Comparisons of three different modes of digital mirror therapy for post-stroke rehabilitation: Preliminary results of randomized controlled trial.

Objective: Technologically adapted mirror therapy shows promising results in improving motor function for stroke survivors. The treatment effects of a newly developed multi-mode stroke rehabilitation system offering multiple training modes in digital mirror therapy remain unknown. This study aimed to examine the effects of unilateral mirror visual feedback (MVF) with unimanual training (UM-UT), unilateral MVF with bimanual training (UM-BT), and bilateral MVF with bimanual training (BM-BT) on clinical outcomes in stroke survivors, compared to classical mirror therapy (CMT). Methods: Thirty-five participants were randomly assigned to one of four groups receiving fifteen 60-minute training sessions for 3-4 weeks. The Fugl-Meyer Assessment for Upper Extremity (FMA-UE), Chedoke Arm and Hand Activity Inventory (CAHAI), Revised Nottingham Sensory Assessment (rNSA), Motor Activity Log (MAL), and EQ-5D-5L were administered at pre- and post-intervention and at 1-month follow-up. Results: After intervention and follow-up, significant within-group treatment efficacies were found on most primary outcomes of the FMA-UE and CAHAI scores in all four groups. Significant within-group improvements in the secondary outcomes were found on the MAL and EQ-5D-5L index in the UM-BT group, and the rNSA tactile sensation and MAL quality of movement subscales in the BM-BT group. No significant between-group treatment efficacies were found. Conclusions: UM-UT, UM-BT, BM-BT, and CMT led to similar clinical effects on the FMA-UE and can be considered effective alternative interventions for post-stroke upper-limb motor rehabilitation. UM-BT and BM-BT showed within-group improvements in functional performance in the patients' affected upper limbs in real-life activities.

Paracrinal regulation of neutrophil functions by coronaviral infection in iPSC-derived alveolar type II epithelial cells.

Coronaviruses (CoVs) are enveloped single-stranded RNA viruses that predominantly attack the human respiratory system. In recent decades, several deadly human CoVs, including SARS-CoV, SARS-CoV-2, and MERS-CoV, have brought great impact on public health and economics. However, their high infectivity and the demand for high biosafety level facilities restrict the pathogenesis research of CoV infection. Exacerbated inflammatory cell infiltration is associated with poor prognosis in CoV-associated diseases. In this study, we used human CoV 229E (HCoV-229E), a CoV associated with relatively fewer biohazards, to investigate the pathogenesis of CoV infection and the regulation of neutrophil functions by CoV-infected lung cells. Induced pluripotent stem cell (iPSC)-derived alveolar epithelial type II cells (iAECIIs) exhibiting specific biomarkers and phenotypes were employed as an experimental model for CoV infection. After infection, the detection of dsRNA, S, and N proteins validated the infection of iAECIIs with HCoV-229E. The culture medium conditioned by the infected iAECIIs promoted the migration of neutrophils as well as their adhesion to the infected iAECIIs. Cytokine array revealed the elevated secretion of cytokines associated with chemotaxis and adhesion into the conditioned media from the infected iAECIIs. The importance of IL-8 secretion and ICAM-1 expression for neutrophil migration and adhesion, respectively, was demonstrated by using neutralizing antibodies. Moreover, next-generation sequencing analysis of the transcriptome revealed the upregulation of genes associated with cytokine signaling. To summarize, we established an in vitro model of CoV infection that can be applied for the study of the immune system perturbations during severe coronaviral disease.

Low-level mosaic trisomy 21 at amniocentesis and cordocentesis in the second trimester in a pregnancy associated with positive non-invasive prenatal testing for trisomy 21, perinatal progressive decrease of the trisomy 21 cell line and a favorable fetal outcome.

