Targeting ESE3/EHF With Nifurtimox Inhibits CXCR2+ Neutrophil Infiltration and Overcomes Pancreatic Cancer Resistance to Chemotherapy and Immunotherapy.

BACKGROUND & AIMS: Because pancreatic cancer responds poorly to chemotherapy and immunotherapy, it is necessary to identify novel targets and compounds to overcome resistance to treatment. METHODS: This study analyzed genomic single nucleotide polymorphism sequencing, single-cell RNA sequencing, and spatial transcriptomics. Ehf-knockout mice, KPC (LSL-KrasG12D/+, LSL-Trp53R172H/+ and Pdx1-Cre) mice, CD45.1+ BALB/C nude mice, and CD34+ humanized mice were also used as subjects. Multiplexed immunohistochemistry and flow cytometry were performed to investigate the proportion of tumor-infiltrated C-X-C motif chemokine receptor 2 (CXCR2)+ neutrophils. In addition, multiplexed cytokines assays and chromatin immunoprecipitation assays were used to examine the mechanism. RESULTS: The TP53 mutation-mediated loss of tumoral EHF increased the recruitment of CXCR2+ neutrophils, modulated their spatial distribution, and further induced chemo- and immunotherapy resistance in clinical cohorts and preclinical syngeneic mice models. Mechanistically, EHF deficiency induced C-X-C motif chemokine ligand 1 (CXCL1) transcription to enhance in vitro and in vivo CXCR2+ neutrophils migration. Moreover, CXCL1 or CXCR2 blockade completely abolished the effect, indicating that EHF regulated CXCR2+ neutrophils migration in a CXCL1-CXCR2-dependent manner. The depletion of CXCR2+ neutrophils also blocked the in vivo effects of EHF deficiency on chemotherapy and immunotherapy resistance. The single-cell RNA-sequencing results of PDAC treated with Nifurtimox highlighted the therapeutic significance of Nifurtimox by elevating the expression of tumoral EHF and decreasing the weightage of CXCL1-CXCR2 pathway within the microenvironment. Importantly, by simultaneously inhibiting the JAK1/STAT1 pathway, it could significantly suppress the recruitment and function of CXCR2+ neutrophils, further sensitizing PDAC to chemotherapy and immunotherapies. CONCLUSIONS: The study demonstrated the role of EHF in the recruitment of CXCR2+ neutrophils and the promising role of Nifurtimox in sensitizing pancreatic cancer to chemotherapy and immunotherapy.

Separation of Halogen Atoms by Sodium from Dehalogenative Reactions on a Au(111) Surface.

On-surface dehalogenative reactions have been promising in the construction of nanostructures with diverse morphologies and intriguing electronic properties, while halogen (X), as the main byproduct, often impedes the formation of extended nanostructures and property characterization, and the reaction usually requires high C-X activation temperatures, especially on relatively inert Au(111). Enormous efforts in precursor design, halogen-to-halide conversion, and the introduction of extrinsic metal atoms have been devoted to either eliminating dissociated halogens or reducing reaction barriers. However, it is still challenging to separate halogens from molecular systems while facilitating C-X activation under mild conditions. Herein, a versatile halogen separation strategy has been developed based on the introduction of extrinsic sodium (Na) into dehalogenative reactions on Au(111) as model systems that both isolates the dissociated halogens and facilitates the C-Br activation under mild conditions. Moreover, the combination of scanning tunneling microscopy imaging and density functional theory calculations reveals the formation of sodium halides (NaX) from halogens in these separation processes as well as the reduction in reaction temperatures and barriers, demonstrating the versatility of extrinsic sodium as an effective "cleaner" and "dehalogenator" of surface halogens. Our study demonstrates a valuable strategy to facilitate the on-surface dehalogenative reactions, which will assist in the precise fabrication of low-dimensional carbon nanostructures.

Chitosan­iodine complexes: Preparation, characterization, and antibacterial activity.

