On-device phase engineering.

In situ tailoring of two-dimensional materials' phases under external stimulus facilitates the manipulation of their properties for electronic, quantum and energy applications. However, current methods are mainly limited to the transitions among phases with unchanged chemical stoichiometry. Here we propose on-device phase engineering that allows us to realize various lattice phases with distinct chemical stoichiometries. Using palladium and selenide as a model system, we show that a PdSe2 channel with prepatterned Pd electrodes can be transformed into Pd17Se15 and Pd4Se by thermally tailoring the chemical composition ratio of the channel. Different phase configurations can be obtained by precisely controlling the thickness and spacing of the electrodes. The device can be thus engineered to implement versatile functions in situ, such as exhibiting superconducting behaviour and achieving ultralow-contact resistance, as well as customizing the synthesis of electrocatalysts. The proposed on-device phase engineering approach exhibits a universal mechanism and can be expanded to 29 element combinations between a metal and chalcogen. Our work highlights on-device phase engineering as a promising research approach through which to exploit fundamental properties as well as their applications.

NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways.

Stringent control of the NF-kappaB and type I interferon signaling pathways is critical to effective host immune responses, yet the molecular mechanisms that negatively regulate these pathways are poorly understood. Here, we show that NLRC5, a member of the highly conserved NOD-like protein family, can inhibit the IKK complex and RIG-I/MDA5 function. NLRC5 inhibited NF-kappaB-dependent responses by interacting with IKKalpha and IKKbeta and blocking their phosphorylation. It also interacted with RIG-I and MDA5, but not with MAVS, to inhibit RLR-mediated type I interferon responses. Consistent with these observations, NLRC5-specific siRNA knockdown not only enhanced the activation of NF-kappaB and its responsive genes, TNF-alpha and IL-6, but also promoted type I interferon signaling and antiviral immunity. Our findings identify NLRC5 as a negative regulator that blocks two central components of the NF-kappaB and type I interferon signaling pathways and suggest an important role for NLRC5 in homeostatic control of innate immunity.

Ultrastable Luminol-OH--(Ni-WOx-CNT) ECL System with High Strength and Its Applications in Sensing.

In traditional luminol electrochemiluminescence (ECL) systems, hydrogen peroxide (H2O2) and dissolved oxygen (DO) are the commonly used coreactants to generate reactive oxygen species (ROS) for ECL emission. However, the self-decomposition of hydrogen peroxide and the limited solubility and content of oxygen in solution undoubtedly restrict the luminescence efficiency and stability of the luminol ECL system. Inspired by the ROS-mediated ECL mechanism, we pioneered hydroxide ion as an advanced luminol ECL coreactant using nickel-doped and carbon nanotube-modified tungsten oxide (Ni-WOx-CNT) as the coreactant accelerator. Owing to the excellent catalytic activity of Ni-WOx-CNT, amounts of ROS were generated from OH- at a low excitation voltage, which subsequently reacted with luminol anion radicals and triggered intense ECL signals. Experiments confirmed an impressive ECL behavior in terms of high luminescent intensity (85,563 a.u.) and super stability over 1300 consecutive tests; both are superior to those recently reported luminol-H2O2 and luminol-DO systems with smaller ECL intensities and consecutive tests less than 25 times. To validate the feasibility and versatility of the developed system in sensor, traditional three-electrodes system and closed bipolar electrodes system with various sensing strategies of direct oxidation, "gate-effect" of molecularly imprinted polymer, immune reaction, and enzyme-catalyzed reaction were proposed to monitor uric acid (UA), C-reactive protein (CRP), immunoglobulin G (IgG), and glucose (Glu). The superior sensing performances confirmed the great application potential of the developed ROS-mediated ECL system.

Transcriptome and metabolome analyses reveal molecular insights into waterlogging tolerance in Barley.

