NQO1 targeting prodrug triggers innate sensing to overcome checkpoint blockade resistance

Lack of proper innate sensing inside tumor microenvironment (TME) limits T cell-targeted immunotherapy. NAD(P)H:quinone oxidoreductase 1 (NQO1) is highly enriched in multiple tumor types and has emerged as a promising target for direct tumor-killing. Here, we demonstrate that NQO1-targeting prodrug β-lapachone triggers tumor-selective innate sensing leading to T cell-dependent tumor control. β-Lapachone is catalyzed and bioactivated by NQO1 to generate ROS in NQO1high tumor cells triggering oxidative stress and release of the damage signals for innate sensing. β-Lapachone-induced high mobility group box 1 (HMGB1) release activates the host TLR4/MyD88/type I interferon pathway and Batf3 dendritic cell-dependent cross-priming to bridge innate and adaptive immune responses against the tumor. Furthermore, targeting NQO1 is very potent to trigger innate sensing for T cell re-activation to overcome checkpoint blockade resistance in well-established tumors. Our study reveals that targeting NQO1 potently triggers innate sensing within TME that synergizes with immunotherapy to overcome adaptive resistance

Effects of PDE4 Pathway Inhibition in Rat Experimental Stroke

PURPOSE: The first genomewide association study indicated that variations in the phosphodiesterase 4D (PDE4D) gene confer risk for ischemic stroke. However, inconsistencies among the studies designed to replicate the findings indicated the need for further investigation to elucidate the role of the PDE4 pathway in stroke pathogenesis. Hence, we studied the effect of global inhibition of the PDE4 pathway in two rat experimental stroke models, using the PDE4 inhibitor rolipram. Further, the specific role of the PDE4D isoform in ischemic stroke pathogenesis was studied using PDE4D knockout rats in experimental stroke. METHODS: Rats were subjected to either the ligation or embolic stroke model and treated with rolipram (3mg/kg; i.p.) prior to the ischemic insult. Similarly, the PDE4D knockout rats were subjected to experimental stroke using the embolic model. RESULTS: Global inhibition of the PDE4 pathway using rolipram produced infarcts that were 225% (pCONCLUSIONS: Despite increase in infarct size after global inhibition of the PDE4 pathway with rolipram, specific inhibition of the PDE4D isoform had no effect on experimental stroke. These findings support a role for the PDE4 pathway, independent of the PDE4D isoform, in ischemic stroke pathogenesis. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page

Impacts of Tibetan Plateau sensible heat and El Niño–Southern Oscillation on precipitation over South China under the background of the PDO

This study aims to investigate the impacts of the spring sensible heat (SH) over the Tibetan Plateau (TP) and the El Niño–Southern Oscillation (ENSO) in the preceding wintertime on midsummer (July–August) precipitation over South China under the different Pacific decadal oscillation (PDO) phases. More specifically, eight classifications are adopted at the demarcation point around 1996 when the spring SH over the TP and the midsummer precipitation in South China occurred as well as the PDO phase transition, including positive and negative SHs and ENSOs under a positive PDO phase (1979–1996) and a negative PDO phase (1997–2019), respectively, based on the Niño-3 index and the spring SH calculated from 48 stations over the central and eastern parts of the TP. The results show that both the spring SH and the ENSO in preceding wintertime have a significant impact on the midsummer precipitation over South China; that is, when the two factors are in their respective positive (negative) phase, the midsummer precipitation in South China is generally less (more). Importantly, the phase change of background field PDO can significantly enhance the effect of the SH and the ENSO on summer precipitation over South China. Moreover, compared with the preceding wintertime ENSO, the spring SH over the TP contributes more to the midsummer precipitation in South China based on analyses of their independent and synergistic effects. The main mechanism responsible for the anomalous midsummer precipitation over South China are the combined effects of the South Asian high (SAH) and the western Pacific subtropical high (WPSH), which are controlled by the spring SH anomaly over the TP and the ENSO, respectively. Deep understanding of the dominant factors of the midsummer precipitation over South China will help understand the local climate change and reduce the losses caused by drought and flood disasters

Association between systemic iron status and β-cell function and insulin sensitivity in patients with newly diagnosed type 2 diabetes

