Claudins (CLDNs) are a family of integral membrane proteins central to the formation of tight junctions, structures that are involved in paracellular transport and cellular growth and ...differentiation, and are critical for the maintenance of cellular polarity. Recent studies have provided evidence that CLDNs are aberrantly expressed in diverse types of human cancers, including hepatocellular carcinomas (HCCs). However, little is known about how CLDN expression is involved in cancer progression. In this study, we show that CLDN1 has a causal role in the epithelial-mesenchymal transition (EMT) in human liver cells, and that the c-Abl-Ras-Raf-1-ERK1/2 signaling axis is critical for the induction of malignant progression by CLDN1. Overexpression of CLDN1 induced expression of the EMT-regulating transcription factors Slug and Zeb1, and thereby led to repression of E-cadherin, β-catenin expression, enhanced expression of N-cadherin and Vimentin, a loss of cell adhesion, and increased cell motility in normal liver cells and HCC cells. In line with these findings, inhibition of either c-Abl or ERK clearly attenuated CLDN1-induced EMT, as evidenced by a reversal of N-cadherin and E-cadherin expression patterns, and restored normal motility. Collectively, these results indicate that CLDN1 is necessary for the induction of EMT in human liver cells, and that activation of the c-Abl-Ras-Raf-1-ERK1/2 signaling pathway is required for CLDN1-induced acquisition of the malignant phenotype. The present observations suggest that CLDN1 could be exploited as a biomarker for liver cancer metastasis and might provide a pivotal point for therapeutic intervention in HCC.
Summary
This study provides long-term evidence that healthcare resource utilization and costs of care in women who experienced incident osteoporotic fractures remained higher than those in women ...without fractures over a span of 5 years. These findings emphasize the importance of early diagnostics and treatment for osteoporosis.
Purpose
To evaluate healthcare resource utilization (HCRU) and costs of care over 5 years after the incident osteoporotic fractures (OF) in postmenopausal women.
Methods
We used data from the National Health Insurance Service databases 2011–2018. Women aged ≥ 50 years with incident OF (OF group) were matched to women without OF (non-OF group). HCRU (inpatient, outpatient, and emergency room ER visits) and costs of care (inpatient, outpatient, and ER visits) during the 5-year follow-up period were derived after propensity score matching (PSM). Additionally, we identified women with subsequent fractures within the first 2 years after the incident OF.
Results
After PSM, 47,238 OF and 134,813 non-OF women were identified. HCRU rates and costs of care were highest in the first year after OF and decreased substantially, but remained higher in the OF group during the entire follow-up period. The increase in cumulative HCRU rates over 5 years was highest in inpatient admissions with ER visits (138% higher in OF vs non-OF). The cumulative total costs over 5 years were 73% higher in the OF group than in the non-OF group, which was mostly driven by inpatient costs. Trends were similar for women with subsequent fractures, but they generally showed higher HCRU and costs than those in the total OF group.
Conclusion
OF imposes a substantial and sustained economic burden on women, resulting in an approximately twofold increase in the cumulative cost over 5 years compared to women without fracture, which highlights the need for early diagnostics and treatment of osteoporosis.
Summary
Background
B cells play many roles in health and disease. However, little is known about the mechanisms that drive B cell responses in the airways, especially in humans. Chronic ...rhinosinusitis (CRS) is an inflammatory disease of the upper airways that affects 10% of Europeans and Americans. A subset of CRS patients develop nasal polyps (NPs), which are characterized by type 2 inflammation, eosinophils and group 2 innate lymphoid cells (ILC2s). We have reported that NP contain elevated levels of B cells and antibodies, making NP an ideal system for studying B cells in the airways.
Objective
We sought to determine the mechanisms that drive B cell activation and antibody production during chronic airway inflammation.
Methods
We analysed B cells from NP or tonsil, or after ILC2 coculture, by flow cytometry. Antibody production from tissue was measured using Luminex assays and the frequency of antibody‐secreting cells by ELISpot. Formation of B cell clusters was assessed using immunohistochemistry. Expression of genes associated with B cell activation and class switch recombination was measured by qRT‐PCR.
