Adaptive optics pre-compensation for orbital angular momentum beams transmitting through simulated atmospheric turbulence.

We propose an adaptive optics (AO) pre-compensation scheme to improve the transmission quality of orbital angular momentum (OAM) beams in atmospheric turbulence. The distortion wavefront caused by atmospheric turbulence is obtained with the Gaussian beacon from the receiver. The AO system imposes the conjugate distortion wavefront onto the outgoing OAM beams at the transmitter, tto achieve the pre-compensation. Using the scheme, we conducted transmission experiments with different OAM beams in the simulated atmospheric turbulence. The experimental results indicated that the AO pre-compensation scheme can improve the transmission quality of the OAM beams in the atmospheric turbulence in real-time. It is found that the turbulence-induced crosstalk effects on neighboring modes are reduced by an average of 6 dB, and the system power penalty is improved by an average of 12.6 dB after pre-compensation.

SETD2 variation correlates with tumor mutational burden and MSI along with improved response to immunotherapy.

BACKGROUND: SETD2 protects against genomic instability via maintenance of homologous recombination repair (HRR) and mismatch repair (MMR) in neoplastic cells. However, it remains unclear whether SETD2 dysfunction is a complementary or independent factor to microsatellite instability-high (MSI-H) and tumor mutational burden-high (TMB-H) for immunocheckpoint inhibitor (ICI) treatment, and little is known regarding whether this type of dysfunction acts differently in various types of cancer. METHODS: This cohort study used multidimensional genomic data of 6726 sequencing samples from our cooperative and non-public GenePlus institute from April 1 through April 10, 2020. MSIsensor score, HRD score, RNAseq, mutational data, and corresponding clinical data were obtained from the TCGA and MSKCC cohort for seven solid tumor types. RESULTS: A total of 1021 genes underwent target panel sequencing reveal that SETD2 mutations were associated with a higher TMB. SETD2 deleterious mutation dysfunction affected ICI treatment prognosis independently of TMB-H (p < 0.01) and had a lower death hazard than TMB-H in pancancer patients (0.511 vs 0.757). Significantly higher MSI and lower homologous recombination deficiency were observed in the SETD2 deleterious mutation group. Improved survival rate was found in the MSKCC-IO cohort (P < 0.0001) and was further confirmed in our Chinese cohort. CONCLUSION: We found that SETD2 dysfunction affects ICI treatment prognosis independently of TMB-H and has a lower death hazard than TMB-H in pancancer patients. Therefore, SETD2 has the potential to serve as a candidate biomarker for ICI treatment. Additionally, SETD2 should be considered when dMMR is detected by immunohistochemistry.

Distorted wavefront detection of orbital angular momentum beams based on a Shack-Hartmann wavefront sensor.

The vortex beams carried Orbital Angular Momentum (OAM) have recently generated considerable interest due to their potential used in communication systems to increase transmission capacity and spectral efficiency. In this paper, the distorted wavefront detection based on Shack-Hartmann wavefront sensor (HWS) for the vortex beams is investigated. The detection slope of the helical phase sub-spot pattern is used as the calibrated slope zero point, and then the distortion phase of the vortex beam is detected by the HWS. Simulation and experimental results demonstrate that this method can detect the distortion phase of vortex beam with high precision and high frame rate, which is expected to accelerate the application of optical communication systems with vortex beams.

Role of PRKDC in cancer initiation, progression, and treatment.

The PRKDC gene encodes the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) protein. DNA-PKcs plays an important role in nonhomologous end joining (NHEJ) of DNA double-strand breaks (DSBs) and is also closely related to the establishment of central immune tolerance and the maintenance of chromosome stability. The occurrence and development of different types of tumors and the results of their treatment are also influenced by DNA-PKcs, and it may also predict the results of radiotherapy, chemotherapy, and therapy with immune checkpoint inhibitors (ICIs). Here, we discuss and review the structure and mechanism of action of PRKDC and DNA-PKcs and their relationship with cancer.

Simultaneous annihilation of microorganisms and volatile organic compounds from municipal solid waste storage rooms with slightly acidic electrolyzed water.

