Body Roundness Index and All-Cause Mortality Among US Adults.

Importance: Obesity, especially visceral obesity, is an established risk factor associated with all-cause mortality. However, the inadequacy of conventional anthropometric measures in assessing fat distribution necessitates a more comprehensive indicator, body roundness index (BRI), to decipher its population-based characteristics and potential association with mortality risk. Objective: To evaluate the temporal trends of BRI among US noninstitutionalized civilian residents and explore its association with all-cause mortality. Design, Setting, and Participants: For this cohort study, information on a nationally representative cohort of 32 995 US adults (age ≥20 years) was extracted from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 and NHANES Linked Mortality File, with mortality ascertained through December 31, 2019. Data were analyzed between April 1 and September 30, 2023. Exposures: Biennial weighted percentage changes in BRI were calculated. Restricted cubic spline curve was used to determine optimal cutoff points for BRI. Main Outcome and Measures: The survival outcome was all-cause mortality. Mortality data were obtained from the Centers for Disease Control and Prevention website and linked to the NHANES database using the unique subject identifier. Weibull regression model was adopted to quantify the association between BRI and all-cause mortality. Results: Among 32 995 US adults, the mean (SD) age was 46.74 (16.92) years, and 16 529 (50.10%) were women. Mean BRI increased gradually from 4.80 (95% CI, 4.62-4.97) to 5.62 (95% CI, 5.37-5.86) from 1999 through 2018, with a biennial change of 0.95% (95% CI, 0.80%-1.09%; P < .001), and this increasing trend was more obvious among women, elderly individuals, and individuals who identified as Mexican American. After a median (IQR) follow-up of 9.98 (5.33-14.33) years, 3452 deaths (10.46% of participants) from all causes occurred. There was a U-shaped association between BRI and all-cause mortality, with the risk increased by 25% (hazard ratio, 1.25; 95% CI, 1.05-1.47) for adults with BRI less than 3.4 and by 49% (hazard ratio, 1.49; 95% CI, 1.31-1.70) for those with BRI of 6.9 or greater compared with the middle quintile of BRI of 4.5 to 5.5 after full adjustment. Conclusions and Relevance: This national cohort study found an increasing trend of BRI during nearly 20-year period among US adults, and importantly, a U-shaped association between BRI and all-cause mortality. These findings provide evidence for proposing BRI as a noninvasive screening tool for mortality risk estimation, an innovative concept that could be incorporated into public health practice pending consistent validation in other independent cohorts.

Trends in urine lead and associated mortality in US adults: NHANES 1999-2018.

Objectives: This study aimed to describe the trends of urine lead among US adults aged ≥45 years and to explore its association with all-cause and disease-specific mortality. Methods: This study enrolled 9,669 participants from the National Health and Nutrition Examination Survey, 1999-2018. Trends in urine lead were described by logistic regression analysis using the survey cycle as a continuous variable. Cox proportional hazard regression analyses were used to quantify the association between urine lead and mortality. Results: There was an obvious decline in urine lead concentrations from 1.203 µg/L (95% confidence interval [CI]: 1.083-1.322) in 1999-2000 to 0.478 µg/L (95% CI: 0.433-0.523) in 2017-2018, and this decline was statistically significant (P < 0.001). Referring to the first tertile of urine lead concentrations, risk magnitude for all-cause mortality was significantly and linearly increased after adjustment (P = 0.026 and 0.020 for partially and fully adjusted models, respectively), and significance was attained for the comparison of the third vs. first tertile after full adjustment (hazard ratio [HR]: 1.17, 95% CI: 1.01 to 1.35). Treating urine lead continuously, the risk for all-cause mortality was statistically significant (HR: 1.18 and 1.19, 95% CI: 1.01 to 1.39 and 1.00 to 1.40 for partially and fully adjusted models). For cardiovascular disease-specific and cancer-specific mortality, there was no hint of statistical significance. Conclusions: Our findings indicated that urine lead exhibited a declining trend from 1999-2000 to 2017-2018 in US adults aged ≥45 years, and high urine lead was a significant and independent risk factor for all-cause mortality.

