Conventional smear (CS) using fine-needle aspiration cytology (FNAC) has been established as the test of choice for diagnosing thyroid lesions, despite low sample adequacy and inter-individual variations. Although a liquid-based preparation (LBP) technique has been recently applied to overcome these limitations, its clinical utility and its accuracy over CS are controversial. This study aimed to determine the true sensitivity and specificity of LBP in thyroid FNAC by meta-analysis.

To assess the quality and completeness of published reports of randomized controlled trials (RCTs) of moxibustion.

Periampullary cancers (PAC) including pancreatic, ampulla of Vater (AOV), and common bile duct (CBD) cancers are highly aggressive with a lack of useful prognostic markers beyond T stage. However, T staging can be biased due to the anatomic complexity of this region. Recently, several markers related to cancer stem cells and epithelial-mesenchymal transition (EMT) such as octamer transcription factor-4 (Oct4) and fibroblast growth factor receptor 1 (FGFR1) respectively, have been proposed as new promising markers in other solid cancers. The aim of this study was to assess the expression and prognostic significance of stem cell/EMT markers in PACs.

To investigate the potential relationship between septal deviation (SD) and headache using nationwide representative cohort sample data.This study used a nationwide cohort sample from the Korean National Health Insurance Service database. The cohort sample was composed of 1 million patients, which is obtained by propensity score matching from 2002 to 2013. There were 9171 individuals in the SD group and 28243 in the control or no SD group. The Kaplan-Meier survival analysis, the log-rank test, and Cox proportional hazard regression analysis were used to calculate the incidence, survival curve, and hazard ratio of headache for each group.There were no statistically significant differences in sex (P = .7708), age (P = .991), residential area (P = .9626), or socioeconomic status (P = .9982) between the 2 groups. The survival curve between SD and control or no SD showed a statistically significant difference. The adjusted hazard ratio for headache incidence during the 10-year follow-up period of the SD group was 1.37 (95% CI: 1.31-1.43).This cohort study suggests that SD is associated with headache. Therefore, these findings suggest that septoplasty can be considered as 1 of the treatment option in SD patients with headache.

Mechanisms of deep brain stimulation (DBS) remain controversial, and spatiotemporal control of brain-wide circuits remains elusive. Adeno-associated viral (AAV) vectors have emerged as vehicles for spatiotemporal expression of exogenous transgenes in several tissues, including specific nuclei in the brain. Coupling DBS with viral vectors to modulate exogenous transgene expression remains unexplored.

Glycosylation alterations are indicative of tissue inflammation and neoplasia, but whether these alterations contribute to disease pathogenesis is largely unknown. To study the role of glycan changes in pancreatic disease, we inducibly expressed human fucosyltransferase 3 and β1,3-galactosyltransferase 5 in mice, reconstituting the glycan sialyl-Lewisa, also known as carbohydrate antigen 19-9 (CA19-9). Notably, CA19-9 expression in mice resulted in rapid and severe pancreatitis with hyperactivation of epidermal growth factor receptor (EGFR) signaling. Mechanistically, CA19-9 modification of the matricellular protein fibulin-3 increased its interaction with EGFR, and blockade of fibulin-3, EGFR ligands, or CA19-9 prevented EGFR hyperactivation in organoids. CA19-9-mediated pancreatitis was reversible and could be suppressed with CA19-9 antibodies. CA19-9 also cooperated with the KrasG12D oncogene to produce aggressive pancreatic cancer. These findings implicate CA19-9 in the etiology of pancreatitis and pancreatic cancer and nominate CA19-9 as a therapeutic target.

Here we report a novel combination of a caspase-cleavable peptide-doxorubicin conjugate (MPD-1) with CD47-antagonizing nanocage therapeutics for the treatment of microsatellite-stable (MSS) colorectal cancer (CRC). MPD-1 (i) upregulated markers of immunogenic cell death (ICD) in tumor, and increased co-stimulatory markers on dendritic cells (DCs), (ii) enhanced CD8+ T cell infiltration and antigen presenting cell (APC) activation, and (iii) showed negligible off-target immune-related toxicity compared to free dox. Then, the CD47 antagonist FS nanocage, a SIRPα-expressing ferritin nanocage, was co-administered with MPD-1 that resulted in 95.2% (p < 0.001) tumor growth inhibition in an established CRC model. T cell-mediated elimination of tumors was also confirmed by the tumor-specific activation of T cells detected by IFNγ and tumor-free mice were observed (95%) that bared a memory response when re-challenged. The strategically developed MPD-1 is an ideal adjuvant to immunotherapy and the combination with FS nanocage triggers potent immunity against MSS CRC. In summary, we present an approach to initiate and stimulate immune-mediated eradication of cancer cells using synergistic immunogenic agents targeting the MSS CRC.

