Tamoxifen (TAM) is the standard anti-hormonal therapy for estrogen receptor-positive breast cancer. However, long-term TAM therapy can make acquisition of TAM resistance and there are still no ...solutions to treat TAM-resistant breast cancer. In this study, we found that protein and mRNA expression of the P2X purinoreceptor 7 (P2X7) was higher in tamoxifen resistant MCF-7 (TAMR-MCF-7) cells than in control MCF-7 cells. P2X7 inhibition potently inhibited the migration of TAMR-MCF-7 cells and the liver metastasis burden of TAMR-MCF-7 cells in the spleen-liver metastasis experiment. However, the P2X7 antagonist did not affect protein expression of matrix metalloproteinase (MMP)-2, MMP-9, and epithelial-mesenchymal transition markers. Here our data indicate a link between small extracellular vesicles (sEV) and P2X7, and suggest a new mechanism of metastasis in TAM-resistant breast cancer cells through P2X7 receptors. The migration of TAMR-MCF-7 cells was increased in a concentration-dependent manner by purified sEV treatment. The number of secreted sEVs and the protein levels of CD63 in TAMR-MCF-7 cells were decreased by the P2X7 antagonist, showing that P2X7 influences the production of sEV. Our results suggest that inhibiting the P2X7 could be considered for metastasis prevention in TAM-resistant cancer patients.
Immunomodulatory cytokines and systemic inflammatory markers are important during cancer development and progression. This study investigated the association and prognostic impact of systemic ...cytokine profiles and inflammatory markers in colorectal cancer (CRC).
Interleukin (IL)-1β, IL-6, IL-8, IL-9, IL-10, tumour necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF) serum levels were measured using multiplex bead assays in CRC patients. Data on systemic inflammatory markers, such as the modified Glasgow prognostic score (mGPS), the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), prognostic nutritional index (PNI) and fibrinogen, were collected. Survival analysis was performed to identify factors associated with progression-free survival (PFS) and overall survival (OS).
There were moderate-to-strong correlations within serum cytokines, as well as within systemic inflammatory markers, whereas the associations between serum cytokines and systemic inflammatory markers were generally weak. IL-8 and the LMR were independent significant prognostic factors for PFS and OS. The low IL-8 and high LMR group had the best survival (both PFS and OS) of all groups.
Systemic cytokine profiles and inflammatory markers have relatively weak intergroup correlations. A composite classification of systemic cytokine profiles and inflammatory markers has an enhanced prognostic value in CRC.
The skin barrier effectively inhibits the penetration of substances; therefore, drug delivery, especially the delivery of drugs that are hydrophilic, through the skin, is challenging. Objectives: ...Physicians in the esthetic field now use the transdermal drug delivery system to attempt to deliver esthetic materials, such as hyaluronic acid and poly‐DL‐lactic acid into the skin. Conventionally, esthetic physicians manually injected these materials using needle syringes into the dermis layer. However, the injection is often irregular, imprecise, slow, and painful. Injector devices have been developed to overcome these limitations. A total of five Korean cadavers (that of three men and two women with a mean age of 69.2 years; range, 60–73 years) underwent laser injection. We used a device called Er:YAG LASER to create the pressure needed for microjet delivery to the skin of the cadaver. Discussion: In this study, the first LASER pressure‐based, needle‐free microjet injector was used to deliver drugs effectively into the dermis of a cadaver. This study showed that a novel needle‐free microjet injector using Er:YAG LASER can introduce beneficial, liquid, esthetic drugs into the papillary dermal layer (depth of 300um) with minimal epidermal damage.
It is unclear whether dietary lutein/zeaxanthin intake in colorectal cancer is associated with microRNA processing involved in DICER1 cleavage for messenger RNA translation. We investigated whether ...dietary lutein/zeaxanthin intake affects colorectal cancer risk in patients with a DICER1 rs3742330 polymorphism. In this hospital-based case-control study, we recruited 923 colorectal cancer patients and 1,846 controls based on eligibility criteria, a semiquantitative food frequency questionnaire and the DICER1 rs3742330 genotype. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusted for confounders. The highest quartile of lutein/zeaxanthin consumption was inversely associated with a reduced colorectal cancer risk (OR, 95% CI = 0.25, 0.18-0.36). Carrying G allele (AG + GG) showed a significantly reduced colorectal cancer incidence compared with that of AA carriers (OR, 95% CI = 0.71, 0.55-0.91). Those carrying the G allele (AG + GG) along with high lutein/zeaxanthin consumption were markedly associated with a decreased colorectal cancer risk (OR, 95% CI = 0.32, 0.22-0.46, P for interaction = 0.018), particularly for rectal cancer (OR, 95% CI = 0.24, 0.15-0.39, P for interaction = 0.004), compared with that of AA carriers with low lutein/zeaxanthin intakes. In conclusion, colorectal cancer risk was related to an interactive effect between dietary lutein/zeaxanthin intake and the DICER1 rs3742330 polymorphism.