TOP2A inhibition reverses drug resistance of hepatocellular carcinoma to regorafenib.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death attributed to high frequency of metastasis and multiple drug resistance. We aim to examine the underlying molecular mechanism and to seek potential strategies to reverse primary/acquired resistance to regorafenib. Topoisomerase IIα (TOP2A) is critical for tumorigenesis and carcinogenesis. Clinically, high-TOP2A expression was correlated to shorter overall survival (OS) of patients, but its role in drug resistance of HCC remains unknown. Here, we screened the expression profiling of TOP2A in HCC and identified TOP2A as an upregulated gene involved in the resistance to regorafenib. Sustained exposure of HCC cells to regorafenib could upregulate the expression of TOP2A. Silencing TOP2A enhanced HCC cells' sensitivity to regorafenib. TOP2A inhibition by doxorubicin or epirubicin synergized with regorafenib to suppress the growth of sorafenib-resistant HCC tumors that possessed the sorafenib-resistant features both in vitro and in vivo. Thus, targeting TOP2A may be a promising therapeutic strategy to alleviate resistance to regorafenib and thus improving the efficacy of HCC treatment.

Adaptive antitumor immune response stimulated by bio-nanoparticle based vaccine and checkpoint blockade.

BACKGROUND: Interactions between tumor and microenvironment determine individual response to immunotherapy. Triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC) have exhibited suboptimal responses to immune checkpoint inhibitors (ICIs). Aspartate ß-hydroxylase (ASPH), an oncofetal protein and tumor associated antigen (TAA), is a potential target for immunotherapy. METHODS: Subcutaneous HCC and orthotopic TNBC murine models were established in immunocompetent BALB/c mice with injection of BNL-T3 and 4 T1 cells, respectively. Immunohistochemistry, immunofluorescence, H&E, flow cytometry, ELISA and in vitro cytotoxicity assays were performed. RESULTS: The ASPH-MYC signaling cascade upregulates PD-L1 expression on breast and liver tumor cells. A bio-nanoparticle based λ phage vaccine targeting ASPH was administrated to mice harboring syngeneic HCC or TNBC tumors, either alone or in combination with PD-1 blockade. In control, autocrine chemokine ligand 13 (CXCL13)-C-X-C chemokine receptor type 5 (CXCR5) axis promoted tumor development and progression in HCC and TNBC. Interactions between PD-L1+ cancer cells and PD-1+ T cells resulted in T cell exhaustion and apoptosis, causing immune evasion of cancer cells. In contrast, combination therapy (Vaccine+PD-1 inhibitor) significantly suppressed primary hepatic or mammary tumor growth (with distant pulmonary metastases in TNBC). Adaptive immune responses were attributed to expansion of activated CD4+ T helper type 1 (Th1)/CD8+ cytotoxic T cells (CTLs) that displayed enhanced effector functions, and maturation of plasma cells that secreted high titers of ASPH-specific antibody. Combination therapy significantly reduced tumor infiltration of immunosuppressive CD4+/CD25+/FOXP3+ Tregs. When the PD-1/PD-L1 signal was inhibited, CXCL13 produced by ASPH+ cancer cells recruited CXCR5+/CD8+ T lymphocytes to tertiary lymphoid structures (TLSs), comprising effector and memory CTLs, T follicular helper cells, B cell germinal center, and follicular dendritic cells. TLSs facilitate activation and maturation of DCs and actively recruit immune subsets to tumor microenvironment. These CTLs secreted CXCL13 to recruit more CXCR5+ immune cells and to lyse CXCR5+ cancer cells. Upon combination treatment, formation of TLSs predicts sensitivity to ICI blockade. Combination therapy substantially prolonged overall survival of mice with HCC or TNBC. CONCLUSIONS: Synergistic antitumor efficacy attributable to a λ phage vaccine specifically targeting ASPH, an ideal TAA, combined with ICIs, inhibits tumor growth and progression of TNBC and HCC.

Bio-nanoparticle based therapeutic vaccine induces immunogenic response against triple negative breast cancer.

Triple negative breast cancer (TNBC) is more aggressive and has a poorer prognosis than other sub-types of breast tumors. This study elucidates how aspartate beta-hydroxylase (ASPH) network promotes drug resistance, and immunotherapy targeting ASPH may improve the efficacy of Doxorubicin (DOX) therapy. An orthotopic model of breast cancer generated by 4T1 cells in immunocompetent mice was used to explore efficacy of immunotherapy in combination with DOX chemotherapy. We evaluated mRNA and protein expression in cultured tumor cells and tissue, as well as assessed cell proliferation, apoptosis, soluble factors/cytokine production, immune cell population diversity and function. We observed that ASPH expression enables TNBC cells to exhibit primary resistance to DOX induced single-/double-strand breaks (SSB/DSB) and enhanced proliferation and survival. Specific bio-nanoparticle based therapeutic vaccine (BNP-TV) promoted ASPH uptake by and maturation of DCs. This BNP-TV combined with DOX induces immunogenic cell death (ICD) in orthotopic xenograft tumors and significantly suppressed primary mammary tumor growth and distant multi-organ metastases. Immunogenic cell death induced by BNP-TV targeting ASPH combined with DOX provides opportunities to treat a highly resistant and metastatic form of breast cancer.

