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Hepatocellular carcinoma (HCC), ranking as the fourth most prevalent cancer globally, has garnered significant attention due to its high invasiveness and mortality rates. However, drug therapies face challenges of inadequate efficacy and unclear mechanisms. Here, we propose a novel biohybrid hydrogel that targets β-klotho (KLB) for HCC treatment. As a dual-network hydrogel, this gel combines gelatin methacryloyl (GelMA) and polyvinyl alcohol (PVA) to ensure biocompatibility while enhancing controlled drug release. Notably, it exhibits good storage stability, high drug load capacity, and efficient water absorption. By introducing the HDAC3 inhibitor RGFP966, we can selectively inhibit the activation of KLB. This deactivation effectively blocks the FGF21-KLB signaling pathway and inhibits the progression of HCC. Importantly, we have successfully validated this unique phenomenon both in vivo and in vitro, providing substantial evidence for the efficacy of this hydrogel-based anti-tumor drug delivery system as a promising strategy for HCC treatment. This innovative research outcome brings new hope to the field of tumor therapy, providing a reliable theoretical foundation for future clinical applications., 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. Published by Elsevier B.V.)

Objective: Identifying early predictive indicators of symptomatic hypocalcemia in patients after thyroidectomy with neck lymph node dissection can help to identify high-risk patients, provide timely intervention, and improve prognosis., Methods: A retrospective analysis of all relevant information was conducted for patients who underwent total thyroidectomy with neck lymph node dissection at our hospital between April 2021 and September 2022. The primary outcome measure was symptomatic hypocalcemia., Results: Of the 210 patients who underwent total thyroidectomy with l neck lymph node dissection, 76 patients (36%) experienced symptoms of hypocalcemia. The analysis confirmed that the rate of parathyroid hormone (PTH) decline (OR = 238.414, 95%CI: 51.904-1095.114, P  = 0.000) was an independent risk factor for symptomatic hypocalcemia after total thyroidectomy with neck lymph node dissection. The ROC curve indicated that a PTH decline cutoff value of 0.7425 was significantly correlated with symptoms of hypocalcemia, with a sensitivity of 89% and specificity of 69%, which could effectively predict symptomatic hypocalcemia., Conclusion: A PTH decline rate greater than the cutoff value of 0.7425 is a predictive factor for symptomatic hypocalcemia in adults and may be considered as a high-risk patient and actively managed to supplement calcium as soon as possible to ensure patient safety.

Glucocorticoids (GCs) are steroid hormones fundamental to the body's normal physiological functions and are pivotal in fetal growth and development. During gestation, the mother's cortisol concentration (active GCs) escalates to accommodate the requirements of fetal organ development and maturation. A natural placental GCs barrier, primarily facilitated by 11β hydroxysteroid dehydrogenase 2, exists between the mother and fetus. This enzyme transforms biologically active cortisol into biologically inactive corticosterone, thereby mitigating fetal GCs exposure. However, during pregnancy, the mother may be vulnerable to adverse factor exposures such as stress, hypoxia, caffeine, and synthetic GCs use. In these instances, maternal serum GCs levels may surge beyond the protective capacity of the placental GCs barrier. Moreover, these adverse factors could directly compromise the placental GCs barrier, resulting in excessive fetal exposure to GCs. It is well-documented that prenatal GCs exposure can detrimentally impact the offspring's cardiovascular system, particularly in relation to blood pressure, vascular function, and heart function. In this review, we succinctly delineate the alterations in GCs levels during pregnancy and the potential mechanisms driving these changes, and also analyze the possible causes of prenatal GCs exposure. Furthermore, we summarize the current advancements in understanding the adverse effects and mechanisms of prenatal GCs exposure on the offspring's cardiovascular system., 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 © 2024 Zhao, He, Li, Deng, Zhang, Wang, Qiu and Gao.)

Gestational hypertension (PIH), especially pre-eclampsia (PE), is a common complication of pregnancy. This condition poses significant risks to the health of both the mother and the fetus. Emerging evidence suggests that epigenetic modifications, particularly DNA methylation, may play a role in initiating the earliest pathophysiology of PIH. This article describes the relationship between DNA methylation and placental trophoblast function, genes associated with the placental microenvironment, the placental vascular system, and maternal blood and vascular function, abnormalities of umbilical cord blood and vascular function in the onset and progression of PIH, as well as changes in DNA methylation in the progeny of PIH, in terms of maternal, fetal, and offspring. We also explore the latest research on DNA methylation-based early detection, diagnosis and potential therapeutic strategies for PIH. This will enable the field of DNA methylation research to continue to enhance our understanding of the epigenetic regulation of PIH genes and identify potential therapeutic targets., (© 2024. The Author(s).)