Autosomal dominant non-syndromic hearing loss (AD-NSHL) is one of the most common genetic diseases in human and is well-known for the considerable genetic heterogeneity. In this study, we utilized ...whole exome sequencing (WES) and linkage analysis for direct genetic diagnosis in AD-NSHL. The Korean family had typical AD-NSHL running over 6 generations. Linkage analysis was performed by using genome-wide single nucleotide polymorphism (SNP) chip and pinpointed a genomic region on 5q31 with a significant linkage signal. Sequential filtering of variants obtained from WES, application of the linkage region, bioinformatic analyses, and Sanger sequencing validation identified a novel missense mutation Arg326Lys (c.977G>A) in the POU homeodomain of the POU4F3 gene as the candidate disease-causing mutation in the family. POU4F3 is a known disease gene causing AD-HSLH (DFNA15) described in 5 unrelated families until now each with a unique mutation. Arg326Lys was the first missense mutation affecting the 3(rd) alpha helix of the POU homeodomain harboring a bipartite nuclear localization signal sequence. The phenotype findings in our family further supported previously noted intrafamilial and interfamilial variability of DFNA15. This study demonstrated that WES in combination with linkage analysis utilizing bi-allelic SNP markers successfully identified the disease locus and causative mutation in AD-NSHL.
The high electrical resistivity of twinning induced plasticity steels makes their resistance spot welding difficult and limits their weldability. Meanwhile, liquid metal embrittlement of Zn-coated ...twinning induced plasticity steel welds is one of the most important challenges facing the scientific community. Liquid metal embrittlement also limits weldability of the steels and influences the mechanical response of welds. This work addresses this challenge by developing an innovative pathway to obtain liquid metal embrittlement-free welds which is able to extend the weldable current range of the steels. Simulations demonstrate that the method can perform a smart management of heating which is critically required to obtain embrittlement-free welds.
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Abstract Circulating tumor cells (CTCs) are recognized as promising biomarkers for diagnosis and indication of the prognosis of several epithelial cancers. However, at present, CTC monitoring is ...available only for advanced-stage patients rather than for those at an early stage of cancer. This is because of the extraordinary rarity of CTCs and the limited sensitivity of current methods. Herein, we report the development of multifunctional magnetic nanowires for the efficient isolation and detection of CTCs from the blood of patients, especially those with non-metastatic early-stage cancer. The nanowires, which are equipped with a high density of magnetic nanoparticles and five different types of antibodies (Ab mixture_mPpyNWs), offer a significant improvement in cell-isolation efficiency, even from very small amounts of blood (250 μL–1 mL). Notably, CTCs were isolated and identified in 29 out of 29 patients (100%) with non-metastatic early breast cancer, indicating that this procedure allowed detection of CTCs with greater accuracy, sensitivity, and specificity. In addition, we demonstrated in situ “naked eye” identification of the captured cancer cells via a simple colorimetric immunoassay. Our results show that antibody-functionalized magnetic nanowires offer great potential for a broad range of practical clinical applications, including early detection, diagnosis, and treatment of cancer.
We set out to investigate whether transcriptome-based molecular subtypes in lung adenocarcinoma and lung squamous cell carcinoma are predictive of the response to programmed cell death 1 blockade.
...Molecular classification of non–small cell lung cancer was performed by unsupervised clustering of mRNA sequencing data from 87 lung adenocarcinoma and 101 lung squamous cell carcinoma specimens, and molecular subtypes were characterized according to their immunogenomic determinants. A prediction algorithm of molecular subtypes was applied to 35 patients with non–small cell lung cancer treated with programmed cell death 1 blockade to test its association with treatment response (GSE93157; the Barcelona cohort).
