USP9X-mediated REV1 deubiquitination promotes lung cancer radioresistance via the action of REV1 as a Rad18 molecular scaffold for cystathionine γ-lyase.

BACKGROUND: Radioresistance is a key clinical constraint on the efficacy of radiotherapy in lung cancer patients. REV1 DNA directed polymerase (REV1) plays an important role in repairing DNA damage and maintaining genomic stability. However, its role in the resistance to radiotherapy in lung cancer is not clear. This study aims to clarify the role of REV1 in lung cancer radioresistance, identify the intrinsic mechanisms involved, and provide a theoretical basis for the clinical translation of this new target for lung cancer treatment. METHODS: The effect of targeting REV1 on the radiosensitivity was verified by in vivo and in vitro experiments. RNA sequencing (RNA-seq) combined with nontargeted metabolomics analysis was used to explore the downstream targets of REV1. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to quantify the content of specific amino acids. The coimmunoprecipitation (co-IP) and GST pull-down assays were used to validate the interaction between proteins. A ubiquitination library screening system was constructed to investigate the regulatory proteins upstream of REV1. RESULTS: Targeting REV1 could enhance the radiosensitivity in vivo, while this effect was not obvious in vitro. RNA sequencing combined with nontargeted metabolomics revealed that the difference result was related to metabolism, and that the expression of glycine, serine, and threonine (Gly/Ser/Thr) metabolism signaling pathways was downregulated following REV1 knockdown. LC-MS/MS demonstrated that REV1 knockdown results in reduced levels of these three amino acids and that cystathionine γ-lyase (CTH) was the key to its function. REV1 enhances the interaction of CTH with the E3 ubiquitin ligase Rad18 and promotes ubiquitination degradation of CTH by Rad18. Screening of the ubiquitination compound library revealed that the ubiquitin-specific peptidase 9 X-linked (USP9X) is the upstream regulatory protein of REV1 by the ubiquitin-proteasome system, which remodels the intracellular Gly/Ser/Thr metabolism. CONCLUSION: USP9X mediates the deubiquitination of REV1, and aberrantly expressed REV1 acts as a scaffolding protein to assist Rad18 in interacting with CTH, promoting the ubiquitination and degradation of CTH and inducing remodeling of the Gly/Ser/Thr metabolism, which leads to radioresistance. A novel inhibitor of REV1, JH-RE-06, was shown to enhance lung cancer cell radiosensitivity, with good prospects for clinical translation.

Three-Dimensional Optothermal Manipulation of Light-Absorbing Particles in Phase-Change Gel Media.

Rational manipulation and assembly of discrete colloidal particles into architected superstructures have enabled several applications in materials science and nanotechnology. Optical manipulation techniques, typically operated in fluid media, facilitate the precise arrangement of colloidal particles into superstructures by using focused laser beams. However, as the optical energy is turned off, the inherent Brownian motion of the particles in fluid media impedes the retention and reconfiguration of such superstructures. Overcoming this fundamental limitation, we present on-demand, three-dimensional (3D) optical manipulation of colloidal particles in a phase-change solid medium made of surfactant bilayers. Unlike liquid crystal media, the lack of fluid flow within the bilayer media enables the assembly and retention of colloids for diverse spatial configurations. By utilizing the optically controlled temperature-dependent interactions between the particles and their surrounding media, we experimentally exhibit the holonomic microscale control of diverse particles for repeatable, reconfigurable, and controlled colloidal arrangements in 3D. Finally, we demonstrate tunable light-matter interactions between the particles and 2D materials by successfully manipulating and retaining these particles at fixed distances from the 2D material layers. Our experimental results demonstrate that the particles can be retained for over 120 days without any change in their relative positions or degradation in the bilayers. With the capability of arranging particles in 3D configurations with long-term stability, our platform pushes the frontiers of optical manipulation for distinct applications such as metamaterial fabrication, information storage, and security.

