Infiltrative vessel co-optive growth pattern induced by IQGAP3 overexpression promotes microvascular invasion in hepatocellular carcinoma.

PURPOSE: Microvascular invasion (MVI) is a major unfavorable prognostic factor for intrahepatic metastasis and postoperative recurrence of hepatocellular carcinoma (HCC). However, the intervention and preoperative prediction for MVI remain clinical challenges due to the absent precise mechanism and molecular marker(s). Herein, we aimed to investigate the mechanisms underlying vascular invasion that can be applied to clinical intervention for MVI in HCC. EXPERIMENTAL DESIGN: The histopathological characteristics of clinical MVI+/HCC specimens were analyzed using multiplex immunofluorescence staining. The liver orthotopic xenograft mouse model and mechanistic experiments on human patient-derived HCC cell lines, including co-culture modeling, RNA-sequencing, and proteomic analysis, were employed to investigate MVI­related genes and mechanisms. RESULTS: IQGAP3 overexpression was correlated significantly with MVI status and reduced survival in HCC. Upregulation of IQGAP3 promoted MVI+-HCC cells to adopt an infiltrative vessel co-optive growth pattern and accessed blood capillaries by inducing detachment of activated hepatic stellate cells (HSCs) from the endothelium. Mechanically, IQGAP3 overexpression contributed to HCC vascular invasion via a dual mechanism, in which IQGAP3 induced HSCs activation and disruption of the HSCs-endothelial interaction via upregulation of multiple cytokines and enhanced the trans-endothelial migration of MVI+-HCC cells by remodeling the cytoskeleton by sustaining GTPase Rac1 activity. Importantly, systemic delivery of IQGAP3-targeting small interfering RNA nanoparticles disrupted the infiltrative vessel co-optive growth pattern and reduced the MVI of HCC. CONCLUSIONS: Our results revealed a plausible mechanism underlying IQGAP3-mediated microvascular invasion in HCC, and provided a potential target to develop therapeutic strategies to treat HCC with MVI.

Effects of oral oligopeptide preparation and exercise intervention in older people with sarcopenia: a randomized controlled trial.

BACKGROUND: Nutrition and exercise are important interventions for sarcopenia. There were few studies on oral oligopeptide nutrition preparations combined with exercise to intervene in the older people with sarcopenia. The aim of this study was to verify the effectiveness of oligopeptide nutrition preparation combined with exercise intervention on the older people with sarcopenia in community. METHODS: A total of 219 subjects aged 65 years or older with sarcopenia were randomly divided into 4 groups. The nutrition group (n = 58) was given individualized nutrition education and oral oligopeptide nutrition preparation. The exercise group (n = 50) received exercise intervention. The combined group (n = 52) received both oral nutrition preparation and exercise interventions. The control group (n = 59) only received individualized nutrition education. The nutrition preparation can provide energy 185kcal and protein 24.2g per day. The exercise intervention including warm-up exercise, resistance exercise and aerobic exercise, the training time was 60min for 5 times every week. The intervention lasted for 16 weeks. Hand grip strength, gait speed, body composition and hematology parameters were measured before and after intervention. RESULTS: A total of 159 subjects completed the study. Compared with baseline, the left grip strength and 6-m walking speed of the subjects in nutrition group increased significantly after the intervention, and the grip strength of both hands in exercise group and combined group increased significantly. The body weight of the subjects in nutrition group, exercise group and combined group increased significantly after intervention, but no increase in soft lean mass (SLM) and skeletal muscle mass (SMM) was observed in any of the four groups. The fat-free mass (FFM) of the legs of the control group, exercise group and nutrition group decreased after intervention, and only the FFM of the legs of the combined group maintained the level before the intervention. CONCLUSION: Both oral peptide nutrition and exercise interventions can improve the muscle strength or function of the older people with sarcopenia. However, there were no increases in muscle mass observed. TRIAL REGISTRATION: ChiCTR, ChiCTR2100052135. Registered 20 October 2021, https://www.chictr.org.cn/showproj.html?proj=135743.