Unsupervised hierarchical clustering of transcriptome sequencing data in lung adenocarcinoma and lung squamous cell carcinoma revealed 3 and 2 distinct clusters, respectively. Cluster 1 in each histology had a higher expression of immune regulatory molecules, increased cytolytic activity, higher interferon-γ signature, and more abundant infiltration of immune cells. Cluster 1 and other cluster(s) in lung adenocarcinoma and lung squamous cell carcinoma had immunologically-hot and immunologically-cold tumor-immune microenvironments, respectively. Immunologically-hot cluster 1 subtype is hereafter referred to as “good-tumor-immune microenvironments” and the other subtypes as “bad-tumor-immune microenvironments.” The “good-tumor–immune microenvironments” subtype in lung adenocarcinoma included a high fraction of CD8 T cells and memory B cells, but a low fraction of regulatory CD4 T cells and tumor-associated myeloid cells. Forward and backward application of our molecular subtyping to the Barcelona cohort revealed that transcriptome-based molecular subtyping is significantly associated with response to programmed cell death 1 blockade.
Molecular stratification by transcriptome sequencing data in non–small cell lung cancer identifies distinct immunomolecular subtypes that predict the response to programmed cell death 1 blockade.
The first edition of the 'Standardized Pathology Report for Colorectal Cancer,' which was developed by the Gastrointestinal Pathology Study Group (GIP) of the Korean Society of Pathologists, was ...published 13 years ago. Meanwhile, there have been many changes in the pathologic diagnosis of colorectal cancer (CRC), pathologic findings included in the pathology report, and immunohistochemical and molecular pathology required for the diagnosis and treatment of colorectal cancer. In order to reflect these changes, we (GIP) decided to make the second edition of the report. The purpose of this standardized pathology report is to provide a practical protocol for Korean pathologists, which could help diagnose and treat CRC patients. This report consists of "standard data elements" and "conditional data elements." Basic pathologic findings and parts necessary for prognostication of CRC patients are classified as "standard data elements," while other prognostic factors and factors related to adjuvant therapy are classified as "conditional data elements" so that each institution could select the contents according to the characteristics of the institution. The Korean version is also provided separately so that Korean pathologists can easily understand and use this report. We hope that this report will be helpful in the daily practice of CRC diagnosis.
Cognitive impairment is associated with a negative prognosis in amyotrophic lateral sclerosis (ALS), as well as with clinical specificity. We investigate neuropsychological function in ALS patients ...without known genetic mutations in a Korean tertiary clinic.
Three hundred and eighteen patients were enrolled in a prospective longitudinal cohort from September 2008 to February 2012. At the time of diagnosis of sporadic ALS, we carried out genetic and comprehensive neuropsychological tests on all patients, and collected demographic and clinical characteristics. Six cognitive domains, namely executive function, attention, language, calculation, visuospatial function and memory were evaluated. ANOVA and t-tests were used to assess differences in clinical characteristics and neuropsychological parameters between sporadic ALS patients. The Kaplan-Meier method and Cox proportional hazard model were used for survival analysis.
One hundred and sixty-six patients were categorized into five subtypes: normal cognition (ALS pure), cognitive impairment (ALSci), behavioral impairment (ALSbi), frontotemporal dementia (ALS-FTD), and other types of dementia. Seventy patients (70/166, 42.2%) were cognitively or behaviorally impaired. Among the impaired patients, eight (8/166, 4.8%) had FTD-type dementia and one (1/166, 0.6%) was Alzheimer's disease-type. The ALS patients with cognitive impairment (ALSci) and with FTD (ALS-FTD) were more severely impaired in executive function, attention, language and memory than the cognitively intact ALS patients (ALS pure). In a survival analysis, ALSci (β = 1.925, p = 0.025) and ALS-FTD groups (β = 4.150, p = 0.019) tended to have shorter survival than the ALS pure group.
About half of ALS patients without known genetic variation have cognitive or behavioral impairment. ALS patients with cognitive abnormalities, especially FTD, have a poorer prognosis than those without cognitive impairment. In neuropsychological profiling, executive tasks were effective in identifying cognitive impairment in the ALS patients. It would be useful for clinicians to classify ALS according to neuropsychological profiles, and screen for subtle cognitive impairment.
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