The purpose of the present study was to investigate the effect of transient receptor potential vanilloid 4 (TRPV4) channel on the permeability of pulmonary microvascular endothelial cells (PMVECs) in rats with chronic hypoxia-induced pulmonary hypertension (CHPH), so as to clarify the mechanism of vascular endothelial dysfunction during the occurrence of pulmonary hypertension (PH). CHPH rat model was established by exposure to chronic hypoxia (CH) for 21 days. Primary PMVECs were cultured by adherent tissue blocks at the edge of the lung. The permeability coefficient of primary cultured PMVECs was detected by fluorescein isothiocyanate (FITC)-dextran. The structure of tight junction (TJ) was observed by transmission electron microscope. The expression of TRPV4 and TJ-related proteins, such as, Occludin, Claudin-5, ZO-1 were examined by real-time fluorescence quantitative PCR and Western blotting. The intracellular calcium concentration ([Ca 2+ ] i ) in PMVECs and its effect on PMVECs permeability were observed after the intervention of TRPV4 specific agonist GSK1016790A (GSK, 10 nmol/L) and specific inhibitor HC-067047 (HC, 1 μmol/L, 0.5 μmol/L). The results showed that the CHPH model was successfully established in rats treated with CH for 21 days. In CHPH rats, the structure of TJ was destroyed, the function of PMVECs barrier was decreased, the intercellular permeability was increased, the expression of TJ-related proteins were significantly decreased and the expression of TRPV4 was significantly increased (P < 0.01). The amplitude of [Ca 2+ ] i in PMVECs of CHPH rats was significantly increased after activation of TRPV4. The inhibition ratio of HC on [Ca 2+ ] i in PMVECs of CHPH rats was significantly higher than that in normal PMVECs. TRPV4 specific inhibitor HC reversed the increase of PMVECs permeability and increased the expression of three TJ-related proteins in CHPH rats (P < 0.01, P < 0.05). These results suggest that TRPV4 channel can induce endothelial dysfunction by increasing the [Ca 2+ ] i , resulting in the destruction of TJ structure and the decrease of TJ-related proteins expression on PMVECs in CHPH rats.

Grain size composition, crack pattern, and crack length have a significant influence on the crack characteristics, mechanical characteristics, and acoustic emission characteristics of rock masses. In this paper, the crack characteristics, mechanical characteristics, and acoustic emission characteristics of rock masses with different grain size compositions, different crack patterns, and different crack lengths were investigated under uniaxial compression. The rock masses were made of rock-like materials. The crack initiation locations and crack propagation directions were different for a specimen comprised of one grain size range compared with specimens comprised of two or three grain size ranges. The specimens comprised of one and three grain size ranges crack progressively. The specimen comprised of two-grain size ranges brittle fracture. The highest peak axial load was found in the specimens comprised of one grain size range. The results showed that tensile wing crack, anti-tensile wing crack, transverse shear crack, compression induced tensile crack, and surface spalling were produced in specimens with different crack orientations. The rock mass with 2 cm long crack started to produce cracks from the tip of the crack extending to the top and bottom surface, soon forming through cracks. The rock was brittle fracture. The axial load reached the maximum and then fell rapidly. The acoustic emission energy reached a rapid maximum and then decreased rapidly. The rock mass with 3 cm long fissures started to produce cracks that only extended from the tip of the fissures to the top surface but not to the bottom surface. The rock mass was progressively fractured. The axial load was progressively decreasing. The acoustic emission energy also rose and fell rapidly several times as the rock mass was progressively fractured. Different rock crack lengths led to different crack processes and crack patterns, resulting in very different acoustic emission characteristics., (© 2021. The Author(s).)

Background and Aims: HBV-pgRNA (pregenomic RNA) has been proposed for predicting the response of nucleos(t)ide analogue (NA) treatment, guiding discontinuation of NA therapy and monitoring the emergence of viral mutations. However, the contributions of HBV-pgRNA to HCC remain open for study., Approach and Results: Double-center cohorts of serum samples with undetectable serum HBV-DNA (below the lower limit of detection) were obtained from long-term NA-treated (≥48 weeks) HBV-related HCC patients. The correlation between serum pgRNA concentration and the prognosis of HCC were analyzed. The role pgRNA played in HCC development was assessed both in vitro and in vivo. Our findings revealed that for patients who underwent long-term NA therapy with undetectable serum HBV-DNA, patients with high serum pgRNA expression had a poorer overall survival rate and higher cumulative recurrence rate after hepatectomy. Experiments demonstrated that pgRNA promotes proliferation, stemness, and tumorigenicity of HCC cells. Mechanistically, we found that pgRNA could up-regulate the expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a well-proven oncoprotein, at the posttranscriptional level. Furthermore, interferon (IFN)-α-2a could degrade the stability of pgRNA through increasing its N6-methyladenosine (m6A) RNA modification. Collectively, our findings uncover that serum pgRNA could serve as a potential biomarker for predicting the prognosis and recurrence of HCC in patients who received long-term NA therapy with undetectable serum HBV-DNA; and the pgRNA-IGF2BP3 axis plays an important role in the development of HBV-related HCC. Moreover, IFN-α-2a could reduce the stability of pgRNA by increasing its m6A RNA modification level, thereby suppressing the development of HBV-related HCC., Conclusions: In conclusion, our studies reveal a significance and mechanism of HBV-pgRNA in increasing stemness features and offer a potential prognostic marker and a therapeutic target for HBV-related HCC., (© 2021 by the American Association for the Study of Liver Diseases.)

