Endothelium-targeted NF-κB siRNA nanogel for magnetic resonance imaging and visualized-anti-inflammation treatment of atherosclerosis.

Atherosclerosis-induced lethal cardiovascular disease remains a severe healthcare threat due to the limited drug efficiency and untimely prediction of high-risk events caused by inadequate target specificity of medications, incapable recognition of insensitive patients, and variable morphology of vulnerable plaques. Therefore, it is necessary to develop efficient strategies to improve the diagnosis accuracy and achieve visualized treatment of atherosclerosis. Herein, we establish an inflamed endothelium-targeted three-in-one nucleic acid nanogel system that can reverse the inflammatory state of endothelial cells (ECs) in plaques and simultaneously achieve real-time monitoring of the therapy process for efficient atherosclerosis diagnosis and treatment. For this purpose, contrast agent (Gd-DOTA) and VCAM-1-targeted peptide (VP) are first covalently conjugated onto DNA strands by click reaction respectively, which could self-assemble into Y-shaped structures (Gd-Y1 and VP-Y2 motifs) with magnetic resonance (MR) imaging and endothelium targeting capacities. Thereafter, NF-κB subunit p65-targeting siRNA (siNF-κB) is crosslinked with Gd-Y1 and VP-Y2 motifs to construct the endothelium-targeting nanogel platform. With contrast agents inside, the nanogel enables MR-based diagnosis and visualized therapy of atherosclerosis, providing accurate prognostic analysis and indications for treatment results, which ensures timely disclosure of insensitive individuals and avoids acute lethal events. By delivering siNF-κB to inflammatory endothelium, the nanogel significantly regresses plaques in both the aorta and carotid artery with reduced inflammation cytokines, collagens, macrophages, and apoptotic cells, providing a potential anti-inflammation strategy to treat atherosclerosis and avoid acute cardiovascular disease.

Posterior short ciliary arteries ischemia following embolization of anterior ethmoid artery to treat dural arteriovenous fistulas: a case report.

BACKGROUND: The Onyx™ Liquid Embolic System is a non-adhesive liquid embolic agent, which has been proved by the US FDA for embolization of lesions in the peripheral and neurovasculature since 2005. We reported a case of ischemic optic neuropathy after using Onyx-18 to embolize the anterior ethmoid arteries that feeding dural arteriovenous fistulas (DAVF). CASE PRESENTATION: A 57-year-old Asian male presented with anterior cranial fossa DAVF underwent embolotherapy by delivering Onyx-18 through a microcatheter into the anterior ethmoid arteries under angiography guidance. The interventional procedure was successful and no clear evidence was found pointing to untargeted occlusive embolus. But after the surgery the patient experienced delayed painless vision loss in the right eye (RE). The fundoscopy showed unilateral papilledema with pale optic disc in RE, accompanied by significant edema and thickening in the retinal nerve fiber layer (RNFL) of macula. The fundus fluorescence angiography showed that most of the optic disc in RE had postponed or absent fluorescence filling. Visual evoked potential (VEP) confirmed that the amplitude of the P100 component was decreased in RE without significant prolongation of the latency. The patient was diagnosed with anterior ischemic optic neuropathy, but immediate pulse steroid therapy failed to rescue his vision. CONCLUSION: Preoperative evaluation of the patient's hemodynamic status and fundus examination are essential for assessing the risk of ischemic ocular complications, and the non-adhesive liquid embolic agent Onyx-18 should be used cautiously during endovascular embolization of intracranial artery.

Graphene-Wrapped Magnetic Multichamber Ti3C2Tx Spheres for Stable Broadband Microwave Absorption.

