Safety and feasibility analysis of rapid daratumumab infusion in Chinese patients with multiple myeloma.

BACKGROUND: With the increasing use of daratumumab (DARA)-containing regimens for multiple myeloma (MM) patients in China, the standard infusion time of DARA is long, with the potential for infusion-related reactions (IRRs) and increased hospitalization and use of resources. Shortening the duration of DARA infusion helps to optimize the hospital stay and enhance the patient treatment experience. The current, commonly used 90-min rapid DARA infusion regimen may not be applicable to Chinese MM patients, and therefore, we explored a new 110-min rapid DARA infusion regimen aimed at reducing the treatment burden on patients to guarantee therapeutic safety. METHODS: MM inpatients treated with the DARA regimen were divided into two groups according to the number of times the DARA regimen was used: a standard infusion regimen for patients treated with the first two doses of DARA and a 110-min rapid infusion regimen for patients treated with more than two doses of DARA. Anti-allergy medications were routinely administered prior to the start of DARA infusion, patient consent, and authorization was obtained for all treatments, and statistical evaluation of the results was conducted via descriptive analyses, one-way ANOVA and chi-square tests. RESULTS: A total of 129 patients were included in this study: 68 in the standard infusion group, with 121 DARA infusions, and 129 in the rapid infusion group (patients who participated in the standard infusion subsequently participated in the rapid infusion), with 738 DARA infusions. The incidence of IRRs was 27.27% (36/121) in the standard infusion group and 1.35% (10/738) in the rapid infusion group, which were significantly different (p < 0.001). The incidence of IRRs after rapid infusion in other studies was <6%. The incidence of grade 1 IRRs in the rapid infusion group was 0.81% (6/738), the incidence of grade 2 IRRs was 0.54% (4/738), and there were no IRRs above grade 3; age, sex, and underlying disease had no effect on the choice of infusion method (p > 0.05). The mean infusion time after the occurrence of IRRs was also shorter in the rapid infusion group than in the standard infusion group (F = 24.781, p < 0.001). CONCLUSION: The 110-min rapid infusion DARA regimen is feasible and safe for use in Chinese MM patients.

The relationship between PM2.5 and the onset and exacerbation of childhood asthma: a short communication.

Much is known about the link between air pollution and asthma in adults, particularly fine particulate matter (PM2.5). Studies have found that certain levels of fine PM2.5 can increase airway responsiveness and worsen asthma. PM2.5 may play a role in the onset and exacerbation of childhood asthma. However, there is little in the literature on how PM2.5 affects asthma attacks and exacerbations in children. Asthma is a common chronic disease in children, and air pollution can aggravate it. The effect of PM2.5 on childhood asthma needs further research. By evaluating, reviewing, and collating existing results in this area, this paper aims to explore the relationship between PM2.5 and asthma onset and exacerbation in children.

Ferrostatin-1 obviates seizures and associated cognitive deficits in ferric chloride-induced posttraumatic epilepsy via suppressing ferroptosis.

Posttraumatic epilepsy (PTE) is a prevalent complication of brain trauma. Current anti-epileptic drugs available do not have satisfactory response to PTE. It is of desperate need to explore novel therapeutic approaches for curing PTE. Our prior work revealed that ferroptosis, a recently discovered mode of cell death, occurs in rodent model of PTE. In the present study, we aimed to further investigate the effect of ferrostatin-1 (Fer-1), a specific ferroptosis inhibitor, on seizure behavior and cognitive deficit in a mouse model of PTE. The preparation of PTE was performed by stereotaxical injection in the somatosensory cortex region of 50 mM FeCl3. Seizure activity was assessed via Racine scoring and electroencephalogram analysis. PTE-related cognitive function was evaluated by novel object recognition and Morris water maze tests. Ferroptosis-related indices including glutathione peroxidase (GPx) activity and protein expressions of 4-hydroxynonenal (4-HNE) were detected using a commercial kit and immunofluorescence, respectively. It was found that treatment with Fer-1 significantly exerted protective effects against acute seizure and memory decline, although no evident effect on epileptic progression. Fer-1 also exhibited good tolerability and safety as we observed that it hardly influenced the body weight. Furthermore, it was noted that administration of Fer-1 suppressed ferroptosis-related indices including GPx activity and protein expressions of 4-HNE in hippocampus. These data altogether indicate that Fer-1 has potent therapeutic effects against seizures and cognitive impairment following PTE-induced brain insult. Fer-1 may act as a promising drug for curing PTE patients.

Factors influencing postembolization syndrome in patients with hepatocellular carcinoma undergoing first transcatheter arterial chemoembolization.

