Modeling of solar UV-induced photodamage on the hair follicles in human skin organoids.

Solar ultraviolet (sUV) exposure is known to cause skin damage. However, the pathological mechanisms of sUV on hair follicles have not been extensively explored. Here, we established a model of sUV-exposed skin and its appendages using human induced pluripotent stem cell-derived skin organoids with planar morphology containing hair follicles. Our model closely recapitulated several symptoms of photodamage, including skin barrier disruption, extracellular matrix degradation, and inflammatory response. Specifically, sUV induced structural damage and catagenic transition in hair follicles. As a potential therapeutic agent for hair follicles, we applied exosomes isolated from human umbilical cord blood-derived mesenchymal stem cells to sUV-exposed organoids. As a result, exosomes effectively alleviated inflammatory responses by inhibiting NF-κB activation, thereby suppressing structural damage and promoting hair follicle regeneration. Ultimately, our model provided a valuable platform to mimic skin diseases, particularly those involving hair follicles, and to evaluate the efficacy and underlying mechanisms of potential therapeutics.

Outcomes of carotid endarterectomy in octogenarians compared to their younger counterparts: a retrospective observational study.

Purpose: This study was performed to analyze the association between age and outcomes of carotid endarterectomy (CEA) by comparing postoperative outcomes between octogenarians and younger patients. Methods: From November 1994 to December 2022, 1,585 internal carotid arteries of 1,434 patients were enrolled. Patients were stratified into 2 groups: octogenarians (≥80 years old) and non-octogenarians (<80 years old). Primary endpoints were early (≤30 days) outcomes of ipsilateral stroke, any stroke, myocardial infarction, death, and major adverse cardiovascular events (MACE). We also compared overall any stroke and death between the 2 groups. Results: One of 132 octogenarians (0.8%) and 17 of 1,453 non-octogenarians (1.1%) experienced ipsilateral stroke within 30 days. Thirty-day MACE occurred in 4 of 132 octogenarians (3%) and 44 of 1,453 non-octogenarians (3%). There were no significant differences in any early (≤30 days) outcomes. Symptomatic status was associated with increased 30-day MACE (odds ratio [OR], 2.610; 95% confidence interval [CI], 1.450-4.696; P = 0.003) and 30-day any stroke (OR, 3.999; 95% CI, 1.627-9.828; P = 0.003). Symptomatic status was also associated with overall any stroke (hazard ratio [HR], 2.885; 95% CI, 1.865-4.463; P < 0.001), but age of ≥80 years was not associated with 30-day MACE, 30-day any stroke, or overall stroke. Age of ≥80 years was only associated with overall survival (HR, 2.644; 95% CI, 1.967-3.555; P < 0.001). Conclusion: CEA would be a safe and effective treatment for octogenarians with low 30-day complications and long-term stroke rates, comparable with that of younger counterparts. Advanced age is not a contraindication for CEA.

CD19 CAR-expressing iPSC-derived NK cells effectively enhance migration and cytotoxicity into glioblastoma by targeting to the pericytes in tumor microenvironment.

In cancer immunotherapy, chimeric antigen receptors (CARs) targeting specific antigens have become a powerful tool for cell-based therapy. CAR-natural killer (NK) cells offer selective anticancer lysis with reduced off-tumor toxicity compared to CAR-T cells, which is beneficial in the heterogeneous milieu of solid tumors. In the tumor microenvironment (TME) of glioblastoma (GBM), pericytes not only support tumor growth but also contribute to immune evasion, underscoring their potential as therapeutic targets in GBM treatment. Given this context, our study aimed to target the GBM TME, with a special focus on pericytes expressing CD19, to evaluate the potential effectiveness of CD19 CAR-iNK cells against GBM. We performed CD19 CAR transduction in induced pluripotent stem cell-derived NK (iNK) cells. To determine whether CD19 CAR targets the TME pericytes in GBM, we developed GBM-blood vessel assembloids (GBVA) by fusing GBM spheroids with blood vessel organoids. When co-cultured with GBVA, CD19 CAR-iNK cells migrated towards the pericytes surrounding the GBM. Using a microfluidic chip, we demonstrated CD19 CAR-iNK cells' targeted action and cytotoxic effects in a perfusion-like environment. GBVA xenografts recapitulated the TME including human CD19-positive pericytes, thereby enabling the application of an in vivo model for validating the efficacy of CD19 CAR-iNK cells against GBM. Compared to GBM spheroids, the presence of pericytes significantly enhanced CD19 CAR-iNK cell migration towards GBM and reduced proliferation. These results underline the efficacy of CD19 CAR-iNK cells in targeting pericytes within the GBM TME, suggesting their potential therapeutic value for GBM treatment.