Two-dimensional transition metal carbides/nitrides (MXenes) have aroused widespread interest in the field of microwave absorption because of their unique layered structures. However, the inherent aggregation, poor impedance matching, and low chemical stability of MXenes inevitably obstruct their practical applications. Herein, a multichamber Fe3O4/Ti3C2Tx@reduced graphene oxide (FT@RGO) hierarchical structure was constructed through self-assembly and sacrificial template strategies where the Ti3C2Tx nanosheets were assembled into hollow microspheres that were decorated with Fe3O4 nanospheres and wrapped by RGO nanosheets. The massive heterointerfaces and interior cavities favor enhanced microwave absorption performance via interfacial polarization, multiple scattering/reflections, and dielectric-magnetic synergistic effects. Consequently, the synthesized ultralight FT@RGO foam (0.009 g/cm3) presents superior microwave absorption ability with the minimum reflection loss of -50.5 dB at the matching thickness of 2.5 mm and effective absorption bandwidth of 8.0 GHz covering the frequency range of 10.0-18.0 GHz at the thickness of 2 mm. Furthermore, the encapsulation of hollow Ti3C2Tx spheres by RGO nanosheets avoids direct contact with external air, which considerably improves the stability of Ti3C2Tx and ensures the long-term application of FT@RGO foam in a conventional environment. This work provides a reference for the structural design of MXene-based materials as broadband and durable microwave absorbers.

Enhanced anti-tumor therapy for hepatocellular carcinoma via sorafenib and KIAA1199-siRNA co-delivery liposomes.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. Sorafenib (Sf) is currently the first-line treatment for HCC. However, due to the side effects and unsatisfied efficiency of Sf, it is urgent to combine different therapeutic agents to inhibit HCC progression and increase the therapeutic efficacy. Here, our study constructed a Sf and KIAA1199-siRNA co-loaded liposome Sf-Lp-KIAA, which was prepared by electrostatic interaction of KIAA1199-siRNA and Sf loaded liposome (Sf-Lp). The particle size, zeta potential, the in vitro cumulative release was investigated. The physical and chemical properties were characterized, and the inhibition of HepG2 growth and metastasis in vitro was investigated. The cellular uptake of the co-loaded liposome was significantly higher than that of free siRNA, and the drug/siRNA could be co-delivered to the target cells. Sf-Lp-KIAA could significantly inhibit the growth, migration, invasion and down-regulate KIAA1199 expression of HepG2 cells in vitro than that of single Sf treated group. In addition, the co-delivery liposome accumulated in the HepG2 subcutaneous tumor model and suppress tumor growth after systemic administration without induce obvious toxicity. The present study implied that the co-delivery of Sf and KIAA1199-siRNA through the co-loaded liposomes exerted synergistic antitumor effects on HCC, which would lay a foundation for HCC therapy in the future.

Preoperative prediction model of lymph node metastasis in the inguinal and femoral region based on radiomics and artificial intelligence.

OBJECTIVE: To predict preoperative inguinal lymph node metastasis in vulvar cancer patients using a machine learning model based on imaging features and clinical data from pelvic magnetic resonance imaging (MRI). METHODS: 52 vulvar cancer patients were divided into a training set (n=37) and validation set (n=15). Clinical data and MRI images were collected, and regions of interest were delineated by experienced radiologists. A total of 1688 quantitative imaging features were extracted using the Radcloud platform. Dimensionality reduction and feature selection were applied, resulting in a radiomics signature. Clinical characteristics were screened, and a combined model integrating the radiomics signature and significant clinical features was constructed using logistic regression. Four machine learning classifiers (K nearest neighbor, random forest, adaptive boosting, and latent dirichlet allocation) were trained and validated. Model performance was evaluated using the receiver operating characteristic curve and the area under the curve (AUC), as well as decision curve analysis. RESULTS: The radiomics score significantly differentiated between lymph node metastasis positive and negative patients in both the training and validation sets. The combined model demonstrated excellent discrimination, with AUC values of 0.941 and 0.933 in the training and validation sets, respectively. The calibration curve and decision curve analysis confirmed the model's high predictive accuracy and clinical utility. Among the machine learning classifiers, latent dirichlet allocation and random forest models achieved AUC values >0.7 in the validation set. Integrating all four classifiers resulted in a total model with an AUC of 0.717 in the validation set. CONCLUSION: Radiomics combined with artificial intelligence can provide a new method for prediction of inguinal lymph node metastasis of vulvar cancer before surgery.

Annexin A family: A new perspective on the regulation of bone metabolism.