OBJECTIVE: We present low-level mosaic trisomy 21 at amniocentesis and cordocentesis in a pregnancy associated with a favorable fetal outcome. CASE REPORT: A 26-year-old, primigravid woman underwent amniocentesis at 17 weeks of gestation because of positive non-invasive prenatal testing (NIPT) for trisomy 21 at 16 weeks of gestation. Amniocentesis revealed a karyotype of 47,XX,+21[3]/46,XX[17], and multiplex ligation-dependent probe amplification (MLPA) on uncultured amniocytes revealed rsa X(P095) × 2, (13, 18, 21) × 2. She underwent cordocentesis (cord blood sampling) at 21 weeks of gestation which revealed a karyotype of 47,XX,+21[2]/46,XX[48]. At 27 weeks of gestation, she was referred to our hospital for genetic counseling, and repeat amniocentesis revealed a karyotype of 46,XX in 20/20 colonies. Quantitative fluorescent polymerase chain reaction (QF-PCR) analysis on the DNA extracted from uncultured amniocytes and parental bloods excluded uniparental disomy (UPD) 21. Array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed arr (1-22,X) × 2, Y × 0 with no genomic imbalance. Interphase fluorescence in situ hybridization (FISH) analysis on 104 uncultured amniocytes detected one cell (1/104 = 0.9%) with trisomy 21, while the rest cells were disomy 21, compared with 0% (0/100) in the normal control. The woman was encouraged to continue the pregnancy. The pregnancy was carried to 38 weeks of gestation, and a 2771-g female baby was delivered no phenotypic abnormality. aCGH analysis on the cord blood showed arr (1-22,X) × 2, Y × 0 with no genomic imbalance. The umbilical cord had a karyotype of 47,XX,+21[3]/46,XX[37]. The placenta had a karyotype of 46,XX. When follow-up at age 3½ months, the neonate was phenotypically normal and had normal development. The peripheral blood had a karyotype of 46,XX in 40/40 cells. Interphase FISH analysis on buccal mucosal cells detected normal disomy 21 cells in 100/100 cells. CONCLUSION: Low-level mosaic trisomy 21 at amniocentesis and cordocentesis in the second trimester can be associated with perinatal progressive decrease of the trisomy 21 cell line and a favorable fetal outcome.

Enhanced versus standard hydration in acute ischaemic stroke: REVIVE - a randomised clinical trial.

RATIONALE: Early neurological deterioration (END) within 72 hours of stroke onset is associated with poor prognosis. Optimising hydration might reduce the risk of END. AIMS: To determine in acute ischaemic stroke patients if enhanced hydration versus standard hydration reduced the incidence of major (primary) and minor (secondary) END, as whether it increased the incidence of early neurological improvement (secondary), at 72 hours after admissionSample Size Estimate: 244 participants per arm. METHODS AND DESIGN: A prospective, double-blinded, multicentre, parallel-group, randomised controlled trial conducted at 4 hospitals from April 2014 to July 2020, with data analysed in August 2020. The sample size estimated was 488 participants (244 per arm). Ischaemic stroke patients with measurable neurological deficits of onset within 12 hours of emergency department presentation and blood urea nitrogen/creatinine (BUN/Cr) ratio ≥15 at point of admission were enrolled and randomised to 0.9% sodium chloride infusions of varying rates - enhanced hydration (20 mL/kg body weight, one-third given via bolus and remainder over 8 hours) versus standard hydration (60 mL/hour for 8 hours), followed by maintenance infusion of 40-80 mL/hour for the subsequent 64 hours. The primary outcome measure was the incidence of major early neurological deterioration at 72 hours after admission, defined as an increase in National Institutes of Health Stroke Scale of ≥4 points from baseline. RESULTS: 487 participants were randomised (median age 67 years; 287 females). At 72 hours: 7 (2.9%) in the enhanced-hydration arm and 5(2.0%) in the standard-hydration developed major early neurological deterioration (p=0.54). The incidence of minor early neurological deterioration and early neurological improvement did not differ between treatment arms. CONCLUSIONS AND RELEVANCE: Enhanced hydration ratio did not reduce END or improve short term outcomes in acute ischaemic stroke. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02099383, https://clinicaltrials.gov/study/NCT02099383).