Bacterial infections have always been a major threat to public health, and the development of effective antibacterial substances from natural polymers is crucial. 2-Aminoisonicotinic acid (AN) was grafted onto chitosan by 1-ethyl-(3-dimethylaminopropyl)carbodiimide-mediated coupling reactions, and then modified chitosan­iodine (CSAN-I) complexes were prepared by solvent-assisted grinding. The samples were characterized using ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy, Raman spectroscopy, proton nuclear magnetic resonance spectroscopy, and X-ray diffraction, confirming that CSAN-I complexes had been successfully prepared. Thermogravimetric (TG) analysis indicated that the chemical modification of chitosan and iodine complexation reduced the thermal stability; X-ray photoelectron spectroscopy (XPS) analysis revealed that 81 % of the iodine in CSAN-I complex was in the form of triiodide ions. The iodine contents of three CSAN-I complexes (CSAN-I-1, CSAN-I-2 and CSAN-I-3) were 1.59 ± 0.22 %, 3.18 ± 0.26 %, and 5.56 ± 0.41 %, respectively. The antibacterial effects were evaluated in vitro, and the results indicated that CSAN-I complexes had strong antibacterial activities against both E. coli and S. aureus. In particular, CSAN-I-3 exhibited the best antibacterial effect. In addition, CSAN-I-3 was nontoxic to L929 cells with good cytocompatibility. Therefore, CSAN-I complexes can be considered as promising candidates for wound management in clinical applications.

Predictive Panel for Immunotherapy in Low-Grade Glioma.

BACKGROUND: The main treatment of low-grade glioma (LGG) is still surgical resection followed by radiotherapy and/or chemotherapy, which has certain limitations, including side effects and drug resistance. Immunotherapy is a promising treatment for LGG, but it is generally hindered by the tumor microenvironment with the limited expression of tumor antigens. METHODS: We integrated RNA sequencing data sets and clinical information and conducted consistent cluster analysis to explore the most suitable patients for immune checkpoint therapy. Gene set enrichment analysis, UMAP analysis, mutation correlation analysis, TIMER analysis, and TIDE analysis were used to identify the immune characteristics of 3 immune subtypes and the feasibility of 5 antigens as immune checkpoint markers. RESULTS: We analyzed the isolation and mutation of homologous recombination repair genes (HRR) of the 3 immune subtypes, and the HRR genes of the 3 subtypes were obviously segregated. Among them, the IS2 subtype has a large number of HRR gene mutations, which increases the immunogenicity of tumors-this is consistent with the results of tumor mutation load analysis of 3 immune subtypes. Then we evaluated the immune cell infiltration of immune subtypes and found that IS2 and IS3 subtypes were rich in immune cells. It is worth noting that there are many Treg cells and NK cells in the IS1 subtype. In addition, when analyzing the immune checkpoint gene expression of the 3 subtypes, we found that they were upregulated most in IS2 subtypes compared with other subtypes. Then when we further confirmed the role of immune-related genes in LGG; through TIDE analysis and TISIDB analysis, we obtained 5 markers that can predict the efficacy of ICB in patients with LGG. In addition, we confirmed that they were associated with poor prognosis through survival analysis. CONCLUSIONS: We obtained 3 reliable immune subtypes, and patients with the IS2 subtype are suitable for immunotherapy, in which NAMPT, SLC11A1, TNC, VIM, and SPP1 are predictive panel markers for ICB in the LGG group. Our findings provide a rationale for immunotherapy selection and prediction of patient prognosis in LGG patients.

Influence of sampling location and processing on the assembly and network of Polygoni Multiflori Radix surface microbiome.

The raw and processed roots of Polygonum multiflorum Thunb is a popular traditional Chinese medicine. However, Polygoni Multiflori Radix is easily contaminated by toxigenic fungi and mycotoxins during harvesting, processing, and transportation, thereby posing a health risk for consumers. This study aims to investigate the presence of fungi on the surface of raw and processed Polygoni Multiflori Radix collected from four producing areas using high-throughput sequencing. Results showed that the phyla Ascomycota and Basidiomycota, the genera Xeromyces, Cystofilobasidium, Eurotium, and Aspergillus were the dominant fungus, and significant differences are presented in four areas and two processed products. Three potential mycotoxin-producing fungi were detected, namely Trichosporon cutaneum, Aspergillus restrictus, and Fusarium oxysporum. The α-diversity and network complexity showed significant differences in four areas. Chao 1 and Shannon were highest in Yunnan (YN), then incrementally decreased from SC (Sichuan) to AH (Anhui) and GD (Guangdong) areas. Meanwhile, α-diversity was also strongly influenced by processing. Chao 1 and Shannon indices were higher in the raw group, however, the network complexity and connectivity were higher in the processed group. In conclusion, the assembly and network of the surface microbiome on Polygoni Multiflori Radix were influenced by sampling location and processing. This work provides details on the surface microbiome of Polygoni Multiflori Radix samples, which could ensure the drug and consumers' safety.

