Anticancer potential of active alkaloids and synthetic analogs derived from marine invertebrates.

In recent years, the number of cancers has soared, becoming one of the leading causes of human death. At the same time, marine anticancer substances have been the focus of marine drug research. Marine alkaloids derived from marine invertebrates like sponges are an important class of secondary metabolites, which have good bioactivities of blocking the cancer cell cycle, inducing autophagy and apoptosis of cancer cells, inhibiting cancer cell invasion and proliferation. They show potential as anticancer drug candidates. Therefore, in this review, we focus on the detailed introduction of bioactive alkaloids and their synthetic analogs from marine invertebrates, such as 4-chloro fascapysin and other 41 kinds of marine alkaloids or marine alkaloid synthetic analogs. They have significant anticancer activities on breast cancer, cervical cancer, colorectal cancer, prostate cancer, lung cancer, liver cancer, and so on. It provides new candidate compounds for anticancer drug research and provides a reference basis for marine drug resources research.

Gastrodin: a comprehensive pharmacological review.

Tianma is the dried tuber of Gastrodia elata Blume (G. elata), which is frequently utilized in clinical practice as a traditional Chinese medicine. Gastrodin (GAS) is the main active ingredient of Tianma, which has good pharmacological activity. Therefore, for the first time, this review focused on the extraction, synthesis, pharmacological effects, and derivatives of GAS and to investigate additional development options for GAS. The use of microorganisms to create GAS is a promising method. GAS has good efficacy in the treatment of neurological diseases, cardiovascular diseases, endocrine diseases, and liver diseases. GAS has significant anti-inflammatory, antioxidant, neuroprotective, vascular protective, blood sugar lowering, lipid-regulating, analgesic, anticancer, and antiviral effects. The mechanism involves various signaling pathways such as Nrf2, NF-κB, PI3K/AKT, and AMPK. In addition, the derivatives of GAS and biomaterials synthesized by GAS and PU suggested a broader application of GAS. The research on GAS is thoroughly summarized in this paper, which has useful applications for tackling a variety of disorders and exhibits good development value.

Toxic warhead-armed antibody for targeted treatment of glioblastoma.

Glioblastoma is a fatal intracranial tumor with a poor prognosis, exhibiting uninterrupted malignant progression, widespread invasion throughout the brain leading to the destruction of normal brain tissue and inevitable death. Monoclonal antibodies alone or conjugated with cytotoxic payloads to treat patients with different solid tumors showed effective. This treatment strategy is being explored for patients with glioblastoma (GBM) to obtain meaningful clinical responses and offer new drug options for the treatment of this devastating disease. In this review, we summarize clinical data (from pubmed.gov database and clinicaltrial.gov database) on the efficacy and toxicity of naked antibodies and antibody-drug conjugates (ADCs) against multiple targets on GBM, elucidate the mechanisms that ADCs act at the site of GBM lesions. Finally, we discuss the potential strategies for ADC therapies currently used to treat GBM patients.

Hypericin as a promising natural bioactive naphthodianthrone: A review of its pharmacology, pharmacokinetics, toxicity, and safety.

Hypericin can be derived from St. John's wort, which is widely spread around the world. As a natural product, it has been put into clinical practice such as wound healing and depression for a long time. In this article, we review the pharmacology, pharmacokinetics, and safety of hypericin, aiming to introduce the research advances and provide a full evaluation of it. Turns out hypericin, as a natural photosensitizer, exhibits an excellent capacity for anticancer, neuroprotection, and elimination of microorganisms, especially when activated by light, potent anticancer and antimicrobial effects are obtained after photodynamic therapy. The mechanisms of its therapeutic effects involve the induction of cell death, inhibition of cell cycle progression, inhibition of the reuptake of amines, and inhibition of virus replication. The pharmacokinetics properties indicate that hypericin has poor water solubility and bioavailability. The distribution and excretion are fast, and it is metabolized in bile. The toxicity of hypericin is rarely reported and the conventional use of it rarely causes adverse effects except for photosensitization. Therefore, we may conclude that hypericin can be used safely and effectively against a variety of diseases. We hope to provide researchers with detailed guidance and enlighten the development of it.