Sputum bacterial microbiota signature as a surrogate for predicting disease progression of nontuberculous mycobacterial lung disease.

OBJECTIVES: Predicting progression of nontuberculous mycobacterial lung disease (NTM-LD) remains challenging. This study evaluated whether sputum bacterial microbiome diversity can be the biomarker and provide novel insights into related phenotypes and treatment timing. METHODS: We analyzed 126 sputum microbiomes of 126 patients with newly diagnosed NTM-LD due to Mycobacterium avium complex, M. abscessus complex, and M. kansasii between May 2020 and December 2021. Patients were followed for 2 years to determine their disease progression status. We identified consistently representative genera that differentiated the progressor and nonprogressor by using six methodologies. These genera were used to construct a prediction model using random forest with 5-fold cross validation. RESULTS: Disease progression occurred in 49 (38.6%) patients. Compared with nonprogressors, α-diversity was lower in the progressors. Significant compositional differences existed in the ß-diversity between groups (p=0.001). The prediction model for NTM-LD progression constructed using seven genera (Burkholderia, Pseudomonas, Sphingomonas, Candidatus Saccharibacteria, Phocaeicola, Pelomonas, and Phascolarctobacterium) with significantly differential abundance achieved an area under curve of 0.871. CONCLUSIONS: Identification of the composition of sputum bacterial microbiome facilitates prediction of the course of NTM-LD, and maybe used to develop precision treatment involving modulating the respiratory microbiome composition to ameliorate NTM-LD.

Cross-site validation of lung cancer diagnosis by electronic nose with deep learning: a multicenter prospective study.

BACKGROUND: Although electronic nose (eNose) has been intensively investigated for diagnosing lung cancer, cross-site validation remains a major obstacle to be overcome and no studies have yet been performed. METHODS: Patients with lung cancer, as well as healthy control and diseased control groups, were prospectively recruited from two referral centers between 2019 and 2022. Deep learning models for detecting lung cancer with eNose breathprint were developed using training cohort from one site and then tested on cohort from the other site. Semi-Supervised Domain-Generalized (Semi-DG) Augmentation (SDA) and Noise-Shift Augmentation (NSA) methods with or without fine-tuning was applied to improve performance. RESULTS: In this study, 231 participants were enrolled, comprising a training/validation cohort of 168 individuals (90 with lung cancer, 16 healthy controls, and 62 diseased controls) and a test cohort of 63 individuals (28 with lung cancer, 10 healthy controls, and 25 diseased controls). The model has satisfactory results in the validation cohort from the same hospital while directly applying the trained model to the test cohort yielded suboptimal results (AUC, 0.61, 95% CI: 0.47─0.76). The performance improved after applying data augmentation methods in the training cohort (SDA, AUC: 0.89 [0.81─0.97]; NSA, AUC:0.90 [0.89─1.00]). Additionally, after applying fine-tuning methods, the performance further improved (SDA plus fine-tuning, AUC:0.95 [0.89─1.00]; NSA plus fine-tuning, AUC:0.95 [0.90─1.00]). CONCLUSION: Our study revealed that deep learning models developed for eNose breathprint can achieve cross-site validation with data augmentation and fine-tuning. Accordingly, eNose breathprints emerge as a convenient, non-invasive, and potentially generalizable solution for lung cancer detection. CLINICAL TRIAL REGISTRATION: This study is not a clinical trial and was therefore not registered.

Discovery of N,N'-diarylurea molecules with activity against multidrug-resistant Staphylococcus aureus.

The emergence and global spread of methicillin-resistant Staphylococcus aureus (MRSA) pose a serious threat to public health, underscoring the urgent need for novel antibacterial interventions. Here, we screened 18 newly synthesized N,N'-diarylurea derivatives to identify compounds with activity against MRSA. Our investigations led to the discovery of a small molecule, SCB-24, which exhibited promising antimicrobial activity against MRSA USA300. Notably, SCB-24 demonstrated high activity even in the presence of 10% fetal bovine serum and showed excellent selectivity for bacterial over mammalian cells. SCB-24 also showed potent activity against various MRSA strains, including those resistant to second- and third-line antibiotics. Importantly, the efficacy of SCB-24 was inferior to that of vancomycin in MRSA-infected Galleria mellonella larvae. Overall, our findings suggest that SCB-24 has great potential as a new therapeutic for multidrug-resistant S. aureus infections.