Transcriptome-wide association studies (TWAS) have identified several genes that are associated with qualitative traits. In this work, we performed TWAS using quantitative traits and predicted gene expressions in six brain subcortical structures in 286 mild cognitive impairment (MCI) samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. The six brain subcortical structures were in the limbic region, basal ganglia region, and cerebellum region. We identified 9, 15, and 6 genes that were stably correlated longitudinally with quantitative traits in these three regions, of which 3, 8, and 6 genes have not been reported in previous Alzheimer's disease (AD) or MCI studies. These genes are potential drug targets for the treatment of early-stage AD. Single-Nucleotide Polymorphism (SNP) analysis results indicated that cis-expression Quantitative Trait Loci (cis-eQTL) SNPs with gene expression predictive abilities may affect the expression of their corresponding genes by specific binding to transcription factors or by modulating promoter and enhancer activities. Further, baseline structure volumes and cis-eQTL SNPs from correlated genes in each region were used to predict the conversion risk of MCI patients. Our results showed that limbic volumes and cis-eQTL SNPs of correlated genes in the limbic region have effective predictive abilities.

Alzheimer's disease (AD) is a neurodegenerative brain disease in the elderly. Identifying patients with mild cognitive impairment (MCI) who are more likely to progress to AD is a key step in AD prevention. Recent studies have shown that AD is a heterogeneous disease. In this study, we propose a subtyping-based prediction strategy to predict the conversion from MCI to AD in three years according to MCI patient subtypes. Structural magnetic resonance imaging (sMRI) data and multi-omics data, including genotype data and gene expression profiling derived from peripheral blood samples, from 125 MCI patients were used in the Alzheimer's Disease Neuroimaging Initiative (ADNI)-1 dataset and from 98 MCI patients in the ADNI-GO/2 dataset. A variational Bayes approximation model based on the multiple kernel learning method was constructed to predict whether an MCI patient will progress to AD within three years. In internal fivefold cross-validation within ADNI-1, we achieved an overall AUC of 0.83 (79.20% accuracy, 81.25% sensitivity, 77.92% specificity) compared to the model without subtyping, which achieved an AUC of 0.78 (76.00% accuracy, 77.08% sensitivity, 75.32% specificity). In external validation using ADNI-1 as a training set and ADNI-GO/2 as an independent test set, we attained an AUC of 0.78 (74.49% accuracy, 74.19% sensitivity, 74.63% specificity). Identifying MCI patient subtypes with omics data would improve the accuracy of predicting the conversion from MCI to AD. In addition to evaluating statistics, obtaining the significant sMRI, single nucleotide polymorphism (SNP) and mRNA expression data from peripheral blood of MCI patients is noninvasive and cost-effective for predicting conversion from MCI to AD.

Background: Alzheimer's Disease (AD) is a neurodegenerative brain disease in the elderly. Recent studies have revealed the heterogeneous nature of AD. Mild Cognitive Impairment (MCI) is the prodromal stage of AD., Objectives: In this study, we identified subtypes of MCI based on genetic polymorphism and gene expression., Methods: We utilized the two types of omics data, namely genetic polymorphism and gene expression profiling, derived from 125 MCI patients' peripheral blood samples from the ADNI-1 dataset. Similarity network fusion (SNF) algorithm was implemented to cluster MCI patient subtypes. And 185 MCI patients in ADNI-2 were utilized to evaluate the effectiveness of this method. Two MCI subtypes were identified by implementing the SNF algorithm., Results: We used Kaplan-Meier analysis and log-rank testing for the conversion from MCI to AD between two subtypes, and p-value is 4.58×10-3. In addition, we compared patients among two MCI subtypes by the following factors: the changes in Alzheimer's Disease cognitive scales and MRI image; significantly enriched pathways based on differentially expressed genes. This study proved that MCI is a heterogeneous disease by concluding that AD development in two MCI subtypes is significantly different., Conclusions: MCI patients with different molecular characteristics have different risks converting to AD. In addition to evaluating statistics, genetic polymorphism and gene expression profiling from MCI patients' peripheral blood are non-invasiveness and cost-effectiveness markers to identify MCI subtypes for clinical application., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Circulating tumor cells (CTCs) with an epithelial-mesenchymal transition phenotype in peripheral blood may be a useful marker of carcinomas with poor prognosis. The aim of this study was to determine the prognostic significance of CTCs expressing Krüppel-like factor 8 (KLF8) and vimentin in pancreatic cancer (PC)., Methods: CTCs were isolated by immunomagnetic separation from the peripheral blood of 40 PC patients before undergoing surgical resection. Immunocytochemistry was performed to identify KLF8 + and vimentin + CTCs. The associations between CTCs and time to recurrence (TTR), clinicopathologic factors, and survival were assessed. Univariate and multivariate analyzes were performed to identify risk factors., Results: Patients with CTCs ( n = 30) had a higher relapse rate compared to those without ( n = 10) (70.0% vs 20.0%; P < 0.01). The proportion of KLF8 + /vimentin + CTCs to total CTCs was inversely related to TTR ( r = -0.646; P < 0.01); TTR was reduced in patients with > 50% of CTCs identified as KLF8 + /vimentin + ( P < 0.01). Independent risk factors for recurrence were perineural invasion and > 50% KLF8 + /vimentin + CTCs (both P < 0.05)., Conclusion: Poor prognosis can be predicted in PC patients when > 50% of CTCs are positive for KLF8 and vimentin.