Recent advances in glucose-oxidase-based nanocomposites for diabetes diagnosis and treatment.

Glucose oxidase (GOx) has attracted a lot of attention in the field of diabetes diagnosis and treatment in recent years owing to its inherent biocompatibility and glucose-specific catalysis. GOx can effectively catalyze the oxidation of glucose in the blood to hydrogen peroxide (H2O2) and glucuronic acid and can be used as a sensitive element in biosensors to detect blood glucose concentrations. Nanomaterials based on the immobilization of GOx can significantly improve the performance of glucose sensors through, for example, reduced electron tunneling distance. Moreover, various insulin-loaded nanomaterials (e.g., metal-organic backbones, and mesoporous silica nanoparticles) have been developed for the control of blood glucose concentrations based on GOx catalytic chemistry. These nano-delivery carriers are capable of releasing insulin in response to GOx-mediated changes in the microenvironment, allowing for a rapid return of the blood microenvironment to a normal state. Therefore, glucose biosensors and insulin delivery vehicles immobilized with GOx are important tools for the diagnosis and treatment of diabetes. This paper reviews the characteristics of various GOx-based nanomaterials developed for glucose biosensing and insulin-responsive release as well as research progress, and also highlights the current challenges and opportunities facing this field.

Nuclear Factor-Kappa B-induced miRNA-518a-5p represses trophoblast cell migration and invasion by the Nuclear Factor-Kappa B pathway.

Preeclampsia is associated with the insufficient invasion of trophoblasts. NF-κB is a transcription factor in almost all mammalian cells and has been validated to be upregulated in the maternal circulation and placenta of women with preeclampsia. MiR-518a-5p is also overexpressed in pre-eclamptic placenta. The present study was designed to explore whether NF-κB can transcriptionally activate miR-518a-5p and investigate the influences of miR-518a-5p on the viability, apoptosis, migration, and invasion of HTR8/SVneo trophoblast. In situ hybridization and real time polymerase chain reaction were used to reveal miR-518a-5p expression in placenta tissues and HTR8/SVneo cells, respectively. Cell migration and invasion were detected using Transwell inserts. Our findings indicated that NF-κB p52, p50, and p65 can bind to miR-518a-5p gene promoter. MiR-518a-5p further influences the levels of p50 and p65 but not p52. HTR8/SVneo cell viability and apoptosis were not influenced by miR-518a-5p. However, miR-518a-5p represses the migratory/invasive capacities of HTR8/SVneo cell and decreased gelatinolytic activity of MMP2 and MMP9, which was reversed by an NF-κB inhibitor. To sum up, miR-518a-5p is induced by NF-κB and represses trophoblast cell migration and invasion by the NF-κB pathway.

Associations of Obesity With Growth and Puberty in Children: A Cross-Sectional Study in Fuzhou, China.

Objectives: To investigate the associations of obesity with growth and puberty in children. Methods: From November 2017 to December 2019, height, weight, and Tanner stages of 26,879 children aged 3-18 years in Fuzhou, China were assessed. Results: The obese group was significantly taller than the non-obese group after age 4 years for both genders, yet there was no significant difference in height between obese and non-obese group after 15.5 years old for boys and 12.5 years old for girls. The inflection points of significant growth deceleration in obese and non-obese groups were 14.4 and 14.6 years old for boys, and 11.8 and 12.8 years old for girls, respectively. The proportions of testicular development in boys with obesity and non-obesity were 7.96% and 5.08% at 8.5-8.9 years old, respectively, while the proportions of breast development in girls were 17.19% and 3.22% at age 7.5-7.9 years old, respectively. Conclusion: Children with obesity were taller in early childhood, earlier onset of puberty and earlier cessation of growth than children with non-obesity of the same age. However, there was sex dimorphism on the effect of obesity on the incidence of precocious puberty.

Effect of the combined application of orthokeratology and single-vision spectacles on slowing the progression of high myopia: A systematic review and meta-analysis.

