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Original citation: J Clin Invest. 2017;127(11):4179-4192. https://doi.org/10.1172/JCI91258. Citation for this corrigendum: J Clin Invest. 2024;134(8):e181338. https://doi.org/10.1172/JCI181338. The authors recently became aware that in the original Figure 2, A and C, [...]

With the insertion a segment of polarization-maintaining fiber (PMF) inside the cavity, abundant dynamics of group velocity locked vector solitons (GVLVSs) in Er-doped fiber laser have been investigated by using graphene oxide/polyvinyl alcohol (GO/PVA) film as a saturable absorber (SA). The generated Kelly sidebands in emission spectra reveal peak-valley or valley-peak alternation and slightly shift in two orthogonal components, which are the characteristics of GVLVSs. Through proper adjustment of polarization controllers (PCs) inside the EDFLs cavity, versatile vector soliton dynamics such as polarization locked GVLVSs (PL-GVLVSs), polarization rotation GVLVSs (PR-GVLVSs), dual wavelength GVLVSs, bound state GVLVSs, bunch GVLVSs and harmonic mode-locking GVLVSs (HML-GVLVSs) have been observed. The separation between two emission peaks from the dual wavelength GVLVSs was controlled by the Lyot filter and related to the insertion length of PMF inside the cavity. Unlike PL-GVLVSs, the period-doubling phenomenon has been found in two orthogonal components of the PR-GVLVSs. Besides, the bound state GVLVSs were generated showing strongly modulated interference fringes in emission spectrum. For the bunch and HML GVLVSs, the number of solitons inside the cavity increased with the pump power, and it showed the quintuple solitons and the 7th HML-GVLVSs at the highest pump power.

Abstract Purpose Adolescent and young adult cancer survivors require lifelong healthcare to address the late effects of therapy. We examined the impact of different provider models of long‐term follow‐up (LTFU) care on adherence to recommended surveillance. Methods We conducted a retrospective cohort study using administrative health databases in Ontario, Canada. Five‐year survivors were identified from IMPACT, a database of patients aged 15–20.9 years at diagnosis of six cancers between 1992 and 2010. We defined three models of LTFU care hierarchically: specialized survivor clinics (SCCs), general cancer clinics (GCCs), and family physician (FP). We assessed adherence to the Children's Oncology Group surveillance guidelines for cardiomyopathy and breast cancer. Multistate models assessed adherence transitions and impacts of LTFU attendance. Results A total of 1574 survivors were followed for a mean of 9.2 years (range 4.3–13.9 years) from index (5‐year survival). The highest level of LTFU attended in the first 2‐years post‐index was a GCC (47%); only 16.7% attended a SCC. By the end of study, 72% no longer attended any of the models of care and only 2% still attended an SCC. Among 188 survivors requiring breast cancer surveillance, 6.9% were adherent to their first required surveillance testing. Attendance at a SCC in the previous year and higher cumulative FP or GCC visits increased the rate of subsequently becoming adherent. Among 857 survivors requiring cardiomyopathy surveillance, 11% were adherent at study entry. Each subsequent SCC visit led to an 11.3% (95% CI: 1.05–1.18) increase in the rate of becoming adherent. Conclusion LTFU attendance and surveillance adherence are sub‐optimal. SCC follow‐up is associated with greater adherence, but few survivors receive such care, and this proportion diminished over time. Interventions are needed to improve LTFU attendance and promote surveillance adherence.

Hundreds of BRAF mutations have been identified in patients with cancer but currently approved drugs only target BRAF V600 mutants. Here, the authors develop a vemurafenib-based PROTAC that induces degradation of all classes of BRAF mutants without affecting wild-type RAF proteins.

