Joker Sign After Drooling Radioactive Saliva.

ABSTRACT: A 28-year-old man underwent high-dose radioactive iodine therapy after total thyroidectomy due to papillary thyroid carcinomas. After 2 weeks, a linear reddish line was observed extending from the right corner of the mouth to the cheek, resembling the appearance of the Joker. Through a detailed interview, it was determined that the patient had developed radiation dermatitis because of radioactive saliva drooling while sleeping on one side. Although this is expected to be infrequent, educating patients on avoiding saliva contact with the skin during and after radioactive iodine therapy is crucial due to the potential skin damage and cancer risk.

Accelerated bone loss in late reproductive-aged and perimenopausal women with vitamin D insufficiency.

INTRODUCTION: The association between serum vitamin D levels and bone mineral density (BMD) varies by race and gender. This study aimed to evaluate this relationship between serum vitamin D levels and BMD, and changes of BMD over time in Korean women. MATERIALS AND METHODS: We analyzed data from 586 generally healthy Korean women aged 29-79 who underwent health check-ups at Seoul National University Gangnam Center between 2010 and 2011 (baseline measurement) and 2015-2016 (follow-up). Dual energy X-ray absorptiometry (DEXA) and serum 25-hydroxyvitamin D (25OH-D) level measurements were conducted. We assessed the association between serum 25OH-D levels and BMD, as well as changes in BMD over time. RESULTS: The mean age of participants was 51.3 ± 7.9 years, with a mean follow-up interval of 4.6 ± 0.7 years, and mean serum 25OH-D level of 20.6 ± 8.5 ng/ml. Baseline serum 25OH-D levels did not correlate with BMD values at the lumbar spine, femoral neck, or total femur, nor with changes in BMD over time. A significant negative association was found between perimenopausal status and BMD changes at all sites, and between premenopausal status and lumbar bone mass, compared to postmenopausal status in the 25OH-D < 20 ng/ml group. This association was not observed in women with higher serum 25OH-D levels. CONCLUSIONS: Serum 25OH-D levels did not correlate with BMD levels or changes in BMD overall. However, in late reproductive-aged and perimenopausal women with serum 25OH-D insufficiency, there was a significant association with accelerated bone loss.

Sodium-glucose cotransporter 2 inhibitors ameliorate ER stress-induced pro-inflammatory cytokine expression by inhibiting CD36 in NAFLD progression in vitro.

Sodium-dependent glucose cotransporter-2 (SGLT2) inhibitors, antidiabetic drugs that reduce blood sugar levels by inhibiting glucose reabsorption in the renal proximal tubules, also ameliorate nonalcoholic fatty liver disease (NAFLD). This study aimed to examine the effects of SGLT2 inhibition on hepatic steatosis and nonalcoholic steatohepatitis (NASH) using an in vitro model of NAFLD progression. HepG2 cells and a coculture of Hepa1c1c7 and Raw 264.7 cells were treated with 400 µM palmitic acid (PA), followed by treatment with or without 10 µM empagliflozin and dapagliflozin. In HepG2 cells, PA increased hepatic lipid accumulation, the expression of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß), exocytosis mediators (VAMP3 and SNAP23), and ER stress markers (GRP78, PERK, IRE1α, ATF6, ATF4, and CHOP), and the gene and protein expression of CD36. SGLT2 inhibitors reversed the effects of PA. SGLT2 inhibition via siRNA reduced proinflammatory-cytokine gene expression in thapsigargin-treated HepG2 cells. Transfection with CD36 siRNA reversed the elevated ATF4 and CHOP expression in PA-treated HepG2 cells. SGLT2 inhibition via an SGTL2 inhibitor and SGLT2 siRNA reduced CD36, Tnf-α, Il-6, Il-1ß, Vamp2, Snap23, Atf4, and Chop expression in the PA-treated Hepa1c1c7-Raw 264.7 cell coculture and suppressed Tnf-α release in the Hepa1c1c7-Raw 264.7 cell coculture treated with lipopolysaccharide and PA. These findings indicate that SGLT2 inhibitors inhibited NAFLD progression by reducing hepatic lipid accumulation and inflammation.