Nuclear translocation of cleaved PCDH9 impairs gastric cancer metastasis by downregulating CDH2 expression.

Loss of Protocadherin 9 (PCDH9) is associated with the metastasis and the prognosis of gastric cancer patients, while the molecular mechanism of PCDH9-impaired gastric cancer metastasis remains unclear. Here we show that PCDH9 is cleaved in gastric cancer cells. Intracellular domain of PCDH9 translocates into nucleus, where it interacts with DNA methyltransferase 1 (DNMT1) and increases DNMT1 activity. Activated DNMT1 downregulates cadherin 2 (CDH2) expression by increasing DNA methylation at its promoter, thereby dampening the migration and in vivo metastasis of gastric cancer cells. In addition, the levels of nuclear PCDH9 correlate with CDH2 expression, lymph node metastasis, and the prognosis of gastric cancer patients. Our finding demonstrates a unique mechanism of nuclear PCDH9-impaired gastric cancer metastasis by promoting DNA methylation of CDH2 promoter.

CircMMP2(6,7) Cooperates with ß-Catenin and PRMT5 to Disrupt Bone Homeostasis and Promote Breast Cancer Bone Metastasis.

The bone is the most common site of distant metastasis of breast cancer, which leads to serious skeletal complications and mortality. Understanding the mechanisms underlying breast cancer bone metastasis would provide potential strategies for the prevention and treatment of breast cancer bone metastasis. In this study, we identified a circular RNA that we named circMMP2(6,7) that was significantly upregulated in bone metastatic breast cancer tissues and correlated with breast cancer-bone metastasis. Upregulation of circMMP2(6,7) dramatically enhanced the metastatic capability of breast cancer cells to the bone via inducing bone metastatic niche formation by disrupting bone homeostasis. Mechanistically, circMMP2(6,7) specifically bound to the promoters of bone-remodeling factors calcium-binding protein S100A4 and carbohydrate-binding protein LGALS3 and formed a complex with ß-catenin and arginine methyltransferase PRMT5, eliciting histone H3R2me1/H3R2me2s-induced transcriptional activation. Treatment with GSK591, a selective PRMT5 inhibitor, effectively inhibited circMMP2(6,7)/ß-catenin/PRMT5 complex-induced breast cancer bone metastasis. These findings reveal a role for circMMP2(6,7) in bone homeostasis disruption and shed light on the mechanisms driving breast cancer bone metastasis. SIGNIFICANCE: Upregulation of bone-remodeling factors S100A4 and LGALS3 mediated by a circMMP2(6,7)/ß-catenin/PRMT5 complex generates a niche that supports breast cancer bone metastasis, identifying PRMT5 as a promising target for treating metastasis.

Lysine lactylation (Kla) might be a novel therapeutic target for breast cancer.

BACKGROUND: Histone lysine lactylation (Kla) is a newly identified histone modification, which plays a crucial role in cancer progression. Hence, we determined the prognostic value of Kla in breast cancer (BC). METHODS: We obtained RNA expression profiles of BC from The Cancer Genome Atlas (TCGA), following screening out Kla-specific genes. Furthermore, we determined the prognostic value of Kla by constructing a cox model based on Kla-specific genes. Subsequently, we identified expression of lactate accumulation-related genes and prognostic Kla-specific genes through Human Protein Atlas (HPA), and further performed a correlation analysis based on their expression. Meanwhile, we explored the effects of Kla on BC tumor microenvironment (TME), drug therapy and immunotherapy. Moreover, we predicted the pathways influenced by Kla via gene set enrichment analysis (GSEA). RESULTS: A total of 1073 BC samples and 112 normal controls were obtained from TCGA, and 23 tumor samples were removed owing to inadequate clinical information. We identified 257 differentially expressed Kla-specific genes (DEKlaGs) in BC. A cox model involved with CCR7, IGFBP6, NDUFAF6, OVOL1 and SDC1 was established, and risk score could be visualized as an independent biomarker for BC. Meanwhile, Kla was remarkably associated with BC immune microenvironment, drug therapy and immunotherapy. Kla was identified to be related to activation of various BC-related KEGG pathways. CONCLUSION: In conclusion, Kla contributes to drug resistance and undesirable immune responses, and plays a crucial role in BC prognosis, suggesting that Kla was expected to be a new therapeutic target for BC.

