Recent antitumor therapy does not increase Omicron COVID-19 severity in cancer patients: a two-center retrospective study in China.

Background: The impact of anticancer therapy and related clinical factors on the severity of COVID-19 in cancer patients during the Omicron pandemic has not been established. The recent outbreak in China caused predominantly by the BA.5.2 and BF.7 strains of Omicron provided us with the opportunity to observe objectively the impact of this strain in oncology patients. We initiated this two-center retrospective study in China to determine the impact of anti-cancer treatment, other clinical factors, and cancer characteristics on COVID-19 severity in cancer patients infected with coronavirus during the SARS-CoV-2 Omicron variant pandemic in China. Methods: We retrospectively included 554 cancer patients infected with COVID-19 from two medical centers. Data on their anticancer treatment prior to COVID-19 infection and general clinical characteristics (sex, age, past medical history, etc.) were collected. Univariate statistical analysis was performed to identify the factors associated with the severity of COVID-19. Results: Among 554 cancer patients infected with COVID-19, there were 15 (2.7%) severe/critical cases, 86 (15.5%) cases with medium severity, and 453 (81.8%) cases with mild severity. Univariate analysis revealed that advanced age, male sex, worse ECOG score, unvaccinated status, and previous liver, kidney, and brain diseases were associated with more severe COVID-19. However, recent antitumor therapy, including cytotoxic chemotherapy within two weeks did not have a significant correlation with the severity of COVID-19 caused by the Omicron variant. Conclusion: The severity of COVID-19 caused by the Omicron variant is not exacerbated by recent anticancer therapy in cancer patients. Therefore, anticancer therapy should not be discontinued in such cases, especially those with mild severity.

Alternative Perspective on Rapid Wine Oxidation through Changes in Gas-Phase Volatile Concentrations, Highlighted by Matrix Component Effects.

A new perspective is presented to investigate the sensorially relevant gas-phase concentrations of volatile compounds in wine. This is achieved by measuring the partition coefficients and matrix-phase concentrations of volatiles using static headspace-gas chromatography-ion mobility spectrometry. Physicochemical properties that can contribute to the partition behaviors of 10 volatile esters, such as hydrophobicity and matrix temperature, are also discussed. Partition coefficients are then linked to quantitative measurements to obtain partial pressures, which describe the availability of volatile compounds in the gas phase. The concept of partition coefficients and partial pressure has then been applied to a time series of aroma changes due to oxidation in commercial wines. As a follow-up study, a full factorial design was devised to inspect the impact of three common wine matrix components, namely, copper, polyphenols, and ascorbic acid, on the partial pressure changes after 30-day oxidation treatment in either full-alcohol or low-alcohol simulated wine matrices. Interesting interactive effects between antioxidant behaviors and alcohol levels were elucidated, especially around the controversial use of ascorbic acid in winemaking. These results can guide winemakers who wish to minimize oxidative damage to wine aroma during wine storage or bulk transport, where ullage may be present or continual oxygen ingress may be occurring.

Validation Study on the Simultaneous Quantitation of Multiple Wine Aroma Compounds with Static Headspace-Gas Chromatography-Ion Mobility Spectrometry.

A new quantitative method based on static headspace-gas chromatography-ion mobility spectrometry (SHS-GC-IMS) is proposed, which enables the simultaneous quantitation of multiple aroma compounds in wine. The method was first evaluated for its stability and the necessity of using internal standards as a quality control measure. The two major hurdles in applying GC-IMS in quantitation studies, namely, nonlinearity and multiple ion species, were also investigated using the Boltzmann function and generalized additive model (GAM) as potential solutions. Metrics characterizing the model performance, including root mean squared error, bias, limit of detection, limit of quantitation, repeatability, reproducibility, and recovery, were investigated. Both nonlinear fitting methods, Boltzmann function and GAM, were able to return desirable analytical outcomes with an acceptable range of error. Potential pitfalls that would cause inaccurate quantitation, that is, effects of ethanol content and competitive ionization, were also discussed. The performance of the SHS-GC-IMS method was subsequently compared against that of a currently established method, namely, GC-MS, using commercial wine samples. These findings provide an initial validation of a GC-IMS-based quantitation method, as well as a starting point for further enhancing the analytical scope of GC-IMS.