Advancing climate-resilient flood mitigation: Utilizing transformer-LSTM for water level forecasting at pumping stations.

Proactive management of pumping stations using artificial intelligence (AI) technology is vital for effectively mitigating the impacts of flood events caused by climate change. Accurate water level forecasts are pivotal in advancing the intelligent operation of pumping stations. This study proposed a novel Transformer-LSTM model to offer accurate multi-step-ahead forecasts of the flood storage pond (FSP) and river water levels for the Zhongshan pumping station in Taipei, Taiwan. A total of 19,647 ten-minute-based datasets of pumping operation and storm sewer, FSP, and river water levels were collected between 2014 and 2020 and further divided into training (70 %), validation (10 %), and test (20 %) datasets for model construction. The results demonstrate that the proposed model dramatically outperforms benchmark models by producing more accurate and reliable water level forecasts at 10-minute (T + 1) to 60-minute (T + 6) horizons. The proposed model effectively enhances the connections between input factors through the Transformer module and increases the connectivity across consecutive time series using the LSTM module. This study reveals interconnected dynamics among pumping operation and storm sewer, FSP, and river water levels, enhancing flood management. Understanding these dynamics is crucial for effective execution of management strategies and infrastructure revitalization against climate impacts. The Transformer-LSTM model's forecasts encourage water practices, resilience, and disaster risk reduction for extreme weather events.

Detection of Interleukin-1 ß (IL-1ß) in Single Human Blastocyst-Conditioned Medium Using Ultrasensitive Bead-Based Digital Microfluidic Chip and Its Relationship with Embryonic Implantation Potential.

The implantation of human embryos is a complex process involving various cytokines and receptors expressed by both endometrium and embryos. However, the role of cytokines produced by a single embryo in successful implantation is largely unknown. This study aimed to investigate the role of IL-1ß expressed in a single-embryo-conditioned medium (ECM) in embryo implantation. Seventy samples of single ECM were analyzed by a specially designed magnetic-beads-based microfluidic chip from 15 women. We discovered that IL-1ß level increased as the embryo developed, and the difference was significant. In addition, receiver operator characteristic (ROC) curves analysis showed a higher chance of pregnancy when the IL-1ß level on day 5 ECM was below 79.37 pg/mL and the difference between day 5 and day 3 was below 24.90 pg/mL. Our study discovered a possible association between embryonic proteomic expression and successful implantation, which might facilitate single-embryo transfer in the future by helping clinicians identify the embryo with the greatest implantation potential.

Brain imaging prior to thrombectomy in the late window of large vessel occlusion ischemic stroke: a systematic review and meta-analysis.

PURPOSE: Optimal imaging modalities to select patients for endovascular thrombectomy (EVT) in the late window of acute ischemic stroke due to large vessel occlusions (AIS-LVO) are not known. We conducted a systematic review comparing outcomes of patients selected by non-contrast computed tomography (NCCT)/CT angiography (CTA) vs. those selected by CT perfusion (CTP) or magnetic resonance imaging (MRI) for EVT in these patients. METHODS: We searched PUBMED, EMBASE, and the Cochrane Library from January 1, 2000, to July 15, 2023, to identify studies comparing outcomes of patients selected for EVT by NCCT/CTA vs. CTP or MRI in the late time window for AIS-LVO. Primary outcome was independence (mRS 0-2) at 90 days or discharge. Secondary outcomes were symptomatic intracranial hemorrhage (sICH) and mortality. We pooled data across studies based on an inverse variance method. RESULTS: Six cohort studies with 4208 patients were included. Pooled results showed no significant difference in the rate of independence at 90 days or discharge (RR 0.96, 95% CI 0.88-1.03) and sICH (RR 1.26, 0.85-1.86) between patients selected by NCCT/CTA vs. CTP or MRI for EVT in the late window of AIS-LVO. However, patients selected by NCCT/CTA vs. CTP or MRI for EVT were associated with a higher risk of mortality (RR 1.21, 1.06-1.39). CONCLUSION: For AIS-LVO in the late window, patients selected by NCCT/CTA compared with those selected by CTP or MRI for EVT might have a comparable rate of functional independence and sICH. Baseline NCCT/CTA may triage AIS-LVO in the late window.