Osteoblast-mediated bone formation and osteoclast-mediated bone resorption are critical processes in bone metabolism. Annexin A, a calcium-phospholipid binding protein, regulates the proliferation and differentiation of bone cells, including bone marrow mesenchymal stem cells, osteoblasts, and osteoclasts, and has gradually become a marker gene for the diagnosis of osteoporosis. As calcium channel proteins, the annexin A family members are closely associated with mechanical stress, which can target annexins A1, A5, and A6 to promote bone cell differentiation. Despite the significant clinical potential of annexin A family members in bone metabolism, few studies have reported on these mechanisms. Therefore, based on a review of relevant literature, this article elaborates on the specific functions and possible mechanisms of annexin A family members in bone metabolism to provide new ideas for their application in the prevention and treatment of bone diseases, such as osteoporosis.

Mefunidone alleviates silica-induced inflammation and fibrosis by inhibiting the TLR4-NF-κB/MAPK pathway and attenuating pyroptosis in murine macrophages.

AIMS: Silicosis is the most common and severe type of pneumoconiosis, imposing a substantial disease burden and economic loss on patients and society. The pathogenesis and key targets of silicosis are not yet clear, and there are currently no effective treatments available. Therefore, we conducted research on mefunidone (MFD), a novel antifibrotic drug, to explore its efficacy and mechanism of action in murine silicosis. METHODS: Acute 7-day and chronic 28-day silicosis models were constructed in C57BL/6J mice by the intratracheal instillation of silica and subsequently treated with MFD to assess its therapeutic potential. The effects of MFD on silica-induced inflammation, pyroptosis, and fibrosis were further investigated using immortalized mouse bone marrow-derived macrophages (iBMDMs). RESULTS: In the 7-day silica-exposed mouse models, MFD treatment significantly alleviated pulmonary inflammation and notably reduced macrophage infiltration into the lung tissue. RNA-sequencing analysis of silica-induced iBMDMs followed by gene set enrichment analysis revealed that MFD profoundly influenced cytokine-cytokine receptor interactions, chemokine signaling, and the toll-like receptor signaling pathways. MFD treatment also markedly reduced the secretion of inflammatory cytokines and chemokines from silica-exposed iBMDMs. Moreover, MFD effectively downregulated the activation of the TLR4-NF-κB/MAPK signaling pathway induced by silica and mitigated the upregulation of pyroptosis markers. Additionally, MFD treatment significantly suppressed the activation of fibroblasts and alveolar epithelial cells co-cultured with silica-exposed mouse macrophages. Ultimately, in the 28-day silica-exposed mouse models, MFD administration led to a substantial reduction in the severity of pulmonary fibrosis. CONCLUSION: MFD mitigates silica-induced pulmonary inflammation and fibrosis in mice by suppressing the TLR4-NF-κB/MAPK signaling pathway and reducing pyroptotic responses in macrophages. MFD could potentially emerge as a novel therapeutic agent for the treatment of silicosis.

Intraperitoneal spread in uterine sarcoma following unprotected laparoscopic transvaginal uterine morcellation: a case report and literature review.

Clinically and through auxiliary examinations, distinguishing uterine leiomyoma from early-stage uterine sarcoma presents significant challenges. A 48-year-old patient underwent a laparoscopic hysterectomy for uterine leiomyoma, during which a large uterus was excised through the vagina and extracted. Four months post-operation, the patient developed abdominal distension, indicative of extensive pelvic-abdominal dissemination of uterine sarcoma. We hypothesize that unprotected fibroid fragmentation increases the risk of uterine sarcoma spread, thereby worsening the prognosis. Our literature review aims to thoroughly understand the risks associated with unprotected transvaginal laparoscopic tumor division.

Insertion with long target duplication in polymyxin B-induced resistant mutant of Salmonella.

OBJECTIVES: A Salmonella enterica subsp. diarizonae (hereafter S. diarizonae) clinical strain S499 demonstrated unique genomic features. The strain S499 was treated with polymyxin B in vitro to investigate the mechanism of resistance. METHODS: S499 was treated with polymyxin B by increasing concentration gradually to obtain a resistant mutant S499V. Whole genomes of the two strains were sequenced using Illumina HiSeq X-10 and PacBio RS II platforms. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to compare the gene expression. RESULTS: The chromosome of strain S499 contained a 40-kb DNA region that was replicated after treatment with polymyxin B and generated a triple tandem DNA repeat region in the chromosome of mutant strain S499V. This repeat region in S499V was flanked by IS1 and contained pmrD, pmrG, and arnBCADTEF operon. In comparison to the homologous 40-kb DNA region of strain S499, a few genes in the repeat DNA region of strain S499V contained truncating mutations that generate two open reading frames (ORFs). The expression of pmrD, pmrG, and arnT was significantly upregulated in S499V. CONCLUSION: The duplication and overexpression of pmrD, pmrG, and arnT operon may be responsible for the polymyxin B resistance of mutant strain S499V.