Volatile-Based Prediction of Sauvignon Blanc Quality Gradings with Static Headspace-Gas Chromatography-Ion Mobility Spectrometry (SHS-GC-IMS) and Interpretable Machine Learning Techniques.

The analytical scope of static headspace-gas chromatography-ion mobility spectrometry (SHS-GC-IMS) was applied to wine aroma analysis for the first time. The method parameters were first fine-tuned to achieve optimal analytical results, before the method stability was demonstrated, in terms of repeatability and reproducibility. Succinct qualitative identification of compounds was also realized, with the identification of several volatiles that have seldom been described previously in Sauvignon Blanc wine, such as methyl acetate, ethyl formate, and amyl acetate. Using the SHS-GC-IMS data in an untargeted approach, computer modeling of large datasets was applied to link aroma chemistry via prediction models to wine sensory quality gradings. Six machine learning models were compared, and artificial neural network (ANN) returned the most promising performance with a prediction accuracy of 95.4%. Despite its inherent complexity, the ANN model offered intriguing insights on the influential volatiles that correlated well with higher and lower sensory gradings. These findings could, in the future, guide winemakers in establishing wine quality, particularly during blending operations prior to bottling.

18F-fluorodeoxyglucose positron emission tomography predicts lymph node responses to definitive chemoradiotherapy in esophageal squamous cell carcinoma patients.

PURPOSE: To evaluate the capability of 18F-fluorodeoxyglucose positron emission tomography/ computed tomography (18F-FDG-PET/CT) to predict the clinical response of metastatic lymph node (mLN) to definitive chemoradiotherapy (dCRT) and guide personalized radiation dose in esophageal squamous cell carcinoma (ESCC) patients. PATIENTS AND METHODS: One hundred and forty-three mLNs from 59 patients with ESCC treated with dCRT and who had undergone a pretreatment 18F-FDG-PET/CT scan were included in the study. All defined mLNs were contoured by nuclear medicine radiologists. Response was evaluated by contrast-enhanced computed tomography and 18F-FDG-PET/CT. RESULTS: Sixty-nine mLNs showed complete response (CR), and 74 mLNs showed non-complete response. The 143 mLNs were divided into 4 groups (Groups 1-4) based on the quartiles of maximum standardized uptake value (SUVmax-G1, SUVmax-G2, SUVmax-G3, and SUVmax-G4) and metabolic tumor volume (MTV-G1, MTV-G2, MTV-G3, and MTV-G4). The CR rate of SUVmax-G2 was significantly higher than the other 3 groups. The escalated radiation dose improved the CR rate of lymph nodes in SUVmax-G3 (55 Gy) and SUVmax-G4 (61 Gy). The lowest CR rate was found in MTV-G4 (the group with the largest MTV). The escalated radiation dose (59.7 Gy) improved the CR rate of lymph node in MTV-Groups 3 and 4. CONCLUSION: Pretreatment metabolic parameters can predict the response of mLNs to dCRT for patients with ESCC. The parameters could also be used to guide personalized dose to mLNs.

A20 Ameliorates Intracerebral Hemorrhage-Induced Inflammatory Injury by Regulating TRAF6 Polyubiquitination.

Reducing excessive inflammation is beneficial for the recovery from intracerebral hemorrhage (ICH). Here, the roles and mechanisms of A20 (TNFAIP3), an important endogenous anti-inflammatory factor, are examined in ICH. A20 expression in the PBMCs of ICH patients and an ICH mouse model was detected, and the correlation between A20 expression and neurologic deficits was analyzed. A20 expression was increased in PBMCs and was negatively related to the modified Rankin Scale score. A20 expression was also increased in mouse perihematomal tissues. A20-/- and A20-overexpressing mice were generated to further analyze A20 function. Compared with wild-type (WT) mice, A20-/- and A20-overexpressing mice showed significant increases and decreases, respectively, in hematoma volume, neurologic deficit score, mortality, neuronal degeneration, and proinflammatory factors. Moreover, WT-A20-/- parabiosis was established to explore the role of A20 in peripheral blood in ICH injury. ICH-induced damage, including brain edema, neurologic deficit score, proinflammatory factors, and neuronal apoptosis, was reduced in A20-/- parabionts compared with A20-/- mice. Finally, the interactions between TRAF6 and Ubc13 and UbcH5c were increased in A20-/- mice compared with WT mice; the opposite occurred in A20-overexpressing mice. Enhanced IκBα degradation and NF-κB activation were observed in A20-/- mice, but the results were reversed in A20-overexpressing mice. These results suggested that A20 is involved in regulating ICH-induced inflammatory injury in both the central and peripheral system and that A20 reduces ICH-induced inflammation by regulating TRAF6 polyubiquitination. Targeting A20 may thus be a promising therapeutic strategy for ICH.

Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3ß/PTEN axis.

Inflammation mediated by the peripheral infiltration of inflammatory cells plays an important role in intracerebral hemorrhage (ICH) induced secondary injury. Previous studies have indicated that regulatory T lymphocytes (Tregs) might reduce ICH-induced inflammation, but the precise mechanisms that contribute to ICH-induced inflammatory injury remain unclear. Our results show that the number of Tregs in the brain increases after ICH. Inducing Tregs deletion using a CD25 antibody or Foxp3DTR-mice increased neurological deficient scores (NDS), the level of inflammatory factors, hematoma volumes, and neuronal degeneration. Meanwhile, boosting Tregs using a CD28 super-agonist antibody reduced the inflammatory injury. Furthermore, Tregs depletion shifted microglia/macrophage polarization toward the M1 phenotype while boosting Tregs shifted this transition toward the M2 phenotype. In vitro, a transwell co-culture model of microglia and Tregs indicated that Tregs changed the polarization of microglia, decreased the expression of MHC-II, IL-6, and TNF-α and increased CD206 expression. IL-10 originating from Tregs mediated the microglia polarization by increasing the expression of Glycogen Synthase Kinase 3 beta (GSK3ß), which phosphorylates and inactivates Phosphatase and Tensin homologue (PTEN) in microglia, TGF-ß did not participate in this conversion. Thus, Tregs ameliorated ICH-induced inflammatory injury by modulating microglia/macrophage polarization toward the M2 phenotype through the IL-10/GSK3ß/PTEN axis.

Interleukin-23 Secreted by Activated Macrophages Drives γδT Cell Production of Interleukin-17 to Aggravate Secondary Injury After Intracerebral Hemorrhage.

BACKGROUND: Neuroinflammation plays a key role in intracerebral hemorrhage (ICH)-induced secondary brain injury, but the specific roles of peripheral inflammatory cells such as macrophages and lymphocytes remain unknown. The purpose of this study was to explore the roles of macrophages, T lymphocytes, and the cytokines they secrete as potential targets for treating secondary brain injury after ICH. METHODS AND RESULTS: Our results showed that peripheral macrophages and T lymphocytes successively infiltrated the brain, with macrophage counts peaking 1 day after ICH and T-lymphocyte counts peaking after 4 days. These peaks in cellular infiltration corresponded to increases in interleukin (IL)-23 and IL-17 expression, respectively. We found that hemoglobin from the hematoma activated IL-23 secretion by infiltrating macrophages by inducing the formation of toll-like receptor (TLR) 2/4 heterodimer. This increased IL-23 expression stimulated γδT-cell production of IL-17, which increased brain edema and neurologic deficits in the model mice as a proinflammatory factor. Finally, we found that sparstolonin B (SsnB) could ameliorate brain edema and neurologic deficits in ICH model mice via inhibition of TLR2/TLR4 heterodimer formation, and notably, SsnB interacted with myeloid differentiation factor 88 Arg196. CONCLUSIONS: Together, our results reveal the importance of the IL-23/IL-17 inflammatory axis in secondary brain injury after ICH and thus provide a new therapeutic target for ICH treatment.

Toll-Like Receptor 4/MyD88-Mediated Signaling of Hepcidin Expression Causing Brain Iron Accumulation, Oxidative Injury, and Cognitive Impairment After Intracerebral Hemorrhage.