Waterlogging stress is one of the major abiotic stresses affecting the productivity and quality of many crops worldwide. However, the mechanisms of waterlogging tolerance are still elusive in barley. In this study, we identify key differentially expressed genes (DEGs) and differential metabolites (DM) that mediate distinct waterlogging tolerance strategies in leaf and root of two barley varieties with contrasting waterlogging tolerance under different waterlogging treatments. Transcriptome profiling revealed that the response of roots was more distinct than that of leaves in both varieties, in which the number of downregulated genes in roots was 7.41-fold higher than that in leaves of waterlogging sensitive variety after 72 h of waterlogging stress. We also found the number of waterlogging stress-induced upregulated DEGs in the waterlogging tolerant variety was higher than that of the waterlogging sensitive variety in both leaves and roots in 1 h and 72 h treatment. This suggested the waterlogging tolerant variety may respond more quickly to waterlogging stress. Meanwhile, phenylpropanoid biosynthesis pathway was identified to play critical roles in waterlogging tolerant variety by improving cell wall biogenesis and peroxidase activity through DEGs such as Peroxidase (PERs) and Cinnamoyl-CoA reductases (CCRs) to improve resistance to waterlogging. Based on metabolomic and transcriptomic analysis, we found the waterlogging tolerant variety can better alleviate the energy deficiency via higher sugar content, reduced lactate accumulation, and improved ethanol fermentation activity compared to the waterlogging sensitive variety. In summary, our results provide waterlogging tolerance strategies in barley to guide the development of elite genetic resources towards waterlogging-tolerant crop varieties.

Mesenchymal stem cells-derived exosomes carrying microRNA-30b confer protection against pulmonary fibrosis by downregulating Runx1 via Spred2.

Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary fibrosis disease that is fatal. Mesenchymal stem cells (MSCs)-secreted exosomes (exos) have been linked to improving PF. Moreover, exosomal microRNAs (miRs) can control the growth of numerous diseases, including lung disorders. Our bioinformatics analysis showed that miR-30b was downregulated in tissue samples from surgical remnants of biopsies or lungs explanted from patients with IPF who underwent pulmonary transplantation. This suggests that miR-30b plays an important role in both the pathogenesis and treatment of IPF. Herein, this research was designed to ascertain the mechanism of MSCs-exos-packaged miR-30b in alleviating PF. The serum was harvested from idiopathic PF (IPF) patients with interstitial pneumonia caused by dermatomyositis and the MLE12 lung epithelial cell fibrosis model was built with TGF-ß1 (10 ng/mL), followed by miR-30b expression determination. TGF-ß1-stimulated MLE12 cells were co-incubated with exos from MSCs with or without Spred2 or Runx1 overexpression, followed by measurement of cell viability and apoptosis. After establishing the IPF mouse model with bleomycin and injecting exos and/or silencing and overexpressing adenovirus vectors, fibrosis evaluation was conducted. In mice and cells, the expression of TGF-ß1, TNF-α, and IL-1ß was tested via ELISA, and the levels of E-cad, ZO-1, α-SMA, and collagen type I via western blot analysis. The promoters of miR-30b, Runx1, and Spred2 were investigated. miR-30b was downregulated in the serum of IPF patients and TGF-ß1-stimulated MLE12 cells. Mechanistically, miR-30b inhibited Spred2 transcription by negatively targeting Runx1. MSCs-exos or MSCs-exo-miR-30b decreased the apoptosis, inflammation, and fibrosis while increasing their viability in TGF-ß1-stimulated MLE12 cells, which was annulled by overexpressing Runx1 or Spred2. Exo-miR-30b decreased Runx1 expression to downregulate Spred2, reducing fibrosis and inflammation in IPF mice. Our results indicated that MSCs-exos-encapsulated miR-30b had a potential function to inhibit PF and part of its function may be achieved by targeting RUNX1 to reduce the Spred2 transcription level. Moreover, this work offered evidence and therapeutic targets for therapeutic strategies for managing clinical PF in patients.

NLRP4 negatively regulates type I interferon signaling by targeting the kinase TBK1 for degradation via the ubiquitin ligase DTX4.