CONTEXT: Postembolization syndrome (PES) is the most common complication in patients with hepatocellular carcinoma (HCC) who had undergone transcatheter arterial chemoembolization (TACE). PES was defined as fever, nausea and/or vomiting, and abdominal pain and these symptoms develop within 1-3 days after TACE. However, few studies have explored the factors influencing PES in patients with TACE for the first time. AIMS: We explored the factors influencing PES in patients with HCC undergoing TACE for the first time. SETTINGS AND DESIGN: The present study was a hospital-based study conducted in the tertiary care hospital of Guangzhou with a retrospective study design. SUBJECTS AND METHODS: In this single-center retrospective study, a total of 242 patients with HCC were included in the first TACE program between November 1, 2018 and November 31, 2019. STATISTICAL ANALYSIS USED: T-test and Chi-square test revealed the factors affecting the occurrence of PES. Correlation analysis (Spearman) explored the relationship between these factors and PES. Binary logistics analyzed the predictive factors of PES. RESULTS: The probability of PES in patients with HCC undergoing TACE for the first time was 55.45%. Types of embolic agents (r = 0.296), types of microspheres (r = 0.510), number of microspheres (r = 0.130), maximum diameter of microspheres used (r = 0.429), type of drug (r = 0.406), and drug loading (r = 0.433) were positively correlated with PES (P < 0.05). Serum albumin was negatively correlated with PES (P = 0.008, r = -0.170). Binary logistic regression analysis revealed that drug loading microspheres (odds ratio [OR] = 0.075, 95% confidence interval [CI] = 0.031-0.180) and serum albumin (OR = 0.182, 95% CI = 0.068-0.487) were the protective factors influencing PES, while drug loading was the risk factor of PES (OR = 1.407, 95% CI = 1.144-1.173). CONCLUSIONS: Drug loading microspheres, serum albumin, and drug loading were the predictors of PES after the first TACE.

Tetramethylpyrazine Alleviates Behavioral and Psychological Symptoms of Dementia Through Facilitating Hippocampal Synaptic Plasticity in Rats With Chronic Cerebral Hypoperfusion.

Behavioral and psychological symptoms of dementia (BPSD) ubiquitously disturb all patients with dementia at some point in the disease course. Although a plethora of non-pharmacological and pharmacological methods targeting the relief BPSD have been developed, the therapeutic effect is still far from ideal. Here, a rat BPSD model combining the physiological changes with mental insults was successfully established. Meanwhile, our results indicated that TMP attenuated anxious behavior using an elevated plus maze (EPM) test, ameliorated recognitive ability and sociability through a novel object recognition test (NORT) and social interaction test (SIT), and improved learning and memory impairments via a Barnes maze in rats with bilateral common carotid arteries occlusion (BCCAO) plus chronic restraint stress (CRS). Given that hippocampus chronic cerebral hypoperfusion (CCH) always causes damage to the hippocampus, and the majority of cognitive impairments, behaviors, and stress responses are associated with pathology in the hippocampus including anxiety and depression, we paid attention to investigate the role of the hippocampus in BPSD. Our results indicated that Tetramethylpyrazine (TMP) attenuated anxiety and ameliorated recognitive ability, sociability, learning, and memory impairments due to alleviating dendritic and spine deficits, and upregulating the expression of synapse-related proteins (including PSD95, SYN, GAP43, SYP) in the hippocampus. We also found that the underlying mechanism was that TMP could activate the TrkB/ERK/CREB signaling pathway to promote synaptic remodeling in vivo and in vitro. Mechanically, the present study enlarges the therapeutic scope of TMP in neurodegenerative disorders and provides basic knowledge and feasible candidates for treating BPSD, particularly for vascular dementia.

The mutual interplay of redox signaling and connexins.

Connexins (Cxs) are ubiquitous transmembrane proteins that possess both channel function (e.g., formations of gap junction and hemichannel) and non-channel properties (e.g., gene transcription and protein-protein interaction). Several factors have been identified to play a role in the regulation of Cxs, which include those acting intracellularly, as redox potential, pH, intramolecular interactions, and post-translational modifications (e.g., phosphorylation, S-nitrosylation) as well as those acting extracellularly, such as Ca2+ and Mg2+. The relationship between redox signaling and Cxs attracts considerable attention in recent years. There is ample evidence showing that redox signaling molecules (e.g., hydrogen peroxide (H2O2), nitric oxide (NO)) affect Cxs-based channel function while the opening of Cx channels also triggers the transfer of various redox-related metabolites (e.g., reactive oxygen species, glutathione, nicotinamide adenine dinucleotide, and NO). On the basis of these evidences, we propose the existence of redox-Cxs crosstalk. In this review, we briefly discuss the interaction between redox signaling and Cxs and the implications of the intersection in disease pathology and future therapeutic interventions.

