Phytic Acid-Promoted Deposition of Gold Nanoparticles with Grafted Cationic Polymer Brushes for the Construction of Synergistic Contact-Killing and Photothermal Bactericidal Coatings.

Medical implants are constantly facing the risk of bacterial infections, especially infections caused by multidrug resistant bacteria. To mitigate this problem, gold nanoparticles with alkyl bromide moieties (Au NPs-Br) on the surfaces were prepared. Xenon light irradiation triggered the plasmon effect of Au NPs-Br to induce free radical graft polymerization of 2-(dimethylamino)ethyl methacrylate (DMAEMA), leading to the formation of poly(DMAEMA) brush-grafted Au NPs (Au NPs-g-PDM). The Au NPs-g-PDM nanocomposites were conjugated with phytic acid (PA) via electrostatic interaction and van der Waals interaction. The as-formed aggregates were deposited on the titanium (Ti) substrates to form the PA/Au NPs-g-PDM (PAP) hybrid coatings through surface adherence of PA and the gravitational effect. Synergistic bactericidal effects of contact-killing caused by the cationic PDM brushes, and local heating generated by the Au NPs under near-infrared irradiation, conferred strong antibacterial effects on the PAP-deposited Ti (Ti-PAP) substrates. The synergistic bactericidal effects reduced the threshold temperature required for the photothermal sterilization, which in turn minimized the secondary damage to the implant site. The Ti-PAP substrates exhibited 97.34% and 99.97% antibacterial and antiadhesive efficacy, respectively, against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli), compared to the control under in vitro antimicrobial assays. Furthermore, the as-constructed Ti-PAP surface exhibited a 99.42% reduction in the inoculated S. aureus under in vivo assays. In addition, the PAP coatings exhibited good biocompatibility in the hemolysis and cytotoxicity assays as well as in the subcutaneous implantation of rats.

Hypofractionated radiotherapy combined with lenalidomide improves systemic antitumor activity in mouse solid tumor models.

Background: Hypofractionated radiotherapy (hRT) can induce a T cell-mediated abscopal effect on non-irradiated tumor lesions, especially in combination with immune checkpoint blockade (ICB). However, clinically, this effect is still rare, and ICB-mediated adverse events are common. Lenalidomide (lena) is an anti-angiogenic and immunomodulatory drug used in the treatment of hematologic malignancies. We here investigated in solid tumor models whether lena can enhance the abscopal effect in double combination with hRT. Methods: In two syngeneic bilateral tumor models (B16-CD133 melanoma and MC38 colon carcinoma), the primary tumor was treated with hRT. Lena was given daily for 3 weeks. Besides tumor size and survival, the dependence of the antitumor effects on CD8+ cells, type-I IFN signaling, and T cell costimulation was determined with depleting or blocking antibodies. Tumor-specific CD8+ T cells were quantified, and their differentiation and effector status were characterized by multicolor flow cytometry using MHC-I tetramers and various antibodies. In addition, dendritic cell (DC)-mediated tumor antigen cross-presentation in vitro and directly ex vivo and the composition of tumor-associated vascular endothelial cells were investigated. Results: In both tumor models, the hRT/lena double combination induced a significant abscopal effect. Control of the non-irradiated secondary tumor and survival were considerably better than with the respective monotherapies. The abscopal effect was strongly dependent on CD8+ cells and associated with an increase in tumor-specific CD8+ T cells in the non-irradiated tumor and its draining lymph nodes. Additionally, we found more tumor-specific T cells with a stem-like (TCF1+ TIM3- PD1+) and a transitory (TCF1- TIM3+ CD101- PD1+) exhausted phenotype and more expressing effector molecules such as GzmB, IFNγ, and TNFα. Moreover, in the non-irradiated tumor, hRT/lena treatment also increased DCs cross-presenting a tumor model antigen. Blocking type-I IFN signaling, which is essential for cross-presentation, completely abrogated the abscopal effect. A gene expression analysis of bone marrow-derived DCs revealed that lena augmented the expression of IFN response genes and genes associated with differentiation, maturation (including CD70, CD83, and CD86), migration to lymph nodes, and T cell activation. Flow cytometry confirmed an increase in CD70+ CD83+ CD86+ DCs in both irradiated and abscopal tumors. Moreover, the hRT/lena-induced abscopal effect was diminished when these costimulatory molecules were blocked simultaneously using antibodies. In line with the enhanced infiltration by DCs and tumor-specific CD8+ T cells, including more stem-like cells, hRT/lena also increased tumor-associated high endothelial cells (TA-HECs) in the non-irradiated tumor. Conclusions: We demonstrate that lena can augment the hRT-induced abscopal effect in mouse solid tumor models in a CD8 T cell- and IFN-I-dependent manner, correlating with enhanced anti-tumor CD8 T cell immunity, DC cross-presentation, and TA-HEC numbers. Our findings may be helpful for the planning of clinical trials in (oligo)metastatic patients.