PURPOSE: The purpose of the study was to conduct a meta-analysis about the effect of the combined application of orthokeratology and single-vision spectacles on slowing the progression of high myopia. METHODS: The literature was searched in PubMed, EMBASE, the Cochrane Library, Wang Fang Data, CNKI and sinoMed. The Cochrane Handbook was used to evaluate the quality of the included randomized clinical trials, and the Newcastle-Ottawa Scale was used to evaluate the included case-control or cohort studies. The results were analyzed by Revman 5.3. RESULTS: Five studies (2 randomized clinical trials, 2 case-controls, and 1 cohort study) with a total of 360 patients were included in this meta-analysis. The follow-up time was at least 1 year. Combined application of orthokeratology and single-vision spectacles were used in the experimental group. The control group used single-vision spectacles only. The pooled estimates indicated that the standardized mean difference between the 2 groups was -1.46 mm (95% confidence interval: -1.88 to -1.05; P < .05) for axial length elongation and -1.85D (95% confidence interval: -2.40 to -1.31; P < .05) for change in spherical equivalent refraction. No serious adverse events were reported in all studies. CONCLUSION: The combined application of orthokeratology and single-vision spectacles is more effective than single-vision spectacles only on slowing the progression of high myopia.

Serum IL-6 Level Predicts the Prognosis and Diagnosis in Cervical Cancer Patients.

Background: Interleukin-6 (IL-6) has been reported to be associated with the prognosis of cancers. As for cervical cancer (CC), previous studies investigated the association between IL-6 expression in CC tumor tissue and CC prognosis; however, no studies assessed the effects of serum IL-6 levels on the survival of CC. This study aimed to explore the effects of serum IL-6 levels on prognosis in patients with CC. Methods: In total, 327 patients with CC and 355 controls were recruited from this hospital from May 2015 to May 2016. Serum IL-6 levels were measured before treatment. The Kaplan-Meier method was utilized to estimate survival rates. The overall survival (OS) and disease-free survival (DFS) were evaluated. The univariate and multivariate Cox regression analyses were used to identify risk factors associated with the prognosis of CC. Results: We found that the serum IL-6 level in the CC group was significantly higher than that in the control group. The diagnostic value of serum IL-6 level in detecting CC patients was moderate, and the specificity and sensitivity were 77.46% and 47.09%, respectively. Data suggested that the serum IL-6 level was significantly linked with the smoking status, FIGO stage, tumor size, treatment methods, and HPV infection. The univariate and multivariate analysis indicated that FIGO stage IIB-IIIC, lymph node metastasis, and high serum IL-6 levels were negatively associated with the OS and DFS in patients with CC. Conclusion: Serum IL-6 has a moderate diagnostic ability for detecting CC and may be a potential CC biomarker. High serum IL-6 level is associated with adverse prognosis in patients with CC and could be a prognosis indicator for CC patients.

Dietary resveratrol improved production performance, egg quality, and intestinal health of laying hens under oxidative stress.

Resveratrol (RV) is associated with protection against oxidative stress to improve health, however the effect of RV in layers under oxidative stress (OS) is limited. The objective of this experiment was to investigate the negative effect of OS and protective effects of RV against OS in laying hens. 40 Lohmann layers (25-wk-old; BW = 1.44±0.10 kg) were allocated to four treatments in a 2 × 2 factorial arrangement with either RV (0 or 600 mg/kg) or intraperitoneal injection of tert-butyl hydroperoxide (tBHP) (0 or 800 µmol/kg BW) for 31 days. The results shown that the hens challenged with tBHP presented lower egg-laying rate, feed intake, feed efficiency and higher defective egg rate (P(tBHP)<0.05). The RV were also observed to attenuated egg laying rate and feed intake reduction together with decreased broken egg rate under t-BHP challenge (P(Interaction)≤0.01). The tBHP challenged layer demonstrated lower intestinal morphology (villus height in duodenum and jejunum), lower antioxidant enzymes activities [total superoxidase (SOD), glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC)], and glutathione (GSH) levels and higher malondialdehyde (MDA) level] (P(tBHP)<0.05). Dietary RV increased jejunal SOD, GSH-Px and T-AOC activities, and reduced MDA concentration (P(RV) ≤0.05). Layers under tBHP challenge up-regulated mRNA expression of pro-inflammatory cytokine [interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)] and nuclear factor NF-κB (P(tBHP)<0.05) in jejunum. Dietary RV supplementation down-regulated mRNA gene expression of IL-1ß, IL-6, TNF-α and NF-κB (P(RV) ≤0.05). Dietary RV up-regulated mRNA expression of jejunal barrier-related proteins (claudin-1, claudin-2, mucin-1, and occludin) and ovarian reproductive hormone receptor [steroidogenic acute regulatory protein (StAR), androgen receptor (AR), estrogen receptor 1 (ESR1), and activin a receptor type 1 (ACVR1)] (P(RV) ≤0.05). Overall, the results indicate that tBHP induced oxidative stress to result in reducing production performance, intestinal health and induced ovarian inflammation; whereas dietary RV was able to maintain intestinal health and mitigate the negative impact of tBHP challenge on production performance and ovarian function.