Dietary nutrition for neurological disease therapy: Current status and future directions.

Adequate food intake and relative abundance of dietary nutrients have undisputed effects on the brain function. There is now substantial evidence that dietary nutrition aids in the prevention and remediation of neurologic symptoms in diverse pathological conditions. The newly described influences of dietary factors on the alterations of mitochondrial dysfunction, epigenetic modification and neuroinflammation are important mechanisms that are responsible for the action of nutrients on the brain health. In this review, we discuss the state of evidence supporting that distinct dietary interventions including dietary supplement and dietary restriction have the ability to tackle neurological disorders using Alzheimer's disease, Parkinson's disease, stroke, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, Huntington's disease and multiple sclerosis as examples. Additionally, it is also highlighting that diverse potential mechanisms such as metabolic control, epigenetic modification, neuroinflammation and gut-brain axis are of utmost importance for nutrient supply to the risk of neurologic condition and therapeutic response. Finally, we also highlight the novel concept that dietary nutrient intervention reshapes metabolism-epigenetics-immunity cycle to remediate brain dysfunction. Targeting metabolism-epigenetics-immunity network will delineate a new blueprint for combating neurological weaknesses.

Corrigendum: Neuroprotective Effects of the Anti-Cancer Drug Lapatinib Against Epileptic Seizures via Suppressing Glutathione Peroxidase 4-Dependent Ferroptosis.

[This corrects the article DOI: 10.3389/fphar.2020.601572.].

Neuroprotective Effects of the Anti-cancer Drug Lapatinib Against Epileptic Seizures via Suppressing Glutathione Peroxidase 4-Dependent Ferroptosis.

Epilepsy is a complex neurological disorder characterized by recurrent and unprovoked seizures. Neuronal death process is implicated in the development of repetitive epileptic seizures. Therefore, cell death can be harnessed for ceasing seizures and epileptogenesis. Oxidative stress is regarded as a contributing factor of neuronal death activation and there is compelling evidence supporting antioxidants hold promise in abrogating seizure-related cell modality. Lapatinib, a well-known anti-cancer drug, has been traditionally reported to exert anti-tumor effect via modulating oxidative stress and a recent work illustrates the improvement of encephalomyelitis in rodent models after lapatinib treatment. However, whether lapatinib is beneficial for inhibiting neuronal death and epileptic seizure remains unknown. Here, we found that lapatinib remarkably prevented kainic acid (KA)-epileptic seizures in mice and ferroptosis, a newly defined cell death which is associated with oxidative stress, was involved in the neuroprotection of lapatinib. In the ferroptotic cell death model, lapatinib exerted neuroprotection via restoring glutathione peroxidase 4 (GPX4). Treatment with GPX4 inhibitor ras-selective lethal small molecule 3 (RSL3) abrogated its anti-ferroptotic potential. In a mouse model of KA-triggered seizure, it was also validated that lapatinib blocked GPX4-dependent ferroptosis. It is concluded that lapatinib has neuroprotective potential against epileptic seizures via suppressing GPX4-mediated ferroptosis.

Antioxidants Targeting Mitochondrial Oxidative Stress: Promising Neuroprotectants for Epilepsy.

Mitochondria are major sources of reactive oxygen species (ROS) within the cell and are especially vulnerable to oxidative stress. Oxidative damage to mitochondria results in disrupted mitochondrial function and cell death signaling, finally triggering diverse pathologies such as epilepsy, a common neurological disease characterized with aberrant electrical brain activity. Antioxidants are considered as promising neuroprotective strategies for epileptic condition via combating the deleterious effects of excessive ROS production in mitochondria. In this review, we provide a brief discussion of the role of mitochondrial oxidative stress in the pathophysiology of epilepsy and evidences that support neuroprotective roles of antioxidants targeting mitochondrial oxidative stress including mitochondria-targeted antioxidants, polyphenols, vitamins, thiols, and nuclear factor E2-related factor 2 (Nrf2) activators in epilepsy. We point out these antioxidative compounds as effectively protective approaches for improving prognosis. In addition, we specially propose that these antioxidants exert neuroprotection against epileptic impairment possibly by modulating cell death interactions, notably autophagy-apoptosis, and autophagy-ferroptosis crosstalk.

Lysyl oxidases: Emerging biomarkers and therapeutic targets for various diseases.