Stringent control of the type I interferon signaling pathway is important for maintaining host immune responses and homeostasis, yet the molecular mechanisms responsible for its tight regulation are still poorly understood. Here we report that the pattern-recognition receptor NLRP4 regulated the activation of type I interferon mediated by double-stranded RNA or DNA by targeting the kinase TBK1 for degradation. NLRP4 recruited the E3 ubiquitin ligase DTX4 to TBK1 for Lys48 (K48)-linked polyubiquitination at Lys670, which led to degradation of TBK1. Knockdown of either DTX4 or NLRP4 abrogated K48-linked ubiquitination and degradation of TBK1 and enhanced the phosphorylation of TBK1 and the transcription factor IRF3. Our results identify a previously unrecognized role for NLRP4 in the regulation of type I interferon signaling and provide molecular insight into the mechanisms by which NLRP4-DTX4 targets TBK1 for degradation.

Hollow CeO2-Base Nanozyme with Self-Accelerated Cascade Reactions for Combined Tumor Therapy.

Nanozymes have obvious advantages in improving the efficiency of cancer treatment. However, due to the lack of tissue specificity, low catalytic efficiency, and so on, their clinical applications are limited. Herein, the nanoplatform CeO2@ICG@GOx@HA (CIGH) with self-accelerated cascade reactions is constructed. The as-prepared nanozyme shows the superior oxidase (OXD)-like, superoxide dismutase (SOD)-like, catalase (CAT)-like, and peroxidase (POD)-like activities. At the same time, under 808 nm near-infrared (NIR) irradiation, the photodynamic and photothermal capabilities are also significantly enhanced due to the presence of indocyanine green (ICG). We demonstrate that the nanozyme CIGH can efficiently accumulate in the tumor and exhibit amplified cascade antitumor effects with negligible systemic toxicity through the combination of photodynamic therapy (PDT), photothermal therapy (PTT), chemodynamic therapy (CDT) and starvation therapy. The nanozyme prepared in this study provides a promising candidate for catalytic nanomedicines for efficient tumor therapy.

Tomoelastography and Pancreatic Extracellular Volume Fraction Derived From MRI for Predicting Clinically Relevant Postoperative Pancreatic Fistula.

BACKGROUND: Pancreatic stiffness and extracellular volume fraction (ECV) are potential imaging biomarkers for pancreatic fibrosis. Clinically relevant postoperative fistula (CR-POPF) is one of the most severe complications after pancreaticoduodenectomy. Which imaging biomarker performs better for predicting the risk of CR-POPF remains unknown. PURPOSE: To evaluate the diagnostic performance of ECV and tomoelastography-derived pancreatic stiffness for predicting the risk of CR-POPF in patients undergoing pancreaticoduodenectomy. STUDY TYPE: Prospective. POPULATION: Eighty patients who underwent multiparametric pancreatic MRI before pancreaticoduodenectomy, among whom 16 developed CR-POPF and 64 did not. FIELD STRENGTH/SEQUENCE: 3 T/tomoelastography and precontrast and postcontrast T1 mapping of the pancreas. ASSESSMENT: Pancreatic stiffness was measured on the tomographic c-map, and pancreatic ECV was calculated from precontrast and postcontrast T1 maps. Pancreatic stiffness and ECV were compared with histological fibrosis grading (F0-F3). The optimal cutoff values for predicting CR-POPF were determined, and the correlation between CR-POPF and imaging parameters was evaluated. STATISTICAL TESTS: The Spearman's rank correlation and multivariate linear regression analysis was conducted. The receiver operating characteristic curve analysis and logistic regression analysis was performed. A double-sided P < 0.05 indicated a statistically significant difference. RESULTS: Pancreatic stiffness and ECV both showed a significantly positive correlation with histological pancreatic fibrosis (r = 0.73 and 0.56, respectively). Patients with advanced pancreatic fibrosis had significantly higher pancreatic stiffness and ECV compared to those with no/mild fibrosis. Pancreatic stiffness and ECV were also correlated with each other (r = 0.58). Lower pancreatic stiffness (<1.38 m/sec), lower ECV (<0.28), nondilated main pancreatic duct (<3 mm) and pathological diagnosis other than pancreatic ductal adenocarcinoma were associated with higher risk of CR-POPF at univariate analysis, and pancreatic stiffness was independently associated with CR-POPF at multivariate analysis (odds ratio: 18.59, 95% confidence interval: 4.45, 77.69). DATA CONCLUSION: Pancreatic stiffness and ECV were associated with histological fibrosis grading, and pancreatic stiffness was an independent predictor for CR-POPF. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 5.

