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•Brain metastases are intracranial recurrence of extracranial malignant tumors.•Clinical diagnosis and treatment modalities of brain metastases are unsatisfactory.•Issues include late ...diagnosis, invasiveness, drug delivery barrier, and resistance.•Nanomedicine possesses great potentials in combating these clinical issues.•Reviewed backgrounds and advances of applying nanomedicine to address these issues.
Brain metastases are intracranial recurrence of extracranial malignant tumors with a high incidence and poor prognosis. Owing to the particularity of intracranial localization, clinical diagnosis (neuroimaging and biopsy) of brain metastases is associated with shortcomings such as delayed diagnosis and biopsy invasiveness. Clinical treatment modalities consist of local therapies (resection and radiotherapy) and systemic therapies (chemotherapy, targeted therapy and immunotherapy). However, the efficiency of clinical therapies is severely hindered by 1) neurological impairment, 2) relapse, 3) blood–brain barrier, and 4) therapy resistance. Nanomedicine possesses great potentials in combating these clinical issues. This article reviewed backgrounds and recent advances of applying nanomedicine to address these above issues in clinical diagnosis and treatment of brain metastases.
Aims
The impact of atrial fibrillation (AF) ablation in early heart failure with preserved ejection fraction (HFpEF) is unknown. Our aim was to determine the impact of AF ablation on symptoms and ...exercise haemodynamic parameters of early HFpEF.
Methods and results
Symptomatic AF patients referred for index AF ablation with ejection fraction ≥50% underwent baseline quality of life questionnaires, echocardiography, cardiac magnetic resonance imaging, exercise right heart catheterisation (exRHC), and brain natriuretic peptide (BNP) testing. HFpEF was defined by resting pulmonary capillary wedge pressure (PCWP) ≥15 mmHg or peak exercise PCWP ≥25 mmHg. Patients with HFpEF were offered AF ablation and follow‐up exRHC ≥6 months post‐ablation. Of 54 patients undergoing baseline evaluation, 35 (65%) had HFpEF identified by exRHC. HFpEF patients were older (64 ± 10 vs. 54 ± 13 years, P < 0.01), and more frequently female (54% vs. 16%, P < 0.01), hypertensive (63% vs. 16%, P < 0.001), and suffering persistent AF (66% vs. 11%, P < 0.001), compared to those without HFpEF. Twenty HFpEF patients underwent AF ablation and follow‐up exRHC 12 ± 6 months post‐ablation. Nine (45%) patients no longer fulfilled exRHC criteria for HFpEF at follow‐up. Patients remaining arrhythmia free (n = 9, 45%) showed significant improvements in peak exercise PCWP (29 ± 4 to 23 ± 2 mmHg, P < 0.01) and Minnesota Living with Heart Failure (MLHF) score (55 ± 30 to 22 ± 30, P < 0.01) while the remainder did not (PCWP 31 ± 5 to 30.0 ± 4 mmHg, P = NS; MLHF score 55 ± 23 to 25 ± 20, P = NS).
Conclusion
Heart failure with preserved ejection fraction frequently coexists in patients with symptomatic AF and preserved ejection fraction. Restoration and maintenance of sinus rhythm in patients with comorbid AF and HFpEF improves haemodynamic parameters, BNP and symptoms associated with HFpEF.
Overview of the study illustrating the proportion of patients referred for consideration of atrial fibrillation (AF) ablation who met the criteria for heart failure with preserved ejection fraction (HFpEF) in panel A. Three‐dimensional reconstruction of the left atrium with radiofrequency lesions used to achieved pulmonary vein electrical isolation at the time of AF ablation in panel B and results of the follow‐up exercise right heart catheterisation at ≥6 months following AF ablation based on arrhythmia recurrence status in panel C. Panel D illustrates the potential interaction between AF and HFpEF. BNP, brain natriuretic peptide; LA, left atrial; LAPW, left atrial posterior wall; LIPV, left inferior pulmonary vein; LSPV, left superior pulmonary vein; PCWP, pulmonary capillary wedge pressure; QoL, quality of life; RIPV, right inferior pulmonary vein; RSPV, right superior pulmonary vein.
Extracellular electron transfer (EET) empowers electrogens to catalyse the bioconversion of a wide range of xenobiotics in the environment. Synthetic bioengineering has proven effective in promoting ...EET output. However, conventional strategies mainly focus on modifications of EET‐related genes or pathways, which leads to a bottleneck due to the intricate nature of electrogenic metabolic properties and intricate pathway regulation that remain unelucidated. Herein, we propose a novel EET pathway‐independent approach, from an energy manipulation perspective, to enhance microbial EET output. The Controlled Hydrolyzation of ATP to Enhance Extracellular Respiration (CHEER) strategy promotes energy utilization and persistently reduces the intracellular ATP level in Shewanella oneidensis, a representative electrogenic microbe. This approach leads to the accelerated consumption of carbon substrate, increased biomass accumulation and an expanded intracellular NADH pool. Both microbial electrolysis cell and microbial fuel cell tests exhibit that the CHEER strain substantially enhances EET capability. Analysis of transcriptome profiles reveals that the CHEER strain considerably bolsters biomass synthesis and metabolic activity. When applied to the bioconversion of model xenobiotics including methyl orange, Cr(VI) and U(VI), the CHEER strain consistently exhibits enhanced removal efficiencies. This work provides a new perspective and a feasible strategy to enhance microbial EET for efficient xenobiotic conversion.