Multi-organ metastasis as destination for breast cancer cells guided by biomechanical architecture.

A majority of breast cancer patients die of widespread aggressive multidrug-resistant tumors. Aspartate ß-hydroxylase (ASPH) is an α-ketoglutarate-dependent dioxygenase and oncofetal antigen involved in embryogenesis. To illustrate if ASPH could be targeted for metastatic breast cancer, embedded and on-top three-dimensional (3-D) cultures, 3-D invasion, mammosphere formation, immunofluorescence, immunohistochemistry, Western blot, co-IP and microarray were conducted. In vitro metastasis was developed to imitate how cancer cells invade basement membrane at the primary site, transendothelially migrate, consequently colonize and outgrow at distant sites. Orthotopic and experimental pulmonary metastatic (tail vein injection) murine models were established using stable breast cancer cell lines. Cox proportional hazards regression models and Kaplan-Meier plots were applied to assess clinical outcome of breast cancer patients. In adult non-cancerous breast tissue, ASPH is undetectable. Pathologically, ASPH expression re-emerged at ductal carcinoma in situ (DCIS), and enhanced with disease progression, from early-stage invasive ductal carcinoma (IDC) to late-stage carcinoma. ASPH at moderate to high levels contribute to aggressive molecular subtypes, early relapse or more frequent progression and metastases, whereas substantially shortened overall survival and disease-free survival of breast cancer patients. Through direct physical interactions with A disintegrin and metalloproteinase domain-containing protein (ADAM)-12/ADAM-15, ASPH could activate SRC cascade, thus upregulating downstream components attributed to multifaceted metastasis. ASPH-SRC axis initiated pro-invasive invadopodium formation causing breakdown/disorganization of extracellular matrix (ECM), simultaneously potentiated epithelial-mesenchymal transition (EMT), induced cancer stem cell markers (CD44 and EpCAM), enhanced mammosphere formation and intensified 3-dimentional invasion. Oncogenic SRC upregulated matrix metallopeptidases (MMPs) were assembled by invadopodia, acting as executive effectors for multi-step metastasis. ASPH-SRC signal guided multi-organ metastases (to lungs, liver, bone, spleen, lymph nodes, mesentery or colon) in immunocompromised mice. Malignant phenotypes induced by ASPH-SRC axis were reversed by the third-generation small molecule inhibitor (SMI) specifically against ß-hydroxylase activity of ASPH in pre-clinical models of metastatic breast cancer. Collectively, ASPH could activate ADAMs-SRC-MMPs cascades to promote breast cancer tumor progression and metastasis. ASPH could direct invadopodium construction as a biomechanical sensor and pro-metastatic outlet. ASPH-mediated cancer progression could be specifically/efficiently subverted by SMIs of ß-hydroxylase activity. Therefore, ASPH emerges as a therapeutic target for breast cancer.

Endothelial progenitor cells-derived exosomal microRNA-21-5p alleviates sepsis-induced acute kidney injury by inhibiting RUNX1 expression.

The role of microRNA-21-5p (miR-21-5p) in sepsis-induced acute kidney injury (AKI) has been seldom discussed. Therefore, the objective of this present study was to investigate the mechanism of endothelial progenitor cells-derived exosomes (EPCs-exos) in sepsis-induced AKI via miR-21-5p/runt-related transcription factor 1 (RUNX1) axis. miR-21-5p was downregulated and RUNX1 was upregulated in the kidney of cecal ligation and puncture (CLP) rats, and miR-21-5p targeted RUNX1. Elevation of miR-21-5p improved renal function and renal tissue pathological damage, attenuated serum inflammatory response, as well as reduced apoptosis and oxidative stress response in renal tissues, and regulated endothelial glycocalyx damage marker proteins syndecan-1 and heparanase-1 in CLP rats. Overexpression of RUNX1 abolished the impacts of elevated miR-21-5p in CLP rats. Also, EPCs-exos upregulated miR-21-5p expression, and functioned similar to elevation of miR-21-5p for CLP rats. Downregulating miR-21-5p partially reversed the effects of EPCs-exos on sepsis-induced AKI. Collectively, our study suggests that EPCs release miR-21-5p-containing exosomes to alleviate sepsis-induced AKI through RUNX1 silencing.