Time to prerandomization seizure count design sufficiently assessed the safety and tolerability of perampanel for the treatment of primary generalized tonic-clonic seizures.

OBJECTIVE: Static assignment of participants in randomized clinical trials to placebo or ineffective treatment confers risk from continued seizures. An alternative trial design of time to exceed prerandomization monthly seizure count (T-PSC) has replicated the efficacy conclusions of traditionally designed trials, with shorter exposure to placebo and ineffective treatment. Trials aim to evaluate efficacy as well as safety and tolerability; therefore, we evaluated whether this T-PSC design also could replicate the trial's safety and tolerability conclusions. METHODS: We retrospectively applied the T-PSC design to analyze treatment-emergent adverse events (TEAEs) from a blinded, placebo-controlled trial of perampanel for primary generalized tonic-clonic seizures (NCT01393743). The safety analysis set consisted of 81 and 82 participants randomized to perampanel and placebo arms, respectively. We evaluated the incidences of TEAEs, treatment-related TEAEs, serious TEAEs, and TEAEs of special interest that occurred before T-PSC relative to those observed during the full-length trial. RESULTS: Of the 67 and 59 participants who experienced TEAEs in the perampanel and placebo arms during full-length trial, 66 (99%) and 54 (92%) participants experienced TEAEs with onset occurring before T-PSC, respectively. When limited to treatment-related TEAEs, 55 of 56 (98%) and 32 of 37 (86%) participants reported treatment-related TEAEs that occurred before T-PSC in the perampanel and placebo arms, respectively. There were more TEAEs after T-PSC with placebo as compared to perampanel (Fisher exact odds ratio = 8.6, p = .035), which resulted in overestimation of the difference in TEAE rate. There was a numerical reduction in serious TEAEs (3/13 occurred after T-PSC, one in placebo and two in perampanel). SIGNIFICANCE: Almost all TEAEs occurred before T-PSC. More treatment-related TEAEs occurred after T-PSC for participants randomized to placebo than perampanel, which may be due to either a shorter T-PSC or delayed time to TEAE for placebo.

Molecular phylogeny and morphology of Sporodiniella sinensis sp. nov. (Syzygitaceae, Mucorales), an invertebrate-associated species from Yunnan, China.

During investigations of invertebrate-associated fungi in Yunnan Province of China, a new species, Sporodiniella sinensis sp. nov., was collected. Morphologically, S. sinensis is similar to Sporodiniella umbellata; however, it is distinguished from S. umbellata by its greater number of sporangiophore branches, longer sporangiophores, larger sporangiospores, and columellae. The novel species exhibits similarities of 91.62 % for internal transcribed spacer (ITS), 98.66-99.10 % for ribosomal small subunit (nrSSU), and 96.36-98.22 % for ribosomal large subunit (nrLSU) sequences, respectively, compared to S. umbellata. Furthermore, phylogenetic analyses based on combined sequences of ITS, nrLSU and nrSSU show that it forms a separate clade in Sporodiniella, and clusters closely with S. umbellata with high statistical support. The phylogenetic and morphological evidence support S. sinensis as a distinct species. Here, it is formally described and illustrated, and compared with other relatives.

Quantitative MR imaging biomarkers for distinguishing inflammatory pancreatic mass and pancreatic cancer-a systematic review and meta-analysis.

