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Raf-1, a multifunctional kinase, regulates various cellular processes, including cell proliferation, apoptosis, and migration, by phosphorylating MAPK/ERK kinase and interacting with specific kinases. Cellular Raf-1 activity is intricately regulated through pathways involving the binding of regulatory proteins, direct phosphorylation, and the ubiquitin–proteasome axis. In this study, we demonstrate that PHI-1, an endogenous inhibitor of protein phosphatase-1 (PP1), plays a pivotal role in modulating Raf-1 proteostasis within cells. Knocking down endogenous PHI-1 in HEK293 cells using siRNA resulted in increased cell proliferation and reduced apoptosis. This heightened cell proliferation was accompanied by a 15-fold increase in ERK1/2 phosphorylation. Importantly, the observed ERK1/2 hyperphosphorylation was attributable to an upregulation of Raf-1 expression, rather than an increase in Ras levels, Raf-1 Ser338 phosphorylation, or B-Raf levels. The elevated Raf-1 expression, stemming from PHI-1 knockdown, enhanced EGF-induced ERK1/2 phosphorylation through MEK. Moreover, PHI-1 knockdown significantly contributed to Raf-1 protein stability without affecting Raf-1 mRNA levels. Conversely, ectopic PHI-1 expression suppressed Raf-1 protein levels in a manner that correlated with PHI-1’s inhibitory potency. Inhibiting PP1 to mimic PHI-1’s function using tautomycin led to a reduction in Raf-1 expression. In summary, our findings highlight that the PHI-1-PP1 signaling axis selectively governs Raf-1 proteostasis and cell survival signals.

The primary cilium, which protrudes from the cell surface, is associated with the pathogenesis of various diseases, including acute kidney injury (AKI). Primary cilium length dynamically changes during the progression of diseases. However, its relevance in disease and the underlying mechanism are largely unknown. In this study, we investigated the role of primary cilia in AKI induced by cisplatin, an effective anticancer drug, and the underlying mechanisms. In addition, we evaluated the usefulness of length alteration and deciliation of primary cilia into the urine for the diagnosis of AKI. Cisplatin induced shortening, elongation, and normalization of the primary cilia in kidney epithelial cells over time. During shortening, primary cilia fragments and ciliary proteins were excreted into the urine. During deciliation, cell proliferation and the expression of cyclin-dependent kinase inhibitor and proliferating cell nuclear antigen were not significantly changed. Shortening and deciliation of primary cilia were observed before significant increases in plasma creatinine and blood urea nitrogen concentration occurred. Pretreatment with Mito-Tempo, a mitochondria-targeted antioxidant, prevented cisplatin-induced primary cilium shortening and inhibited the increases in superoxide formation, lipid peroxidation, blood urea nitrogen, and tissue damage. In contrast, isocitrate dehydrogenase 2 (Idh2) gene deletion, which results in defect of the NADPH-associated mitochondrial antioxidant system, exacerbated cisplatin-induced changes in mice. Taken together, our findings demonstrate that cisplatin induces deciliation into the urine and antioxidant treatment prevents this deciliation, renal dysfunction, and tissue damage after cisplatin injection. These results suggest that cisplatin-induced AKI is associated with primary cilia and urine primary cilia proteins might be a non-invasive biomarker of kidney injury. Keywords: Primary cilia, ROS, Deciliation, Acute kidney injury, Cisplatin, Acetylated a-tubulin, IDH2

The development of hypertension is associated with mitochondrial redox balance disruptions. NADP+-dependent isocitrate dehydrogenase 2 (IDH2) plays an important role in the maintenance of mitochondrial redox balance by producing mitochondrial NADPH, which is an essential cofactor in the reduction of glutathione (from GSSG to GSH) to reduced form of glutathione (GSH). We investigated the association of IDH2 between the development of prolonged high-fat diet (HFD)-induced hypertension. Idh2 gene-deleted (Idh2−/−) male mice and wild-type (Idh2+/+) littermates were fed either HFD or low-fat diet (LFD). Some mice were administrated with Mito-TEMPO, a mitochondria-specific antioxidant. HFD feeding increased blood pressure (BP) in both Idh2−/− mice and Idh2+/+ mice. HFD-induced BP increase was greater in Idh2−/− than Idh2+/+ mice. HFD intake decreased IDH2 activity, NADPH levels, and the GSH/(GSH + GSSG) ratio in the renal mitochondria. However, HFD intake increased mitochondrial ROS levels, along with the accompanying oxidative stress and damage. HFD intake increased angiotensin II receptor 1 type 1 mRNA levels in the kidneys and plasma renin and angiotensin II concentrations. These HFD-induced changes were more prominent in Idh2−/− mice than Idh2+/+ mice. Mito-TEMPO mitigated the HFD-induced changes in both Idh2−/− and Idh2+/+ mice, with greater effects in Idh2−/− mice than Idh2+/+ mice. These results indicate that prolonged HFD intake disrupts the IDH2-NADPH-GSH-associated antioxidant system and activates the renin-angiotensin system in the kidney, leading to increased BP, suggesting that IDH2 is a critical enzyme in the development of hypertension and that the IDH2-associated antioxidant system could serve as a potential hypertension treatment target.

Mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2) is a major producer of mitochondrial NADPH, required for glutathione (GSH)-associated mitochondrial antioxidant systems including glutathione peroxidase (GPx) and glutathione reductase (GR). Here, we investigated the role of IDH2 in hepatic ischemia-reperfusion (HIR)-associated mitochondrial injury using Idh2-knockout (Idh2-/-) mice and wild-type (Idh2+/+) littermates. Mice were subjected to either 60 min of partial liver ischemia or sham-operation. Some mice were administered with 2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride (mito-TEMPO, a mitochondria-targeting antioxidant). HIR induced severe histological and functional damages of liver in both Idh2+/+ mice and Idh2-/- mice and those damages were more severe in Idh2-/- mice than in wild-type littermates. HIR induces dysfunction of IDH2, leading to the decreases of NADPH level and mitochondrial GR and GPx functions, consequently resulting in mitochondrial and cellular oxidative injury as reflected by mitochondrial cristae loss, mitochondrial fragmentation, shift in mitochondrial fission, cytochrome c release, and cell death. These HIR-induced changes were greater in Idh2-/- mice than wild-type mice. The mito-TEMPO supplement significantly attenuated the aforementioned changes, and these attenuations were much greater in Idh2-/- mice when compared with wild-type littermates. Taken together, results have demonstrated that HIR impairs in the IDH2-NADPH-GSH mitochondrial antioxidant system, resulting in increased mitochondrial oxidative damage and dysfunction, suggesting that IDH2 plays a critical role in mitochondrial redox balance and HIR-induced impairment of IDH2 function is associated with the pathogenesis of ischemia-reperfusion-induced liver failure. Keywords: Liver ischemia, Mitochondria, Oxidative stress, Apoptosis, IDH2

ABSTRACT Introduction This study aimed to compare the long‐term effects of neoadjuvant therapy and upfront surgery on overall survival (OS) and progression‐free survival (PFS) in patients with resectable pancreatic ductal adenocarcinoma (PDAC). Methods We retrospectively analyzed 202 patients, including 167 who had upfront surgery and 35 who received neoadjuvant therapy followed by surgery. Surgical outcomes and survival rates were compared using propensity score matching to minimize selection bias. Results Neoadjuvant therapy showed significantly longer 75% OS (72.7 months vs. 28.3 months, p = 0.032) and PFS (29.6 months vs. 13.2 months, p

Abstract Background Preclinical data have shown the immunomodulatory effects of metformin and dipeptidyl peptidase 4 (DPP4) inhibitors in patients with diabetes. However, its clinical impact remains unclear in lung cancer. Methods Between 2017 and 2021, 466 patients received ICI monotherapy. Patients were categorized into concurrent (MET; metformin or combination of metformin and DPP4 inhibitor) and without concomitant (NMET; nonmetformin/DPP4 inhibitors) administration of metformin and DPP4 inhibitors groups at least 8 weeks before and during ICI therapy. The primary objectives were the objective response rate (ORR) and progression‐free survival (PFS). The second objective was to evaluate the overall survival (OS) and the occurrence of immune‐related adverse events (irAEs). Results Among 466 patients, 89 (19.0%) and 377 (81%) were categorized into the MET and NMET groups, respectively. MET group had a significantly higher ORR (MET group: 24.7% vs. NMET group: 14.8%, p = 0.025) and longer PFS than those in the NMET group (MET group 5.1 month vs. NMET group 2.8 months, p = 0.018). After patients were stratified based on the prior line of therapy and PD L1 expression status, the PFS of the second‐line therapy and PD L1 ≥50 was significantly higher in the MET than in the NMET group. The proportion of patients experiencing all‐grade irAEs was numerically higher in the MET group (19.1%) than in the NMET group (14.3%), without statistical significance (p = 0.382). Conclusions Concurrent use of metformin and DPP4 inhibitors with ICIs significantly improved the clinical outcomes without increasing the incidence of irAEs in NSCLC.

Background/Aims: Anastomotic stricture at the esophagus and the conduit anastomosis site after the surgical resection of esophageal cancer is relatively common. This study examined whether a hypertrophic scar or keloid formation at a surgical wound is related to an anastomotic stricture. Methods: From March 2007 to July 2017, 59 patients underwent curative surgery for esophageal cancer. In 38 patients, end-to-end anastomosis (EEA) of the esophagus and the conduit was performed using EEA 25 mm. A hypertrophic wound scar was defined when the width of the midline laparotomy wound scar exceeded 2 mm. The relationship between the hypertrophic scar and stricture and the other risk factors for anastomotic stricture in these 38 patients was analyzed. Results: Of the 38 patients, eight patients (21.1%) had an anastomotic stricture, and a hypertrophic skin scar was observed in 14 patients (36.8%). Univariate analysis revealed lower BMI and hypertrophic scars as risk factors (p=0.032, p=0.001 respectively). Multivariate analysis revealed a hypertrophic scar as an independent risk factor for an anastomotic stricture (p=0.010, OR=27.06, 95% CI 2.19-334.40). Conclusions: Hypertrophic wound scars can be a risk factor for anastomotic stricture after surgery for esophageal cancer. An earlier prediction of anastomotic stricture by detecting hypertrophic wound healing in patients undergoing esophagectomy may improve the patients’ quality of life and surgical outcomes by earlier treatments.