Spectral Graph Neural Network-Based Multi-Atlas Brain Network Fusion for Major Depressive Disorder Diagnosis.

Major Depressive Disorder (MDD) imposes a substantial burden within the healthcare domain, impacting millions of individuals worldwide. Functional Magnetic Resonance Imaging (fMRI) has emerged as a promising tool for the objective diagnosis of MDD, enabling the investigation of functional connectivity patterns in the brain associated with this disorder. However, most existing methods focus on a single brain atlas, which limits their ability to capture the complex, multi-scale nature of functional brain networks. To address these limitations, we propose a novel multi-atlas fusion method that incorporates early and late fusion in a unified framework. Our method introduces the concept of the holistic Functional Connectivity Network (FCN), which captures both intra-atlas relationships within individual atlases and inter-regional relationships between atlases with different brain parcellation scales. This comprehensive representation enables the identification of potential disease-related patterns associated with MDD in the early stage of our framework. Moreover, by decoding the holistic FCN from various perspectives through multiple spectral Graph Convolutional Neural Networks and fusing their results with decision-level ensembles, we further improve the performance of MDD diagnosis. Our approach is easily implemented with minimal modifications to existing model structures and demonstrates a robust performance across different baseline models. Our method, evaluated on public resting-state fMRI datasets, surpasses the current multi-atlas fusion methods, enhancing the accuracy of MDD diagnosis. The proposed novel multi-atlas fusion framework provides a more reliable MDD diagnostic technique. Experimental results show our approach outperforms both single- and multi-atlas-based methods, demonstrating its effectiveness in advancing MDD diagnosis.

Transcriptomic and metabolomic analysis unveils nanoplastic-induced gut barrier dysfunction via STAT1/6 and ERK pathways.

The widespread prevalence of micro and nanoplastics in the environment raises concerns about their potential impact on human health. Recent evidence demonstrates the presence of nanoplastics in human blood and tissues following ingestion and inhalation, yet the specific risks and mechanisms of nanoplastic toxicity remain inadequately understood. In this study, we aimed to explore the molecular mechanisms underlying the toxicity of nanoplastics at both systemic and molecular levels by analyzing the transcriptomic/metabolomic responses and signaling pathways in the intestines of mice after oral administration of nanoplastics. Transcriptome analysis in nanoplastic-administered mice revealed a notable upregulation of genes involved in pro-inflammatory immune responses. In addition, nanoplastics substantially reduced the expression of tight junction proteins, including occludin, zonula occluden-1, and tricellulin, which are crucial for maintaining gut barrier integrity and function. Importantly, nanoplastic administration increased gut permeability and exacerbated dextran sulfate sodium-induced colitis. Further investigation into the underlying molecular mechanisms highlighted significant activation of signaling transsducer and activator of transcription (STAT)1 and STAT6 by nanoplastic administration, which was in line with the elevation of interferon and JAK-STAT pathway signatures identified through transcriptome enrichment analysis. Additionally, the consumption of nanoplastics specifically induced nuclear factor kappa-B (NF-κB) and extracellular signal-regulated kinase (ERK)1/2 signaling pathways in the intestines. Collectively, this study identifies molecular mechanisms contributing to adverse effects mediated by nanoplastics in the intestine, providing novel insights into the pathophysiological consequences of nanoplastic exposure.

Disseminated Intravascular Coagulation as a Risk Factor for Clinical Outcome After Liver Transplantation in Pediatric Patients With Kasai Portoenterostomy Failure.

