Dienogest treatment in women with endometriosis: A retrospective cohort study in Taiwan.

OBJECTIVE: To assess the treatment efficacy of dienogest specifically in the Taiwanese population with endometriosis. MATERIALS AND METHODS: Eighty-eight patients diagnosed with endometriosis receiving at least 3 months of dienogest 2 mg once daily, from January 2018 to June 2022, were enrolled. They were divided into two groups: surgery group and non-surgery group. The assessment of pain improvement was based on visual analog scale (VAS) scores (0-100 mm) recorded at 0, 3, 6, and 12 months following the initiation of dienogest. Serum CA-125 value and ovarian endometrioma size were analyzed at 0 and 6 months. RESULTS: A total of 65 patients with endometriosis presented painful symptoms. In the surgery group (N = 28), the initial VAS score was 47.5 mm, which significantly declined to 9.6 mm at 3 months (p < 0.01), then to 7.5 mm, 2.9 mm, and 2.1 mm at 6, 9, and 12 months, respectively. In the non-surgery group (N = 37), the initial VAS score was 65.7 mm, which significantly declined to 13.2 mm at 3 months (p < 0.01) and 4.9 mm at 6 months (p < 0.05), remained low at 0.3 mm at both 9 and 12 months. Endometrioma size (N = 33) exhibited a significant 35% decrease from 38.2 mm to 24.8 mm after 6 months treatment (p < 0.01). Serum CA-125 levels showed significant improvement from 86.5 to 30.2 U/ml (p < 0.01) at 6 months. CONCLUSION: This retrospective cohort study proved that dienogest is effective in reducing endometriosis-associated pain and endometrioma size in Taiwanese population.

Drop the shortcuts: image augmentation improves fairness and decreases AI detection of race and other demographics from medical images.

BACKGROUND: It has been shown that AI models can learn race on medical images, leading to algorithmic bias. Our aim in this study was to enhance the fairness of medical image models by eliminating bias related to race, age, and sex. We hypothesise models may be learning demographics via shortcut learning and combat this using image augmentation. METHODS: This study included 44,953 patients who identified as Asian, Black, or White (mean age, 60.68 years ±18.21; 23,499 women) for a total of 194,359 chest X-rays (CXRs) from MIMIC-CXR database. The included CheXpert images comprised 45,095 patients (mean age 63.10 years ±18.14; 20,437 women) for a total of 134,300 CXRs were used for external validation. We also collected 1195 3D brain magnetic resonance imaging (MRI) data from the ADNI database, which included 273 participants with an average age of 76.97 years ±14.22, and 142 females. DL models were trained on either non-augmented or augmented images and assessed using disparity metrics. The features learned by the models were analysed using task transfer experiments and model visualisation techniques. FINDINGS: In the detection of radiological findings, training a model using augmented CXR images was shown to reduce disparities in error rate among racial groups (-5.45%), age groups (-13.94%), and sex (-22.22%). For AD detection, the model trained with augmented MRI images was shown 53.11% and 31.01% reduction of disparities in error rate among age and sex groups, respectively. Image augmentation led to a reduction in the model's ability to identify demographic attributes and resulted in the model trained for clinical purposes incorporating fewer demographic features. INTERPRETATION: The model trained using the augmented images was less likely to be influenced by demographic information in detecting image labels. These results demonstrate that the proposed augmentation scheme could enhance the fairness of interpretations by DL models when dealing with data from patients with different demographic backgrounds. FUNDING: National Science and Technology Council (Taiwan), National Institutes of Health.

Cordycepin Inhibits Enterovirus A71 Replication and Protects Host Cell from Virus-Induced Cytotoxicity through Adenosine Action Pathway.