Recent studies showed that the deubiquitinase ubiquitin-specific protease 34 (USP34) was involved in the tumorigenesis of several tumors, but its function and mechanism are still unclear in laryngeal squamous cell carcinoma (LSCC). In this study, we found that USP34 and SOX2 were elevated in LSCC tumor tissues, and we also found that USP34 expression was positively correlated with SOX2 expression. Our further studies showed that USP34 regulated the protein level of SOX2 in LSCC cells, but not the mRNA level, which suggested that USP34 stabilized SOX2. Moreover, USP34, as a deubiquitinase, could interact with SOX2, and reduce the polyubiquitination of SOX2. In addition, knockdown of USP34 could significantly inhibit LSCC cell growth, but overexpression of SOX2 could reverse this effect. Finally, we also found that USP34 and SOX2 were upregulated in cisplatin-resistant LSCC cells, but knockdown of USP34 could enhance the drug sensitivity of cisplatin in the resistant cells. Collectively, targeting USP34/SOX2 axis may be a promising strategy for the treatment of LSCC., (© 2020 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

Objective: To evaluate the importance of preoperative blood platelet to lymphocyte ratio (PLR) in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after liver surgery and to examine the connection with CD8 + lymph cell infiltration. Methods: Between 2009 and 2014, consecutive HCC patients who received curative liver surgery were included into this retrospective study. Baseline clinicopathological characteristics were analyzed to identify predictors of recurrence-free and overall patient survival rate after liver resection. The samples of all patients were under Tissue Microarray (TMA) construction and immunohistochemical staining for CD8+.The association of the number of CD8+T-cells in the cancer nests and peritumoral stroma with PLR level was analyzed. Results: A total of 1,174 HBV-related HCC patients who received a liver resection without any peri-operative adjuvant therapy were enrolled into this retrospective study. Univariate and Multivariate analysis using Cox regression model showed that PLR was an independent factor affecting recurrence and overall survivals. The optimal cutoff of PLR using the receiver operating characteristic curve was 150. There were 236 patients (20.1%) who had a PLR of 150 or more. The 5-year survival rate after liver resection was 71.8% in patients with a PLR of < 150 and it was 57.2% in those with a PLR of 150 or more ( P < 0.001). Both 5-year recurrence-free and overall survival rates in liver cancer stage A patients at Barcelona Clinic with different PLR group were also significantly different ( P = 0.007 for recurrence and P = 0.001 for overall survival). Similar results were also observed in stage B patients ( P < 0.001 for recurrence and P = 0.033 for overall survival). To determine the association between PLR and the severity of liver inflammation, an immuno-histological examination using CD8 + staining was performed on the liver specimens of 1,174 patients. Compared with low PLR (<150) group, more CD8 + T-cells were found in the peritumoral tissue in high PLR (≥ 150) group. Conclusions: PLR played as an independent factor for predicting the survival after hepatectomy for HCC patients. A high PLR was associated with an accumulation of CD8 + T-cells in the peritumoral stroma., (Copyright © 2020 Yang, Wang, Tian, Huang, Yuan, Liu, Zhu, Gu, Fu, Jiang, Liu, Pan and Zhou.)

Objective: To examine the relationship of prenatal environmental tobacco smoke (ETS) exposure and full-term low birth weight (FT-LBW) when taking anthropometric proportionality into consideration, and explore whether appetite mediates their association. Study design: We conducted a case-control study among pregnant women at two Women and Children's Hospitals in Guangdong, China. Information was collected through interview and medical records review. A series of logistic and linear regressions were used to examine the relationships of prenatal ETS exposure, appetite, and FT-LBW. Results: After adjusting for the potential confounders, prenatal ETS exposure was significantly negatively associated with FT-LBW (OR: 1.83, 95%CI: 1.35-2.48) and negatively correlated with maternal appetite in second and third trimester during pregnancy (β: -0.11, standard error: 0.03). Moreover, mediation analysis illustrated that maternal appetite partially mediated 12.00% of their relationship. However, subgroup analysis showed that prenatal ETS exposure was linked to higher risk of symmetric FT-LBW (OR: 2.26, 95%CI: 1.56-3.26) but not asymmetric FT-LBW. And maternal appetite explained only 6.45% of their relationship. Conclusions: Maternal prenatal ETS exposure increased risk of having symmetric FT-LBW infant, and appetite might mediate their relationship partially. This study emphasizes the importance of sample homogeneity and stresses the needs to improve the public awareness of the harmful effects of ETS.

This paper was originally published in Aging Advance Online Publications on February 2, 2020. In compliance with Aging's withdrawal policy, the paper was withdrawn in its entirety. It will not appear in Aging internal or any external indexes or archives.

Objectives: The objective of this study was to establish a reliable and effective nomogram for predicting prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) with postoperative adjuvant transarterial chemoembolization (TACE)., Patients and Methods: A derivation cohort of 370 HCC patients treated with postoperative TACE in the Eastern Hepatobiliary Surgery Hospital from January 2009 to December 2012 were retrospectively analyzed. Univariate and multivariate analysis were performed by Cox regression and independent prognostic factors for overall survival were determined to construct the nomogram. Concordance index (C-index), calibration curve and decision curve analysis were performed to evaluate the capability of the nomogram and the established nomogram was compared with TNM stage and Barcelona Clinic Liver Cancer (BCLC) stage to identify the superior model. The results were validated in a validation cohort of 123 HCC patients in the same center., Results: Multivariate analysis indicated that γ-glutamyl transferase, α-fetoprotein, tumor number, tumor size, satellite lesions, microvascular invasion, and HBV-DNA were independent prognostic factors for overall survival in the derivation cohort, and all these factors were selected into the nomogram. The C-index was 0.755 for survival prediction of the nomogram, which was significantly higher than the TNM stage (0.636, P<0.001) and BCLC stage (0.594, P<0.001). A fair uniformity and a superior net benefit with wide range threshold probabilities were showed in the calibration curves and decision curve analysis. In the validation cohort, the C-index of the nomogram (0.785) also had a higher predictive accuracy than TNM stage (0.744, P=0.019) and BCLC stage (0.616, P<0.001)., Conclusions: The nomogram with accurate and reasonable performance was proposed for predicting survival of HBV-related HCC with postoperative adjuvant TACE.

