Weyl semimetals provide the realization of Weyl fermions in solid-state physics. Among all the physical phenomena that are enabled by Weyl semimetals, the chiral anomaly is the most unusual one. ...Here, we report signatures of the chiral anomaly in the magneto-transport measurements on the first Weyl semimetal TaAs. We show negative magnetoresistance under parallel electric and magnetic fields, that is, unlike most metals whose resistivity increases under an external magnetic field, we observe that our high mobility TaAs samples become more conductive as a magnetic field is applied along the direction of the current for certain ranges of the field strength. We present systematically detailed data and careful analyses, which allow us to exclude other possible origins of the observed negative magnetoresistance. Our transport data, corroborated by photoemission measurements, first-principles calculations and theoretical analyses, collectively demonstrate signatures of the Weyl fermion chiral anomaly in the magneto-transport of TaAs.
Gemcitabine (GEM) resistance in pancreatic adenocarcinoma mediated by the receptor for advanced glycation end products (RAGE) has been demonstrated. Therefore, investigating the safety and the ...potential of new auxiliary methods for pancreatic cancer treatment is urgent. Ursolic acid (UA), a natural pentacyclic triterpenoid found in apple peels, rosemary, and thyme, has been reported to have anticancer capacity. This study aimed to reveal the underlying mechanisms of UA in cell death and drug enhancement, especially in GEM‐resistant pancreatic cancer cells. First, GEM‐resistant cells (MIA Paca‐2GEMR cells) were established by incrementally increasing GEM culture concentrations. UA treatment reduced cell viability through cell cycle arrest and endoplasmic reticulum (ER) stress, resulting in apoptosis and autophagy in a dose‐dependent manner in MIA Paca‐2 and MIA Paca‐2GEMR cells. High RAGE expression in MIA Paca‐2GEMR cells was suppressed by UA treatment. Interestingly, knocking down RAGE expression showed similar UA‐induced effects in both cell lines. Remarkably, UA had a drug‐enhancing effect by decreasing cell viability and increasing cell cytotoxicity when combined with GEM treatment. In conclusions, UA triggered ER stress, subsequently regulating apoptosis‐ and autophagy‐related pathways and increasing GEM chemosensitivity in pancreatic cancer cells by inhibiting the expression of RAGE.
In this study, we aimed to develop a multifunctional drug/gene delivery system for the treatment of glioblastoma multiforme by combining the ligand-mediated active targeting and the pH-triggered drug ...release features of graphene oxide (GO). Toward this end, we load irinotecan (CPT-11) to cetuximab (CET)-conjugated GO (GO-CET/CPT11) for pH-responsive drug release after endocytosis by epidermal growth factor receptor (EGFR) over-expressed U87 human glioblastoma cells. The ultimate injectable drug/gene delivery system was designed by co-entrapping stomatin-like protein 2 (SLP2) short hairpin RNA (shRNA) and GO-CET/CPT11 in thermosensitive chitosan-
-poly(
-isopropylacrylamide) (CPN) polymer solution, which offers a hydrogel depot for localized, sustained delivery of the therapeutics after the in situ formation of CPN@GO-CET/CPT11@shRNA hydrogel. An optimal drug formulation was achieved by considering both the loading efficiency and loading content of CPT-11 on GO-CET. A sustained and controlled release behavior was found for CPT-11 and shRNA from CPN hydrogel. Confocal microscopy analysis confirmed the intracellular trafficking for the targeted delivery of CPT-11 through interactions of CET with EGFR on the U87 cell surface. The efficient transfection of U87 using SLP2 shRNA was achieved using CPN as a delivery milieu, possibly by the formation of shRNA/CPN polyplex after hydrogel degradation. In vitro cell culture experiments confirmed cell apoptosis induced by CPT-11 released from acid organelles in the cytoplasm by flow cytometry, as well as reduced SLP2 protein expression and inhibited cell migration due to gene silencing. Finally, in vivo therapeutic efficacy was demonstrated using the xenograft of U87 tumor-bearing nude mice through non-invasive intratumoral delivery of CPN@GO-CET/CPT11@shRNA by injection. Overall, we have demonstrated the novelty of this thermosensitive hydrogel to be an excellent depot for the co-delivery of anticancer drugs and siRNA. The in situ forming hydrogel will not only provide extended drug release but also combine the advantages offered by the chitosan-based copolymer structure for siRNA delivery to broaden treatment modalities in cancer therapy.