Plant P450 forms indigo and indirubin when expressed in Escherichia coli.

Indigo and indirubin are derived from indoxyl molecules, which generally occur as indoxyl glycosides in woad (Isatis tinctoria L.) and other indigo-producing plants. Indoxyl glycosides are biosynthesized from indole via 3-hydroxylation to form indoxyl, followed by one or more glycosylations. Enzymes that attach and remove sugars to and from indoxyl have already been isolated and characterized, while enzymes that convert indole into indoxyl in plants have remained elusive, until the identification of P450s and flavin-containing monooxygenases that hydroxylate indole. A P450 gene from woad (named CYP71B102) was heterologously expressed in E. coli, resulting in the formation of indigo and indirubin, as well as isatin and 2-oxindole, which along with indoxyl are putative precursors of indirubin. The addition of either isatin or 2-oxindole to the recombinant E. coli reduced the levels of indigo and increased the amount of indirubin, whereas coexpression of CYP71B102 with isatin hydroxylase (which degrades isatin) increased the levels of indigo and decreased the amount of indirubin, albeit slightly. The results suggest that CYP71B102 hydroxylates indole at both the 2- and 3- positions to produce 2-oxindole and indoxyl, respectively, and that the coupling of indoxyl with either 2-oxindole or isatin forms indirubin, while dimerization of indoxyl forms indigo. This P450 gene is thus likely involved in the biosynthesis of indirubin in woad, as well as the formation of indigo and its glycosidic precursors, even if other types of enzymes, such as flavin-containing monooxygenases, may be involved in indole hydroxylation in other indigo-producing plants.

First Nationwide Mpox Vaccination Program in the Republic of Korea: Implications for an Enhanced Public Health Response.

On May 1, 2024, the Republic of Korea lifted the infectious disease crisis alert for mpox, almost two years after the first case was reported. The Korea Disease Control and Prevention Agency (KDCA) has led the response, which included diagnosis, epidemiological investigations, treatment, and vaccination. This article particularly reviews the vaccination strategy implemented and proposes suggestions for enhancing future response efforts. Initially, the KDCA recommended pre-exposure prophylaxis for high-risk groups, later expanding to include broader demographics as domestic cases rose. By April 2024, a total of 6,863 individuals had received their first vaccine dose, with 3,875 completing the second dose of third-generation vaccines. Strategies to improve future responses include addressing stigma, securing nationally representative safety data, and conducting vaccine cost-benefit analyses. These measures will help ensure a robust and effective response to future outbreaks.

Fibroadipogenic progenitors: a potential target for preventing breast muscle myopathies in broilers.

Genetic selection for high growth rate, breast muscle yield, and feed efficiency in modern broilers has been a double-edged sword. While it has resulted in marked benefits in production, it has also introduced widespread incidence of breast muscle myopathies. Broiler myopathies are phenotypically characterized by myodegeneration and fibrofatty infiltration, which compromise meat quality. These lesions resemble those of various myopathies found in humans, such as Duchenne muscular dystrophy, Limb-girdle muscular dystrophy, and sarcopenia. Fibroadipogenic progenitors (FAPs) are interstitial muscle-resident mesenchymal stem cells that are named because of their ability to differentiate into both fibroblasts and adipocytes. This cell population has clearly been established to play a role in the development and progression of myopathies in mice and humans. Gene expression studies of wooden breast and other related disorders have implicated FAPs in broilers, but to our knowledge this cell population have not been characterized in chickens. In this review, we summarize the evidence that FAPs may be a novel, new target for interventions that reduce the incidence and development of chicken breast muscle myopathies.

Expanding RNAi to Kidneys, Lungs, and Spleen via Selective ORgan Targeting (SORT) siRNA Lipid Nanoparticles.