Benzene-Linked Polymeric Carbon Nitride for Enhanced Photocatalytic Hydrogen Production.

Cross-linking with functional molecular species in polymeric carbon nitride (PCN) could offer a positive strategy that tunes its molecular structure with excellent conductivity to improve photocatalytic activity. Herein, the benzene ring-cross-linked photocatalyst is obtained via the polymerization of urea, melamine, and trimesic acid. Benzene ring-cross-linked PCN narrows the band gap and augments the push-pull effect of carriers, thus enhancing visible light harvesting and transfer easiness of photogenerated electron/hole pairs. Notably, the amount of trimesic acid was optimized during the benzene ring-cross-linked photocatalyst preparation (marked as 01T/A-CN, 02T/A-CN, and 03T/A-CN). Among them, 02T/A-CN photocatalyst achieved an excellent hydrogen production rate of 1931 µmol/h·g, which is higher than that of CN under visible light and beyond most reported. Theoretical calculations further confirmed that the introduction of benzene ring significantly reduces the band gap of PCN, bringing the delocalized electron, a longer intramolecular electron transition distance, and molecular bending. All those factors made benzene ring-cross-linked PCN with improved photocatalytic hydrogen production under visible light irradiation.

Phytic Acid-Promoted Exfoliation of Black Phosphorus Nanosheets for the Fabrication of Photothermal Antibacterial Coatings.

Medical device-associated infections (MDAI) caused by planktonic pathogens are of serious concern worldwide due to the emergence of drug resistance resulting from continuous overuse or misuse of antibiotics. Therefore, the design of non-antibiotics-based treatment for MDAI is of crucial importance. Black phosphorus (BP), a novel 2D material, has recently received much attention owing to its remarkable physical, chemical, mechanical, and functional features. However, the intricacy of the fabrication process has severely hampered the development of BP in prospective applications. In this study, a simple and eco-friendly liquid-phase exfoliation method of phytic acid (PA)-promoted exfoliation of BP nanosheets (PA@BP NSs) is developed for their potential application in antibacterial photothermal therapy. To impart the antimicrobial effects, the polydimethylsiloxane surfaces are functionalized with quaternized polymer (polyquaternium-2 or PQ) and PA@BP NSs, leading to the formation of PA-BP-PQ composite coatings. In addition to the contact-killing antibacterial effect of the cationic PQ, the PA-BP-PQ coating exhibits remarkable near-infrared irradiation-triggered bactericidal effects with low cytotoxicity both in vitro and in vivo. This study proposes a simple liquid-phase exfoliation technique for the fabrication of BP NSs and a one-step approach for the construction of PA-BP-PQ composite coatings for bi-modal (contact-killing and photothermal) antimicrobial therapy.

Krüppel-like factor 5 activates chick intestinal stem cell and promotes mucosal repair after impairment.