Results
NP contained significantly elevated frequencies of plasmablasts, especially those that expressed the extrafollicular marker Epstein–Barr virus‐induced protein 2 (EBI2), but significantly fewer germinal centre (GC) B cells compared with tonsil. Antibody production and the frequency of antibody‐secreting cells were significantly elevated in NP, and there was evidence for local class switch recombination in NP. Finally, ILC2s directly induced EBI2 expression on B cells in vitro.
Conclusions and Clinical Relevance
Our data suggest there is a unique B cell activation environment within NP that is distinct from classic GC‐mediated mechanisms. We show for the first time that ILC2s directly induce EBI2 expression on B cells, indicating that ILC2s may play an important role in B cell responses. B cell‐targeted therapies may provide new treatment options for CRSwNP.
There have been inconsistencies on the prognosis and controversies as to the proper management of acute basilar artery dissection. The aim of this study was to evaluate acute basilar artery ...dissection and its outcome after management.
A total of 21 patients (mean age, 53 years; range, 24-78 years) with acute basilar artery dissection were identified between January 2001 and October 2007. Clinical presentation, management, and outcomes were retrospectively evaluated.
The patients presented with subarachnoid hemorrhage (n = 10), brain stem ischemia (n = 10), or stem compression sign (n = 1). Ruptured basilar artery dissections were treated by stent placement with coiling (n = 4), single stent placement (n = 3), or conservatively (n = 3). Of the patients treated with endovascular technique, 6 had favorable outcome (modified Rankin scale mRS, 0-2) and the remaining patient, who was treated by single stent placement, died from rebleeding. All 3 conservatively managed patients experienced rebleeding, of whom 2 died and the other was moderately disabled. Unruptured basilar artery dissections were treated conservatively (n = 7) or by stent placement (n = 4). Of the patients with unruptured basilar artery dissection, 9 had favorable outcome and the remaining 2 patients, both of whom were conservatively managed, had poor outcome because of infarct progression. The group with the ruptured basilar artery dissection revealed a higher mortality rate than the group with the unruptured dissection (30% vs 0%). The group treated with endovascular means revealed more favorable outcome than the group that was treated with conservative measures (90.9% vs 50%).
The ruptured basilar artery dissections were at high risk for rebleeding, resulting in a grave outcome. Stent placement with or without coiling may be considered to prevent rebleeding in ruptured basilar dissections and judiciously considered in unruptured dissections with signs of progressive brain stem ischemia.
Approximately half of generalised anxiety disorder (GAD) patients do not recover from first-line treatments, and no validated prediction models exist to inform individuals or clinicians of potential ...treatment benefits. This study aimed to develop and validate an accurate and explainable prediction model of post-treatment GAD symptom severity. Data from adults receiving treatment for GAD in eight Improving Access to Psychological Therapies (IAPT) services (n=15,859) were separated into training, validation and holdout datasets. Thirteen machine learning algorithms were compared using 10-fold cross-validation, against two simple clinically relevant comparison models. The best-performing model was tested on the holdout dataset and model-specific explainability measures identified the most important predictors. A Bayesian Additive Regression Trees model out-performed all comparison models (MSE=16.54 95 % CI=15.58; 17.51; MAE=3.19; R²=0.33, including a single predictor linear regression model: MSE=20.70 95 % CI=19.58; 21.82; MAE=3.94; R²=0.14). The five most important predictors were: PHQ-9 anhedonia, GAD-7 annoyance/irritability, restlessness and fear items, then the referral-assessment waiting time. The best-performing model accurately predicted post-treatment GAD symptom severity using only pre-treatment data, outperforming comparison models that approximated clinical judgement and remaining within the GAD-7 error of measurement and minimal clinically important differences. This model could inform treatment decision-making and provide desired information to clinicians and patients receiving treatment for GAD.
Summary
Fracture-related costs vary by country. A standardized methodology and presentations were proposed to fairly assess the economic burden of osteoporotic fracture. Results indicated substantial ...costs of osteoporotic fractures for pharmacy, hospitalization, emergency care, and outpatient visits in women aged ≥ 50 years in Australia, Germany, South Korea, Spain, and the USA.
Purpose
The objective of this multinational, retrospective matched cohort study was to use a standardized methodology across different healthcare systems to estimate the burden of osteoporotic fracture (OF) in women aged ≥ 50 years in Australia, Germany, South Korea, Spain, and the USA.