Flexible Hybrid Wearable Sensors for Pressure and Thermal Sensing Based on a Double-Network Hydrogel.

Flexible sensors have attracted great attention due to their wide applications in various fields such as motion monitoring and medical health. It is reasonable to develop a sensor with good flexibility, sensitivity, and biocompatibility for wearable device applications. In this study, a double-network hydrogel was obtained by blending poly(vinyl alcohol) (PVA) with poly(ethylene glycol) diacrylate (PEGDA), which combines the flexibility of the PVA network and the fast photocuring ability of PEGDA. Subsequently, polydopamine-coated carbon nanotubes were used as conductive fillers of the PVA-PEG hydrogel matrix to prepare a flexible sensor that exhibits an effective mechanical response and significant stability in mechanics and conductivity. More importantly, the resistance of the sensor is very sensitive to pressure and thermal changes due to the optimized conductive network in the hydrogel. A motion monitoring test showed that the flexible sensor not only responds quickly to the motion of different joints but also keeps the output signal stable after many cycles. In addition, the excellent cell affinity of the hybrid hydrogel also encourages its application in health monitoring and motion sensors.

Visualizing the Hierarchical Evolution of Aryl-Metal Bonding in Organometallic Nanostructures on Ag(111).

On-surface dehalogenative coupling reactions are promising for constructing nanostructures with diverse properties and functionalities. Extensive efforts have been devoted to single aryl-halogen (C-X) substituents and substitutions at various functionalization sites (typically including meta- and para-substitutions) to generate aryl-aryl single bonds. Moreover, multiple C-X substituents at the ortho-site and the peri- and bay-regions have been applied to create a variety of ring scaffolds. However, for multiple C-X substituents, the hierarchy of aryl-metal bond formation and dissociation remains elusive. Herein, by combining scanning tunneling microscopy imaging and density functional theory calculations, we have visualized and demonstrated the hierarchical evolution of aryl-metal bonding in organometallic intermediates involved in a dehalogenative coupling reaction on Ag(111), using a molecular precursor with both para-substitution and potential bay-region substitution. Our results elucidate how metal atoms are progressively embedded into and removed from organometallic intermediates, enhancing the understanding of on-surface dehalogenative coupling reactions for the controlled construction of the desired nanostructures.

Diversities of disability caused by lung cancer in the 66 Belt and Road initiative countries: a secondary analysis from the Global Burden of Disease Study 2019.

Objectives: Due to the increase in life expectancy and the aging of the global population, the "Belt and Road" ("B&R") countries are faced with varying degrees of lung cancer threat. The purpose of this study is to analyze the differences in the burden and trend of lung cancer disability in the "B&R" countries from 1990 to 2019 so as to provide an analytical strategic basis to build a healthy "B&R". Methods: Data were derived from the Global Burden of Disease 2019 (GBD 2019). Incidence, mortality, prevalence, the years lived with disability (YLDs), and disability-adjusted life years (DALYs) of lung cancer and those attributable to different risk factors were measured from 1990 to 2019. Trends of disease burden were estimated by using the average annual percent change (AAPC), and the 95% uncertainty interval (UI) was reported. Results: China, India, and the Russian Federation were the three countries with the highest burden of lung cancer in 2019. From 1990 to 2019, the AAPC of incidence, prevalence, mortality, and DALYs generally showed a downward trend in Central Asia (except Georgia) and Eastern Europe, while in China, South Asia (except Bangladesh), most countries in North Africa, and the Middle East, the trend was mainly upward. The AAPC of age-standardized incidence was 1.33% (1.15%-1.50%); the AAPC of prevalence, mortality, and DALYs from lung cancer in China increased by 24% (2.10%-2.38%), 0.94% (0.74%-1.14%), and 0.42% (0.25%-0.59%), respectively. A downward trend of the AAPC values of age-standardized YLD rate in men was shown in the vast majority of "B&R" countries, but for women, most countries had an upward trend. For adults aged 75 years or older, the age-standardized YLD rate showed an increasing trend in most of the "B&R" countries. Except for the DALY rate of lung cancer attributable to metabolic risks, a downward trend of the DALY rate attributable to all risk factors, behavioral risks, and environmental/occupational risks was shown in the vast majority of "B&R" countries. Conclusion: The burden of lung cancer in "B&R" countries varied significantly between regions, genders, and risk factors. Strengthening health cooperation among the "B&R" countries will help to jointly build a community with a shared future for mankind.