The mucosal renewal, which depends on the intestinal stem cell (ISC) activity, is the foundation of mucosal repairment. Importantly, activation of reserve ISCs (rISCs) plays a vital role in initiating mucosal repair after injury. However, the underlying regulatory mechanism of rISCs activation in chickens remains unclear. In this study, immediately after lipopolysaccharide (LPS) challenge, mitochondrial morphological destruction and dysfunction appeared in the crypt, accompanied by decreased epithelial secretion (decreased Muc2 mRNA abundance and LYSOZYME protein level). However, immediately after mucosal injury, the mucosal renewal accelerated, as indicated by the increased BrdU positive rate, proliferating cell nuclear antigen (PCNA) protein level and mRNA abundance of cell cycle markers (Ccnd1, Cdk2). Concerning the ISCs activity, during the early period of injury, there appeared a reduction of active ISCs (aISCs) marker Lgr5 mRNA and protein, and an increasing of rISCs marker Hopx mRNA and protein. Strikingly, upon LPS challenge, increased mRNA transcriptional level of Krüppel-like factor 5 (Klf5) was detected in the crypt. Moreover, under LPS treatment in organoids, the KLF5 inhibitor (ML264) would decrease the mRNA and protein levels of Stat5a and Hopx, the STAT5A inhibitor (AC-4-130) would suppress the Lgr5 mRNA and protein levels. Furthermore, the Dual-Luciferase Reporter assay confirmed that, KLF5 would bind to Hopx promoter and activate the rISCs, STAT5A would trigger Lgr5 promoter and activate the aISCs. Collectively, KLF5 was upregulated during the early period of injury, further activate the rISCs directly and activate aISCs via STAT5A indirectly, thus initiate mucosal repair after injury.

Study of the impact of digitization on the carbon emission intensity of agricultural production in China.

The digital economy is an important engine for China's economic and social development, accelerating the development of agricultural digitization and promoting the integration of agricultural digitization. Low-carbon production is an inevitable trend in China's current economic development. The article takes 30 provinces (cities and districts) in China as research objects, constructing and measuring indicators of digitization level and carbon emission intensity of agricultural production from 2006 to 2018. It classifies agricultural production into planting and animal husbandry and uses a basic regression model to study their dynamic relationships. A mediating effect model is used to explore the specific mechanism path of the digital economy affecting carbon emission intensity, and a regional heterogeneity analysis is conducted. The study found that: (1) The level of digitalization can significantly reduce the carbon intensity of agricultural production; (2) Digitalization can reduce China's carbon intensity by promoting the level of agricultural technological inputs, the level of human capital and the urbanization rate. (3) There are regional and sectoral differences in the impact of digitization on the carbon intensity of agricultural production. The impact on the plantation sector is greater than that on the livestock sector, and the carbon reduction effect is slightly greater in the central and western regions than in the eastern regions.

VAPB-mediated ER-targeting stabilizes IRS-1 signalosomes to regulate insulin/IGF signaling.

The scaffold protein IRS-1 is an essential node in insulin/IGF signaling. It has long been recognized that the stability of IRS-1 is dependent on its endomembrane targeting. However, how IRS-1 targets the intracellular membrane, and what type of intracellular membrane is actually targeted, remains poorly understood. Here, we found that the phase separation-mediated IRS-1 puncta attached to endoplasmic reticulum (ER). VAPB, an ER-anchored protein that mediates tethers between ER and membranes of other organelles, was identified as a direct interacting partner of IRS-1. VAPB mainly binds active IRS-1 because IGF-1 enhanced the VAPB-IRS-1 association and replacing of the nine tyrosine residues of YXXM motifs disrupted the VAPB-IRS-1 association. We further delineated that the Y745 and Y746 residues in the FFAT-like motif of IRS-1 mediated the association with VAPB. Notably, VAPB targeted IRS-1 to the ER and subsequently maintained its stability. Consistently, ablation of VAPB in mice led to downregulation of IRS-1, suppression of insulin signaling, and glucose intolerance. The amyotrophic lateral sclerosis (ALS)-derived VAPB P56S mutant also impaired IRS-1 stability by interfering with the ER-tethering of IRS-1. Our findings thus revealed a previously unappreciated condensate-membrane contact (CMC), by which VAPB stabilizes the membraneless IRS-1 signalosome through targeting it to ER membrane.

Adding liposomal doxorubicin enhances the abscopal effect induced by radiation/αPD1 therapy depending on tumor cell mitochondrial DNA and cGAS/STING.