E-cadherin interacts with EGFR resulting in hyper-activation of ERK in multiple models of breast cancer.

The loss of intercellular adhesion molecule E-cadherin is a hallmark of the epithelial-mesenchymal transition (EMT), during which tumor cells transition into an invasive phenotype. Accordingly, E-cadherin has long been considered a tumor suppressor gene; however, E-cadherin expression is paradoxically correlated with breast cancer survival rates. Using novel multi-compartment organoids and multiple in vivo models, we show that E-cadherin promotes a hyper-proliferative phenotype in breast cancer cells via interaction with the transmembrane receptor EGFR. The E-cad and EGFR interaction results in activation of the MEK/ERK signaling pathway, leading to a significant increase in proliferation via activation of transcription factors, including c-Fos. Pharmacological inhibition of MEK activity in E-cadherin positive breast cancer significantly decreases both tumor growth and macro-metastasis in vivo. This work provides evidence for a novel role of E-cadherin in breast tumor progression and identifies a new target to treat hyper-proliferative E-cadherin-positive breast tumors, thus providing the foundation to utilize E-cadherin as a biomarker for specific therapeutic success.

Establishment of a cobia (Rachycentron canadum) gill cell line: A valuable tool for immune response studies.

Cobia (Rachycentron canadum), a commercially important marine fish, has been used to develop a novel gill cell line, designated CG, for the first time. The CG cell line was cultured in Leibovitz's-15 medium with 5% fetal bovine serum (FBS) and successfully sub-cultured more than 110 passages. It underwent verification through sequencing of the mitochondrial cytochrome C oxidase subunit I (COI) gene. Optimal growth rate was achieved when the CG cell line was cultured in a medium supplemented with 5% FBS, 1% Penicillin-Streptomycin (P/S), and 5 parts per thousand (ppt) of coral sea salt water, maintained at a temperature of 27 °C. The addition of 5 ppt of salt in the growth medium suggests that this cell line could be a viable in vitro tool for marine ecosystem toxicological studies or for culturing marine parasitic microorganisms. The CG cell line was also successfully transfected using the pTurbo-GFP plasmids, showing an 18% efficiency, with observable GFP expression. Furthermore, the cell line has been effectively cryopreserved. Gene expression analysis indicated that the CG cell line exhibits responsive regulation of immune gene expression when exposured to various stimulants, highlighting its potential as an in vitro platform for immune response studies. This makes it suitable for exploring dynamic immune signaling pathways and host-pathogen interactions, thereby offering valuable insights for therapeutic development.

Deep Learning-based Diagnosis of Pulmonary Tuberculosis on Chest X-ray in the Emergency Department: A Retrospective Study.