Enhancing the Antitumor Efficacy of Oncolytic Adenovirus Through Sonodynamic Therapy-Augmented Virus Replication.

The therapeutic efficacy of oncolytic adenoviruses (OAs) relies on efficient viral transduction and replication. However, the limited expression of coxsackie-adenovirus receptors in many tumors, along with the intracellular antiviral signaling, poses significant obstacles to OA infection and oncolysis. Here, we present sonosensitizer-armed OAs (saOAs) that potentiate the antitumor efficacy of oncolytic virotherapy through sonodynamic therapy-augmented virus replication. The saOAs could not only efficiently infect tumor cells via transferrin receptor-mediated endocytosis but also exhibit enhanced viral replication and tumor oncolysis under ultrasound irradiation. We revealed that the sonosensitizer loaded on the viruses induced the generation of ROS within tumor cells, which triggered JNK-mediated autophagy, ultimately leading to the enhanced viral replication. In mouse models of malignant melanoma, the combination of saOAs and sonodynamic therapy elicited a robust antitumor immune response, resulting in significant inhibition of melanoma growth and improved host survival. This work highlights the potential of sonodynamic therapy in enhancing the effectiveness of OAs and provides a promising platform for fully exploiting the antitumor efficacy of oncolytic virotherapy.

Application of dezocine patient-controlled epidural analgesia in postoperative analgesia in patients with total myomectomy.

BACKGROUND: Uterine fibroids are common benign gynecological conditions. Patients who experience excessive menstruation, anemia, and pressure symptoms should be administered medication, and severe cases require a total hysterectomy. This procedure is invasive and causes severe postoperative pain, which can affect the patient's postoperative sleep quality and, thus, the recovery process. AIM: To evaluate use of dezocine in patient-controlled epidural analgesia (PCEA) for postoperative pain management in patients undergoing total myomectomy. METHODS: We selected 100 patients undergoing total abdominal hysterectomy for uterine fibroids and randomized them into two groups: A control group receiving 0.2% ropivacaine plus 0.06 mg/mL of morphine and an observation group receiving 0.2% ropivacaine plus 0.3 mg/mL of diazoxide in their PCEA. Outcomes assessed included pain levels, sedation, recovery indices, PCEA usage, stress factors, and sleep quality. RESULTS: The observation group showed lower visual analog scale scores, shorter postoperative recovery indices, fewer mean PCEA compressions, lower cortisol and blood glucose levels, and better polysomnographic parameters compared to the control group (P < 0.05). The cumulative incidence of adverse reactions was lower in the observation group than in the control group (P < 0.05). CONCLUSION: Dezocine PCEA can effectively control the pain associated with total myomectomy, reduce the negative impact of stress factors, and have less impact on patients' sleep, consequently resulting in fewer adverse effects.

Ferroelectric polarization and magnetic structure at domain walls in a multiferroic film.

Domain walls affect significantly ferroelectric and magnetic properties of magnetoelectric multiferroics. The stereotype is that the ferroelectric polarization will reduce at the domain walls due to the incomplete shielding of depolarization field or the effects of gradient energy. By combining transmission electron microscopy and first-principles calculations, we demonstrate that the ferroelectric polarization of tail-to-tail 180° domain walls in ε-Fe2O3 is regulated by the bound charge density. A huge enhancement (43%) of ferroelectric polarization is observed in the type I domain wall with a low bound charge density, while the ferroelectric polarization is reduced to almost zero at the type II domain wall with a high bound charge density. The magnetic coupling across the type I and type II ferroelectric domain walls are antiferromagnetic and ferromagnetic, respectively. Revealing mechanisms for enhancing ferroelectric polarization and magnetic behaviors at ferroelectric domain walls may promote the fundamental research and potential applications of magnetoelectric multiferroics.

Peptide-TLR7/8a-Coordinated DNA Vaccines Elicit Enhanced Immune Responses against Infectious Diseases.