BACKGROUND: Localized radiotherapy (RT) can cause a T cell-mediated abscopal effect on non-irradiated tumor lesions, especially in combination with immune checkpoint blockade. However, this effect is still clinically rare and improvements are highly desirable. We investigated whether triple combination with a low dose of clinically approved liposomal doxorubicin (Doxil) could augment abscopal responses compared with RT/αPD-1 and Doxil/αPD-1. We also investigated whether the enhanced abscopal responses depended on the mitochondrial DNA (mtDNA)/cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING)/IFN-I pathway. MATERIALS/METHODS: We used Doxil in combination with RT and αPD-1 in two tumor models (B16-CD133 melanoma and MC38 colon carcinoma) with mice bearing two tumors, only one of which was irradiated. Mechanistic studies on the role of the mtDNA/cGAS/STING/IFN-I axis were performed using inhibitors and knockout cells in vitro as well as in mice. RESULTS: Addition of a single low dose of Doxil to RT and αPD-1 strongly enhanced the RT/αPD-1-induced abscopal effect in both models. Complete cures of non-irradiated tumors were mainly observed in triple-treated mice. Triple therapy induced more cross-presenting dendritic cells (DCs) and more tumor-specific CD8+ T cells than RT/αPD-1 and Doxil/αPD-1, particularly in non-irradiated tumors. Coincubation of Doxil-treated and/or RT-treated tumor cells with DCs enhanced DC antigen cross-presentation which is crucial for inducing CD8+ T cells. CD8+ T cell depletion or implantation of cGAS-deficient or STING-deficient tumor cells abolished the abscopal effect. Doxorubicin-induced/Doxil-induced IFNß1 markedly depended on the cGAS/STING pathway. Doxorubicin-treated/Doxil-treated tumor cells depleted of mtDNA secreted less IFNß1, of the related T cell-recruiting chemokine CXCL10, and ATP; coincubation with mtDNA-depleted tumor cells strongly reduced IFNß1 secretion by DCs. Implantation of mtDNA-depleted tumor cells, particularly at the non-irradiated/abscopal site, substantially diminished the Doxil-enhanced abscopal effect and tumor infiltration by tumor-specific CD8+ T cells. CONCLUSIONS: These data show that single low-dose Doxil can substantially enhance the RT/αPD-1-induced abscopal effect, with a strong increase in cross-presenting DCs and CD8+ tumor-specific T cells particularly in abscopal tumors compared with RT/αPD-1 and Doxil/αPD-1. Moreover, they indicate that the mtDNA/cGAS/STING/IFN-I axis is important for the immunogenic/immunomodulatory doxorubicin effects. Our findings may be helpful for the planning of clinical radiochemoimmunotherapy trials in (oligo)metastatic patients.

Clinical and Genomic Characteristics of Patients with Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer Following Progression on Cyclin-Dependent Kinase 4 and 6 Inhibitors.

PURPOSE: We explored the clinical and genomic characteristics of hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC) after progression on cyclin-dependent kinase 4 and 6 inhibitors (CDK4 and 6i) ± endocrine therapy (ET) to understand potential resistance mechanisms that may aid in identifying treatment options. EXPERIMENTAL DESIGN: Patients in the United States with HR+, HER2- MBC had tumor biopsies collected from a metastatic site during routine care following progression on a CDK4 and 6i ± ET (CohortPost) or prior to initiating CDK4 and 6i treatment (CohortPre) and analyzed using a targeted mutation panel and RNA-sequencing. Clinical and genomic characteristics were described. RESULTS: The mean age at MBC diagnosis was 59 years in CohortPre (n = 133) and 56 years in CohortPost (n = 223); 14% and 45% of patients had prior chemotherapy/ET, and 35% and 26% had de novo stage IV MBC, respectively. The most common biopsy site was liver (CohortPre, 23%; CohortPost, 56%). CohortPost had significantly higher tumor mutational burden (TMB; median 3.16 vs. 1.67 Mut/Mb, P < 0.0001), ESR1 alteration frequency (mutations: 37% vs. 10%, FDR < 0.0001; fusions: 9% vs. 2%, P = 0.0176), and higher copy-number amplification of genes on chr12q15, including MDM2, FRS2, and YEATS4 versus patients in the CohortPre group. In addition, CDK4 copy-number gain on chr12q13 was significantly higher in CohortPost versus CohortPre (27% vs. 11%, P = 0.0005). CONCLUSIONS: Distinct mechanisms potentially associated with resistance to CDK4 and 6i ± ET, including alterations in ESR1 and amplification of chr12q15 and CDK4 copy-number gain, were identified.