Inhibition of disease-causing mutations using RNA interference (RNAi) has resulted in clinically approved medicines with additional candidates in late stage trials. However, targetable tissues currently in preclinical development are limited to liver following systemic intravenous (IV) administration because predictable delivery of siRNA to non-liver tissues remains an unsolved challenge. Here, evidence of durable extrahepatic gene silencing enabled by siRNA Selective ORgan Targeting lipid nanoparticles (siRNA SORT LNPs) to the kidneys, lungs, and spleen is provided. LNPs excel at dose-dependent silencing of tissue-enriched endogenous targets resulting in 60%-80% maximal knockdown after a single IV injection and up to 88% downregulation of protein expression in mouse lungs after two doses. To examine knockdown potency and unbiased organ targeting, B6.129TdTom/EGFP mice that constitutively express the TdTomato transgene across all cell types are utilized to demonstrate 58%, 45%, and 15% reduction in TdTomato fluorescence in lungs, spleen, and kidneys, respectively. Finally, physiological relevance of siRNA SORT LNP-mediated gene silencing is established via acute suppression of endogenous Tie2 which induces lung-specific phenotypic alteration of vascular endothelial barrier. Due to plethora of extrahepatic diseases that may benefit from RNAi interventions, it is anticipated that the findings will expand preclinical landscape of therapeutic targets beyond the liver.

Effect of patent complete revascularization on the akinetic myocardial segments.

OBJECTIVES: The aims of the study were (i) to examine the changes in echocardiographic parameters and (ii) to compare the fate of myocardial segments with akinesia and without akinesia on preoperative echocardiography after coronary artery bypass grafting. METHODS: One hundred one patients who underwent complete revascularization, who were assessed by preoperative, before discharge, postoperative 3- and 12-month echocardiographic examinations, and who showed all patent grafts at postoperative 1-year angiograms were included. Echocardiographic left ventricular ejection fraction was assessed, and a 16-segment model was adopted for regional analysis of the left ventricle. A total of 1616 segments were analysed based on a 6-point scale: 1 = normal (N = 1083), 2 = mild hypokinesia (N = 2), 3 = moderate hypokinesia (N = 74), 4 = severe hypokinesia (N = 150), 5 = akinesia without thinning (N = 259) and 6 = akinesia with thinning (N = 48). RESULTS: The serial left ventricular ejection fraction measured preoperatively, before discharge, at postoperative 3- and 12-months were 0.48 ± 0.14, 0.49 ± 0.12, 0.49 ± 0.10 and 0.54 ± 0.10, respectively. The left ventricular ejection fraction significantly increased over time during the postoperative 12 months (P < 0.001). Wall motion scores tended to decrease over time in both segment groups with akinesia and without akinesia (P < 0.001), and improvement of the wall motion was significantly higher in the segment group with akinesia than in the segment group without akinesia (P < 0.001). CONCLUSIONS: The left ventricular ejection fraction and regional wall motion improved over time during the postoperative 12 months, regardless of the presence of an akinetic segment. Complete revascularization including akinetic myocardium should be considered when performing coronary artery bypass grafting.

Graves' orbitopathy development in thyroid cancer patients: a 16-year nationwide cohort study in South Korea.

BACKGROUND/OBJECTIVES: We aimed to investigate the prevalence, risk factors, and prognosis of Graves' orbitopathy (GO) in patients with thyroid cancer without a history of hyperthyroidism. SUBJECTS/METHODS: This retrospective cohort study analysed a sample from the Korean National Health Insurance Service database, which included 1,137,861 subjects from 2002 through 2019. Patients diagnosed with thyroid cancer, without a history of hyperthyroidism, were identified according to the Korean Standard Classification of Disease codes. The study compared the type of surgery, dose of radioactive iodine (RAI), and daily average thyroid hormone dose between patients who developed GO after being diagnosed with thyroid cancer and those who did not develop GO. We analysed the course of GO and the type of treatment. RESULTS: A total of 8499 cancer patients without a history of hyperthyroidism were identified, among whom 7836 underwent thyroidectomy. Of those who underwent thyroidectomy, 12 developed GO postoperatively. Among the 663 patients who did not undergo thyroidectomy, none developed GO. The prevalence of GO among thyroid cancer patients was 0.14%. The GO group received a significantly higher total RAI dose than the non-GO group (p = 0.036). There were no significant differences in sex, age, type of surgery, rate of RAI treatment, or average thyroid hormone dose between the two groups. One of the 12 patients who developed GO required intravenous steroids. CONCLUSIONS: Although GO rarely develops in thyroid cancer patients without coexisting hyperthyroidism, the total RAI dose may increase its risk. Further research would help clarify GO's association with thyroid cancer.