The mutation of K‐RAS represents one of the most frequent genetic alterations in cancer. Targeting of downstream effectors of RAS, including of MEK and ERK, has limited clinical success in cancer patients with K‐RAS mutations. The reduced sensitivity of K‐RAS‐mutated cells to certain MEK inhibitors (MEKi) is associated with the feedback phosphorylation of MEK by C‐RAF and with the reactivation of mitogen‐activated protein kinase (MAPK) signaling. Here, we report that the RAF dimer inhibitors lifirafenib (BGB‐283) and compound C show a strong synergistic effect with MEKi, including mirdametinib (PD‐0325901) and selumetinib, in suppressing the proliferation of K‐RAS‐mutated non‐small‐cell lung cancer and colorectal cancer (CRC) cell lines. This synergistic effect was not observed with the B‐RAFV600E selective inhibitor vemurafenib. Our mechanistic analysis revealed that RAF dimer inhibition suppresses RAF‐dependent MEK reactivation and leads to the sustained inhibition of MAPK signaling in K‐RAS‐mutated cells. This synergistic effect was also observed in several K‐RAS mutant mouse xenograft models. A pharmacodynamic analysis supported a role for the synergistic phospho‐ERK blockade in enhancing the antitumor activity observed in the K‐RAS mutant models. These findings support a vertical inhibition strategy in which RAF dimer and MEKi are combined to target K‐RAS‐mutated cancers, and have led to a Phase 1b/2 combination therapy study of lifirafenib and mirdametinib in solid tumor patients with K‐RAS mutations and other MAPK pathway aberrations.

Objective To assess the efficacy of tranexamic acid (TXA) in reducing total blood loss and transfusion, and the risk of thromboembolic events in patients undergoing periacetabular osteotomy (PAO) and high tibial osteotomy (HTO). Methods A systematic literature search was performed using PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase (Ovid), Medline (Ovid), and Web of Science. ClinicalTrials.gov, American Academy of Orthopaedic Surgeons (AAOS), and Orthopaedic Trauma Association (OTA) conference proceedings were also searched to gain more eligible studies. The primary outcome measure was total blood loss and the blood transfusion rate of the TXA group versus control. The meta‐analysis was conducted using the RevMan 5.3 and Stata 14.0 software. Results A total of six studies were included involving 665 patients. Three studies were PAO, and the other three were HTO. The total blood loss in PAO (WMD, −330.49; 95% CI, −390.16 to −270.83; P

Objective To study the efficacy and safety of hematoma puncture catheter drainage under CT real-time guide for treatment of intracerebral hemorrhage (ICH). Methods A total of 80 ICH patients with hematoma volume 15-30 ml were given conservative treatment (control group, 40 cases including 6 cases with hematoma volume 15-20 ml and 34 cases with hematoma volume > 20-30 ml) and hematoma puncture and catheter drainage under CT real-time guide (operation group, 40 cases with hematoma volume > 20-30 ml). Conscious states were evaluated by Glasgow Coma Scale (GCS) on admission and 3 d after onset. Neurological deficits of patients were evaluated by National Institutes of Health Stroke Scale (NIHSS) on admission and discharge. Hospitalization days and complications (including rebleeding, epilepsy, intracranial infection, severe pulmonary infection and bleeding caused by digestive tract stress ulcer) were recorded. Results The GCS scores 3 d after onset (P = 0.000) and NIHSS scores on discharge (P = 0.000) of 2 groups were significantly lower than those on admission. The GCS score of operation group was significantly higher (P = 0.003) and NIHSS score was significantly lower (P = 0.000) than that of control group. The hospitalization time of operation group was significantly lower than those of control group [(10.53 ± 2.64) d vs. (17.30 ± 4.92) d; t = 7.673, P = 0.000]. Complications including rebleeding, intracranial infection, severe pulmonary infection and bleeding caused by digestive tract stress ulcer did not occur in patients of 2 groups. Conclusions For supratentorial hemorrhage patients withhematoma volume 15-30 ml, in comparison with conservative treatment, operation with hematoma puncture and catheter drainage under CT real-time guide can save hospitalization days, relieve edema peak response and improve the prognosis. DOI: 10.3969/j.issn.1672-6731.2018.11.007