Neuroendocrine tumors in a patient with multiple endocrine neoplasia type 1 syndrome: A case report and review of the literature.

RATIONALE: Hyperparathyroidism is caused by parathyroid tumors combined with gastroenteropancreatic tumors and pituitary tumors, which is common in patients with multiple endocrine neoplasia 1 syndrome (MEN-1). As its main pathogenic factor involves genetic mutations, it can cause a variety of different clinical symptoms. However, cases with negative genetic testing results and multiple nonfunctional malignant neuroendocrine tumors (NETs) with metastasis are relatively rare. PATIENT CONCERNS: A 33-year-old man was admitted to the hospital for hyperparathyroidism. Imaging examination revealed multiple nodules in the parathyroid gland, pancreas, thymus, and adrenal gland, and multiple metastases to the lung, liver, thoracolumbar, as well as mediastinal lymph nodes. DIAGNOSES: After multidisciplinary consultation, this patient was diagnosed with MEN-1 syndrome with various original tumors and multiple systemic metastases. INTERVENTIONS: The patient underwent parathyroid tumor resection and metastasis biopsy. OUTCOMES: The patient received denosumab and sorafenib treatment. LESSONS: As an autosomal dominant hereditary disease, MEN-1 patients present with parathyroid hyperplasia, pancreatic and intestinal tumors, pituitary tumors, and so on, which are caused by genetic mutations. These patients would have hyperparathyroidism, hypoglycemia, gastric ulcer, and gastrointestinal diseases. However, some patients with MEN-1 syndrome cannot be diagnosed by genetic testing and simultaneously present with multiple nonfunctional NETs with systemic metastasis. This increases the difficulty of diagnosis and the subsequent treatment.

Comparison of immune cell profiles associated with heatstroke, sepsis, or cardiopulmonary bypass: Study protocol for an exploratory, case-control study trial.

Introduction: Heatstroke is a life-threatening illness involving extreme hyperthermia and multi-organ failure, and it is associated with high mortality. The immune profiles of heatstroke have not been fully elucidated, and diagnostic and prognostic biomarkers of heatstroke are lacking. This study will analyze immune profiles in heatstroke patients as they differ from profiles in patients with sepsis or aseptic inflammation patients in order to identify diagnostic and prognostic biomarkers. Methods: This exploratory, case-control study will recruit patients with heatstroke, patients with sepsis, patients undergoing cardiopulmonary bypass as well as healthy controls at West China Hospital of Sichuan University from 1 January 2023 to 31 October 2023. The four cohorts will be profiled at one time point in terms of lymphocytes, monocytes, natural killer cells, and granulocytes using flow cytometry, and cell populations will be visualized in two dimensions using t-SNE and UMAP, then clustered using PhenoGraph and FlowSOM. Gene expression in the specific immune cell populations will also be compared across the four cohorts, as will levels of plasma cytokines using enzyme-linked immunosorbent assays. Outcomes in the cohorts will be monitored during 30-day follow-up. Discussion: This trial is, to our knowledge, the first attempt to improve the diagnosis of heatstroke and prediction of prognosis based on immune cell profiles. The study is also likely to generate new insights into immune responses during heatstroke, which may help clarify the disease process and lay the foundation for immunotherapies.

SLC27A4-mediated selective uptake of mono-unsaturated fatty acids promotes ferroptosis defense in hepatocellular carcinoma.

