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Introduction: Angiolipoleiomyoma (ALLM) is a rare hamartomatous tumor of mesenchymal origin composed of smooth muscle, mature adipose tissue, and blood vessels in various proportions. Because of its histologic similarity to renal angiomyolipoma (AML), it is also called uterine angiomyolipoma. Preoperative diagnosis of uterine ALLM is very challenging due to its uncommon incidence and absence of established characteristic imaging findings. Case Description: A 50-year-old multiparous female patient visited our institution for gynecologic screening. Transvaginal sonography (TVS), Abdominopelvic computed tomography (CT), and pelvic magnetic resonance imaging (MRI) revealed large well-defined masses involving the posterior uterine wall with rectal indentation. The patient underwent a total abdominal hysterectomy for this tumor and the histopathological diagnosis was uterine ALLM. Conclusion: This report would contribute to understanding and establishing the radiologic findings of the uterine ALLM. Considering the benign characteristics and favorable prognosis of this rare tumor, familiarity with its imaging findings by radiologists will guide clinicians in better patient management and prevention of unnecessary radical surgery.

Introduction: Clear cell hepatocellular carcinoma (HCC) is a rare subtype of HCC. Histologically, clear cell HCC is characterized by the cytoplasmic accumulation of glycogen with a clear cell appearance, constituting > 80% of tumor cells. Radiologically, clear cell HCC demonstrates early enhancement and washout similar to conventional HCC. Occasionally, enhancing capsule and intratumoral fat are accompanied by clear cell HCC. Case description: A 57-year-old male presented to our hospital with right upper quadrant abdominal pain. Ultrasonography, computed tomography, and magnetic resonance imaging revealed a large mass with a well-defined margin in the right hemiliver. The patient underwent a right hemihepatectomy, and the final histopathology revealed clear cell-type HCC. Conclusion: Distinguishing clear cell types from other types of HCC solely based on radiological findings is challenging. If hepatic tumors exhibit encapsulated margins, enhancing rims, intratumoral fat, and arterial phase hyperenhancement/washout pattern despite their large size, consideration of clear cell subtypes in the differential diagnosis list will aid patient management, implying better prognosis than not-otherwise-specified HCC.

The progression of neurodegenerative disorders can lead to impaired neurotransmission; however, the role of pathogenic factors associated with these diseases and their impact on the structures and functions of neurotransmitters have not been clearly established. Here we report the discovery that conformational and functional changes of a native neuropeptide, somatostatin (SST), occur in the presence of copper ions, metal-free amyloid-β (Aβ) and metal-bound Aβ (metal-Aβ) found as pathological factors in the brains of patients with Alzheimer's disease. These pathological elements induce the self-assembly of SST and, consequently, prevent it from binding to the receptor. In the reverse direction, SST notably modifies the aggregation profiles of Aβ species in the presence of metal ions, attenuating their cytotoxicity and interactions with cell membranes. Our work demonstrates a loss of normal function of SST as a neurotransmitter and a gain of its modulative function against metal-Aβ under pathological conditions.

BACKGROUND Timely pulmonary tuberculosis (PTB) diagnosis is a global health priority for interrupting transmission and optimising treatment outcomes. The dichotomous time-divided approach for time delay has limited clinical application. OBJECTIVE We aimed to re-evaluate the time delay based on the PTB disease spectrum using a novel scoring system at the national level in the Republic of Korea. METHODS The PTB Spectrum Score (PTBSS) was designed based on previously published proposals for disease spectrum and was validated by mortality. We analysed the data by substituting the PTBSS into the Korea Tuberculosis Cohort Registry, and assessed time delays and related system variables using multivariate regression according to PTBSS. RESULTS Among the 14,031 active PTB Korean patients whose data were analysed from 2018 to 2020, patients with active PTB were diagnosed with mild (37.0%), moderate (38.0%), or severe (25.0%) disease status according to the PTBSS. The time delay patterns differed according to the PTBSS. Healthcare delays showed that greater PTB progression was associated with earlier diagnosis. Presentation delay showed a U-shaped pattern of elapsed time with PTB progression, wherein a remarkable presentation delay in the real-world setting might occur at both apical ends: mild and severe PTB. Independent risk factors for severe PTB pattern were age (adjusted OR, 1.014) and male sex (adjusted OR, 1.422), whereas no remarkable risk factor was found for mild PTB. CONCLUSIONS Timely pulmonary tuberculosis diagnosis should be accomplished. It could be improved with PTBSS, a simple and intuitive scoring system, and more helpful clinical and public applications rather than the traditional dichotomous time-only approach.