In vivo editing of lung stem cells for durable gene correction in mice.

In vivo genome correction holds promise for generating durable disease cures; yet, effective stem cell editing remains challenging. In this work, we demonstrate that optimized lung-targeting lipid nanoparticles (LNPs) enable high levels of genome editing in stem cells, yielding durable responses. Intravenously administered gene-editing LNPs in activatable tdTomato mice achieved >70% lung stem cell editing, sustaining tdTomato expression in >80% of lung epithelial cells for 660 days. Addressing cystic fibrosis (CF), NG-ABE8e messenger RNA (mRNA)-sgR553X LNPs mediated >95% cystic fibrosis transmembrane conductance regulator (CFTR) DNA correction, restored CFTR function in primary patient-derived bronchial epithelial cells equivalent to Trikafta for F508del, corrected intestinal organoids and corrected R553X nonsense mutations in 50% of lung stem cells in CF mice. These findings introduce LNP-enabled tissue stem cell editing for disease-modifying genome correction.

Artificial Intelligence-Powered Imaging Biomarker Based on Mammography for Breast Cancer Risk Prediction.

The purposes of this study were to develop an artificial intelligence (AI) model for future breast cancer risk prediction based on mammographic images, investigate the feasibility of the AI model, and compare the AI model, clinical statistical risk models, and Mirai, a state of-the art deep learning algorithm based on screening mammograms for 1-5-year breast cancer risk prediction. We trained and developed a deep learning model using a total of 36,995 serial mammographic examinations from 21,438 women (cancer-enriched mammograms, 17.5%). To determine the feasibility of the AI prediction model, mammograms and detailed clinical information were collected. C-indices and area under the receiver operating characteristic curves (AUCs) for 1-5-year outcomes were obtained. We compared the AUCs of our AI prediction model, Mirai, and clinical statistical risk models, including the Tyrer-Cuzick (TC) model and Gail model, using DeLong's test. A total of 16,894 mammograms were independently collected for external validation, of which 4002 were followed by a cancer diagnosis within 5 years. Our AI prediction model obtained a C-index of 0.76, with AUCs of 0.90, 0.84, 0.81, 0.78, and 0.81, to predict the 1-5-year risks. Our AI prediction model showed significantly higher AUCs than those of the TC model (AUC: 0.57; p < 0.001) and Gail model (AUC: 0.52; p < 0.001), and achieved similar performance to Mirai. The deep learning AI model using mammograms and AI-powered imaging biomarkers has substantial potential to advance accurate breast cancer risk prediction.

DEHP (di(2-ethylhexyl)phthalate) stimulates skin pigmentation by perturbing cytoskeletal homeostasis.