Enterovirus A71 (EV-A71) infection typically causes mild illnesses, such as hand-foot-and-mouth disease (HFMD), but occasionally leads to severe or fatal neurological complications in infants and young children. Currently, there is no specific antiviral treatment available for EV-A71 infection. Thus, the development of an effective anti-EV-A71 drug is required urgently. Cordycepin, a major bioactive compound found in Cordyceps fungus, has been reported to possess antiviral activity. However, its specific activity against EV-A71 is unknown. In this study, the potency and role of cordycepin treatment on EV-A71 infection were investigated. Results demonstrated that cordycepin treatment significantly reduced the viral load and viral ribonucleic acid (RNA) level in EV-A71-infected Vero cells. In addition, EV-A71-mediated cytotoxicity was significantly inhibited in the presence of cordycepin in a dose-dependent manner. The protective effect can also be extended to Caco-2 intestinal cells, as evidenced by the higher median tissue culture infectious dose (TCID50) values in the cordycepin-treated groups. Furthermore, cordycepin inhibited EV-A71 replication by acting on the adenosine pathway at the post-infection stage. Taken together, our findings reveal that cordycepin could be a potential antiviral candidate for the treatment of EV-A71 infection.

RNA four-way junction (4WJ) for spontaneous cancer-targeting, effective tumor-regression, metastasis suppression, fast renal excretion and undetectable toxicity.

The field of RNA therapeutics has been emerging as the third milestone in pharmaceutical drug development. RNA nanoparticles have displayed motile and deformable properties to allow for high tumor accumulation with undetectable healthy organ accumulation. Therefore, RNA nanoparticles have the potential to serve as potent drug delivery vehicles with strong anti-cancer responses. Herein, we report the physicochemical basis for the rational design of a branched RNA four-way junction (4WJ) nanoparticle that results in advantageous high-thermostability and -drug payload for cancer therapy, including metastatic tumors in the lung. The 4WJ nanostructure displayed versatility through functionalization with an anti-cancer chemical drug, SN38, for the treatment of two different cancer models including colorectal cancer xenograft and orthotopic lung metastases of colon cancer. The resulting 4WJ RNA drug complex spontaneously targeted cancers effectively for cancer inhibition with and without ligands. The 4WJ displayed fast renal excretion, rapid body clearance, and little organ accumulation with undetectable toxicity and immunogenicity. The safety parameters were documented by organ histology, blood biochemistry, and pathological analysis. The highly efficient cancer inhibition, undetectable drug toxicity, and favorable Chemical, Manufacturing, and Control (CMC) production of RNA nanoparticles document a candidate with high potential for translation in cancer therapy.

In Vitro and In Vivo Evaluation of the Pathology and Safety Aspects of Three- and Four-Way Junction RNA Nanoparticles.

RNA therapeutics has advanced into the third milestone in pharmaceutical drug development, following chemical and protein therapeutics. RNA itself can serve as therapeutics, carriers, regulators, or substrates in drug development. Due to RNA's motile, dynamic, and deformable properties, RNA nanoparticles have demonstrated spontaneous targeting and accumulation in cancer vasculature and fast excretion through the kidney glomerulus to urine to prevent possible interactions with healthy organs. Furthermore, the negatively charged phosphate backbone of RNA results in general repulsion from negatively charged lipid cell membranes for further avoidance of vital organs. Thus, RNA nanoparticles can spontaneously enrich tumor vasculature and efficiently enter tumor cells via specific targeting, while those not entering the tumor tissue will clear from the body quickly. These favorable parameters have led to the expectation that RNA has low or little toxicity. RNA nanoparticles have been well characterized for their anticancer efficacy; however, little detail on RNA nanoparticle pathology and safety is known. Here, we report the in vitro and in vivo assessment of the pathology and safety aspects of different RNA nanoparticles including RNA three-way junction (3WJ) harboring 2'-F modified pyrimidine, folic acid, and Survivin siRNA, as well as the RNA four-way junction (4WJ) harboring 2'-F modified pyrimidine and 24 copies of SN38. Both animal models and patient serum were investigated. In vitro studies include hemolysis, platelet aggregation, complement activation, plasma coagulation, and interferon induction. In vivo studies include hematoxylin and eosin (H&E) staining, hematological and biochemical analysis as the serum profiling, and animal organ weight study. No significant toxicity, side effect, or immune responses were detected during the extensive safety evaluations of RNA nanoparticles. These results further complement previous cancer inhibition studies and demonstrate RNA nanoparticles as an effective and safe drug delivery vehicle for future clinical translations.