DNA vaccines represent an innovative approach for the immunization of diverse diseases. However, their clinical trial outcomes are constrained by suboptimal transfection efficiency and immunogenicity. In this work, we present a universal methodology involving the codelivery of Toll-like receptor 7/8 agonists (TLR7/8a) and antigen gene using TLR7/8a-conjugated peptide-coated poly(ß-amino ester) (PBAE) nanoparticles (NPs) to augment delivery efficiency and immune response. Peptide-TLR7/8a-coated PBAE NPs exhibit advantageous biophysical attributes, encompassing diminutive particle dimensions, nearly neutral ζ potential, and stability in the physiological environment. This synergistic approach not only ameliorates the stability of plasmid DNA (pDNA) and gene delivery efficacy but also facilitates subsequent antigen production. Furthermore, under optimal formulation conditions, the TLR7/8a-conjugated peptide coated PBAE NPs exhibit a potent capacity to induce robust immune responses. Collectively, this nanoparticulate gene delivery system demonstrates heightened transfection efficacy, stability, biodegradability, immunostimulatory effect, and low toxicity, making it a promising platform for the clinical advancement of DNA vaccines.

Succinate promotes pulmonary fibrosis through GPR91 and predicts death in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is believed to be associated with a notable disruption of cellular energy metabolism. By detecting the changes of energy metabolites in the serum of patients with pulmonary fibrosis, we aimed to investigate the diagnostic and prognostic value of energy metabolites in IPF, and further elucidated the mechanism of their involvement in pulmonary fibrosis. Through metabolomics research, it was discovered that the TCA cycle intermediates changed dramatically in IPF patients. In another validation cohort of 55 patients with IPF compared to 19 healthy controls, it was found that succinate, an intermediate product of TCA cycle, has diagnostic and prognostic value in IPF. The cut-off levels of serum succinate were 98.36 µM for distinguishing IPF from healthy controls (sensitivity, 83.64%; specificity, 63.16%; likelihood ratio, 2.27, respectively). Moreover, a high serum succinate level was independently associated with higher rates of disease progression (OR 13.087, 95%CI (2.819-60.761)) and mortality (HR 3.418, 95% CI (1.308-8.927)). In addition, accumulation of succinate and increased expression of the succinate receptor GPR91 were found in both IPF patients and BLM mouse models of pulmonary fibrosis. Reducing succinate accumulation in BLM mice alleviated pulmonary fibrosis and 21d mortality, while exogenous administration of succinate can aggravate pulmonary fibrosis in BLM mice. Furthermore, GPR91 deficiency protected against lung fibrosis caused by BLM. In vitro, succinate promoted the activation of lung fibroblasts by activating ERK pathway through GPR91. In summary, succinate is a promising biomarker for diagnosis and prognosis of IPF. The accumulation of succinate may promote fibroblast activation through GPR91 and pulmonary fibrosis.

Smoking-Attributable Health Care Expenditures for US Adults With Chronic Lower Respiratory Disease.

Importance: Cigarette smoking is a primary risk factor for chronic lower respiratory disease (CLRD) and is associated with worse symptoms among people with CLRD. It is important to evaluate the economic outcomes of smoking in this population. Objective: To estimate smoking prevalence and cigarette smoking-attributable health care expenditures (SAHEs) for adults with CLRD in the US. Design, Setting, and Participants: This cross-sectional study used data from the 2014-2018 and 2020 National Health Interview Surveys (NHIS) and the 2020 Medical Expenditure Panel Survey. The final study population, stratified by age 35 to 64 years and 65 years or older, was extracted from the 2014-2018 NHIS data. The data analysis was performed between February 1 and March 31, 2024. Exposures: Cigarette smoking, as classified into 4 categories: current smokers, former smokers who quit less than 15 years ago, former smokers who quit 15 or more years ago, and never smokers. Main Outcomes and Measures: Smoking-attributable health care expenditures were assessed using a prevalence-based annual cost approach. Econometric models for the association between cigarette smoking and health care utilization were estimated for 4 types of health care services: inpatient care, emergency department visits, physician visits, and home health visits. Results: In the 2014-2018 NHIS study sample of 13 017 adults, 7400 (weighted 62.4%) were aged 35 to 64 years, 5617 (weighted 37.6%) were 65 years or older, and 8239 (weighted 61.9%) were female. In 2020, among 11 211 222 adults aged 35 to 64 with CLRD, 3 508 504 (31.3%) were current smokers and 3 496 790 (31.2%) were former smokers. Total SAHEs in 2020 for this age group were $13.6 billion, averaging $2752 per current smoker and $1083 per former smoker. In 2020, 7 561 909 adults aged 65 years or older had CLRD, with 1 451 033 (19.2%) being current smokers and 4 104 904 (54.3%) being former smokers. Total SAHEs in 2020 for the older age group were $5.3 billion, averaging $1704 per current smoker and $682 per former smoker. In sum, SAHEs for adults with CLRD aged 35 years or older amounted to $18.9 billion in 2020. Conclusions and Relevance: In this cross-sectional study of adults with CLRD, cigarette smoking was associated with a substantial health care burden. The higher per-person SAHEs for current smokers compared with former smokers suggest potential cost savings of developing targeted smoking cessation interventions for this population.