Phthalates are extensively employed plasticizers crucial for conferring flexibility and plasticity to polyvinyl chloride. Phthalates, including DEHP (di(2-ethylhexyl)phthalate), present in diverse products, have been identified in fine dust and are capable of infiltrating the body, potentially posing health hazards. Importantly, melanocytes, existing at the basal layer of the epidermis, are susceptible to toxic substances. In our study, we employed the 3D human pigmented epidermis model, MelanoDerm™, along with the B16F10 murine melanoma cell line, to examine the influence of DEHP exposure on melanocytes. The exposure to low concentrations of DEHP (~ 5 µM), resulted in the extension of melanocyte dendrites, indicating the stimulation of melanocytes. Analysis of gene expression and protein profiles unveiled the up-regulation of MITF, Arpc2, and TRP1 genes subsequent to DEHP exposure, indicating alterations in cytoskeletal and melanosome-related genetic and protein components in melanocytes. Notably, increased pigmentation was observed in MelanoDerm™ following DEHP exposure. DEHP-stimulated reactive oxygen species generation appeared to be involved in these events since the antioxidant, ascorbic acid attenuated ROS generation and MITF upregulation. Collectively, our study demonstrated that DEHP exposure can induce cytoskeletal disturbance and skin pigmentation through oxidative stress.

TauFlowNet: Revealing latent propagation mechanism of tau aggregates using deep neural transport equations.

Mounting evidence shows that Alzheimer's disease (AD) is characterized by the propagation of tau aggregates throughout the brain in a prion-like manner. Since current pathology imaging technologies only provide a spatial mapping of tau accumulation, computational modeling becomes indispensable in analyzing the spatiotemporal propagation patterns of widespread tau aggregates from the longitudinal data. However, current state-of-the-art works focus on the longitudinal change of focal patterns, lacking a system-level understanding of the tau propagation mechanism that can explain and forecast the cascade of tau accumulation. To address this limitation, we conceptualize that the intercellular spreading of tau pathology forms a dynamic system where each node (brain region) is ubiquitously wired with other nodes while interacting with the build-up of pathological burdens. In this context, we formulate the biological process of tau spreading in a principled potential energy transport model (constrained by brain network topology), which allows us to develop an explainable neural network for uncovering the spatiotemporal dynamics of tau propagation from the longitudinal tau-PET scans. Specifically, we first translate the transport equation into a GNN (graph neural network) backbone, where the spreading flows are essentially driven by the potential energy of tau accumulation at each node. Conventional GNNs employ a l2-norm graph smoothness prior, resulting in nearly equal potential energies across nodes, leading to vanishing flows. Following this clue, we introduce the total variation (TV) into the graph transport model, where the nature of system's Euler-Lagrange equations is to maximize the spreading flow while minimizing the overall potential energy. On top of this min-max optimization scenario, we design a generative adversarial network (GAN-like) to characterize the TV-based spreading flow of tau aggregates, coined TauFlowNet. We evaluate our TauFlowNet on ADNI and OASIS datasets in terms of the prediction accuracy of future tau accumulation and explore the propagation mechanism of tau aggregates as the disease progresses. Compared to the current counterpart methods, our physics-informed deep model yields more accurate and interpretable results, demonstrating great potential in discovering novel neurobiological mechanisms through the lens of machine learning.

Soft Bioelectronics Using Nanomaterials and Nanostructures for Neuroengineering.