Assessment of transient elastography in diagnosing MAFLD and the early effects of sleeve gastrectomy on MAFLD among the Chinese population.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) has become a prevalent chronic liver disease among patients with obesity. Bariatric surgery, such as sleeve gastrectomy (SG), shows promise in improving the unfavorable condition of MAFLD. Transient elastography (TE) can be utilized to assess the extent of steatosis and liver fibrosis, providing a noninvasive method for preoperative prediction and postoperative evaluation of MAFLD. This study aims to investigate the effectiveness of TE in diagnosing MAFLD by evaluating liver steatosis and tissue stiffness, as well as assessing the early impact of SG in the treatment of obesity-associated MAFLD. METHODS: In this study, the authors collected preoperative and 6-month postoperative data from patients with obesity who were diagnosed with MAFLD by intraoperative liver biopsy. The patients underwent SG at our hospital between August 2021 and April 2023. The authors estimated the diagnostic accuracy for the steatosis and fibrosis categories using the area under the receiver operating characteristic curve (AUROC). The authors also evaluated the influence of disease prevalence on the positive predictive value and negative predictive value. MAFLD diagnosis was based on the liver steatosis activity and fibrosis scoring system. The authors used univariate and multivariate logistic regression analyses to identify factors contributing to severe MAFLD. To visualize the results, the authors created a nomogram and enhanced it with bootstrap resampling for internal validation. Additionally, the authors plotted receiver operating characteristic and calibration curves. The authors compared preoperative and postoperative data, including general information, laboratory tests, and TE results, to assess the early impact of SG in the treatment of obesity-associated MAFLD. RESULTS: Based on the results of liver biopsy, the AUROC for controlled attenuation parameter (CAP) in identifying steatosis was found to be 0.843 (95% CI: 0.729-0.957) for S≥S1, 0.863 (95% CI: 0.786-0.940) for S≥S2, and 0.872 (95% CI: 0.810-0.934) for S=S3. The Youden limits for S≥S1, S≥S2, and S≥S3 were determined to be 271 dB/m, 292 dB/m, and 301 dB/m, respectively. Similarly, the AUROC for liver stiffness measurement (LSM)/E in detecting liver fibrosis was 0.927 (95% CI: 0.869-0.984) for F≥F2, 0.919 (95% CI: 0.824-0.979) for F≥F3, and 0.949 (95% CI: 0.861-0.982) for F=F4, with Youden cutoff values of 7.5 kPa, 8.3 kPa, and 10.4 kPa, respectively. Patients with A≥3 and/or F≥3 were classified as having severe MAFLD. Multivariate logistic regression analysis identified CAP, E, LDL, and AST as the best diagnostic factors for severe MAFLD, and a nomogram was constructed based on these factors. The AUROC of the nomogram for the assessment of severe MAFLD was 0.824 (95% CI: 0.761-0.887), which was further validated by 1000 bootstrap resamplings with a bootstrap model area under curve of 0.823. Finally, after a 6-month follow-up period, the steatosis grade and fibrosis stage of the patients were graded based on the optimal cutoff values for CAP and LSM. Significant reductions in BMI, waist circumference, HbA1c, fasting glycemia, triglycerides, high density lipoprotein (HDL), glutamic pyruvic transaminase (ALT), glutamic oxaloacetic transaminase (AST), gamma glutamyl transpeptidase (GGT), CAP, LSM, steatosis grade, and fibrosis stage were observed compared to the preoperative values. CONCLUSION: In this prospective study, the authors investigated the use of CAP and LSM as alternatives to liver biopsy for evaluating hepatic steatosis and fibrosis in patients with obesity combined with MAFLD. Furthermore, the authors examined the impact of SG on metabolic indicators and the progression of fatty liver disease during the early postoperative period, and observed significant improvements in both aspects.

Light-driven C-H activation mediated by 2D transition metal dichalcogenides.

C-H bond activation enables the facile synthesis of new chemicals. While C-H activation in short-chain alkanes has been widely investigated, it remains largely unexplored for long-chain organic molecules. Here, we report light-driven C-H activation in complex organic materials mediated by 2D transition metal dichalcogenides (TMDCs) and the resultant solid-state synthesis of luminescent carbon dots in a spatially-resolved fashion. We unravel the efficient H adsorption and a lowered energy barrier of C-C coupling mediated by 2D TMDCs to promote C-H activation. Our results shed light on 2D materials for C-H activation in organic compounds for applications in organic chemistry, environmental remediation, and photonic materials.

Targeting FBXO22 enhances radiosensitivity in non-small cell lung cancer by inhibiting the FOXM1/Rad51 axis.