BACKGROUND: Disseminated intravascular coagulation (DIC) is a serious complication in critically ill pediatric patients. This study aimed to evaluate the association between pretransplant DIC and perioperative clinical outcomes of liver transplantation (LT) in pediatric patients with Kasai portoenterostomy (KPE) failure. METHODS: We enrolled pediatric patients who received LT after KPE failure between January 2005 and April 2021. We retrospectively reviewed the electronic medical records of included patients and evaluated the presence of DIC using the International Society on Thrombosis and Hemostasis (ISTH) criteria and association with perioperative clinical outcome. RESULTS: The study included 106 patients. Their median age and body weight at the time of pediatric intensive care unit (PICU) admission were 28.7 months and 9.25 kg, respectively. Of these patients, 23 had undergone pretransplant DIC (22%). Patients with pretransplant DIC required significantly more blood transfusions during operation. They had significantly higher serum lactate levels, pediatric end-stage liver disease scores, pediatric risk for mortality III (PRISM III) scores, longer durations of mechanical ventilator support, and longer PICU stays (all P < .05). CONCLUSIONS: The presence of pretransplant DIC in pediatric patients requiring LT after KPE failure was associated with poor clinical outcomes, which required more intensive and meticulous supportive management in the perioperative period of LT. DIC would be a promising prognostic factor in these patients.

Fabrication and Evaluation of a pH-Responsive Nanocomposite-Based Colonic Delivery System for Improving the Oral Efficacy of Liraglutide.

Purpose: Oral administration of liraglutide, a protein drug, suffers from low intestinal absorption and instability in the gastrointestinal tract, resulting in low bioavailability. The present study aimed to develop a pH-responsive nanocomposite based-colonic delivery system to improve the oral efficacy of liraglutide. Methods: Nanocomplex (AC-Lira) between aminoclay and liraglutide was prepared by a spontaneous self-assembly. After surface charge reversal using citric acid, AC-Lira was coated with poly(methacrylic acid-co-methyl methacrylate) (1:2). The fabricated nanocomplex underwent various in vitro studies to characterize its physicochemical properties, drug release, and cellular transport. In vivo efficacy studies were also conducted using streptozotocin-induced diabetic rats. Results: Both uncoated (AC-Lira) and coated nanocomplex (EAC-Lira) achieved high entrapment efficiency (> 90%) and showed a narrow size distribution. While exhibiting low drug release at pH 1.2 (approximately 30%), EAC-Lira achieved rapid and extensive drug release (~90%) at pH 7.4, displaying pH-dependent drug release. EAC-Lira showed significant size reduction and surface charge reversal during dissolution at pH 7.4, probably due to the removal of the outer coating layer. Furthermore, EAC-Lira was effective at protecting the entrapped proteins against enzymatic degradation. EAC-Lira also increased the membrane transport of liraglutide by 3.5 folds in Caco-2 cells. Owing to enhanced membrane transport and metabolic stability, EAC-Lira improved in vivo efficacy of orally administered liraglutide, significantly reducing blood glucose concentrations, intake of food and water, and body weight in type 2 diabetes rats. Conclusion: These results suggest EAC-Lira is a promising approach to improving the oral bioavailability and efficacy of liraglutide.

Comparison of the clinical characteristics and clinical outcomes of culture-positive septic shock and culture-negative septic shock among pediatric patients.

OBJECTIVES: Among pediatric patients with septic shock, culture-negative septic shock (CNSS) is common but there have been limited data on its clinical characteristics and prognosis. We compared the clinical characteristics and clinical outcomes between culture-positive septic shock (CPSS) and CNSS in pediatric patients. DESIGN: Retrospective single-center study. SETTING: Pediatric intensive care unit (PICU) of a tertiary referral hospital. PATIENTS: All pediatric patients who were admitted to the PICU due to septic shock between January 2010 and November 2021, except for those with fungal or viral infections and those who expired on the day of admittance to the PICU. The primary outcome was 30-day mortality and in-hospital mortality. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 294 patients (CPSS group, n = 185 [62.9%]; CNSS group, n = 109 [37.1%]) were included. The rates of 30-day mortality and in-hospital mortality (30-day mortality 22.7% vs 22%, in-hospital mortality 29.7% vs 25.7%) were not significantly different between the CPSS group and the CNSS group. The two groups showed comparable results in clinical outcomes such as the requirement for mechanical ventilator and renal replacement therapy, PICU stay duration, and the duration of MV and vasopressor/inotrope support. Among the CPSS group, 98 (53%) patients who were infected with multi-drug resistance (MDR) bacteria had significantly higher rates of 30-day mortality and in-hospital mortality than those infected with non-MDR bacteria. CONCLUSIONS: Among pediatric patients, the CPSS group and CNSS group did not show significant differences in clinical features and mortality. Among the CPSS group, those with MDR bacteria had poorer prognosis.