Room-temperature continuous-wave topological Dirac-vortex microcavity lasers on silicon.

Robust laser sources are a fundamental building block for contemporary information technologies. Originating from condensed-matter physics, the concept of topology has recently entered the realm of optics, offering fundamentally new design principles for lasers with enhanced robustness. In analogy to the well-known Majorana fermions in topological superconductors, Dirac-vortex states have recently been investigated in passive photonic systems and are now considered as a promising candidate for robust lasers. Here, we experimentally realize the topological Dirac-vortex microcavity lasers in InAs/InGaAs quantum-dot materials monolithically grown on a silicon substrate. We observe room-temperature continuous-wave linearly polarized vertical laser emission at a telecom wavelength. We confirm that the wavelength of the Dirac-vortex laser is topologically robust against variations in the cavity size, and its free spectral range defies the universal inverse scaling law with the cavity size. These lasers will play an important role in CMOS-compatible photonic and optoelectronic systems on a chip.

2-Pyridinecarboxaldehyde-Modified Chitosan-Silver Complexes: Optimized Preparation, Characterization, and Antibacterial Activity.

The widespread prevalence of infectious bacteria is one of the greatest threats to public health, and consequently, there is an urgent need for efficient and broad-spectrum antibacterial materials that are antibiotic-free. In this study, 2-pyridinecarboxaldehyde (PCA) was grafted onto chitosan (CS) and the modified CS coordinated with silver ions to prepare PCA-CS-Ag complexes with antibacterial activity. To obtain complexes with a high silver content, the preparation process was optimized using single-factor experiments and response surface methodology. Under the optimal preparation conditions (an additional amount of silver nitrate (58 mg), a solution pH of 3.9, and a reaction temperature of 69 °C), the silver content of the PCA-CS-Ag complex reached 13.27 mg/g. The structure of the PCA-CS-Ag complex was subsequently verified using ultraviolet-visible spectroscopy, Fourier-transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, and thermogravimetric analysis. Furthermore, three possible complexation modes of the PCA-CS-Ag complex were proposed using molecular mechanics calculations. The results of the antibacterial assay in vitro showed that the PCA-CS-Ag complex exhibited strong antibacterial activity against both Gram-positive and Gram-negative bacteria, exerting the synergistic antibacterial effect of modified chitosan and silver ions. Therefore, the PCA-CS-Ag complex is expected to be developed as an effective antibacterial material with promising applications in food films, packaging, medical dressings, and other fields.

Fungal microbiome related to mycotoxin contamination in medicinal and edible seed Semen Persicae.

Medicinal and edible seed Semen Persicae is susceptible to mycotoxin and fungal contamination. However, the occurrence of mycotoxin contamination and fungal infection is still unclear. In this paper, ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometry and high-throughput sequencing were conducted to determine the mycotoxin contents and fungal abundances of Semen Persicae. 42.86% of samples were positive for aflatoxin B1 (26.48-48.37 µg/kg) and 28.57% of samples were positive for aflatoxin B2 (1.47-4.82 µg/kg). Ochratoxin A and fumonisin B1 were only detected in one sample (91.02 and 34.61 µg/kg, respectively). Chao 1 and Shannon indices were significantly higher in the Dalian of Liaoning, Baotou of Innermongolia and Langfang of Hebei regions than in other groups. Ascomycota, Basidiomycota, Wallemia, Candica, Saccharomyces and Aspergillus were the predominant fungi and they were significantly region-specific. Simultaneously, the diversity, composition and co-occurrence network complexity in the mycotoxin-free group were significantly higher than those in the mycotoxin-contaminated group. Spearman correlation analysis showed aflatoxins, ochratoxin A and fumonisins contents were positively and significantly correlated with the abundances of Aspergillus, Rhodotorula, Wallemia and Candida. In conclusion, this study reported the prevalence of mycotoxin contamination and the great diversity of fungi associated with Semen Persicae for the first time, providing an early warning for subsequent potential mycotoxin biosynthesis.