Preeclampsia (PE) is a complex human-specific complication frequently associated with placental pathology. The local renin-angiotensin system (RAS) in the human placenta, which plays a crucial role in regulating placental function, has been extensively documented. Glucocorticoids (GCs) are a class of steroid hormones. PE cases often have abnormalities in GCs levels and placental GCs barrier. Despite extensive speculation, there is currently no robust evidence indicating that GCs regulate placental RAS. This study aims to investigate these potential relationships. Plasma and placental samples were collected from both normal and PE pregnancies. The levels of angiotensin-converting enzyme (ACE), angiotensin II (Ang II), cortisol, and 11β-hydroxysteroid dehydrogenases (11βHSD) were analyzed. In PE placentas, cortisol, ACE, and Ang II levels were elevated, while 11βHSD2 expression was reduced. Interestingly, a positive correlation was observed between ACE and cortisol levels in the placenta. A significant inverse correlation was found between the methylation statuses within the 11βHSD2 gene promoter and its expression, meanwhile, 11βHSD2 expression was negatively correlated with cortisol and ACE levels. In vitro experiments using placental trophoblast cells confirmed that active GCs can stimulate ACE transcription and expression through the GR pathway. Furthermore, 11βHSD2 knockdown could enhance this activating effect. An in vivo study using a rat model of intrauterine GCs overexposure during mid-to-late gestation suggested that excess GCs in utero lead to increased ACE and Ang II levels in the placenta. Collectively, this study provides the first evidence of the relationships between 11βHSD2 expression, GCs barrier, ACE, and Ang II levels in the placenta. It not only contributes to understanding the pathological features of the placental GCs barrier and RAS under PE conditions, also provides important information for revealing the pathological mechanism of PE., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Objective: To explore the impact of anemia on the incidence of perioperative lower limb deep vein thrombosis (DVT) in patients undergoing total hip arthroplasty (THA)., Methods: A retrospective analysis was conducted on clinical data of 1 916 non-fracture patients who underwent THA between September 2015 and December 2021, meeting the selection criteria. Among them, there were 811 male and 1 105 female patients, aged between 18 and 94 years with an average of 59.2 years. Among the patients, 213 were diagnosed with anemia, while 1 703 were not. Preoperative DVT was observed in 55 patients, while 1 861 patients did not have DVT preoperatively (of which 75 patients developed new-onset DVT postoperatively). Univariate analysis was performed on variables including age, gender, body mass index (BMI), diabetes, hypertension, history of tumors, history of thrombosis, history of smoking, revision surgery, preoperative D-dimer positivity (≥0.5 mg/L), presence of anemia, operation time, intraoperative blood loss, transfusion requirement, and pre- and post-operative levels of red blood cells, hemoglobin, hematocrit, and platelets. Furthermore, logistic regression was utilized for multivariate analysis to identify risk factors associated with DVT formation., Results: Univariate analysis showed that age, gender, hypertension, revision surgery, preoperative levels of red blood cells, preoperative hemoglobin, preoperative D-dimer positivity, and anemia were influencing factors for preoperative DVT ( P <0.05). Further logistic regression analysis indicated that age (>60 years old), female, preoperative D-dimer positivity, and anemia were risk factors for preoperative DVT ( P <0.05). Univariate analysis also revealed that age, female, revision surgery, preoperative D-dimer positivity, anemia, transfusion requirement, postoperative level of red blood cells, and postoperative hemoglobin level were influencing factors for postoperative new-onset DVT ( P <0.05). Further logistic regression analysis indicated that age (>60 years old), female, and revision surgery were risk factors for postoperative new-onset DVT ( P <0.05)., Conclusion: The incidence of anemia is higher among patients with preoperative DVT for THA, and anemia is an independent risk factor for preoperative DVT occurrence in THA. While anemia may not be an independent risk factor for THA postoperative new-onset DVT, the incidence of anemia is higher among patients with postoperative new-onset DVT.

Ovarian cancer (OC) is a deadly disease. The poor prognosis and high lethality of OC are attributed to its high degrees of aggressiveness, resistance to chemotherapy and recurrence rates. Calcium ion (Ca 2+ ) signaling has received attention in recent years, as it appears to form an essential part of various aspects of cancer pathophysiology and is a potential therapeutic target for OC treatment. Disruption of normal Ca 2+ signaling pathways can induce changes in cell cycle progression, apoptosis, proliferation and migration and invasion, leading to the development of the malignant phenotype of tumors. In the present review, the main roles of ion channel/receptor/pump‑triggered Ca 2+ signaling pathways located at the plasma membrane and organelle Ca 2+ transport in OC are summarized. In addition, the potential of Ca 2+ signaling as a novel target for the development of effective treatment strategies for OC was discussed. Furthering the understanding into the role of Ca 2+ signaling in OC is expected to facilitated the identification of novel therapeutic targets and improved clinical outcomes for patients.

