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Abstract Introduction Current treatment guidelines for patients with epidermal growth factor receptor (EGFR)-mutated metastatic non-small cell lung cancer (mNSCLC) recommend EGFR tyrosine kinase inhibitors (TKIs) as the standard of care for first-line treatment, with third-generation osimertinib the preferred choice. However, most patients develop resistance to targeted therapy, and subsequent systemic chemotherapy is recommended. The aim of this study was to characterize the subsequent line of therapy (LOT) following osimertinib in patients with EGFR-mNSCLC. Methods Medical and pharmacy claims of adults who initiated a subsequent LOT (index) after initial osimertinib discontinuation between November 2015 and September 2019 were analyzed retrospectively. Results A total of 135 patients met the inclusion criteria. After metastatic diagnosis, 22.2% and 49.6% of patients were treated with osimertinib in the first and second line, respectively. After osimertinib discontinuation, most patients were treated with a platinum-based chemotherapy regimen (57%), of which 40.3% included immuno-oncology therapy. Reuse or continuation of EGFR TKIs was also common (24%). Overall, the median time to treatment discontinuation for the index LOT was 2.4 months. Proportions of patients with ≥ 1 inpatient or emergency department visit were 31.9% and 35.6%, respectively. Conclusions The duration of the LOT following osimertinib was short and associated with tolerability issues underscoring a high unmet need for new therapies to address EGFR TKI resistance.

Abstract Background Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR TKIs) are established first-line treatments among patients with metastatic non-small cell lung cancer harboring EGFR-sensitizing mutations. Upon EGFR TKI resistance, there are scant data supporting a standard of care in subsequent lines of therapy. Objective We aimed to characterize real-world treatment patterns and adverse events associated with hospitalization in later lines of therapy. Methods This retrospective analysis of administrative claims included adults with metastatic non-small cell lung cancer who initiated a next line of therapy (index line of therapy) following EGFR TKI and platinum-based chemotherapy discontinuation on/after 1 November, 2015. Treatment regimens and adverse event rates during the index line of therapy were described. Results Among 195 eligible patients (median age: 59 years; female: 60%), the five most common index line of therapy regimens were immune checkpoint inhibitor monotherapy (29%), EGFR TKI monotherapy (21%), platinum-based chemotherapy (19%), non-platinum-chemotherapy (13%), and EGFR TKI combinations (9%). The overall median (95% confidence interval) time to discontinuation of the index line of therapy was 2.8 (2.1–3.2) months. Common adverse events associated with hospitalizations included infection/sepsis, pneumonia/pneumonitis, and anemia (2.9, 2.8, and 2.0 per 100 person-months, respectively). Conclusions Among EGFR TKI-resistant patients who discontinued platinum-based chemotherapy, the duration of the next line of therapy was short, treatment was highly variable, and re-treatment with EGFR TKIs and platinum-based regimens was common, suggesting a lack of standard of care in later lines. Adverse event rates associated with hospitalization were high, especially among platinum-treated patients. These results underscore the unmet need for new therapies in a later line of treatment to reduce the clinical burden among patients in this population.

Abstract Introduction Atopic dermatitis (AD) can require long-term therapy. Few real-world studies have evaluated long-term effectiveness from the patients’ perspective. The aim of this study was to evaluate patient-reported outcomes (PROs) during long-term dupilumab treatment. Methods Adults with moderate-to-severe AD who initiated dupilumab through the US manufacturer patient support program and participated in RELIEVE-AD (a prospective patient survey study with a 12-month follow-up) were recontacted 30–36 months post-initiation regardless of current dupilumab use. The online questionnaire consisted of PROs, including the Atopic Dermatitis Control Tool (ADCT), use of concomitant AD therapies, satisfaction with current therapy, global change in itch relative to before dupilumab initiation, non-itch skin symptoms (skin pain/soreness, hot/burning feeling, and sensitivity to touch), flares, Dermatology Life Quality Index, sleep problems, and the AD-specific Work Productivity and Activity Impairment Questionnaire. Results Of 698 patients who initiated dupilumab (baseline) and were recontacted, 425 completed the 30–36-month survey. Significant reductions from baseline were reported in concomitant AD therapy use (P