Safety and efficacy of pediatric sedation protocol for diagnostic examination in a pediatric emergency room: A retrospective study.

Pediatric patients undergoing diagnostic tests in the pediatric emergency room are frequently sedated. Although efforts are made to prevent adverse events, no sedation protocol has specified the optimal regimen, dosage, and interval of medication to prevent adverse events. This study analyzed the safety and efficacy of sequential pediatric sedation protocols for pediatric patients undergoing diagnostic tests in the pediatric emergency room of a single tertiary medical center. The medical records of patients aged < 18 years who visited the pediatric emergency room of Seoul Asan Medical Center between January and December 2019 for diagnostic testing were retrospectively reviewed. Sedation protocols consisted of 50 mg/kg and 25 mg/kg chloral hydrate, 0.1 mg/kg and 0.1 mg/kg midazolam, and 1 mg/kg and 0.5 to 1 mg/kg ketamine, administered sequentially at intervals of 30, 20, 10, 10, and 10 minutes, respectively. Patients were assessed prior to sedation, and adverse events were investigated. Of the 289 included patients, 20 (6.9%) experienced adverse events, none serious, and nine (3.1%) failed to reach the depth of sedation required to complete the test. The regimen (P = .622) and dosage (P = .777) of the sedatives were unrelated to the occurrence of adverse events when sedation was performed according to protocol. The sedation protocol used in these patients, consisting of sequential administration of minimum dosages, achieved a sufficient depth of sedation with relatively few adverse events, indicating that this protocol can be used safely and effectively for painless sedation in pediatric patients undergoing diagnostic testing.

Bridging the BCI illiteracy gap: a subject-to-subject semantic style transfer for EEG-based motor imagery classification.

Introduction: Brain-computer interfaces (BCIs) facilitate direct interaction between the human brain and computers, enabling individuals to control external devices through cognitive processes. Despite its potential, the problem of BCI illiteracy remains one of the major challenges due to inter-subject EEG variability, which hinders many users from effectively utilizing BCI systems. In this study, we propose a subject-to-subject semantic style transfer network (SSSTN) at the feature-level to address the BCI illiteracy problem in electroencephalogram (EEG)-based motor imagery (MI) classification tasks. Methods: Our approach uses the continuous wavelet transform method to convert high-dimensional EEG data into images as input data. The SSSTN 1) trains a classifier for each subject, 2) transfers the distribution of class discrimination styles from the source subject (the best-performing subject for the classifier, i.e., BCI expert) to each subject of the target domain (the remaining subjects except the source subject, specifically BCI illiterates) through the proposed style loss, and applies a modified content loss to preserve the class-relevant semantic information of the target domain, and 3) finally merges the classifier predictions of both source and target subject using an ensemble technique. Results and discussion: We evaluate the proposed method on the BCI Competition IV-2a and IV-2b datasets and demonstrate improved classification performance over existing methods, especially for BCI illiterate users. The ablation experiments and t-SNE visualizations further highlight the effectiveness of the proposed method in achieving meaningful feature-level semantic style transfer.

Quantitative analysis of therapeutic proteins in biological fluids: recent advancement in analytical techniques.

Pharmaceutical application of therapeutic proteins has been continuously expanded for the treatment of various diseases. Efficient and reliable bioanalytical methods are essential to expedite the identification and successful clinical development of therapeutic proteins. In particular, selective quantitative assays in a high-throughput format are critical for the pharmacokinetic and pharmacodynamic evaluation of protein drugs and to meet the regulatory requirements for new drug approval. However, the inherent complexity of proteins and many interfering substances presented in biological matrices have a great impact on the specificity, sensitivity, accuracy, and robustness of analytical assays, thereby hindering the quantification of proteins. To overcome these issues, various protein assays and sample preparation methods are currently available in a medium- or high-throughput format. While there is no standard or universal approach suitable for all circumstances, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay often becomes a method of choice for the identification and quantitative analysis of therapeutic proteins in complex biological samples, owing to its high sensitivity, specificity, and throughput. Accordingly, its application as an essential analytical tool is continuously expanded in pharmaceutical R&D processes. Proper sample preparation is also important since clean samples can minimize the interference from co-existing substances and improve the specificity and sensitivity of LC-MS/MS assays. A combination of different methods can be utilized to improve bioanalytical performance and ensure more accurate quantification. This review provides an overview of various protein assays and sample preparation methods, with particular emphasis on quantitative protein analysis by LC-MS/MS.

