A predicted-loss based active learning approach for robust cancer pathology image analysis in the workplace.

BACKGROUND: Convolutional neural network-based image processing research is actively being conducted for pathology image analysis. As a convolutional neural network model requires a large amount of image data for training, active learning (AL) has been developed to produce efficient learning with a small amount of training data. However, existing studies have not specifically considered the characteristics of pathological data collected from the workplace. For various reasons, noisy patches can be selected instead of clean patches during AL, thereby reducing its efficiency. This study proposes an effective AL method for cancer pathology that works robustly on noisy datasets. METHODS: Our proposed method to develop a robust AL approach for noisy histopathology datasets consists of the following three steps: 1) training a loss prediction module, 2) collecting predicted loss values, and 3) sampling data for labeling. This proposed method calculates the amount of information in unlabeled data as predicted loss values and removes noisy data based on predicted loss values to reduce the rate at which noisy data are selected from the unlabeled dataset. We identified a suitable threshold for optimizing the efficiency of AL through sensitivity analysis. RESULTS: We compared the results obtained with the identified threshold with those of existing representative AL methods. In the final iteration, the proposed method achieved a performance of 91.7% on the noisy dataset and 92.4% on the clean dataset, resulting in a performance reduction of less than 1%. Concomitantly, the noise selection ratio averaged only 2.93% on each iteration. CONCLUSIONS: The proposed AL method showed robust performance on datasets containing noisy data by avoiding data selection in predictive loss intervals where noisy data are likely to be distributed. The proposed method contributes to medical image analysis by screening data and producing a robust and effective classification model tailored for cancer pathology image processing in the workplace.

Learning Curve for Endoscopic Transsphenoidal Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Endoscopic transsphenoidal surgery (ETSS) is emerging as an effective, minimally invasive surgery technique for brain tumors of the pituitary fossa. Using a surgical endoscope, surgeons can obtain a broader, nearer, and more apparent visual field with minimal keyhole entrance. However, ETSS may require a steep learning curve to achieve technical competence and relevant outcomes. Moreover, there is no consensus on the learning process of ETSS. We aimed to review and determine the technical proficiency points of ETSS and discuss how to accelerate the learning curve. METHODS: Core databases, including PubMed, Embase, and the Cochrane Library, were systematically searched for learning curve studies that demonstrated the clinical outcomes and learning status of ETSS for pituitary adenomas using numerical data. Quality assessments of the included articles were performed using the Newcastle-Ottawa scale. The cutoff points were evaluated based on various outcome measures. RESULTS: Eleven full-text articles, representing 2780 cases, were selected from 317 screened studies. The outcome measures were operative time, tumor removal, endocrinological results, visual field, and surgical complications. The plateaus or cutoff points in the learning curve varied with a mean of 103 ± 139.43 (range, 9-500) cases. CONCLUSIONS: ETSS is an efficient and minimally invasive alternative surgical option for pituitary tumors. Plateau points may differ according to outcome measures, patient selection, training status, and surgical conditions. Therefore, great care should be taken when interpreting the learning curve. A systematic training program is essential to improve the learning process of endoscopic neurosurgical procedures.

Analysis of Quality and Color Properties according to the Gas Composition (Modified Atmosphere Packaging) of Pork Sous-Vide Ham Preserved in Natural Brine.

The purpose of this study was to analyze whether seawater has positive effects on appearance characteristics, such as CIE a*, and to determine the gas composition concentration that is suitable for maintaining it. Pork hind meat was cured with four types of curing agent for 5 d at 4°C. The different curing agents comprised the control salt, control nitrite pickling salt (CN), treatment brine, and treatment bittern (BT). The cured hams were cooked at 65°C for 4 h and packaged at O2:N2 gas ratios of 7:3, 8:2, and 9:1 for 3 wk. The physicochemical properties were assessed immediately after heating the sample, and the color properties were measured after a 3 wk storage period. Based on the correlation results of the physicochemical properties, BT had a higher curing and cooking yield than the other treatments, owing to its high salinity. Results of color properties for BT (7:3) and CN (8:2) showed similar color CIE L*, CIE a* chroma, and hue angle values. Therefore, BT can be said to be a sous-vide curing agent suitable for preserving the color of ham, and a high nitrogen concentration of 30% helps to maintain the appearance of seawater sous-vide ham.