Radioresistance is a major constraint on the efficacy of lung cancer radiotherapy, but its mechanism has not been fully elucidated. Here, we found that FBXO22 was aberrantly highly expressed in lung cancer and that FBXO22 knockdown increased the radiosensitivity of lung cancer cells. Mechanistically, FBXO22 promoted Rad51 gene transcription by increasing the level of FOXM1 at the Rad51 promoter, thereby inducing the formation of lung cancer radioresistance. Furthermore, we found that deguelin, a potential inhibitor of FBXO22, enhanced radiosensitivity in an FBXO22/Rad51-dependent manner and was safely tolerated in vivo. Collectively, our results illustrate that FBXO22 induces lung cancer radioresistance by activating the FOXM1/Rad51 axis and provide preclinical evidence for the clinical translation of this critical target.

Near-Infrared Light-Induced Reversible Deactivation Radical Polymerization: Expanding Frontiers in Photopolymerization.

Photoinduced reversible deactivation radical polymerization (photo-RDRP) or photoinduced controlled/living radical polymerization has emerged as a versatile and powerful technique for preparing functional and advanced polymer materials under mild conditions by harnessing light energy. While UV and visible light (λ = 400-700 nm) are extensively employed in photo-RDRP, the utilization of near-infrared (NIR) wavelengths (λ = 700-2500 nm) beyond the visible region remains relatively unexplored. NIR light possesses unique properties, including enhanced light penetration, reduced light scattering, and low biomolecule absorption, thereby providing opportunities for applying photo-RDRP in the fields of manufacturing and medicine. This comprehensive review categorizes all known NIR light-induced RDRP (NIR-RDRP) systems into four mechanism-based types: mediation by upconversion nanoparticles, mediation by photocatalysts, photothermal conversion, and two-photon absorption. The distinct photoinitiation pathways associated with each mechanism are discussed. Furthermore, this review highlights the diverse applications of NIR-RDRP reported to date, including 3D printing, polymer brush fabrication, drug delivery, nanoparticle synthesis, and hydrogel formation. By presenting these applications, the review underscores the exceptional capabilities of NIR-RDRP and offers guidance for developing high-performance and versatile photopolymerization systems. Exploiting the unique properties of NIR light unlocks new opportunities for synthesizing functional and advanced polymer materials.

Design of an Oxygen-Tolerant Photo-RAFT System for Protein-Polymer Conjugation Achieving High Bioactivity.

Protein-polymer conjugates have significant potential in pharmaceutical and biomedical applications. To enable their widespread use, robust conjugation techniques are crucial. This study introduces a photo-initiated reversible addition-fragmentation chain-transfer (Photo-RAFT) polymerization system that exhibits excellent oxygen tolerance. This system allows for the synthesis of protein-polymer conjugates with high bioactivity under mild and aerobic conditions. Three photocatalytic systems utilizing Eosin Y (EY) as the photocatalyst with two different cocatalysts (ascorbic acid and triethanolamine) were investigated, each generating distinct reactive oxygen species (ROS) such as singlet oxygen, superoxide, hydrogen peroxide, and hydroxyl radicals. The impact of these ROS on three model proteins (lysozyme, albumin, and myoglobin) was evaluated, demonstrating varying bioactivities based on the ROS produced. The EY/TEOA system was identified as the optimal photo-RAFT initiating system, enabling the preparation of protein-polymer conjugates under aerobic conditions while maintaining high protein enzymatic activity. To showcase the potential of this approach, lysozyme-poly(dimethylaminoethyl acrylate) conjugates were successfully prepared and exhibited enhanced antimicrobial property against Gram-positive and Gram-negative bacteria.

A Three-Dimensional Neuromorphic Photosensor Array for Nonvolatile In-Sensor Computing.

In-sensor computing hardware based on emerging reconfigurable photosensors can effectively reduce redundant data and decrease power consumption, which can greatly promote the evolution of machine vision. However, because of the complex device structures and low integration abilities, the common architectures mainly lie in two dimensions, resulting in low time and area efficiencies. Here we propose a three-dimensional (3D) neuromorphic photosensor array for parallel in-sensor image processing. It is constructed on a vertical Graphite/CuInP2S6/Graphite photosensor unit, where the directional Cu+ ion migrations after voltage pulse programming enable a reconfigurable photovoltaic effect and an in-sensor computing capability. With a memristor-like device structure, van der Waals interfaces, and a high uniformity with a low crosstalk problem, a 10 × 10 array is fabricated for intelligent image recognition. Furthermore, using a vertically stacked 3D 3 × 3 × 3 array, we demonstrate an in-sensor convolution strategy with high time and area efficiencies.