Revealing the Orientation Selectivity of Tetrapyridyl-Substituted Porphyrins Constrained in Molecular "Klotski Puzzles".

Understanding and controlling molecular orientations in self-assembled organic nanostructures are crucial to the development of advanced functional nanodevices. Scanning tunneling microscopy (STM) provides a powerful toolbox to recognize molecular orientations and to induce orientation changes on surfaces at the single-molecule level. Enormous effort has been devoted to directly controlling the molecular orientations of isolated single molecules in free space. However, revealing and further controlling molecular orientation selectivity in constrained environments remain elusive. In this study, by a combination of STM imaging/manipulations and density functional theory calculations, we report the orientation selectivity of tetrapyridyl-substituted porphyrins in response to various local molecular environments in artificially constructed molecular "Klotski puzzles" on Au(111). With the assistance of STM lateral manipulations, "sliding-block" molecules were able to enter predefined positions, and specific molecular orientations were adopted to fit the local molecular environments, in which the intermolecular interaction was revealed to be the key to achieving the eventual molecular orientation selectivity. Our results demonstrate the essential role of local molecular environments in directing single-molecule orientations, which would shed light on the design of molecular structures to control preferred orientations for further applications in molecular nanodevices.

Highly anisotropic and elastic cellulosic scaffold guiding cell orientation and osteogenic differentiation via topological and mechanical cues.

Inspired by the similarity of anisotropic channels in wood to the canals of bone, the elastic wood-derived (EW) scaffolds with anisotropic channels were prepared via simple delignification treatment of natural wood (NW). We hypothesize that the degree of delignification will lead to differences in mechanical properties of scaffolds, which in turn directly affect the behaviors and fate of stem cells. The delignification process did not destroy the anisotropic channel structure of the scaffolds, but endowed the scaffolds with good elasticity and rapid stress relaxation. Interestingly, the micron-scale anisotropic channels of the scaffolds can highly promote the polarization of cells along the direction of channels. We also found that the alkaline phosphatase of EW scaffold can reach to about 13.1 U/gprot, which was about double that of NW scaffold. Moreover, the longer the delignification time, the better the osteogenic activity of the EW scaffolds. We further hypothesize that the osteogenic activity of scaffolds is related to the stress relaxation properties. The immunofluorescence staining showed that when the stress relaxation time of scaffold was shortened to about 10 s, the nuclear ratio of YAP of scaffold increased to 0.22, which well supports our hypothesis.

Lithium Bis(oxalate)borate Additive for Self-repairing Zincophilic Solid Electrolyte Interphases towards Ultrahigh-rate and Ultra-stable Zinc Anodes.

The artificial solid electrolyte interphase (SEI) plays a pivotal role in Zn anode stabilization but its long-term effectiveness at high rates is still challenged. Herein, to achieve superior long-life and high-rate Zn anode, an exquisite electrolyte additive, lithium bis(oxalate)borate (LiBOB), is proposed to in situ derive a highly Zn2+ -conductive SEI and to dynamically patrol its cycling-initiated defects. Profiting from the as-constructed real-time, automatic SEI repairing mechanism, the Zn anode can be cycled with distinct reversibility over 1800 h at an ultrahigh current density of 50 mA cm-2 , presenting a record-high cumulative capacity up to 45 Ah cm-2 . The superiority of the formulated electrolyte is further demonstrated in the Zn||MnO2 and Zn||NaV3 O8 full batteries, even when tested under harsh conditions (limited Zn supply (N/P≈3), 2500 cycles). This work brings inspiration for developing fast-charging Zn batteries toward grid-scale storage of renewable energy sources.

A B- and F-enriched buffering interphase enables a high-rate and high-stability SiOx/C anode.

A facile, universal surface engineering strategy is proposed to address the volume expansion and slow kinetic issues encountered by SiOx/C anodes. A B-/F-enriched buffering interphase is introduced onto SiOx/C by thermal treatment of pre-adsorbed lithium salts at 400 °C. The as-prepared anode integrates both high-rate performance and long-term cycling durability.

Sampling locations and processing methods shape fungi microbiome on the surface of edible and medicinal Arecae semen.