The identification of neural networks for large areas and the regulation of neuronal activity at the single-neuron scale have garnered considerable attention in neuroscience. In addition, detecting biochemical molecules and electrically, optically, and chemically controlling neural functions are key research issues. However, conventional rigid and bulky bioelectronics face challenges for neural applications, including mechanical mismatch, unsatisfactory signal-to-noise ratio, and poor integration of multifunctional components, thereby degrading the sensing and modulation performance, long-term stability and biocompatibility, and diagnosis and therapy efficacy. Implantable bioelectronics have been developed to be mechanically compatible with the brain environment by adopting advanced geometric designs and utilizing intrinsically stretchable materials, but such advances have not been able to address all of the aforementioned challenges.Recently, the exploration of nanomaterial synthesis and nanoscale fabrication strategies has facilitated the design of unconventional soft bioelectronics with mechanical properties similar to those of neural tissues and submicrometer-scale resolution comparable to typical neuron sizes. The introduction of nanotechnology has provided bioelectronics with improved spatial resolution, selectivity, single neuron targeting, and even multifunctionality. As a result, this state-of-the-art nanotechnology has been integrated with bioelectronics in two main types, i.e., bioelectronics integrated with synthesized nanomaterials and bioelectronics with nanoscale structures. The functional nanomaterials can be synthesized and assembled to compose bioelectronics, allowing easy customization of their functionality to meet specific requirements. The unique nanoscale structures implemented with the bioelectronics could maximize the performance in terms of sensing and stimulation. Such soft nanobioelectronics have demonstrated their applicability for neuronal recording and modulation over a long period at the intracellular level and incorporation of multiple functions, such as electrical, optical, and chemical sensing and stimulation functions.In this Account, we will discuss the technical pathways in soft bioelectronics integrated with nanomaterials and implementing nanostructures for application to neuroengineering. We traced the historical development of bioelectronics from rigid and bulky structures to soft and deformable devices to conform to neuroengineering requirements. Recent approaches that introduced nanotechnology into neural devices enhanced the spatiotemporal resolution and endowed various device functions. These soft nanobioelectronic technologies are discussed in two categories: bioelectronics with synthesized nanomaterials and bioelectronics with nanoscale structures. We describe nanomaterial-integrated soft bioelectronics exhibiting various functionalities and modalities depending on the integrated nanomaterials. Meanwhile, soft bioelectronics with nanoscale structures are explained with their superior resolution and unique administration methods. We also exemplified the neural sensing and stimulation applications of soft nanobioelectronics across various modalities, showcasing their clinical applications in the treatment of neurological diseases, such as brain tumors, epilepsy, and Parkinson's disease. Finally, we discussed the challenges and direction of next-generation technologies.

Screening mammography performance according to breast density: a comparison between radiologists versus standalone intelligence detection.

BACKGROUND: Artificial intelligence (AI) algorithms for the independent assessment of screening mammograms have not been well established in a large screening cohort of Asian women. We compared the performance of screening digital mammography considering breast density, between radiologists and AI standalone detection among Korean women. METHODS: We retrospectively included 89,855 Korean women who underwent their initial screening digital mammography from 2009 to 2020. Breast cancer within 12 months of the screening mammography was the reference standard, according to the National Cancer Registry. Lunit software was used to determine the probability of malignancy scores, with a cutoff of 10% for breast cancer detection. The AI's performance was compared with that of the final Breast Imaging Reporting and Data System category, as recorded by breast radiologists. Breast density was classified into four categories (A-D) based on the radiologist and AI-based assessments. The performance metrics (cancer detection rate [CDR], sensitivity, specificity, positive predictive value [PPV], recall rate, and area under the receiver operating characteristic curve [AUC]) were compared across breast density categories. RESULTS: Mean participant age was 43.5 ± 8.7 years; 143 breast cancer cases were identified within 12 months. The CDRs (1.1/1000 examination) and sensitivity values showed no significant differences between radiologist and AI-based results (69.9% [95% confidence interval [CI], 61.7-77.3] vs. 67.1% [95% CI, 58.8-74.8]). However, the AI algorithm showed better specificity (93.0% [95% CI, 92.9-93.2] vs. 77.6% [95% CI, 61.7-77.9]), PPV (1.5% [95% CI, 1.2-1.9] vs. 0.5% [95% CI, 0.4-0.6]), recall rate (7.1% [95% CI, 6.9-7.2] vs. 22.5% [95% CI, 22.2-22.7]), and AUC values (0.8 [95% CI, 0.76-0.84] vs. 0.74 [95% CI, 0.7-0.78]) (all P < 0.05). Radiologist and AI-based results showed the best performance in the non-dense category; the CDR and sensitivity were higher for radiologists in the heterogeneously dense category (P = 0.059). However, the specificity, PPV, and recall rate consistently favored AI-based results across all categories, including the extremely dense category. CONCLUSIONS: AI-based software showed slightly lower sensitivity, although the difference was not statistically significant. However, it outperformed radiologists in recall rate, specificity, PPV, and AUC, with disparities most prominent in extremely dense breast tissue.