Inhibitory effect of fucoidan on TNF-α-induced inflammation in human retinal pigment epithelium cells.

Sargassum horneri (S. horneri) is a brown seaweed that contains a fucose-rich sulfated polysaccharide called fucoidan and is known to possess beneficial bioactivities, such as anti-inflammatory, antiviral, antioxidative, and antitumoral effects. This study aimed to determine the anti-inflammatory effects of AB_SH (hydrothermal extracts from S. horneri) and its bioactive compound (fucoidan) against tumor necrosis factor alpha (TNF-α)-induced inflammation in human retinal pigment epithelial (RPE) cells. AB_SH did not exhibit any cytotoxicity, and it decreased the mRNA expression of interleukin (IL)-6 and IL-8 and the production of the cytokines IL-6 and TNF-α. It also suppressed the expression levels of phosphorylated nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs), including c-Jun amino-terminal kinases (JNK), p38 protein kinases (p38), and extracellular signal-regulated kinase (ERK) proteins, suggesting that AB_SH inhibits activation of the NF-kB/MAPK signaling pathway. Since fucoidan was identified in the composition analysis of AB_SH, it was additionally shown to be required for its anti-inflammatory effects in TNF-α-stimulated human RPE cells. In line with the AB_SH results, fucoidan reduced the mRNA levels of IL-6, IL-1ß, and IL-8 and production of the cytokines IL-6, TNF-α, and IL-8 through the downregulation of the NF-kB/MAPK signaling pathway in a dose-dependent manner. Collectively, the ability of AB_SH from S. horneri hydrothermal extracts to reduce inflammation indicates that it may be a good functional ingredient for managing ocular disorders.

A Masquerade Case: Choroidal Hemangioma Misdiagnosed As Central Serous Retinopathy.

Purpose: To report a case of misdiagnosed choroidal hemangioma, initially treated as central serous retinopathy (CSR) complicated by choroidal neovascularization (CNV), and to improve the proper identification of this disorder. Observations: Fundus images revealed a subtle, elevated choroidal lesion with an associated exudative detachment and choroidal vascular lesion on indocyanine green (ICG) angiography. Combined treatment with photodynamic therapy (PDT) and anti-VEGF therapy led to resolution of fluid and improvement in VA from 20/50 to 20/25. Conclusion: It is critical to understand the clinical features of choroidal hemangiomas and their physical presentation on retinal testing to diagnose and treat them in a timely and appropriate manner.

Drastic Gas Sensing Selectivity in 2-Dimensional MoS2 Nanoflakes by Noble Metal Decoration.

Noble metal nanoparticle decoration is a representative strategy to enhance selectivity for fabricating chemical sensor arrays based on the 2-dimensional (2D) semiconductor material, represented by molybdenum disulfide (MoS2). However, the mechanism of selectivity tuning by noble metal decoration on 2D materials has not been fully elucidated. Here, we successfully decorated noble metal nanoparticles on MoS2 flakes by the solution process without using reducing agents. The MoS2 flakes showed drastic selectivity changes after surface decoration and distinguished ammonia, hydrogen, and ethanol gases clearly, which were not observed in general 3D metal oxide nanostructures. The role of noble metal nanoparticle decoration on the selectivity change is investigated by first-principles density functional theory (DFT) calculations. While the H2 sensitivity shows a similar tendency with the calculated binding energy, that of NH3 is strongly related to the binding site deactivation due to preferred noble metal particle decoration at the MoS2 edge. This finding is a specific phenomenon which originates from the distinguished structure of the 2D material, with highly active edge sites. We believe that our study will provide the fundamental comprehension for the strategy to devise the highly efficient sensor array based on 2D materials.