Abstract Background Dutasteride is a potent inhibitor of 5-alpha reductase enzymes that reduces concentrations of dihydrotestosterone to a greater extent than finasteride. Whether this has adverse implications for bone health is unknown. We compared the risk of osteoporosis and fractures in older men treated with dutasteride or finasteride. Methods We conducted a population-based retrospective cohort study with high-dimensional propensity score matching of Ontario men aged 66 years or older who started treatment with dutasteride or finasteride between January 1, 2006 and December 31, 2012. The primary outcome was a diagnosis of osteoporosis within 2 years of treatment initiation. A secondary outcome was osteoporotic or fragility fractures. Results We studied 31,615 men treated with dutasteride and an equal number of men treated with finasteride. Dutasteride-treated patients had a lower incidence of osteoporosis than those receiving finasteride [2.2 versus 2.6 per 100 person years; hazard ratio (HR) 0.82; 95% confidence interval (CI) 0.72 to 0.93]. This effect was no longer statistically significant following adjustment for specialty of prescribing physician (HR 0.90; 95% CI 0.78 to 1.02)]. There was no differential risk of fractures with dutasteride (HR 1.04; 95% 0.86 to 1.25). Conclusions Despite differential effects on 5-alpha reductase, dutasteride is not associated with an increased risk of osteoporosis or fractures in older men relative to finasteride. These findings suggest that dutasteride does not adversely affect bone health.

The clinical significance of BRAF alterations in well-differentiated (WD) metastatic pancreatic neuroendocrine tumor (panNET) is unknown, but BRAF-mutated panNET could represent a subset characterized by an identifiable and clinically actionable driver. Following the identification of two patients with WD metastatic panNET whose tumors harbored BRAF mutations, we queried the MSK-IMPACT series of 80 patients with WD metastatic panNET for additional mutations in BRAF, and in other genes involved in RAS/ RTK/ PI3K signaling pathways. BRAF mutations were identified in six samples (7.5%): two tumors harbored V600E mutations, one tumor each expressed K601E, T599K, and T310I mutations, and one tumor expressed both G596D and E451K BRAF. Few additional actionable driver alterations were identified. To determine the ERK activating capability of four BRAF mutations not previously characterized, mutant constructs were tested in model systems. Biochemical characterization of BRAF mutations revealed both high and low activity mutants. Engineered cells expressing BRAF K601E and V600E were used for in vitro drug testing of RAF and MEK inhibitors currently in clinical use. BRAF K601E demonstrated reduced sensitivity to dabrafenib compared to BRAF V600E, but the combination of RAF plus MEK inhibition was effective in cells expressing this mutation. Herein, we describe the clinical course of a patient with BRAF K601E and a patient with BRAF V600E WD metastatic panNET, and the identification of four mutations in BRAF not previously characterized. The combined clinical and biochemical data support a potential role for RAF and MEK inhibitors, or a combination of these, in a selected panNET population.

The most prevalent method used for tea production makes it difficult to guarantee the tea quality due to the fact that the natural environment is bad and artificial technology level is poor. There is a pressing need to find a feasible way that can estimate tea production schedule and quality. Against this backdrop, this paper introduces the image processing technology into the quality judgment in the tea production to predict chemical constituent changes in tea such that the most appropriate production model will be available. In this study, image processing technology extracts the tea color information in the production process. PCA (principal component analysis) simulates the relationship between the color change information and the chemical composition, based on which to train the BP neural network, and also successfully predict the contents of sugars, starch, total nitrogen, alkalis, and other principal chemical components in the phases of the tea production process. This study provides a reference for tea quality judgment.