A semiconductor-electrocatalyst nano interface constructed for successive photoelectrochemical water oxidation.

Photoelectrochemical water splitting has long been considered an ideal approach to producing green hydrogen by utilizing solar energy. However, the limited photocurrents and large overpotentials of the anodes seriously impede large-scale application of this technology. Here, we use an interfacial engineering strategy to construct a nanostructural photoelectrochemical catalyst by incorporating a semiconductor CdS/CdSe-MoS2 and NiFe layered double hydroxide for the oxygen evolution reaction. Impressively, the as-prepared photoelectrode requires an low potential of 1.001 V vs. reversible hydrogen electrode for a photocurrent density of 10 mA cm-2, and this is 228 mV lower than the theoretical water splitting potential (1.229 vs. reversible hydrogen electrode). Additionally, the generated current density (15 mA cm-2) of the photoelectrode at a given overpotential of 0.2 V remains at 95% after long-term testing (100 h). Operando X-ray absorption spectroscopy revealed that the formation of highly oxidized Ni species under illumination provides large photocurrent gains. This finding opens an avenue for designing high-efficiency photoelectrochemical catalysts for successive water splitting.

Liver Transplantation Outcomes of HBV-, HCV-, and Alcohol-induced Hepatocellular Carcinoma in the United States: Analysis of National Inpatient Samples.

OBJECTIVE: Liver transplantation is a current treatment option for hepatocellular carcinoma (HCC). The United States National Inpatient Sample database was utilized to identify risk factors that influence the outcome of liver transplantation, including locoregional recurrence, distant metastasis, and in-hospital mortality, in HCC patients with concurrent hepatitis B infection, hepatitis C infection, or alcoholic cirrhosis. METHODS: This retrospective cohort study included HCC patients (n=2391) from the National Inpatient Sample database who underwent liver transplantation and were diagnosed with hepatitis B or C virus infection, co-infection with hepatitis B and C, or alcoholic cirrhosis of the liver between 2005 and 2014. Associations between HCC etiology and post-transplant outcomes were examined with multivariate analysis models. RESULTS: Liver cirrhosis was due to alcohol in 10.5% of patients, hepatitis B in 6.6%, hepatitis C in 10.8%, and combined hepatitis B and C infection in 24.3%. Distant metastasis was found in 16.7% of patients infected with hepatitis B and 9% of hepatitis C patients. Local recurrence of HCC was significantly more likely to occur in patients with hepatitis B than in those with alcohol-induced disease. CONCLUSION: After liver transplantation, patients with hepatitis B infection have a higher risk of local recurrence and distant metastasis. Postoperative care and patient tracking are essential for liver transplant patients with hepatitis B infection.

Detection and analysis of chiral molecules as disease biomarkers.

The chirality of small metabolic molecules is important in controlling physiological processes and indicating the health status of humans. Abnormal enantiomeric ratios of chiral molecules in biofluids and tissues occur in many diseases, including cancers and kidney and brain diseases. Thus, chiral small molecules are promising biomarkers for disease diagnosis, prognosis, adverse drug-effect monitoring, pharmacodynamic studies and personalized medicine. However, it remains difficult to achieve cost-effective and reliable analysis of small chiral molecules in clinical procedures, in part owing to their large variety and low concentration. In this Review, we describe current and emerging techniques that detect and quantify small-molecule enantiomers and their biological importance.

Photo-RAFT Polymerization for Hydrogel Synthesis through Barriers and Development of Light-Regulated Healable Hydrogels under NIR Irradiation.