Background & Aims: Whether the intake of docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, is beneficial for ovarian cancer (OC) remains controversial and we hope to disentangle this puzzle using genetic data from large-scale populations in European and Asian., Methods: We employed, for the first time, a systematic Mendelian randomization (MR) design to comprehensively evaluate the causal effect of plasma DHA levels, an objective biomarker of DHA intake, on OC risk in European and then verified the extrapolation of the results in the Asian. Data in the analysis included genetic association data obtained from large-scale genome-wide association studies with 13,499 individuals for plasma DHA measurements and 66,450 individuals for OC in the European population, and 1361 individuals for plasma DHA measurements and 61,457 individuals for OC in the Asian population. The causal relationship between DHA and OC was estimated using the inverse-variance weighted approach, together with extensive validation and sensitivity analyses to verify the main results., Results: In the European population, MR evidence suggested a causal relationship between higher plasma DHA levels and lower OC risk (OR, 0.89 for OC per one-SD increment in DHA; 95% CI, 0.83 to 0.96; P = 0.003). Subgroup analysis by histological type of OC indicated that this observed association was stronger among endometrioid ovarian cancer (EOC) (OR, 0.82; 95% CI, 0.69 to 0.96; P = 0.014). A similar causal association of borderline significance was reached in the Asian replication set. The above results were consistently supported by a series of validation and sensitivity analyses., Conclusion: Our study provided robust genetic evidence for a protective association between plasma DHA levels and lower risk of OC, especially EOC, in the European population. These findings may inform prevention strategies and interventions directed towards DHA intake and OC., Competing Interests: Conflict of Interest The authors declare no potential conflicts of interest., (Copyright © 2023 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Observational studies have demonstrated that basal metabolic rate (BMR) is associated with the risk of endometrial cancer (EC) and ovarian cancer (OC). However, it is unclear whether these associations reflect a causal relationship., Objective: To reveal the causality between BMR and EC and OC, we performed the first comprehensive two-sample Mendelian randomization (MR) analyses., Methods: Genetic variants were used as proxies of BMR. GWAS summary statistics of BMR, EC and OC were obtained from the UK Biobank Consortium, Endometrial Cancer Association Consortium and Ovarian Cancer Association Consortium respectively. The inverse variance weighted method was employed as the main approach for MR analysis. A series of sensitivity analyses were implemented to validate the robustness and reliability of the results., Results: BMR was significantly related to an increased risk of EC (OR SD  = 1.49; 95% CI: 1.29-1.72; p-Value < .001) and OC (OR SD  = 1.21; 95% CI: 1.08-1.35; p-Value < .001). Furthermore, the stratified analysis indicated that BMR was positively associated with endometrioid endometrial cancer (EEC) (OR SD  = 1.45; 95% CI, 1.23-1.70; p-Value < .001), clear cell ovarian cancer(CCOC) (OR SD  = 1.89; 95% CI:1.35-2.64; p-Value < .001) and endometrioid ovarian cancer risk (EOC) (OR SD  = 1.45; 95% CI: 1.12-1.88; p-Value = .005). However, there were no significant associations of BMR with invasive mucinous ovarian cancer (IMOC), high-grade serous ovarian cancer (HGSOC) and low-grade serous ovarian cancer (LGSOC). The robustness of the above results was further verified in sensitivity analyses., Conclusion: The MR study provided etiological evidence for the positive association of BMR with the risk of EC, EEC, OC, CCOC and EOC. But this study did not provide enough evidence suggesting the causal associations of BMR with IMOC, HGSOC and LGSOC., (© 2023 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Background: Regulatory T cells (Tregs) play an important role in regulation of immune response and immunologic tolerance in cancer. Gastrointestinal cancer is still a leading cause of cancer-related death in the world. This study aimed to detect Tregs in patients with gastrointestinal cancer., Methods: In this study, 45 gastric cancer patients, 50 colorectal cancer patients and 50 healthy controls were enrolled. Flow cytometry was used to detect CD4 + CD25 hi CD127 low Tregs, CD4 + CD25 hi , and CD4 + cells in peripheral blood. Cytokine interleukin-10 (IL-10) and transforming growth factor-β1 (TGF-β1) in peripheral blood and in the supernatant of Tregs cultures were measured by enzyme linked immunosorbent assay., Results: Compared with healthy controls, the levels of CD4 + CD25 hi CD127 low Tregs and CD4 + CD25 hi cells increased significantly in patients with gastrointestinal cancer. Patients with gastrointestinal cancer also showed a significantly increased levels of IL-10 and TGF-β1 in both peripheral blood and CD4 + CD25 hi CD127 low Tregs culture medium., Conclusion: The present study firstly demonstrated that gastrointestinal patients have a compromised immune status where the CD4 + CD25 hi CD127 low Tregs, as well as levels of IL-10 and TGF-β1 are elevated. The data offered new information for understanding the immunological features of gastrointestinal patients, as well as provided new insights into approaches to develop new immunotherapies for patients with gastrointestinal cancer., (© 2023. The Author(s).)