Various real-world data (RWD) sources have emerged in China with the intention of generating real-world evidence (RWE) that can be used in clinical and regulatory decision-making. Despite these efforts, significant barriers remain that hinder high-quality healthcare research. A workshop with 30 representatives from healthcare research agencies, technology companies focused on healthcare big data and pharmaceutical companies was held in December 2020 to identify strategies to overcome the barriers associated with the usability and quality of RWD in China. Across all sectors, examples of barriers identified included inconsistencies in terminology and non-standardised coding practices; the absence of longitudinal data; the absence of transparent data processing and validation practices; and the inability to access and share RWD. While cutting-edge technological innovations and data solutions provided powerful tools, the development of collaborative and synergistic research networks across multiple stakeholders is key to generate accessible, high-quality RWD in China. RWD has the potential to provide clinical, regulatory and reimbursement decision-makers with critical insights that can improve healthcare delivery in China. However, barriers to its access, collection and use must be addressed to generate RWE to guide healthcare stakeholders.

Abstract Mast cells are potent mediators of allergy and asthma, yet their role in regulating adaptive immunity remains ambiguous. On the surface of mast cells, the crosslinking of IgE bound to FcεRI by a specific antigen recognized by that IgE triggers the release of immune mediators such as histamine and cytokines capable of activating other immune cells; however, little is known about the mast cell contribution to the induction of endogenous, antigen-specific CD4+ T cells. Here we examined the effects of specific mast cell activation in vivo on the initiation of an antigen-specific CD4+ T cell response. While CD4+ T cells were not enhanced by FcεRI stimulation alone, their activation was synergistically enhanced when FcεRI activation was combined with TLR4 stimulation. This enhanced activation was dependent on global TLR4 stimulation but appeared to be less dependent on mast cell expressed TLR4. This study provides important new evidence to support the role of mast cells as mediators of the antigen-specific adaptive immune response.

Design methods for large industrial pumps are well developed, but they cannot be relied upon when designing specialised miniature pumps, due to scaling issues. Therefore, the design and development phase of small pumps demand numerous experimental tests to ensure a viable prototype. Of initial interest is hydraulic design in the form of pump performance and efficiency curves. This project aimed to produce an automated test rig capable of generating both the performance (P-Q – pressure vs. flow rate) and efficiency curves that are reliable and repeatable. The apparatus is largely customizable and suitable for a range of smaller pump sizes. The pump impeller and volute were 3D printed, allowing for design flexibility and rapid prototyping and testing.The test loop was automated which allowed the flow rate to be incremented from 0 L/min to the maximum flow rate. At each step the pressure, flow rate, voltage and current were recorded to generate the P – Q and efficiency curves. Repeatability results showed low variations of ±3 mmHg (400 Pa) in pressure and ± 2% in hydraulic efficiency. The given setup can be used to compare and evaluate the hydraulic performance of various pump designs.