ObjectiveAbnormal iron metabolism is related to the risk of diabetes, but the underlying mechanism of this association remains uncertain. This study was conducted to evaluate the contributions of systemic iron status to β-cell function and insulin sensitivity of patients with newly diagnosed T2DM.MethodsA total of 162 patients with newly diagnosed T2DM and 162 healthy controls were enrolled in the study. Basic characteristics, biochemical indicators, and iron metabolism biomarkers, including serum iron (SI), ferritin (SF), transferrin (Trf), and transferrin saturation (TS), were collected. All patients underwent a 75 g oral glucose tolerance test. A series of parameters for assessing β-cell function and insulin sensitivity were calculated. The multivariate stepwise linear regression model was used to investigate the contributions of iron metabolism to β-cell function and insulin sensitivity.ResultsCompared with healthy controls, patients with newly diagnosed T2DM had significantly higher levels of SF. Among the diabetic patients, the SI and TS levels were higher, and the percentage of Trf levels below normal values was lower in men than in women. In all diabetic patients, SF was the independent risk factor associated with impaired β-cell function. Further stratification analysis showed that Trf was an independent protective factor for β-cell function in male patients, while SF was an independent risk factor for impaired β-cell function in female patients. However, systemic iron status did not affect insulin sensitivity.ConclusionElevated SF levels and decreased Trf levels had a profound effect on impaired β-cell function in Chinese patients with newly diagnosed T2DM

Role of the ISKpn element in mediating mgrB gene mutations in ST11 hypervirulent colistin-resistant Klebsiella pneumoniae

BackgroundColistin has emerged as a last-resort therapeutic against antibiotic-resistant bacterial infections, particularly those attributed to carbapenem-resistant Enterobacteriaceae (CRE) like CRKP. Yet, alarmingly, approximately 45% of multidrug-resistant Klebsiella pneumoniae strains now manifest resistance to colistin. Through our study, we discerned that the synergy between carbapenemase and IS elements amplifies resistance in Klebsiella pneumoniae, thereby narrowing the existing therapeutic avenues. This underscores the instrumental role of IS elements in enhancing colistin resistance through mgrB disruption.MethodsFrom 2021 to 2023, 127 colistin-resistant Klebsiella pneumoniae isolates underwent meticulous examination. We embarked on an exhaustive genetic probe, targeting genes associated with both plasmid-mediated mobile resistance-encompassing blaKPC, blaNDM, blaIMP, blaVIM, blaOXA-48-like, and mcr-1 to mcr-8-and chromosome-mediated resistance systems, including PhoP/Q, PmrA/B, and mgrB. PCR amplification revealed the presence of virulence-associated genes from the pLVPK plasmid, such as rmpA, rmpA2, iucA, iroB, and peg344. mgrB sequencing was delegated to Sangon Biotech, Shanghai, and the sequences procured were validated using BLAST. Our search for IS elements was navigated through the IS finder portal. Phenotypically, we harnessed broth microdilution (BMD) to ascertain the MICs of colistin. To sketch the clonal lineage of mgrB-mutated CoR-Kp isolates, sophisticated methodologies like MLST and PFGE were deployed. S1-PFGE unraveled the intrinsic plasmids in these isolates. Our battery of virulence assessment techniques ranged from the string test and capsular serotyping to the serum killing assay and the Galleria mellonella larval infection model.ResultsAmong the 127 analyzed isolates, 20 showed an enlarged mgrB PCR amplicon compared to wild-type strains. These emerged over a three-year period: three in 2021, thirteen in 2022, and four in 2023. Antimicrobial susceptibility tests revealed that these isolates consistently resisted several drugs, notably TCC, TZP, CAZ, and COL. Additionally, 85% resisted both DOX and TOB. The MICs for colistin across these strains ranged between 16 to 64 mg/L, with a median of 40 mg/L. From a genetic perspective, MLST unanimously categorized these mgrB-mutated CoR-hvKp isolates as ST11. PFGE further delineated them into six distinct clusters, with clusters A and D being predominant. This distribution suggests potential horizontal and clonal genetic transmission. Intriguingly, every mgrB-mutated CoR-hvKP isolate possessed at least two virulence genes akin to the pLVPK-like virulence plasmid, with iroB and rmpA2 standing out. Their virulence was empirically validated both in vitro and in vivo. A pivotal discovery was the identification of three distinct insertion sequence (IS) elements within or near the mgrB gene. These were:ISKpn26 in eleven isolates, mainly in cluster A, with various insertion sites including +74, +125, and an upstream −35.ISKpn14 in four isolates with insertions at +93, −35, and two upstream at −60.IS903B present in five isolates, marking positions like +74, +125, +116, and −35 in the promoter region. These diverse insertions, spanning six unique locations in or near the mgrB gene, underscore its remarkable adaptability.ConclusionOur exploration spotlights the ISKpn element’s paramount role in fostering mgrB gene mutations in ST11 hypervirulent colistin-resistant Klebsiella pneumoniae. Employing MLST and PFGE, we unearthed two primary genetic conduits: clonal and horizontal. A striking observation was the ubiquitous presence of the KPC carbapenemase gene in all the evaluated ST11 hypervirulent colistin-resistant Klebsiella pneumoniae strains, with a majority also harboring the NDM gene. The myriad mgrB gene insertion locales accentuate its flexibility and the overarching influence of IS elements, notably the pervasive IS5-like variants ISKpn26 and IS903B. Our revelations illuminate the escalating role of IS elements in antibiotic resistance within ST11 hypervirulent colistin-resistant Klebsiella pneumoniae, advocating for innovative interventions to counteract these burgeoning resistance paradigms given their profound ramifications for prevailing treatment modalities