Impacts of sleeve gastrectomy on gastroesophageal reflux disease in severely obese Korean patients.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has established popularity as a bariatric and metabolic surgery. However, the incidence of gastroesophageal reflux disease (GERD) following LSG is controversial. This study aims to describe the prevalence of de novo GERD after LSG. METHODS: A retrospective chart review was performed for 130 patients who underwent a routine endoscopic surveillance before and after LSG between January 2013 and October 2018. The diagnosis of GERD was determined by presence of symptoms, history of PPI treatment, and endoscopic findings. The esophagogastroduodenoscopy (EGD) was performed annually after LSG and/or when the patients complained of severe reflux symptoms. RESULTS: The prevalence of GERD before surgery was 18.5%. At 1 year after LSG, GERD was present in 70 (53.8%) of the 130 patients. GERD consisted of 55 patients with newly developed GERD, and 15 with preexisting GERD. 9 (37.5%) out of pre-existing GERD patients were free of symptoms and abnormal finding at EGD following LSG. During the LSG, 66 (50.8%) patients with hiatal hernia underwent re-approximation of the diaphragmatic crura. There was no significant relationship between hiatal hernia repair and postoperative GERD (p = 0.39). Number of patients taking PPI medication before and after LSG were 34 (26.2%) and 49 (37.7%). Out of 56 (43.1%) patients with endoscopic lesions, LA grade A was 31 (23.9%), B = 15 (11.5%), C = 4 (3.1%), and D = 6 (4.6%). CONCLUSION: In this study, 42.3% (n = 55) of total patients developed newly developed GERD, and 7.7% (n = 10) had LA grade C or D esophagitis.

Loliolide in Sargassum horneri Alleviates Ultrafine Urban Particulate Matter (PM 0.1)-Induced Inflammation in Human RPE Cells.

Owing to increasing air pollution due to industrial development, fine dust has been associated with threatening public health. In particular, ultrafine urban particulate matter (uf-UP, PM 0.1) can easily enter our bodies, causing inflammation-related diseases. Therefore, in the present study, we evaluated the effects of hydrothermal extracts of Sargassum horneri and its bioactive compound, loliolide, on uf-UP-induced inflammation as a potential treatment strategy for retinal disorders. Human retinal pigment epithelial cells (ARPE-19) stimulated with TNF-α or uf-UPs were treated with S. horneri extract and loliolide. S. horneri extracts exhibited anti-inflammatory effects on uf-UP-induced inflammation without cell toxicity through downregulating the mRNA expression of MCP-1, IL-8, IL-6, and TNF-α. UPLC-QTOF/MS analysis confirmed that the hydrothermal extract of S. horneri contained loliolide, which has anti-inflammatory effects. Loliolide effectively reduced the mRNA expression and production of proinflammatory chemokines (IL-8) and cytokines (IL-1ß and IL-6) by downregulating the MAPK/NF-ĸB signaling pathway on TNF-α-stimulated inflammatory ARPE-19 cells. These effects were further confirmed in inflammatory ARPE-19 cells after stimulation with uf-UPs. Collectively, these results suggested the application of S. horneri as a functional ingredient for treating ocular disorders caused by particular matters.

Comprehensive Evaluation of The Infinium Human MethylationEPIC v2 BeadChip.

Infinium Methylation BeadChips are widely used to profile DNA cytosine modifications in large cohort studies for reasons of cost-effectiveness, accurate quantification, and user-friendly data analysis in characterizing these canonical epigenetic marks. In this work, we conducted a comprehensive evaluation of the updated Infinium MethylationEPIC v2 BeadChip (EPICv2). Our evaluation revealed that EPICv2 offers significant improvements over its predecessors, including expanded enhancer coverage, applicability to diverse ancestry groups, support for low-input DNA down to one nanogram, coverage of existing epigenetic clocks, cell type deconvolution panels, and human trait associations, while maintaining accuracy and reproducibility. Using EPICv2, we were able to identify epigenome and sequence signatures in cell line models of DNMT and SETD2 loss and/or hypomorphism. Furthermore, we provided probe-wise evaluation and annotation to facilitate the use of new features on this array for studying the interplay between somatic mutations and epigenetic landscape in cancer genomics. In conclusion, EPICv2 provides researchers with a valuable tool for studying epigenetic modifications and their role in development and disease.

