The incidence and risk of cardiovascular events associated with immune checkpoint inhibitors in Asian populations.

OBJECTIVES: Immune checkpoint inhibitors are associated with adverse cardiovascular events. However, there are no data characterizing cardiovascular events among Asians on immune checkpoint inhibitors. We aim to determine the incidence and risk of cardiac events associated with immune checkpoint inhibitors in an Asian population. METHODS: We performed a retrospective, propensity score-matched cohort study at two tertiary referral centers in Taiwan. Immune checkpoint inhibitor users were matched with non-immune checkpoint inhibitor users based on predetermined clinical variables. The primary outcome was major adverse cardiovascular events, defined as a composite of myocardial infarction, ischemic stroke, acute peripheral occlusive disease, pulmonary embolism, deep venous thrombosis, heart failure, pericardial disease, myocarditis, cardiac arrhythmias and conduction block. RESULTS: Between January 2010 and November 2021, 868 immune checkpoint inhibitor users were matched 1:1 with non-immune checkpoint inhibitor users. Among immune checkpoint inhibitor users, 67 (7.7%) patients developed major adverse cardiovascular events. During a median follow-up period of 188 days, the incidence rate of major adverse cardiovascular events for immune checkpoint inhibitor and non-immune checkpoint inhibitor users was 94.8 and 46.2 per 1000 patient-years, respectively, resulting in an incidence rate ratio of 2.1 [95% confidence interval: 1.5-2.9]. In multivariate Cox proportional hazard models, immune checkpoint inhibitor users had a 60% increased risk for major adverse cardiovascular events [hazard ratio, 1.6 (95% confidence interval: 1.1-2.3)]. Immune checkpoint inhibitors use was independently associated with increased risk of ischemic stroke [hazard ratio, 3.0 (95% confidence interval: 1.0-9.0)] and pulmonary embolism [hazard ratio, 5.5 (95% confidence interval: 1.4-21.3)]. In multivariate logistic regression analysis, age > 65, metastatic disease, hypertension and baseline platelet-to-lymphocyte ratio < 180 were risk factors for major adverse cardiovascular events. CONCLUSIONS: Among Asians, immune checkpoint inhibitors were associated with an increased risk of major adverse cardiovascular events, particularly ischemic stroke and pulmonary embolism.

A Genome-Centric Approach Reveals a Novel Glycosyltransferase from the GA A07 Strain of Bacillus thuringiensis Responsible for Catalyzing 15-O-Glycosylation of Ganoderic Acid A.

Strain GA A07 was identified as an intestinal Bacillus bacterium of zebrafish, which has high efficiency to biotransform the triterpenoid, ganoderic acid A (GAA), into GAA-15-O-ß-glucoside. To date, only two known enzymes (BsUGT398 and BsUGT489) of Bacillus subtilis ATCC 6633 strain can biotransform GAA. It is thus worthwhile to identify the responsible genes of strain GA A07 by whole genome sequencing. A complete genome of strain GA A07 was successfully assembled. A phylogenomic analysis revealed the species of the GA A07 strain to be Bacillus thuringiensis. Forty glycosyltransferase (GT) family genes were identified from the complete genome, among which three genes (FQZ25_16345, FQZ25_19840, and FQZ25_19010) were closely related to BsUGT398 and BsUGT489. Two of the three candidate genes, FQZ25_16345 and FQZ25_19010, were successfully cloned and expressed in a soluble form in Escherichia coli, and the corresponding proteins, BtGT_16345 and BtGT_19010, were purified for a biotransformation activity assay. An ultra-performance liquid chromatographic analysis further confirmed that only the purified BtGT_16345 had the key biotransformation activity of catalyzing GAA into GAA-15-O-ß-glucoside. The suitable conditions for this enzyme activity were pH 7.5, 10 mM of magnesium ions, and 30 °C. In addition, BtGT_16345 showed glycosylation activity toward seven flavonoids (apigenein, quercetein, naringenein, resveratrol, genistein, daidzein, and 8-hydroxydaidzein) and two triterpenoids (GAA and antcin K). A kinetic study showed that the catalytic efficiency (kcat/KM) of BtGT_16345 was not significantly different compared with either BsUGT398 or BsUGT489. In short, this study identified BtGT_16345 from B. thuringiensis GA A07 is the catalytic enzyme responsible for the 15-O-glycosylation of GAA and it was also regioselective toward triterpenoid substrates.

New Triterpenoid from Novel Triterpenoid 15-O-Glycosylation on Ganoderic Acid A by Intestinal Bacteria of Zebrafish.