This study aimed to evaluate the risk of developing chronic otitis media with effusion (OME) in individuals with gastroesophageal reflux disease (GERD).A retrospective propensity score-matched cohort study was performed using data from the Korea National Health Insurance Service. The GERD group (n = 3532) included certain individuals who had been diagnosed with GERD between January 2002 and December 2005. A comparison control group (n = 14,128) was calculated by 1:4 propensity score matching considering age, sex, and comorbidities and year of enrollment. Each patient was monitored until 2013. Survival analysis, the Log-rank test, and Cox proportional hazard regression models were used to calculate the incidence, survival rate, and hazard ratio (HR) of chronic OME for each group.Among the 17,660 individuals included in the study population (53.2% men), the overall incidence of chronic OME during the 11-year follow-up was 1.84-fold higher in the GERD group than in the non-GERD group (1.8 vs 3.0 per 1000 person-year; adjusted HR 1.84; 95% confidence interval [CI], 1.46-2.31). Moreover, the adjusted HRs of developing chronic OME (allergic rhinitis, 1.69 [95% CI, 1.37-2.10]; asthma, 1.29 [95% CI, 1.02-1.64]; chronic rhinosinusitis, 1.61 [95% CI, 1.26-2.05]) were greater in study population with comorbidities.From long-term follow-up, the prevalence of chronic OME in adults was 1.84 times higher in the GERD group compared with the non-GERD group. Specifically, it found that allergic rhinitis, asthma, or chronic rhinosinusitis showed increase the risk of developing chronic OME than those without these conditions.

Screening programs for colorectal cancer (CRC) often rely on detection of blood in stools, which is unspecific and leads to a large number of colonoscopies of healthy subjects. Painstaking research has led to the identification of a large number of different types of biomarkers, few of which are in general clinical use. Here, we searched for highly accurate combinations of biomarkers by meta-analyses of genome- and proteome-wide data from CRC tumors. We focused on secreted proteins identified by the Human Protein Atlas and used our recently described algorithms to find optimal combinations of proteins. We identified nine proteins, three of which had been previously identified as potential biomarkers for CRC, namely CEACAM5, LCN2 and TRIM28. The remaining proteins were PLOD1, MAD1L1, P4HA1, GNS, C12orf10 and P3H1. We analyzed these proteins in plasma from 80 patients with newly diagnosed CRC and 80 healthy controls. A combination of four of these proteins, TRIM28, PLOD1, CEACAM5 and P4HA1, separated a training set consisting of 90% patients and 90% of the controls with high accuracy, which was verified in a test set consisting of the remaining 10%. Further studies are warranted to test our algorithms and proteins for early CRC diagnosis.

Few attempts have been made to investigate the prognostic value of dynamic contrast-enhanced (DCE) MRI or dynamic susceptibility contrast (DSC) MRI of non-enhancing, T2-high-signal-intensity (T2-HSI) lesions of glioblastoma multiforme (GBM) in newly diagnosed patients. This study aimed to investigate the prognostic values of DCE MRI and DSC MRI parameters from non-enhancing, T2-HSI lesions of GBM.

To investigate the association between peripheral vasospasm and the visual field (VF) progression rate in patients with normal-tension glaucoma (NTG) with low-teen intraocular pressure (IOP).