Aberrant lipid metabolism mediated by the selective transport of fatty acids plays vital roles in cancer initiation, progression, and therapeutic failure. However, the biological function and clinical significance of abnormal fatty acid transporters in human cancer remain unclear. In the present study, we reported that solute carrier family 27 member 4 (SLC27A4) is significantly overexpressed in 21 types of human cancer, especially in the fatty acids-enriched microenvironment surrounding hepatocellular carcinoma (HCC), breast cancer, and ovarian cancer. Upregulated SLC27A4 expression correlated with shorter overall and relapse-free survival of patients with HCC, breast cancer, or ovarian cancer. Lipidomic analysis revealed that overexpression of SLC27A4 significantly promoted the selective uptake of mono-unsaturated fatty acids (MUFAs), which induced a high level of MUFA-containing phosphatidylcholine and phosphatidylethanolamine in HCC cells, consequently resulting in resistance to lipid peroxidation and ferroptosis. Importantly, silencing SLC27A4 significantly promoted the sensitivity of HCC to sorafenib treatment, both in vitro and in vivo. Our findings revealed a plausible role for SLC27A4 in ferroptosis defense via lipid remodeling, which might represent an attractive therapeutic target to increase the effectiveness of sorafenib treatment in HCC.

Downregulation of BASP1 Promotes Temozolomide Resistance in Gliomas via Epigenetic Activation of the FBXO32/NF-κB/MGMT Axis.

The chemoresistance of temozolomide-based therapy is a serious limitation for lasting effective treatment of gliomas, while the underlying mechanisms remain unclear. In this study, we showed that downregulation of BASP1 correlated negatively with the response to temozolomide therapy and disease-free survival (DFS) of patients with gliomas. Silencing BASP1 significantly enhanced the temozolomide resistance of glioma cells both in vitro and in vivo through repair of temozolomide-induced DNA damage via activation of the FBXO32/NF-κB/MGMT axis in both MGMT-methylated and -unmethylated gliomas. We demonstrated that loss of BASP1 resulted in removal of TRIM37/EZH2 complex-induced repressive histone modifications, including H2A-ub and H3K27me3, but addition of WDR5/MLL complex-mediated active histone modifications, including H3K4me3 and H3K9ac, on the FBXO32 promoter, which elicited in FBXO32 upregulation and further activated NF-κB/MGMT signaling via ubiquitin-dependent degradation of IκBα. Importantly, treatment with OICR-9429, an antagonist of the WDR5-MLL interaction, impaired the FBXO32/NF-κB/MGMT axis-mediated repair of temozolomide-induced DNA damage, leading to significant apoptosis of BASP1-downregulated glioma cells. These findings shed light on the molecular mechanism underlying BASP1-mediated epigenetic transcriptional repression and may represent a potential strategy in the fight against temozolomide-resistant gliomas. IMPLICATIONS: BASP1 downregulation promotes temozolomide resistance in gliomas through WDR5/MLL complex-mediated epigenetic activation of the FBXO32/NF-κB/MGMT axis, providing new target for improving outcomes in patients with temozolomide-resistant gliomas.

Telehealth utilization in U.S. medicare beneficiaries aged 65 years and older during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has become a serious public health concern for older adults and amplified the value of deploying telehealth solutions. The purpose of this study was to investigate telehealth offered by providers among U.S. Medicare beneficiaries aged 65 years and older during the COVID-19 pandemic. METHODS: This cross-sectional study analyzed Medicare beneficiaries aged 65 years and older using data from the Medicare Current Beneficiary Survey, Winter 2021 COVID-19 Supplement ([Formula: see text]). We identified variables that were associated with telehealth offered by primary care physicians and beneficiaries' access to the Internet through a multivariate classification analysis utilizing Random Forest machine learning techniques. FINDINGS: For study participants interviewed by telephone, 81.06% of primary care providers provided telehealth services, and 84.62% of the Medicare beneficiaries had access to the Internet. The survey response rates for each outcome were 74.86% and 99.55% respectively. The two outcomes were positively correlated ([Formula: see text]). The Our machine learning model predicted the outcomes accurately utilizing 44 variables. Residing area and race/ethnicity were most informative for predicting telehealth coverage, and Medicare-Medicaid dual eligibility and income were most informative for predicting Internet access. Other strong correlates included age, ability to access basic needs and certain mental and physical health conditions. Interactions were found among statuses of residing area, age, Medicare Advantage and heart conditions that intensified the disparity of outcomes. CONCLUSIONS: We found that telehealth offered by providers likely increased during the COVID-19 pandemic for older beneficiaries, providing important access to care for certain subgroups. Policymakers must continue to identify effective means of delivering telehealth services, modernize the framework of regulatory, accreditation and reimbursement, and address disparities in access to telehealth with a particular focus on underserved communities.