Gut Microbiota Variations between Henoch-Schonlein Purpura and Henoch-Schonlein Purpura Nephritis.

Background: In China, little is known regarding the differences between children with Henoch-Schonlein purpura (HSP) and Henoch-Schonlein purpura nephritis (HSPN) concerning their gut microbiota. Methods: We recruited 25 children with HSP, 25 children with HSPN, and 25 healthy children to investigate the differences. Fecal samples were collected and analyzed by sequencing the V3-V4 region of the 16S rRNA gene. The diversity of the fecal gut microbiota was compared between the patient groups. Results: Rarefaction curves showed that the gut microbial diversity between the three groups differed significantly (P = 0.0224). The top five most abundant gut microbial genera were Bacteroides, Faecalibacterium, Prevotella, Ruminococcaceae, and Megamonas in children with HSP; Bacteroides, Faecalibacterium, Prevotella, Bifidobacterium, and Ruminococcaceae in children with HSPN; and Bacteroides, Prevotella, Faecalibacterium, Ruminococcaceae, and Bifidobacterium in healthy children. Children with HSP had the lowest Bifidobacterium abundance among the three groups (P < 0.05). Children with HSPN had a lower abundance of Akkermansia than children with HSP (P < 0.05), whereas children with HSPN had a higher Alistipes abundance than children with HSP (P < 0.05). Fecal microbial community composition did not differ significantly between groups (ANOSIM, R = -0.002, P = 0.46). Despite the small sample size, our results indicate that children with HSP or HSPN displayed dysbiosis of the gut microbiota. Conclusion: This study provides valuable insights that will benefit the development of future microbe-based therapies to improve clinical outcomes or prevent the incidence of HSP or HSPN in children.

Subthreshold micropulse laser photocoagulation versus half-dose photodynamic therapy for acute central serous chorioretinopathy.

PURPOSE: To compare the efficacy and safety of subthreshold micropulse (STMP) laser photocoagulation and half-dose photodynamic therapy (PDT) in the treatment of acute central serous chorioretinopathy (CSC). METHODS: A total of 39 acute CSC patients were included. 18 patients were treated with STMP laser and 21 patients were treated with half-dose PDT. The main outcome measures were best-corrected visual acuity (BCVA) according to Early Treatment Diabetic Retinopathy Study (ETDRS) chart, the proportion of eyes with complete resolution of subretinal fluid, the number of treatments, and the retinal sensitivity by microperimetry during the 12-month study period. RESULTS: The mean number of treatments during the 12-month period was 1.6 in STMP group and 1.3 in half-dose PDT group, respectively (P = 0.174). The proportion of eyes with complete resolution of subretinal fluid was 83.3% in STMP group compared with 90.5% in half-dose PDT group at 12-month (P = 0.647). The mean BCVA at 12-month after treatment was 75.28 ± 12.58 for STMP group and 76.62 ± 11.57 for half-dose PDT group, respectively (P = 0.731). No statistically significant difference was found in the mean retinal sensitivity between the two groups during the 12 months follow-up (P = 0.701 at 3 months; P = 0.725 at 6 months; P = 0.695 at 12 months). CONCLUSIONS: Subthreshold micropulse Laser Photocoagulation is as effective as half-dose PDT for acute CSC, while minimizing the damage effect on retinal.

Data-independent acquisition-based proteomics analysis correlating type 2 diabetes mellitus with osteoarthritis in total knee arthroplasty patients.