Phase-Stabilized Nickel-Molybdenum Electrocatalyst by Samarium Doping for Hydrogen Evolution in Alkaline Water Electrolysis.

Although the nickel-molybdenum electrocatalyst exhibits excellent activity in the alkaline hydrogen evolution reaction (HER), its stability is poor mainly due to molybdenum leaching. This work reports that doping samarium into nickel-molybdenum electrocatalyst effectively suppresses molybdenum leaching by forming a stable phase consisting of Sm, Mo, and O elements. The resulting electrode displays no noticeable activity degradation during the long-term testing (> 850 h) under a current density of 500 mA cm-2 in 1 м KOH. This enhanced stability is ascribed to the formation of a robust phase within the HER potential windows in alkaline electrolytes, as evidenced by the Pourbaix diagram. Furthermore, the samarium-modified electrocatalyst exhibits increased activity, with the overpotential decreasing by ≈59 mV from 159 to 100 mV at 500 mA cm-2 compared to the unmodified counterpart. These remarkable properties stem from samarium doping, which not only facilitates the formation of a stable phase to inhibit molybdenum leaching but also adjusts the electronic properties of molybdenum to enhance water dissociation.

Shexiang Baoxin Pill enriches Lactobacillus to regulate purine metabolism in patients with stable coronary artery disease.

BACKGROUND: It has been clinically confirmed that the Shexiang Baoxin Pill (SBP) dramatically reduces the frequency of angina in patients with stable coronary artery disease (SCAD). However, potential therapeutic mechanism of SBP has not been fully explored. PURPOSE: The study explored the therapeutic mechanism of SBP in the treatment of SCAD patients. METHODS: We examined the serum metabolic profiles of patients with SCAD following SBP treatment. A rat model of acute myocardial infarction (AMI) was established, and the potential therapeutic mechanism of SBP was explored using metabolomics, transcriptomics, and 16S rRNA sequencing. RESULTS: SBP decreased inosine production and improved purine metabolic disorders in patients with SCAD and in animal models of AMI. Inosine was implicated as a potential biomarker for SBP efficacy. Furthermore, SBP inhibited the expression of genes involved in purine metabolism, which are closely associated with thrombosis, inflammation, and platelet function. The regulation of purine metabolism by SBP was associated with the enrichment of Lactobacillus. Finally, the effects of SBP on inosine production and vascular function could be transmitted through the transplantation of fecal microbiota. CONCLUSION: Our study reveals a novel mechanism by which SBP regulates purine metabolism by enriching Lactobacillus to exert cardioprotective effects in patients with SCAD. The data also provide previously undocumented evidence indicating that inosine is a potential biomarker for evaluating the efficacy of SBP in the treatment of SCAD.

Association between tobacco product use and respiratory health and asthma-related interference with activities among U.S. Adolescents.