Therapeutic targeting of extracellular proteins has attracted huge attention in treating human diseases. The lysyl oxidases (LOXs) are a family of secreted copper-dependent enzymes which initiate the covalent crosslinking of collagen and elastin fibers in the extracellular microenvironment, thereby facilitating extracellular matrix (ECM) remodeling and ECM homeostasis. Apart from ECM-dependent roles, LOXs are also involved in other biological processes such as epithelial-to-mesenchymal transition (EMT) and transcriptional regulation, especially following hypoxic stress. Dysregulation of LOXs is found to underlie the onset and progression of multiple pathologies, such as carcinogenesis and cancer metastasis, fibrotic diseases, neurodegeneration and cardiovascular diseases. In this review, we make a comprehensive summarization of clinical and experimental evidences that support roles of for LOXs in disease pathology and points out LOXs as promising therapeutic targets for improving prognosis. Additionally, we also propose that LOXs reshape cell-ECM interaction or cell-cell interaction due to ECM-dependent and ECM-independent roles for LOXs. Therapeutic intervention of LOXs may have advantages in the maintenance of communication between ECM and cell or intercellular signaling, finally recovering organ function.

Vascular Endothelial Growth Factor (VEGF) as a Vital Target for Brain Inflammation during the COVID-19 Outbreak.

The coronavirus disease 19 (COVID-19) pandemic has brought a great threat to global public health. Currently, mounting evidence has shown the occurrence of neurological symptoms in patients with COVID-19. However, the detailed mechanism by which the SARS-CoV-2 attacks the brain is not well characterized. Recent investigations have revealed that a cytokine storm contributes to brain inflammation and subsequently triggers neurological manifestations during the COVID-19 outbreak. Targeting brain inflammation may provide significant clues to the treatment of neurologic complications caused by SARS-CoV-2. Vascular growth factor (VEGF), which is widely distributed in the brain, probably plays a crucial role in brain inflammation via facilitating the recruitment of inflammatory cells and regulating the level of angiopoietins II (Ang II). Also, Ang II is considered as the products of SARS-CoV-2-attacking target, angiotensin-converting enzyme 2 (ACE2). Further investigation of the therapeutic potential and the underlying mechanisms of VEGF-targeted drugs on the neurological signs of COVID-19 are warranted. In any case, VEGF is deemed a promising therapeutic target in suppressing inflammation during SARS-CoV-2 infection with neurological symptoms.

The Effect of HRE-Regulated VEGF Expression and Transfection on Neural Stem Cells in Rats.

In this study, we analyzed neural stem cells transfected with the HRE-VEGF gene in groups experiencing different periods of hypoxia. The results of RT-PCR showed that the expression of vascular endothelial growth factor (VEGF) mRNA gradually increased with the prolonged period of hypoxia (p < 0.05). The results from the western-blot test showed that expression of the VEGF protein increased with as the period of hypoxia increased (p < 0.05). The results of MTT combined with Elisa reagent showed that with the prolonged period of hypoxia, the secretion of VEGF protein increased, and that the proliferation of target cells and neural stem cells was better promoted (p < 0.05). These results imply that HRE can safely and effectively regulate VEGF expression. By controlling the period of hypoxia, we can increase the expression level, and limit it in more safe values to avoid the possibility of cancer caused by the over-enhancement of proliferation of target cells due to the overexpression of the VEGF protein.

Consensus in Identification and Stability of Symptom Clusters Using Different Symptom Dimensions in Newly Diagnosed Acute Myeloid Leukemia Patients Undergoing Induction Therapy.

CONTEXT: An unresolved issue in symptom cluster (SC) research is that the numbers and types of SCs vary based on the multiple dimensions of the experienced symptoms that are used for SC identification. OBJECTIVE: This study aimed to identify SCs using the ratings of occurrence, severity, and distress in newly diagnosed acute myeloid leukemia (AML) patients at three stages of their induction therapy (i.e., T1, T2, and T3). Then, we evaluated the consensus among the numbers and types of symptoms in each SC identified by multiple dimensions over time. METHOD: The Chinese version of the Memorial Symptom Assessment Scale was used to evaluate the occurrence, severity, and distress ratings of 32 symptoms in patients newly diagnosed with AML during their induction therapy. Exploratory factor analysis was used for SCs identification. RESULTS: Using the three dimensions in the AML patients (n = 126), four SCs were identified at T1 and T3 and three SCs were identified at T2. The number of symptoms in individual SCs varied over time, whereas the specific symptoms in SCs remained similar over time. The severity ratings fit the data better than did the ratings of occurrence and distress. CONCLUSION: These findings provided insights into the most common SCs in AML patients undergoing induction therapy by multidimensional evaluation and could lay the foundation for future targeted symptom interventions. Further studies are needed to explore the mechanisms of SCs in AML patients undergoing the chemotherapy.