Great deal pathogenic bacteria and malodorous gases are hidden in municipal solid waste (MSW), which poses excellent environmental sanitation risks for sanitation workers and residents, and preventive measures should be implemented. In this study, the simultaneous annihilation of microorganisms and volatile organic compounds (VOCs) with slightly acidic electrolyzed water (SAEW) was investigated in an MSW storage room of a residential community in Shanghai, China. The microbial population of airborne, surfaces and handles of waste bins, hands of sanitation workers and the main components of VOCs were measured. The results indicated that the bacterial reduction efficiencies of SAEW with an available chlorine concentration (ACC) of 50-100 mg/L on surfaces and handles of waste bins and sanitation workers' hands were 22.7%-84.1%. Also, SAEW effectively reduced the average population of airborne bacteria and fungi by 358 and 378 colony-forming units (CFU)/m3 and decreased the detection rates of coliforms by 14.2%-51.9%. The concentrations of most VOCs were reduced by 21.4%-88.3% after spraying SAEW. And the accumulated values of carcinogenic and noncarcinogenic risks also tended to decrease with spraying SAEW. These findings imply that SAEW has significant application potential to control environmental sanitation risks in MSW storage rooms.

Low-Dose X-ray Excited Photodynamic Therapy Based on NaLuF4:Tb3+-Rose Bengal Nanocomposite.

X-ray excited photodynamic therapy (X-PDT), which utilizes X-rays as the energy source and X-ray luminescent nanoparticles (XLNPs) as the transducer to excite photosensitizers (PS), resolves the penetration problem of light in traditional PDT to enable the treatment of deep-seated tumors. Nevertheless, the high X-ray dosage used in X-PDT hampers its potential applications in clinics. In this study, to alleviate the dose problem, ß-NaLuF4:Tb3+ spherical nanoparticles (NPs) with ultrastrong green X-ray excited optical luminescence (XEOL) due to the less nonradiative relaxation probability and high X-ray absorption mass coefficient, which perfectly matches the absorption spectrum of a photosensitizer named rose bengal (RB), were synthesized and employed as the energy transducer for X-PDT. After covalent conjugation of NPs with RB, high Förster resonant energy transfer (FRET) efficiency up to 94.29% was achieved, leading to high production of singlet oxygen. In vivo X-PDT efficacy was evaluated by nude mice with a HepG2 tumor xenograft. With excellent biocompatibility, the synthesized NPs-RB nanocomposite showed significant antitumor efficiency up to 80 ± 12.3% with a total X-ray dose of only 0.19 Gy, demonstrating the feasibility of low-dose X-PDT in vivo for the first time. The present work provides a promising platform for X-PDT in deep-seated tumors.

Mixed organic ligand-based colorimetric and ratiometric chemosensors for Co2+: structure-activity relationships.

In this work, chemosensors based on mixed ligands were proposed for the cooperative detection of Co2+. The relationship between the specifically selected mixed organic ligands and the detection activities is discussed. Diverse responses to metal ions can be tuned by controlling the structural features of organic ligands, such as different sizes, geometries, substituents, and connectivity. Among the nine investigated systems, DHAB-Tpy, DHAB-Phen, and DHAB-Dpa displayed high selectivity and sensitivity for Co2+, with detection limits of 4.5 × 10-7 M, 1.1 × 10-7 M, and 8.0 × 10-8 M, respectively. The detection of Co2+ was not affected by other metal ions, anions, amino acids, proteins, nucleic acids, lipids and pH conditions. Furthermore, the proposed method was validated in the analysis of Co2+ in real water samples with satisfactory recovery and relative standard deviation values. TAC-Phen and TAC-Dpa could recognize Co2+ qualitatively, but could not detect Co2+ quantitatively. While TAC-Tpy, PAN-Tpy, PAN-Phen, and PAN-Dpa showed no metal ion selectivity. The experimental results were also rationalized by theoretical studies. A mixed ligand system can be used to produce a ratiometric absorption signal to avoid most ambiguities, such as the chemosensor environment and concentration, via self-calibration of two absorption bands. Structural insights derived from detection activities can provide valuable information for the design of new metal ion chemosensors by varying the type of organic ligands. Graphical abstracts The work represents a simple strategy for obtaining synthesis-free, inexpensive, and sensitivity-tunable chemosensors through mixing organic ligands of different sizes, substitutions, geometries, and connectivity to modulate the sensing behaviors.