TONSL Is an Immortalizing Oncogene and a Therapeutic Target in Breast Cancer.

Study of genomic aberrations leading to immortalization of epithelial cells has been technically challenging due to the lack of isogenic models. To address this, we used healthy primary breast luminal epithelial cells of different genetic ancestry and their hTERT-immortalized counterparts to identify transcriptomic changes associated with immortalization. Elevated expression of TONSL (Tonsoku-like, DNA repair protein) was identified as one of the earliest events during immortalization. TONSL, which is located on chromosome 8q24.3, was found to be amplified in approximately 20% of breast cancers. TONSL alone immortalized primary breast epithelial cells and increased telomerase activity, but overexpression was insufficient for neoplastic transformation. However, TONSL-immortalized primary cells overexpressing defined oncogenes generated estrogen receptor-positive adenocarcinomas in mice. Analysis of a breast tumor microarray with approximately 600 tumors revealed poor overall and progression-free survival of patients with TONSL-overexpressing tumors. TONSL increased chromatin accessibility to pro-oncogenic transcription factors, including NF-κB and limited access to the tumor-suppressor p53. TONSL overexpression resulted in significant changes in the expression of genes associated with DNA repair hubs, including upregulation of several genes in the homologous recombination (HR) and Fanconi anemia pathways. Consistent with these results, TONSL-overexpressing primary cells exhibited upregulated DNA repair via HR. Moreover, TONSL was essential for growth of TONSL-amplified breast cancer cell lines in vivo, and these cells were sensitive to TONSL-FACT complex inhibitor CBL0137. Together, these findings identify TONSL as a regulator of epithelial cell immortalization to facilitate cancer initiation and as a target for breast cancer therapy. SIGNIFICANCE: The chr.8q24.3 amplicon-resident gene TONSL is upregulated during the initial steps of tumorigenesis to support neoplastic transformation by increasing DNA repair and represents a potential therapeutic target for treating breast cancer.

Bimodal Antimicrobial Surfaces of Phytic Acid-Prussian Blue Nanoparticles-Cationic Polymer Networks.

Surface modification plays a pivotal role in tailoring the functionalities of a solid material. Introduction of antimicrobial function on material surfaces can provide additional protection against life-threatening bacterial infections. Herein, a simple and universal surface modification method based on surface adhesion and electrostatic interaction of phytic acid (PA) is developed. PA is first functionalized with Prussian blue nanoparticles (PB NPs) via metal chelation and then conjugates with cationic polymers (CPs) through electrostatic interaction. With the aid of surface adherent PA and gravitation effect, the as-formed PA-PB-CP network aggregates are deposited on the solid materials in a substrate-independent manner. Synergistic bactericidal effects of "contact-killing" induced by the CPs and localized photothermal effect caused by the PB NPs endow the substrates with strong antibacterial performance. Membrane integrity, enzymatic activity, and metabolism function of the bacteria are disturbed in contact with the PA-PB-CP coating under near-infrared (NIR) irradiation. The PA-PB-CP modified biomedical implant surfaces exhibit good biocompatibility and synergistic antibacterial effect under NIR irradiation, and eliminate the adhered bacteria both in vitro and in vivo.

LiFePO4/C twin microspheres as cathode materials with enhanced electrochemical performance.