Melanomas commonly undergo a phenotype switch, from a proliferative to an invasive state. Such tumor cell plasticity contributes to immunotherapy resistance; however, the mechanisms are not completely understood and thus are therapeutically unexploited. Using melanoma mouse models, we demonstrated that blocking the MNK1/2-eIF4E axis inhibited melanoma phenotype switching and sensitized melanoma to anti-PD-1 immunotherapy. We showed that phosphoeIF4E-deficient murine melanomas expressed high levels of melanocytic antigens, with similar results verified in patient melanomas. Mechanistically, we identified phospho-eIF4E-mediated translational control of NGFR, a critical effector of phenotype switching. Genetic ablation of phospho-eIF4E reprogrammed the immunosuppressive microenvironment, exemplified by lowered production of inflammatory factors, decreased PD-L1 expression on dendritic cells and myeloid-derived suppressor cells, and increased [CD8.sup.+] T cell infiltrates. Finally, dual blockade of the MNK1/2-eIF4E axis and the PD-1/ PD-L1 immune checkpoint demonstrated efficacy in multiple melanoma models regardless of their genomic classification. An increase in the presence of intratumoral stem-like [TCF1.sup.+][PD-1.sup.+][CD8.sup.+] T cells, a characteristic essential for durable antitumor immunity, was detected in mice given a MNK1/2 inhibitor and anti-PD-1 therapy. Using MNK1/2 inhibitors to repress phospho-eIF4E thus offers a strategy to inhibit melanoma plasticity and improve response to anti-PD-1 immunotherapy., Introduction Malignant melanoma is the deadliest form of skin cancer. In melanoma, the major signaling pathways, RAS/RAF/MAPK and PI3K/AKT, are constitutively activated through numerous avenues, including genetic alterations in BRAF [...]

Melanoma can be stratified into unique subtypes based on distinct pathologies. The acral/mucosal melanoma subtype is characterized by aberrant and constitutive activation of the proto-oncogene receptor tyrosine kinase C-KIT, which drives tumorigenesis. Treatment of these melanoma patients with C-KIT inhibitors has proven challenging, prompting us to investigate the downstream effectors of the C-KIT receptor. We determined that C-KIT stimulates MAP kinase-interacting serine/threonine kinases 1 and 2 (MNK1/2), which phosphorylate eukaryotic translation initiation factor 4E (eIF4E) and render it oncogenic. Depletion of MNK1/2 in melanoma cells with oncogenic C-KIT inhibited cell migration and mRNA translation of the transcriptional repressor SNA/1 and the cell cycle gene CCNE1. This suggested that blocking MNK1/2 activity may inhibit tumor progression, at least in part, by blocking translation initiation of mRNAs encoding cell migration proteins. Moreover, we developed an MNK1/2 inhibitor (SEL201), and found that SEL201-treated KIT-mutant melanoma cells had lower oncogenicity and reduced metastatic ability. Clinically, tumors from melanoma patients harboring K/T mutations displayed a marked increase in MNK1 and phospho-eIF4E. Thus, our studies indicate that blocking MNK1/2 exerts potent antimelanoma effects and support blocking MNK1/2 as a potential strategy to treat patients positive for K/T mutations., Introduction Early-stage melanoma can be cured by surgery, but patients often develop advanced disease that requires effective systemic treatment. Melanoma arising on acral and mucosal anatomical sites accounts for about [...]

Purpose: To determine the effect of procyanidin A1 (PCA1) on sepsis. Methods: Dulbecco's Modified Eagle Medium (DMEM) was employed to incubate mouse hepatic cell line AML12. The AML12 cells treated with lipopolysaccharide (LPS, 50 µg/mL) was used to establish a sepsis cell model. Cell viability was evaluated using CCK-8 assay, while cell apoptosis was assessed by flow cytometry. Aspartate transaminase (AST), alanine aminotransferase (ALT), IL-6 and TNF-a levels were evaluated by enzyme linked immunosorbent assay (ELISA). Protein expressions were assessed using western blot assay. Results: The viability of AML12 cells decreased following treatment with IL-1ß, but this change was offset by PCA1 treatment (40 or 80 µM). Similarly, cell apoptosis was enhanced after LPS treatment, but this change was attenuated by PCA1 treatment. The AST, ALT, IL-6 and TNF-a levels were all elevated after LPS treatment, but these changes were also reversed by PCA1 treatment, indicating that PCA1 suppressed LPS-induced liver injury and inflammation. Furthermore, the protein levels of p-p65/p65 and p-IκBa increased, and IκBa lowered following LPS treatment, but these effects were reversed by PCA1 treatment, indicating that PCA1 retarded NF-κB pathway. Conclusion: PCA1 alleviates sepsis-induced liver injury by inhibiting inflammation through NF-κB pathway. This suggestes that PCA1 may be an therapeutic agent for the treatment of sepsis. [ABSTRACT FROM AUTHOR]