We report an aqueous and near-infrared (NIR) light mediated photoinduced reversible addition-fragmentation chain transfer (photo-RAFT) polymerization system catalyzed by tetrasulfonated zinc phthalocyanine (ZnPcS4 - ) in the presence of peroxides. Taking advantage of its fast polymerization rates and high oxygen tolerance, this system is successfully applied for the preparation of hydrogels. Exploiting the enhanced penetration of NIR light, photoinduced gelation is effectively performed through non-transparent biological barriers. Notably, the RAFT agents embedded in these hydrogel networks can be reactivated on-demand, enabling the hydrogel healing under NIR light irradiation. In contrast to the minimal healing capability (<15 %) of hydrogels prepared by free radical polymerization (FRP), RAFT-mediated networks display more than 80 % recovery of tensile strength. Although healable polymer networks under UV and blue lights have already been established, this work is the first photochemistry system using NIR light, facilitating photoinduced healing of hydrogels through thick non-transparent barriers.

Targeting diacylglycerol kinase α impairs lung tumorigenesis by inhibiting cyclin D3.

BACKGROUND: Diacylglycerol kinase α (DGKA) is the first member discovered from the diacylglycerol kinase family, and it has been linked to the progression of various types of tumors. However, it is unclear whether DGKA is linked to the development of lung cancer. METHODS: We investigated the levels of DGKA in the lung cancer tissues. Cell growth assay, colony formation assay and EdU assay were used to examine the effects of DGKA-targeted siRNAs/shRNAs/drugs on the proliferation of lung cancer cells in vitro. Xenograft mouse model was used to investigate the role of DGKA inhibitor ritanserin on the proliferation of lung cancer cells in vivo. The downstream target of DGKA in lung tumorigenesis was identified by RNA sequencing. RESULTS: DGKA is upregulated in the lung cancer cells. Functional assays and xenograft mouse model indicated that the proliferation ability of lung cancer cells was impaired after inhibiting DGKA. And cyclin D3(CCND3) is the downstream target of DGKA promoting lung cancer. CONCLUSIONS: Our study demonstrated that DGKA promotes lung tumorigenesis by regulating the CCND3 expression and hence it can be considered as a potential molecular biomarker to evaluate the prognosis of lung cancer patients. What's more, we also demonstrated the efficacy of ritanserin as a promising new medication for treating lung cancer.

Targeting polymerase θ impairs tumorigenesis and enhances radiosensitivity in lung adenocarcinoma.

Radioresistance remains a major obstacle to efficacious radiotherapy in non-small-cell lung cancer (NSCLC). DNA replication proteins are novel targets for radiosensitizers. POLQ is a DNA polymerase involved in DNA damage response and repair. We found that POLQ is overexpressed in NSCLC and is clinically correlated with high tumor stage, poor prognosis, increased tumor mutational burden, and ALK and TP5 mutation status; POLQ inhibition impaired lung tumorigenesis. Notably, POLQ expression was higher in radioresistant lung cancer cells than in wild-type cancer cells. Moreover, POLQ expression was further increased in radioresistant cells after radiation. Enhanced radioresistance is through a prolonged G2/M phase and faster repair of DNA damage, leading to reduced radiation-induced apoptosis. Novobiocin (NVB), a POLQ inhibitor, specifically targeted cancer cells. Genetic knockdown of POLQ or pharmacological inhibition by NVB decreased radioresistance in lung adenocarcinoma while causing little toxicity to normal pulmonary epithelial cells. In conclusion, POLQ is a promising and practical cancer-specific target to impair tumorigenesis and enhance radiosensitivity in NSCLC.

Exosomal circ-PTPN22 and circ-ADAMTS6 mark T cell exhaustion and neutrophil extracellular traps in Asian intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a liver tumor featured by challenges of non-invasive early diagnosis and a higher prevalence rate in Asian countries. These characteristics necessitate the development of liquid biopsy and immunotherapy methods to improve the prognosis of patients with ICC. Herein, we conducted a pilot study on the transcriptome of tumor tissues, adjacent normal tissues, and plasma exosomes of Asian patients with ICC from northern and southern China. We identified a subgroup of immunogenic Asian ICC, which is different from Caucasian ICC and is characterized by T cell exhaustion and neutrophil extracellular traps. The levels of circ-PTPN22 (hsa_circ_0110529) and circ-ADAMTS6 (hsa_circ_0072688), potential circRNA biomarkers, were elevated in the ICC tumor tissues and plasma exosomes of this subgroup than in the other subgroups and normal controls. These circRNAs were derived from post-transcriptional backsplicing of PTPN22 and ADAMTS6 that were expressed in T cells and endothelial cells, respectively, in the ICC microenvironment. Our results revealed a subgroup of Asian ICC characterized by T cell exhaustion and neutrophil extracellular traps and marked by elevated levels of circ-PTPN22 and circ-ADAMTS6 in tumor tissues and plasma exosomes. This subgroup is potentially detectable by plasma exosomal circRNAs and treatable with immune checkpoint blockade.