Abstract Background Increasing attention is being given to assessing treatment effect heterogeneity among individuals belonging to qualitatively different latent subgroups. Inference routinely proceeds by first partitioning the individuals into subgroups, then estimating the subgroup-specific average treatment effects. However, because the subgroups are only latently associated with the observed variables, the actual individual subgroup memberships are rarely known with certainty in practice and thus have to be imputed. Ignoring the uncertainty in the imputed memberships precludes misclassification errors, potentially leading to biased results and incorrect conclusions. Methods We propose a strategy for assessing the sensitivity of inference to classification uncertainty when using such classify-analyze approaches for subgroup effect analyses. We exploit each individual’s typically nonzero predictive or posterior subgroup membership probabilities to gauge the stability of the resultant subgroup-specific average causal effects estimates over different, carefully selected subsets of the individuals. Because the membership probabilities are subject to sampling variability, we propose Monte Carlo confidence intervals that explicitly acknowledge the imprecision in the estimated subgroup memberships via perturbations using a parametric bootstrap. The proposal is widely applicable and avoids stringent causal or structural assumptions that existing bias-adjustment or bias-correction methods rely on. Results Using two different publicly available real-world datasets, we illustrate how the proposed strategy supplements existing latent subgroup effect analyses to shed light on the potential impact of classification uncertainty on inference. First, individuals are partitioned into latent subgroups based on their medical and health history. Then within each fixed latent subgroup, the average treatment effect is assessed using an augmented inverse propensity score weighted estimator. Finally, utilizing the proposed sensitivity analysis reveals different subgroup-specific effects that are mostly insensitive to potential misclassification. Conclusions Our proposed sensitivity analysis is straightforward to implement, provides both graphical and numerical summaries, and readily permits assessing the sensitivity of any machine learning-based causal effect estimator to classification uncertainty. We recommend making such sensitivity analyses more routine in latent subgroup effect analyses.

Objectives Monkeypox outbreaks in nonendemic countries have been reported since early May 2022. The first case of monkeypox in the Republic of Korea was confirmed in a patient who traveled to Europe in June 2022, and an attempt was made to isolate and identify the monkeypox virus (MPXV) from the patient’s specimens. Methods Clinical specimens from the patient were inoculated in Vero E6 cells. The isolated virus was identified as MPXV by the observation of cytopathic effects on Vero E6 cells, transmission electron microscopy, conventional polymerase chain reaction (PCR), and sequencing of PCR products. Results Cytopathic effects were observed in Vero E6 cells that were inoculated with skin lesion swab eluates. After multiple passages from the primary culture, orthopoxvirus morphology was observed using transmission electron microscopy. In addition, both MPXV-specific (F3L and ATI) and orthopoxvirus-specific genes (A39R, B2R, and HA) were confirmed by conventional PCR and Sanger sequencing. Conclusion These results indicate the successful isolation and identification of MPXV from the first patient in the Republic of Korea. The isolated virus was named MPXV-ROK-P1-2022.

Abstract Background In clinical practice, we often observed that patients who underwent total thyroidectomy due to clinically involved nodal disease (cN1a) actually had less extensive CLNM on final pathology. This study investigates whether total thyroidectomy and therapeutic bilateral CND are necessary for all PTC patients with cN1a. Methods This study retrospectively reviewed 899 PTC patients who underwent total thyroidectomy with bilateral CND from January 2012 to June 2017. The patients were divided into two groups according to pre-operative central lymph node (CLN) status: cN0, no suspicious CLNM; cN1a, suspicious CLNM. We compared the clinicopathological features of these two groups. Results There was no significant difference in recurrence between cN0 and cN1a groups after a mean follow-up time of 59.1 months. Unilateral cN1a was related to the largest central LN size ≥ 2 mm (OR = 3.67, p 5(OR = 2.24, p = 0.006). On the other hand, unilateral cN1a was not associated with an increased risk of contralateral lobe involvement (OR = 1.35, p = 0.364) and contralateral CLNM (OR = 1.31, p = 0.359). Among 106 unilateral cN1a patients, 33 (31.1%) were found to be pN0 or had ≤ 5 metastatic CLNs with the largest node smaller than 2 mm. Conclusions Most cN1a patients were in an intermediate risk group for recurrence and required total thyroidectomy. However, lobectomy with CND should have performed in approximately 30% of the cN1a patients. Pre-operative clinical examination, meticulous radiologic evaluation, and intra-operative frozen sections to check the nodal status are prerequisites for this approach.

Background: Palbociclib plus endocrine therapy (ET) demonstrated significant progression-free survival (PFS) benefit in Young Pearl, a randomized phase ll trial comparing palbociclib + ET versus capecitabine in premenopausal women with hormone receptor positive, HER2 negative metastatic breast cancer (MBC). This exploratory analysis investigated potential biomarkers of palbociclib plus ET on PFS. Patients and methods: Of 178 patients randomized (92 palbociclib plus ET; 86 capecitabine), we performed targeted sequencing (141 patients) and whole transcriptome sequencing (165 patients) using baseline tumor samples to examine genomic alteration in relation to drug response on PFS. Hazard ratios (HRs) were estimated using unstratified Cox proportional hazards models. Results: PIK3CA (41%) and TP53 (33%) mutations and CCND1 copy number variation (29%) were found most frequently in targeted sequencing of 141 patients. ESR1 mutations were found only in 3.5% of patients of this population. Luminal type showed better prognosis in palbociclib + ET arm but no impact on PFS difference in capecitabine arm. High TMB, TP53 mutation, PTEN loss of function mutation and RB1 pathway alteration showed worse prognosis in palbociclib plus ET arm. Patients with BRCA2 pathogenic mutations showed worse prognosis regardless of PAM50 subtypes. AURKA mutation/amplification, BRIP1/MYC/RAD51C amplification were significantly associated to the patients with short PFS