Self-assembled lithium iron phosphate (LiFePO4) with tunable microstructure is an effective way to improve the electrochemical performance of cathode materials for lithium ion batteries. Herein, self-assembled LiFePO4/C twin microspheres are synthesized by a hydrothermal method using a mixed solution of phosphoric acid and phytic acid as the phosphorus source. The twin microspheres are hierarchical structures composed of primary nano-sized capsule-like particles (about 100 nm in diameter and 200 nm in length). The uniform thin carbon layer on the surface of the particles improves the charge transport capacity. The channel between the particles facilitates the electrolyte infiltration, and the high electrolyte accessibility enables the electrode material to obtain excellent ion transport. The optimal LiFePO4/C-60 exhibits excellent rate performance with discharge capacity of 156.3 mA h g-1 and 118.5 mA h g-1 respectively at 0.2C and 10C, and low temperature performances with discharge capacity of 90.67 mA h g-1 and 66.7 mA h g-1 at -15 °C and -25 °C, respectively. This research may provide a new pathway to improve the performance of LiFePO4 by tuning the micro-structures by adjusting the relative content of phosphoric acid and phytic acid.

Adjuvant chemotherapy benefits on patients with elevated carcinoembryonic antigen in stage IIA colon cancer: a SEER-based analysis.

OBJECTIVE: Indications for adjuvant chemotherapy in stage IIA (T3N0M0) colon cancer are still controversial. The purpose of this study was to evaluate the prognostic value of elevated carcinoembryonic antigen (CEA) levels for cancer-specific survival (CSS) and overall survival (OS) in patients with stage IIA colon cancer. We aimed to examine the impact of adjuvant chemotherapy on OS in stage IIA colon cancer patients with elevated CEA levels. METHODS: Patients with stage IIA colon cancer (N = 3477) diagnosed between 2010 and 2015 were identified using the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier and Cox proportional hazards regression models were used to assess the prognostic effect of CEA on CSS and OS. RESULTS: Cox regression analysis demonstrated that CEA was an independent risk factor for CSS and OS in patients with stage IIA colon cancer (CSS: HR = 2.001, 95% CI 1.603-2.499, P < 0.001; OS: HR = 1.530, 95% CI 1.335-1.752, P < 0.001). In the subgroup with elevated CEA, patients received adjuvant chemotherapy had a better OS compared with those did not (χ2 = 10.585, p = 0.001). CONCLUSION: CEA was an independent risk factor for CSS and OS in patients with stage IIA colon cancer. Patients with stage IIA colon cancer with an elevated CEA level might benefit from adjuvant chemotherapy.

Nitrogen defect-containing polymeric carbon nitride for efficient photocatalytic H2 evolution and RhB degradation under visible light irradiation.

Introducing defects in polymeric carbon nitride (CN) in a predetermined way is a great challenge to explicate the effect of defects on the photocatalytic activity. Herein, we provide a pathway to synthesize g-C3N4 with nitrogen defects by simply calcining melamine and trithiocyanuric acid at elevated temperature. Nitrogen defects at the N-bridging sites lead to an intermediate energy gap between the valence band and the conduction band, which greatly increases the photon absorption in the visible light range. Electron paramagnetic resonance (EPR) and photoluminescence (PL) verify that the significantly improved light utilization efficiency and rapid charge transfer correlate with nitrogen defects. The hydrogen evolution rate of 2SCN reached 41.4 µmol h-1, about 20.7 times that of pure g-C3N4, and its degradation rate for rhodamine B (RhB) is about 2.5 times that of CN. The experimental results proved that the photoinduced electron-hole pairs react with adsorbed O2 to form ˙O2 -, facilitating the photodegradation of organic pollutants.

Patient-Derived Organoid Facilitating Personalized Medicine in Gastrointestinal Stromal Tumor With Liver Metastasis: A Case Report.