OTX2 (orthodenticle homeobox 2) haplodeficiency causes diverse defects in mammalian visual systems ranging from retinal dysfunction to anophthalmia. We find that the retinal dystrophy of Otx2(+/GFP) heterozygous knockin mice is mainly due to the loss of bipolar cells and consequent deficits in retinal activity. Among bipolar cell types, OFF-cone bipolar subsets, which lack autonomous Otx2 gene expression but receive Otx2 proteins from photoreceptors, degenerate most rapidly in Otx2(+/GFP) mouse retinas, suggesting a neuroprotective effect of the imported Otx2 protein. In support of this hypothesis, retinal dystrophy in Otx2(+/GFP) mice is prevented by intraocular injection of Otx2 protein, which localizes to the mitochondria of bipolar cells and facilitates ATP synthesis as a part of mitochondrial ATP synthase complex. Taken together, our findings demonstrate a mitochondrial function for Otx2 and suggest a potential therapeutic application of OTX2 protein delivery in human retinal dystrophy.

The aim of this study was to determine factors influencing the hand hygiene compliance of a physician. We found a strong correlation between a leader's (staff member's or fellow's) and a follower's (resident's) hand hygiene compliance. Followers' appropriate hand hygiene compliance was significantly associated with the compliance of the leader (P = .01).

T helper (Th) 17 cells are a subset of T helper cells that express interleukin (IL)-17 and initiate the inflammatory response in autoimmune diseases. Regulatory T cells (Tregs) are a subpopulation of T cells that produce forkhead box P3 (FOXP3) and inhibit the immune response. Graft versus host disease (GVHD) is a complication of allogeneic tissue transplantation, and Th17 cells and their proinflammatory activity play a central role in the pathogenesis of GVHD. Gene associated with retinoid-interferon-induced mortality (GRIM) 19, originally identified as a nuclear protein, is expressed ubiquitously in various human tissues and regulate signal transducer and activator of transcription (STAT)3 activity.

Xylose, the second most abundant sugar in lignocellulosic biomass hydrolysates, can be fermented by Saccharomyces cerevisiae expressing one of two heterologous xylose pathways: a xylose oxidoreductase pathway and a xylose isomerase pathway. Depending on the type of the pathway, its optimization strategies and the fermentation efficiencies vary significantly. In the present study, we constructed two isogenic strains expressing either the oxidoreductase pathway (XYL123) or the isomerase pathway (XI-XYL3), and delved into simple and reproducible ways to improve the resulting strains. First, the strains were subjected to the deletion of PHO13, overexpression of TAL1, and adaptive evolution, but those individual approaches were only effective in the XYL123 strain but not in the XI-XYL3 strain. Among other optimization strategies of the XI-XYL3 strain, we found that increasing the copy number of the xylose isomerase gene (xylA) is the most promising but yet preliminary strategy for the improvement. These results suggest that the oxidoreductase pathway might provide a simpler metabolic engineering strategy than the isomerase pathway for the development of efficient xylose-fermenting strains under the conditions tested in the present study.

Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness, generally affecting people over 50 years of age in industrialized countries. Despite the effectiveness of anti-vascular endothelial growth factor (VEGF) therapy in attenuating the growth of new blood vessels, substantial visual improvements are rare with this complex disease. Furthermore, the current regimen of repeated monthly intravitreal injections of drugs can result in serious side effects. Combination therapies-to complement anti-VEGF alone-with a prolonged therapeutic effect and efficient delivery to the intended site are urgently needed, which could be realized through the use of carefully designed nanocarriers. To understand the physicochemical effects (e.g., size, charge, geometry) of intravitreally administered nanocarriers on their bioavailability, distribution, and targeting efficiency across multiple layers of the retina, here we prepared seven different types of surface-functionalized water-soluble dendritic nanocarriers with hydrodynamic sizes mostly under 5 nm. A similar stoichiometric amount of fluorophore was covalently attached to each of these biocompatible nanocarriers for quantitative analyses by confocal microscopy of cryosectioned healthy mouse eyes. Interestingly, at 24 h post-injection, the nanocarrier with multiple copies of glucosamine on the surface (DNSG) accumulated predominantly in the photoreceptor layer and the retinal pigment epithelium (RPE), which are speculated to be associated with AMD pathogenesis (i.e., target sites). Furthermore, extended residence at these outer retinal layers was demonstrated by DNSG, which appeared to gradually turn into micron-scale particles potentially through aggregation. Our systematic findings may provide useful guidelines for the rational design of intravitreal nanocarriers to treat vision-threatening retinal diseases, including AMD.