Purpose The purpose of this study is to investigate the physical activity (PA) and exercise barriers of stages 0-3 breast cancer survivors according to the Transtheoretical Model (TTM). Methods This cross-sectional study that included data from a total of 295 breast cancer survivors (Age: 52.2±8.2 years, BMI: 23.5±3.3 kg/m2), at Shinchon Severance Hospital, Seoul, Korea. The levels of PA and exercise barriers according to TTM were investigated using questionnaires. Results PA participation increased in the TTM stage. The proportion of participants categorized according to TTM stage differed according to the time since cancer diagnosis: a higher proportion of participants were in pre-contemplation/contemplation within one year after diagnosis, while a higher proportion of participants were in maintenance after three three years since diagnosis. The five most prevalent exercise barriers were fatigue, low level of physical fitness, poor health, lack of interest, and tendency to be physically inactive. Fatigue is the most prevalent exercise barrier regardless of TTM stage, while most exercise barriers tend to reduce as participants are in the preparation/action and maintenance stages. Conclusions In this study, we confirmed that the participants in the maintenance stage were the most active, while the proportion of participants in the TTM stage varied according to time since diagnosis. Since PA and exercise barriers vary according to the TTM stage, the TTM stage may increase PA participation in breast cancer patients.

Abstract Background This study was conducted to compare the reported adverse event (AE) profiles and unexpected use of medical services during chemotherapy between before and after the healthcare reimbursement of AE evaluation in patients with cancer. Patients and Methods Using the electronic medical record database system, extracted patients with breast, lung, gastric, and colorectal cancers receiving neoadjuvant or adjuvant chemotherapy between September 2013 and December 2016 at four centers in Korea were matched using the 1:1 greedy method: pre‐reimbursement group (n = 1084) and post‐reimbursement group (n = 1084). Unexpected outpatient department (OPD), emergency room (ER) visit, hospitalization rates, and chemotherapy completion rates were compared between the groups. Results The baseline characteristics were well‐balanced between the groups. By chemotherapy cycle, hospitalization (1.8% vs. 2.3%; p = 0.039), and ER visit rates (3.3% vs. 3.9%; p = 0.064) were lower in the post‐reimbursement group than that in the pre‐reimbursement group. In particular, since cycle 2, ER visit and hospitalization rates were significantly lower in the post‐reimbursement group than those in the pre‐reimbursement group (2.6% vs. 3.3%; p = 0.020 and 1.4% vs. 2.0%; p = 0.007, respectively), although no significant differences were observed during cycle 1. The OPD visit rates were similar between both groups, regardless of cycles. The post‐reimbursement group had a higher proportion of patients who completed chemotherapy as planned than the pre‐reimbursement group (93.5% vs. 90.1%; p = 0.006). Post‐reimbursement group had more AEs reported, including alopecia, fatigue, diarrhea, anorexia, and peripheral neuropathy, during cycle 1 than the pre‐reimbursement group, which significantly decreased after cycle 2. Conclusion The introduction of healthcare reimbursement for AE evaluation may help physicians capture and appropriately manage AEs, consequently, decreasing hospital utilization and increasing chemotherapy completion rates.

Abstract We investigated the association between TP53 mutation and 21-gene recurrence score (RS) in ER-positive/HER2-negative breast cancer (BC) using data from 141 patients who underwent TP53 sequencing and Oncotype DX® tests. We detected TP53 mutations in 18 (12.8%) patients. Most patients with TP53 mutation had a high 21-gene RS (≥26). The average 21-gene RS was higher in TP53 mutant tumors. Multivariate analysis showed that mutated TP53 is an independent factor for a high 21-gene RS. Mutated TP53 remained closely associated with high 21-gene RS in patients with low pathological risk (n = 103). In the ER+/PR+/HER2-negative subset (n = 356) of The Cancer Genome Atlas, the non-luminal A intrinsic subtype was more prevalent in the group with mutant TP53. mRNA levels of p53-regulated senescence gatekeeper and cell cycle-related genes were increased in BC with mutated TP53. Mutational analysis of TP53 helped identify endocrine-resistant tumors.

Abstract Amphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand. The aim of this study was to investigate the effects of baseline plasma AREG levels in KRAS, NRAS, and BRAF wild-type metastatic colorectal cancer (CRC) on treatment outcome with palliative first-line cetuximab + FOLFIRI chemotherapy. Chemotherapy outcomes were analyzed based on baseline plasma AREG levels. The clinical findings were further validated using an in vitro model of CRC. Among 35 patients, the progression-free survival (PFS) was significantly inferior in patients with high AREG than in those with low AREG levels: 10.9 vs. 24.2 months, respectively (p = 0.008). However, after failure of first-line chemotherapy, AREG levels were associated with neither PFS (4.8 vs. 11.6 months; p = 0.215) nor overall survival (8.4 vs. 13.3 months; p = 0.975). In SNU-C4 and Caco-2 cells which were relatively sensitive to cetuximab among the seven CRC cell lines tested, AREG significantly decreased the anti-proliferative effect of cetuximab (p