The mechanism of hepatocellular carcinoma (HCC) metastasis remains poorly understood. Tropomodulin 3 (TMOD3) is a member of the pointed end capping protein family that contributes to invasion and metastasis in several types of malignancies. It has been found to be crucial for the membranous skeleton and embryonic development, although, its role in HCC progression remains largely unclear. We observed increased levels of Tmod3 in HCCs, especially in extrahepatic metastasis. High Tmod3 expression correlated with aggressive carcinoma and poor patient with HCC survival. Loss-of-function studies conducted by us determined Tmod3 as an oncogene that promoted HCC growth and metastasis. Mechanistically, Tmod3 increases transcription of matrix metalloproteinase-2, -7, and -9 which required PI3K-AKT. Interaction between Tmod3 and epidermal growth factor receptor (EGFR) that supports the activation of EGFR phosphorylation, is essential for signaling activation of PI3K-AKT viral oncogene homolog. These findings reveal that Tmod3 enhances aggressive behavior of HCC both in vitro and in vivo by interacting with EFGR and by activating the PI3K-AKT signaling pathway., (© 2019 Wiley Periodicals, Inc.)

Objective: To examine the interaction effects of prenatal exposed to environmental tobacco smoke (ETS) and genotypes of cytochrome P4501A1 (CYP1A1), glutathione S-transferases (GSTs) on the risk of full-term low birth weight (FT-LBW)., Study Design: We conducted a case-control study among pregnant women at two Women and Children's Hospitals in Guangdong, China (n = 910). Information was collected through interview, medical records review, and blood lab tests. Maternal selfreport and serum cotinine concentration were combined to define prenatal exposed to ETS. Logistic regression approach was applied for statistical analysis., Results: Our results showed that regardless of genotypes, prenatal exposed to ETS significantly increased the risk of FT-LBW. Then, two-way interactions showed increased prevalence of FT-LBW in prenatal exposed to ETS mothers with the CYP1A1 variant genotype (MspI "CC"), or with GSTT1-null genotype. Furthermore, three-way interactions showed that women with CYP1A1 variant (MspI "TC" or BsrDI "AG") genotypes and GSTT1 "null" genotype had higher risk to give birth of FT-LBW. Additionally, among nonexposed ETS mothers, genotype did not independently confer adverse effects on FT-LBW., Conclusions: Our results revealed that prenatal exposed to ETS is independently associated with FT-LBW while gene polymorphisms of CYP1A1 and GSTs merely play modified roles in this process. This study extends understanding of three-way interaction, and stresses the need to tobacco control toward pregnant women for better pregnant outcomes.

Background & Aims: Genetic variability in the hepatitis B virus X gene (HBx) is frequently observed and is associated with hepatocellular carcinoma (HCC) progression. However, a genotype classification based on the full-length HBx sequence and the impact of genotypes on hepatitis B virus (HBV)-related HCC prognosis remain unclear. We therefore aimed to perform this genotype classification and assess its clinical impact., Methods: We classified the genotypes of the full-length HBx gene through sequencing and a cluster analysis of HBx DNA from a cohort of patients with HBV-related HCC, which served as the primary cohort (n = 284). Two independent HBV-related HCC cohorts, a validation cohort (n = 171) and a serum cohort (n = 168), were used to verify the results. Protein microarray assay analysis was performed to explore the underlying mechanism., Results: In the primary cohort, the HBx DNA was classified into 3 genotypes: HBx-EHBH1, HBx-EHBH2, and HBx-EHBH3. HBx-EHBH2 (HBx-E2) indicated better recurrence-free survival and overall survival for patients with HCC. HBx-E2 was significantly correlated with the absence of liver cirrhosis, a small tumor size, a solitary tumor, complete encapsulation and Barcelona Clinic Liver Cancer (BCLC) stage A-0 tumors. Additionally, HBx-E2 served as a significant prognostic factor for patients with BCLC stage B HCC after hepatectomy. Mechanistically, HBx-E2 is unable to promote proliferation in HCC cells and normal hepatocytes. It also fails to activate the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3)/STAT5 pathway., Conclusion: Our study identifies a novel HBx genotype that is unable to promote the proliferation of HCC cells and suggests a potential marker to preoperatively predict the prognosis of patients with BCLC stage B, HBV-associated, HCC., Lay Summary: We classified a novel genotype of the full-length hepatitis B virus X gene (HBx), HBx-E2. This genotype was identified in tumor and nontumor tissues from patients with hepatitis B virus-related hepatocellular carcinoma. HBx-E2 could preoperatively predict the prognosis of patients with intermediate stage hepatocellular carcinoma, after resection., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objective: The extent of research on maternal exercise during pregnancy and the risk of preterm birth (PTB) have grown substantially, but conclusions still remained controversial. Thus, this study aims to examine the relationship of maternal exercise during pregnancy and PTB and explore whether placenta mediates their relationship., Study Design: We investigated 849 pregnant women delivering PTB newborns (cases) and 1306 delivering full-term appropriate for gestational age newborns (controls) in this case-control study. Information concerning maternal exercise during pregnancy, sociodemographics and obstetric characteristics were collected at Women and Children's Hospitals of Shenzhen and Foshan in Guangdong, China. A series of logistic and linear regressions were used to examine the relationships of maternal exercise during pregnancy, placenta, and PTB., Results: After adjusting for the potential confounders, maternal exercise frequency and duration during pregnancy were negatively associated with PTB. Moreover, compared with mother taking no exercise during pregnancy, those taking exercise lowered the risk of PTB except those taking low/medium frequency and short duration exercise, and their adjusted ORs ranged from 0.43 to 0.65. Furthermore, mediation analysis illustrated that placental weight partially mediated 65.20% of the effects of maternal exercise frequency on PTB, as well as 41.98% of the association between maternal exercise duration and PTB., Conclusions: Maternal exercise during pregnancy is beneficial for lowering the risk of PTB, especially when taking appropriate and enough exercise. Placenta weight may partially mediate the association between maternal exercise during pregnancy and PTB.