Activation of T cell immune response is critical for the therapeutic efficacy of cancer immunotherapy. Current immunotherapies have shown remarkable clinical success against several cancers; however, significant responses remain restricted to a minority of patients. Here, we show a therapeutic strategy that combines enhancing the phagocytic activity of antigen-presenting cells with immunogenic cell death to trigger efficient antitumour immunity. Rho-kinase (ROCK) blockade increases cancer cell phagocytosis and induces antitumour immunity through enhancement of T cell priming by dendritic cells (DCs), leading to suppression of tumour growth in syngeneic tumour models. Combining ROCK blockade with immunogenic chemotherapy leads to increased DC maturation and synergistic CD8+ cytotoxic T cell priming and infiltration into tumours. This therapeutic strategy effectively suppresses tumour growth and improves overall survival in a genetic mouse mammary tumour virus/Neu tumour model. Collectively, these results suggest that boosting intrinsic cancer immunity using immunogenic killing and enhanced phagocytosis is a promising therapeutic strategy for cancer immunotherapy.

Tumor-specific apoptosis-inducing ligands have attracted considerable attention in cancer therapy. But, the evasion of apoptosis by tumors can cause acquired resistance to the therapy. TNF-related apoptosis-inducing ligand (TRAIL) has been investigated as an ideal antitumor agent owing to its inherent tumor cell-specific apoptotic activity. However, there are several barriers to its wider application, including the inability for stable formation of the trimeric structure, poor stability and pharmacokinetics, and differences in the sensitivity of different tumor types. Especially, almost 70% of tumor cells have acquired resistance to TRAIL, leading to failure of TRAIL-based therapeutics in clinical trials. To overcome therapeutic efficiency limitations against TRAIL-resistant tumors, we exploited the characteristic of a naturally derived nanocage that not only delivers TRAIL in its native-like trimeric structure, but also delivers a drug (doxorubicin [DOX]) that re-sensitizes TRAIL-resistant tumor cells. These TRAIL-presenting nanocages (TTPNs) showed high loading efficiency, pH-dependent release profiles, and effective intracellular delivery of the re-sensitizing agent DOX. As a result, DOX-TTPNs efficiently re-sensitized TRAIL-resistant tumor cells to TRAIL-mediated apoptosis in vitro by regulating levels of the TRAIL receptor, DR5, and anti- and pro-apoptotic proteins involved in extrinsic and intrinsic apoptosis pathways. We further demonstrated the antitumor efficacy of DOX-TTPNs in vivo, showing that even at a very low dose, the incorporated DOX successfully re-sensitized tumors to the apoptotic effects of TRAIL, underscoring the potential of this platform as an antitumor agent. Given that other homotrimeric TNF superfamily ligands and immunotherapeutic agents can be substituted for TRAIL ligand and re-sensitizing drugs on the surface and in the inner cavity of the nanocage, respectively, this platform is potentially suitable for development of a broad range of anticancer or immunotherapeutic combinations.

Recently, the stem cell-derived secretome, which is the set of proteins expressed by stem cells and secreted into the extracellular space, has been demonstrated as a critical contributor for tissue repair. In this study, we have produced two sets of high concentration secretomes from adipose-derived mesenchymal stem cells (ADSCs) that contain bovine serum or free of exogenous molecules. Through proteomic analysis, we elucidated that proteins related to extracellular matrix organization and growth factor-related proteins are highly secreted by ADSCs. Additionally, the application of ADSC secretome to full skin defect showed accelerated wound closure, enhanced angiogenic response, and complete regeneration of epithelial gaps. Furthermore, the ADSC secretome was capable of reducing scar formation. Finally, we show high-dose injection of ADSC secretome via intraperitoneal or transdermal delivery demonstrated no detectable pathological conditions in various tissues/organs, which supports the notion that ADSC secretome can be safely utilized for tissue repair and regeneration.

Wound healing after Ahmed glaucoma valve (AGV) implantation often entails fibrosis as a foreign body reaction to the silicone plate. Poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) forms an antifouling surface that inhibits fibrosis during wound healing. In this study, we aimed to compare the effects of the implantation of AGV coated with PMPC (wPMPC) versus AGV without PMPC (woPMPC) in rabbits.