Background: Liver metastasis is an important cause of death in patients with colorectal cancer (CRC). Increasing evidence indicates that microRNAs (miRNAs) are involved in the pathogenesis of colorectal cancer liver metastasis (CRLM). This study is aimed at exploring the potential miRNA-mRNA regulatory network., Methods: From the GEO database, we downloaded the microarray datasets GSE56350 and GSE73178. GEO2R was used to conduct differentially expressed miRNAs (DEMs) between CRC and CRLM using the GEO2R tool. Then, GO and KEGG pathway analysis for differentially expressed genes (DEGs) performed via DAVID. A protein-protein interaction (PPI) network was constructed by the STRING and identified by Cytoscape. Hub genes were identified by miRNA-mRNA network. Finally, the expression of the hub gene expression was assessed in the GSE81558., Results: The four DEMs (hsa-miR-204-5p, hsa-miR-122-5p, hsa-miR-95-3p, and hsa-miR-552-3p) were identified as common DEMs in GSE56350 and GSE73178 datasets. The SP1 was likely to adjust the upregulated DEMs; however, the YY1 could regulate both the upregulated and downregulated DEMs. A total of 3925 genes (3447 upregulated DEM genes and 478 downregulated DEM genes) were screened. These predicted genes were mainly linked to Platinum drug resistance, Cellular senescence, and ErbB signaling pathway. Through the gene network construction, most of the hub genes were found to be modulated by hsa-miR-204-5p, hsa-miR-122-5p, hsa-miR-95-3p, and hsa-miR-552-3p. Among the top 20 hub genes, the expression of CREB1, RHOA, and EGFR was significantly different in the GSE81558 dataset., Conclusion: In this study, miRNA-mRNA networks in CRLM were screened between CRC patients and CRLM patients to provide a new method to predict for the pathogenesis and development of CRC., Competing Interests: The authors declare that there is no conflict of interest., (Copyright © 2023 Si-ming Zhang et al.)

Background: A fundamental principle of pain management is to determine the distribution and causes of pain. However, relevant data among postoperative cancer patients based on a large amount of data remain sparse., Objective: We aimed to investigate the incidence of postoperative pain in cancer patients and to explore the associated risk factors., Methods: We retrospectively collected information on postoperative pain-evaluation records of cancer patients who underwent surgery between 1 January 2014 and 31 December 2019. Descriptive statistics were presented, and multinominal logistic regression analysis was performed to explore the risk factors associated with postoperative pain., Results: Among the 11,383 patients included in the study, the incidence of mild/moderate to severe pain at the 24th hour after surgery was 74.9% and 18.3%, respectively. At the 48th and 72nd hour after surgery, the incidence of mild pain increased slightly, while the incidence of moderate to severe pain continued to decrease. Female patients experienced a higher risk of pain (ORs: 1.37-1.58). Undergoing endoscopic surgery was associated with a higher risk of pain (ORs: 1.40-1.56). Patients with surgical sites located in the respiratory system had a higher risk of pain compared to in the digestive system (ORs: 1.35-2.13), and other patients had a relatively lower risk of pain (ORs: 0.11-0.61)., Conclusion: The majority of cancer patients experienced varying degrees of postoperative pain but may not receive adequate attention and timely treatment. Female, young age and endoscopic surgery were associated with increased pain risk, and effective identification of these high-risk groups had positive implications for enhanced postoperative pain management.

Intracellular calcium (Ca 2+ ) concentration ([Ca 2+ ]i) is implicated in proliferation, invasion, and metastasis in cancerous tissues. A variety of oncologic therapies and some candidate drugs induce their antitumor effects (in part or in whole) through the modulation of [Ca 2+ ]i. Cervical cancer is one of most common cancers among women worldwide. Recently, major research advances relating to the Ca 2+ signals in cervical cancer are emerging. In this review, we comprehensively describe the current progress concerning the roles of Ca 2+ signals in the occurrence, development, and prognosis of cervical cancer. It will enhance our understanding of the causative mechanism of Ca 2+ signals in cervical cancer and thus provide new sights for identifying potential therapeutic targets for drug discovery., Competing Interests: The authors declare no conflicts of interest.