The Role of Exosomes in Pancreatic Cancer.

Pancreatic cancer remains one of the deadliest cancers in the world, as a consequence of late diagnosis, early metastasis and limited response to chemotherapy, under which conditions the potential mechanism of pancreatic cancer progression requires further study. Exosomes are membrane vesicles which are important in the progression, metastasis and chemoresistance in pancreatic cancer. Additionally, they have been verified to be potential as biomarkers, targets and drug carriers for pancreatic cancer treatment. Thus, studying the role of exosomes in pancreatic cancer is significant. This paper focuses on the role of exosomes in the proliferation, metastasis and chemoresistance, as well as their potential applications for pancreatic cancer.

Chemoresistance in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC), generally known as pancreatic cancer (PC), ranks the fourth leading cause of cancer-related deaths in the western world. While the incidence of pancreatic cancer is displaying a rising tendency every year, the mortality rate has not decreased significantly because of late diagnosis, early metastasis, and limited reaction to chemotherapy or radiotherapy. Adjuvant chemotherapy after surgical resection is typically the preferred option to treat early pancreatic cancer. Although 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel can profoundly improve the prognosis of advanced pancreatic cancer, the development of chemoresistance still leads to poor clinical outcomes. Chemoresistance is multifactorial as a result of the interaction among pancreatic cancer cells, cancer stem cells, and the tumor microenvironment. Nevertheless, more pancreatic cancer patients will benefit from precision treatment and targeted drugs. Therefore, we outline new perspectives for enhancing the efficacy of gemcitabine after reviewing the related factors of gemcitabine metabolism, mechanism of action, and chemoresistance.

Combination therapy with BH3 mimetic and hyperthermia tends to be more effective on anti-melanoma treatment.

Malignant melanoma has shown increased incidence and high mortality rate in the last three decades. In this study, we investigated whether combination therapy with ch282-5 (a novel BH3 mimetic) and microwave hyperthermia could display synergistic antitumor effects against melanoma. Our results indicated that combination therapy reduced the viability and proliferation of melanoma cells. Through inhibiting the expression of anti-apoptotic proteins of Bcl-2 and IAP family and activating MAPK proteins, combined hyperthermia enhanced ch282-5-induced apoptosis. Combination therapy also synergistically disturbed the mTOR/p70S6k signaling pathway, which is important for cell survival and migration. Moreover, our results showed that combination therapy remarkably suppressed melanoma cell migration in vitro and significantly reduced experimental pulmonary metastasis in vivo. In conclusion, our results indicate that combination therapy with ch282-5 and hyperthermia has synergistic antitumor effects and provides a possible therapeutic strategy for advanced melanoma.

Identification of Serum Biomarkers for Gastric Cancer Diagnosis Using a Human Proteome Microarray.

We aimed to globally discover serum biomarkers for diagnosis of gastric cancer (GC). GC serum autoantibodies were discovered and validated using serum samples from independent patient cohorts encompassing 1,401 participants divided into three groups, i.e. healthy, GC patients, and GC-related disease group. To discover biomarkers for GC, the human proteome microarray was first applied to screen specific autoantibodies in a total of 87 serum samples from GC patients and healthy controls. Potential biomarkers were identified via a statistical analysis protocol. Targeted protein microarrays with only the potential biomarkers were constructed and used to validate the candidate biomarkers using 914 samples. To provide further validation, the abundance of autoantibodies specific to the biomarker candidates was analyzed using enzyme-linked immunosorbent assays. Receiver operating characteristic curves were generated to evaluate the diagnostic accuracy of the serum biomarkers. Finally, the efficacy of prognosis efficacy of the final four biomarkers was evaluated by analyzing the clinical records. The final panel of biomarkers consisting of COPS2, CTSF, NT5E, and TERF1 provides high diagnostic power, with 95% sensitivity and 92% specificity to differentiate GC patients from healthy individuals. Prognosis analysis showed that the panel could also serve as independent predictors of the overall GC patient survival. The panel of four serum biomarkers (COPS2, CTSF, NT5E, and TERF1) could serve as a noninvasive diagnostic index for GC, and the combination of them could potentially be used as a predictor of the overall GC survival rate.