Background: Air pollution control is necessary to decrease the burden on older adults with cognitive impairment, especially in low- and middle-income countries (LMICs). Objective: This study retrospectively examined the effect of cumulative exposure to air pollution, including NO2, SO2, CO, fine particulate matter (PM)10, PM2.5, and O3, on cognitive function in older individuals. Methods: Community-dwelling older adults who underwent the Mini-Mental State Examination (MMSE) from 2007 to 2018 were included in the analyses. We excluded older individuals diagnosed with dementia at baseline, while those who had completed more than two MMSE tests were included in the longitudinal analyses. Baseline MMSE and changes in MMSE scores were analyzed according to 5-year average concentrations of the district-level air pollutants, after controlling for covariates associated with cognitive decline in older adults. Results: In total, 884,053 (74.3±7.1 years; 64.1% females) and 398,889 (72.3±6.4 years; 67.0% females) older individuals were included in the cross-sectional and longitudinal analyses, respectively. Older individuals exposed to higher levels of NO2, SO2, CO, and PM10 showed lower baseline MMSE scores. During follow-up, exposure to higher levels of NO2, SO2, CO, and PM10 was associated with greater decreases in MMSE scores in older individuals; for O3, the opposite pattern was observed. Conclusion: Our findings suggest that exposure to high levels of air pollutants can worsen the cognitive performance of older adults without dementia. Efforts to reduce air pollution in LMICs that have similar levels of pollutants to South Korea are necessary to reduce the burden on older adults with cognitive impairment.

Background/Aims: Although the incidence and mortality of tuberculosis are decreasing in South Korea, the number of applications for financial assistance with the cost of tuberculosis treatment made by individuals from vulnerable groups was 3.8 times higher in 2019 compared to 2017 (Tuberculosis Relief Belt Project, 2019).Methods: We analyzed the data of patients who received financial aid for tuberculosis treatment (in the period 2014-2018) from the Tuberculosis Relief Belt Project, which was designed to assist vulnerable groups. This study analyzed 137 subjects, and the independent variables included patient factors (age, gender, nationality, tuberculosis type, number of comorbidities, and place of residence) and treatment type (outpatient or inpatient). The dependent variable was the treatment outcome.Results: The likelihood of treatment success was significantly lower for patients with one (odds ratio [OR] 0.202), two (OR 0.147), or three or more (OR 0.070) comorbidities compared to those with no comorbidities. This was also the case for patients living alone (OR 0.097), and for those classified as homeless (OR 0.053). Korean patients (OR 8.512) had a significantly higher probability of a successful treatment outcome than foreigners.Conclusions: Appropriate community-based management of individuals with tuberculosis from vulnerable groups, including foreigners, people with comorbidities, people living alone, and people with an unstable residential situation or homeless status, is important.

PURPOSE To quantitatively evaluate macular and peripapillary microvascular alterations in patients with indirect traumatic optic neuropathy (TON) compared to normal controls using optical coherence tomography angiography (OCT-A [Topcon DRI OCT; Triton]) and determine their associations with other ocular parameters. METHODS We enrolled 33 eyes of 33 patients with TON and 34 eyes of 34 healthy controls. OCT-A was used to generate microvascular structure images of the superficial retinal capillary plexus (SRCP), deep retinal capillary plexus (DRCP), and radial peripapillary capillary (RPC) segment in the macula and peripapillary area. Age, gender, and spherical equivalent refractive errors were statistically adjusted for the analysis. RESULTS OCT-A revealed a significant reduction of the average vessel density in the RPC segment in TON patients compared to controls (48.5% ± 6.28 vs. 57.88% ± 3.06%, P P P = 0.0253) and visual acuity (P = 0.0369). The temporal sector vessel density of DRCP was also associated with visual field defects (P = 0.0377). The RPC segment in the temporal, superior, and inferior sector vessel density had a significant association with the average pRNFL thickness (P = 0.0092, 0.0171, and

The misfolding and aggregation of amyloid-β (Aβ) peptides are histopathological features found in the brains of Alzheimer's disease (AD). To discover effective therapeutics for AD, numerous efforts have been made to control the aggregation of Aβ species and their interactions with other pathological factors, including metal ions. Metal ions, such as Cu(II) and Zn(II), can bind to Aβ peptides forming metal-bound Aβ (metal–Aβ) complexes and, subsequently, alter their aggregation pathways. In particular, redox-active metal ions bound to Aβ species can produce reactive oxygen species leading to oxidative stress. In this review, we briefly illustrate some experimental approaches for characterizing the coordination and aggregation properties of metal–Aβ complexes.