Rationale & Objective: Since the change in erythropoiesis-stimulating agent (ESA) labeling and bundling of dialysis services in the United States, few studies have addressed the clinical importance of ESA hyporesponsiveness and none have considered health care resource use in this population. We aimed to further explore ESA hyporesponsiveness and its consequences. Study Design: Retrospective observational cohort study. Setting & Participants: US Renal Data System Medicare participants receiving dialysis with a minimum 6 months of continuous ESA use from 2012 to 2014. Predictors: Erythropoietin resistance index (≥2.0 U/kg/wk/g/L) and ESA dose were used to identify ESA hyporesponders and hyporesponsive subgroups: isolated, intermittent, and chronic. Outcomes: Associations between ESA responsiveness and mortality, cardiovascular hospitalization rates, and health care resource use were evaluated and compared across subgroups. Analytical Approach: Baseline characteristics were compared using Wilcoxon rank sum tests for continuous variables and χ2 tests for categorical variables. Incidence rates of health care resource use were modeled using an unadjusted and adjusted generalized linear model. Results: Of 834,115 dialysis patients in the CROWNWeb database, 38,891 ESA hyporesponders and 59,412 normoresponders met all inclusion criteria. Compared with normoresponders, hyporesponders were younger women, weighed less, and had longer durations of dialysis (all P < 0.001). Hyporesponders received 3.8-fold higher ESA doses (mean, 94,831 U/mo) and erythropoietin resistance index was almost 5 times higher than in normoresponders. Hyporesponders had lower hemoglobin levels and parathyroid hormone levels > 800 pg/mL, and iron deficiency was present in 26.5% versus 10.9% in normoresponders. One-year mortality was higher among hypo- compared with normoresponders (25.3% vs 22.6%). Hyporesponders also had significantly higher rates of hospitalization for cardiovascular events, emergency department visits, inpatient stays, home health agency visits, skilled nursing facility, and hospice days. Limitations: Only US Medicare patients were included and different hyporesponder definitions may have influenced the results. Conclusions: This study explored ESA hyporesponsiveness using new definitions and incorporated clinical and economic outcomes. It established that ESA-hyporesponsive dialysis patients had higher mortality, cardiovascular hospitalization rates, and health care costs as compared with ESA-normoresponsive patients.

Adenovirus is a common cause of acute febrile respiratory infection in children and are generally self-limiting although pneumonia can occur in neonates and adults with compromised immunity. However, severe adenovirus pneumonia in healthy adults has been rarely described. Here, we report a case of severe community-acquired adenovirus pneumonia in a previously healthy patient successfully treated with intravenous Cidofovir.

We report a case of a patient with pulmonary melioidosis which radiologically mirrored a bronchogenic carcinoma with mediastinal lymphadenopathy. Such findings were observed in a Computed Tomography (CT) scan (Thorax) and Positron Emission Tomography (PET) scan (Body) in a previously healthy 57-year-old man with no significant medical risk factors for melioidosis other than his previous exposures to soil during outfield military training in Thailand, 37 and 28 years ago. He presented with acute symptoms of dry cough, pleuritic pain and fever. A CT Scan thorax revealed a left lower lobe mass with left pleural and pericardial effusion and mediastinal lymph nodes. Similarly, the PET scan showed various fluorodeoxyglucose (FDG)-positron uptake in these areas. However the lung mass biopsy cultured Burkholderia pseudomallei concurrently with a Melioidosis serology titre of >1:1024. He responded to intravenous Meropenem followed by Co-Trimoxazole and Doxycycline over the course of 21 weeks, ultimately leading to the resolution of any significant radiological findings. Keywords: Melioidosis, Pulmonary mass, Burkholderia pseudomallei

Vedolizumab is the first gut-selective integrin blocker indicated for patients with Crohn's disease (CD) and ulcerative colitis (UC). This study aimed to examine the adverse events (AEs) profile of vedolizumab compared to anti-tumor necrosis factors (anti-TNFs) indicated for CD and UC using the FDA Adverse Event Reporting System (FAERS) database. AE reports with vedolizumab (5/20/2014-6/30/2015) and CD/UC-indicated anti-TNF drugs (adalimumab, infliximab, certolizumab pegol, and golimumab, during 8/1/1998-6/30/2015) as primary suspects were extracted from the FAERS database. AEs associated with vedolizumab were compared for signals of disproportionate reporting against anti-TNF drugs and all other drugs (1969-6/30/2015), using the proportional reporting ratio (PRR) and the empirical Bayesian geometric mean (EBGM) algorithms. The search retrieved 499 reports for vedolizumab and 119,620 reports for anti-TNFs, with 35.9% and 32.1% of these, respectively, being serious AEs. With the PRR approach, vedolizumab-associated reports had signals for 22 groups of AEs (9 were associated with serious outcomes) relative to anti-TNFs and had 34 signals relative to all other drugs. Signals detected included those reported as warnings in prescribing information and new AEs related to cardiovascular disease. Due to the voluntary nature of FAERS, this finding should be considered hypothesis generating (rather than hypothesis testing). Longer-term observational studies are required to evaluate the safety of vedolizumab.