Influence of axial-force errors on the deformation of the 4 m lightweight mirror and its correction.

The lightweight primary mirror of the four meter Chinese telescope is supported axially by a passive hydraulic system, in parallel with an active system. The figure is sensitive to the errors in the axial forces, which can be effectively corrected using active optics. The squared RMS of this figure approximately follows the χ2 distribution, as verified by Monte Carlo analysis. The probability distributions of the squared norm of the active-forces vector, of the squared norm of the leg-lengths vector in the hexapod platform, and of the squared RMS of the residual figure are discussed in terms of the bending modes obtained by singular-value decomposition of the influence matrix, the optical sensitivity matrix deduced through ray trace, and the Jacobian matrix of the hexapod platform. The results show that, within the 90% confidence interval, the RMS of the figure caused by the axial-force errors is less than 232.38 nm and is corrected to less than 3.26 nm by the active optics. The maximum values of the corresponding squared norms of the active-force vector and of the leg-lengths vector are deduced.

Molecular mechanisms of synergistic induction of apoptosis by the combination therapy with hyperthermia and cisplatin in prostate cancer cells.

Prostate Cancer has become the second leading cause of male cancer-related incidence and mortality in United States. Hyperthermia (HT) is known to serve as a powerful tool in treatment of prostate cancer in clinical. The combination treatment with HT and cisplatin has a synergistic effect to inhibit prostate cancer progression and demonstrates better clinical effectiveness than HT or chemotherapy alone. But molecular mechanisms of this phenomenon have not been illuminated clearly. In this study, we used MTS assay to examine cell viabilities of PC-3, LNCaP, DU-145 and RM-1 cells after treated by HT and cisplatin. Then colony formation of PC-3 and DU-145 cells after treated with HT and cisplatin were photographed. To investigate whether the combination therapy would enhance apoptosis of PC-3 and DU-145 cells, we used Western blot analysis to detect expression level of proteins on apoptosis-regulated signaling pathway in PC-3 and DU-145 cells. Our results showed that the combination treatment decreased cell viabilities and colony formation of prostate cancer cells in a dose-dependent manner and this combination therapy enhanced apoptosis of PC-3 and DU-145 cells via activation of Caspase-3 and cleavage of PARP. We also found that the combination therapy could down-regulate the anti-apoptotic Bcl-2 and IAP family proteins. At last, the combination therapy activated AMPKα-JNK signaling pathway and inhibited Akt-mTOR-p70s6k signaling pathway to promote apoptosis of PC-3 and DU-145 cells. In conclusion, this study clearly elucidated how the combination therapy with HT and cisplatin promoted apoptosis of prostate cancer cells in synergy.

[Pharmacokinetic study on combined application of gastrodin and puerarin in rats].