StAR-related lipid transfer domain protein 3 (STARD3) regulates HER2 and promotes HER2-positive breast cancer progression through interaction with HSP90 and SRC signaling.

Although various HER2-targeted therapies have been approved clinically, drug resistance remains a considerable challenge. Studies have found that the cause of drug resistance is related to the expression of genes co-amplified with HER2 in breast cancer cells. Our study found that STARD3 was highly expressed in tumor tissues (n = 130, P < 0.001), especially in the HER2+ subtype (n = 35, P < 0.05), and correlated with poorer overall survival (HR = 1.47, P < 0.001). We discovered the interaction mechanism between STARD3 and HER2 proteins. We found that STARD3 overexpression increases HER2 levels by directly interacting with the HSP90 protein and inducing phosphorylated SRC, which may protect HER2 from degradation. Conversely, loss of STARD3 attenuates HER2 expression through lysosomal degradation. In addition, STARD3 overexpression induced cell cycle progression by inducing cyclin D1 and reducing p27. Therefore, the development of STARD3-specific targeted anti-cancer drugs would be helpful in the treatment of HER2+ patients. We further found that curcumin (15 µM) is a potent STARD3 inhibitor. STARD3-knockdown cells treated with curcumin (5 µM) showed a significant synergistic effect in inhibiting cancer cell growth and migration. The results suggest that targeting STARD3 would aid in treating HER2-positive breast cancer patients. This article uses curcumin as an example to prove that the targeted inhibition of STARD3 expression can be an option for the clinical treatment of HER2+ breast cancer patients.

Enabling chronic obstructive pulmonary disease diagnosis through chest X-rays: A multi-site and multi-modality study.

PURPOSE: Chronic obstructive pulmonary disease (COPD) is one of the most common chronic illnesses in the world. Unfortunately, COPD is often difficult to diagnose early when interventions can alter the disease course, and it is underdiagnosed or only diagnosed too late for effective treatment. Currently, spirometry is the gold standard for diagnosing COPD but it can be challenging to obtain, especially in resource-poor countries. Chest X-rays (CXRs), however, are readily available and may have the potential as a screening tool to identify patients with COPD who should undergo further testing or intervention. In this study, we used three CXR datasets alongside their respective electronic health records (EHR) to develop and externally validate our models. METHOD: To leverage the performance of convolutional neural network models, we proposed two fusion schemes: (1) model-level fusion, using Bootstrap aggregating to aggregate predictions from two models, (2) data-level fusion, using CXR image data from different institutions or multi-modal data, CXR image data, and EHR data for model training. Fairness analysis was then performed to evaluate the models across different demographic groups. RESULTS: Our results demonstrate that DL models can detect COPD using CXRs with an area under the curve of over 0.75, which could facilitate patient screening for COPD, especially in low-resource regions where CXRs are more accessible than spirometry. CONCLUSIONS: By using a ubiquitous test, future research could build on this work to detect COPD in patients early who would not otherwise have been diagnosed or treated, altering the course of this highly morbid disease.

Tumor targeting and therapeutic assessments of RNA nanoparticles carrying α9-nAChR aptamer and anti-miR-21 in triple-negative breast cancers.