OBJECTIVES:In 2009, the FDA issued a warning that omeprazole--a proton pump inhibitor (PPI)--reduces the antithrombotic effect of clopidogrel by almost half when taken concomitantly. This study aims to analyze the impact of the FDA Safety Communications on prescribing clopidogrel together with PPIs. METHODS:This retrospective study identified clopidogrel users from the Truven Health Analytics MarketScan Databases (01/2006-12/2012). Rates of clopidogrel-PPI combination therapy were estimated in 6-month intervals for patients with ≥1 clopidogrel prescription fill, then were analyzed pre- and post-safety communication (11/17/2009). Analyses were also conducted by grouping PPIs into CYP2C19 inhibitors (omeprazole and esomeprazole) and CYP2C19 non-inhibitors (pantoprazole, lansoprazole, dexlansoprazole, and rabeprazole). RESULTS:Overall, 483,074 patients met the selection criteria; of these, 157,248 used a clopidogrel-PPI combination. On average, 30.5% of patients in the pre- and 19.9% in the post-communication period used a clopidogrel-PPI combination therapy. Among clopidogrel users, the probability of using clopidogrel-PPI combinations fell by over 40% in the post-communication period (OR = 0.57; p

In this paper we present the REQS package which is an interface between the R environment of statistical computing and the EQS software for structural equation modeling. The package consists of three main functions that read EQS script files and import the results into R, call EQS script �files from R, and, �finally, run EQS script �files from R and, again, import the results after EQS computation. The components a user needs are R and EQS. We give a short introduction to R and EQS, elaborate the functionalities of the package, and show how to use the package by means of several examples with special emphasis on simulations.

In this paper we present the REQS package which is an interface between the R environment of statistical computing and the EQS software for structural equation modeling. The package consists of three main functions that read EQS script files and import the results into R, call EQS script �files from R, and, �finally, run EQS script �files from R and, again, import the results after EQS computation. The components a user needs are R and EQS. We give a short introduction to R and EQS, elaborate the functionalities of the package, and show how to use the package by means of several examples with special emphasis on simulations.

Abstract Efficient and accurate algorithms are necessary to reconstruct particles in the highly granular detectors anticipated at the High-Luminosity Large Hadron Collider and the Future Circular Collider. We study scalable machine learning models for event reconstruction in electron-positron collisions based on a full detector simulation. Particle-flow reconstruction can be formulated as a supervised learning task using tracks and calorimeter clusters. We compare a graph neural network and kernel-based transformer and demonstrate that we can avoid quadratic operations while achieving realistic reconstruction. We show that hyperparameter tuning significantly improves the performance of the models. The best graph neural network model shows improvement in the jet transverse momentum resolution by up to 50% compared to the rule-based algorithm. The resulting model is portable across Nvidia, AMD and Habana hardware. Accurate and fast machine-learning based reconstruction can significantly improve future measurements at colliders.

Abstract BackgroundPseudonymization has become a best practice to securely manage the identities of patients and study participants in medical research projects and data sharing initiatives. This method offers the advantage of not requiring the direct identification of data to support various research processes while still allowing for advanced processing activities, such as data linkage. Often, pseudonymization and related functionalities are bundled in specific technical and organization units known as trusted third parties (TTPs). However, pseudonymization can significantly increase the complexity of data management and research workflows, necessitating adequate tool support. Common tasks of TTPs include supporting the secure registration and pseudonymization of patient and sample identities as well as managing consent. ObjectiveDespite the challenges involved, little has been published about successful architectures and functional tools for implementing TTPs in large university hospitals. The aim of this paper is to fill this research gap by describing the software architecture and tool set developed and deployed as part of a TTP established at Charité – Universitätsmedizin Berlin. MethodsThe infrastructure for the TTP was designed to provide a modular structure while keeping maintenance requirements low. Basic functionalities were realized with the free MOSAIC tools. However, supporting common study processes requires implementing workflows that span different basic services, such as patient registration, followed by pseudonym generation and concluded by consent collection. To achieve this, an integration layer was developed to provide a unified Representational state transfer (REST) application programming interface (API) as a basis for more complex workflows. Based on this API, a unified graphical user interface was also implemented, providing an integrated view of information objects and workflows supported by the TTP. The API was implemented using Java and Spring Boot, while the graphical user interface was implemented in PHP and Laravel. Both services use a shared Keycloak instance as a unified management system for roles and rights. ResultsBy the end of 2022, the TTP has already supported more than 10 research projects since its launch in December 2019. Within these projects, more than 3000 identities were stored, more than 30,000 pseudonyms were generated, and more than 1500 consent forms were submitted. In total, more than 150 people regularly work with the software platform. By implementing the integration layer and the unified user interface, together with comprehensive roles and rights management, the effort for operating the TTP could be significantly reduced, as personnel of the supported research projects can use many functionalities independently. ConclusionsWith the architecture and components described, we created a user-friendly and compliant environment for supporting research projects. We believe that the insights into the design and implementation of our TTP can help other institutions to efficiently and effectively set up corresponding structures.