Background Papillary breast lesions (PBLs) comprise diverse entities from benign and atypical lesions to malignant tumors. Although PBLs are characterized by a papillary growth pattern, it is challenging to achieve high diagnostic accuracy and reproducibility. Thus, we investigated the diagnostic reproducibility of PBLs in core needle biopsy (CNB) specimens with World Health Organization (WHO) classification. Methods Diagnostic reproducibility was assessed using interobserver variability (kappa value, κ) and agreement rate in the pathologic diagnosis of 60 PBL cases on CNB among 20 breast pathologists affiliated with 20 medical institutions in Korea. This analysis was performed using hematoxylin and eosin (H&E) staining and immunohistochemical (IHC) staining for cytokeratin 5 (CK5) and p63. The pathologic diagnosis of PBLs was based on WHO classification, which was used to establish simple classifications (4-tier, 3-tier, and 2-tier). Results On WHO classification, H&E staining exhibited ‘fair agreement’ (κ = 0.21) with a 47.0% agreement rate. Simple classifications presented improvement in interobserver variability and agreement rate. IHC staining increased the kappa value and agreement rate in all the classifications. Despite IHC staining, the encapsulated/solid papillary carcinoma (EPC/SPC) subgroup (κ = 0.16) exhibited lower agreement compared to the non-EPC/SPC subgroup (κ = 0.35) with WHO classification, which was similar to the results of any other classification systems. Conclusions Although the use of IHC staining for CK5 and p63 increased the diagnostic agreement of PBLs in CNB specimens, WHO classification exhibited a higher discordance rate compared to any other classifications. Therefore, this result warrants further intensive consensus studies to improve the diagnostic reproducibility of PBLs with WHO classification.

Testicular carcinoid tumors are very rare, accounting for less than 1% of all testicular tumors. We report a rare case of a testicular carcinoid tumor with extensive lymphatic invasion. A 42-year-old man presented with a painless, enlarged right testicular mass. There was no history of injury or discomfort in this region. Right radical orchiectomy was performed, which showed a well-defined, non-encapsulated solid white mass with calcification (7.0 × 4.5 × 3.5 cm) and absence of cystic components. Microscopic examination using hematoxylin and eosin staining of the tumor sections identified organoid, trabecular, and solid patterns with rosette formation. Extensive multifocal lymphatic invasion was observed. Immunohistochemistry was positive for synaptophysin, chromogranin, and CD56. Testicular carcinoid tumors usually show good prognoses; however, there was extensive lymphovascular invasion in this case. Thus, in the case of unusual presentation of the disease, close follow-up is necessary.

Abstract Background Despite the known associations between zinc levels and Alzheimer’s disease (AD) dementia and related cognitive impairment, the underlying neuropathological links remain poorly understood. We tested the hypothesis that serum zinc level is associated with cerebral beta-amyloid protein (Aβ) deposition. Additionally, we explored associations between serum zinc levels and other AD pathologies [i.e., tau deposition and AD-signature cerebral glucose metabolism (AD-CM)] and white matter hyperintensities (WMHs), which are measures of cerebrovascular injury. Methods A total of 241 cognitively normal older adults between 55 and 90 years of age were enrolled. All the participants underwent comprehensive clinical assessments, serum zinc level measurement, and multimodal brain imaging, including Pittsburgh compound B-positron emission tomography (PET), AV-1451 PET, fluorodeoxyglucose (FDG)-PET, and magnetic resonance imaging. Zinc levels were stratified into three categories: 90 μg/dL (high). Results A low serum zinc level was significantly associated with increased Aβ retention. In addition, apolipoprotein E ε4 allele (APOE4) status moderated the association: the relationship between low zinc level and Aβ retention was significant only in APOE4 carriers. Although a low zinc level appeared to reduce AD-CM, the relationship became insignificant on sensitivity analysis including only individuals with no nutritional deficiency. The serum zinc level was associated with neither tau deposition nor the WMH volume. Conclusions Our findings suggest that decreased serum zinc levels are associated with elevation of brain amyloid deposition. In terms of AD prevention, more attention needs to be paid to the role of zinc.

The interpretation of MRI of partial-thickness rotator cuff tears can be challenging. This review describes the anatomic considerations for diagnosing partial-thickness tears, especially supraspinatus and infraspinatus tendon and summarizes the classification of partial-thickness rotator cuff tears, as well as provides an overview on partial-thickness tears with delamination.