Objectives: Synergism between the metabolic syndrome (MetSyn) components and cancer incidence still remains inconclusive. We aimed to investigate the unique or joint role of MetSyn components in cancer onset., Design: We conducted a prospective nested case-control study based on the China Health and Retirement Longitudinal Study., Setting: An ongoing national representative longitudinal study included follow-up survey of people aged 45 years and older and their partners living in private households in China., Participants: There were 17 708 individuals included at baseline. A total of 306 incident cancers was identified during the follow-up. For every case, we used incidence-density sampling to match three concurrent cancer-free controls by age, sex, and both duration and calendar time of follow-up. Exposure of interest was any MetSyn diagnosis at baseline., Results: We observed elevation in cancer risk associated with MetSyn in a significant way when the number of MetSyn components was over three (OR: 1.88; 95% CI: 1.19 to 2.97), or when components contained any of elevated triglycerides (OR: 1.61; 95% CI: 1.05 to 2.48), reduced high-density lipoprotein (HDL) cholesterol (OR: 2.33; 95% CI: 1.40 to 3.86) or elevated blood pressure (OR: 1.65; 95% CI: 1.04 to 2.59) after consistent multiple adjustments in different models. The highest cancer risk was in the female reproductive system and breast cancer (OR: 4.22; 95% CI: 1.62 to 10.95) followed by digestive system (OR: 1.67; 95% CI: 1.11 to 2.53). Sensitivity analyses showed similar results after first follow-up was excluded. However, any unique MetSyn component was not associated with increased cancer risk. Interestingly, the reduced HDL was observed to be widely associated with over twofold increased risk of cancer, only when together with other MetSyn components., Conclusion: MetSyn components, in a collaborative manner rather than its unique component, were associated with elevated cancer risk. Not only obesity but even subtle metabolic disturbances may give rise to cancer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The placenta is a vital organ for fetal development, providing the fetus with nutrients, oxygen, and other important factors. Placenta is rich in blood vessels. Abnormal placental vascular function and blood circulation may lead to insufficient blood supply to the fetus in the uterus, leading to serious consequences such as pregnancy complications, fetal distress and even stillbirth. Pregnancy-induced hypertension (PIH) and gestational diabetes mellitus (GDM) are common complications of pregnancy. Recent studies report that pregnancy complications are often accompanied by changes in placental vascular structure and function. What are the physiological characteristics of human placental blood vessels? What are the pathological changes in the state of PIH and GDM? What are the relationships between these pathological changes and the occurrence of these pregnancy complications? Answers to these questions not only increase the understanding of placental vascular characteristics, but also provide important information for revealing the pathological mechanism of PIH and GDM. This article will summarize the research on the pathological changes of placental blood vessels in PIH and GDM, hoping to further unravel the physiological and pathological characteristics of placental blood vessels in the state of PIH and GDM, provide information for guiding clinical treatment for PIH and GDM., 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 © 2022 Lei, Zhao, Li, Ji, Xu, Sun, Chen, Qiu and Gao.)

Prenatal hypoxia is the most common stress in mid-late gestation that usually arise from maternal, placental and/or fetal factors. As a multifunctional organ enabling optimal fetal growth, placenta must adapt to diverse environmental stressors. Excessive glucocorticoids exposure is known to have adverse effects on fetal growth. The fetus is shielded by a placental glucocorticoid barrier by 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2). However, the effects and underlying mechanisms of intrauterine hypoxia on placental glucocorticoid barrier are largely unknown. This study was the first to determine the effects and its mechanisms. Pregnant rats were exposed to hypoxia (10.5% O2) from gestational day (GD)10-20. At GD20, expression of 11-βHSD2 were determined in placenta, and corticosterone levels were measured in maternal and fetal plasma. Prenatal hypoxia disrupted the placental glucocorticoid barrier by suppressing 11-βHSD2 expression. Meanwhile, the decreased 11-βHSD2 was correlated with an increased DNA methylation within its gene promoter. Together, these results indicated that prenatal hypoxia impair placental glucocorticoid barrier, was strongly associated with reprogrammed 11-βHSD2 expression via a DNA methylation-mediated epigenetic mechanism., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Although radical cystectomy (RC) is the clinical practice guideline-recommended treatment of muscle-invasive bladder cancer (MIBC), bladder-sparing trimodality therapy (TMT) has emerged as a valid treatment option. Findings comparing the survival outcomes for MIBC patients who underwent RC and TMT are inconclusive., Objective: We designed a large hospital-based multicohort study to compare the effectiveness of TMT with RC., Methods: Information on deaths was jointly retrieved from EMR (electronic medical record), cause of death registry, and chronic disease surveillance as well as study-specific questionnaire. To avoid the systematical difference between patients who received two modalities, RC-MIBC cohort was propensity score-matched to TMT-MIBC cohort, and the Cox proportional hazard regression was used to calculate the overall survival (OS) and disease-specific survival (DSS)., Results: There were 891 MIBC patients treated with RC and another 891 MIBC patients who underwent with TMT in the propensity score matching. Comparable effectiveness between two modalities was observed for DSS (HR, 1.20; 95% confidence interval (CI), 0.94 to 1.49) and OS (HR, 1.17; 95% CI, 0.91 to 1.43) according to multiple adjustment after a median follow-up of approximately 9.3 years. However, a relatively higher mortality rate around 5 years after TMT treatment was found compared to RC (HR, 1.26; 95% CI, 1.01 to 1.53). The respective 5-year OS rates were 69% and 73% for TMT cohort and RC cohort, respectively., Conclusions: Our findings supported that MIBC patients with TMT yielded survival outcomes comparable to MIBC patients who underwent RC overall. Treatment options should be suggested considering patients' age and willingness., Competing Interests: Authors declared that they had no conflicts of interest., (Copyright © 2022 Junlan Qiu et al.)