Associations between Chronic Kidney Disease and Migraine Incidence: Findings from a Korean Longitudinal Big Data Study.

While headaches frequently occur in individuals with chronic kidney disease (CKD), there are few statistical evaluations of their connection to migraines in population-based studies. In this nationwide longitudinal follow-up study of Korean health examination data (2002-2019), a total of 15,443 participants with CKD and 61,772 matched controls were enrolled. We applied overlap-weighted Cox proportional hazard regression models to assess hazard ratios, examining the correlation between CKD and the development of migraines. After accounting for various factors, we observed a modest reduction of approximately 11% in the likelihood of migraine occurrence among CKD patients (95% confidence intervals = 0.81-0.97) during the 16-year monitoring period. Subgroup analysis revealed a significant association among specific demographic and health conditions, including individuals aged 70 or older, females, overweight individuals, nonsmokers, and those without hypertension or diabetes. Our research may indicate a potential relationship between CKD and the onset of migraines in Korean adults, suggesting a slight reduction in the probability of the occurrence of migraines among those with CKD. These findings emphasize the need for attentive follow-up and preventive management in individuals without the identified protective factors, particularly in male CKD patients under the age of 70 with hypertension.

Disentangling sex-dependent effects of APOE on diverse trajectories of cognitive decline in Alzheimer's disease.

Current diagnostic systems for Alzheimer's disease (AD) rely upon clinical signs and symptoms, despite the fact that the multiplicity of clinical symptoms renders various neuropsychological assessments inadequate to reflect the underlying pathophysiological mechanisms. Since putative neuroimaging biomarkers play a crucial role in understanding the etiology of AD, we sought to stratify the diverse relationships between AD biomarkers and cognitive decline in the aging population and uncover risk factors contributing to the diversities in AD. To do so, we capitalized on a large amount of neuroimaging data from the ADNI study to examine the inflection points along the dynamic relationship between cognitive decline trajectories and whole-brain neuroimaging biomarkers, using a state-of-the-art statistical model of change point detection. Our findings indicated that the temporal relationship between AD biomarkers and cognitive decline may differ depending on the synergistic effect of genetic risk and biological sex. Specifically, tauopathy-PET biomarkers exhibit a more dynamic and age-dependent association with Mini-Mental State Examination scores (p<0.05), with inflection points at 72, 78, and 83 years old, compared with amyloid-PET and neurodegeneration (cortical thickness from MRI) biomarkers. In the landscape of health disparities in AD, our analysis indicated that biological sex moderates the rate of cognitive decline associated with APOE4 genotype. Meanwhile, we found that higher education levels may moderate the effect of APOE4, acting as a marker of cognitive reserve.

FXR Agonism with Bile Acid Mimetic Reduces Pre-Clinical Triple-Negative Breast Cancer Burden.

Bariatric surgery is associated with improved outcomes for several cancers, including breast cancer (BC), although the mechanisms mediating this protection are unknown. We hypothesized that elevated bile acid pools detected after bariatric surgery may be factors that contribute to improved BC outcomes. Patients with greater expression of the bile acid receptor FXR displayed improved survival in specific aggressive BC subtypes. FXR is a nuclear hormone receptor activated by primary bile acids. Therefore, we posited that activating FXR using an established FDA-approved agonist would induce anticancer effects. Using in vivo and in vitro approaches, we determined the anti-tumor potential of bile acid receptor agonism. Indeed, FXR agonism by the bile acid mimetic known commercially as Ocaliva ("OCA"), or Obeticholic acid (INT-747), significantly reduced BC progression and overall tumor burden in a pre-clinical model. The transcriptomic analysis of tumors in mice subjected to OCA treatment revealed differential gene expression patterns compared to vehicle controls. Notably, there was a significant down-regulation of the oncogenic transcription factor MAX (MYC-associated factor X), which interacts with the oncogene MYC. Gene set enrichment analysis (GSEA) further demonstrated a statistically significant downregulation of the Hallmark MYC-related gene set (MYC Target V1) following OCA treatment. In human and murine BC analyses in vitro, agonism of FXR significantly and dose-dependently inhibited proliferation, migration, and viability. In contrast, the synthetic agonism of another common bile acid receptor, the G protein-coupled bile acid receptor TGR5 (GPBAR1) which is mainly activated by secondary bile acids, failed to significantly alter cancer cell dynamics. In conclusion, agonism of FXR by primary bile acid memetic OCA yields potent anti-tumor effects potentially through inhibition of proliferation and migration and reduced cell viability. These findings suggest that FXR is a tumor suppressor gene with a high potential for use in personalized therapeutic strategies for individuals with BC.