BACKGROUND: Disturbance of brain iron metabolism after intracerebral hemorrhage (ICH) results in oxidative brain injury and cognition impairment. Hepcidin plays an important role in regulating iron metabolism, and we have reported that serum hepcidin is positively correlated with poor outcomes in patients with ICH. However, the roles of hepcidin in brain iron metabolism after ICH remain largely unknown. METHODS: Parabiosis and ICH models combined with in vivo and in vitro experiments were used to investigate the roles of hepcidin in brain iron metabolism after ICH. RESULTS: Increased hepcidin-25 was found in serum and primarily in astrocytes after ICH. The brain iron efflux, oxidative brain injury, and cognition impairment were improved in Hepc-/- ICH mice but aggravated by the human hepcidin-25 peptide in C57BL/6 ICH mice. Data obtained in in vitro studies showed that increased hepcidin inhibited the intracellular iron efflux of brain microvascular endothelial cells but was rescued by a hepcidin antagonist, fursultiamine. Using parabiosis ICH models also shows that increased serum hepcidin prevents brain iron efflux. In addition, Toll-like receptor 4 (TLR4)/MyD88 signaling pathway increased hepcidin expression by promoting interleukin-6 expression and signal transducer and activator of transcription 3 phosphorylation. TLR4-/- and MyD88-/- mice exhibited improvement in brain iron efflux at 7, 14, and 28 days after ICH, and the TLR4 antagonist (6R)-6-[N-(2-chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate significantly decreased brain iron levels at days 14 and 28 after ICH and improved cognition impairment at day 28. CONCLUSIONS: The results presented here show that increased hepcidin expression caused by inflammation prevents brain iron efflux via inhibition of the intracellular iron efflux of brain microvascular endothelial cells entering into circulation and aggravating oxidative brain injury and cognition impairment, which identifies a mechanistic target for muting inflammation to promote brain iron efflux and to attenuate oxidative brain injury after ICH.

Association of CYP2C19 Polymorphisms with the Clinical Efficacy of Clopidogrel Therapy in Patients Undergoing Carotid Artery Stenting in Asia.

The CYP2C19 gene plays a detrimental role in the metabolism of clopidogrel. This study aimed to investigate the association between CYP2C19 polymorphisms and the clinical efficacy of clopidogrel therapy in patients who have undergone carotid artery stenting (CAS). CYP2C19 genotype screening was performed on 959 ischemic stroke patients. Of these patients, 241 who had undergone CAS were enrolled in the study. They were all followed up for 1 year after stent surgery, and the primary clinical end-points were ischemic events. The frequencies of the CYP2C19*2 and *3 alleles among the 959 patients were 31.80% and 5.06%, respectively. Regarding the 241 participants who had undergone CAS, multivariate Cox regression analysis showed that the CYP2C19 loss-of-function (LOF) alleles (*2 and *3) were risk factors for post-CAS prognosis. Within 1 year of follow-up, the patients carrying the CYP2C19 LOF alleles were more likely to experience ischemic events than those carrying none. The occurrence of ischemic events did not significantly differ between the *2 and *3 allele carriers. Our results suggest that CYP2C19 LOF alleles (*2 and *3) significantly impact the prognosis of patients on clopidogrel therapy after CAS and that the CYP2C19*2 and CYP2C19*3 alleles have the same effects on prognosis.

Serum hepcidin concentrations correlate with serum iron level and outcome in patients with intracerebral hemorrhage.

Iron plays a detrimental role in the intracerebral hemorrhage (ICH)-induced brain damage, while hepcidin is the most important iron-regulated hormone. Here, we investigate the association between serum hepcidin and serum iron, outcome in patients with ICH. Serum samples of 81 cases with ICH were obtained on consecutive days to detect the levels of hepcidin, iron, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The National Institutes of Health Stroke Scale score (NIHSS) was measured at admission and on days 7 and 30, and the modified Rankin Scale (mRS) score was evaluated at 3 months after ICH. Additionally, the correlations of serum hepcidin with serum iron and the mRS score were analyzed by a generalized linear model. Higher serum hepcidin levels were detected in patients with poor outcomes (P < 0.001), and the mRS score increased by a mean of 1.135 points (95% CI 1.021-1.247, P < 0.001) for every serum hepcidin quartile after adjusting for other prognostic variables. Pearson correlation analysis showed that serum hepcidin was negatively correlated with serum iron (r = -0.5301, P < 0.001), and a significantly lower concentration of serum iron was found in patients with poor outcomes (P = 0.007). Additionally, serum hepcidin was independently correlated with mRS scores of ICH patients (OR 1.115, 95% CI 0.995-1.249, P = 0.021). Our results suggest that serum hepcidin is closely related to the outcome of patients with ICH and may be a biological marker for outcome prediction.