Triple-negative breast cancer (TNBC) is highly aggressive with a poor prognosis because of a lack of cell markers as drug targets. α9-Nicotinic acetylcholine receptor (nAChR) is expressed abundantly in TNBC; thus, it is a valuable biomarker for TNBC detection and treatment. In this study, we utilized thermodynamically stable three-way junction (3WJ) packaging RNA (pRNA) as the core to construct RNA nanoparticles with an α9-nAChR RNA aptamer as a targeting ligand and an anti-microRNA-21 (miR-21) as a therapeutic module. We compared the configuration of the two RNA nanoparticles and found that 3WJ-B-α9-nAChR-aptamer fluorescent RNA nanoparticles (3WJ-B-α9-apt-Alexa) exhibited better specificity for α9-nAChR in TNBC cells compared with 3WJ-C-α9-nAChR. Furthermore, 3WJ-B-α9-apt-Alexa bound more efficiently to TNBC patient-derived xenograft (PDX) tumors than 3WJ fluorescent RNA nanoparticles (3WJ-Alexa) with little or no accumulation in healthy organs after systemic injection in mice. Moreover, 3WJ-B-α9-nAChR-aptamer RNA nanoparticles carrying anti-miR-21 (3WJ-B-α9-apt-anti-miR-21) significantly suppressed TNBC-PDX tumor growth and induced cell apoptosis because of reduced miR-21 gene expression and upregulated the phosphatase and tensin homolog (PTEN) and programmed cell death 4 (PDCD4) proteins. In addition, no pathological changes were detected upon toxicity examination of treated mice. In conclusion, the 3WJ-B-α9-nAChR-aptamer RNA nanoparticles established in this study efficiently deliver therapeutic anti-miR-21, indicating their potential as a novel TNBC therapy.

A Hemodynamic Pulse Wave Simulator Designed for Calibration of Local Pulse Wave Velocities Measurement for Cuffless Techniques.

OBJECTIVE: Devices for cuffless blood pressure (BP) measurement have become increasingly widespread in recent years. Non-invasive continuous BP monitor (BPM) devices can diagnose potential hypertensive patients at an early stage; however, these cuffless BPMs require more reliable pulse wave simulation equipment and verification methods. Therefore, we propose a device to simulate human pulse wave signals that can test the accuracy of cuffless BPM devices using pulse wave velocity (PWV). METHODS: We design and develop a simulator capable of simulating human pulse waves comprising an electromechanical system to simulate the circulatory system and an arm model-embedded arterial phantom. These parts form a pulse wave simulator with hemodynamic characteristics. We use a cuffless device for measuring local PWV as the device under test to measure the PWV of the pulse wave simulator. We then use a hemodynamic model to fit the cuffless BPM and pulse wave simulator results; this model can rapidly calibrate the cuffless BPM's hemodynamic measurement performance. RESULTS: We first used multiple linear regression (MLR) to generate a cuffless BPM calibration model and then investigated differences between the measured PWV with and without MLR model calibration. The mean absolute error of the studied cuffless BPM without the MLR model is 0.77 m/s, which improves to 0.06 m/s when using the model for calibration. The measurement error of the cuffless BPM at BPs of 100-180 mmHg is 1.7-5.99 mmHg before calibration, which decreases to 0.14-0.48 mmHg after calibration. CONCLUSION: This study proposes a design of a pulse wave simulator based on hemodynamic characteristics and provides a standard performance verification method for cuffless BPMs that requires only MLR modeling on the cuffless BPM and pulse wave simulator. The pulse wave simulator proposed in this study can be used to quantitively assess the performance of cuffless BPMs. The proposed pulse wave simulator is suitable for mass production for the verification of cuffless BPMs. As cuffless BPMs become increasingly widespread, this study can provide performance testing standards for cuffless devices.

Pyomyoma associated with bacteremia and puerperal pyrexia: A case report.

OBJECTIVE: To report a case of pyomyoma, a serious complication of the uterine leiomyoma, in a postpartum woman. As the occurrence of pyomyoma in association with pregnancy is rather rare, a brief literature review of the condition in pregnant women is provided. CASE REPORT: A 41-year-old woman was found to have pyomyoma following persistent fever during the postpartum period of a first-time vaginal delivery. Her pregnancy course was complicated by preterm labor, for which the patient had received tocolysis since 30-week gestation. The pyomyoma was promptly removed by myomectomy on day-6 postpartum. CONCLUSION: Pyomyoma can occur in both pre- and post-menopausal women, and may even complicate pregnancies. Therefore, obstetricians and gynecologists should be wary of pyomyoma in postpartum women with histories of leiomyoma that present with sepsis of unknown focus that is refractory to standard antibiotics. Fertility may be preserved through timely diagnosis, followed by a prompt intervention.