HIF-1α inhibits mitochondria-mediated apoptosis and improves the survival of human adipose-derived stem cells in ischemic microenvironments.

BACKGROUND: Human adipose mesenchymal stem cells (hADSCs) show poor survival after transplantation, limiting their clinical application. Tissue regeneration resulting from stem cell treatment may be caused by attenuation of hypoxia-inducible factor-1α (HIF-1α). In this study, we constructed hADSCs stably expressing HIF-1α and investigated the potential effects of HIF-1α expression in the ischemic microenvironment on mitochondrial apoptosis and survival of hADSCs, and studied the mechanisms involved. METHOD: Apoptosis was induced by an ischemic microenvironment in vitro. ADSCs with stable HIF-1α expression were established. Cell survival and apoptosis were observed by CCK-8 assay, western blotting, flow cytometry, and fluorescence staining. ADSCs were subcutaneously transplanted into nude mice in the location where a hypoxia ischemic microenvironment was simulated in vivo. After 1, 3, and 7 d, mitochondrial apoptotic proteins were evaluated by immunohistochemistry and immunofluorescence staining. RESULTS: Exogenous HIF-1α downregulated mitochondrial reactive oxygen species, cytochrome c, caspase-9, and caspase-3, but inhibited mitochondrial membrane potential depolarization and increased the Bcl-2/bax ratio. HIF-1α prevented apoptosis and promoted vascular endothelial growth factor (VEGF) secretion as demonstrated by enzyme-linked immunosorbent assay (ELISA), terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and flow cytometry analysis. HIF-1α enhanced the survival of transplanted ADSCs in nude mice. CONCLUSION: We have shown that through inhibition of the mitochondria-mediated apoptotic pathway and promotion of VEGF secretion in hADSCs in an ischemic microenvironment, HIF-1α may potentially be applied in clinical therapy and as an alternative strategy for improving hADSC therapy.

Author Correction: Prediction of disulfide bond engineering sites using a machine learning method.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Prediction of disulfide bond engineering sites using a machine learning method.

Disulfide bonds are covalently bonded sulfur atoms from cysteine pairs in protein structures. Due to the importance of disulfide bonds in protein folding and structural stability, artificial disulfide bonds are often engineered by cysteine mutation to enhance protein structural stability. To facilitate the experimental design, we implemented a method based on neural networks to predict amino acid pairs for cysteine mutations to form engineered disulfide bonds. The designed neural network was trained with high-resolution structures curated from the Protein Data Bank. The testing results reveal that the proposed method recognizes 99% of natural disulfide bonds. In the test with engineered disulfide bonds, the algorithm achieves similar accuracy levels with other state-of-the-art algorithms in published dataset and better performance for two comprehensively studied proteins with 70% accuracy, demonstrating potential applications in protein engineering. The neural network framework allows exploiting the full features in distance space, and therefore improves accuracy of the disulfide bond engineering site prediction. The source code and a web server are available at http://liulab.csrc.ac.cn/ssbondpre.

Prometastatic secretome trafficking via exosomes initiates pancreatic cancer pulmonary metastasis.

To demonstrate multifaceted contribution of aspartate ß-hydroxylase (ASPH) to pancreatic ductal adenocarcinoma (PDAC) pathogenesis, in vitro metastasis assay and patient derived xenograft (PDX) murine models were established. ASPH propagates aggressive phenotypes characterized by enhanced epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, extracellular matrix (ECM) degradation/remodeling, angiogenesis, stemness, transendothelial migration and metastatic colonization/outgrowth at distant sites. Mechanistically, ASPH activates Notch cascade through direct physical interactions with Notch1/JAGs and ADAMs. The ASPH-Notch axis enables prometastatic secretome trafficking via exosomes, subsequently initiates MMPs mediated ECM degradation/remodeling as an effector for invasiveness. Consequently, ASPH fosters primary tumor development and pulmonary metastasis in PDX models, which was blocked by a newly developed small molecule inhibitor (SMI) specifically against ASPH's ß-hydroxylase activity. Clinically, ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stage PDAC. Relatively high levels of ASPH-Notch network components independently/jointly predict curtailed overall survival (OS) in PDAC patients (log-rank test, Ps < 0.001; Cox proportional hazards regression, P < 0.001). Therefore, ASPH-Notch axis is essential for propagating multiple-steps of metastasis and predicts prognosis of PDAC patients. A specific SMI targeting ASPH offers a novel therapeutic approach to substantially retard PDAC development/progression.