Functional bacteria that could biotransform triterpenoids may exist in the diverse microflora of fish intestines. Ganoderic acid A (GAA) is a major triterpenoid from the medicinal fungus Ganoderma lucidum. In studying the microbial biotransformation of GAA, dozens of intestinal bacteria were isolated from the excreta of zebrafish. The bacteria's ability to catalyze GAA were determined using ultra-performance liquid chromatography analysis. One positive strain, GA A07, was selected for functional studies. GA A07 was confirmed as Bacillus sp., based on the DNA sequences of the 16S rRNA gene. The biotransformed metabolite was purified with the preparative high-performance liquid chromatography method and identified as GAA-15-O-ß-glucoside, based on the mass and nuclear magnetic resonance spectral data. The present study is the first to report the glycosylation of Ganoderma triterpenoids. Moreover, 15-O-glycosylation is a new microbial biotransformation of triterpenoids, and the biotransformed metabolite, GAA-15-O-ß-glucoside, is a new compound.

Magnetic impurity in a triple-component semimetal.

We investigate the effects of a magnetic impurity in a multiband touching fermion system, specifically, a triple-component semimetal with a flat band, which can be realized in a family of transition metal silicides (CoSi family). When the chemical potential coincides with the flat band, it is expected that the impurity response of this system will be very different from that of an ordinary Dirac or Weyl semimetal of which the density of states at the Fermi level vanishes. We first determine the phase diagram within the mean-field approximation. Then, we study the local moment regime by employing two different methods. In the low temperature regime, the Kondo screening is analyzed by the variational wavefunction approach and the impurity contributions to the magnetic susceptibility and heat capacity are obtained, while at higher temperature, we use the equation of motion approach to calculate the occupation number of the impurity site and the impurity magnetic susceptibility. The results are compared and contrasted with those in the usual Fermi liquid and the Dirac/Weyl semimetals.

Characterization of hepatitis C virus core protein multimerization and membrane envelopment: revelation of a cascade of core-membrane interactions.

The molecular basis underlying hepatitis C virus (HCV) core protein maturation and morphogenesis remains elusive. We characterized the concerted events associated with core protein multimerization and interaction with membranes. Analyses of core proteins expressed from a subgenomic system showed that the signal sequence located between the core and envelope glycoprotein E1 is critical for core association with endoplasmic reticula (ER)/late endosomes and the core's envelopment by membranes, which was judged by the core's acquisition of resistance to proteinase K digestion. Despite exerting an inhibitory effect on the core's association with membranes, (Z-LL)(2)-ketone, a specific inhibitor of signal peptide peptidase (SPP), did not affect core multimeric complex formation, suggesting that oligomeric core complex formation proceeds prior to or upon core attachment to membranes. Protease-resistant core complexes that contained both innate and processed proteins were detected in the presence of (Z-LL)(2)-ketone, implying that core envelopment occurs after intramembrane cleavage. Mutations of the core that prevent signal peptide cleavage or coexpression with an SPP loss-of-function D219A mutant decreased the core's envelopment, demonstrating that SPP-mediated cleavage is required for core envelopment. Analyses of core mutants with a deletion in domain I revealed that this domain contains sequences crucial for core envelopment. The core proteins expressed by infectious JFH1 and Jc1 RNAs in Huh7 cells also assembled into a multimeric complex, associated with ER/late-endosomal membranes, and were enveloped by membranes. Treatment with (Z-LL)(2)-ketone or coexpression with D219A mutant SPP interfered with both core envelopment and infectious HCV production, indicating a critical role of core envelopment in HCV morphogenesis. The results provide mechanistic insights into the sequential and coordinated processes during the association of the HCV core protein with membranes in the early phase of virus maturation and morphogenesis.

Functional Near-Infrared Spectroscopy and Its Clinical Application in the Field of Neuroscience: Advances and Future Directions.

Similar to functional magnetic resonance imaging (fMRI), functional near-infrared spectroscopy (fNIRS) detects the changes of hemoglobin species inside the brain, but via differences in optical absorption. Within the near-infrared spectrum, light can penetrate biological tissues and be absorbed by chromophores, such as oxyhemoglobin and deoxyhemoglobin. What makes fNIRS more advantageous is its portability and potential for long-term monitoring. This paper reviews the basic mechanisms of fNIRS and its current clinical applications, the limitations toward more widespread clinical usage of fNIRS, and current efforts to improve the temporal and spatial resolution of fNIRS toward robust clinical usage within subjects. Oligochannel fNIRS is adequate for estimating global cerebral function and it has become an important tool in the critical care setting for evaluating cerebral oxygenation and autoregulation in patients with stroke and traumatic brain injury. When it comes to a more sophisticated utilization, spatial and temporal resolution becomes critical. Multichannel NIRS has improved the spatial resolution of fNIRS for brain mapping in certain task modalities, such as language mapping. However, averaging and group analysis are currently required, limiting its clinical use for monitoring and real-time event detection in individual subjects. Advances in signal processing have moved fNIRS toward individual clinical use for detecting certain types of seizures, assessing autonomic function and cortical spreading depression. However, its lack of accuracy and precision has been the major obstacle toward more sophisticated clinical use of fNIRS. The use of high-density whole head optode arrays, precise sensor locations relative to the head, anatomical co-registration, short-distance channels, and multi-dimensional signal processing can be combined to improve the sensitivity of fNIRS and increase its use as a wide-spread clinical tool for the robust assessment of brain function.