Leveraging electronic health records for data science: common pitfalls and how to avoid them.

Analysis of electronic health records (EHRs) is an increasingly common approach for studying real-world patient data. Use of routinely collected data offers several advantages compared with other study designs, including reduced administrative costs, the ability to update analysis as practice patterns evolve, and larger sample sizes. Methodologically, EHR analysis is subject to distinct challenges because data are not collected for research purposes. In this Viewpoint, we elaborate on the importance of in-depth knowledge of clinical workflows and describe six potential pitfalls to be avoided when working with EHR data, drawing on examples from the literature and our experience. We propose solutions for prevention or mitigation of factors associated with each of these six pitfalls-sample selection bias, imprecise variable definitions, limitations to deployment, variable measurement frequency, subjective treatment allocation, and model overfitting. Ultimately, we hope that this Viewpoint will guide researchers to further improve the methodological robustness of EHR analysis.

Lithosepermic Acid Restored the Skin Barrier Functions in the Imiquimod-Induced Psoriasis-like Animal Model.

(1) Background: Psoriasis is a T helper 1/T helper 17 cells-involved immune-mediated genetic disease. Lithospermic acid, one of the major phenolic acid compounds of Danshen, has antioxidation and anti-inflammation abilities. Due to the inappropriate molecular weight for topical penetration through the stratum corneum, lithospermic acid was loaded into the well-developed microemulsion delivery system for IMQ-induced psoriasis-like dermatitis treatment. (2) Methods: BALB/c mice were administered with topical imiquimod to induce psoriasis-like dermatitis. Skin barrier function, disease severity, histology assessment, autophagy-related protein expression, and skin and spleen cytokine expression were evaluated. (3) Results: The morphology, histopathology, and skin barrier function results showed that 0.1% lithospermic acid treatment ameliorated the IMQ-induced psoriasis-like dermatitis and restored the skin barrier function. The cytokines array results confirmed that 0.1% lithospermic acid treatment inhibited the cutaneous T helper-17/Interleukin-23 axis related cytokines cascades. (4) Conclusions: The results implied that lithospermic acid might represent a possible new therapeutic agent for psoriasis treatment.

AI recognition of patient race in medical imaging: a modelling study.

BACKGROUND: Previous studies in medical imaging have shown disparate abilities of artificial intelligence (AI) to detect a person's race, yet there is no known correlation for race on medical imaging that would be obvious to human experts when interpreting the images. We aimed to conduct a comprehensive evaluation of the ability of AI to recognise a patient's racial identity from medical images. METHODS: Using private (Emory CXR, Emory Chest CT, Emory Cervical Spine, and Emory Mammogram) and public (MIMIC-CXR, CheXpert, National Lung Cancer Screening Trial, RSNA Pulmonary Embolism CT, and Digital Hand Atlas) datasets, we evaluated, first, performance quantification of deep learning models in detecting race from medical images, including the ability of these models to generalise to external environments and across multiple imaging modalities. Second, we assessed possible confounding of anatomic and phenotypic population features by assessing the ability of these hypothesised confounders to detect race in isolation using regression models, and by re-evaluating the deep learning models by testing them on datasets stratified by these hypothesised confounding variables. Last, by exploring the effect of image corruptions on model performance, we investigated the underlying mechanism by which AI models can recognise race. FINDINGS: In our study, we show that standard AI deep learning models can be trained to predict race from medical images with high performance across multiple imaging modalities, which was sustained under external validation conditions (x-ray imaging [area under the receiver operating characteristics curve (AUC) range 0·91-0·99], CT chest imaging [0·87-0·96], and mammography [0·81]). We also showed that this detection is not due to proxies or imaging-related surrogate covariates for race (eg, performance of possible confounders: body-mass index [AUC 0·55], disease distribution [0·61], and breast density [0·61]). Finally, we provide evidence to show that the ability of AI deep learning models persisted over all anatomical regions and frequency spectrums of the images, suggesting the efforts to control this behaviour when it is undesirable will be challenging and demand further study. INTERPRETATION: The results from our study emphasise that the ability of AI deep learning models to predict self-reported race is itself not the issue of importance. However, our finding that AI can accurately predict self-reported race, even from corrupted, cropped, and noised medical images, often when clinical experts cannot, creates an enormous risk for all model deployments in medical imaging. FUNDING: National Institute of Biomedical Imaging and Bioengineering, MIDRC grant of National Institutes of Health, US National Science Foundation, National Library of Medicine of the National Institutes of Health, and Taiwan Ministry of Science and Technology.