The Fully Mediating Role of Psychological Resilience between Self-Efficacy and Mental Health: Evidence from the Study of College Students during the COVID-19 Pandemic.

Student populations are susceptible to the COVID-19 pandemic and may easy develop mental health problems related to their immaturity of psychological development and fluctuation of mood. However, little has been known about the effects of the pandemic on college students and the associated influencing factors. This study aimed to explore the role of psychological resilience as a mediator between general self-efficacy and mental health. A cross-sectional survey was conducted with 480 Chinese college students from 12 universities in Hunan province of China. The participants responded anonymously to the Generalized Self-Efficacy Scale (GSES), the Chinese version of the Resilience Scale for College Students (RSCS), and the 12-item General Health Questionnaire (GHQ-12). Hierarchical linear regression and structural equation modeling were used in this study. The average of GSES and RSCS scores of college students were 25.00 ± 4.68 and 137.97 ± 15.50, which were at a medium level. The average score for the GHQ-12 was 1.59 ± 1.59, and 22.03% of the college students scored ≥ 3 on the GHQ-12, indicating that they were at risk of developing mental disorders. According to the analyses of mediation effect, psychological resilience played a fully mediating role in the relationship between general self-efficacy and mental health. In conclusion, Chinese college students were at high risk of developing mental disorders during the COVID-19 period. General self-efficacy was positively associated with psychological resilience, and psychological resilience played a fully mediating role in the relationship between general self-efficacy and mental health. Future studies and interventions should aim to promote psychological resilience and general self-efficacy.

Selective adsorption of antibiotics on manganese oxide-loaded biochar and mechanism based on quantitative structure-property relationship model.

In this study, MnCl2-impregnated biomass was oxygen-limited pyrolyzed to produce manganese oxide-loaded biochar (MBC), its adsorption behaviors and influencing factors on tetracycline (TTC), norfloxacin (NOR), and sulfamethoxazole (SMX) were systematically investigated. Three antibiotics exhibited enhanced adsorption behavior on MBC, with maximum adsorption capacity as accurately described by Sips isotherm: TTC (534 mg/g) > NOR (67 mg/g) > SMX (28 mg/g). Hydrogen bonding, n/π-π interactions, electrostatic interaction, surface coordination, and hydrophobic interaction are the major mechanisms for the improved adsorption. Manganese oxide particles on MBC promoted surface coordination and hydrogen bonding. Antibiotic molecules with more hydroxyl oxygen-containing functional groups are more susceptible to migrate to biochar surfaces and to be adhered. Moreover, the quantitative structure-property relationship (QSPR) model was constructed and revealed that hydrogen bonding and π-π interactions were crucial for tetracycline antibiotics selective adsorption. Hence, MBC was a prospective adsorbent with promising applications for antibiotic removal in sewage processing.

Mental health resources and its equity in Central South of China: A case study of Hunan Province.

OBJECTIVES: Mental health resources are an important basis for coping with mental health services. The equity is an important index of a reasonable allocation of health resources. This study aims to evaluate the mental health resources and its equity allocation in Hunan Province, which is one of the typical central south areas of China, so as to provide reference for the development of mental health in China and other areas. METHODS: Data related to mental health resources was obtained from the Project of Mental Health Resources in Hunan Province, which was conducted by the Department of Hunan Mental Health Center in 2019. The Gini coefficient, the Theil index and other indicators were employed to quantitatively evaluate the equity of mental health resources' allocation. RESULTS: By the end of 2018, there were a total of 141 mental health institutions in Hunan Province of China, the bed density was 5.31 beds per 10,000 people, the ratio of doctors to nurses was 2.20, the number of outpatients of mental health institutions was 1288,047 per year. The mental health resources' allocation in terms of demographic dimension were in a preferred status with the Gini values all less than 0.3, and the Gini values for mental health resources`allocation in terms of geographical dimension ranged from 0.24 to 0.35. The Theil index for mental health allocation in terms of demographic dimension was lower than 0.05, and the Theil index for mental health allocation in terms of geographical dimension ranged from 0.04 to 0.11. CONCLUSIONS: The shortage of mental health resources is still the priority issue to be increased and optimized by policy-makers in Hunan in the future, especially the human resources. Moreover, the utilization of mental health resources was low though its equity was fair. Policy-makers need to consider the high utilization and geographical accessibility of health resources among different regions to ensure people in different regions could get access to available health services.