Combined DNA Methylation and Gastric Microbiome Marker Predicts Helicobacter pylori-Negative Gastric Cancer.

Background/Aims: While DNA methylation and gastric microbiome are each associated with gastric cancer (GC), their combined role in predicting GC remains unclear. This study investigated the potential of a combined DNA methylation and gastric microbiome signature to predict Helicobacter pylori-negative GC. Methods: In this case-control study, we conducted quantitative methylation-specific polymerase chain reaction to measure the methylation levels of DKK3, SFRP1, EMX1, NKX6-1, MIR124-3, and TWIST1 in the gastric mucosa from 75 H. pylori-negative patients, including chronic gastritis (CG), intestinal metaplasia (IM), and GC. A combined analysis of DNA methylation and gastric microbiome, using 16S rRNA gene sequencing, was performed in 30 of 75 patients. Results: The methylation levels of DKK3, SFRP1, EMX1, MIR124-3, and TWIST1 were significantly higher in patients with GC than in controls (all q<0.05). MIR124-3 and TWIST1 methylation levels were higher in patients with IM than those with CG and also in those with GC than in those with IM (all q<0.05). A higher methylation level of TWIST1 was an independent predictor for H. pylori-negative GC after adjusting for age, sex, and atrophy (odds ratio [OR], 15.15; 95% confidence interval [CI], 1.58 to 145.46; p=0.018). The combination of TWIST1 methylation and GC microbiome index (a microbiome marker) was significantly associated with H. pylori-negative GC after adjusting for age, sex, and atrophy (OR, 50.00; 95% CI, 1.69 to 1,476; p=0.024). Conclusions: The combination of TWIST1 methylation and GC microbiome index may offer potential as a biomarker for predicting H. pylori-negative GC.

Investigation of the Approaches to Optimal Exercise Interventions Based on Dementia Type: A Theoretical Review.

The aim of this study is to enhance comprehension of the different types and features of dementia, including their symptoms, diagnosis and medical treatment, and to propose various evidence-based exercise interventions and their clinical applications tailored to each specific type of dementia. The theoretical review includes the analysis of publications in the scientific databases PubMed/Medline, Ebsco, Scielo, and Google. A total of 177 articles were found, of which 84 were studied in depth. With the prevalence of all forms of dementia projected to increase from 57.4 million in 2019 to 152.8 million in 2050, personalized treatment strategies are needed. This review discusses various forms of dementia, including their pathologies, diagnostic criteria, and prevalence rates. The importance of accurate diagnosis and tailored care is emphasized, as well as the effectiveness of physical exercise in improving cognitive function in dementia patients. For Alzheimer's, a combination of drug therapies and exercises is recommended to enhance cerebral blood flow and neurotransmitter activity. To improve cognitive and motor functions in Lewy body dementia, a combination of pharmacological and physical therapies is recommended. For managing frontotemporal dementia, a mix of medication and exercises aimed at emotion regulation, including aerobic exercises, and a unified protocol, is suggested. For mild cognitive impairment, aerobic and functional exercises are important in delaying cognitive decline and enhancing cognitive performance. In conclusion, individualized care and treatment plans tailored to the specific characteristics of each disease type can improve the quality of life for individuals with this condition and effectively manage this growing global health issue.