ConspectusAlzheimer's disease (AD) is the most common form of dementia and is characterized by memory loss and cognitive decline. Approximately 50 million people worldwide are suffering from AD and related dementias. Very recently, the first new drug targeting amyloid-β (Aβ) aggregates has been approved by the United States Food and Drug Administration, but its efficacy against AD is still debatable. Other available treatments temporarily relieve the symptoms of AD. The difficulty in discovering effective therapeutics for AD originates from its complicated nature, which results from the interrelated pathogenic pathways led by multiple factors. Therefore, to develop potent disease-modifying drugs, multiple pathological features found in AD should be fully elucidated.Our laboratory has been designing small molecules as chemical tools to investigate the individual and interrelated pathologies triggered by four pathogenic elements found in the AD-affected brain: metal-free Aβ, metal-bound Aβ, reactive oxygen species (ROS), and acetylcholinesterase (AChE). Aβ peptides are partially folded and aggregate into oligomers, protofibrils, and fibrils. Aβ aggregates are considered to be neurotoxic, causing membrane disruption, aberrant cellular signaling, and organelle dysfunction. In addition, highly concentrated metal ions accumulate in senile plaques mainly composed of Aβ aggregates, which indicates that metal ions can directly interact with Aβ. Metal binding to Aβ affects the aggregation and conformation of the peptide. Moreover, the impaired homeostasis of redox-active Fe(II/III) and Cu(I/II) induces the overproduction of ROS through Fenton chemistry and Fenton-like reactions, respectively. Dysregulated ROS prompt oxidative-stress-damaging biological components such as lipids, proteins, and nucleic acids and, consequently, lead to neuronal death. Finally, the loss of cholinergic transmission mediated by the neurotransmitter acetylcholine (ACh) contributes to cognitive deficits observed in AD.In this Account, we illustrate the design principles for small-molecule-based chemical tools with reactivities against metal-free Aβ, metal-bound Aβ, ROS, and AChE. More importantly, mechanistic details at the molecular level are highlighted with some examples of chemical tools that were developed by our group. The aggregation of metal-free Aβ can be modulated by modifying amino acid residues responsible for self-assembling Aβ or disassembling preformed fibrils. To alter the aggregation and cytotoxicity profiles of metal-bound Aβ, ternary complexation, metal chelation, and modifications onto metal-binding residues can be effective tactics. The presence and production of ROS are able to be controlled by small molecules with antioxidant and metal-binding properties. Finally, inhibiting substrate access or substrate binding at the active site of AChE can diminish its activity, which restores the levels of ACh. Overall, our rational approaches demonstrate the feasibility of developing small molecules as chemical tools that can target and modulate multiple pathological factors associated with AD and can be useful for gaining a greater understanding of the multifaceted pathology of the disease.

Particulate matter (PM) is the main component of air pollution. Children are vulnerable to PM and acute otitis media (AOM), which is one of the most common diseases in children. However, studies on the relationship between AOM in children and PM are rare and their results are inconsistent. The aim of this study is to investigate the effect of PM on AOM in children on the basis of the Korea National Health Insurance service (NHIS) claims data. NHIS claim data from 2008 to 2015 was used to identify outpatient visits, antibiotic use to treat AOM, and demographic data. This data was combined with the data on PM2.5 (≤ 2.5 μm) and PM10 (≤ 10 μm according to its aerodynamic diameter) level extracted from air pollution data from Korean National Institute of Environmental Research for 16 administrative regions. The children with AOM were divided into three age groups (2.5 of 10 μg/m3, the relative risk of OM increased by 4.5% in children under 2 years of age. The effect of PM2.5 was strongest influence on the day of exposure. The exposure to PM10 was related to the incidence of AOM on the day of exposure and the following seven days in all three age groups. The PM concentrations did not strongly affect either AOM duration or the use of antibiotics to cure AOM. The RR in the each lag day after exposure to PM10 was diverse according to the age groups. Regardless of PM size and children’s age, the PM levels are positively related to the incidence of AOM. Both PM2.5 and PM10 have the most adverse effects on children under 2 years of age and on the day of exposure.