Abstract Background Expanding access to medications for opioid use disorder (MOUD), such as buprenorphine and extended release (XR) naltrexone, is critical to addressing the US opioid epidemic, but little is known about prescriber satisfaction with delivering these two types of MOUD. The current study describes the satisfaction of prescribers delivering buprenorphine and XR-naltrexone while examining whether satisfaction is associated with current patient census and organizational environment. Methods As part of a cluster randomized clinical trial (RCT) focused on expanding access to medication for opioid use disorder, 41 MOUD prescribers in Florida, Ohio, and Wisconsin completed a web-based survey. The survey included measures of prescriber satisfaction with delivering buprenorphine treatment and XR-naltrexone. In addition, the survey measured several prescriber characteristics and their perceptions of the organizational environment. Results Prescribers were generally satisfied with their work in delivering these two types of MOUD. Prescribers reporting a greater number of patients (r = .46, p = .006), those who would recommend the center to others (r = .56, p < .001), and those reporting positive relationships with staff (r = .56, p < .001) reported significantly greater overall satisfaction with delivering buprenorphine treatment. Prescribers who more strongly endorsed feeling overburdened reported lower overall buprenorphine satisfaction (r = -.37, p = .02). None of the prescriber characteristics or perceptions of the organizational environment were significantly associated with overall satisfaction with delivering XR-naltrexone treatment. Conclusions The generally high levels of satisfaction with both types of MOUD is notable given that prescriber dissatisfaction can lead to turnover and impact intentions to leave the profession. Future research should continue to explore the prescriber characteristics and organizational factors associated with satisfaction in providing different types of MOUD. Registration ClinicalTrials.gov. NCT02926482. Date of registration: September 9, 2016. https://clinicaltrials.gov/ct2/show/NCT02926482 .

We aimed to elucidate the evolutionary trajectories of gallbladder adenocarcinoma (GBAC) using multi-regional and longitudinal tumor samples. Using whole-exome sequencing data, we constructed phylogenetic trees in each patient and analyzed mutational signatures. A total of 11 patients including 2 rapid autopsy cases were enrolled. The most frequently altered gene in primary tumors was ERBB2 and TP53 (54.5%), followed by FBXW7 (27.3%). Most mutations in frequently altered genes in primary tumors were detectable in concurrent precancerous lesions (biliary intraepithelial neoplasia [BilIN]), but a substantial proportion was subclonal. Subclonal diversity was common in BilIN (n=4). However, among subclones in BilIN, a certain subclone commonly shrank in concurrent primary tumors. In addition, selected subclones underwent linear and branching evolution, maintaining subclonal diversity. Combined analysis with metastatic tumors (n=11) identified branching evolution in nine patients (81.8%). Of these, eight patients (88.9%) had a total of 11 subclones expanded at least sevenfold during metastasis. These subclones harbored putative metastasis-driving mutations in cancer-related genes such as SMAD4, ROBO1, and DICER1. In mutational signature analysis, six mutational signatures were identified: 1, 3, 7, 13, 22, and 24 (cosine similarity >0.9). Signatures 1 (age) and 13 (APOBEC) decreased during metastasis while signatures 22 (aristolochic acid) and 24 (aflatoxin) were relatively highlighted. Subclonal diversity arose early in precancerous lesions and clonal selection was a common event during malignant transformation in GBAC. However, selected cancer clones continued to evolve and thus maintained subclonal diversity in metastatic tumors.

ABSTRACT Many mechanisms have been proposed to be involved in the formation of bacterial persister cells. In this study, we investigated the impact of dam encoding DNA methylation on persister cell formation in Acinetobacter. We constructed plasmids overexpressing dam encoding DNA-(adenine N6)-methyltransferase and four genes as possibly involved in persistence and introduced them into three A. baumannii strains. For persister cell formation assays, bacteria were exposed to ciprofloxacin, imipenem, cefotaxime, and rifampin, and the transcription levels of the genes were measured by qRT-PCR. In addition, growth curves of strains were determined. We found that all five genes were upregulated following antibiotic exposure. Dam overexpression increased persister cell formation rates and activated the four persister cell-involved genes. Among the four persister cell-involved genes, only RecC overexpression increase persister cell formation rates. While recC-overexpressing strains showed higher growth rates, dam-overexpressing strains showed decreased growth rates. In this study, we revealed that a DNA methyltransferase may regulate persister cell formation in A. baumannii, while RecC seems to mediate epigenetic regulation of persister cell formation. However, Dam and RecC may act at different persister cell formation states. IMPORTANCE Bacterial persister cells are not killed by high concentration of antibiotics, despite its antibiotic susceptibility. It has been known that they may cause antibiotic treatment failure and contribute to the evolution of antibiotic resistance. Although many mechanisms have been suggested and verified for persister cell formation, many remains to be uncovered. In this study, we report that DNA methyltransferase leads to an increase in persister cell formation, through transcriptional activation of several regulatory genes. Our results suggest that DNA methyltransferases could be target proteins to prevent formation of persister cells.

BackgroundIt has been suggested that diabetes mellitus (DM) and the apolipoprotein E (APOE) ε4 allele (APOE4) increase the risk for Alzheimer’s disease (AD) and cognitive decline. However, the evidence is sparse. We explored whether APOE4 status modulated the effects of midlife and late-life DM on global cognition of non-demented older adults.MethodsIn all, 176 non-demented adults (age 65–90 years) were enrolled. All the participants underwent comprehensive clinical assessments including midlife and late-life DM evaluation and APOE genotyping. The global cognitive performance index was assessed by the total score (TS) of the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery.ResultsWe found a significant midlife DM × APOE4 interaction effect on the global cognitive performance. Subgroup analyses indicated that an association between midlife DM and decreased global cognitive performance was apparent only in older adults who were APOE4-positive, and not in those with APOE4-negative.ConclusionOur findings from non-demented older adults suggest that midlife DM increases the risk for AD and cognitive decline, and this risk is modulated by APOE4 status. To prevent AD and cognitive decline, physicians should check for the possible coexistence of midlife DM and APOE4-positive status.