TiN Films Deposited on Uranium by High Power Pulsed Magnetron Sputtering under Low Temperature.

Depleted uranium (DU) is oxidized readily due to its chemical activities, which limits its applications in nuclear industry. TiN film has been applied widely due to its good mechanical properties and its excellent corrosion resistance. In this work, TiN protection films were deposited on DU by direct current magnetron sputtering (DCMS) and high power pulsed magnetron sputtering (HPPMS), respectively. The surface morphology and microstructures were investigated by atomic force microscope (AFM), scanning electron microscopy (SEM), and grazing incidence X-ray diffraction (GIXRD). The hardness and Young's modulus were determined by nano-Indenter. The wear behavior and adhesion was analyzed by pin-on-disc tests and scratch adhesion tests and the corrosion resistance was evaluated by electrochemical measurements. The results show that the TiN films that were deposited by HPPMS outperformed TiN film deposited by DCMS, with improvements on surface roughness, mechanical properties, wear behavior, adhesion strength, and corrosion resistance, thanks to its much denser columnar grain growth structure and preferred orientation of (111) plane with the lowest strain energy. Besides, the process of Ti interlayer deposition by HPPMS can enhance the film properties to an extent as compared to DCMS, which is attributed to the enhanced ion bombardment during the HPPMS.

Secure Indoor Localization Based on Extracting Trusted Fingerprint.

[-5]Indoor localization based on WiFi has attracted a lot of research effort because of the widespread application of WiFi. Fingerprinting techniques have received much attention due to their simplicity and compatibility with existing hardware. However, existing fingerprinting localization algorithms may not resist abnormal received signal strength indication (RSSI), such as unexpected environmental changes, impaired access points (APs) or the introduction of new APs. Traditional fingerprinting algorithms do not consider the problem of new APs and impaired APs in the environment when using RSSI. In this paper, we propose a secure fingerprinting localization (SFL) method that is robust to variable environments, impaired APs and the introduction of new APs. In the offline phase, a voting mechanism and a fingerprint database update method are proposed. We use the mutual cooperation between reference anchor nodes to update the fingerprint database, which can reduce the interference caused by the user measurement data. We analyze the standard deviation of RSSI, mobilize the reference points in the database to vote on APs and then calculate the trust factors of APs based on the voting results. In the online phase, we first make a judgment about the new APs and the broken APs, then extract the secure fingerprints according to the trusted factors of APs and obtain the localization results by using the trusted fingerprints. In the experiment section, we demonstrate the proposed method and find that the proposed strategy can resist abnormal RSSI and can improve the localization accuracy effectively compared with the existing fingerprinting localization algorithms.

Induction of RIP-2 kinase by proinflammatory cytokines is mediated via NF-kappaB signaling pathways and involves a novel feed-forward regulatory mechanism.

The transcription factor NF-kappaB (nuclear factor kappaB) is a central mediator of inflammatory and apoptotic signaling in the cell. The protein kinase RIP-2 is a member of the CARD protein family (caspase activation and recruitment domain, also known as CARD3, Ripk2, CARDIAK, RICK, and CCK), and has been shown to be an activator of NF-kappaB. In this study, it was demonstrated by transcriptional profiling and protein expression analysis that the inflammatory cytokines TNF-alpha, IL-1 beta, and IFN-gamma induced RIP-2 transcription and translation in endothelial cells. Two mechanistically distinct inhibitors of NF-kappaB signaling, sulfasalazine (NF-kappaB inhibitor) and WY-14643 [PPAR alpha (peroxisome proliferator-activated receptor alpha) agonist] that interfere with the transcription factor RELA (p65), suppressed TNF-alpha induced RIP-2 gene expression, which indicated that NF-kappaB signaling was involved in the cytokine-induced transcriptional activation of RIP-2 gene expression. Consistent with these observations, multiple NF-kappaB response elements were found in the upstream regions of the human and mouse RIP-2 genes. NF-kappaB-mediated regulation of RIP-2 gene and protein expression suggests an additional step in the regulation of NF-kappaB function as RIP-2 has been shown to positively modulate NF-kappaB by binding IKK gamma (I kappaB kinase gamma), a component of the IKK complex. These findings support a positive feed-forward mechanism of NF-kappaB regulation that involves NF-kappaB-dependent induction of RIP-2 transcription and a subsequent increase in RIP-2 protein levels in response to inflammatory cytokines. Elevated RIP-2 protein levels are then available to promote NF-kappaB function via interaction with IKK gamma. RIP-2 is the first reported NF-kappaB-dependent protein kinase that positively regulates NF-kappaB activity.