Tobacco use adversely affects long-term respiratory health. We examined the relationship between sole and dual tobacco product use and both respiratory health and respiratory-related quality of life during adolescence in the U.S. Using adolescent data (baseline age 12-17) from Waves 4.5 (data collected from December 2017-December 2018) and 5 (data collected from December 2018-November 2019) of the Population Assessment of Tobacco and Health Study, we examined the associations between combustible (i.e., cigarette or cigar), vaped, and dual (i.e., both cigar/cigarette and e-cigarette) tobacco/nicotine use at baseline and two respiratory symptoms (all adolescents, n = 11,748) and new asthma diagnosis (adolescents with no baseline diagnosis, n = 9,422) at follow-up. Among adolescents with asthma (Wave 5, n = 2,421), we estimated the association between current tobacco use and the extent to which asthma interfered with daily activities. At follow-up, 12.3 % of adolescents reported past 12-month wheezing/whistling, 17.4 % reported past 12-month dry cough, and 1.9 % reported newly diagnosed asthma. Baseline current cigarette/cigar smoking was associated with subsequent wheezing/whistling and baseline report of another tobacco product use pattern was associated with subsequent asthma diagnosis. Among adolescents with asthma, 5.7 % reported it interfering with activities some of the time and 3.1 % reported interference most/all of the time in the past 30 days. Past 30-day sole cigarette/cigar smoking and dual use was positively associated with asthma-related interference with activities compared to never tobacco use and sole e-cigarette use. Combustible and dual tobacco use pose direct risk to respiratory health and indirect risk to quality of life through respiratory health.

Phase 1/2 multicenter trial of acalabrutinib in Chinese patients with relapsed/refractory mantle cell lymphoma.

Acalabrutinib studies have limited Asian participation. This phase 1/2 study (NCT03932331) assessed acalabrutinib in Chinese patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL). Primary endpoint was blinded independent central review (BICR)-assessed overall response rate (ORR). Overall, 34 patients were enrolled. Most patients were men (88%); median age was 63 years and 59% had ≥3 prior treatments. Median treatment duration was 14 months (range, 1-24). Any-grade adverse events (AEs) and grade ≥3 AEs occurred in 85.3% and 44.1% of patients, respectively. AEs causing treatment discontinuation were aplastic anemia, thrombocytopenia, and gastrointestinal infection (n = 1 each). Fatal AEs occurred in 2 patients (aplastic anemia and multiple organ dysfunction syndrome [n = 1 each]). BICR-assessed ORR was 82.4% (95% confidence interval [CI]: 65.5, 93.2); 12 (35.3%) patients achieved complete response. Estimated 12-month OS was 84.5% (95% CI: 66.6, 93.3). Acalabrutinib yielded tolerable safety and high response rates in Chinese patients with R/R MCL.

Dishevelled Segment Polarity Protein 3 (DVL3) Induced by Bacterial LPS Promotes the Proliferation and Migration of Prostate Cancer Cells through the TLR4 Pathway.

BACKGROUND: Chronic inflammation is associated with various malignant tumors. Bacterial lipopolysaccharides (LPSs) play a significant part in the event and development of prostate cancer. Dishevelled segment polarity protein 3 (DVL3) is a shared component of the Wnt/ß-catenin and Notch signaling pathways, which are involved in tumor progression, chemoresistance, and maintenance of stem cell-like properties. According to reports, prostatic cancer cell invasion and proliferation are mediated by toll-like receptor 4 (TLR4). However, the role and regulation of DVL3 in prostate cancer and its relationship with TLR4 remain unclear. METHODS: Survival curves were plotted to evaluate the relationship between DVL3 expression and prognosis in patients with prostate cancer. DVL3 was silenced in PC3 and DU145 cells using small interfering RNAs (siRNAs). Subsequently, cell counting kit-8 (CCK-8) assay, colony formation assay, transwell migration assay, and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) were performed to investigate the role of DVL3 in cell proliferation and migration in vitro. The protein markers of potential pathways were analyzed via western blotting. RESULTS: DVL3 expression was linked to prognosis in patients with prostate cancer; In particular, patients with high DVL3 expression had a poor prognosis. LPS stimulation increased (p < 0.01) the expression of DVL3 in PC3 cells. DVL3 regulated tumor cell proliferation and migration by mediating the increase (p < 0.01) in TLR4 expression. Knockout of TLR4 validated that TLR4 played a crucial role in LPS-induced DVL3 expression. Silencing of DVL3 decreased (p < 0.01) the LPS-induced proliferation and migration of PC3 cells. CONCLUSIONS: Bacterial LPS-induced DVL3 promoted the multiplication and migration of prostate cancer cells through the TLR4 pathway. This study offers a valuable reference for the development and clinical application of targeted drugs for prostate cancer.