Large Oncosome-Loaded VAPA Promotes Bone-Tropic Metastasis of Hepatocellular Carcinoma Via Formation of Osteoclastic Pre-Metastatic Niche.

Tumor-derived extracellular vesicles (EVs) function as critical mediators in selective modulation of the microenvironment of distant organs to generate a pre-metastatic niche that facilitates organotropic metastasis. Identifying the organ-specific molecular determinants of EVs can develop potential anti-metastatic therapeutic targets. In the current study, large oncosomes (LOs), atypically large cancer-derived EVs, are found to play a crucial role in facilitating bone-tropic metastasis of hepatocellular carcinoma (HCC) cells by engineering an osteoclastic pre-metastatic niche and establishing a vicious cycle between the osteoclasts and HCC cells. Transmembrane protein, VAMP-associated protein A (VAPA), is significantly enriched on LOs surface via direct interaction with LOs marker αV-integrin. VAPA-enriched LOs-induced pre-metastatic education transforms the bone into a fertile milieu, which supports the growth of metastatic HCC cells. Mechanically, LOs-delivered VAPA integrates to plasma membrane of osteoclasts and directly interacts with and activates neural Wiskott-Aldrich syndrome protein (N-WASP) via dual mechanisms, consequently resulting in ARP2/3 complex-mediated reorganization of actin cytoskeleton in osteoclasts and osteoclastogenesis. Importantly, treatment with N-WASP inhibitor 187-1-packaged LOs (LOs/187-1) dramatically abolishes the inductive effect of VAPA-enriched LOs on pre-metastatic niche formation and precludes HCC bone metastasis. These findings reveal a plausible mechanism for bone-tropism of HCC and can represent a potential strategy to prevent HCC bone metastasis.

Access to care through telehealth among U.S. Medicare beneficiaries in the wake of the COVID-19 pandemic.

Background: The coronavirus disease 2019 (COVID-19) public health emergency has amplified the potential value of deploying telehealth solutions. Less is known about how trends in access to care through telehealth changed over time. Objectives: To investigate trends in forgone care and telehealth coverage among Medicare beneficiaries during the COVID-19 pandemic. Methods: A cross-sectional study design was used to analyze the outcomes of 31,907 Medicare beneficiaries using data from three waves of survey data from the Medicare Current Beneficiary Survey COVID-19 Supplement (Summer 2020, Fall 2020, and Winter 2021). We identified informative variables through a multivariate classification analysis utilizing Random Forest machine learning techniques. Findings: The rate of reported forgone medical care because of COVID-19 decreased largely (22.89-3.31%) with a small increase in telehealth coverage (56.24-61.84%) from the week of June 7, 2020, to the week of April 4 to 25, 2021. Overall, there were 21.97% of respondents did not know whether their primary care providers offered telehealth services; the rates of forgone care and telehealth coverage were 11.68 and 59.52% (11.73 and 81.18% from yes and no responses). Our machine learning model predicted the outcomes accurately utilizing 43 variables. Informative factors included Medicare beneficiaries' age, Medicare-Medicaid dual eligibility, ability to access basic needs, certain mental and physical health conditions, and interview date. Conclusions: This cross-sectional survey study found proliferation and utilization of telehealth services in certain subgroups during the COVID-19 pandemic, providing important access to care. There is a need to confront traditional barriers to the proliferation of telehealth. Policymakers must continue to identify effective means of maintaining continuity of care and growth of telehealth services.