In recent years, glycative stress from exogenous or endogenous advanced glycation end products (AGEs) and highly reactive dicarbonyls has gained great attention for its putative effects on cancer ...development. AGEs are a group of compounds formed from the complex chemical reaction of reducing sugars with compounds containing an amino group. AGEs bind to and activate the receptor for AGEs (RAGE), which is a predominant modulator of inflammation‐associated cancer, and AGEs induce reactive oxygen species that are an important regulator of the hallmarks of cancer. Dicarbonyls, which are formed during glycolysis, lipid oxidation, or protein degradation, include glyoxal, methylglyoxal, and 3‐deoxyglucosone and are regarded as major precursors of AGEs. These dicarbonyls not only fuel the AGE pool in living organisms but also evoke carbonyl stress, which may contribute to the carbonylative damage of carbohydrates, lipids, proteins, or DNA. Carbonylative damage then leads to many lesions, some of which are implicated in the pathogenesis of cancer. In this review, studies regarding the effects of AGEs and dicarbonyls on cancer onset or progression are systematically discussed, and the utilization of AGE inhibitors and dicarbonyl scavengers in cancer therapy are noted.
The scheme of AGEs, dicarbonyls, ROS, and inflammation in cancer onset and progression. Exogenous and endogenous AGEs/dicarbonyls induce bursts of ROS and create a chronic inflammatory state. In such conditions, AGEs, dicarbonyls, ROS and pro‐inflammatory mediators interact in a positive feedback loop, leading to cancer onset or the enhancement of cancer progression.
Pelvic radiograph (PXR) is essential for detecting proximal femur and pelvis injuries in trauma patients, which is also the key component for trauma survey. None of the currently available algorithms ...can accurately detect all kinds of trauma-related radiographic findings on PXRs. Here, we show a universal algorithm can detect most types of trauma-related radiographic findings on PXRs. We develop a multiscale deep learning algorithm called PelviXNet trained with 5204 PXRs with weakly supervised point annotation. PelviXNet yields an area under the receiver operating characteristic curve (AUROC) of 0.973 (95% CI, 0.960-0.983) and an area under the precision-recall curve (AUPRC) of 0.963 (95% CI, 0.948-0.974) in the clinical population test set of 1888 PXRs. The accuracy, sensitivity, and specificity at the cutoff value are 0.924 (95% CI, 0.912-0.936), 0.908 (95% CI, 0.885-0.908), and 0.932 (95% CI, 0.919-0.946), respectively. PelviXNet demonstrates comparable performance with radiologists and orthopedics in detecting pelvic and hip fractures.
Athletes often take sport supplements to reduce fatigue and immune disturbances during or after training. This study evaluated the acute effects of concurrent ingestion of alkaline water and ...L-glutamine on the salivary immunity and hormone responses of boxers after training. Twelve male boxing athletes were recruited in this study. During regular training, the participants were randomly divided into three groups and asked to consume 400 mL of alkaline water (Group A), 0.15 g/kg body weight of L-glutamine with 400 mL of water (Group G), and 0.15 g/kg of L-glutamine with 400 mL of alkaline water (Group A+G) at the same time each day for three consecutive weeks. Before and immediately after the training, saliva, heart rates, and the rate of perceived exertion were investigated. The activity of α-amylase and concentrations of lactoferrin, immunoglobulin A (IgA), testosterone, and cortisol in saliva were measured. The results showed that the ratio of α-amylase activity/total protein (TP) significantly increased after training in Group A+G but not in Group A or G, whereas the ratios of lactoferrin/TP and IgA/TP were unaffected in all three groups. The concentrations of salivary testosterone after training increased significantly in Group A+G but not in Group A or G, whereas the salivary cortisol concentrations were unaltered in all groups. In conclusion, concurrent ingestion of 400 mL of alkaline water and 0.15 g/kg of L-glutamine before training enhanced the salivary α-amylase activity and testosterone concentration of boxers, which would be beneficial for post-exercise recovery.