Background: The exact role of laparoscopic liver resection (LLR) in patients with hepatocellular carcinoma (HCC) and underlying liver cirrhosis (LC) is not well defined. In this meta-analysis, both long- and short-term outcomes following LLR versus open liver resection (OLR) were analysed. Methods: PubMed, EMBASE, Scopus and Web of Science databases were searched systematically for randomised controlled trials (RCTs) and propensity-score matched (PSM) studies reporting outcomes of LLR versus OLR of HCC in patients with cirrhosis. Primary outcome was overall survival (OS). This was analysed using one-stage (individual participant data meta-analysis) and two-stage (aggregate data meta-analysis) approaches. Secondary outcomes were operation duration, blood loss, blood transfusion, Pringle manoeuvre utilization, overall and major complications, length of hospital stay (LOHS), 90-day mortality and R0 resection rates. Results: Eleven studies comprising 1618 patients (690 LLR versus 928 OLR) were included for analysis. In the one-stage meta-analysis, an approximately 18.7 per cent lower hazard rate (HR) of death in the LLR group (random effects: HR 0.81, 95 per cent confidence interval [C.I.] 0.68 to 0.96; P=0.018) was observed. Two-stage meta-analysis resulted in a pooled HR of 0.84 (95 per cent C.I. 0.74 to 0.96; P=0.01) in the overall LLR cohort. This indicated a 16-26 per cent reduction in the HR of death for patients with HCC and cirrhosis who underwent LLR. For secondary outcomes, LLR was associated with less blood loss (mean difference [MD] -99 ml, 95 per cent C.I. -182 to -16 ml), reduced overall complications (odds ratio 0.49, 95 per cent C.I. 0.37 to 0.66) and major complications (odds ratio 0.45, 95 per cent C.I. 0.26 to 0.79), and shorter LOHS (MD -3.22 days, 95 per cent C.I. -4.38 to -2.06 days). Conclusion: Laparoscopic resection of HCC in patients with cirrhosis is associated with improved survival and perioperative outcomes. [ABSTRACT FROM AUTHOR]

Objective: To assess treatment persistence, hospitalization outcomes and mean healthcare costs of geriatric major depressive disorder (MDD) patients treated with escitalopram compared to other selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs).Research design and methods: Patients aged ≥ 65 years with at least one inpatient claim or two independent claims associated with MDD diagnosis were identified in the IHCIS National Managed Care Database (2003–2005). Patients were continuously enrolled for at least ≥ 12 months, filled at least one prescription for an SSRI/SNRI and did not use any second-generation antidepressant during the 6 months pre-index date. Unadjusted and multivariate analyses adjusting for baseline characteristics were conducted.Main outcome measures: Treatment persistence, hospitalization utilization, and average prescription drug, medical, and total healthcare costs were compared between patients initiated on escitalopram versus other SSRI/SNRIs.Results: Escitalopram-treated patients (N = 459) were less likely to discontinue treatment (HR = 0.85, p = 0.012) or switch to another second-generation antidepressant (HR = 0.76, p = 0.006) compared to patients treated with other SSRI/SNRIs (N = 1517). Escitalopram-treated patients had 39% fewer hospitalization days (p = 0.004). Both groups had similar mean prescription drug costs ($1659 vs. $1630, p = 0.687). After controlling for baseline characteristics, escitalopram-treated patients had lower mean total medical service costs ($9425 vs. $12 703, p < 0.001) and mean total healthcare costs ($11 043 vs. $14 163, p < 0.001).Limitations: This study''s limitations include its small sample size, short observational periods and exclusivity of indirect costs.Conclusions: Geriatric patients treated with escitalopram had higher treatment persistence, fewer hospitalization days and lower total healthcare costs than patients on other SSRI/SNRIs after controlling for baseline characteristics. Most of the cost savings were due to reductions in hospitalizations. [ABSTRACT FROM AUTHOR]