Recent advances in flexible and stretchable electronics have led to a surge of electronic skin (e-skin)–based health monitoring platforms. Conventional wireless e-skins rely on rigid integrated circuit chips that compromise the overall flexibility and consume considerable power. Chip-less wireless e-skins based on inductor-capacitor resonators are limited to mechanical sensors with low sensitivities. We report a chip-less wireless e-skin based on surface acoustic wave sensors made of freestanding ultrathin single-crystalline piezoelectric gallium nitride membranes. Surface acoustic wave–based e-skin offers highly sensitive, low-power, and long-term sensing of strain, ultraviolet light, and ion concentrations in sweat. We demonstrate weeklong monitoring of pulse. These results present routes to inexpensive and versatile low-power, high-sensitivity platforms for wireless health monitoring devices.

Nonprofit social service agencies in South Korea have dramatically improved their service quality in the last few decades. However, with increasing competition among nonprofit social service agenci...

Ocular axial length (AL) is an important property of eyes used for determining their health prior to surgery. Estimation of AL is also crucial while making artificial lenses to replace impaired natural lenses. However, accurate measurement of AL requires a costly and bulky benchtop optical system. The complex structural features of eyes can be captured by fundus images, which can be easily captured nowadays with portable cameras. Here, we suggest a deep learning method for predicting AL based on fundus images with evidence of decision. This visual interpretation of predictions is achieved by post-processing, separated from the training process, to ensure that the architecture can be freely designed. Through the visualization technique, discriminative regions on input images can be localized to demonstrate specific areas of interest for predictions. In the experiments, we found a significant relationship between the fundus images and AL with achieving a coefficient of determination ( R2 ) of 0.67 and accuracy of 90%, within an error margin of $ \pm 1$ mm. Furthermore, visual evidence proves that the network uses consistent regions for predicting AL. The visual results of this study also point to a link between AL and biological structure of eyes, which paves the way for future research.

Background Lung adenocarcinoma (LUAD) with brain metastasis (BM) occurs frequently and has a poor prognosis. In this study, we aimed to assess the correlation between gene expression signatures and the development of BM after surgical resection of LUAD. Methods We analyzed the immune-related gene expression profiles of 72 LUADs with and without BM after surgery and verified them using NanoString method and immunohistochemistry (IHC). We matched the Tumor, Node, Metastasis (TNM) stage in the groups with and without BM to minimize the effect of TNM stage. Pathway enrichment studies were also performed. Results In the NanoString results, we identified 11 upregulated immune-related gene signature that correlated specifically with BM in the discovery and validation sets [area under the curve (AUC) =0.750 and 0.787, respectively]. The discovery set achieved 94% sensitivity and 62% specificity and the validation set displayed 100% sensitivity and 50% specificity. Eight out of the 11 genes were verified by IHC and had profiles similar to the gene expression profile results (AUC =0.844 for the discovery set and AUC =0.795 for the validation set). Subgroup analysis revealed that 11 immune-related gene signature enabled prediction of BM at all TNM stages. There were no differences in the 11 immune-related gene expression signatures between the primary LUAD samples and the matched brain samples. Pathway enrichment analysis revealed that the cytokine-cytokine receptor interaction pathway was closely correlated with BM. Conclusions The 11 identified immune-related gene expression signatures may be potentially clinically useful predictors for BM and can provide patient-specific treatment options.

BackgroundPenile carcinoma is a rare malignant neoplasm and its molecular pathogenetic mechanism is largely unknown. Telomerase reverse transcriptase (TERT) promoter mutations have been detected in several types of human malignancies, including malignant melanoma, non-melanoma skin cancer, thyroid carcinoma, glioma, and bladder carcinoma. However, TERT-p mutation in penile squamous cell carcinoma (SCC) has not been investigated to date. The aim of this study was to investigate the presence of TERT promoter mutations in penile squamous cell carcinomas and their associations with clinicopathologic features. MethodsSanger sequencing was performed to detect TERT promoter mutations in formalin-fixed paraffin-embedded tissue samples from 37 cases of penile SCC, 16 cases of cutaneous SCC, and 4 cases of non-neoplastic penile/skin tissue. The expression of p16 and Ki67 were investigated by immunohistochemistry. Associations of TERT promoter mutation with clinicopathological factors, immunohistochemical results, and clinical outcome were statistically analyzed. ResultsRecurrent TERT promoter mutations were identified in 18 of 37 (48.6%) penile SCCs, including all three carcinoma in situ cases. TERT promoter mutations were significantly more frequent in non-human papilloma virus (HPV)-related penile SCC types based on both histologic classification and p16INK4a immunoreactivity. Furthermore, TERT promoter mutation was associated with a low histologic grade, low mitotic count, absence of necrosis, and low Ki67/MIB-1 labelling index. Univariate Cox regression analysis and Kaplan-Meier analysis with the log-rank test indicated that TERT promoter mutation was a favorable factor for disease-free survival. ConclusionsOur study shows TERT-p mutations are the most frequent somatic mutations in penile SCC. In addition, TERT-p mutations are far more frequent in non-HPV-related penile SCC, indicating that in case of non-HPV-related penile SCC, TERT-p mutations may have a role in tumorigenesis distinct from HPV-related penile SCC.