BACKGROUND: To explore the effects of type 2 diabetes mellitus (T2DM) on osteoarthritis (OA), 12 bone tissue samples were obtained surgically from the human total knee arthroplasty patients and analyzed by quantitative proteomics. METHODS: Based on patient clinical histories, patient samples were assigned to diabetes mellitus osteoarthritis (DMOA) and OA groups. A data-independent acquisition method for data collection was used with proteomic data analysis to assess intergroup proteomic differences. Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genome pathway enrichment analysis were used to further find the correlation between T2DM and OA. RESULTS: GO functional analysis found 153 differentially expressed proteins between DMOA and OA groups, of which 92 differentially expressed proteins were significantly up-regulated and 61 were significantly down-regulated. Kyoto Encyclopedia of Genes and Genome pathway analysis found 180 pathways, including 9 pathways significantly enriched. Further data analysis revealed that 6 signaling pathways were closely associated with T2DM and OA. CONCLUSION: OA and DMOA onset and progression were closely related to synthesis and metabolism of extracellular matrix components (e.g., fibronectin, decorin, etc.). The effects of T2DM on OA occur though 2 major ways of oxidative stress and low-grade chronic inflammation, involving in 2 inhibited signaling pathways and 4 activated signaling pathways.

A randomized controlled trial to optimize patient's selection for endovascular treatment in acute ischemic stroke (SELECT2): Study protocol.

RATIONALE: Randomized evidence for endovascular thrombectomy safety and efficacy in patients with large core strokes is lacking. AIMS: To demonstrate endovascular thrombectomy efficacy and safety in patients with large core on non-contrast CT or perfusion imaging (CT/MR) and determine if there is heterogeneity of treatment effect in large cores based on the imaging modality. DESIGN: SELECT2 is a prospective, randomized, multi-center, assessor-blinded controlled trial with adaptive enrichment design, enrolling up to 560 patients. PROCEDURE: Patients who meet the clinical criteria and have anterior circulation large vessel occlusions with large core on either NCCT (ASPECTS 3-5) or perfusion imaging (CTP [rCBF < 30%] and/or MRI [ADC < 620] ≥ 50 cc) will be randomized in a 1:1 ratio to undergo endovascular thrombectomy or medical management (MM) only up to 24 h of last known well. STUDY OUTCOMES: The distribution of 90-day mRS scores is the primary outcome. Functional independence (mRS = 0-2) rate is a secondary outcome. Other secondary outcomes include safety (symptomatic ICH, neurological worsening, mortality) and imaging outcomes. ANALYSIS: A normal approximation of the Wilcoxon-Mann-Whitney test (the generalized likelihood ratio test) to assess the primary outcome. Functional independence rates, safety and imaging outcomes will also be compared. DISCUSSION: The SELECT2 trial will evaluate endovascular thrombectomy safety and efficacy in large cores on either CT or perfusion imaging and may provide randomized evidence to extend endovascular thrombectomy eligibility to larger population.Registration: ClinicalTrials.gov-NCT03876457.

Knocking down Sterol regulatory element binding protein 2 (SREBF2) inhibits the Serine Protease 8 (PRSS8) /sodium channel epithelial 1alpha subunit (SCNN1A) axis to reduce the cell proliferation, migration and epithelial-mesenchymal transformation of ovarian cancer.

The pathogenesis of ovarian cancer (OC) is complex. Serine Protease 8 (PRSS8) is a potential biomarker for early detection of OC. Multiple databases were used to predict the expression of PRSS8, Sterol regulatory element binding protein (SREBP) and sodium channel epithelial 1alpha subunit (SCNN1A) in OC patients and to detect the relationship among the three. The expressions of PRSS8, SREBF2, SCNN1A and related factors of the pathway were detected by RT-qPCR and Western blot. The cell transfection was used to overexpress or inhibit the expression of PRSS8 and SREBF2, so as to explore its mechanism. MTT assay and Colony formation assay were used to detect cell proliferation. The Transwell and Wound Healing assays were utilized to measure cell invasion and migration. We have further confirmed cell-level studies in animals. We found that PRSS8 expression was up-regulated in OC patients and cell lines. Knocking down PRSS8 reduced the proliferation, migration and epithelial-mesenchymal transition (EMT) of OC cells, which was realized by SREBF2 transcriptional regulation. Knocking down SREBF2 reduced PRSS8 and then inhibited the expression of SCNN1A, thus affecting the proliferation, migration and EMT of OC cells. These results also applied to animals experiments. In conclusion, SREBF2 activates the PRSS8/SCNN1A axis to accelerate cell proliferation, migration and EMT of OC.