To establish a HPLC method for simultaneously determining plasma concentrations of gastrodin (Gas) and its metabolites hydroxybenzyl alcohol (HBA), puerarin (Pur) and internal standard (IS) p-hydroxyphenylethanol (Tyr) in rats and studying the pharmacokinetic process and interactions of gastrodin and puerarin after single and combined intravenous injection and oral administration. With Tyr as the internal standard, plasma samples were processed with methanol for protein precipitation, supernatant was dried with N2, and residues were re-dissolved with acetonitrile-0.05% phosphoric acid (20: 80). Chromatography was carried out on an Agilent ZORBAX SB-Aq C18 column (4.6 mm x 250 mm, 5 µm), with acetonitrile-0.05% phosphoric acid as the gradient mobile phase for the gradient elution. The UV detector wavelength was set at 221 nm for Gas HBA and IS and 250 nm for Pur. After the single or combined administration of Gas and Pur, their plasma concentrations in rats were detected. WinNonlin 5.2 pharmacokinetic software and SPSS 17. 0 software were used to respectively calculate pharmacokinetic parameters of each group, make a statistical analysis and compare the pharmacokinetic processes of Gas and Pur after the single or combined administration. According to the results, the absolute recoveries between low, media and high concentrations of Gas, HBA and Pur and IS as well as Tyr were more than 77.20%, with a good linearity (r > 0.999 6, n = 5) for Gas, HBA and Pur within concentration ranges of 0.10-101, 0.03-7.58 and 0.05-5.98 mg xL ('1) respectively. The lower limits of quantification for Gas, HBA and Pur were 0.10, 0.03, 0.05 mg x L(-1), respectively. Their in-ra-day and inter-day precisions were less than 12% with the accuracy between 85. 1% -1 10. %. All of the three substances and IS were stable during the whole analysis process. The findings showed significant differences in the main in vivo pharmacokinetic parame-ers in rats (AUC, C.(max) T,½ T.(max) MRT) after the single and combined administration of Gas and Pur. Either after the oral adminis-ration or after the intravenous injection, parameters showed a lower clearance rate ( L) longer mean residence time ( RT) and higher relative bioavailability, especially after the oral administration. Specifically, the relative bioavailability of the combined oral ad-inistration of Pur was 10. 7 times of that of the single administration, while that of Gas was 1. times of that of the single administra-ion. The combined administration of Gas and Pur can promote the absorption, decrease the elimination rate and prolong the mean resi-ence time. The method is simple and accurate and can be applied in the simultaneous determination of plasma concentrations of Gas, HBA and Pur in rats and the pharmacokinetic studies.

Pharmacokinetics of Maxing Shigan decoction in normal rats and RSV pneumonia model rats by HPLC-MS/MS.

To establish a LC-MS/MS method to determine the concentrations of liquiritin, glycyrrhizin, glycyrrhetinic acid, amygdalin, amygdalin prunasin, ephedrine, pseudoephedrine and methylephedrine of Maxing Shigan decoction in rat plasma, and study the differences on their pharmacokinetic process in normal rats and RSV pneumonia model rats. After normal rats and RSV pneumonia model rats were orally administered with Maxing Shigan decoction, the blood was collected from retinal vein plexus of different time points. Specifically, tetrahydropalmatine was taken as internal standard for determining ephedrine, while chloramphenicol was taken as internal standard for determining other components. After plasma samples were pre-treated as the above, the supernatant was dried with nitrogen blowing concentrator and then redissolved with methylalcohol. The chromatography was eluted with mobile phase consisted of acetonitrile and 0.1% formic acid solution in a gradient manner. ESI sources were adopted to scan ingredients in ephedra in a positive ion scanning mode and other ingredientsin a negative ion scanning mode. The multiple-reaction monitoring (MRM) method was developed the plasma concentration of each active component. The pharmacokinetic parameters of each group were calculated by using Win-Nonlin 4.1 software and put into the statistical analysis. The result showed the plasma concentration of the eight active ingredients, i.e., liquiritin, glycyrrhizin, glycyrrhetinic acid, amygdalin, amygdalin prunasin, ephedrine, pseudoephedrine and methylephedrine within the ranges of 1.04-1040, 1.04-1040, 0.89-445, 1.05-4200, 1.25-2490, 0.3-480, 0.3-480, 0.3-480 microg x L(-1), with a good linearity and satisfactory precision, recovery and stability in the above ingredients. After modeling, except for glycyrrhetinic acid whose pharmacokinetic parameters were lacked due to the data missing, all of the rest components showed significant higher Cmax, AUC(0-1) and lower clearance rate (CL) than that of the normal group, indicating the increase in absorption in rats in the pathological state by reducing the clearance rate. The method is accurate and sensitive and so can be used to determine the plasma concentrations of the eight active ingredients in Maxing Shigan decoction. RSV pneumonia-infected rats absorbed more ingredients in Maxing Shigan decoction.