Purpose This study investigated the association of insulin, metformin, and statin use with survival and whether the association was modified by the hormone receptor status of the tumor in patients with breast cancer.Materials and Methods We studied 7,452 patients who had undergone surgery for breast cancer at Seoul National University Hospital from 2008 to 2015 using the nationwide claims database. Exposure was defined as a recorded prescription of each drug within 12 months before the diagnosis of breast cancer.Results Patients with prior insulin or statin use were more likely to be older than 50 years at diagnosis and had a higher comorbidity index than those without it (p < 0.01 for both). The hazard ratio (HR) for death with insulin use was 5.7 (p < 0.01), and the effect was attenuated with both insulin and metformin exposure with an HR of 1.2 (p=0.60). In the subgroup analyses, a heightened risk of death with insulin was further prominent with an HR of 17.9 (p < 0.01) and was offset by co-administration of metformin with an HR of 1.3 (p=0.67) in patients with estrogen receptor (ER)–negative breast cancer. Statin use was associated with increased overall mortality only in patients with ER-positive breast cancer with HR for death of 1.5 (p=0.05).Conclusion Insulin or statin use before the diagnosis of breast cancer was associated with an increase in all-cause mortality. Subsequent analyses suggested that metformin or statin use may have been protective in patients with ER-negative disease, which warrants further studies.

Pathophysiological shifts in the cerebral levels of sphingolipids in Alzheimer's disease (AD) patients suggest a link between sphingolipid metabolism and the disease pathology. Sphingosine (SP), a structural backbone of sphingolipids, is an amphiphilic molecule that is able to undergo aggregation into micelles and micellar aggregates. Considering its structural properties and cellular localization, we hypothesized that SP potentially interacts with amyloid-β (Aβ) and metal ions that are found as pathological components in AD-affected brains, with manifesting its reactivity towards metal-free Aβ and metal-bound Aβ (metal–Aβ). Herein, we report, for the first time, that SP is capable of interacting with both Aβ and metal ions and consequently affects the aggregation of metal-free Aβ and metal–Aβ. Moreover, incubation of SP with Aβ in the absence and presence of metal ions results in the aggravation of toxicity induced by metal-free Aβ and metal–Aβ in living cells. As the simplest acyl derivatives of SP, N-acetylsphingosine and 3-O-acetylsphingosine also influence metal-free Aβ and metal–Aβ aggregation to different degrees, compared to SP. Such slight structural modifications of SP neutralize its ability to exacerbate the cytotoxicity triggered by metal-free Aβ and metal–Aβ. Notably, the reactivity of SP and the acetylsphingosines towards metal-free Aβ and metal–Aβ is determined to be dependent on their formation of micelles and micellar aggregates. Our overall studies demonstrate that SP and its derivatives could directly interact with pathological factors in AD and modify their pathogenic properties at concentrations below and above critical aggregation concentrations., The reactivity of sphingosine and acetylsphingosines towards both metal-free and metal-treated amyloid-β is demonstrated showing a correlation of their micellization properties.

With a growing number of nonprofit social service agencies in South Korea, leaders are required to networking among agencies to provide quality services. On the other hand, increasing competitive e...

Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and a heterogeneous disease with a variety of molecular aberrations and diverse clinical outcomes. BCL2 expression has been implicated for a poor prognosis among patients with DLBCL. However, there is no consensus regarding the interpretation of BCL2 expression in DLBCL. In previous studies, the range of BCL2-positive cases, determined by immunohistochemistry (IHC), was highly variable (24 - 80%) due to subjective and semiquantitative interpretation and the absence of the established cutoff value for BCL2 expression. Consequently, the prognostic impact of BCL2 varies between studies. In addition, only the proportion of BCL2 positive tumor cells are considered in determining the BCL2 positivity. We aimed to define BCL2 positivity by quantitative analysis integrating both the intensity and proportion of BCL2 expression. Methods We retrospectively collected formalin-fixed, paraffin-embedded (FFPE) diagnostic biopsies from 221 patients with de novo DLBCL between January 2007 and December 2012 at our institute. All patients were treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as first-line treatment. A separate validation set included 111 patients with de novo DLBCL who received first-line R-CHOP at another tertiary hospital in South Korea. BCL2 expression was analyzed using the tumor-specific Automated Quantitative Analysis (AQUA) scoring system based on multiplex immunofluorescence. The tumor-specific quantified intensity information in pixels was converted to protein expression information on a cell basis using the AQUA scoring system. The AQUA scores for BCL2 was calculated as the signal intensities of BCL2 in the target compartment divided by the pixel area of the target compartment. Cell of origin (COO) was determined according to the Hans classification using IHC. Results Ninety-eight patients (44.3%) were > 60 years old of age, 126 patients (57.0%) were male and 81 patients (36.7%) had an International Prognostic Index of 3-5 in the training set. With a median follow-up duration of 59 months, the 5-year event-free survival (EFS) and overall survival (OS) rate were 62.2% and 69.0%, respectively. The BCL2 AQUA score of 41.47 was determined as the optimal cutoff value in the ROC analysis. A total of 86 patients (38.9%) were classified as high BCL2 AQUA score group according to the determined cutoff value. High BCL2 AQUA score was significantly associated with worse OS and EFS (P = 0.00015; OS, P = 0.00012; EFS) (Figure 1A, B). Multivariate analysis revealed that high BCL2 AQUA score was a significant poor prognostic factor for both OS and EFS independent of the IPI, and COO (P = 0.01; OS, P = 0.015; EFS). The high BCL2 AQUA score group in the validation set was also significantly associated with worse OS and EFS (P = 0.0075; OS, P = 0.0049; EFS) (Figure 1C, D). The poor prognostic impact of BCL2 AQUA score was also in good correlation with both OS and EFS in the entire cohort (P < 0.0001; OS, P < 0.0001; EFS) (Figure 1E, F). The adverse impact of high BCL2 AQUA score was identified within both low (IPI 0-2) and high IPI (IPI 3-5) groups (Figure 2A-D). The high BCL2 AQUA score was also associated with poor prognosis within both GCB (P = 0.0077; OS, P = 0.0055; EFS) and non-GCB type DLBCL (P = 0.059; OS, P = 0.04; EFS), although a marginal statistical significance was observed regarding OS in the non-GCB type (Figure 2E-H). Conclusion Our study demonstrated that BCL2 expression analyzed by AQUA scoring system, incorporating both intensity and proportion, is an independent prognostic factor for patients with DLBCL. Given the growing clinical implications of BCL2 and the therapeutic progress in targeting BCL2 in hematologic malignancies, the concrete definition of BCL2 positivity in DLBCL holds great promise for the study of the pathophysiology of DLBCL and could be used to establish new therapeutic strategies. Disclosures No relevant conflicts of interest to declare.

Neurotoxic implications of the interactions between Cu(I/II) and amyloid-β (Aβ) indicate a connection between amyloid cascade hypothesis and metal ion hypothesis with respect to the neurodegeneration associated with Alzheimer's disease (AD). Herein, we report a mechanistic strategy for modifying the first coordination sphere of Cu(II) bound to Aβ utilizing a rationally designed peptide modifier, L1. Upon reacting with L1, a metal-binding histidine (His) residue, His14, in Cu(II)-Aβ was modified through either covalent adduct formation, oxidation, or both. Consequently, the reactivity of L1 with Cu(II)-Aβ was able to disrupt binding of Cu(II) to Aβ and result in chemically modified Aβ with altered aggregation and toxicity profiles. Our molecular-level mechanistic studies revealed that such L1-mediated modifications toward Cu(II)-Aβ could stem from the molecule's ability to 1) interact with Cu(II)-Aβ and 2) foster copper-O2 chemistry. Collectively, our work demonstrates the development of an effective approach to modify Cu(II)-Aβ at a metal-binding amino acid residue and consequently alter Aβ's coordination to copper, aggregation, and toxicity, supplemented with an in-depth mechanistic perspective regarding such reactivity.