ASPH-notch Axis guided Exosomal delivery of Prometastatic Secretome renders breast Cancer multi-organ metastasis.

BACKGROUND: Aspartate ß-hydroxylase (ASPH) is silent in normal adult tissues only to re-emerge during oncogenesis where its function is required for generation and maintenance of malignant phenotypes. Exosomes enable prooncogenic secretome delivering and trafficking for long-distance cell-to-cell communication. This study aims to explore molecular mechanisms underlying how ASPH network regulates designated exosomes to program development and progression of breast cancer. METHODS: Stable cell lines overexpressing or knocking-out of ASPH were established using lentivirus transfection or CRISPR-CAS9 systems. Western blot, MTT, immunofluorescence, luciferase reporter, co-immunoprecipitation, 2D/3-D invasion, tube formation, mammosphere formation, immunohistochemistry and newly developed in vitro metastasis were applied. RESULTS: Through physical interactions with Notch receptors, ligands (JAGs) and regulators (ADAM10/17), ASPH activates Notch cascade to provide raw materials (especially MMPs/ADAMs) for synthesis/release of pro-metastatic exosomes. Exosomes orchestrate EMT, 2-D/3-D invasion, stemness, angiogenesis, and premetastatic niche formation. Small molecule inhibitors (SMIs) of ASPH's ß-hydroxylase specifically/efficiently abrogated in vitro metastasis, which mimics basement membrane invasion at primary site, intravasation/extravasation (transendothelial migration), and colonization/outgrowth at distant sites. Multiple organ-metastases in orthotopic and tail vein injection murine models were substantially blocked by a specific SMI. ASPH is silenced in normal adult breast, upregulated from in situ malignancies to highly expressed in invasive/advanced ductal carcinoma. Moderate-high expression of ASPH confers more aggressive molecular subtypes (TNBC or Her2 amplified), early recurrence/progression and devastating outcome (reduced overall/disease-free survival) of breast cancer. Expression profiling of Notch signaling components positively correlates with ASPH expression in breast cancer patients, confirming that ASPH-Notch axis acts functionally in breast tumorigenesis. CONCLUSIONS: ASPH-Notch axis guides particularly selective exosomes to potentiate multifaceted metastasis. ASPH's pro-oncogenic/pro-metastatic properties are essential for breast cancer development/progression, revealing a potential target for therapy.

Correction: Aspartate ß-hydroxylase expression promotes a malignant pancreatic cellular phenotype.

[This corrects the article DOI: 10.18632/oncotarget.2840.].

Expression Profiles of lncRNAs and circRNAs in Keloid.

BACKGROUND: We hypothesized that crosstalk between noncoding RNAs, including microRNA (miRNA), lncRNA, and circRNA, might play a critical role in keloids development and physiology. To reveal the molecular mechanisms involved in the pathogenesis of keloids, we compared their gene expression profiles and differential expressions in keloid and normal skin tissues. METHODS: Expression profiles of mRNAs and lncRNAs and circRNAs in 2 pairs (identification set) of keloid and matched normal skin tissues were analyzed through sequencing. Real-time quantitative PCR was performed to validate the sequencing results using 5 pairs (validation set) of keloid and matched normal skin tissues. Presumed targets of differentially expressed lncRNAs and circRNAs were functionally annotated by bioinformatics approaches. RESULTS: The differential expression of mRNAs in keloid and normal skin by high-throughput sequencing was 2,528, of which 1,271 were downregulated, whereas 1,257 were upregulated. In the meantime, sequencing identified 2,227 differentially expressed lncRNAs, including 1,224 upregulated and 1,003 downregulated in keloid tissue compared with normal skin tissue. Additionally, 154 differentially expressed circRNAs were identified, including 81 upregulated and 73 downregulated in keloid tissue compared with normal skin tissue. Functional annotations of differentially expressed circRNA targets revealed their enrichment in several signaling pathways important for scar wound healing. CONCLUSIONS: Expression profiles of mRNAs, lncRNAs, and circRNAs were altered in keloid tissue, which may partly contribute to the etiology of keloids by affecting several signaling pathways relevant to scar wound healing. A better understanding of keloids pathogenesis may identify new therapeutic targets for keloids.