Introduction: Arecae semen, which is derived from the dried ripe seed of Areca catechu L., has been commonly used as one of the major traditional Chinese medicines (TCMs). Three types of crude herbal preparations, namely, raw Arecae semen (AS), Arecae semen tostum (SAS), and Arecae semen carbonisata (FAS), are available for different clinical applications in TCMs. Although aflatoxin contamination in Arecae semen has been reported preliminarily, only a few studies have been conducted on fungal contamination. Methods: In this study, the presence of fungi on the surface of three Arecae semen (AS, SAS, and FAS) that collected from four provinces were investigated using high-throughput sequencing and internal transcribed spacer 2. Results: Results showed that the phyla Ascomycota (75.45%) and Basidiomycota (14.29%) and the genera Wallemia (7.56%), Botryosphaeria (6.91%), Davidiella (5.14%), and Symbiotaphrina (4.87%) were the dominant fungi, and they presented significant differences in four areas and three processed products (p < 0.05). The α-diversity and network complexity exhibited significant differences in the four sampling locations (p < 0.05), with higher in Yunnan (Chao 1, 213.45; Shannon, 4.61; average degree, 19.96) and Hainan (Chao 1, 198.27; Shannon, 4.21; average degree, 22.46) provinces. Significant differences were noted in the three processed samples; and SAS group had highest α-diversity (Chao 1, 167.80; Shannon, 4.54) and network complexity (average degree, 18.32). Conclusions: In conclusion, the diversity and composition of microbiome on the surface of Arecae semen were shaped by sampling location and processing methods. This work provides details on the surface microbiome of Arecae semen samples and highlights the importance of roles of origin and processing methods in microbiomes, ensuring drug efficacy and food safety.

Nuclear PLD1 combined with NPM1 induces gemcitabine resistance through tumorigenic IL7R in pancreatic adenocarcinoma.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant gastrointestinal cancer with a 5-year survival rate of only 9%. Of PDAC patients, 15%-20% are eligible for radical surgery. Gemcitabine is an important chemotherapeutic agent for patients with PDAC; however, the efficacy of gemcitabine is limited due to resistance. Therefore, reducing gemcitabine resistance is essential for improving survival of patients with PDAC. Identifying the key target that determines gemcitabine resistance in PDAC and reversing gemcitabine resistance using target inhibitors in combination with gemcitabine are crucial steps in the quest to improve survival prognosis in patients with PDAC. METHODS: We constructed a human genome-wide CRISPRa/dCas 9 overexpression library in PDAC cell lines to screen key targets of drug resistance based on sgRNA abundance and enrichment. Then, co-IP, ChIP, ChIP-seq, transcriptome sequencing, and qPCR were used to determine the specific mechanism by which phospholipase D1 (PLD1) confers resistance to gemcitabine. RESULTS: PLD1 combines with nucleophosmin 1 (NPM1) and triggers NPM1 nuclear translocation, where NPM1 acts as a transcription factor to upregulate interleukin 7 receptor (IL7R) expression. Upon interleukin 7 (IL-7) binding, IL7R activates the JAK1/STAT5 signaling pathway to increase the expression of the anti-apoptotic protein, BCL-2, and induce gemcitabine resistance. The PLD1 inhibitor, Vu0155069, targets PLD1 to induce apoptosis in gemcitabine-resistant PDAC cells. CONCLUSIONS: PLD1 is an enzyme that has a critical role in PDAC-associated gemcitabine resistance through a non-enzymatic interaction with NPM1, further promoting the downstream JAK1/STAT5/Bcl-2 pathway. Inhibiting any of the participants of this pathway can increase gemcitabine sensitivity.

Irbesartan overcomes gemcitabine resistance in pancreatic cancer by suppressing stemness and iron metabolism via inhibition of the Hippo/YAP1/c-Jun axis.