Many lines of evidence have indicated that both genetic and non-genetic determinants can contribute to intra-tumor heterogeneity and influence cancer outcomes. Among the best described sub-population of cancer cells generated by non-genetic mechanisms are cells characterized by a CD44+/CD24− cell surface marker profile. Here, we report that human CD44+/CD24− cancer cells are genetically highly unstable because of intrinsic defects in their DNA-repair capabilities. In fact, in CD44+/CD24− cells, constitutive activation of the TGF-beta axis was both necessary and sufficient to reduce the expression of genes that are crucial in coordinating DNA damage repair mechanisms. Consequently, we observed that cancer cells that reside in a CD44+/CD24− state are characterized by increased accumulation of DNA copy number alterations, greater genetic diversity and improved adaptability to drug treatment. Together, these data suggest that the transition into a CD44+/CD24− cell state can promote intra-tumor genetic heterogeneity, spur tumor evolution and increase tumor fitness.

Background. There are no Canadian prevalence studies on pulmonary arterial hypertension (PAH) to date. We described the characteristics of treated PAH patients and the healthcare utilization and costs associated with PAH in a population of public drug plan beneficiaries in Ontario, Canada. Methods. A retrospective cross-sectional analysis was conducted between April 2010 and March 2011 to identify treated PAH patients using population-based health administrative databases. We investigated demographic and clinical characteristics of treated PAH patients and conducted a cohort study to determine treatment patterns, healthcare utilization, and associated costs, over a one-year follow-up period (March 2012). Results. We identified 326 treated PAH cases in Ontario’s publicly funded drug plan. Overall mean age was 59.4 years (±20.3 years) and over 77% of cases were women (n=251). Combination therapy was used to treat 22.9% (n=69) of cases, costing an average of $4,569 (SD $1,544) per month. Median monthly healthcare costs were $264 (IQR $96–$747) for those who survived and $2,021 (IQR $993–$6,399) for those who died over a one-year period, respectively (p

IMPORTANCE:Without third-party insurance, access to marketed drugs is limited to those who can afford to pay. We examined this phenomenon in the context of anticoagulation for patients with nonvalvular atrial fibrillation (NVAF). OBJECTIVE:To determine whether, among older Ontarians receiving anticoagulation for NVAF, patients of higher socioeconomic status (SES) were more likely to switch from warfarin to dabigatran prior to its addition to the provincial formulary. DESIGN, SETTING AND PARTICIPANTS:Population-based retrospective cohort study of Ontarians aged 66 years and older, between 2008 and 2012. EXPOSURE:Socioeconomic status, as approximated by median neighborhood income. MAIN OUTCOMES AND MEASURE:We identified two groups of older adults with nonvalvular atrial fibrillation: those who appeared to switch from warfarin to dabigatran after its market approval but prior to its inclusion on the provincial formulary ("switchers"), and those with ongoing warfarin use during the same interval ("non-switchers"). RESULTS:We studied 34,797 patients, including 3183 "switchers" and 31,614 "non-switchers". We found that higher SES was associated with switching to dabigatran prior to its coverage on the provincial formulary (p

BACKGROUND:Smoking remains a serious public health concern. Pharmacotherapy for smoking cessation, including bupropion and varenicline, are proven means to increase quit rates. Post-marketing reports describing suicidal behaviours have raised concerns about the safety of varenicline. However, whether varenicline imparts a higher risk of suicide relative to bupropion remains uncertain. METHODS:A population-based nested case-control study in Ontario, Canada, from April 1, 2011 to March 31, 2015 was conducted. Subjects were residents of Ontario aged 18 years and older with publicly funded drug coverage receiving either bupropion or varenicline for smoking cessation. We defined cases were those with a hospitalization or emergency department visit for suicide or non-fatal self-harm within 90 days of treatment. For each case, we identified up to fifty controls from the same cohort matched on age, sex, history of self-harm, use of selected psychotropic medications, alcohol abuse and prior admission to a mental health unit. Adjusted odds ratio were used to compare the risk of suicide/self-harm of varenicline to bupropion. RESULTS:We identified 331 cases and 5,346 matched-controls. Following adjustment for potential confounders, we found that varenicline was not associated with an increased risk of suicide/self-harm relative to bupropion (adjusted odds ratio 1.15; 95% confidence interval 0.71 to 1.87). INTERPRETATION:Treatment with varenicline does not appear to significantly increase the risk of suicide or self-harm relative to bupropion.