Downregulation of cell division cycle-associated protein 7 (CDCA7) suppresses cell proliferation, arrests cell cycle of ovarian cancer, and restrains angiogenesis by modulating enhancer of zeste homolog 2 (EZH2) expression.

The purpose of the current study was to investigate the biological function of cell division cycle-associated protein 7 (CDCA7) on ovarian cancer (OC) progression and analyze the molecular mechanism of CDCA7 on OC cellular processes and angiogenesis. CDCA7 expression in OC tissues and adjacent normal tissues was obtained from Gene Expression Profiling Interactive Analysis (GEPIA) and in various cancer cell lines was obtained from Cancer Cell Line Encyclopedia (CCLE). Moreover, CDCA7 expression in adjacent normal tissues and tumor tissues of OC patients as well as in normal ovarian epithelial cells (NOEC) and ovarian cancer cells (OVCAR3, SKOV3, CAOV-3, A2780) was further confirmed via Western blot assay and Reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In addition, Immunohistochemistry (IHC) was also applied for determination of CDCA7 expression in tissues of OC patients. Then, SKOV3 cells were introduced with shRNA-CDCA7 for functional experiments. GeneMANIA database analysis and coimmunoprecipitation (Co-IP) assay verified the interaction between CDCA7 and enhancer of zeste homolog 2 (EZH2) to probe the potential mechanism. CDCA7 expression was elevated in tumor tissues of OC patients and OC cell lines. CDCA7 silencing restrained the proliferative, migrative and invasive capacities and arrested cell cycle of OC cells. In addition, CDCA7 knockdown induced a weaker in vitro angiogenesis of HUVECs. Mechanistically, CDCA7 interacted with EZH2. Downregulation of CDCA7 arrested angiogenesis by suppressing EZH2 expression. To sum up, the current study revealed the impact and potential mechanism of CDCA7 on OC cellular processes, developing a promising molecular target for OC therapies.

Direct to Angiography vs Repeated Imaging Approaches in Transferred Patients Undergoing Endovascular Thrombectomy.

Importance: A direct to angiography (DTA) treatment paradigm without repeated imaging for transferred patients with large vessel occlusion (LVO) may reduce time to endovascular thrombectomy (EVT). Whether DTA is safe and associated with better outcomes in the late (>6 hours) window is unknown. Also, DTA feasibility and effectiveness in reducing time to EVT during on-call vs regular-work hours and the association of interfacility transfer times with DTA outcomes have not been established. Objective: To evaluate the functional and safety outcomes of DTA vs repeated imaging in the different treatment windows and on-call hours vs regular hours. Design, Setting, and Participants: This pooled retrospective cohort study at 6 US and European comprehensive stroke centers enrolled adults (aged ≥18 years) with anterior circulation LVO (internal cerebral artery or middle cerebral artery subdivisions M1/M2) and transferred for EVT within 24 hours of the last-known-well time from January 1, 2014, to February 29, 2020. Exposures: Repeated imaging (computed tomography with or without computed tomographic angiography or computed tomography perfusion) before EVT vs DTA. Main Outcomes and Measures: Functional independence (90-day modified Rankin Scale score, 0-2) was the primary outcome. Symptomatic intracerebral hemorrhage, mortality, and time metrics were also compared between the DTA and repeated imaging groups. Results: A total of 1140 patients with LVO received EVT after transfer, including 327 (28.7%) in the DTA group and 813 (71.3%) in the repeated imaging group. The median age was 69 (interquartile range [IQR], 59-78) years; 529 were female (46.4%) and 609 (53.4%) were male. Patients undergoing DTA had greater use of intravenous alteplase (200 of 327 [61.2%] vs 412 of 808 [51.0%]; P = .002), but otherwise groups were similar. Median time from EVT center arrival to groin puncture was faster with DTA (34 [IQR, 20-62] vs 60 [IQR, 37-95] minutes; P < .001), overall and in both regular and on-call hours. Three-month functional independence was higher with DTA overall (164 of 312 [52.6%] vs 282 of 763 [37.0%]; adjusted odds ratio [aOR], 1.85 [95% CI, 1.33-2.57]; P < .001) and during regular (77 of 143 [53.8%] vs 118 of 292 [40.4%]; P = .008) and on-call (87 of 169 [51.5%] vs 164 of 471 [34.8%]; P < .001) hours. The results did not vary by time window (0-6 vs >6 to 24 hours; P = .88 for interaction). Three-month mortality was lower with DTA (53 of 312 [17.0%] vs 186 of 763 [24.4%]; P = .008). A 10-minute increase in EVT-center arrival to groin puncture in the repeated imaging group correlated with 5% reduction in the functional independence odds (aOR, 0.95 [95% CI, 0.91-0.99]; P = .01). The rates of modified Rankin Scale score of 0 to 2 decreased with interfacility transfer times of greater than 3 hours in the DTA group (96 of 161 [59.6%] vs 15 of 42 [35.7%]; P = .006), but not in the repeated imaging group (75 of 208 [36.1%] vs 71 of 192 [37.0%]; P = .85). Conclusions and Relevance: The DTA approach may be associated with faster treatment and better functional outcomes during all hours and treatment windows, and repeated imaging may be reasonable with prolonged transfer times. Optimal EVT workflow in transfers may be associated with faster, safe reperfusion with improved outcomes.