Associations between gene expression of magnesium transporters and glucose metabolism in pregnancy.

BACKGROUND/PURPOSE: To assess the relationship between gene expressions of the magnesium transporters and glucose parameters in pregnant women. METHODS: A cohort of women without ongoing or prior medical illnesses was recruited at the start of an early singleton pregnancy. Expression levels of the magnesium transporters-SLC41A1, CNNM2, MAGT1, TRPM6, and TRPM7-were assessed in the peripheral leukocytes, while total calcium and magnesium were assessed in the serum between 10 and 13 weeks gestation. Glucose parameters were assessed between 24 and 28 weeks gestation using the 75 g oral glucose tolerance test. RESULTS: A total of 208 patients were included in the study. The expressions of the magnesium transports were generally unrelated to age, body mass index (BMI), or serum levels of calcium and magnesium. The magnesium transporters were correlated with each other at baseline (correlation coefficients: 0.31 to 0.51). BMI was a strong predictor of fasting glucose levels, while both BMI and age were strong predictors of post-load glucose levels. The expression of TRPM7 was found to be predictive of 1-h post-load blood glucose after accounting for the effects of age and BMI (ß = -0.196, p = 0.020). CONCLUSION: The increased maternal expression of the magnesium transporter TRPM7 may be associated with decreased glucose tolerance in pregnant women. In particular, the association between TRPM7 and 1-h post-load glucose levels was found to be independent of the effects of age and BMI. Future studies are needed to determine whether a mechanistic relationship can be demonstrated between TRPM7 and glucose metabolism.

Type-3 Hyaluronan Synthase Attenuates Tumor Cells Invasion in Human Mammary Parenchymal Tissues.

The microenvironment for tumor growth and developing metastasis should be essential. This study demonstrated that the hyaluronic acid synthase 3 (HAS3) protein and its enzymatic product hyaluronic acid (HA) encompassed in the subcutaneous extracellular matrix can attenuate the invasion of human breast tumor cells. Decreased HA levels in subcutaneous Has3-KO mouse tissues promoted orthotopic breast cancer (E0771) cell-derived allograft tumor growth. MDA-MB-231 cells premixed with higher concentration HA attenuate tumor growth in xenografted nude mice. Human patient-derived xenotransplantation (PDX) experiments found that HA selected the highly migratory breast cancer cells with CD44 expression accumulated in the tumor/stroma junction. In conclusion, HAS3 and HA were detected in the stroma breast tissues at a high level attenuates effects for induced breast cancer cell death, and inhibit the cancer cells invasion at the initial stage. However, the highly migratory cancer cells were resistant to the HA-mediated effects with unknown mechanisms.

Endothelial-specific insulin receptor substrate-1 overexpression worsens neonatal hypoxic-ischemic brain injury via mTOR-mediated tight junction disassembly.