Prompt and correct detection of pulmonary tuberculosis (PTB) is critical in preventing its spread. We aimed to develop a deep learning-based algorithm for detecting PTB on chest X-ray (CXRs) in the emergency department. This retrospective study included 3498 CXRs acquired from the National Taiwan University Hospital (NTUH). The images were chronologically split into a training dataset, NTUH-1519 (images acquired during the years 2015 to 2019; n = 2144), and a testing dataset, NTUH-20 (images acquired during the year 2020; n = 1354). Public databases, including the NIH ChestX-ray14 dataset (model training; 112,120 images), Montgomery County (model testing; 138 images), and Shenzhen (model testing; 662 images), were also used in model development. EfficientNetV2 was the basic architecture of the algorithm. Images from ChestX-ray14 were employed for pseudo-labelling to perform semi-supervised learning. The algorithm demonstrated excellent performance in detecting PTB (area under the receiver operating characteristic curve [AUC] 0.878, 95% confidence interval [CI] 0.854-0.900) in NTUH-20. The algorithm showed significantly better performance in posterior-anterior (PA) CXR (AUC 0.940, 95% CI 0.912-0.965, p-value < 0.001) compared with anterior-posterior (AUC 0.782, 95% CI 0.644-0.897) or portable anterior-posterior (AUC 0.869, 95% CI 0.814-0.918) CXR. The algorithm accurately detected cases of bacteriologically confirmed PTB (AUC 0.854, 95% CI 0.823-0.883). Finally, the algorithm tested favourably in Montgomery County (AUC 0.838, 95% CI 0.765-0.904) and Shenzhen (AUC 0.806, 95% CI 0.771-0.839). A deep learning-based algorithm could detect PTB on CXR with excellent performance, which may help shorten the interval between detection and airborne isolation for patients with PTB.

Dysregulation of the circRNA_0087207/miR-548c-3p/PLSR1-TGFB2 axis in Leber hereditary optic neuropathy in vitro.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is mainly the degeneration of retinal ganglion cells (RGCs) associated with high apoptosis and reactive oxygen species (ROS) levels, which is accepted to be caused by the mutations in the subunits of complex I of the mitochondrial electron transport chain. The treatment is still infant while efforts of correcting genes or using antioxidants do not bring good and consistent results. Unaffected carrier carries LHON mutation but shows normal phenotype, suggesting that the disease's pathogenesis is complex, in which secondary factors exist and cooperate with the primary complex I dysfunction. METHODS: Using LHON patient-specific induced pluripotent stem cells (iPSCs) as the in vitro disease model, we previously demonstrated that circRNA_0087207 had the most significantly higher expression level in the LHON patient-iPSC-derived RGCs compared with the unaffected carrier-iPSC-derived RGCs. To elaborate the underlying pathologies regulated by circRNA_008720 mechanistically, bioinformatics analysis was conducted and elucidated that circRNA_0087207 could act as a sponge of miR-548c-3p and modulate PLSCR1/TGFB2 levels in ND4 mutation-carrying LHON patient-iPSC-derived RGCs. RESULTS: Using LHON iPSC-derived RGCs as the disease-based platform, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis on targeted mRNA of miR-548c-3p showed the connection with apoptosis, suggesting downregulation of miR548c-3p contributes to the apoptosis of LHON patient RGCs. CONCLUSION: We showed that the downregulation of miR548c-3p plays a critical role in modulating cellular dysfunction and the apoptotic program of RGCs in LHON.

Quantifying the contribution of smear-negative, culture-positive pulmonary tuberculosis to nosocomial transmission.

BACKGROUND: Despite current guidelines for tuberculosis (TB) control in health care settings, which focused on smear-positive cases, prevention of nosocomial TB transmission continues to be a challenge. Here, we report the results of the first hospital-wide prospective study applying interferon-gamma release assay to investigate the role of smear-negative, culture-positive index cases in nosocomial TB transmission. METHODS: We prospectively identified cases of culture-confirmed smear-negative pulmonary TB receiving aerosol-generating procedures (AGPs) and cases of culture-confirmed smear-positive pulmonary TB admitted at a medical center. Nosocomial transmission was evaluated by screening their close contacts for latent TB infection (LTBI) using an interferon-gamma release assay. RESULTS: A total of 93 smear-negative index receiving AGP and 122 smear-positive index were enrolled. Among them, 13 (14.0%) and 43 (35.2%) index cases, respectively, had secondary cases of LTBI (P < .001). Sputum smear negativity (adjusted odds ratio: 0.20 [0.08-0.48]) and AGP (sputum suction; adjusted odds ratio: 3.48 [1.34-9.05]) are independent factors of transmission. A similar proportion in the close contacts of the 2 index groups had LTBI (17 [15.3%] and 63 [16.0%], respectively), and the former index group contributed to 21.3% of the nosocomial transmission. CONCLUSIONS: Smear-negative, culture-positive index cases receiving AGPs could be as infectious as smear-positive index cases. Hospital TB control policy should also focus on the former group.