A Bayesian hierarchical monitoring design for phase II cancer clinical trials: Incorporating information on response duration into monitoring rules.

We propose a Bayesian hierarchical monitoring design for single-arm phase II clinical trials of cancer treatments that incorporates the information on the duration of response (DOR) into the monitoring rules. To screen a new treatment by evaluating its preliminary therapeutic effect, futility monitoring rules are commonly used in phase II clinical trials to make "go/no-go" decisions timely and efficiently. These futility monitoring rules are usually focused on a single outcome (eg, response rate), although a single outcome may not adequately determine the efficacy of the experimental treatment. For example, targeted agents with a long response duration but a similar response rate may be worth further evaluation in cancer research. To address this issue, we propose Bayesian hierarchical futility monitoring rules to consider both the response rate and duration. The first level of monitoring evaluates whether the response rate provides evidence that the experimental treatment is worthy of further evaluation. If the evidence from the response rate does not support continuing the trial, the second level monitoring rule, which is based on the DOR, will be triggered. If both stopping rules are satisfied, the trial will be stopped for futility. We conducted simulation studies to evaluate the operating characteristics of the proposed monitoring rules and compared them to those of standard method. We illustrated the proposed design with a single-arm phase II cancer clinical trial to assess the safety and efficacy of combined treatment of nivolumab and azacitidine in patients with relapsed/refractory acute myeloid leukemia. The proposed design avoids an aggressive early termination for futility when the experimental treatment substantially prolongs the DOR but fails to improve the response rate.

A Combination of Atorvastatin and Aspirin Enhances the Pro-Regenerative Interactions of Marrow Stromal Cells and Stroke-Derived Monocytes In Vitro.

Background and Purpose: Marrow stromal cells (MSCs) are being tested in clinical trials for stroke patients. MSCs appear to promote recovery through secretomes that promote modulation of immune cells, including myeloid phagocytes. Many stroke patients have comorbidities such as metabolic syndrome, hypertension, hypercholesterolemia, and diabetes for which they are prescribed medications that might affect the function of MSCs and monocytes (Mo) when they are administered in stroke patients. We studied the effects of the two most commonly prescribed stroke medications, statin and statin plus aspirin, on the secretomes of MSCs and their modulation of Mo derived from stroke patients. Methods: Human MSCs, Mo and their co-cultures were exposed to atorvastatin or atorvastatin plus aspirin followed by secretome analysis at 24 h. Monocytes were isolated from healthy controls as well as stroke patients with NIHSS ranging from 11 to 20. Secretome composition was measured using multiplex immunoassay. We used MTT assay to measure proliferation of monocytes. The mixed model was used to analyze experimental data. p-values less than 0.05 were considered significant. Results: Atorvastatin and aspirin combination increased the release of IL-1RA from stroke Mo. In MSCs, atorvastatin and aspirin combination reduced the release of pro-inflammatory cytokines such as IL-6, IL-8, MCP-1 and IFN-γ. Atorvastatin alone reduced the release of IL-6, IL-8 and MCP-1 from co-cultures of stroke monocytes and MSCs. Combination of atorvastatin and aspirin had additive effect on reducing the secretion of IL-6 from co-cultures of stroke Mo and MSCs. Conclusion: Atorvastatin, alone and in combination with aspirin can promote anti-inflammatory effect by modulating the secretome profile of Mo and MSCs. Our results suggest that stroke trials involving the use of intravenous MSCs should consider the effect of aspirin and atorvastatin, both of which are administered to the majority of hospitalized ischemic stroke patients.