BACKGROUND: Chemoresistance is the main reason for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Thus, there is an urgent need to screen out new targets and compounds to reverse chemotherapeutic resistance. METHODS: We established a bio-bank of human PDAC organoid models, covering a representative range of PDAC tumor subtypes. We screened a library of 1304 FDA-approved compounds to identify candidates efficiently overcoming chemotherapy resistance. The effects of the compounds were evaluated with a CellTiter-Glo-3D assay, organoid apoptosis assay and in vivo patient-derived xenograft (PDX), patient-derived organoid (PDO) and LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) genetically engineered mouse models. RNA-sequencing, genome editing, sphere formation assays, iron assays and luciferase assays were conducted to elucidate the mechanism. RESULTS: High-throughput drug screening of chemotherapy-resistant PDOs identified irbesartan, an angiotensin ‖ type 1 (AT1) receptor antagonist, which could synergistically enhance the ability of chemotherapy to kill PDAC cells. In vitro and in vivo validation using PDO, PDX and KPC mouse models showed that irbesartan efficiently sensitized PDAC tumors to chemotherapy. Mechanistically, we found that irbesartan decreased c-Jun expression by inhibiting the Hippo/YAP1 pathway and further overcame chemotherapy resistance in PDAC. We also explored c-Jun, a potential target of irbesartan, which can transcriptionally upregulate the expression of key genes involved in stemness maintenance (SOX9/SOX2/OCT4) and iron metabolism (FTH1/FTL/TFRC). More importantly, we observed that PDAC patients with high levels of c-Jun expression demonstrated poor responses to the current standard chemotherapy regimen (gemcitabine plus nab-paclitaxel). Moreover, patients with PDAC had significant survival benefits from treatment with irbesartan plus a standard chemotherapy regimen in two-center retrospective clinical cohorts and patients with high c-Jun expression exhibited a better response to combination chemotherapy. CONCLUSIONS: Irbesartan could be used in combination with chemotherapy to improve the therapeutic efficacy in PDAC patients with high levels of c-Jun expression. Irbesartan effectively inhibited chemotherapy resistance by suppressing the Hippo/YAP1/c-Jun/stemness/iron metabolism axis. Based on our findings, we are designing an investigator-initiated phase II clinical trial on the efficacy and safety of irbesartan plus a standard gemcitabine/nab-paclitaxel regimen in the treatment of patients with advanced III/IV staged PDAC and are hopeful that we will observe patient benefits.

The burden of congenital birth defects between 1990 and 2019 in China: an observational study.

Background: Congenital birth defects (CBDs) are a major public health issue. This study aims to assess trends in the burden of CBDs between 1990 and 2019 across China based on the Global Burden of Disease Study 2019 (GBD 2019). Methods: Indicators of the burden of CBDs included incidence, mortality, and disability-adjusted life years (DALYs). Metrics included number, rate, and age-standardized rate with 95% uncertainty intervals (UIs). Data were stratified by region [China, global, high-, middle-, low-socio-demographic index (SDI)], age, sex, and type of CBD. Average annual percentage changes (AAPC) and trends were evaluated. Results: In China, between 1990 and 2019, the age-standardized incidence rate for CBDs showed an increasing trend, with an AAPC of 0.26% (0.11% to 0.41%), reaching 148.12 per 105 person-years (124.03 to 176.33) in 2019. Most CBDs were congenital heart anomalies, with an AAPC of 0.12% (-0.08% to 0.32%). The age-standardized mortality rate for CBDs showed a decreasing trend, with an AAPC of -4.57% (-4.97% to -4.17%), reaching 4.62 per 105 person-years (3.88 to 5.57) in 2019. Most mortality was associated with congenital heart anomalies, with an AAPC of -3.77% (-4.35% to -3.19%). The age-standardized DALYs rate for CBDs showed a decreasing trend, with an AAPC of -3.74% (-3.95% to -3.52%), reaching 480.95 per 105 person-years (407.69 to 570.04) in 2019. Conclusions: Morbidity associated with CBDs increased in China between 1990 and 2019, accelerated by the adoption of the two-child policy, and ranked high globally. These findings emphasize the need for prenatal screening and primary and secondary prevention strategies.

Monolithically integrated photonic crystal surface emitters on silicon with a vortex beam by using bound states in the continuum.

Optical resonant cavities with high quality factor (Q-factor) are widely used in science and technology for their capabilities of strong confinement of light and enhanced light-matter interaction. The 2D photonic crystal structure with bound states in the continuum (BICs) is a novel concept for resonators with ultra-compact device size, which can be used to generate surface emitting vortex beams based on symmetry-protected BICs at the Γ point. Here, to the best of our knowledge, we demonstrate the first photonic crystal surface emitter with a vortex beam by using BICs monolithically grown on CMOS-compatible silicon substrate. The fabricated quantum-dot BICs-based surface emitter operates at 1.3 µm under room temperature (RT) with a low continuous wave (CW) optically pumped condition. We also reveal the BIC's amplified spontaneous emission with the property of a polarization vortex beam, which is promising to provide a novel degree of freedom in classical and quantum realms.