Background: Epidemiological evidence about hormone replacement therapy and colorectal carcinogenesis by demographic and clinical traits remains unclear. We aimed to assess this postulated association in a large multicentre study and further explore the modification effect by BMI and others., Methods: We retrospectively collected records of women diagnosed with colorectal cancer (CRC) at the age of 50 years and older during 2014-2017 and their HRT dispensing prior to CRC diagnosis in three tertiary hospitals in China. CRC cases were matched with controls at a ratio of 1:3 using nearest neighbour propensity scores matching to better control for the remaining imbalance between groups, which generated a total of 824 cases with 2472 controls., Results: Our study confirmed the inversed association between colorectal cancer risk and hormone replacement therapy (OR, 0.62; 95% CI, 0.54-0.75), which was more prominent among women having multiple HRT dispenses (OR, 0.60; 95% CI, 0.52-0.76). Furthermore, significant associations were consistently observed for the short-term (OR, 0.69; 95% CI, 0.57-0.88), middle-term (OR, 0.51; 95% CI, 0.41-0.66), and long-term HRT users (OR, 0.70; 95% CI, 0.43-0.90). Estrogen-related regimen reduced CRC risk more than progestogen-only. We, for the first time, found that the modifying effect of BMI on HRT use and CRC risk was in different ways when BMI was categorized by a medium level of 27., Conclusion: Our findings mainly suggest that there might be a different mechanism for the reversed association between HRT and colorectal tumorigenesis by BMI level, providing thoughts on clinical treatment of CRC., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

The biological active form of vitamin D3, 1α,25-dehydroxyvitamin D3 [1α,25(OH) 2 D 3 ], exerts pleiotropic effects including bone mineralization, anti-tumor, as well as immunomodulator. This study aimed to explore the potential impact of 1α,25(OH) 2 D 3 on tumor-associated macrophages (TAMs) infiltration in ovarian cancer. Firstly, human monocytic THP-1 cells were differentiated into macrophages (M0) in the presence of phorbol 12-myristate 13-acetate (PMA). In Vivo , 1α,25(OH) 2 D 3 not only reversed the polarization of M2 macrophages, but also decreased the proliferation and migration abilities of ovarian cancer cells induced by M2 macrophages supernatant. Furthermore, 1α,25(OH) 2 D 3 dramatically decreased the secretion of TGF-β1 and MMP-9 in M2 macrophages. However, no significant effect was observed in 1α,25(OH) 2 D 3 treated M1 macrophages. In Vivo , vitamin D3 had an inhibitive effect of 1α,25(OH) 2 D 3 -treated M2 macrophages on tumorigenesis. In addition, we conducted the association of TAMs with the poor prognosis of patients with ovarian cancer by meta-analysis, which suggested the higher proportion of M2 macrophages was related to the poorer prognosis in ovarian cancer. Collectively, these results identified distinct roles of 1α,25(OH) 2 D 3 treated M1 and M2 macrophages on cell proliferation and migration abilities in ovarian cancer.

Objective: Dexamethasone (DEX), a synthetic glucocorticoid, has been widely used as a medication for premature delivery. However, the side effects of antenatal DEX treatment on fetal bone development, as well as the underlying mechanisms still remain to be elucidated. Here, we aimed to explore the effects and the related mechanisms of antenatal DEX exposure during late pregnancy on fetal bone growth and development., Methods: Pregnant Sprague-Dawley rats were randomly divided into DEX group and vehicle group from gestational day 14 (GD14). Pregnant rats in DEX group were intraperitoneally injected once with DEX (200 µg/kg body weight) on GD14, 16, 18, and 20. The vehicle group rats were administered the same amount of normal saline at the same time. Pregnant rats were anesthetized at GD21 to harvest fetal femurs for analysis., Results: Antenatal DEX treatment delayed fetal skeletal growth via inhibiting extracellular matrix (ECM) synthesis and downregulating insulin-like growth factor 1 (IGF1) signaling. Several components of IGF1 signaling pathway, including IGF1 receptor, insulin receptor substrate, as well as serine-threonine protein kinase, were down-regulated in fetal growth plate chondrocytes following DEX treatment., Conclusion: This study indicated that antenatal DEX treatment-retarded fetal skeletal growth was associated with the down-regulation of IGF1 signaling in growth plate chondrocytes, providing important information about the impact of antenatal DEX application four courses on premature infant.

Purpose: The prevalence of multi-morbidities with colorectal cancer (CRC) is known to be increasing. Particularly prognosis of CRC patients co-diagnosed with metabolic syndrome (MetSyn) was largely unknown. We aimed to examine the death risk of CRC patients according to the multiple MetSyn morbidities., Materials and Methods: We identified CRC patients with MetSyn from the electronic medical records (EMR) systems in five independent hospitals during 2006-2011. Information on deaths was jointly retrieved from EMR, cause of death registry and chronic disease surveillance as well as study-specific questionnaire. Cox proportional hazards regression was used to calculate the overall and CRC-specific hazards ratios (HR) comparing MetSyn CRC cohort with reference CRC cohort., Results: A total of 682 CRC patients in MetSyn CRC cohort were identified from 24 months before CRC diagnosis to 1 month after. During a median follow-up of 92 months, we totally observed 584 deaths from CRC, 245 being in MetSyn cohort and 339 in reference cohort. Overall, MetSyn CRC cohort had an elevated risk of CRC-specific mortality (HR, 1.49; 95% confidence interval [CI], 1.07 to 1.90) and overall mortality (HR, 1.43; 95% CI, 1.09 to 1.84) compared to reference cohort after multiple adjustment. Stratified analyses showed higher mortality risk among women (HR, 1.87; 95% CI, 1.04 to 2.27) and specific components of MetSyn. Notably, the number of MetSyn components was observed to be significantly related to CRC prognosis., Conclusion: Our findings supported that multi-morbidities of MetSyn associated with elevated death risk after CRC. MetSyn should be considered as an integrated medical condition more than its components in CRC prognostic management.