Objective: To analyze the epidemiological genotype features of human papillomavirus (HPV) in cervical infection and their risks for cervical precancers among women in Shenzhen area. Methods: A total of 2 717 individuals ranging in age from 30~59 years were recruited in 18 community health centers of Shenzhen city from March 1 to June 15, 2015 by a cluster sampling method. The results of genotype of HPV, liquid-based cytology (LBC), colposcopy and pathology were analyzed. The clinical sensitivity and specificity as well as positive (PPV) and negative (NPV) predictive values of the combination of different HPV genotype in screening the cervical intraepithelial neoplasia (CIN) 2 and above were estimated. Results: The HPV infection rate in Shenzhen area was 15.9% (432/2 717). The most common HPV genotype was HPV52 (22.9%), followed by HPV16 (12.7%), HPV53 (10.0%), HPV51 (8.6%) and HPV58 (8.1%). Compared with HPV16/18 genotyping, HPV33/16 genotyping had a higher sensitivity (57.1% vs. 42.9%, P <0.05) and an analogous specificity (87.3% vs. 86.9%, P >0.05) in predicting CIN2+ . The sensitivity of combination of HPV33/16 genotyping and low grade squamous intraepithelial lesion (LSIL) positive tested by LBC in predicting CIN2+ was 75.0%, significantly higher than 64.3% of atypical squamous cells of undetermined significance (ASC-US) positive tested by LBC alone ( P <0.05). The specificities of these two methods mentioned above in predicting CIN2+ were 83.5% and 89.2%, respectively, without statistical difference ( P >0.05). Conclusions: Women infected by HPV have distinct risks for CIN2+ according to different high-risk HPV genotypes. The top five risks were HPV 33, 16, 58, 56, and 68. HPV-positive women triaged by LBC LSIL+ combined with HPV33/16 genotyping may be a potential strategy for cervical cancer screening in developed urban area.

We previously demonstrated that interleukin-17A (IL-17A) is associated with the progression of hepatocellular carcinoma (HCC). However, its role in the invasion-metastasis cascade of HCC and the efficacy of IL-17A-targeting therapeutics in HCC remain largely unknown. In this study, we found that IL-17A promoted intrahepatic and pulmonary metastasesis of HCC cells in an orthotopic implant model. Moreover, our results showed that IL-17A induced epithelial-mesenchymal transition (EMT) and promoted HCC cell colonization in vitro and in vivo, and the role of IL-17A in invasion-metastasis was dependent on activation of the AKT pathway. Remarkably, combined therapy using both secukinumab and sorafenib has better inhibition on tumour growth and metastasis compared to sorafenib monotherapy. Additionally, the combination of intratumoral IL-17A+ cells and E-cadherin predicted the outcome of patients with HCC at an early stage after hepatectomy based on tissue microarray and immunohistochemistry. In conclusion, our studies reveal that IL-17A induces early EMT and promotes late colonization of HCC metastasis by activating AKT signalling. Secukinumab is a promising candidate for clinical development in combination with sorafenib for the management of HCC., (© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Objective: To analyze the distribution and associated factors of high-risk genotypes of HPV in cervical infection among women in Shenzhen. Methods: The information on sociodemographic characteristics and HPV genotypes of HPV-positive women who participated cervical screening test from January 2014 to December 2016 was downloaded from Shenzhen Maternity and Child Healthcare Management Information System. According to the pathogenicity, the high-risk HPV genotypes were divided into 15 types including HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66 and 68; and there were 6 low-risk genotypes including HPV 6, 11, 42, 43, 44, and 81. Chi-square tests were applied to compare the proportions of high-risk HPV infection among women who had different sociodemographic characteristics. A non-conditional logistic regression model was used to analyze the associated factors for high-risk HPV infection. Results: In total, all HIV positives received HPV genotyping, with an average age of (38.08±9.38) years old. There were 9 979 (93.9%) high-risk and 645 (6.1%) low-risk HPV infections. The proportions of HPV infections for high-risk type in each year were 91.5%, 93.8%, and 95.6%, increasing with the screening years (χ(2)=54.79, P< 0.001). Multivariate logistic regression analysis showed that compared with women younger than 25 years old, women in other age groups (at age 26 to 30 years, 31 to 35 years, 36 to 40 years, 41 to 45 years, and 50 years or older) had increased risks of high-risk HPV infection, with OR (95 %CI ) of 1.67 (1.20-2.31), 1.49 (1.09-2.03), 1.71 (1.23-2.37), 1.65 (1.19-2.31), and 1.84 (1.26-2.67), respectively; compared with the married, single women had a decreased risk of high-risk HPV infection ( OR (95 %CI ): 0.71 (0.50-1.00)); women received HPV testing in 2015 and 2016 showed higher risk of high-risk HPV infection than those in 2014 ( OR (95 %CI ): 1.43 (1.17-1.74) and 2.03 (1.68-2.46)). The 5 most common HPV genotypes were HPV52 (25.1%, 2 670 cases), followed by HPV16 (19.2%, 2 041 cases), HPV58 (13.3%, 1 413 cases), HPV18 (9.9%, 1 048 cases), and HPV51 (9.3%, 993 cases). Conclusion: Age, marital status, and screening year were associated with high-risk HPV infections. Besides HPV16 and HPV18, the prevention and control on HPV infections for HPV52, HPV58, and HPV51 should be prioritized in Shenzhen area.