Extract of Marsdenia tenacissima (Roxb.) Moon [Apocynaceae] Suppresses Hepatocellular Carcinoma by Inhibiting Angiogenesis.

The extract of Marsdenia tenacissima (Roxb.) Moon [Apocynaceae] (MTE) has shown a significant anti-cancer effect on hepatocellular carcinoma (HCC), but its mechanism remains unclear. In this study, we used transcriptomics methods to investigate the underlying mechanism of MTE against HCC. Both MHCC97H and HepG2 cell lines were treated with MTE. The cell viability and migration were measured using the cell counting kit-8 assay and transwell assay. RNA-sequencing was used to identify differentially expressed genes (DEGs) between HepG2 cells treated with and without MTE. The expression levels of selected DEGs-vascular endothelial growth factor-A (VEGFA), platelet-derived growth factor receptor-ß (PDGFRB), and von Willebrand factor (VWF)-were verified by RT-PCR and Western blot. The effect of conditioned medium from HCC cells with MTE treatment (CM-MTE) on blood vessels was observed by tube formation assay of HUVECs and chick chorioallantoic membrane (CAM) assay. A mouse model of HCC patient-derived tumor xenograft (PDX) was established and treated with MTE. The effect of MTE on the growth and angiogenesis of HCC-PDX was analyzed. The results demonstrated that MTE inhibited the viability and migration of HCC cells. RNA-seq showed that MTE treatment downregulated multiple genes associated with metabolism and angiogenesis. The expression levels of VEGFA, VWF, PDGFB, and PDGFRB in HCC cells were significantly suppressed by MTE. Meanwhile, MTE effectively inhibited the tube-forming capability of HUVECs and the angiogenesis of chick CAM. In vivo experiments revealed that the extract reduced tumor volume, inhibited the proliferation of HCC cells, and expanded the necrotic area of the tumor. Immunohistochemical results showed that the expression levels of CD31, PDGFB, VEGF, VWF, and PDGFRB in the HCC-PDX tumor tissues were all downregulated by MTE in a dose-dependent manner. Taken together, MTE could inhibit angiogenesis by repressing the expression of VEGF, VWF, PDGF, and PDGFRB in HCC cells, a mechanism that may enable MTE to counter HCC development.

The Chemopreventive Role of ß-Elemene in Cholangiocarcinoma by Restoring PCDH9 Expression.

Background: ß-Elemene, an effective anticancer component isolated from the Chinese herbal medicine Rhizoma Zedoariae, has been proved to have therapeutic potential against multiple cancers by extensive clinical trials and experimental research. However, its preventive role in cholangiocarcinoma (CCA) and the mechanisms of action of ß-elemene on CCA need to be further investigated. Methods: A thioacetamide (TAA)-induced pre-CCA animal model was well-established, and a low dosage of ß-elemene was intragastrically (i.g.) administered for 6 months. Livers were harvested and examined histologically by a deep-learning convolutional neural network (CNN). cDNA array was used to analyze the genetic changes of CCA cells following ß-elemene treatment. Immunohistochemical methods were applied to detect ß-elemene-targeted protein PCDH9 in CCA specimens, and its predictive role was analyzed. ß-Elemene treatment at the cellular or animal level was performed to test the effect of this traditional Chinese medicine on CCA cells. Results: In the rat model of pre-CCA, the ratio of cholangiolar proliferation lesions was 0.98% ± 0.72% in the control group, significantly higher than that of the ß-elemene (0. 47% ± 0.30%) groups (p = 0.0471). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the top 10 pathways affected by ß-elemene treatment were associated with energy metabolism, and one was associated with the cell cycle. ß-Elemene inactivated a number of oncogenes and restored the expression of multiple tumor suppressors. PCDH9 is a target of ß-elemene and displays an important role in predicting tumor recurrence in CCA patients. Conclusions: These findings proved that long-term use of ß-elemene has the potential to interrupt the progression of CCA and improve the life quality of rats. Moreover, ß-elemene exerted its anticancer potential partially by restoring the expression of PCDH9.