Background: Non-small cell lung cancer (NSCLC) ranks first for mortality among all malignancies. Squamous cell carcinoma (SCC) is one of the main types of NSCLC. Previous studies have found that fibroblast growth factor 9 ( FGF9 ) is closely related to lung SCC via different molecular regulatory mechanisms. This study aimed to explore the relationship between microRNA-155-5p (miR-155-5p) and FGF9 gene expression and their effects on the proliferation and invasion of lung SCC through experiments, in order to provide theoretical basis for overcoming this disease., Methods: Fluorescence quantitative polymerase chain reaction was employed for the detection miR-155-5p and FGF9 expression in lung SCC tissues (n=40) and the corresponding adjacent normal tissues. The expression of FGF9 in the cancerous and adjacent tissues was detected by western blot. Transwell assay used to verify the effect of miR-155-5p on FGF-induced invasion and migration. Finally, subcutaneous tumor formation experiments in nude mice were used to verify how miR-155-5p and FGF9 affect the proliferative ability of lung SCC cells., Results: The results of fluorescence quantitative PCR revealed that miR-155-5p and FGF9 were expressed at high and low levels, respectively, in lung SCC tissue samples relative to normal adjacent tissue samples. Western blot analysis of 6 lung SCC tissue samples revealed a significantly reduced level of FGF9 . Correlation analysis uncovered that miR-155-5p and FGF9 share a significant negative correlation in lung SCC. At the messenger RNA and protein levels miR-155-5p could negatively regulate the expression of FGF9 . Bioinformatics and dual luciferase reporter assay results confirmed FGF9 to be a downstream regulatory gene targeted by miR-155-5p. Our in vitro and in vivo results demonstrated that FGF9 overexpression exerted a significant inhibitory effect on miR-155-5p's ability to promote lung cancer cell growth, invasion, and proliferation., Conclusions: Our results show that miR-155-5p, as an oncogene, negative regulates FGF9 expression to promote SCC occurrence and development in the lungs., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/jtd-21-882). The authors have no conflicts of interest to declare., (2021 Journal of Thoracic Disease. All rights reserved.)

Long noncoding RNA NUTM2A-AS1 has been shown to be dysregulated in non-small cell lung carcinoma. To date, it is unclear whether NUTM2A-AS1 plays a role in gastric cancer progression. The purpose of this study is to elucidate the molecular mechanism of the role of NUTM2A-AS1 in gastric cancer. mRNA and protein levels were measured by RT-qPCR and western blot methods. Invasion ability was examined by transwell assay. Cell viability was determined by MTT assay. Dual-luciferase assay, RNA pull down, and RNA immunoprecipitation were used to confirm direct binding of between miR-376a and NUTM2A-AS1 or TET1. Xenografting tumor assay and TCGA analysis showed the contributory role of NUTM2A-AS1 in vivo and human clinical setting. Our results suggested that NUTM2A-AS1 promoted cell viability, invasion, and drug resistance of gastric cancer cells, which was largely rescued by miR-376a. More interestingly, TET1 and HIF-1A were negatively regulated by miR-376a. TET1 could interact with HIF-1A to modulate PD-L1. Finally, we revealed that PD-L1 was key to NUTM2A-AS1- and miR-376a-mediated tumorigenesis and drug resistance. In summary, our conclusions facilitate us understand the underlying mechanism and develop novel treatment strategy for gastric cancer., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: It is known that there are insufficient prognostic factors for non-small cell lung cancer (NSCLC). It was reported that PD-L1 was a prognostic factor for NSCLC,and c-Myc regulated the expression of PD-L1. Herein, we investigated c-Myc and PD-L1 expression and their association with overall survival (OS) in NSCLC., Methods: Formalin-fixed paraffin-embedded specimens were obtained from 128 patients with surgically resected primary NSCLC. Immunohistochemistry was used to assess the expression of PD-L1 and c-Myc in this study. Pearson's Chi squared test or Fisher's exact test was used to analyze the correlation of the expression of PD-L1 and c-Myc with clinicopathologic features. The relationship between OS and the expression of PD-L1 and c-Myc was evaluated by the Kaplan-Meier method and Cox proportional hazards model, respectively., Results: Positive expression of PD-L1 was detected in 59 patients (46.1%). Patients with negative expression of PD-L1 had remarkably longer OS than those with positive expression of PD-L1. The positive expression rate of c-Myc in NSCLC accounted for 58.6% (75/128) and its expression was significantly more frequent in males (p = 0.002) and patients with lymph node metastasis (p = 0.029). PD-L1 expression was positively correlated with c-Myc expression (r = 0.459, p < 0.001). The PD-L1 and c-Myc double-positive group had a worse prognosis than other subgroups (p < 0.05), and the PD-L1 and c-Myc double-negative group had a better OS than other subgroups (p < 0.05)., Conclusion: Conjoint analysis of the expression of PD-L1 and c-Myc was a better prognostic approach for NSCLC patients.