Photodynamic therapy (PDT) is a relatively novel type of tumor therapy method with low toxicity and limited side‑effects. The aim of the present study was to investigate the underlying mechanism and potential microRNAs (miRNAs) involved in the treatment of glioma by PDT with hematoporphyrin, a clinical photosensitizer. The photodynamic activity of hematoporphyrin on the cell viability and apoptosis of gliomas was investigated by MTT, and flow cytometry and fluorescence microscopy, respectively. Alterations in singlet oxygen and mitochondrial membrane potential were detected. The differentially expressed miRNAs and proteins were evaluated by miRNA gene chip and apoptosis‑associated protein chip, respectively. The results demonstrated that cell viability significantly decreased with hematoporphyrin concentration. PDT with hematoporphyrin significantly increased cell apoptosis at a later stage, induced the content of reactive oxygen species (ROS) and decreased the mitochondrial membrane potential, indicating that PDT with hematoporphyrin inhibited cell growth via induction of radical oxygen, decreased the mitochondrial membrane potential and induced apoptosis. The upregulated miRNAs, including hsa‑miR‑7641, hsa‑miR‑9500, hsa‑miR‑4459, hsa‑miR‑21‑5p, hsa‑miR‑663a and hsa‑miR‑205‑5p may be important in PDT‑induced cell apoptosis in glioma. Transporter 1, ATP binding cassette subfamily B member‑ and nuclear factor‑κB‑mediated apoptosis signaling pathways were the most significant pathways. Thus, the current study presents PDT as a potential therapeutic approach for the treatment of malignant glioma, and identified miRNAs for the molecular design and development of a third‑generation photosensitizer (PS).

Background: Few studies have investigated the association between puerperal women's living situation and postpartum depression. The aim of this study was to examine the association between living with parents or with parents-in-law and postpartum depression among Chinese puerperal women., Methods: A total of 1126 participants who completed questionnaire were included in our analysis. Postpartum depression status was assessed using the Edinburgh Postnatal Depression Scale. Logistic regression models were used to estimate the association between living with puerperal women's parents or with parents-in-law and risk of postpartum depression after adjustment for potential confounders., Results: The prevalence of postpartum depression among participants was 11.8%. Of the 1126 participants, 524 (46.5%) lived only with their husbands, 387 (34.4%) lived with their parents-in-law, and 215 (19.1%) lived with their parents. Compared with those living only with their husbands, puerperal women living with their parents-in-law had higher risk of postpartum depression after adjustment for potential confounders (OR=2.48; 95% CI: 1.20, 5.15). No association between living with puerperal women's parents and postpartum depression was found after adjustment for confounders (OR=1.05; 95%CI: 0.42, 2.65)., Limitations: Although we adjusted for a wide range of potential confounders, we cannot rule out the possibility of residual confounding by other unmeasured factors, such as breastfeeding, intimate partner violence, and marital relationship., Conclusions: Our findings suggest that living with parents-in-law may be a risk factor for postpartum depression among Chinese puerperal women. Future preventive interventions should include strategies that target the puerperal women who lived with parents-in-law., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Low-altitude unmanned aerial vehicles (UAV) remote sensing system overcomes the deficiencies of space and aerial remote sensing system in resolution, revisit period, cloud cover and cost, which provides a novel method for ecological research on mesoscale. This study introduced the composition of UAV remote sensing system, reviewed its applications in species, population, community and ecosystem ecology research. Challenges and opportunities of UAV ecology were identified to direct future research. The promising research area of UAV ecology includes the establishment of species morphology and spectral characteristic data base, species automatic identification, the revelation of relationship between spectral index and plant physiological processes, three-dimension monitoring of ecosystem, and the integration of remote sensing data from multi resources and multi scales. With the development of UAV platform, data transformation and sensors, UAV remote sensing technology will have wide application in ecology research.