Cigarette Smoking and Carotid Plaque Echodensity in the Northern Manhattan Study

BACKGROUND: We sought to determine the association between cigarette smoking and carotid plaque ultrasound morphology in a multi-ethnic cohort. METHODS: We analyzed 1,743 stroke-free participants (mean age, 65.5±8.9 years; 60% women; 18% white, 63% Hispanic, 19% black; 14% current and 38% former smokers, 48% never smoked) from the Northern Manhattan Study using an ultrasound index of plaque echodensity, the Gray-Scale Median (GSM). Echolucent plaque (low GSM) represents soft plaque and echodense (high GSM) more calcified plaque. The mean GSM weighted by plaque area for each plaque was calculated for those with multiple plaques. Quintiles of GSM were compared to no plaque. Multinomial logistic regression models were used to assess associations of cigarette smoking with GSM, adjusting for demographics and vascular risk factors. RESULTS: Among subjects with carotid plaque (58%), the mean GSM scores for quintiles 1 to 5 were 48, 72, 90, 105, and 128, respectively. Current smokers had over a 2-fold increased risk of having GSM in quintile 1 (Odds Ratio [OR]=2.17; 95% Confidence Interval [CI], 1.34–3.52), quintile 2 (OR=2.33; CI, 1.42–3.83), quintile 4 (OR=2.05; CI, 1.19–3.51), and quintile 5 (OR=2.13; CI, 1.27–3.56) but not in quintile 3 (OR=1.18; CI, 0.67–2.10) as compared to never smokers in fully adjusted models. Former smokers had increased risk in quintile 2 (OR=1.46; CI, 1.00–2.12), quintile 3 (OR=1.56; CI, 1.09–2.24), quintile 4 (OR=1.66; CI, 1.13–2.42), and quintile 5 (OR=1.73; CI, 1.19–2.51), but not in quintile 1 (OR=1.05; CI, 0.72–1.55). CONCLUSIONS: A non-linear, Vshaped like relationship between current cigarette smoking and plaque echodensity was observed. Former smokers were at highest risk for plaques in high GSM quintiles. Thus, current smokers were more likely to have either soft or calcified plaques and former smokers were at greater risk of only echodense plaques when compared against never smokers. Further research is needed to determine if plaque morphology mediates an association between smoking and clinical vascular events

AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells

Mutations in STK11/LKB1 in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB), and introduction of a Stk11/Lkb1 (L) mutation into murine lung adenocarcinomas driven by mutant Kras and Trp53 loss (KP) resulted in an ICB refractory syngeneic KPL tumor. Mechanistically this occurred because KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human STK11/LKB1 mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+PD-1+CD8 T cells, restoring therapeutic response to PD-1 ICB in KPL tumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumor xenografts. NSCLC-affected individuals with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.publishedVersio

Working Vibration Analysis of the Bearing Plate on Roadheader Test Bed

In order to research the vibration characteristics of the bearing plate on roadheader test bed to bear the roadheaders with different parameters, this paper establishes a multi-body dynamic model for the bearing plate to bear the roadheaders by using the theory of multi-body dynamics, and analyzes and determines a mathematical model of loads between the track and the bearing plate. By modal analysis of multi-body dynamic model of the roadheader, this paper extracts the modal shape of the system, and draws a frequency response diagram for system vibration, and obtains a larger vibration frequency range. To further explore the vibration characteristics, this paper researches the damping of different hydraulic systems, different mass, stiffness parameters and the impact of the roadheader on the vibration of the bearing plate on the test bed by using the computer numerical simulation, and obtains the longitudinal vibration characteristics of three test points in the geometric center, namely, cutting head, cantilever and engine body. The research results show that the mass of the road-header on the test bed is increased by 6%, and the longitudinal amplitudes of the cutting head and cantilever are respectively reduced by 37% and 19%; the damping of the hydraulic system of the roadheader is increased by 19%, and the longitudinal amplitudes of the cutting head, cantilever and engine body are respectively reduced by 33%, 23% and 16%; the stiffness of the engine body doubles, and the longitudinal amplitudes of the cutting head and cantilever are respectively reduced by 35.8% and 27%. The results are consistent with the underground industrial test so as to provide a regularity basis for load analysis of the test bed bearing the roadheaders with different parameters