The Controlled Hydrolyzation of ATP to Enhance Extracellular Respiration (CHEER) strategy is designed based on the principle that extracellular respiration is conversely coupled with carbon substrate consumption and energy generation. It can significantly enhance both microbial extracellular electron transfer (EET) and pollutant bioconversion capabilities and is broadly applicable and extendable to other non‐model electrogens due to its independence from any specific EET pathways.
Abstract
Background
Adding radiotherapy (RT) to systemic therapy improves progression-free survival (PFS) and overall survival (OS) in oligometastatic non-small cell lung cancer (NSCLC). Whether ...these findings translate to epidermal growth factor receptor (EGFR)–mutated NSCLC remains unknown. The SINDAS trial (NCT02893332) evaluated first-line tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated synchronous oligometastatic NSCLC and randomized to upfront RT vs no RT; we now report the prespecified interim analysis at 68% accrual.
Methods
Inclusion criteria were biopsy-proven EGFR-mutated adenocarcinoma (per amplification refractory mutation system or next generation sequencing), with synchronous (newly diagnosed, treatment naïve) oligometastatic (≤5 metastases; ≤2 lesions in any one organ) NSCLC without brain metastases. All patients received a first-generation TKI (gefitinib, erlotinib, or icotinib), and randomization was between no RT vs RT (25-40 Gy in 5 fractions depending on tumor size and location) to all metastases and the primary tumor/involved regional lymphatics. The primary endpoint (intention to treat) was PFS. Secondary endpoints included OS and toxicities. All statistical tests were 2-sided.
Results
A total of 133 patients (n = 65 TKI only, n = 68 TKI with RT) were enrolled (2016-2019). The median follow-up was 23.6 months. The respective median PFS was 12.5 months vs 20.2 months (P < .001), and the median OS was 17.4 months vs 25.5 months (P < .001) for TKI only vs TKI with RT. Treatment yielded no grade 5 events and a 6% rate of symptomatic grade 3-4 pneumonitis in the TKI with RT arm. Based on the efficacy results of this prespecified interim analysis, the ethics committee recommended premature cessation of this trial.
Conclusions
As compared with a first-line TKI alone, addition of upfront local therapy using RT statistically significantly improved PFS and OS for EGFR-mutated NSCLC.
Slope stability prediction plays a significant role in landslide disaster prevention and mitigation. This study develops an ensemble learning-based method to predict the slope stability by ...introducing the random forest (RF) and extreme gradient boosting (XGBoost). As an illustration, the proposed approach is applied to the stability prediction of 786 landslide cases in Yunyang County, Chongqing, China. For comparison, the predictive performance of RF, XGBoost, support vector machine (SVM), and logistic regression (LR) is systematically investigated based on the well-established confusion matrix, which contains the known indices of recall rate, precision, and accuracy. Furthermore, the feature importance of the 12 influencing variables is also explored. Results show that the accuracy of the XGBoost and RF for both the training and testing data is superior to that of SVM and LR, revealing the superiority of the ensemble learning models (i.e. XGBoost and RF) in the slope stability prediction of Yunyang County. Among the 12 influencing factors, the profile shape is the most important one. The proposed ensemble learning-based method offers a promising way to rationally capture the slope status. It can be extended to the prediction of slope stability of other landslide-prone areas of interest.
Mast cells are primary effectors in allergic reactions, and may have important roles in disease by secreting histamine and various inflammatory and immunomodulatory substances. Although they are ...classically activated by immunoglobulin (Ig)E antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. The pathogenic roles of these substances have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, Mrgprb2, the orthologue of the human G-protein-coupled receptor MRGPRX2. Secretagogue-induced histamine release, inflammation and airway contraction are abolished in Mrgprb2-null mutant mice. Furthermore, we show that most classes of US Food and Drug Administration (FDA)-approved peptidergic drugs associated with allergic-type injection-site reactions also activate Mrgprb2 and MRGPRX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that Mrgprb2 and MRGPRX2 are targets of many small-molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice; and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.
RNA editing is a major post‐transcriptional mechanism that changes specific nucleotides at the RNA level. The most common RNA editing type in humans is adenosine (A) to inosine (I) editing, which is ...mediated by ADAR enzymes. RNA editing events can not only change amino acids in proteins, but also affect the functions of non‐coding RNAs such as miRNAs. Recent studies have characterized thousands of miRNA RNA editing events across different cancer types. Importantly, individual cases of miRNA editing have been reported to play a role in cancer development. In this review, we summarize the current knowledge of miRNA editing in cancer, and discuss the mechanisms on how miRNA‐related editing events modulate the initiation and progression of human cancer. Finally, we discuss the challenges and future directions of studying miRNA editing in cancer.