Helicobacter pylori infection is associated with chronic gastritis, peptic ulcers, and gastric cancer. The flavonoid compounds baicalin and baicalein found in many medicinal plants exhibit an ...anti‐inflammatory effect. The administration of Lactobacillus strains reducing the risk of H. pylori infection is well accepted. In this study, the therapeutic effects against H. pylori infection of baicalin, baicalein, and L. rhamnosus JB3 (LR‐JB3), isolated from a dairy product, were investigated. Compared to baicalin, baicalein exhibited stronger anti‐H. pylori activity and cytotoxicity on human gastric cancer epithelial AGS cells. Baicalin and baicalein both suppressed the vacA gene expression of H. pylori and interfered with the adhesion and invasion ability of H. pylori to AGS cells, as well as decreased H. pylori‐induced interleukin (IL)‐8 expression. In the mice infection model, high dosages of baicalin and baicalein inhibited H. pylori growth in the mice stomachs. Serum IL‐1β levels and H. pylori‐specific serum IgM and IgA levels in mice treated with baicalin and baicalein were decreased. Moreover, a synergistic therapeutic effect of baicalein and LR‐JB3 on eradicating H. pylori infections was observed. Thus, administrating baicalin, baicalein, or LR‐JB3 for an H. pylori infection could offer similar therapeutic effects to administering antibiotics while not disturbing the balance of gut microbiota. This study revealed the effects of baicalin, baicalein, and LR‐JB3 on attenuating the virulence of H. pylori. The synergistic effect with baicalein and LR‐JB3 provides the experimental rationale for testing the reliability, safety, and efficacy of this approach in higher animals and perhaps ultimately in humans to eradicate H. pylori infections.
Practical Application
Baicalin and baicalein exert health promotion and avoidance of H. pylori infections by interfering with H. pylori growth and virulence. Lactobacillus rhamnosus JB3 was used to reduce the gastric inflammation caused by H. pylori infection.
What is known and objective
Gut microbiota plays an important role in shaping immune responses. Several studies have reported that antibiotics may alter gut microbiota diversity and compromise the ...therapeutic response to immune checkpoint inhibitors (ICIs). Nevertheless, the impact of a specific class of antibiotics on ICIs therapy is still not known. The aim of this study was to analyse the influence of antibiotics on the clinical outcomes of non‐small cell lung cancer (NSCLC) patients treated with ICIs and to compare the effects of fluoroquinolones vs. other broad‐spectrum antibiotics.
Methods
This retrospective cohort study (n = 340) analysed data from Chang Gung Research Database, which comprises work from seven medical institutions in Taiwan. Patients with NSCLC who received ICIs between January 2016 and March 2019 were evaluated. The data of patients who received antibiotics (ie fluoroquinolone) within 30 days prior to ICIs therapy were analysed. Overall survival (OS) was the goal of our study and was calculated from the time the ICIs therapy start. Survival analysis was estimated using the Kaplan‐Meier and Cox statistics.