An anionic three-dimensional framework {(Me2NH2)2[Zn8(L)6(ad)4(μ4-O)]·10DMF·11H2O}(Zn-MOF, L2− = 4,4′-(3-aminopyridine-2,5-diyl)dibenzoic acid; ad− = adeninate) with a column-layered structure was synthesized. Structural studies show that the Zn-MOF has octahedral cages [Zn8(ad)4(μ4-O)], the adjacent cages are connected by O atoms to form 1D columnar SBUs, and every four SBUs are connected by L2− to form a square channel 3D framework. Gas adsorption studies show that the BET and Langmuir surface areas of Zn-MOF are 1370.31 and 1478.04 m2 g−1, respectively, and the total pore volume for single-point adsorption is 0.528 cm3 g−1. The surface of the pores of the Zn-MOF is occupied by open metal sites and uncoordinated carboxyl groups, showing good capture ability for C2H2 and good adsorption selectivity for C2H2/CH4. More importantly, the free (CH3)2NH2+ ions present in the pores of the columnar layered Zn-MOF can cation-exchange with MB, MV, and RhB ions in aqueous solution. Therefore, Zn-MOF can not only effectively adsorb the cationic dyes MB, MV, and RhB, but also exhibit particularly selective sorption towards the mixed anion and cation dyes MB/MO and MV/MO. In addition, a series of fluorescence experiments show that Zn-MOF has good fluorescence properties, exhibiting highly selective and sensitive fluorescence detection and recognition performance for Fe3+ ions in aqueous solution with a low detection limit. [ABSTRACT FROM AUTHOR]

BACKGROUND: The knee plays an essential role in movement. There are four major ligaments in the knee which all have crucial functionalities for human activities. The anterior cruciate ligament (ACL) is the most commonly injured ligament in the knee, especially in athletes. OBJECTIVE: The aim of this study was to investigate the dynamic tensile response of the porcine ACL at strain rates from 800 to 1500 s−1 for simulations of acute injury from sudden impact or collision. METHODS: Split Hopkinson Tension Bar (SHTB) was utilized to create a dynamic tensile wave on the ACL. Stress–strain curves of strain rates between 800 s−1 to 1500 s−1 were recorded. RESULTS: The results demonstrated that the elastic modulus of the porcine ACL at higher strain rates was six to eight times higher than that of porcine and human specimens at quasi-static strain rate. However, the failure stress was quite similar while the strain was much smaller than that at the lower strain rate. CONCLUSIONS: ACL is highly strain rate sensitive and easier to break with lower failure strain when the strain rates increased to more than 1000 s−1. The stress–strain curves indicated that the sketching crimps at the slack region did not happen but switched to the sliding process of collagen fibers and was accompanied by some ruptures, which can develop into tears when strain and stress were large enough. On the other hand, the viscoelastic properties of the ligament, depending on the proteoglycan matrix and the cross-link, showed a limited value in the studied strain rate range. [ABSTRACT FROM AUTHOR]

Exosomes are small membrane vesicles released by many cells. These vesicles can mediate cellular communications by transmitting active molecules including long non‐coding RNAs (lncRNAs). In this study, our aim was to identify a panel of lncRNAs in serum exosomes for the diagnosis and recurrence prediction of bladder cancer (BC). The expressions of 11 candidate lncRNAs in exosome were investigated in training set (n = 200) and an independent validation set (n = 320) via quantitative real‐time PCR. A three‐lncRNA panel (PCAT‐1, UBC1 and SNHG16) was finally identified by multivariate logistic regression model to provide high diagnostic accuracy for BC with an area under the receiver‐operating characteristic curve (AUC) of 0.857 and 0.826 in training set and validation set, respectively, which was significantly higher than that of urine cytology. The corresponding AUCs of this panel for patients with Ta, T1 and T2‐T4 were 0.760, 0.827 and 0.878, respectively. In addition, Kaplan‐Meier analysis showed that non‐muscle‐invasive BC (NMIBC) patients with high UBC1 expression had significantly lower recurrence‐free survival (P = 0.01). Multivariate Cox analysis demonstrated that UBC1 was independently associated with tumour recurrence of NMIBC (P = 0.018). Our study suggested that lncRNAs in serum exosomes may serve as considerable diagnostic and prognostic biomarkers of BC. [ABSTRACT FROM AUTHOR]