PKR-Mediated Phosphorylation of eIF2a and CHK1 Is Associated with Doxorubicin-Mediated Apoptosis in HCC1143 Triple-Negative Breast Cancer Cells.

Triple-negative breast cancer is more aggressive than other types of breast cancer. Protein kinase R (PKR), which is activated by dsRNA, is known to play a role in doxorubicin-mediated apoptosis; however, its role in DNA damage-mediated apoptosis is not well understood. In this study, we investigated the roles of PKR and its downstream players in doxorubicin-treated HCC1143 triple-negative breast cancer cells. Doxorubicin treatment induces DNA damage and apoptosis. Interestingly, doxorubicin treatment induced the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) via PKR, whereas the inhibition of PKR with inhibitor C16 reduced eIF2α phosphorylation. Under these conditions, doxorubicin-mediated DNA fragmentation, cell death, and poly(ADP ribose) polymerase and caspase 7 levels were recovered. In addition, phosphorylation of checkpoint kinase 1 (CHK1), which is known to be involved in doxorubicin-mediated DNA damage, was increased by doxorubicin treatment, but blocked by PKR inhibition. Protein translation was downregulated by doxorubicin treatment and upregulated by blocking PKR phosphorylation. These results suggest that PKR activation induces apoptosis by increasing the phosphorylation of eIF2α and CHK1 and decreasing the global protein translation in doxorubicin-treated HCC1143 triple-negative breast cancer cells.

Learning curve for minimally invasive transforaminal lumbar interbody fusion: a systematic review.

PURPOSE: Minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) is commonly used to treat degenerative lumbar spinal disorders. It facilitates a full-scale spinal decompression and interbody fusion with minimal neural retraction using the tubular retractor system. Despite the benefits of surgical efficiency and minimalism, this technique requires a long learning curve. There is currently no consensus on the learning curve characteristics and proper training methods for MI-TLIF. Thus, this systematic review aimed to discuss the cutoff point at which technical proficiency is achieved and ways to enhance the learning process. METHODS: Major databases, including PubMed, Embase, and Cochrane Library, were searched for learning curve studies that have evaluated the clinical outcome and learning progress of MI-TLIF using quantitative data. The qualities of the selected studies were assessed using the Newcastle‒Ottawa scale. The plateau points in the "learning curve" were analyzed according to various outcome measures. RESULTS: Nine full-text articles, representing 753 cases, were included from 9743 screened studies. The most commonly used outcome measures were the operative time, followed by the complication rate. The mean cutoff point for the operative time was 31.33 ± 11.98 (range 13‒45) cases. CONCLUSION: The plateau point in the learning curve for MI-TLIF may differ according to the outcome measures used. Most studies have demonstrated the learning progress based on simple task efficiency, rather than patient outcomes. Moreover, the learning rate may be affected by the patients' and technical conditions. Therefore, great care is required in interpreting the learning curve and cutoff point for MI-TLIF proficiency.

DNA methylation dynamics and dysregulation delineated by high-throughput profiling in the mouse.