Risk Factors and Pregnancy Outcomes of Antepartum Hemorrhage in Women with Placenta Previa.

Placenta previa (PP) is one such complication related to several adverse pregnancy outcomes. Adverse outcomes are likely greater if PP coexists with antepartum hemorrhage (APH). This study aims to evaluate the risk factors and pregnancy outcomes of APH in women with PP. This retrospective case-control study included 125 singleton pregnancies with PP who delivered between 2017 and 2019. Women with PP were divided into two groups: PP without APH (n = 59) and PP with APH (n = 66). We investigated the risk factors associated with APH and compared the differences between both groups in placental histopathology lesions due to APH and the resulting maternal and neonatal outcomes. Women with APH had more frequent antepartum uterine contractions (33.3% vs. 10.2%, P = .002) and short cervical length (< 2.5 cm) at admission (53.0% vs. 27.1%, P = .003). The placentas from the APH group had lower weight (442.9 ± 110.1 vs. 488.3 ± 117.7 g, P = .03) in the gross findings, and a higher rate of villous agglutination lesions (42.4% vs. 22.0%, P = .01) in the histopathologic findings. Women with APH in PP had higher rates of composite adverse pregnancy outcomes (83.3% vs. 49.2%, P = .0001). Neonates born to women with APH in PP had worse neonatal outcomes (59.1% vs. 23.9%, P = .0001). Preterm uterine contractions and short cervical length were the most significant risk factors for APH in PP.

Bioengineered liver crosslinked with nano-graphene oxide enables efficient liver regeneration via MMP suppression and immunomodulation.

Decellularized extracellular matrix scaffold, widely utilized for organ engineering, often undergoes matrix decomposition after transplantation and produces byproducts that cause inflammation, leading to clinical failure. Here we propose a strategy using nano-graphene oxide to modify the biophysical properties of decellularized liver scaffolds. Notably, we demonstrate that scaffolds crosslinked with nano-graphene oxide show high resistance to enzymatic degradation via direct inhibition of matrix metalloproteinase activity and increased mechanical rigidity. We find that M2-like macrophage polarization is promoted within the crosslinked scaffolds, which reduces graft-elicited inflammation. Moreover, we show that low activities of matrix metalloproteinases, attributed to both nano-graphene oxide and tissue inhibitors of metalloproteinases expressed by M2c, can protect the crosslinked scaffolds against in vivo degradation. Lastly, we demonstrate that bioengineered livers fabricated with the crosslinked scaffolds remain functional, thereby effectively regenerating damaged livers after transplantation into liver failure mouse models. Overall, nano-graphene oxide crosslinking prolongs allograft survival and ultimately improves therapeutic effects of bioengineered livers, which offer an alternative for donor organs.

Cortical-blood vessel assembloids exhibit Alzheimer's disease phenotypes by activating glia after SARS-CoV-2 infection.

A correlation between COVID-19 and Alzheimer's disease (AD) has been proposed recently. Although the number of case reports on neuroinflammation in COVID-19 patients has increased, studies of SARS-CoV-2 neurotrophic pathology using brain organoids have restricted recapitulation of those phenotypes due to insufficiency of immune cells and absence of vasculature. Cerebral pericytes and endothelial cells, the major components of blood-brain barrier, express viral entry receptors for SARS-CoV-2 and response to systemic inflammation including direct cell death. To overcome the limitations, we developed cortical-blood vessel assembloids by fusing cortical organoid with blood vessel organoid to provide vasculature to brain organoids a nd obtained the characteristics of increased expression of microglia and astrocytes in brain organoids. Furthermore, we observed AD pathologies, including ß-amyloid plaques, which were affected by the inflammatory response from SARS-CoV-2 infection. These findings provide an advanced platform to investigate human neurotrophic diseases, including COVID-19, and suggest that neuroinflammation caused by viral infection facilitates AD pathology.