Lung cancer is the first leading cause of cancer deaths worldwide. Non‐small cell lung cancer (NSCLC) is the most common type of lung cancer. Increasing evidence shows that long noncoding RNA (lncRNA) are capable of modulating tumor initiation, proliferation and metastasis. In the present study, we aimed to evaluate whether circulating lncRNA could be used as biomarkers for diagnosis and prognosis of NSCLC. Expression profiles of 14 lncRNA selected from other studies were validated in 20 pairs of tissues by quantitative real‐time PCR, and the dysregulated lncRNA thus identified were further validated in serum samples from two independent cohorts along with three tumor makers (CEA, CYFRA21‐1, and SCCA). Receiver‐operating characteristic analysis was utilized to estimate the diagnostic efficiency of the candidate lncRNA and tumor markers. Importantly, we observed an association between lncRNA expression and overall survival (OS) rate of NSCLC. The expressions of SOX2 overlapping transcript (SOX2OT) and ANRIL were obviously upregulated in NSCLC tissues and serum samples compared with normal controls (P < 0.01). Based on the data from the training set, we next used a logistic regression model to construct an NSCLC diagnostic panel consisting of two lncRNA and three tumor markers. The area under the curve of this panel was 0.853 (95% confidence interval = 0.804–0.894, sensitivity = 77.1%, specificity = 79.2%), and this was distinctly superior to any biomarker alone (all at P < 0.05). Similar results were observed in the validation set. Intriguingly, Kaplan–Meier analysis demonstrated that low expressions of SOX2OT and ANRIL were both associated with higher OS rate (P = 0.008 and 0.017, respectively), and SOX2OT could be used as an independent prognostic factor (P = 0.036). Taken together, our study demonstrated that the newly developed diagnostic panel consisting of SOX2OT, ANRIL, CEA, CYFRA21‐1, and SCCA could be valuable in NSCLC diagnosis. LncRNA SOX2OT and ANRIL might be ideal biomarkers for NSCLC prognosis. [ABSTRACT FROM AUTHOR]

Background: Dabigatran etexilate is a prodrug whose absorption is opposed by intestinal P-glycoprotein and which is converted by carboxylesterase to its active form, dabigatran. Unlike other statins, simvastatin and lovastatin are potent inhibitors of P-glycoprotein and carboxylesterase, and might either increase the risk of hemorrhage with dabigatran etexilate or decrease its effectiveness.Methods: We conducted 2 population-based, nested case-control studies involving Ontario residents 66 years of age and older who started dabigatran etexilate between May 1, 2012, and Mar. 31, 2014. In the first study, cases were patients with ischemic stroke; in the second, cases were patients with major hemorrhage. Each case was matched with up to 4 controls by age and sex. All cases and controls received a single statin in the 60 days preceding the index date. We determined the association between each outcome and the use of simvastatin or lovastatin, relative to other statins.Results: Among 45 991 patients taking dabigatran etexilate, we identified 397 cases with ischemic stroke and 1117 cases with major hemorrhage. After multivariable adjustment, use of simvastatin or lovastatin was not associated with an increased risk of stroke (adjusted odds ratio [OR] 1.33, 95% confidence interval [CI] 0.88 to 2.01). In contrast, use of simvastatin and lovastatin were associated with a higher risk of major hemorrhage (adjusted OR 1.46, 95% CI 1.17 to 1.82).Interpretation: In patients receiving dabigatran etexilate, simvastatin and lovastatin were associated with a higher risk of major hemorrhage relative to other statins. Preferential use of the other statins should be considered in these patients. [ABSTRACT FROM AUTHOR]