OBJECTIVES: To evaluate the diagnostic performance of quantitative magnetic resonance (MR) imaging biomarkers in distinguishing between inflammatory pancreatic masses (IPM) and pancreatic cancer (PC). METHODS: A literature search was conducted using PubMed, Embase, the Cochrane Library, and Web of Science through August 2023. Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) was used to evaluate the risk of bias and applicability of the studies. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were calculated using the DerSimonian-Laird method. Univariate meta-regression analysis was used to identify the potential factors of heterogeneity. RESULTS: Twenty-four studies were included in this meta-analysis. The two main types of IPM, mass-forming pancreatitis (MFP) and autoimmune pancreatitis (AIP), differ in their apparent diffusion coefficient (ADC) values. Compared with PC, the ADC value was higher in MFP but lower in AIP. The pooled sensitivity/specificity of ADC were 0.80/0.85 for distinguishing MFP from PC and 0.82/0.84 for distinguishing AIP from PC. The pooled sensitivity/specificity for the maximal diameter of the upstream main pancreatic duct (dMPD) was 0.86/0.74, with a cutoff of dMPD ≤ 4 mm, and 0.97/0.52, with a cutoff of dMPD ≤ 5 mm. The pooled sensitivity/specificity for perfusion fraction (f) was 0.82/0.68, and 0.82/0.77 for mass stiffness values. CONCLUSIONS: Quantitative MR imaging biomarkers are useful in distinguishing between IPM and PC. ADC values differ between MFP and AIP, and they should be separated for consideration in future studies. CLINICAL RELEVANCE STATEMENT: Quantitative MR parameters could serve as non-invasive imaging biomarkers for differentiating malignant pancreatic neoplasms from inflammatory masses of the pancreas, and hence help to avoid unnecessary surgery. KEY POINTS: • Several quantitative MR imaging biomarkers performed well in differential diagnosis between inflammatory pancreatic mass and pancreatic cancer. • The ADC value could discern pancreatic cancer from mass-forming pancreatitis or autoimmune pancreatitis, if the two inflammatory mass types are not combined. • The diameter of main pancreatic duct had the highest specificity for differentiating autoimmune pancreatitis from pancreatic cancer.

Bias-dependent photoresponse of Td-WTe2grown by Chemical Vapor Deposition.

The type-II Weyl semimetal Td-WTe2is one of the wonder materials for high-performance optoelectronic devices. We report the self-powered Td-WTe2photodetectors and their bias-dependent photoresponse in the visible region (405 nm, 520 nm, 638 nm) driven by the bulk photovoltaic effect (BPE). The device shows the responsivity of 15.8 mAW-1and detectivity of 5.2×109Jones at 520 nm. Besides, the response time of the WTe2photodetector shows a strong bias-voltage dependent property. This work offers a physical reference for understanding the photoresponse process of Td-WTe2photodetectors.

Trimethylamine from Subtropical Forests Rival Total Farmland Emissions in China.

Many types of living plants release gaseous trimethylamine (TMA), making it a potentially important contributor to new particle formation (NPF) in remote areas. However, a panoramic view of the importance of forest biogenic TMA at the regional scale is lacking. Here, we pioneered nationwide mobile measurements of TMA across a transect of contiguous farmland in eastern China and a transect of subtropical forests in southern China. In contrast to the farmland route, TMA concentrations measured during the subtropical forest route correlated significantly with isoprene, suggesting potential TMA emissions from leaves. Our high time-resolved concentrations obtained from a weak photo-oxidizing atmosphere reflected freshly emitted TMA, indicating the highest emission intensity from irrigated dryland (set as the baseline of 10), followed by paddy field (7.1), subtropical evergreen forests (5.9), and subtropical broadleaf and mixed forests (4.3). Extrapolating their proportions roughly to China, subtropical forests alone, which constitute half of the total forest area, account for nearly 70% of the TMA emissions from the nation's total farmland. Our estimates, despite the uncertainties, take the first step toward large-scale assessment of forest biogenic amines, highlighting the need for observational and modeling studies to consider this hitherto overlooked source of TMA.