Comparing Low- or Standard-Dose Alteplase in Endovascular Thrombectomy: Insights From a Nationwide Registry.

BACKGROUND: Timely intravenous thrombolysis and endovascular thrombectomy are the standard reperfusion treatments for large vessel occlusion stroke. Currently, it is unknown whether a low-dose thrombolytic agent (0.6 mg/kg alteplase) can offer similar efficacy to the standard dose (0.9 mg/kg alteplase). METHODS: We enrolled consecutive patients in the multicenter Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke who had received combined thrombolysis (within 4.5 hours of onset) and thrombectomy treatment from January 2019 to April 2023. The choice of low- or standard-dose alteplase was based on the physician's discretion. The outcomes included successful reperfusion (modified Thrombolysis in Cerebral Infarction score, 2b-3), symptomatic intracerebral hemorrhage, 90-day modified Rankin Scale score, and 90-day mortality. The outcomes between the 2 groups were compared using multivariable logistic regression and inverse probability of treatment weighting-adjusted analysis. RESULTS: Among the 2242 patients in the Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke, 734 (33%) received intravenous alteplase. Patients in the low-dose group (n=360) were older, had more women, more atrial fibrillation, and longer onset-to-needle time compared with the standard-dose group (n=374). In comparison to low-dose alteplase, standard-dose alteplase was associated with a lower rate of successful reperfusion (81% versus 87%; adjusted odds ratio, 0.63 [95% CI, 0.40-0.98]), a numerically higher incidence of symptomatic intracerebral hemorrhage (6.7% versus 3.9%; adjusted odds ratio, 1.81 [95% CI, 0.88-3.69]), but better 90-day modified Rankin Scale score (functional independence [modified Rankin Scale score, 0-2], 47% versus 31%; adjusted odds ratio, 1.91 [95% CI, 1.28-2.86]), and a numerically lower mortality rate (9% versus 15%; adjusted odds ratio, 0.73 [95% CI, 0.43-1.25]) after adjusting for covariates. Similar results were observed in the inverse probability of treatment weighting-adjusted models. The results were consistent across predefined subgroups and age strata. CONCLUSIONS: Despite the lower rate of successful reperfusion and higher risk of symptomatic intracerebral hemorrhage with standard-dose alteplase, standard-dose alteplase was associated with a better functional outcome in patients receiving combined thrombolysis and thrombectomy.

Multipathway regulation induced by 4-(phenylsulfonyl)morpholine derivatives against triple-negative breast cancer.

Phenotypic drug discovery (PDD) is an effective drug discovery approach by observation of therapeutic effects on disease phenotypes, especially in complex disease systems. Triple-negative breast cancer (TNBC) is composed of several complex disease features, including high tumor heterogeneity, high invasive and metastatic potential, and a lack of effective therapeutic targets. Therefore, identifying effective and novel agents through PDD is a current trend in TNBC drug development. In this study, 23 novel small molecules were synthesized using 4-(phenylsulfonyl)morpholine as a pharmacophore. Among these derivatives, GL24 (4m) exhibited the lowest half-maximal inhibitory concentration value (0.90 µM) in MDA-MB-231 cells. To investigate the tumor-suppressive mechanisms of GL24, transcriptomic analyses were used to detect the perturbation for gene expression upon GL24 treatment. Followed by gene ontology (GO) analysis, gene set enrichment analysis (GSEA), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, multiple ER stress-dependent tumor suppressive signals were identified, such as unfolded protein response (UPR), p53 pathway, G2/M checkpoint, and E2F targets. Most of the identified pathways triggered by GL24 eventually led to cell-cycle arrest and then to apoptosis. In summary, we developed a novel 4-(phenylsulfonyl)morpholine derivative GL24 with a strong potential for inhibiting TNBC cell growth through ER stress-dependent tumor suppressive signals.