Objective: To compare escitalopram versus citalopram for the treatment of major depressive disorder (MDD) in geriatric patients.Research design and methods: Administrative claims data (2003–2005) were analyzed for patients aged ≥65 years with at least one inpatient claim or two independent medical claims associated with MDD diagnosis. Patients were continuously enrolled for at least 12 months, filled at least one prescription for citalopram or escitalopram and had no second generation antidepressant use during the 6-month pre-index date. Contingency table analysis and survival analysis were used to compare outcomes between the two treatment groups.Main outcome measures: Treatment persistence, hospitalization utilization, and prescription drug, medical, and total healthcare costs were analyzed. Outcomes were compared between patients initiated on escitalopram and those initiated on citalopram both descriptively and using multivariate analysis adjusting for baseline characteristics.Results: Among 691 geriatric patients, escitalopram-treated patients (n=459) were less likely to discontinue treatment (hazard ratio [HR]=0.83, p=0.049) or switch to another second generation antidepressant (HR=0.62, p=0.001) compared to patients treated with citalopram (n=232). Patients treated with escitalopram had a significantly lower hospitalization rate (31.2% vs. 38.8%, p=0.045) and 66% fewer hospitalization days based on negative binomial regression (p<0.001). While escitalopram patients had comparable prescription drug costs, they had lower total medical service costs (regression: $9748 vs. $19 208, p<0.001) and lower total healthcare costs (regression: $11 434 vs. $20 601, p<0.001).Limitations: This study''s limitations include its small sample size, short observational periods and exclusivity of indirect costs.Conclusions: Geriatric patients treated with escitalopram had better treatment persistence, fewer hospitalizations, and lower medical and total healthcare costs than patients treated with citalopram. Most of the cost reduction was attributable to significantly lower hospitalizations and total medical costs. [ABSTRACT FROM AUTHOR]

Objective: To describe dosing patterns for tumor necrosis factor (TNF) antagonists in patients with rheumatoid arthritis from health care provider and payer point of interest.Research design and methods: Using privately insured US claims data from 31 large employers covering 31 companies across the US, rheumatoid arthritis (RA) patients were identified and three cohorts were defined based on first TNF-antagonist treatment (adalimumab, etanercept, or infliximab) administered after January 1, 2003. Dosageadjustment patterns were assessed during the following 12-month period. Changes in dosage (both increases and decreases) and maintenance of a stable dosage were evaluated. For the health care provider point of interest, a new algorithm was developed to assess treatment patterns with chronic injectable therapies that incorporated the potential inconsistency between days of supply and prescription-gap data, thus providing the actual use of TNFantagonist treatment. For the payer, usage data addressed whether the TNF antagonist was used at a greater dosage than recommended. Differences in baseline characteristics and dosage change rates between cohorts were tested using Chi-Square tests for categorical variables and Wilcoxon tests for continuous variables.Results: From the health care provider point of interest, 83.4% of adalimumab-treated patients (n = 205) initially received the recommended dosage, 10.2% received less, and 6.3% received more; 87.7% of etanercept-treated patients (n = 455) initially received the recommended dosage, 11.2% received less, and 1.1% received more; and 83.8% of infliximab-treated patients (n = 148) started with 2–4 vials (the recommended dosage is based on the weight of the patient, not total milligrams). All treatments had similar dosage decrease and discontinuation rates. Maintenance of stable dosage was lower for infliximab (20.9%) than adalimumab (37.1%) and etanercept (39.1%); both p < 0.01. The infliximab dosage-increase rate (35.1%) was greater than adalimumab (3.9%) and etanercept (0); both p < 0.01. From the payer point of interest, dosage-increase rate was greater for infliximab (28.3%) than adalimumab (8.7%) and etanercept (6.9%), both p < 0.01.Conclusions: Infliximab had greater dosage-increase rates than adalimumab and etanercept. Adalimumab and etanercept had similar dosage-increase rates. All treatments had similar dosage-decrease and discontinuation rates. Maintenance of stable dosage was lower for infliximab than for adalimumab and etanercept. The study has the usual limitation of claims data analysis in that clinical details might be insufficient to draw causal inference. [ABSTRACT FROM AUTHOR]