Paper-based fluorescence sensor array with functionalized carbon quantum dots for bacterial discrimination using a machine learning algorithm.

The rapid discrimination of bacteria is currently an emerging trend in the fields of food safety, medical detection, and environmental observation. Traditional methods often require lengthy culturing processes, specialized analytical equipment, and bacterial recognition receptors. In response to this need, we have developed a paper-based fluorescence sensor array platform for identifying different bacteria. The sensor array is based on three unique carbon quantum dots (CQDs) as sensing units, each modified with a different antibiotic (polymyxin B, ampicillin, and gentamicin). These antibiotic-modified CQDs can aggregate on the bacterial surface, triggering aggregation-induced fluorescence quenching. The sensor array exhibits varying fluorescent responses to different bacterial species. To achieve low-cost and portable detection, CQDs were formulated into fluorescent ink and used with an inkjet printer to manufacture paper-based sensor arrays. A smartphone was used to collect the responses generated by the bacteria and platform. Diverse machine learning algorithms were utilized to discriminate bacterial types. Our findings showcase the platform's remarkable capability to differentiate among five bacterial strains, within a detection range spanning from 1.0 × 103 CFU/mL to 1.0 × 107 CFU/mL. Its practicality is further validated through the accurate identification of blind bacterial samples. With its cost-effectiveness, ease of fabrication, and high degree of integration, this platform holds significant promise for on-site detection of diverse bacteria.

Strategies for secondary use of real-world clinical and administrative data for outcome ascertainment in pragmatic clinical trials.

BACKGROUND: Pragmatic trials are gaining popularity as a cost-effective way to examine treatment effectiveness and generate timely comparative evidence. Incorporating supplementary real-world data is recommended for robust outcome monitoring. However, detailed operational guidelines are needed to inform effective use and integration of heterogeneous databases. OBJECTIVE: Lessons learned from the Veterans Affairs (VA) Diuretic Comparison Project (DCP) are reviewed, providing adaptable recommendations to capture clinical outcomes from real-world data. METHODS: Non-cancer deaths and major cardiovascular (CV) outcomes were determined using VA, Medicare, and National Death Index (NDI) data. Multiple ascertainment strategies were applied, including claims-based algorithms, natural language processing, and systematic chart review. RESULTS: During a mean follow-up of 2.4 (SD = 1.4) years, 907 CV events were identified within the VA healthcare system. Slight delays (∼1 year) were expected in obtaining Medicare data. An additional 298 patients were found having a CV event outside of the VA in 2016 - 2021, increasing the CV event rate from 3.5 % to 5.7 % (770 of 13,523 randomized). NDI data required âˆ¼2 years waiting period. Such inclusion did not increase the number of deaths identified (all 894 deaths were captured by VA data) but enhanced the accuracy in determining cause of death. CONCLUSION: Our experience supports the recommendation of integrating multiple data sources to improve clinical outcome ascertainment. While this approach is promising, hierarchical data aggregation is required when facing different acquisition timelines, information availability/completeness, coding practice, and system configurations. It may not be feasible to implement comparable applications and solutions to studies conducted under different constraints and practice. The recommendations provide guidance and possible action plans for researchers who are interested in applying cross-source data to ascertain all study outcomes.

Experimental and Theoretical Study of the OH-Initiated Degradation of Piperidine under Simulated Atmospheric Conditions.