Objective: To compare the therapeutic effects of ultrasound-guided and non-guided catheter-directed thrombolysis in the treatment of deep venous thrombosis of lower extremity., Methods: From August 2015 to April 2016, 60 patients with lower extremity deep venous thrombosis were randomly divided into two groups ( n = 30 for each) to receive catheter-directed thrombolysis. Group A was treated under the ultrasound guidance, while Group B was treated without guidance., Results: Catheter-directed thrombolysis was successfully performed by only one intubate in Group A but by 5.9 intubates in Group B. It took 15.4 ± 3.2 min in Group A, significantly less than that in Group B (30.8 ± 6.6 min, p < 0.05). The incidences of hematoma were also remarkably different between the two groups (3.33% vs. 26.67%, p = 0.026). No pseudoaneurysm or arteriovenous fistula was found in Group A, but there were two cases of pseudoaneurysm and two cases of arteriovenous fistula in Group B (both 6.67%, p = 0.492). The circumference differences of the affected limb between before and after thrombolysis were 49.47 ± 2.484 mm in Group A, significantly higher than that in Group B (28.40 ± 2.856 mm, p < 0.001). After treatment, the venous unobstructed improvement rates and deep vein patency rate were both better than those in Group B (77 + 2.603% vs. 57.23 + 1.828% and 80% vs. 46.67%, respectively; p < 0.001). There were only three cases of PTS in Group A (10%, 3/30), but there were 11 cases in Group B (36.67%, 11/30)., Conclusion: Ultrasound-guided catheter-directed thrombolysis has advantages, with improvement of venous patency and decrease of the incidence of PTS.

Aim: To investigate the efficacy and safety of dendritic cell (DC) vaccine combined with cytokine-induced killer (CIK) cell therapy in colorectal carcinoma (CRC)., Patients and Methods: PubMed, Embase, and Cochrane Library databases were searched systematically for clinical trials of DC vaccine and CIK cell therapy combined with chemotherapy for CRC. The primary and secondary endpoints were overall survival (OS) and disease-free survival (DFS), respectively. Pooled risk ratios were used to assess the treatment efficacy. Both random and fixed effects models were used for statistical analysis. The study population consisted of 871 CRC patients enrolled in four trials., Results: OS and DFS were significantly improved in patients who received chemotherapy combined with DC vaccine and CIK cells, and no severe adverse events were shown., Conclusions: The study demonstrated that the addition of DC vaccine and CIK cell therapy to chemotherapy is feasible and effective in patients with CRC., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

ADP-ribosylation factor 6 (Arf6), a member of the ADP-ribosylation factor family, is overexpressed in different types of cancer cell and promotes invasion, metastasis and drug resistance. However, the potential functions of Arf6 in gastric cancer (GC), and the molecular mechanism underlying these functions, remain to be fully elucidated. In the present study, the results demonstrated that in vitro knockdown of Arf6 decreased proliferation, colony formation, migration and invasion in SGC-7901 cells. Arf6 knockdown also markedly decreased the activity of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. Furthermore, knockdown of Arf6 was associated with elevated chemosensitivity of SGC-7901 cells to 5-fluorouracil through inactivation of the ERK1/2 signaling pathway. Taken together, these results suggest that Arf6 is involved in regulating proliferation, migration, invasion and drug resistance in GC, and may be a potential therapeutic target for the treatment of GC.

The aim of this study was to assess sensitivity and responsiveness of power Doppler ultrasound (PDUS) in detecting enthesitis for ankylosing spondylitis (AS) patients compared to clinical examinations. Twenty AS patients initiating etanerceptunderwent clinical and PDUS examinations of six bilateral entheseal sites at baseline and after 1, 2 and 3 months of treatment. Clinical and PDUS examinations identified at least one entheseal lesion in nine (45%) and 19 (95%) patients, respectively. Furthermore, of 240 entheseal sites examined in these 20 patients, PDUS detected 123 entheseal lesions (51.3% of sites), compared with only 47 entheseal lesions (19.6%) detected by clinical examination (P<0.05). The entheseal lesions found on PDUS were most commonly identified by calcification (33.3%), tendon edema (29.2%), abnormal blood flow (25.8%), a thickened tendon (22.1%), cortical irregularity (12.9%), bony erosions (9.6%) and bursitis at the tendon insertion to the bone cortex (7.1%). Improvements in clinical symptoms and laboratory parameters, and significant decreases in PDUS scores were observed following treatment with etanercept. Improvements in PDUS scores continued during follow-up in patients who entered remission following treatment. In conclusion, PDUS improves detection of structural and inflammatory abnormalities of the enthesis in AS compared to physical examination. In addition, PDUS may be useful inascertaining medications.