Higher neutrophil-derived cytokine lipocalin-2 (LCN2) expression possesses a versatile role in a myriad of cancers, but little is known about the role of LCN2 on osteosarcoma metastasis. In this study, we demonstrated that higher LCN2 inhibited cellular motility, migration, and invasion of osteosarcoma cells. Moreover, using RNA sequencing technology, we found that LCN2 repressed MET gene expression in U2OS cells. Manipulation of LCN2 levels influenced the migratory potential of osteosarcoma cells as cellular migration was enhanced by transfecting with vectors containing a constitutively active LCN2 cDNA and recombinant human LCN2. Moreover, the phosphorylation of mitogen-activated protein kinases/extracellular signal-regulated kinase (ERK) kinase (MEK) 1/2 and ERK 1/2 was decreased by LCN2 knockdown. Furthermore, the use of ERK inhibitor (U0126) and activator (tBHQ) confirmed that the pharmaceutic inhibition of MEK–ERK augmented the LCN2-mediated MET suppression and migration of U2OS and HOS cells. Conclusively, LCN2 inhibits osteosarcoma cell metastasis by suppressing MET via the MEK–ERK pathway.

Osteosarcoma is the most common primary bone malignancy in teenagers and continues to confer a generally poor prognosis due to its highly metastatic potential. Poor solubility in water and instability of curcumin limits its bioavailability for use in the adjuvant situation to improve the prognosis and the long-term survival of patients with osteosarcoma. To further obtain information regarding the apoptosis induced by a new curcumin analog, GO-Y078, in human osteosarcoma cells, flow cytometric analysis, annexin V-FITC/PI apoptosis staining assay, human apoptosis array, and Western blotting were employed. GO-Y078 dose-dependently decreased viabilities of human osteosarcoma U2OS, MG-63, 143B, and Saos-2 cells and induced sub-G1 fraction arrest and apoptosis in U2OS and 143B cells. In addition to the effector caspase 3 and poly adenosine diphosphate-ribose polymerase, GO-Y078 significantly activated both initiators of extrinsic caspase 8 and intrinsic caspase 9, whereas cellular inhibitors of apoptosis 1 (cIAP-1) and X-chromosome-linked IAP (XIAP) in U2OS and 143B cells were significantly repressed. Moreover, GO-Y078 increased phosphorylation of extracellular signal-regulated protein kinases (ERK)1/2, c-Jun N-terminal kinases (JNK)1/2, and p38 in U2OS and 143B cells. Using inhibitors of JNK (JNK-in-8) and p38 (SB203580), GO-Y078′s increases in cleaved caspases 8, 9, and 3 could be expectedly suppressed, but they could not be affected by co-treatment with the ERK inhibitor (U0126). Altogether, GO-Y078 simultaneously induces both apoptotic pathways and cell arrest in U2OS and 143B cells through activating JNK and p38 signaling and repressing IAPs. These findings contribute to a better understanding of the mechanisms responsible for GO-Y078′s apoptotic effects on human osteosarcoma cells.