The OH-initiated photo-oxidation of piperidine and the photolysis of 1-nitrosopiperidine were investigated in a large atmospheric simulation chamber and in theoretical calculations based on CCSD(T*)-F12a/aug-cc-pVTZ//M062X/aug-cc-pVTZ quantum chemistry results and master equation modeling of the pivotal reaction steps. The rate coefficient for the reaction of piperidine with OH radicals was determined by the relative rate method to be kOH-piperidine = (1.19 ± 0.27) × 10-10 cm3 molecule-1 s-1 at 304 ± 2 K and 1014 ± 2 hPa. Product studies show the piperidine + OH reaction to proceed via H-abstraction from both CH2 and NH groups, resulting in the formation of the corresponding imine (2,3,4,5-tetrahydropyridine) as the major product and in the nitramine (1-nitropiperidine) and nitrosamine (1-nitrosopiperidine) as minor products. Analysis of 1-nitrosopiperidine photolysis experiments under natural sunlight conditions gave the relative rates jrel = j1-nitrosoperidine/jNO2 = 0.342 ± 0.007, k3/k4a = 0.53 ± 0.05 and k2/k4a = (7.66 ± 0.18) × 10-8 that were subsequently employed in modeling the piperidine photo-oxidation experiments, from which the initial branchings between H-abstraction from the NH and CH2 groups, kN-H/ktot = 0.38 ± 0.08 and kC2-H/ktot = 0.49 ± 0.19, were derived. All photo-oxidation experiments were accompanied by particle formation that was initiated by the acid-base reaction of piperidine with nitric acid. Primary photo-oxidation products including both 1-nitrosopiperidine and 1-nitropiperidine were detected in the particles formed. Quantum chemistry calculations on the OH initiated atmospheric photo-oxidation of piperidine suggest the branching in the initial H-abstraction routes to be ∼35% N1, ∼50% C2, ∼13% C3, and ∼2% C4. The theoretical study produced an atmospheric photo-oxidation mechanism, according to which H-abstraction from the C2 position predominantly leads to 2,3,4,5-tetrahydropyridine and H-abstraction from the C3 position results in ring opening followed by a complex autoxidation, of which the first few steps are mapped in detail. H-abstraction from the C4 position is shown to result mainly in the formation of piperidin-4-one and 2,3,4,5-tetrahydropyridin-4-ol, whereas H-abstraction from N1 under atmospheric conditions primarily leads to 2,3,4,5-tetrahydropyridine and in minor amounts of 1-nitrosopiperidine and 1-nitropiperidine. The calculated rate coefficient for the piperidine + OH reaction agrees with the experimental value within 35%, and aligning the theoretical numbers to the experimental value results in k(T) = 2.46 × 10-12 × exp(486 K/T) cm3 molecule-1 s-1 (200-400 K).

Mechanical models and measurement methods of solid stress in tumors.

In addition to genetic mutations, biomechanical factors also affect the structures and functions of the tumors during tumor growth, including solid stress, interstitial fluid pressure, stiffness, and microarchitecture. Solid stress affects tumors by compressing cancer and stromal cells and deforming blood and lymphatic vessels which reduce supply of oxygen, nutrients and drug delivery, making resistant to treatment. Researchers simulate the stress by creating mechanical models both in vitro and in vivo. Cell models in vitro are divided into two dimensions (2D) and three dimensions (3D). 2D models are simple to operate but exert pressure on apical surface of the cells. 3D models, the multicellular tumor spheres, are more consistent with the actual pathological state in human body. However, the models are more difficult to establish compared with the 2D models. Besides, the procedure of the animal models in vivo is even more complex and tougher to operate. Then, researchers challenged to quantify the solid stress through some measurement methods. We compared the advantages and limitations of these models and methods, which may help to explore new therapeutic targets for normalizing the tumor's physical microenvironment. KEY POINTS: •This is the first review to conclude the mechanical models and measurement methods in tumors. •The merit and demerit of these models and methods are compared. •Insights into further models are discussed.

Group sequential designs for cancer immunotherapy trial with delayed treatment effect.

Cancer immunotherapy trials are frequently characterized by delayed treatment effects such that the proportional hazards assumption is violated and the log-rank test suffers a substantial loss of statistical power. To increase the efficacy of the trial design, a variety of weighted log-rank tests have been proposed for fixed sample and group sequential trial designs. However, in such a group sequential design, it is often not recommended for futility interim monitoring due to possible delayed treatment effect which could result a high false-negative rate. To resolve this problem, we propose a group sequential design using a piecewise weighted log-rank test which provides an event-driven approach based on number of events after the delayed time. That is, the interim looks will not be conducted until the planned number of events observed after the delay time. Thus, it avoids the possibility of false-negative rate due to the delayed treatment effect. Furthermore, with an event-driven approach, the proposed group sequential design is robust against the underlying survival, accrual and censoring distributions. The group sequential designs using Fleming-Harrington-(ρ,γ) weighted log-rank test and a new weighted log-rank test are also discussed.