BackgroundAtrial fibrillation (AF) is occasionally diagnosed in individuals with Graves’ disease. Definite treatments, including radioactive iodine therapy (RAIT) or surgery might lower the risk of AF in the literature. However, no studies have compared the effects of anti-thyroid drugs (ATDs), RAIT, and surgery on the risk of AF.MethodsThis retrospective cohort study included 94,060 newly diagnosed Graves’ disease patients and 470,300 controls from the Korean National Health Insurance database. The incidence of AF was evaluated in patients and controls. Patients were categorized based on treatment method into ATD (95.6%), RAIT (3.5%), and surgery (0.9%) groups. In the ATD group, the dose and duration of ATDs were calculated for each patient. In the RAIT and surgery groups, remission was defined as levothyroxine prescription.ResultsGraves’ disease patients had a 2.2-fold higher risk of developing AF than controls. Regardless of demographic factors, the patient group had a consistently higher risk of AF than controls, with the highest risk of AF (HR, 5.49) in the younger patient group. The surgery group had a similar risk of AF compared with controls, whereas the ATD (HR, 2.23) and RAIT (HR, 2.00) groups had increased risks of AF, even in patients reaching hypothyroid status after RAIT. Patients with higher dose or longer treatment duration of ATDs were at greater risk of AF.ConclusionWe observed differing risks of AF according to methods of treatment for Graves’ disease, and that definite treatment can be an option for subjects needing sustained medical treatment considering the risk of AF.

Summary: Little is known about the association between meal frequency and Alzheimer’s disease (AD) in humans. We tested the hypothesis that low meal frequency (LMF) is associated with reduced in vivo AD pathology in human brain, and additionally investigated the mediation of serum ghrelin, a hunger-related hormone, for the association. A total of 411 non-demented older adults were systematically interviewed to identify their dietary patterns including meal frequency and underwent multi-modal neuroimaging for cerebral beta-amyloid (Aβ) and tau deposition, glucose metabolism, and cerebrovascular injury. LMF (less than three meals a day) was significantly associated with lower Aβ deposition compared to high meal frequency (HMF). In addition, both LMF and reduced Aβ deposition were significantly related to elevated serum ghrelin. Our findings suggest that LMF may be related to the lower risk of AD through reduced brain amyloid deposition. Additionally, ghrelin appears mediate the association between LMF and lower amyloid deposition.

Abstract Little is known about the effects of parenchymal or vascular amyloid β peptide (Aβ) deposition in the brain. We hypothesized that Aβ strain-specific information defines whether Aβ deposits on the brain parenchyma or blood vessels. We investigated 12 autopsied patients with different severities of Aβ plaques and cerebral amyloid angiopathy (CAA), and performed a seeding study using an Alzheimer’s disease (AD) mouse model in which brain homogenates derived from the autopsied patients were injected intracerebrally. Based on the predominant pathological features, we classified the autopsied patients into four groups: AD, CAA, AD + CAA, and less Aβ. One year after the injection, the pathological and biochemical features of Aβ in the autopsied human brains were not preserved in the human brain extract-injected mice. The CAA counts in the mice injected with all four types of human brain extracts were significantly higher than those in mice injected with PBS. Interestingly, parenchymal and vascular Aβ depositions were observed in the mice that were injected with the human brain homogenate from the less Aβ group. The Aβ and CAA seeding activities, which had significant positive correlations with the Aβ oligomer ratio in the human brain extracts, were significantly higher in the human brain homogenate from the less Aβ group than in the other three groups. These results indicate that exogenous Aβ seeds from different Aβ pathologies induced Aβ deposition in the blood vessels rather than the brain parenchyma without being influenced by Aβ strain-specific information, which might be why CAA is a predominant feature of Aβ pathology in iatrogenic transmission cases. Furthermore, our results suggest that iatrogenic transmission of Aβ pathology might occur due to contamination of brain tissues from patients with little Aβ pathology, and the development of inactivation methods for Aβ seeding activity to prevent iatrogenic transmission is urgently required.

PM2.5 is a WHO-designated first-class carcinogen and coping with high-concentration situations with high human risk is becoming more important. In particular, Korea has a high concentration of PM2.5 in winter due to its geographical characteristics, which can be largely divided into foreign inflows and domestic atmospheric stability. To determine this, wind patterns and air pressure data were analyzed representatively and episodes about high concentration phenomena were classified. In this study, high-concentration PM2.5 episodes, where the daily average PM2.5 concentration in Seoul exceeded 35 μg/m3 between October 2019 to March 2020, were analyzed case-by-case. The criteria for the separation of consecutive episodes were established. Then, the designated episodes were classified into four categories based on cause: atmospheric stagnation, combination of causes, penetration from abroad, and accumulation. To identify the causes of the episodes, wind direction, wind speed data, wind roses, and air quality forecast modeling data obtained from “Air Korea” were studied. Fifteen episodes were identified and analyzed and each were given a classification type. Furthermore, the phenomenon of high-concentration episodes was summarized after detailed individual analysis of the episodes. As a result of case analysis, just before there was an inflow from abroad due to strong wind speed, a characteristic of low PM2.5 concentration of air quality as a kind of cleaning effect could be found. In addition, alarm-level PM2.5 concentrations of 75 μg/m3 or higher were often made by external inflow. This will contribute towards identifying the main causes of high PM2.5 concentration episodes in Korea when it is applied over a longer time period.