We have developed a mouse DNA methylation array that contains 296,070 probes representing the diversity of mouse DNA methylation biology. We present a mouse methylation atlas as a rich reference resource of 1,239 DNA samples encompassing distinct tissues, strains, ages, sexes, and pathologies. We describe applications for comparative epigenomics, genomic imprinting, epigenetic inhibitors, patient-derived xenograft assessment, backcross tracing, and epigenetic clocks. We dissect DNA methylation processes associated with differentiation, aging, and tumorigenesis. Notably, we find that tissue-specific methylation signatures localize to binding sites for transcription factors controlling the corresponding tissue development. Age-associated hypermethylation is enriched at regions of Polycomb repression, while hypomethylation is enhanced at regions bound by cohesin complex members. Apc Min/+ polyp-associated hypermethylation affects enhancers regulating intestinal differentiation, while hypomethylation targets AP-1 binding sites. This Infinium Mouse Methylation BeadChip (version MM285) is widely accessible to the research community and will accelerate high-sample-throughput studies in this important model organism.

Anti-Melanogenic and Antioxidant Effects of Cell-Free Supernatant from Lactobacillus gasseri BNR17.

In recent years, there has been considerable interest in the use of cell-free supernatant of probiotics culture for nutritional and functional applications. In this study, we investigated the effect of the cell-free supernatant from Lactobacillus gasseri BNR17 (CFS) on anti-melanogenesis and reducing oxidative stress in B16-F10 murine melanoma cells and HaCaT human keratinocytes. Treatment with CFS significantly inhibited the production of extracellular and intracellular melanin without cytotoxicity during melanogenesis induced by the α-MSH in B16-F10 cells. The CFS dramatically reduced tyrosinase activity and the melanogenesis-related gene expression. Further, it showed antioxidative effects in a dose-dependent manner in DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) assays and significantly increased the mRNA levels of HO-1 and CAT in HaCaT cells. Furthermore, the CFS increased HO-1 and anti-oxidative-related gene expression during H2O2-induced oxidative stress in HaCaT cells. Together, this study suggests that the CFS reduces hyperpigmentation and inhibits oxidative stress, and thus can be used as a potential skincare product in the future.

Platycodin D inhibits autophagy and increases glioblastoma cell death via LDLR upregulation.

Targeting autophagy is a promising therapeutic approach in cancer therapy. Here, we screened 30 traditional herbal medicines to identify novel autophagy regulators and found that Platycodon grandiflorus (PG) and platycodin D (PD), a triterpenoid saponin from PG, inhibited autophagy in glioblastoma multiforme (GBM) cells. Mechanistically, PD prevented lysosomal degradation and the fusion between autophagosomes and lysosomes by inducing sequestration of free cholesterol in lysosomes. The autophagy inhibitory effect of PD was mimicked by both genetic and pharmacological inhibition of Niemann-Pick C1 (NPC1), which exports low-density lipoprotein (LDL)-derived cholesterol from lysosomes. Moreover, PD promoted the uptake of exogenous LDL cholesterol via upregulation of LDL receptor (LDLR), leading to further accumulation of cholesterol within lysosomes and GBM cell death. Importantly, these phenomena were more pronounced in LDLR-overexpressing GBM cells than in normal astrocytes. Finally, blockade of cholesterol uptake by LDLR knockdown reversed the PD-induced inhibition of autophagy and GBM cell growth. Our study proposes that PD could be a potent anti-GBM drug by disrupting cholesterol trafficking and autophagy.

Activation of ERK and p38 Reduces AZD8055-Mediated Inhibition of Protein Synthesis in Hepatocellular Carcinoma HepG2 Cell Line.

Protein synthesis is important for maintaining cellular homeostasis under various stress responses. In this study, we screened an anticancer drug library to select compounds with translational repression functions. AZD8055, an ATP-competitive mechanistic target of rapamycin complex 1/2 (mTORC1/2) inhibitor, was selected as a translational suppressor. AZD8055 inhibited protein synthesis in mouse embryonic fibroblasts and hepatocellular carcinoma HepG2 cells. Extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) were activated during the early phase of mTORC1/2 inhibition by AZD8055 treatment. Combined treatment of AZD8055 with the MAPK kinase1/2 (MEK1/2) inhibitor refametinib or the p38 inhibitor SB203580 markedly decreased translation in HepG2 cells. Thus, the inhibition of ERK1/2 or p38 may enhance the efficacy of AZD8055-mediated inhibition of protein synthesis. In addition, AZD8055 down-regulated the phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), and AZD8055-induced phosphorylation of ERK1/2 and p38 had no effect on phosphorylation status of 4E-BP1. Interestingly, AZD8055 modulated the 4E-BP1 mRNA pool by up-regulating ERK1/2 and p38 pathways. Together, these results suggest that AZD8055-induced activation of MAPKs interferes with inhibition of protein synthesis at an early stage of mTORC1/2 inhibition, and that it may contribute to the development of resistance to mTORC1/2 inhibitors.