A phosphoglycerate mutase 1 allosteric inhibitor overcomes drug resistance to EGFR-targeted therapy via disrupting IL-6/JAK2/STAT3 signaling pathway in lung adenocarcinoma.

Resistance to epidermal growth factor receptor (EGFR) inhibitors, from the first-generation erlotinib to the third generation osimertinib, is a clinical challenge in the treatment of patients with EGFR-mutant lung adenocarcinoma. Our previous work found that a novel allosteric inhibitor of phosphoglycerate mutase 1 (PGAM1), HKB99, restrains erlotinib resistance in lung adenocarcinoma cells. However, the role of HKB99 in osimertinib resistance and its underlying molecular mechanism remains to be elucidated. Herein, we found that IL-6/JAK2/STAT3 signaling pathway is aberrantly activated in both erlotinib and osimertinib resistant cells. Importantly, HKB99 significantly blocks the interaction of PGAM1 with JAK2 and STAT3 via the allosteric sites of PGAM1, which leads to inactivation of JAK2/STAT3 and thereby disrupts IL-6/JAK2/STAT3 signaling pathway. Consequently, HKB99 remarkably restores EGFR inhibitor sensitivity and exerts synergistic tumoricidal effect. Additionally, HKB99 alone or in combination with osimertinib down-regulated the level of p-STAT3 in xenograft tumor models. Collectively, this study identifies PGAM1 as a key regulator in IL-6/JAK2/STAT3 axis in the development of resistance to EGFR inhibitors, which could serve as a therapeutic target in lung adenocarcinoma with acquired resistance to EGFR inhibitors.

The vacated space of volume/price of the drugs centralized procurement with quantity in secondary and above public hospitals of China.

BACKGROUND: In 2018, the National Centralized Drug Procurement (NCDP) policy has been implemented in 11 provinces, and promoted across the country in 2019. The main feature of the policy is "volume for price", therefore, it is necessary to measure the price relationship, not only to reduce the price of drugs, reduce the burden of patients' medical costs, but also facilitate pharmaceutical companies to access enough innovation incentives. The aim of this study was to assess the vacated space effect of the drug centralized procurement by national organizations in exchange of price for quantity. METHODS: A difference-in-differences (DID) model was employed to analyze the effect of the 4 + 7 pilot drugs centralized purchasing policy on drug sales volume and selected versus clinically substitutable unselected varieties, using observational data from 2018 to 2019. We compared drug procurement data between secondary and above public hospitals in pilot and non-pilot cities throughout China. RESULTS: The study showed that the average treatment effect (ATE) of sales in the in-hospital market for the selected supply varieties in centralized purchasing is -0.42, and with a sales volume of 0.49. This indicates a volume-price vacated space of 1.16 ~ 1.17 DDD (defined daily dose)/Yuan, implying that for every 1 defined daily dose (DDD) increase in reported volume, the standardized price decreased by 1.16-1.17 Yuan. The ATE of in-hospital market sales for drugs not selected in centralized procurement shows a decrease of 0.13. This finding highlights the presence of the price linkage effect. The ATE of sales volume is 0.57, indicating a volume-price space of 4.38 ~ 4.39 DDD/Yuan for unselected drugs, approximately 3.75 higher relative to that of the selected ones. CONCLUSIONS: The ratio of the volume-price space of clinically substitutable unselected and selected drugs may serve as direct evidence for evaluating the shift from centralized purchasing of drug varieties to clinically substitutable other ones. To strengthen the volume-based negotiation approach and maximize the effectiveness of centralized purchasing policies, we recommend the strategic implementation of a three-tiered centralized purchasing system, the expansion of drug coverage, and the introduction of relevant constraints and incentives.