Abstract DHP107 is a newly developed lipid‐based oral formulation of paclitaxel. We evaluated the in vivo tissue pharmacokinetics (PKs) of DHP107 in mice and patients using positron emission tomography (PET). Radioisotope‐labeled [3H]DHP107 and [18F]DHP107 for oral administration were formulated in the same manner as the manufacturing process of DHP107. In vivo tissue PK were assessed in healthy ICR mice and breast cancer xenografted SCID mice. Two patients with metastatic breast cancer were clinically evaluated for absorption at the target lesion after internal absorbed dose estimation. Whole‐body PET/computed tomography data were acquired in healthy and xenografted mice and in patients up to 10–24 h after administration. Tissue [18F]DHP107 signals were plotted against time and PK parameters were determined. The amounts of radioactivity in various organs and excreta were determined using a beta‐counter and are expressed as the percentage of injected dose (ID). Oral [18F]DHP107 was well‐absorbed and reached the target lesion in mice and patients with breast cancer. Significant amounts of radioactivity were found in the stomach, intestine, and liver after oral administration of [3H]‐ and [18F]DHP107 in healthy mice. The [18F]DHP107 reached a peak distribution of 0.7–0.8%ID in the tumor at 5.6–7.3 h in the xenograft model. The [18F]DHP107 distribution in patients with metastatic breast cancer was the highest at 3–4 h postadministration. Systemic exposures after administration of a DHP107 therapeutic dose were comparable with those in previous studies. PET using radioisotope‐labeled drug candidates is useful for drug development and can provide valuable information that can complement plasma PK data, particularly in early phase clinical trials.

Abstract Background Malignant transformation of endometriosis in extraovarian sites remains rare. Furthermore, the process is not definitely understood. Case presentation Herein, we report the case of a 40-year-old premenopausal nulligravida woman who presented with vaginal bleeding and who was finally diagnosed with a vaginal cancer originating from endometriosis and with a synchronous endometrial cancer. A gynecologic examination revealed a multiple polypoid mass on the posterior vaginal fornix. Magnetic Resonance Imaging of the pelvis showed two masses abutting respectively on the anterior uterine wall, and in the rectovaginal septum. The patient underwent a total laparoscopic excision of the rectovaginal mass, radical hysterectomy and low anterior resection of the rectum. The lesions were diagnosed as endometriosis, endometriosis-associated complex hyperplasia and endometrioid cancer. Furthermore, a synchronous endometrioid endometrial cancer was reported. Conclusions This case revealed the multistep process of malignant transformation of deep infiltrating endometriosis. The progression was individualized between implantation sites and in the same organ.

High-altitude cerebral edema (HACE) is a potentially fatal neurological syndrome that develops in persons traveling to a high altitude. We report the case of a 49-year-old male who had traveled to a high altitude, and lost consciousness for a few hours. Susceptibility-weighted images revealed multiple, fine black pepper like microbleeds along the corpus callosum with several microbleeds in the left frontal and parietal subcortical white matter. The T2-weighted images did not show any abnormal signal intensities along the corpus callosum. The diffusion-weighted images revealed small nodular high signal intensities in the basal ganglia. This report describes the atypical radiologic findings of HACE showing multiple microbleeds along the corpus callosum, without abnormal high-signal intensity on T2-weighted images.

We report a case of Immunoglobulin G4 (IgG4) related disease involving the pterygoplataine fossa. A 83-year-old male presented with left ocular pain and visual disturbance. CT showed an isodense soft tissue lesion in the left pterygopalatine fossa with bony sclerotic changes and erosion. MRI revealed an infiltrative soft tissue mass in the left pterygopalatine fossa as a T2 slightly low signal intensity and heterogeneous enhancement. The patient underwent left ethmoidectomy, and biopsy of the mass was conducted. The histopathological diagnosis was IgG4-related disease. In this case, it was difficult to differentiate invasive aspergillosis, which is common in immunocompromised patients, considering the patient’s clinical history of diabetes mellitus. This report describes the imaging findings of IgG4-related disease mimicking invasive sinusitis such as invasive aspergillosis.

Introduction There is an increased demand for services for hospitalised older patients with acute medical conditions due to rapidly ageing population. The COMPrehensive geriatric AsseSSment and multidisciplinary team intervention for hospitalised older adults (COMPASS) study will test the effectiveness of comprehensive geriatric assessment (CGA) and multidisciplinary intervention by comparing it with conventional care among acute hospitalised older adults in Korea.Methods and analysis A multicentre trial within a cohort comprising three substudies (randomised controlled trials) will be conducted. The intervention includes CGA and CGA-based multidisciplinary interventions by physicians (geriatricians, oncologists), nurses, nutritionists and pharmacists. The multidisciplinary intervention includes nutritional support, medication review and adjustment, rehabilitation, early discharge planning and prevention of geriatric syndromes (falls, delirium, pressure sore and urinary retention). The analysis will be based on an intention-to-treat principle. The primary outcome is living at home 3 months after discharge. In addition to assessing the economic effects of the intervention, a cost-utility analysis will be conducted.Ethics and dissemination The study protocol was reviewed and approved by the ethics committees of Seoul National University Bundang Hospital and each study site. The study findings will be published in peer-reviewed journals. Subgroup and further in-depth analyses will subsequently be published.Trial registration number KCT0006270.