Macular Hole Surgery in Dome-Shaped Maculopathy.

PURPOSE: To present a successful case of macular hole surgery in a patient with dome-shaped maculopathy (DSM). OBSERVATIONS: Patient with DSM had successful closure of a full-thickness macular hole with surgery. There was persistent subretinal fluid after the surgery, which showed some response to a combination of a diuretic and a nonsteroidal anti-inflammatory drug (NSAID). CONCLUSIONS AND IMPORTANCE: Full-thickness macular hole in DSM may be effectively managed with modern surgical techniques.

Learning Curve for Interlaminar Endoscopic Lumbar Discectomy: A Systematic Review.

BACKGROUND: Interlaminar endoscopic lumbar discectomy (IELD) is an efficient surgical treatment for lumbar disc herniation. However, this minimally invasive procedure requires a considerable learning curve that has not yet been standardized. This review aimed to evaluate the learning curve's characteristics, including the cutoff point required to achieve technical proficiency and to discuss appropriate training methods. METHODS: We systematically searched the core databases (PubMed, Embase, and Cochrane Library) for clinical studies that evaluated the learning curve using quantitative data. We performed a quality assessment using the Newcastle-Ottawa scale. We also compared descriptive statistics, including operative time and other variables before and after the cutoff point. RESULTS: Six studies reporting 302 cases of IELD were selected from 7188 screened articles. The cutoff point was randomly set in 3 studies and determined as the curve's asymptote in 3 studies. The mean value for the cutoff point was 22.17 ± 12.40 cases (range: 10-43 cases) and mainly determined based on the operative time, which was shorter in the late group than that in the early group (P < 0.05). The cutoff points were not significant for patient outcome parameters such as pain score, functional result, surgical failure, or complications. CONCLUSIONS: The evidence of published studies regarding the learning curve for the IELD technique is insufficient. The reported cutoff points may be significant only for task efficiency. Moreover, they may not represent the asymptote of the curve. Future studies should evaluate the actual plateau points using patient outcome data.

Association of the Risk of Osteoarthritis and Hypertension in the Korean Adult Population Aged 40-59 in Pre- and Postmenopausal Women: Using Korea National Health and Nutrition Examination Survey 2012-2016 Data.

PURPOSE: Previous studies reported the relation of osteoarthritis (OA) and hypertension (HTN) mostly in postmenopausal women. This study aimed to identify the association between OA and HTN in pre- and postmenopausal women. METHODS: We used data of 4,627 middle-aged (40-59 years) women from the Korea National Health and Nutrition Examination Survey (KNHANES) from 2012 to 2016. Chi-square and t-test compared the characteristics of the participants. Binomial logistic regression was used to identify an association between OA and HTN under controlling covariates such as age, tobacco smoking, alcohol consumption, and obesity. RESULTS: There were 1,859 participants with non-OA and menopause, 104 with OA and nonmenopause, and 375 with OA and menopause, respectively. The number of women with OA and HTN was 129. OA was significantly associated with HTN diagnosis in postmenopausal women under controlling covariates (odds ratio: 1.408, 95% CI: 1.092-1.815, p=0.008). However, this relationship was weakened in premenopausal women (odds ratio: 1.651, 95% CI: 0.950-2.869, p=0.075). CONCLUSION: In conclusion, women with HTN showed a distinct association with OA than the normotensives, and this relationship was more apparent among postmenopausal women. Further research is needed for a preventive approach.