Frequency of serous tubal intraepithelial carcinoma (STIC) in patients with high grade serous ovarian cancer.

OBJECTIVE: Serous tubal intraepithelial carcinoma (STIC) is a known precursor of high-grade serous ovarian cancer (HGSOC). This study aimed to evaluate the proportion of STIC in patients with HGSOC and analyze the STIC-related prognosis in patients with HGSOC. MATERIALS AND METHODS: All pathology reports at our institution that included bilateral salpingectomies of patients with HGSOC from January 2013 to December 2018 were reviewed by two experienced pathologists. The specimens from the ovaries and the salpinx including fimbria were examined. We analyzed the correlation between STIC and HGSOC and compared the clinical characteristics and STIC-related prognostic outcomes in patients with HGSOC. RESULTS: Eleven of the 76 cases were STIC. BRCA mutations were found in 16.9% of patients with HGSOC. STIC was observed in 30.0% of patients with BRCA mutations and in 14.3% of patients without BRCA mutations. The incidence of STIC in patients with BRCA mutations was approximately twice that in patients without BRCA mutations; however, the difference was not statistically significant (P = 0.231). Further, the 5-year survival rate of patients without STIC appeared to be high; nevertheless, the difference was not statistically significant (59.7% vs. 47.4%, P = 0.633). Moreover, there was no significant difference in disease-free survival rate according to STIC (36.4% vs. 33.1%, P = 0.956). CONCLUSION: STIC was identified in patients with HGSOC, and STIC incidence was prominent in HGSOC related to BRCA mutation. Although low frequency, STIC was detected in patients without BRCA mutation. Therefore, prophylactic salpingectomy may be useful for prevention of HGSOC.

3D microengineered vascularized tumor spheroids for drug delivery and efficacy testing.

Tumor angiogenesis is regarded as a promising target for limiting cancer progression because tumor-associated vasculature supplies blood and provides a path for metastasis. Thus, in vitro recapitulation of vascularized tumors is critical to understand the pathology of cancer and identify the mechanisms by which tumor cells proliferate, metastasize, and respond to drugs. In this study, we microengineered a vascularized tumor spheroid (VTS) model to reproduce the pathological features of solid tumors. We first generated tumor-EC hybrid spheroids with self-assembled intratumoral vessels, which enhanced the uniformity of the spheroids and peritumoral angiogenic capacity compared to spheroids composed only with cancer cells. Notably, the hybrid spheroids also exhibited expression profiles associated with aggressive behavior. The blood vessels sprouting around the hybrid spheroids on the VTS chip displayed the distinctive characteristics of leaky tumor vessels. With the VTS chip showing a progressive tumor phenotype, we validated the suppressive effects of axitinib on tumor growth and angiogenesis, which depended on exposure dose and time, highlighting the significance of tumor vascularization to predict the efficacy of anticancer drugs. Ultimately, we effectively induced both lymphangiogenesis and angiogenesis around the tumor spheroid by promoting interstitial flow. Thus, our VTS model is a valuable platform with which to investigate the interactions between tumor microenvironments and explore therapeutic strategies in cancer. STATEMENT OF SIGNIFICANCE: We conducted an integrative study within a vascularized tumor spheroid (VTS) model. We first generated tumor-EC hybrid spheroids with self-assembled intratumoral vessels, which enhanced the uniformity of the spheroids and peritumoral angiogenic capacity compared to spheroids composed only with cancer cells. Through RNA sequencing, we elucidated that the tumor-EC hybrid spheroids exhibited expression profiles associated with aggressive behavior such as cancer progression, invasion and metastasis. The blood vessels sprouting around the hybrid spheroids on the VTS chip displayed the distinctive characteristics of leaky tumor vessels. We further validated the suppressive effects of axitinib on tumor growth and angiogenesis, depending on exposure dose and time. Ultimately, we effectively induced both lymphangiogenesis and angiogenesis around the tumor spheroid by promoting interstitial flow.