Paraoxonase 3 (PON3) exerts prominent anti-inflammation and anti-oxidation properties mainly at the cellular level, and is primarily expressed in the liver. However, its role in HCC remains unexplored. Here, we investigated the expression pattern, clinical significance, and function of PON3 in HCC. PON3 mRNA and protein levels were respectively determined in two large cohorts using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) of tissue microarray. We found that PON3 was downregulated in most HCCs. Kaplan-Meier and log-rank test showed that PON3 downregulation predicted shorter recurrence-free survival (RFS) and overall survival (OS) time in all HCC patients, especially early-stage HCC patients. Cox regression analysis revealed that the PON3 downregulation was an independent risk factor for RFS and OS. Gain- and loss-of-function experiments revealed that PON3 suppressed cell proliferation in vivo and in vitro, which was attributed to its cell-cycle arrest effect. In addition, microarray analysis showed that some pro-proliferative genes were elevated when PON3 was knockdown, and these genes possibly involved in the underlying mechanisms. In conclusion, our studies reveal the cell proliferation inhibitory function of PON3 and offer a potential prognostic predictor and therapeutic target for HCC.

Hepatitis B virus (HBV) can integrate into the human genome, contributing to genomic instability and hepatocarcinogenesis. Here by conducting high-throughput viral integration detection and RNA sequencing, we identify 4,225 HBV integration events in tumour and adjacent non-tumour samples from 426 patients with HCC. We show that HBV is prone to integrate into rare fragile sites and functional genomic regions including CpG islands. We observe a distinct pattern in the preferential sites of HBV integration between tumour and non-tumour tissues. HBV insertional sites are significantly enriched in the proximity of telomeres in tumours. Recurrent HBV target genes are identified with few that overlap. The overall HBV integration frequency is much higher in tumour genomes of males than in females, with a significant enrichment of integration into chromosome 17. Furthermore, a cirrhosis-dependent HBV integration pattern is observed, affecting distinct targeted genes. Our data suggest that HBV integration has a high potential to drive oncogenic transformation.

Objective: To discuss the application of liver visualization technology in complex liver tumor resection at the second hepatic portal area., Methods: Clinical data of 80 cases who received surgery at the second hepatic portal area from August 2014 to September 2015 in the Third Department of Hepatic Surgery of Eastern Hepatobiliary Surgery Hospital were analyzed retrospectively. There were 58 male and 22 female patients aged from 21 to 70 years with median age of 52 years. Median maximum diameter of tumor was 7.6 cm (3.0 to 17.0 cm). Before surgery, liver dimensional graphics produced by liver visualization technology were taken on all patients to observe the relationship between intrahepatic vasculars and the liver tumor, and to calculate the intended resection range and the remaining liver volume in order to make a proper surgery plan. Suitable hepatic vascular occlusion was applied in the tumor resection. Intrahepatic vessel shape and variation, surgical operation, surgical operation time, manner and time of hepatic vascular occlusion, blood loss, liver resection volume, postoperative complications were observed., Results: There were 23 patients who changed surgery plan after liver visualization technology.There were 44 cases with single main hepatic vein compressed by tumors, 32 cases with 2 main hepatic veins, 4 cases with 3 main hepatic veins compressed by tumors.And there were 58 cases with both hepatic vein and inferior vena cava compressed by tumor. Hepatic segments 6 and 7 was removed in 12 cases, 14 cases, hepatic segments 4, 5 and 8 were removed in 8 cases.Right hepatectomy was carried out in 9 patients and left hepatectomy was carried out in 8 patients. Right trisectionectomy was carried out in 3 patients and left trisectionectomy was applied in 5 patients.Local hepatectomy was performed in 12 patients. Nine patients received associating liver partition and portal vein ligation for staged hepatectomy. Four patients underwent total hepatic vascular exclusion, while 16 patients underwent selective hepatic vascular exclusion. The median surgical time was 132 minutes(80 to 240 minutes). Median blood loss volume was 580 ml(100-5 000 ml). Median volume of hepatic resection was 750 ml(30 to 2 000 ml). One patient needed secondary surgery to stop bleeding as a result of postoperative abdominal bleeding.Complication of postoperative bile leakage occurred in 14 cases.Five patients had pleural effusion requiring invasive therapy.Four patients had ascites requiring invasive therapy. Besides, 5 patients had incisive infection while 2 patients were found with pulmonary infection after surgery and two patients occurred biliary obstruction. There was no death case occurred a result of surgery., Conclusions: Using liver visualization technology to make surgical operation plan can improve surgical safety of the second hepatic portal area and optimize the operation plan. It can also reduce the risk of blood loss and postoperative complications such as liver failure.

The epigenetic mechanism that incorporates DNA methylation alterations, histone modifications, and non-coding RNA expression has been identified as a major characteristic in distinguishing physiological and pathological settings of cancers including hepatocellular carcinoma (HCC), the third leading cause of mortality related cancer. The advance in methylation modification of chromatin elements (for both genomic DNA and histone tails) and the emerging roles of long noncoding RNA (lncRNA) have given us a better understanding of molecular mechanisms underlying HCC. Recently, methods like genome-wide lncRNA profiling and histone hallmark detection were reported to discover mass tumor-associated lncRNAs epigenetically deregulated by differential chromosome modification, mainly by genomic DNA and histone methylation. Therefore, aberrant methylation modification of certain particular lncRNA genes could be crucial events correlating with unfavorable outcomes in HCC. In addition, amount of lncRNAs could act as a manipulator for DNA methylation or a scaffold for histone modification to affect key signaling pathways in hepatocarcinogenesis. This suggests that methylation modification of chromatin elements may have functional crosstalk with lncRNA. Here, we aim to outline the emerging role of the methylation and lncRNA, and their crosstalk of molecular mechanism., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