Examining the Utility of Resective Epilepsy Surgery in Children With Electrical Status Epilepticus in Sleep: Long Term Clinical and Electrophysiological Outcomes.

Background: Electrical Status Epilepticus in Sleep (ESES) is an epileptic encephalopathy syndrome characterized by infrequent clinical seizures and prominent interictal burden during slow wave sleep associated with cognitive deficits and behavioral dysfunction. Medical treatment with anti-epileptic drugs is often unsuccessful. Resective surgery may be a valuable option in carefully selected patients. This case series aims to describe the indications, long term results and utility of resective surgery for ESES. Methods: Information on 14 patients who underwent surgery for epilepsy and ESES at the Children's Hospital of Wisconsin between 2007 and 2017 is included. Clinical, electrographic and neuropsychological features and outcomes are described in detail. Results: The most common pathology was encephalomalacia due to perinatal middle cerebral artery stoke (5/14). Twelve patients had imaging findings of perinatal pathologies; however, two patients had normal magnetic resonance imaging. Surgery was performed to control refractory epilepsy in eight patients. Six patients had no clinical seizures for 1-6 years prior to surgery, one of which had no known clinical seizures at all. All showed cognitive declines (6/14) or impairment (8/14) on neuropsychological assessments, and surgery was suggested to minimize further cognitive declines. The most common surgical procedure was hemispherotomy (10/14). Temporo-parieto-occipital disconnection, frontal lobectomy, parieto-occipital resection, and limited corticectomy were also used, with good outcomes for the first three procedures. Clinical follow up mean was 4.4 years and 12 patients had excellent seizure outcome. Electroencephalography (EEG) follow up mean was 3 years and ESES resolved in 12/14 patients. All patients completed post-surgical neuropsychological evaluation with mean follow-up of 17.46 months. Conclusions: Resective surgery is an effective treatment for selected cases of ESES, producing long term seizure freedom, resolution of ESES and stabilization of cognitive and behavioral functioning in most patients. Our case series is the largest single center cohort description addressing resective surgery for ESES. Outcomes in this sample suggest that good long-term seizure, EEG and cognitive/behavioral outcomes can be achieved in patients with normal brain imaging and in limited lobar or multi-lobar resections. Moreover, patients with ESES and very infrequent clinical seizures can benefit from surgery with stabilization of cognitive and behavioral functioning.

Characterization and comparability of stress-induced oxidation and deamidation on vulnerable sites of etanercept products.

An etanercept biosimilar, TuNEX(®), was compared to the innovator drug, Enbrel(®), for its reaction to stress-induced oxidation and deamidation, which may affect drug efficacy. A tryptic peptide map of both etanercept products was generated by liquid chromatography (LC) using mass spectrometry (MS) and ultraviolet (UV) spectrophotometry detection methods. The sequence of each modified or non-modified peptide peak was assigned based on accurate measurement of the mass of the protein and analysis utilizing tandem MS. Similar profiles of intrinsic oxidation on methionine (M) and deamidation on asparagine (N) were obtained for the two products, regardless of a two-amino acid (AA) residue variance in the heavy chain (Fc) between them. The level of oxidative stress exerted by tert-butyl hydroperoxide (tBHP), and alkaline stress exerted by a pH 10.4 solution, was examined using an LC-UV method. The results indicated that TuNEX(®) demonstrated a similar stress-induced modification profile compared to that of Enbrel(®). For both products, oxidative stress increased the oxidation from an intrinsically low (0-6.9%) to moderate or high (42-100%) level for almost all M residues (M30, M174, M187, M223, M272, and M448); alkaline stress increased the deamidation level of N404 from a low (0.0 or 1.7%) to moderate (19-26%) level. Based the results of a cell-based bioactivity assay, TuNEX(®) also exhibited a similar level of bioactivity as Enbrel(®) in unstressed, oxidative-stressed, or alkaline-stressed conditions. The bioactivity of both products remained unaltered by oxidative stress but was reduced by alkali stress. In conclusion, our data indicated that TuNEX(®) exhibits a similar chemical stress profile as that of Enbrel(®) in terms of oxidation and deamidation as well as bioactivity.