RNA editing is introduced by ADAR or APOBEC enzymes, leading to specific nucleotide changes, respectively. The interplays between RNA editing and miRNAs may play important roles in cancer. This graphical shows four major mechanisms through which miRNAs interact with RNA editing to confer a functional impact on tumor development.
A surface plasmon resonance (SPR) sensor based on a D-shaped photonic crystal fiber (PCF) with an uncomplicated structure is proposed to detect the change of refractive index of liquid analytes, and ...numerical simulation is carried out by the finite element method (FEM). Using silver as the plasmonic metal, the performances of the SPR-PCF sensor coated with a graphene layer and zinc oxide (ZnO) layer were assessed. The sensor designed is only coated with material on the polished surface, which makes the sensor production uncomplicated and solves the problems of filling material in the hole and coating on the hole wall. The effects of structural parameters such as graphene layer thickness, silver layer thickness, ZnO thickness, lattice spacing and manufacturing tolerance of blowhole diameter on the sensor performance were numerically simulated. The numerical results show that the sensitivity of the SPR-PCF sensor coated with 25 nm ZnO is highest in the ZnO thickness range from 10 to 25 nm. In the refractive index range of 1.37-1.41 for liquid analyte, the maximum sensitivity and corresponding resolution reach 6000 nm/RIU and 1.667 × 10
, respectively. In addition, the sensor has good stability and high structural tolerance under the tolerance of ±5% of blowhole diameter. This work has wide application value in the detection of biochemical analytes, water pollution monitoring, food quality, and medical diagnosis.
Background
The diagnostic work‐up for cardiac arrest from ventricular tachyarrhythmias occurring in younger adults and structurally normal hearts is variable and often incomplete.
Methods
We reviewed ...records for all recipients of a secondary prevention implantable cardiac defibrillator (ICD) younger than 60 years at a single quaternary referral hospital from 2010 to 2021. Patients with unexplained ventricular arrhythmias (UVA) were identified as those with no structural heart disease on echocardiogram, no obstructive coronary disease, and no clear diagnostic features on ECG. We specifically evaluated the adoption rate of five modalities of “second‐line” cardiac investigations: cardiac magnetic resonance imaging (CMR), exercise ECG, flecainide challenge, electrophysiology study (EPS), and genetic testing. We also evaluated patterns of antiarrhythmic drug therapy and device‐detected arrhythmias and compared them with secondary prevention ICD recipients with a clear etiology found on initial assessment.
Results
One hundred and two recipients of a secondary prevention ICD under the age of 60 were analyzed. Thirty‐nine patients (38.2%) were identified with UVA and were compared with the remaining 63 patients with VA of clear etiology (61.8%). UVA patients were younger (35.6 ± 13.0 vs. 46.0 ± 8.6 years, p < .001) and were more often female (48.7% vs. 28.6%, p = .04). CMR was performed in 32 patients with UVA (82.1%), whereas flecainide challenge, stress ECG, genetic testing, and EPS were only performed in a minority of patients. Overall, the use of a second‐line investigation suggested an etiology in 17 patients with UVA (43.5%). Compared to patients with VA of clear etiology, UVA patients had lower rates of antiarrhythmic drug prescription (64.1% vs. 88.9%, p = .003) and had a higher rate of device‐delivered tachy‐therapies (30.8% vs. 14.3%, p = .045).
Conclusion
In this real‐world analysis of patients with UVA, the diagnostic work‐up is often incomplete. While CMR was increasingly utilized at our institution, investigations for channelopathies and genetic causes appear to be underutilized. Implementation of a systematic protocol for work‐up of these patients requires further study.
Diagnotic yield of second‐line investigations in the workup of unexplained ventricular tachyarrhythmia. Of 102 recipients of secondary prevention implantable cardiac defibrillators aged under the age of 60 years, 39 patients met criteria for unexplained ventricular arrhythmia. Seventeen of these 39 patients had an underlying diagnosis suggested by a second‐line investigation. Cardiac MRI was the most frequently utilized test, while the remaining investigations were utilized less commonly.
The growing knowledge of ferroptosis has suggested the role and therapeutic potential of ferroptosis in cancer, but has not been translated into effective therapy. Liver cancer, primarily ...hepatocellular carcinoma (HCC), is highly lethal with limited treatment options. LIFR is frequently downregulated in HCC. Here, by studying hepatocyte-specific and inducible Lifr-knockout mice, we show that loss of Lifr promotes liver tumorigenesis and confers resistance to drug-induced ferroptosis. Mechanistically, loss of LIFR activates NF-κB signaling through SHP1, leading to upregulation of the iron-sequestering cytokine LCN2, which depletes iron and renders insensitivity to ferroptosis inducers. Notably, an LCN2-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on HCC patient-derived xenograft tumors with low LIFR expression and high LCN2 expression. Thus, anti-LCN2 therapy is a promising way to improve liver cancer treatment by targeting ferroptosis.
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