Results
A total of 340 patients were identified for analysis. Of the 340 patients, only over one third (38%) of patients received antibiotics 30 days prior to ICI therapy. These patients exhibited a shorter OS compared with those not receiving antibiotics (median OS, 266 days vs. 455 days; hazard ratio (HR), 2.9; 95% confidence interval (CI), 1.1–8.1, p = 0.003). In this study, 127 out of 128 patients who were exposed to antibiotics had received at least one broad‐spectrum antibiotic. We observed patients who had received fluoroquinolone had a shorter OS compared with those receiving other broad‐spectrum antibiotics (median OS, 121 days vs. 370 days; HR, 1.582; 95% CI 1.007–2.841; p = 0.047).
What is new and conclusion
Antibiotic treatment, especially fluoroquinolone, prior to ICIs therapy was associated with poorer clinical efficacy in NSCLC patients. Antibiotics should not be withheld when there is a clear need for them despite the possibility of interfering with the microbiome, which may, in turn, adversely affect the ICI’s effectiveness. However, one should consider avoiding the use of fluoroquinolones antibiotics.
Antibiotics may alter gut microbiota diversity and compromise the therapeutic response to immune checkpoint inhibitors (ICIs). Compared to other broad‐spectrum antibiotics, fluoroquinolone prior to ICIs therapy was associated with the worst clinical efficacy in NSCLC patients.
Abstract
Background
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron variant, designated as a variant of concern by the World Health Organization, carries numerous spike ...mutations that are known to evade neutralizing antibodies elicited by coronavirus disease 2019 (COVID-19) vaccines. A deeper understanding of the susceptibility of omicron variant to vaccine-induced neutralizing antibodies is urgently needed for risk assessment.
Methods
Omicron variant strains HKU691 and HKU344-R346K were isolated from patients using TMPRSS2-overexpressing VeroE6 cells. Whole genome sequence was determined using nanopore sequencing. Neutralization susceptibility of ancestral lineage A virus and the omicron, delta and beta variants to sera from 25 BNT162b2 and 25 CoronaVac vaccine recipients was determined using a live virus microneutralization assay.
Results
The omicron variant strain HKU344-R346K has an additional spike R346K mutation, which is present in 8.5% of strains deposited in the GISAID database. Only 20% and 24% of BNT162b2 recipients had detectable neutralizing antibody against the omicron variant HKU691 and HKU344-R346K, respectively, whereas none of the CoronaVac recipients had detectable neutralizing antibody titer against either omicron isolate. For BNT162b2 recipients, the geometric mean neutralization antibody titers (GMTs) of the omicron variant isolates (5.43 and 6.42) were 35.7–39.9-fold lower than that of the ancestral virus (229.4), and the GMTs of both omicron variant isolates were significantly lower than those of the beta and delta variants. There was no significant difference in the GMTs between HKU691 and HKU344-R346K.
Conclusions
Omicron variant escapes neutralizing antibodies elicited by BNT162b2 or CoronaVac. The additional R346K mutation did not affect the neutralization susceptibility. Our data suggest that the omicron variant may be associated with lower COVID-19 vaccine effectiveness.
Immune sera from BNT162b2 and Coronavac recipients had substantially reduced neutralizing antibody titers against the omicron variant. There was no statistically significant difference between the geometric mean neutralization titers against omicron variant strains with or without spike R346K mutation.
Detecting the spectroscopic signatures of relativistic quasiparticles in emergent topological materials is crucial for searching their potential applications. Magnetometry is a powerful tool for ...fathoming electrons in solids, by which a clear method for discerning relativistic quasiparticles has not yet been established. Adopting the probes of magnetic torque and parallel magnetization for the archetype Weyl semimetal TaAs in strong magnetic field, we observed a quasi-linear field dependent effective transverse magnetization and a non-saturating parallel magnetization when the system enters the quantum limit. Distinct from the saturating magnetic responses for non-relativistic quasiparticles, the non-saturating signals of TaAs in strong field is consistent with our newly developed magnetization calculation for a Weyl fermion system in an arbitrary angle. Our results establish a high-field thermodynamic method for detecting the magnetic response of relativistic quasiparticles in topological materials.
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