Establishment of an animal model of vascular restenosis with bilateral carotid artery grafting.

BACKGROUND: Vascular restenosis occurring after CABG is a major clinical problem that needs to be addressed. Vein grafts are associated with a higher degree of stenosis than artery grafts. However, the mechanism responsible for this effect has not been elucidated. We aimed to establish a rabbit model of vascular restenosis after bilateral carotid artery grafting, and to investigate the associated spatiotemporal changes of intimal hyperplasia in carotid artery and jugular vein grafts after surgery. MATERIAL AND METHODS: Twenty adult New Zealand white rabbits (10 males; 10 females), weighing 2.0-2.5 kg, were obtained from the Experimental Animal Center of Southern Medical University, Guangzhou, China (License No.: scxk-Guangdong-2006-0015). We quantitatively analyzed intimal thickness, area, and degree of stenosis in carotid artery and jugular vein bridges. RESULTS: After 8 weeks of a high-fat diet, rabbit carotid arteries showed early atherosclerotic lesions. With increasing time after surgery, carotid artery and jugular vein grafts showed histopathological and morphological changes, including smooth muscle cell migration, lipid deposition, intimal hyperplasia, and vascular stenosis. The degree of vascular stenosis was significantly higher in vein grafts than in artery grafts at all time points - 35.1±6.7% vs. 16.1±2.6% at Week 12, 56.2±8.5% vs. 23.4±3.4% at Week 16, and 71.2±1.3% vs. 25.2±5.3% at Week 20. CONCLUSIONS: Rabbit bilateral carotid arteries were grafted with carotid artery and jugular vein bridges to simulate pathophysiological processes that occur in people after CABG surgery.

Magnetic integrated double-trap filter utilizing the mutual inductance for reducing current harmonics in high-speed railway traction inverters.

Current harmonics are generated at the switching frequency and its multiples when the traction converters are modulated. To address this, multi-trap filters are introduced, which are capable of selectively eliminating these specific harmonics to the limits set by IEEE 519-2014. This targeted removal significantly reduces the need for high total inductance, thereby allowing for a more compact filter design. Comparatively, to traditional inductor-capacitor-inductor (LCL) filters, more magnetic cores are needed for trap inductors. Furthermore, the traction systems have not been examined in conjunction with multi-trap filters. To reduce the filter size and investigate its application in traction converters, this paper presents an integrated double-trap LCL (DTLCL) filter. A tiny capacitor is connected in parallel with the grid-side inductor to form one LC-trap. In addition, another LC-trap is formed by connecting the equivalent trap inductor, introduced through the magnetic coupling between inverter-side and grid-side inductors, in series with the filter capacitor. The presented filters' features are thoroughly analyzed, and the design method has been developed. Finally, the simulation and hardware-in-the-loop (HIL) experiment results validate the proposed method's viability and efficacy. Compared to the discrete windings, the integrated ones enable a size decrease of two cores. Furthermore, the proposed filters can meet IEEE 519-2014 criteria with 0.3% for all the current switching harmonics and total harmonic distortion (THD) of 2.36% of the grid-side current.

A senescence-related lncRNA signature predicts prognosis and reflects immune landscape in HNSCC.

OBJECTIVE: Long noncoding RNAs (lncRNAs) regulate cancer cell senescence in many cancers. However, their specific involvement in head and neck squamous cell carcinoma (HNSCC) remains unclear. We are looking for an ingenious prognostic signature that utilizes senescence-related lncRNAs (SRlncRNAs) to predict prognosis and provide insights into the immune landscape in HNSCC. MATERIALS AND METHODS: HNSCC clinical and Cellular senescence genes information were collected from The Cancer Genome Atlas and Human Aging Genomic Resources. Then we performed Cox and Lasso regression to locate SRlncRNAs related to the prognosis of HNSCC and built a predictive signature. Further, prognosis assessment, potential mechanisms, and immune status were assessed by Kaplan-Meier analysis, Gene Set Enrichment Analysis (GSEA), and CIBERSORT, respectively. RESULTS: A prognosis prediction model based on sixteen SRlncRNAs was identified and internally validated. Then, patients with high-risk scores suffered an unfavorable overall survival (All p < 0.05). The risk score, age, and stage were independent prognostic parameters (all p < 0.001). Our model has good predictive ability (The AUC (area under the curves) 1-year = 0.707, AUC3-year = 0.748 and AUC5-year = 0.779). Subsequently, GESA revealed SRlncRNAs regulated immune responses. Patients in the high-risk group had higher tumor mutation burden and Tumor Immune Dysfunction and Exclusion but lower levels of 37 immune checkpoint genes, immune scores, and immune cells like CD8 + T cells, follicular helper T cells, and regulatory T cells. CONCLUSIONS: A prognostic model based on SRlncRNAs is the potential target for improving immunotherapy outcomes for HNSCC.