Activation of NLRP3 inflammasome in lung epithelial cells triggers radiation-induced lung injury.

BACKGROUND: Radiation-induced lung injury (RILI) is the most common and serious complication of chest radiotherapy. However, reported radioprotective agents usually lead to radiation resistance in tumor cells. The key to solving this problem is to distinguish between the response of tumor cells and normal lung epithelial cells to radiation damage. METHODS: RNA-Seq was used to recognize potential target of alleviating the progression of RILI as well as inhibiting tumor growth. The activation of NLRP3 inflammasome in lung epithelial cells was screened by qRT-PCR, western blotting, immunofluorescence, and ELISA. An in vivo model of RILI and in vitro conditioned culture model were constructed to evaluate the effect of NLRP3/interleukin-1ß on fibroblasts activation. ROS, ATP, and (NADP)+/NADP(H) level in lung epithelial cells was detected to explore the mechanism of NLRP3 inflammasome activation. The lung macrophages of the mice were deleted to evaluate the role of lung epithelial cells in RILI. Moreover, primary cells were extracted to validate the results obtained from cell lines. RESULTS: NLRP3 activation in epithelial cells after radiation depends on glycolysis-related reactive oxygen species accumulation. DPYSL4 is activated and acts as a negative regulator of this process. The NLRP3 inflammasome triggers interleukin-1ß secretion, which directly affects fibroblast activation, proliferation, and migration, eventually leading to lung fibrosis. CONCLUSIONS: Our study suggests that NLRP3 inflammasome activation in lung epithelial cells is essential for radiation-induced lung injury. These data strongly indicate that targeting NLRP3 may be effective in reducing radiation-induced lung injury in clinical settings.

Deficiency of Carbamoyl Phosphate Synthetase 1 Engenders Radioresistance in Hepatocellular Carcinoma via Deubiquitinating c-Myc.

PURPOSE: Tumor radiation resistance is the main obstacle to effective radiation therapy for patients with hepatocellular carcinoma (HCC). We identified the role of urea cycle key enzyme carbamoyl phosphate synthetase 1 (CPS1) in radioresistance of HCC and explored its mechanism, aiming to provide a novel radiosensitization strategy for the CPS1-deficiency HCC subtype. METHODS AND MATERIALS: The expression of CPS1 was measured by western blot and immunohistochemistry. Cell growth assay, EdU assay, cell apoptosis assay, cell cycle assay, clone formation assay, and subcutaneous tumor assay were performed to explore the relationship between CPS1 and radioresistance of HCC cells. Lipid metabonomic analysis was used for investigating the effects of CPS1 on lipid synthesis of HCC cells. RNA sequencing and coimmunoprecipitation assay were carried out to reveal the mechanism of CPS1 participating in the regulation of HCC radiation therapy resistance. Furthermore, 10074-G5, the specific inhibitor of c-Myc, was administered to HCC cells to investigate the role of c-Myc in CPS1-deficiency HCC cells. RESULTS: We found that urea cycle key enzyme CPS1 was frequently lower in human HCC samples and positively associated with the patient's prognosis. Functionally, the present study proved that CPS1 depletion could accelerate the development of HCC and induce radiation resistance of HCC in vitro and in vivo, and deficiency of CPS1 promoted the synthesis of some lipid molecules. Regarding the mechanism, we uncovered that inhibition of CPS1 upregulated CyclinA2 and CyclinD1 by stabilizing oncoprotein c-Myc at the posttranscriptional level and generated radioresistance of HCC cells. Moreover, inactivation of c-Myc using 10074-G5, a specific c-Myc inhibitor, could partially attenuate the proliferation and radioresistance induced by depletion of CPS1. CONCLUSIONS: Our results recapitulated that silencing CPS1 could promote HCC progression and radioresistance via c-Myc stability mediated by the ubiquitin-proteasome system, suggesting that targeting c-Myc in CPS1-deficiency HCC subtype may be a valuable radiosensitization strategy in the treatment of HCC.