Anti-tumor activity of antibody drug conjugate targeting aspartate-ß-hydroxylase in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy with very limited treatment options. Antibody drug conjugates (ADCs) are promising cytotoxic agents capable of highly selective delivery. Aspartate-ß-hydroxylase (ASPH) is a type II transmembrane protein highly expressed in PDACs (97.1%) but not normal pancreas. We investigated anti-tumor effects of an ADC guided by a human monoclonal antibody (SNS-622) against ASPH in human PDAC cell lines and derived subcutaneous (s.c.) xenograft as well as a patient-derived xenograft (PDX) murine model with spontaneous pulmonary metastasis. The cytotoxic effects exhibited by several candidate payloads linked to SNS-622 antibody targeting ASPH+ PDACs were analyzed. After i.v. administration of SNS-622-emtansine (DM1) ADC, the primary PDAC tumor growth and progression (number and size of pulmonary metastases) were determined. The PDAC cell lines, s.c. and PDX tumors treated with ADC were tested for cell proliferation, cytotoxicity and apoptosis by MTS and immunohistochemistry (IHC) assays. SNS-622-DM1 construct has demonstrated optimal anti-tumor effects in vitro. In the PDX model of human PDAC, SNS-622-DM1 ADC exerted substantially inhibitory effects on tumor growth and pulmonary metastasis through attenuating proliferation and promoting apoptosis.

Aspartate ß-hydroxylase promotes pancreatic ductal adenocarcinoma metastasis through activation of SRC signaling pathway.

BACKGROUND: Signaling pathways critical for embryonic development re-emerge in adult pancreas during tumorigenesis. Aspartate ß-hydroxylase (ASPH) drives embryonic cell motility/invasion in pancreatic development/differentiation. We explored if dysregulated ASPH is critically involved in pancreatic cancer pathogenesis. METHODS: To demonstrate if/how ASPH mediates malignant phenotypes, proliferation, migration, 2-D/3-D invasion, pancreatosphere formation, immunofluorescence, Western blot, co-immunoprecipitation, invadopodia formation/maturation/function, qRT-PCR, immunohistochemistry (IHC), and self-developed in vitro metastasis assays were performed. Patient-derived xenograft (PDX) models of human pancreatic ductal adenocarcinoma (PDAC) were established to illustrate in vivo antitumor effects of the third-generation small molecule inhibitor specifically against ASPH's ß-hydroxylase activity. Prognostic values of ASPH network components were evaluated with Kaplan-Meier plots, log-rank tests, and Cox proportional hazards regression models. RESULTS: ASPH renders pancreatic cancer cells more aggressive phenotypes characterized by epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, invadopodia formation/function as demonstrated by extracellular matrix (ECM) degradation, stemness (cancer stem cell marker upregulation and pancreatosphere formation), transendothelial migration (mimicking intravasation/extravasation), and sphere formation (mimicking metastatic colonization/outgrowth at distant sites). Mechanistically, ASPH activates SRC cascade through direct physical interaction with ADAM12/ADAM15 independent of FAK. The ASPH-SRC axis enables invadopodia construction and initiates MMP-mediated ECM degradation/remodeling as executors for invasiveness. Pharmacologic inhibition of invadopodia attenuates in vitro metastasis. ASPH fosters primary tumor development and pulmonary metastasis in PDX models of PDAC, which is blocked by a leading compound specifically against ASPH enzymatic activity. ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stages of PDAC. Expression profiling of ASPH-SRC network components independently/jointly predicts clinical outcome of PDAC patients. Compared to a negative-low level, a moderate-very high level of ASPH, ADAM12, activated SRC, and MMPs correlated with curtailed overall survival (OS) of pancreatic cancer patients (log-rank test, ps < 0.001). The more unfavorable molecules patients carry, the more deleterious prognosis is destinated. Patients with 0-2 (n = 4), 3-5 (n = 8), 6-8 (n = 24), and 9-12 (n = 73) unfavorable expression scores of the 5 molecules had median survival time of 55.4, 15.9, 9.7, and 5.0 months, respectively (p < 0.001). CONCLUSION: Targeting the ASPH-SRC axis, which is essential for propagating multi-step PDAC metastasis, may specifically/substantially retard development/progression and thus improve prognosis of PDAC.