Endowing Polyetheretherketone with Anti-Infection and Immunomodulatory Properties through Guanidination Carbon Dots Modification to Promote Osseointegration in Diabetes with MRSA Infection.

Methicillin-resistant Staphylococcus aureus (MRSA) infection and compromised immunity are the severe complications associated with implantation surgery in diabetes mellitus. Enhancing the antibacterial and immunomodulatory properties of implants represents an effective approach to improve the osseointegration of implant in diabetes mellitus. Herein, guanidination carbon dots (GCDs) with antibacterial and immunoregulatory functions are synthesized. The GCDs demonstrate killing effect on MRSA without detectable induced resistance. Additionally, they promote the polarization of macrophages from the M1 to M2 subtype, with the inhibiting pro-inflammatory cytokines and promoting anti-inflammatory factors. Correspondingly, GCDs are immobilized onto sulfonated polyether ether ketone (SP@GCDs) using a polyvinyl butyraldehyde (PVB) coating layer through soaking-drying technique. SP@GCDs maintain stable antibacterial efficacy against MRSA for six consecutive days and retain the immunomodulatory function, while also possessing the long-term storage stability and biocompatibility of more than 6 months. Moreover, SP@GCDs significantly promote the proliferation and mineralization of osteoblasts. SP@GCDs facilitate osteogenesis through immunoregulatory. Additionally, SP@GCDs exert stable antibacterial and immune regulatory functions in implantation site of a diabetes rat, effectively promoting implant osseointegration regardless of the MRSA infection. These findings provide valuable insights into implant modification through designing nanomaterials with multifunction for enhancing osseointegration of diabetes mellitus, suggesting the promising clinical application prospects.

Roflumilast inhibits tumor growth and migration in STK11/LKB1 deficient pancreatic cancer.

Pancreatic cancer is a malignant tumor of the digestive system. It is highly aggressive, easily metastasizes, and extremely difficult to treat. This study aimed to analyze the genes that might regulate pancreatic cancer migration to provide an essential basis for the prognostic assessment of pancreatic cancer and individualized treatment. A CRISPR knockout library directed against 915 murine genes was transfected into TB 32047 cell line to screen which gene loss promoted cell migration. Next-generation sequencing and PinAPL.py- analysis was performed to identify candidate genes. We then assessed the effect of serine/threonine kinase 11 (STK11) knockout on pancreatic cancer by wound-healing assay, chick agnosia (CAM) assay, and orthotopic mouse pancreatic cancer model. We performed RNA sequence and Western blotting for mechanistic studies to identify and verify the pathways. After accelerated Transwell migration screening, STK11 was identified as one of the top candidate genes. Further experiments showed that targeted knockout of STK11 promoted the cell migration and increased liver metastasis in mice. Mechanistic analyses revealed that STK11 knockout influences blood vessel morphogenesis and is closely associated with the enhanced expression of phosphodiesterases (PDEs), especially PDE4D, PDE4B, and PDE10A. PDE4 inhibitor Roflumilast inhibited STK11-KO cell migration and tumor size, further demonstrating that PDEs are essential for STK11-deficient cell migration. Our findings support the adoption of therapeutic strategies, including Roflumilast, for patients with STK11-mutated pancreatic cancer in order to improve treatment efficacy and ultimately prolong survival.