Hypoxic-ischemic (HI) encephalopathy is the major cause of mortality and disability in newborns. The neurovascular unit is a major target of acute and chronic brain injury, and therapies that protect simultaneously both neurons and vascular endothelial cells from neonatal HI injury are in demand. Insulin receptors and its key downstream molecule-insulin receptor substrate -1 (IRS-1) are potential neuroprotective targets and expressed both in neuron and endothelial cells. To investigate whether IRS-1 can act similarly in neurons and vascular endothelial cells in protecting neurovascular units and brain form HI injury, we found that neuron-specific IRS-1 transgenic rats showed reduced neurovascular injury and infarct volumes, whereas endothelial-specific IRS-1 transgenic rats showed increased blood-brain barrier (BBB) disruption and exaggerated neurovascular injury after neonatal HI brain injury. Endothelial-specific IRS-1 overexpression increased vascular permeability and disassembled the tight junction protein (zonula occludens-1) complex. Inhibition of mammalian target of rapamycin (mTOR) by rapamycin preserved tight junction proteins and attenuated BBB leakage and neuronal apoptosis after HI in the endothelial-specific IRS-1 transgenic pups. Together, our findings suggested that neuronal and endothelial IRS-1 had opposite effects on the neurovascular integrity and damage after neonatal HI brain injury and that endothelial IRS-1 worsens neurovascular integrity after HI via mTOR-mediated tight junction protein disassembly.

Thermostability, Tunability, and Tenacity of RNA as Rubbery Anionic Polymeric Materials in Nanotechnology and Nanomedicine-Specific Cancer Targeting with Undetectable Toxicity.

RNA nanotechnology is the bottom-up self-assembly of nanometer-scale architectures, resembling LEGOs, composed mainly of RNA. The ideal building material should be (1) versatile and controllable in shape and stoichiometry, (2) spontaneously self-assemble, and (3) thermodynamically, chemically, and enzymatically stable with a long shelf life. RNA building blocks exhibit each of the above. RNA is a polynucleic acid, making it a polymer, and its negative-charge prevents nonspecific binding to negatively charged cell membranes. The thermostability makes it suitable for logic gates, resistive memory, sensor set-ups, and NEM devices. RNA can be designed and manipulated with a level of simplicity of DNA while displaying versatile structure and enzyme activity of proteins. RNA can fold into single-stranded loops or bulges to serve as mounting dovetails for intermolecular or domain interactions without external linking dowels. RNA nanoparticles display rubber- and amoeba-like properties and are stretchable and shrinkable through multiple repeats, leading to enhanced tumor targeting and fast renal excretion to reduce toxicities. It was predicted in 2014 that RNA would be the third milestone in pharmaceutical drug development. The recent approval of several RNA drugs and COVID-19 mRNA vaccines by FDA suggests that this milestone is being realized. Here, we review the unique properties of RNA nanotechnology, summarize its recent advancements, describe its distinct attributes inside or outside the body and discuss potential applications in nanotechnology, medicine, and material science.

Validation of ICD-10-CM Diagnosis Codes for Identification of Patients with Acute Hemorrhagic Stroke in a National Health Insurance Claims Database.

PURPOSE: The performance of the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes for identifying acute hemorrhagic stroke in Taiwan's National Health Insurance claims database has not been assessed. This study aimed to construct and validate the case definitions for acute hemorrhagic stroke based on ICD-10-CM diagnostic codes. PATIENTS AND METHODS: From January 2018 to December 2019, all inpatient records with ICD-10-CM code of I60 or I61 in any field of the discharge diagnoses were retrieved from the hospitalization claims data and all hospitalizations with a final diagnosis of subarachnoid hemorrhage (SAH) or intracerebral hemorrhage (ICH) were identified from the stroke registry databases. The clinical diagnosis in the stroke registry was treated as the reference standard. For hospitalizations not recorded in the stroke registry, manual review of the medical records and images was done to ascertain the diagnosis. The positive predictive value (PPV) and sensitivity of various case definitions for acute hemorrhagic stroke were estimated. RESULTS: Among the 983 hospitalizations, 860, 111, and 12 were determined to be true-positive, false-positive, and false-negative episodes of acute hemorrhagic stroke, respectively. The PPV and sensitivity of the ICD-10-CM codes of I60 or I61 for identifying acute hemorrhagic stroke were 88.6% and 98.6%, respectively. The PPV increased to 98.2%, whereas the sensitivity decreased to 93.1% when acute hemorrhagic stroke was defined as hospitalizations in which the primary diagnosis field contained I60 or I61. Hemorrhagic transformation of ischemic stroke and concomitant cerebrovascular diseases other than SAH or ICH were the main reasons for a false-positive and false-negative diagnosis of acute hemorrhagic stroke, respectively. CONCLUSION: This study demonstrated the performance of ICD-10-CM codes for identifying acute hemorrhagic stroke and may offer a reference for future claims-based stroke studies.