The microRNA miR-181c enhances chemosensitivity and reduces chemoresistance in breast cancer cells via down-regulating osteopontin.

Acquired resistance to chemotherapy is a frequent challenge in cancer care and one of the leading causes for failing breast cancer therapies. There is accumulative clinical and experimental evidence indicating that microRNAs (miRNAs) play a crucial role in developing therapeutic resistance in cancer cells. We aimed to explore key miRNAs and associated mechanisms by which breast cancer develops chemoresistance. In this study, we found that a particular miRNA species, miR-181c, was significantly low-expressed in breast cancer cell line MCF-7 which developed chemoresistance towards doxorubicin (Adriamycin, ADR, subclone renamed as MCF-7/ADR) than in the wild-type MCF-7 cells. Induced overexpression of miR-181c significantly inhibited cell proliferation, reversed the chemoresistance towards doxorubicin, and reduced the growth of resistant breast cancer xenograft tumors in vitro and in vivo. Using a bioinformatics approach, we also identified osteopontin (OPN) as a direct target of miR-181c. In contrast to low miR-181c expression in MCF-7/ADR cells, OPN showed a reversely high expression in resistant MCF-7/ADR cells. Our results suggest that miR-181c may regulate chemosensitivity and chemoresistance by downregulating OPN, resulting in enhanced p53-dependent transactivation and apoptosis in resistant breast cancer cells. This study provides new insights to develop effective interventions for cancer patients with acquired resistance to chemotherapy.

Benefits of Early Treatment for Patients with Hepatic Myelopathy Secondary to TIPS: A Retrospective Study in Northern China.

Transjugular intrahepatic portosystemic shunt (TIPS) is an effective therapy for reducing portal pressure. Hepatic myelopathy (HM), a rare complication of chronic liver diseases, remains obscure in terms of treatment and prognosis. We aimed to determine an optimal treat strategy for patients with HM after TIPS. Twenty-nine patients who developed HM after TIPS were stratified by time-lapse from onset to treatment: group A (n = 16), <6 months; group B (n = 13), ≥6 months. Therapeutic measures included shunt-limiting and medical treatments. Overall survival, lower-limb muscle strength, Fugl-Meyer score, Barthel index, and serum ammonia were recorded. Median survival time in group A or B was 30 months or 16.5 months, respectively (log rank p = 0.0172). All patients in group A obtained improvement in grading of muscle strength (p < 0.0001), Fugl-Meyer score (p = 0.0021), and Barthel index (p = 0.0003), particularly male patients and those subjected to shunt-limiting. Serum ammonia levels were decreased significantly in both group A (p = 0.0007) and group B (p = 0.0007). Collectively, once HM is confirmed after TIPS, active intervention is imperative and urgent, especially within the first 6 months from onset of symptom. TIPS shunt-limiting is particularly beneficial for rehabilitation in patients with early-onset HM.

Knockdown of lncRNA H19 restores chemo-sensitivity in paclitaxel-resistant triple-negative breast cancer through triggering apoptosis and regulating Akt signaling pathway.

Triple negative breast cancer (TNBC) is associated with poor prognosis and systemic chemotherapy is the only treatment for TNBC. However, development of chemo-resistance remains a major obstacle for TNBC treatment. Paclitaxel-resistance is mainly related to the activation of the Akt signaling pathway and deregulation of apoptotic regulatory proteins. LncRNAs are frequently dysregulated in various malignancies, including breast cancer, facilitating cell proliferation, metastasis and drug resistance. LncRNA H19 is overexpressed in approximately 70% of breast cancer patients, and has been reported to confer chemo-resistance in breast cancer. In the present study, we investigated the expression level of lncRNA H19 in paclitaxel-resistant and paclitaxel-sensitive cell lines. The results showed that the level of lncRNA H19 expression in paclitaxel-resistant cells was significantly higher than that in paclitaxel-sensitive cells, and knockdown of lncRNA H19 might restore chemo-sensitivity in paclitaxel-resistant TNBC by mediating the AKT signaling pathway. Thus, lncRNA H19 might be an efficient therapeutic target in paclitaxel-resistant TNBC treatment.