Methods
Within each country, healthcare resource utilization and direct costs of care were compared between patients with newly identified OF and a propensity score–matched cohort without OF during follow-up periods of up to 5 years.
Results
Across all five countries, the OF cohort had significantly higher rates and length of inpatient admissions compared with the non-OF cohort. In each country, the adjusted total costs of care ratio between OF and non-OF cohorts were significant. The adjusted cost ratios for pharmacy, inpatient care, emergency care, and outpatient visits were similarly higher in the OF cohort across countries.
Conclusion
The current study demonstrates the substantial economic burden of OF across different countries when compared with matched non-OF patients. The findings would assist stakeholders and policymakers in developing appropriate health policies.
Uncovering the mechanisms that govern the maintenance of stem-like cancer cells is critical for developing therapeutic strategies for targeting these cells. Constitutive activation of c-Jun ...N-terminal kinase (JNK) has been reported in gliomas and correlates with histological grade. Here, we found that JNK signaling is crucial for the maintenance of 'stemness' in glioma cells. Sphere-cultured glioma cells showed more phosphorylation of JNK compared with serum-containing monolayer cultures. Importantly, blockade of JNK signaling with SP600125 or small interfering RNAs targeting JNK1 or JNK2 significantly reduced the CD133(+)/Nestin(+) population and suppressed sphere formation, colony formation in soft agar, and expression of stem cell markers in sphere-cultured glioma cells. Intriguingly, sphere-cultured glioma cells exhibited enhanced expression of Notch-2, but not Notch-1, -3 or -4, and JNK inhibition almost completely abrogated this increase. Blocking the phosphoinoside 3-kinase (PI3K)/Akt pathway with LY294002 or si-Akt also suppressed the self-renewal of sphere-cultured glioma cells. PI3K, but not Akt, had a role as an upstream kinase in JNK1/2 activation. In addition, treatment with si-JNK greatly increased etoposide- and ionizing radiation (IR)-induced cell death in glioma spheres. Consistent with glioma cell lines, glioma stem-like cells isolated from primary patient glioma cells also had a higher activity of JNK and Notch-2 expression. Importantly, inhibition of JNK2 led to a decrease of Notch-2 expression and suppressed the CD133(+)/Nestin(+) cell population in patient-derived primary glioma cells. Finally, downregulation of JNK2 almost completely suppressed intracranial tumor formation by glioma cells in nude mice. Taken together, these data demonstrate that JNK signaling is crucial for the maintenance of self-renewal and tumorigenicity of glioma stem-like cells and drug/IR resistance, and can be considered a promising target for eliminating stem-like cancer cells in gliomas.
Endocrine treatment is recommended by clinical guidelines as the preferred treatment option for premenopausal as well as postmenopausal women with hormone receptor-positive, HER2-negative metastatic ...breast cancer. In real-world clinical practice, however, a substantial number of patients are treated with chemotherapy. We aimed to compare the clinical antitumour activity and safety of palbociclib plus endocrine therapy with that of capecitabine chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.
This multicentre, open-label, randomised, phase 2 study was done in 14 academic institutions in South Korea. Premenopausal women aged 19 years or older with hormone receptor-positive, HER2-negative breast cancer that had relapsed or progressed during previous tamoxifen therapy and with an Eastern Cooperative Oncology Group performance status of 0–2 were included. One line of previous chemotherapy for metastatic breast cancer was allowed. Patients were randomly assigned, using a random permuted block design (with a block size of two), to receive palbociclib plus combination endocrine therapy (oral exemestane 25 mg per day for 28 days and oral palbociclib 125 mg per day for 21 days every 4 weeks plus leuprolide 3·75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks). Randomisation was stratified by previous chemotherapy for metastatic breast cancer and visceral metastasis. The primary endpoint was progression-free survival. All analyses were done in a modified intention-to-treat population that excluded patients who did not receive study medication. This study is registered with ClinicalTrials.gov, NCT02592746, and is ongoing for follow-up of overall survival.
Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled, of whom 184 were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92). Six patients in the capecitabine group withdrew from the study before drug administration; therefore, 92 patients in the palbociclib plus endocrine therapy group and 86 patients in the capecitabine group were included in the modified intention-to-treat analyses. 46 (50%) of 92 patients in the palbociclib plus endocrine therapy group and 45 (51%) of 92 in the capecitabine group were treatment naive for metastatic breast cancer. During a median follow-up of 17 months (IQR 9–22), median progression-free survival was 20·1 months (95% CI 14·2–21·8) in the palbociclib plus endocrine therapy group versus 14·4 months (12·1–17·0) in the capecitabine group (hazard ratio 0·659 95% CI 0·437–0·994, one-sided log-rank p=0·0235). Treatment-related grade 3 or worse neutropenia was more common in the palbociclib plus endocrine therapy group than in the capecitabine group (69 75% of 92 vs 14 16% of 86 patients). 2 (2%) patients in the palbociclib plus endocrine therapy group and 15 (17%) patients in the capecitabine group had treatment-related serious adverse events. No treatment-related deaths occurred.
Exemestane plus palbociclib with ovarian function suppression showed clinical benefit compared with capecitabine in terms of improved progression-free survival in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Palbociclib plus exemestane with ovarian suppression is an active treatment option in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have been pretreated with tamoxifen.
Pfizer, Shinpoong, and Daewoong Korea and Takeda.
ABSTRACT
Neptunian Trojans (NTs), trans-Neptunian objects in 1:1 mean-motion resonance with Neptune, are generally thought to have been captured from the original trans-Neptunian protoplanetary disc ...into co-orbital resonance with the ice giant during its outward migration. It is possible, therefore, that the colour distribution of NTs is a constraint on the location of any colour transition zones that may have been present in the disc. In support of this possible test, we obtained g, r, and i-band observations of 18 NTs, more than doubling the sample of NTs with known visible colours to 31 objects. Out of the combined sample, we found ≈4 objects with g –i colours of >1.2 mags placing them in the very red (VR) category as typically defined. We find, without taking observational selection effects into account, that the NT g – i colour distribution is statistically distinct from other trans-Neptunian dynamical classes. The optical colours of Jovian Trojans and NTs are shown to be less similar than previously claimed with additional VR NTs. The presence of VR objects among the NTs may suggest that the location of the red to VR colour transition zone in the protoplanetary disc was interior to 30 – 35 au.
Antibiotic stewardship programmes (ASPs) are necessary in hospitals to improve the judicious use of antibiotics. While ASPs require complex change of key behaviours on individual, team organization ...and policy levels, evidence from the behavioural sciences is underutilized in antibiotic stewardship studies across the world, including high-income countries (HICs). A consensus procedure was performed to propose research priority areas for optimizing effective implementation of ASPs in hospital settings using a behavioural perspective.
A workgroup for behavioural approaches to ASPs was convened in response to the fourth call for leading expert network proposals by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR). Eighteen clinical and academic specialists in antibiotic stewardship, implementation science and behaviour change from four HICs with publicly funded healthcare systems (e.g. Canada, Germany, Norway and the UK) met face-to-face to agree on broad research priority areas using a structured consensus method.
Question addressed and recommendations: The consensus process assessing the ten identified research priority areas resulted in recommendations that need urgent scientific interest and funding to optimize effective implementation of ASPs for hospital inpatients in HICs with publicly funded healthcare systems. We suggest and detail behavioural science evidence–guided research efforts in the following areas: (a) comprehensively identifying barriers and facilitators to implementing ASPs and clinical recommendations intended to optimize antibiotic prescribing; (b) identifying actors (‘who’) and actions (‘what needs to be done’) of ASPs and clinical teams; (c) synthesizing available evidence to support future research and planning for ASPs; (d) specifying the activities in current ASPs with the purpose of defining a control group for comparison with new initiatives; (e) defining a balanced set of outcomes and measures to evaluate the effects of interventions focused on reducing unnecessary exposure to antibiotics; (f) conducting robust evaluations of ASPs with built-in process evaluations and fidelity assessments; (g) defining and designing ASPs; (h) establishing the evidence base for impact of ASPs on resistance; (i) investigating the role and impact of government and policy contexts on ASPs; and (j) understanding what matters to patients in ASPs in hospitals.
Assessment, revisions and updates of our priority-setting exercise should be considered at intervals of 2 years. To propose research priority areas in low- and middle-income countries, the methodology reported here could be applied.
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