Curcumin-induced antitumor effects on triple-negative breast cancer patient-derived xenograft tumor mice through inhibiting salt-induced kinase-3 protein.

This study demonstrated for the first time that curcumin effectively inhibits the growth of triple-negative breast cancer (TNBC) tumors by inhibiting the expression of salt-induced kinase-3 (SIK3) protein in patient-derived xenografted tumor mice (TNBC-PDX). For TNBC patients, chemotherapy is the only option for postoperative adjuvant treatment. In this study, we detected the SIK3 mRNA expression in paired-breast cancer tissues by qPCR analysis. The results revealed that SIK3 mRNA expression was significantly higher in tumor tissues when compared to the normal adjacent tissues (73.25 times, n = 183). Thus, it is proposed for the first time that the antitumor effect induced by curcumin by targeting SIK3 can be used as a novel strategy for the therapy of TNBC tumors. In vitro mechanism studies have shown that curcumin (>25 µM) inhibits the SIK3-mediated cyclin D upregulation, thereby inhibiting the G1/S cell cycle and arresting TNBC (MDA-MB-231) cancer cell growth. The SIK3 overexpression was associated with increased mesenchymal markers (i.e., Vimentin, α-SMA, MMP3, and Twist) during epithelial-mesenchymal transition (EMT). Our results demonstrated that curcumin inhibits the SIK3-mediated EMT, effectively attenuating the tumor migration. For clinical indications, dietary nutrients (such as curcumin) as an adjuvant to chemotherapy should be helpful to TNBC patients because the current trend is to shrink the tumor with preoperative chemotherapy and then perform surgery. In addition, from the perspective of chemoprevention, curcumin has excellent clinical application value.

Tea polyphenol epigallocatechin-3-gallate inhibits cell proliferation in a patient-derived triple-negative breast cancer xenograft mouse model via inhibition of proline-dehydrogenase-induced effects.

Triple-negative breast cancers (TNBCs) lack specific targeted therapy options and have evolved into highly chemo-resistant tumors that metastasize to multiple organs. The present study demonstrated that the proline dehydrogenase (PRODH) mRNA level in paired (tumor vs. normal) human breast tissue samples (n=234) was 6.6-fold greater than normal cells (*p=0.021). We established stable PRODH-overexpressing TNBC (HS578T) cells, and the malignant phenotypes were evaluated using soft agar colony formation and Transwell migration assays. The results demonstrated that PRODH induced epithelial-mesenchymal transition in cancer cells and increased cell proliferation. The present study found that the tea polyphenol epigallocatechin-3-gallate (EGCG) significantly inhibited PRODH and its regulated proteins, such as alpha-smooth muscle actin (alpha-SMA) expression in TNBC cells. These findings support the targeting of the PRODH signaling pathway as a potential therapeutic strategy in preventing cancer cell metastasis. The patient-derived xenograft (PDX) mouse model is highly relevant to real human tumor growth. We established a TNBC-PDX (F4, n=4 in each group)mouse model. The PDX mice were treated with EGCG (50 mg/kg), and the results indicated that EGCG significantly inhibited PDX tumor growth (*p = 0.013). These experiments provide additional evidence to evaluate the antitumor effects of EGCG-induced PRODH inhibition for clinical therapeutic application, especially in TNBC patients.