The gastrointestinal stromal tumors (GIST) are a rare gastrointestinal tract malignancy. The two primary mutation sites are found in KIT and platelet-derived growth factor receptor-α (PDGFR-α) genes. The current study reports on a point mutation within the exon 11 of KIT, named KIT p.V560E. Patient-derived organoids (PDOs) are potential 3D in vitro models of tissues that can be used to identify sensitivity toward specific targets in patients with tumors and allow for personalized medicine when drugs specific for newly identified genetic locus mutations are not yet available. This study describes a 68-year-old patient who complained of diffused abdominal pain and intermittent melena lasting more than 10 days. He has no other gastrointestinal abnormalities, prior abdominal surgery, or related family history. Surgery was conducted first to remove the lesions and ascertain the disease through histology and immunohistochemical stains of the mass. Immunohistochemistry revealed that the tumor was positive for CD117 and Dog-1. Based on the above findings, he was diagnosed with GISTs. Gene detection analysis and organoid culture were then performed to verify clinical decisions. KIT p.V560E and the reduced number of RB1 copies were identified as two obvious mutations, so the patient was administrated first-line treatment of imatinib 400 mg/d. However, progressive disease prompted us to switch to sunitinib, and his condition gradually improved. Meanwhile, organoid culture showed sensitivity to sunitinib and tolerance to imatinib with half-maximal inhibitory concentration (IC50) values of 0.89 and >20, respectively. In summary, to the best of our knowledge, this is the first time that the established organoid culture indicated that the GISTs organoid could identify the sensitivity to target therapies and facilitate individual-based treatment.

Case Report: Complete Remission of a Patient With Metastatic Gastric Cancer Treated With Nivolumab Combined With Chemotherapy After Palliative Surgery.

Metastatic advanced gastric cancer, for which treatment strategies are extremely limited, has a poor prognosis. Complete remission is rare. Patients usually lose the opportunity of therapeutic surgery because the lesions cannot be completely removed, although it can greatly prolong their survival time. Palliative surgery usually suggests bad outcomes. In recent years, the immune checkpoint inhibitor (ICI) nivolumab has shown significant efficacy in the treatment of advanced gastric cancer. However, its applicable conditions and optimal withdrawal time remain controversial owing to its low response rate and high incidence of immune-related adverse events. Herein, we introduce a 66-year-old male patient with advanced gastric cancer with multiple liver metastases who underwent laparoscopic total gastrectomy for acute gastric bleeding. The patient received eight cycles of S-1 plus oxaliplatin (SOX) and switched to eight cycles of SOX plus nivolumab combined regimen in a stable state, later achieving complete remission. There was no recurrence for 32 months after the surgery. This is the first reported case of gastric cancer with multiple liver metastases with long-term complete remission with nivolumab treatment after palliative surgery. The potential mechanism of complete remission was discussed through clinical, genomic, and immune characteristics. The patient had a history of psoriasis and was positive for programmed death ligand 1 (PD-L1), and the interaction of TP53 mutation and HER-2 (-) gene may be associated with complete remission.

Phase separation of insulin receptor substrate 1 drives the formation of insulin/IGF-1 signalosomes.

As a critical node for insulin/IGF signaling, insulin receptor substrate 1 (IRS-1) is essential for metabolic regulation. A long and unstructured C-terminal region of IRS-1 recruits downstream effectors for promoting insulin/IGF signals. However, the underlying molecular basis for this remains elusive. Here, we found that the C-terminus of IRS-1 undergoes liquid-liquid phase separation (LLPS). Both electrostatic and hydrophobic interactions were seen to drive IRS-1 LLPS. Self-association of IRS-1, which was mainly mediated by the 301-600 region, drives IRS-1 LLPS to form insulin/IGF-1 signalosomes. Moreover, tyrosine residues of YXXM motifs, which recruit downstream effectors, also contributed to IRS-1 self-association and LLPS. Impairment of IRS-1 LLPS attenuated its positive effects on insulin/IGF-1 signaling. The metabolic disease-associated G972R mutation impaired the self-association and LLPS of IRS-1. Our findings delineate a mechanism in which LLPS of IRS-1-mediated signalosomes serves as an organizing center for insulin/IGF-1 signaling and implicate the role of aberrant IRS-1 LLPS in metabolic diseases.

Combined BRM270 and endostatin inhibit relapse of NSCLC while suppressing lung cancer stem cell proliferation induced by endostatin.