LncRNA CTBP1-DT-encoded microprotein DDUP sustains DNA damage response signalling to trigger dual DNA repair mechanisms.

Sustaining DNA damage response (DDR) signalling via retention of DDR factors at damaged sites is important for transmitting damage-sensing and repair signals. Herein, we found that DNA damage provoked the association of ribosomes with IRES region in lncRNA CTBP1-DT, which overcame the negative effect of upstream open reading frames (uORFs), and elicited the novel microprotein DNA damage-upregulated protein (DDUP) translation via a cap-independent translation mechanism. Activated ATR kinase-mediated phosphorylation of DDUP induced a drastic 'dense-to-loose' conformational change, which sustained the RAD18/RAD51C and RAD18/PCNA complex at damaged sites and initiated RAD51C-mediated homologous recombination and PCNA-mediated post-replication repair mechanisms. Importantly, treatment with ATR inhibitor abolished the effect of DDUP on chromatin retention of RAD51C and PCNA, thereby leading to hypersensitivity of cancer cells to DNA-damaging chemotherapeutics. Taken together, our results uncover a plausible mechanism underlying the DDR sustaining and might represent an attractive therapeutic strategy in improvement of DNA damage-based anticancer therapies.

NKX2-8/PTHrP Axis-Mediated Osteoclastogenesis and Bone Metastasis in Breast Cancer.

Bone metastasis is one of the most common distant metastasis of breast cancer, which could cause serious skeletal disease and increased cancer-related death. Therefore, identification of novel target(s) to develop therapeutics would improve patient outcomes. The role of NKX2-8 in modulation of bone remodeling was determined using osteoclastogenesis and micro-CT assays. The expression of NKX2-8 was examined via immunohistochemistry analysis in 344 breast cancer tissues. The mechanism underlying NKX2-8-mediated PTHrP downregulation was investigated using biotinylated deactivated Cas9 capture analysis, chromatin immunoprecipitation, co-immunoprecipitation assays. A bone-metastatic mouse model was used to examine the effect of NKX2-8 dysregulation on breast cancer bone metastasis and the impact of three PTHrP inhibitor on prevention of breast cancer bone metastasis. The downregulated expression of NKX2-8 was significantly correlated with breast cancer bone metastasis. In vivo bone-metastatic mouse model indicated that silencing NKX2-8 promoted, but overexpressing NKX2-8 inhibited, breast cancer osteolytic bone metastasis and osteoclastogenesis. Mechanistically, NKX2-8 directly interacted with HDAC1 on the PTHrP promoter, which resulted in a reduction of histone H3K27 acetylation, consequently transcriptionally downregulated PTHrP expression in breast cancer cells. Furthermore, targeting PTHrP effectively inhibited NKX2-8-downregulation-mediated breast cancer bone metastasis. Taken together, our results uncover a novel mechanism underlying NKX2-8 downregulation-mediated breast cancer bone metastasis and represent that the targeting PTHrP might be a tailored treatment for NKX2-8 silencing-induced breast cancer bone metastasis.

Integrated Analysis of Glutathione Metabolic Pathway in Pancreatic Cancer.

Metabolic enzyme-genes (MEs) play critical roles in various types of cancers. However, MEs have not been systematically and thoroughly studied in pancreatic cancer (PC). Global analysis of MEs in PC will help us to understand PC progressing and provide new insights into PC therapy. In this study, we systematically analyzed RNA sequencing data from The Cancer Genome Atlas (TCGA) (n = 180 + 4) and GSE15471 (n = 36 + 36) and discovered that metabolic pathways are disordered in PC. Co-expression network modules of MEs were constructed using weighted gene co-expression network analysis (WGCNA), which identified two key modules. Both modules revealed that the glutathione signaling pathway is disordered in PC and correlated with PC stages. Notably, glutathione peroxidase 2 (GPX2), an important gene involved in glutathione signaling pathway, is a hub gene of the key modules. Analysis of immune microenvironment components reveals that PC stage is associated with M2 macrophages, the marker gene of which is significantly correlated with GPX2. The results indicated that GPX2 is associated with PC progression, providing new insights for future targeted therapy.