Clinical and Neuroimaging Outcomes of Direct Thrombectomy vs Bridging Therapy in Large Vessel Occlusion: Analysis of the SELECT Cohort Study.

OBJECTIVE: To evaluate the comparative safety and efficacy of direct endovascular thrombectomy (dEVT) compared to bridging therapy (BT; IV tissue plasminogen activator + EVT) and to assess whether BT potential benefit relates to stroke severity, size, and initial presentation to EVT vs non-EVT center. METHODS: In a prospective multicenter cohort study of imaging selection for endovascular thrombectomy (Optimizing Patient Selection for Endovascular Treatment in Acute Ischemic Stroke [SELECT]), patients with anterior circulation large vessel occlusion (LVO) presenting to EVT-capable centers within 4.5 hours from last known well were stratified into BT vs dEVT. The primary outcome was 90-day functional independence (modified Rankin Scale [mRS] score 0-2). Secondary outcomes included a shift across 90-day mRS grades, mortality, and symptomatic intracranial hemorrhage. We also performed subgroup analyses according to initial presentation to EVT-capable center (direct vs transfer), stroke severity, and baseline infarct core volume. RESULTS: We identified 226 LVOs (54% men, mean age 65.6 ± 14.6 years, median NIH Stroke Scale [NIHSS] score 17, 28% received dEVT). Median time from arrival to groin puncture did not differ in patients with BT when presenting directly (dEVT 1.43 [interquartile range (IQR) 1.13-1.90] hours vs BT 1.58 [IQR 1.27-2.02] hours, p = 0.40) or transferred to EVT-capable centers (dEVT 1.17 [IQR 0.90-1.48] hours vs BT 1.27 [IQR 0.97-1.87] hours, p = 0.24). BT was associated with higher odds of 90-day functional independence (57% vs 44%, adjusted odds ratio [aOR] 2.02, 95% confidence interval [CI] 1.01-4.03, p = 0.046) and functional improvement (adjusted common OR 2.06, 95% CI 1.18-3.60, p = 0.011) and lower likelihood of 90-day mortality (11% vs 23%, aOR 0.20, 95% CI 0.07-0.58, p = 0.003). No differences in any other outcomes were detected. In subgroup analyses, patients with BT with baseline NIHSS scores <15 had higher functional independence likelihood compared to those with dEVT (aOR 4.87, 95% CI 1.56-15.18, p = 0.006); this association was not evident for patients with NIHSS scores ≥15 (aOR 1.05, 95% CI 0.40-2.74, p = 0.92). Similarly, functional outcomes improvements with BT were detected in patients with core volume strata (ischemic core <50 cm3: aOR 2.10, 95% CI 1.02-4.33, p = 0.044 vs ischemic core ≥50 cm3: aOR 0.41, 95% CI 0.01-16.02, p = 0.64) and transfer status (transferred: aOR 2.21, 95% CI 0.93-9.65, p = 0.29 vs direct to EVT center: aOR 1.84, 95% CI 0.80-4.23, p = 0.15). CONCLUSIONS: BT appears to be associated with better clinical outcomes, especially with milder NIHSS scores, smaller presentation core volumes, and those who were "dripped and shipped." We did not observe any potential benefit of BT in patients with more severe strokes. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02446587. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with ischemic stroke from anterior circulation LVO within 4.5 hours from last known well, BT compared to dEVT leads to better 90-day functional outcomes.