Endostatin (ES, ENDO) has been reported to suppress the growth of tumors while inducing the proliferation of lung cancer stem cells (LCSCs), causing a poor prognosis for lung cancer. In this study, we aimed to clarify whether BRM270 can inhibit the proliferation of cancer stem cells (CSCs). Endostatin + BRM270 showed anti-tumor effects by reducing tumor volume and increasing survival. Administration of BRM270 reduced the number of aldehyde dehydrogenase-positive (ALDH+) cells and the level of ALDH1A1 expression in tumors by increasing the level of miR-128 while decreasing the levels of BMI-1, ABCC-5, E2F3, and c-MET. The luciferase activity of miR-128 promoter was increased by an increasing concentration of BRM270. In addition, BMI-1, ABCC-5, E2F3, and c-MET were identified as candidate targets of miR-128, and the overexpression of miR-128 significantly reduced mRNA/protein levels of BMI-1, ABCC-5, E2F3, and c-MET in A549 and H460 cells. Administration of BRM270 inhibited the expression of BMI-1, ABCC-5, E2F3, and c-MET in a dose-dependent manner. In this study, we showed for the first time that the combined administration of endostatin and BRM270 achieved anti-tumor effects while suppressing the proliferation of stem cells.

Outbreak of the South American tomato leafminer, Tuta absoluta, in the Chinese mainland: geographic and potential host range expansion.

BACKGROUND: In 2017 Tuta absoluta was identified as an invasive species in China. Due to its rapid geographic expansion and the severe crop damage it causes, T. absoluta poses a serious threat to China's tomato production industry. To determine its geographic distribution and host range, intensive surveys and routine monitoring were conducted across the Chinese mainland between 2018 and 2019. The population colonization coefficient (PCC; ratio of colonized sites and prefectures) and population occurrence index (POI; ratio of infested host species and PCCs) were calculated. RESULTS: In northwestern China, T. absoluta populations established in Xinjiang exhibited a medium PCC value (~0.03). In southwestern China, populations in Yunnan and its five neighboring provinces exhibited high (~0.50 in Yunnan and Guizhou), or low (<0.02 in Guangxi, Sichuan, Hunan, and Chongqing) PCC values. In the Chinese mainland, infestations of four crop plant species (tomato, eggplant, potato, and Chinese lantern) and two wild plant species (black nightshade and Dutch eggplant) were identified; tomatoes were infested in every colonized province. Chinese lantern and Dutch eggplant are potentially novel hosts. Yunnan, Guizhou, and Xinjiang experienced the most serious damage (POI). In southwestern China, observed damage significantly decreased with increased distance from the first discovery site of T. absoluta to the farthest county of an infested province increased. CONCLUSION: T. absoluta populations are well-established and could potentially spread to other regions of China. The present study helps to inform the establishment of better pest management guidelines and strategies in China and tomato-producing regions worldwide. © 2021 Society of Chemical Industry.

AMPK-mediated phosphorylation enhances the auto-inhibition of TBC1D17 to promote Rab5-dependent glucose uptake.

Dysregulation of glucose homeostasis contributes to insulin resistance and type 2 diabetes. Whilst exercise stimulated activation of AMP-activated protein kinase (AMPK), an important energy sensor, has been highlighted for its potential to promote insulin-stimulated glucose uptake, the underlying mechanisms for this remain largely unknown. Here we found that AMPK positively regulates the activation of Rab5, a small GTPase which is involved in regulating Glut4 translocation, in both myoblasts and skeletal muscles. We further verified that TBC1D17, identified as a potential interacting partner of Rab5 in our recent study, is a novel GTPase activating protein (GAP) of Rab5. TBC1D17-Rab5 axis regulates transport of Glut1, Glut4, and transferrin receptor. TBC1D17 interacts with Rab5 or AMPK via its TBC domain or N-terminal 1-306 region (N-Ter), respectively. Moreover, AMPK phosphorylates the Ser 168 residue of TBC1D17 which matches the predicted AMPK consensus motif. N-Ter of TBC1D17 acts as an inhibitory region by directly interacting with the TBC domain. Ser168 phosphorylation promotes intra-molecular interaction and therefore enhances the auto-inhibition of TBC1D17. Our findings reveal that TBC1D17 acts as a molecular bridge that links AMPK and Rab5 and delineate a previously unappreciated mechanism by which the activation of TBC/RabGAP is regulated.