Functional ligands for improving anticancer drug therapy: current status and applications to drug delivery systems.

Conventional chemotherapy lacking target selectivity often leads to severe side effects, limiting the effectiveness of chemotherapy. Therefore, drug delivery systems ensuring both selective drug release and efficient intracellular uptake at the target sites are highly demanded in chemotherapy to improve the quality of life of patients with low toxicity. One of the effective approaches for tumor-selective drug delivery is the adoption of functional ligands that can interact with specific receptors overexpressed in malignant cancer cells. Various functional ligands including folic acid, hyaluronic acid, transferrin, peptides, and antibodies, have been extensively explored to develop tumor-selective drug delivery systems. Furthermore, cell-penetrating peptides or ligands for tight junction opening are also actively pursued to improve the intracellular trafficking of anticancer drugs. Sometimes, multiple ligands with different roles are used in combination to enhance the cellular uptake as well as target selectivity of anticancer drugs. In this review, the current status of various functional ligands applicable to improve the effectiveness of cancer chemotherapy is overviewed with a focus on their roles, characteristics, and preclinical/clinical applications.

Functional foods with antiviral activity.

Viruses are known to cause a variety of diseases, ranging from mild respiratory diseases, such as the common cold, to fatal illnesses. Although the development of vaccines and targeted drugs have significantly improved the mortality rate and disease severity against a number of viral infections, there are still many viruses without proper treatment/prevention options and newly emerging viruses can pose serious health threats. For instance, the coronavirus disease 2019 (COVID-19) pandemic is producing significant healthcare and socio-economic burden worldwide, which may jeopardize the lives and livelihoods for years to come. Studies have identified functional foods with antiviral activity. Certain foods may target the viral life cycle or modulate the host immune system to enhance defense against viral infections. In this review, we will discuss some of the food products reported to display protective effects against viruses including the influenza virus, human immunodeficiency virus, and severe acute respiratory syndrome coronavirus 2.

Reduced miR-371b-5p expression drives tumor progression via CSDE1/RAC1 regulation in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer; however, specific prognostic biomarkers have not yet been developed. In this study, we identified dysregulated microRNAs (miRNAs) in TNBC by profiling miRNA and mRNA expression. In patients with TNBC, miR-371b-5p expression was reduced, and miR-371b-5p overexpression significantly mitigated TNBC cell growth, migration, and invasion. In addition, we found that expression of cold shock domain-containing protein E1 (CSDE1), a direct target gene of miR-371b-5p, was upregulated in TNBC cells, and inhibition of CSDE1 expression alleviated TNBC cell growth by regulating RAC1 transcription. Mechanistically, CSDE1, phosphorylated C-terminal domain (p-CTD) of RNA polymerase II (RNAPII), and CDK7 form a complex, and downregulation of CSDE1 leads to weak interaction between RNAPII p-CTD and CDK7, resulting in a decrease in RNAPII p-CTD expression to reduce RAC1 transcript levels in CSDE1-deficient TNBC cells. Our data demonstrate that miR-371b-5p is a tumor-suppressive miRNA that regulates the CSDE1/Rac1 axis and could be a potential prognostic biomarker for TNBC.

Generation of Cortical Brain Organoid with Vascularization by Assembling with Vascular Spheroid.

BACKGROUND AND OBJECTIVES: Brain organoids have the potential to improve our understanding of brain development and neurological disease. Despite the importance of brain organoids, the effect of vascularization on brain organoids is largely unknown. The objective of this study is to develop vascularized organoids by assembling vascular spheroids with cerebral organoids. METHODS AND RESULTS: In this study, vascularized spheroids were generated from non-adherent microwell culture system of human umbilical vein endothelial cells, human dermal fibroblasts and human umbilical cord blood derived mesenchymal stem cells. These vascular spheroids were used for fusion with iPSCs induced cerebral organoids. Immunostaining studies of vascularized organoids demonstrated well organized vascular structures and reduced apoptosis. We showed that the vascularization in cerebral organoids up-regulated the Wnt/ß-catenin signaling. CONCLUSIONS: We developed vascularized cerebral organoids through assembly of brain organoids with vascular spheroids. This method could not only provide a model to study human cortical development but also represent an opportunity to explore neurological disease.