The caudal-type homeobox 1 (CDX1) transcription factor is a member of the caudal-related homeobox transcription factor gene family and has been reported to be down-regulated in a variety of cancers. However, the expression status and significance of CDX1 in hepatocellular carcinoma (HCC) is still controversial, and little is known about the role of CDX1 in HCC·In our previous study, we investigated the expression and clinical significance of CDX1 in HCC samples from 313 HCC patients. We found CDX1 was strikingly down-regulated in HCC samples. CDX1 expression was associated with poor differentiation (P = 0.002), and patients with low CDX1 expression had a significantly poorer prognosis. A subgroup analysis revealed a difference in prognosis between groups with low and high CDX1 expression among patients who had tumors <5 cm in size and who were alpha-fetoprotein (AFP) negative. Moreover, low expression was more frequently observed in the early recurrence group (within 2 years, P = 0.002). In addition, multivariate Cox regression analysis indicated that the CDX1 expression level, tumor size, presence of hepatitis B e antigen (HBeAg), vascular invasion, and presence of hepatitis B surface antigen (HBsAg) were independent risk factors for HCC recurrence, and the CDX1 expression level, tumor size, tumor number, and presence of HBsAg were independent predictor of overall survival of HCC patients. In conclusion, the downregulation of CDX1 is associated with poor prognosis; and it may serve as a novel predictor of the prognosis of HCC patients after curative resection., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Zinc finger CCCH-type containing 15 (ZC3H15), also known as DRG family regulatory protein 1 (DFRP1), is a highly conserved eukaryotic protein that associates with active translation machinery. The aim of our study was to explore the clinical relevance and intrinsic functions of ZC3H15 in hepatocellular carcinoma (HCC). We constructed a cohort with 261 tumor and matched normal tissues from HCC patients. ZC3H15 protein and mRNA levels were determined using immunohistochemistry, western blot analysis, and quantitative polymerase chain reaction. ZC3H15 was highly expressed in the majority of HCC cases, and high ZC3H15 levels were significantly associated with high serum a-fetoprotein (AFP) levels (>20 ng/mL) and vascular invasion. Kaplan-Meier and Cox regression data indicated that elevated ZC3H15 was an independent predictor for HCC-specific disease-free survival (hazards ratio [HR], 1.789; 95% confidence interval [95% CI], 1.298-2.466 [P=0.0004]) and overall survival (HR, 1.613; 95% CI, 1.120-2.322 [P=0.0101]). Interaction of ZC3H15 with TRAF2 increased activation of NFκB signaling. These results suggest ZC3H15 is an independent prognostic marker in HCC patients that is clinicopathologically associated with tumor invasion and serum AFP levels., Competing Interests: No potential conflicts of interest were disclosed.

Oridonin (ORI) has been reported as an antiproliferation and apoptosis-inducing natural product in various cancer cells. However, the exact molecular mechanism underlying these effects remains unclear. In the present study, we demonstrated the antiproliferation effect of ORI in HCT116 cells, and analyzed the possible molecular mechanism which mediates this effect. We found that ORI inhibits proliferation, induces cell cycle arrest and apoptosis in HCT116 cells, thus also tumor growth. Mechanically, we found that ORI has no substantial effect on mRNA expression of phosphatase and tensin homologue (PTEN), but increases the total protein level of PTEN and markedly reduces the phosphorylation of PTEN; Exogenous expression of PTEN potentiates the anticancer effect of ORI, while knockdown of PTEN attenuates it. ORI also increases the phosphorylation of p38 MAPK, and p38 MAPK-specific inhibitor reduces the antiproliferation effect ORI in HCT116 cells. Moreover, inhibition of p38 MAPK increases the phosphorylation of PTEN, and reverses ORI-induced decrease of PTEN phosphorylation. Our findings suggested that ORI may be a potential anticancer drug for colon cancer, this effect may be mediated by enhancing the function of PTEN through reducing its phosphorylation, which may be resulted from the ORI-induced activation of p38 MAPK.

Oridonin (ORI), a diterpenoid purified from Rabdosia rubescens, has been reported as a promising chemotherapy drug for colon cancer treatment; yet, the precise mechanisms underlying this anticancer activity remain unclear. In the present study, we investigated the anticancer effect of ORI in HCT116 cells, and dissected the possible molecular mechanisms underlying this activity. With crystal violet staining, flow cytometry and western blot assay, we found that ORI effectively inhibited the proliferation and induced the apoptosis of HCT116 cells. Further analysis of the results indicated that BMP7 was greatly upregulated by ORI in the HCT116 cells, but its endogenous expression in FHC cells was apparently lower than that in the colon cancer cell lines. Exogenous expression of BMP7 inhibited the proliferation of the HCT116 cells, and substantially potentiated the anticancer effect of ORI. However, the specific antibody of BMP7 nearly abolished this anticancer activity of ORI in the HCT116 cells. Meanwhile, ORI exerted no significant effect on the level of phosphorylated Smad1/5/8 or total p38 MAPK, but greatly increased the level of phosphorylated p38 MAPK in the HCT116 cells. A p38 MAPK-specific inhibitor partly reversed the antiproliferative effect of BMP7 in the HCT116 cells, but prominently promoted the effect of the BMP7 antibody on proliferation. Exogenous expression of BMP7 increased the ORI-induced phosphorylation of p38 MAPK, while the BMP7 antibody almost abolished the ORI-elevated p38 MAPK phosphorylation. Our findings suggest that ORI may be an efficacious drug for colon cancer treatment. This anticancer activity of ORI may be mediated by upregulating BMP7 at least to increase the activation of p38 MAPK.