An aqueous photo-controlled polymerization under NIR wavelengths: synthesis of polymeric nanoparticles through thick barriers.

We report an aqueous and near-infrared (NIR) light mediated photoinduced reversible addition-fragmentation chain transfer (photo-RAFT) polymerization system using tetrasulfonated zinc phthalocyanine (ZnPcS4 -) as a photocatalyst. Owing to the high catalytic efficiency and excellent oxygen tolerance of this system, well-controlled polyacrylamides, polyacrylates, and polymethacrylates were synthesized at fast rates without requiring deoxygenation. Notably, NIR wavelengths possess enhanced light penetration through non-transparent barriers compared to UV and visible light, allowing high polymerization rates through barriers. Using 6.0 mm pig skin as a barrier, the polymerization rate was only reduced from 0.36 to 0.21 h-1, indicating potential for biomedical applications. Furthermore, longer wavelengths (higher λ) can be considered an ideal light source for dispersion photopolymerization, especially for the synthesis of large diameter (d) nanoparticles, as light scattering is proportional to d 6/λ 4. Therefore, this aqueous photo-RAFT system was applied to photoinduced polymerization-induced self-assembly (photo-PISA), enabling the synthesis of polymeric nanoparticles with various morphologies, including spheres, worms, and vesicles. Taking advantage of high penetration and reduced light scattering of NIR wavelengths, we demonstrate the first syntheses of polymeric nanoparticles with consistent morphologies through thick barriers.

NLRP6 is required for cancer-derived exosome-modified macrophage M2 polarization and promotes metastasis in small cell lung cancer.

Metastasis remains the primary cause of small cell lung cancer (SCLC)-related deaths. Growing evidence links tumor metastasis with a pre-metastatic microenvironment characterized by an anti-inflammatory response, immunosuppression, and the presence of tumor-derived exosomes. To clarify the relationships among these factors in SCLC, we analyzed SCLC patient samples as well as a mouse model. Among the infiltrating immune cells, our study focused on the tumor-associated macrophages (TAMs), that are well-known to promote tumor progression and metastasis. We found that high expression of the alternatively activated (M2) TAM marker, CD206+ was associated clinically with a poorer prognosis and metastasis state in patients with SCLC. Moreover, infiltrating macrophages (MØ) were found in the metastatic foci of an SCLC mouse model. Additionally, we observed dominant switching to M2 phenotype, accompanied by increased NLRP6 expression. Since tumor-derived exosomes are the key links between the tumor and its immune microenvironment, we further investigated whether SCLC-derived exosomes contributed to the MØ phenotype switch. Our findings showed for the first time that SCLC-derived exosomes induce the M2 switch via the NLRP6/NF-κB pathway, and thus, promote SCLC metastasis in vitro and in vivo. Collectively, these results indicate a novel mechanism by which SCLC-derived exosomes induce immunosuppression of distant MØ to promote systemic metastasis by activating NLRP6. Here, we highlight the close relationship between the tumor-derived exosomes, inflammasomes and immune microenvironment in SCLC metastasis.

Vertical Barrier Heterostructures for Reliable, Robust, and High-Performance Ultraviolet Detection.

Photodetectors based on low-dimensional materials usually suffer from serious optical power-dependent photoresponse and low reliability, particularly in the ultraviolet regime. The barrier photodetector is an effective and reliable strategy where the barrier layer can block the low-energy charge carriers while allowing for a flow of the high-energy photocarriers. Here, vertical barrier heterostructure photodetectors (VBHPs), consisting of a graphene bottom electrode, a MoS2 light absorber, and an h-BN energy barrier, for reliable, robust, and high-performance ultraviolet detection are reported. The asymmetric barrier distribution in the conduction/valence band at the MoS2 /h-BN interface results in an ultralow noise current of 1.69 × 10-15 A Hz-1/2 at room temperature, stable photo on/off states exceeding 104 cycles at 300 K and 400 K, a light power-independent high responsivity of 416.2 mA W-1 at 360 nm, a high photo on-off ratio of 1.2 × 105 at 360 nm, high measured detectivities (3.2 × 1010 Jones at 266 nm and 9.9 × 1010 Jones at 360 nm), and wide linear dynamic ranges. The VBHPs show a high potential for new-type reliable ultraviolet detection.