Predictive value of positive lymph node ratio in patients with locally advanced gastric remnant cancer.

BACKGROUND: Traditional lymph node stage (N stage) has limitations in advanced gastric remnant cancer (GRC) patients; therefore, establishing a new predictive stage is necessary. AIM: To explore the predictive value of positive lymph node ratio (LNR) according to clinicopathological characteristics and prognosis of locally advanced GRC. METHODS: Seventy-four patients who underwent radical gastrectomy and lymphadenectomy for locally advanced GRC were retrospectively reviewed. The relationship between LNR and clinicopathological characteristics was analyzed. The survival analysis was performed using Kaplan-Meier survival curves and Cox regression model. RESULTS: Number of metastatic LNs, tumor diameter, depth of tumor invasion, Borrmann type, serum tumor biomarkers, and tumor-node-metastasis (TNM) stage were correlated with LNR stage and N stage. Univariate analysis revealed that the factors affecting survival included tumor diameter, anemia, serum tumor biomarkers, vascular or neural invasion, combined resection, LNR stage, N stage, and TNM stage (all P < 0.05). The median survival time for those with LNR0, LNR1, LNR2 and LNR3 stage were 61, 31, 23 and 17 mo, respectively, and the differences were significant (P = 0.000). Anemia, tumor biomarkers and LNR stage were independent prognostic factors for survival in multivariable analysis (all P < 0.05). CONCLUSION: The new LNR stage is uniquely based on number of metastatic LNs, with significant prognostic value for locally advanced GRC, and could better differentiate overall survival, compared with N stage.

Safety and efficacy of parsaclisib in combination with rituximab, bendamustine + rituximab, or ibrutinib in patients with previously treated B-cell lymphoma: analysis of a phase 1 dose-finding study (CITADEL­112).

Parsaclisib, a potent and highly selective phosphoinositide 3-kinase δ inhibitor, has shown clinical activity in relapsed/refractory (R/R) B-cell lymphoma. The phase 1 CITADEL-112 (NCT03424122) study assessed safety and efficacy of parsaclisib in combination with investigator choice standard of care (SOC; rituximab [Treatment A], rituximab plus bendamustine [Treatment B], or ibrutinib [Treatment C]) in 50 patients with R/R B-cell lymphoma. The most common treatment-emergent adverse events included neutropenia (62.5%, 50.0%, and 50.0% of patients in Treatments A, B, and C, respectively); diarrhea (37.5%) and anemia (31.3%) in Treatment A; abdominal pain, asthenia, diarrhea, and nausea (each 33.3%) in Treatment B; and increased alanine and aspartate aminotransferase (each 37.5%) in Treatment C. Objective responses were observed in 13 patients (81.3%) in Treatment A, 10 (55.6%) in Treatment B, and 8 (50.0%) in Treatment C. Parsaclisib combined with SOC therapies had an expected safety profile and promising efficacy in patients with R/R B-cell lymphomas.

Mitochondria-Modulating Liposomes Reverse Radio-Resistance for Colorectal Cancer.

Complete remission of colorectal cancer (CRC) is still unachievable in the majority of patients by common fractionated radiotherapy, leaving risks of tumor metastasis and recurrence. Herein, clinical CRC samples demonstrated a difference in the phosphorylation of translation initiation factor eIF2α (p-eIF2α) and the activating transcription factor 4 (ATF4), whose increased expression by initial X-ray irradiation led to the resistance to subsequent radiotherapy. The underlying mechanism is studied in radio-resistant CT26 cells, revealing that the incomplete mitochondrial outer membrane permeabilization (iMOMP) triggered by X-ray irradiation is key for the elevated expression of p-eIF2α and ATF4, and therefore radio-resistance. This finding guided to discover that metformin and 2-DG are synergistic in reversing radio resistance by inhibiting p-eIF2α and ATF4. Liposomes loaded with metformin and 2-DG (M/D-Lipo) are thus prepared for enhancing fractionated radiotherapy of CRC, which achieved satisfactory therapeutic efficacy in both local and metastatic CRC tumors by reversing radio-resistance and preventing T lymphocyte exhaustion.

Radionuclide-Labeled Antisilencing Function 1a Inhibitory Peptides for Tumor Identification and Individualized Therapy.

Immune checkpoint blockade (ICB) therapy is promising to revolutionize cancer regimens, but the low response rate and the lack of a suitable patient stratification method have impeded universal profit to cancer patients. Noninvasive positron emission tomography (PET) imaging in the whole body, upon coupling with specific biomarkers closely related to the immune response, could provide spatiotemporal information to prescribe cancer therapy. Herein, we demonstrate that antisilencing function 1a (ASF1a) could serve as a biomarker target to delineate tumor immune microenvironments by immune PET (iPET). The iPET radiotracer (68Ga-AP1) is designed to target ASF1a in tumors and predict immune response, and the signal intensity predicts anti-PD-1 (αPD-1) therapy response in a negative correlation manner. The ICB-resistant tumors with a high level of ASF1a as revealed by iPET (ASF1aHigh-iPET) are prescribed to be treated by either the combined 177Lu-labeled AP1 and αPD-1 or the standalone α particle-emitting 225Ac-labeled AP1, both achieving enhanced therapeutic efficacy and prolonged survival time. Our study not only replenishes the iPET arsenal for immune-related response evaluation by designing a reliable biomarker and a facile radiotracer but also provides optional therapeutic strategies for ICB-resistant tumors with versatile radionuclide-labeled AP1 peptides, which is promising for real-time clinical diagnosis and individualized therapy planning simultaneously.

Total weight loss rather than preoperative body mass index correlates with remission of irregular menstruation after sleeve gastrectomy in patients with polycystic ovary syndrome.

Introduction: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting reproductive-aged women. Some retrospective studies with small sample sizes have reported that bariatric metabolic surgery is effective in remission of irregular menstruation in patients with PCOS and obesity. However, the correlation between preoperative body mass index (BMI), postoperative weight loss, and remission of irregular menstruation in patients with obesity and PCOS after sleeve gastrectomy (SG) is lack of consensus. Methods: We enrolled 229 participants with obesity and PCOS who underwent SG. All patients were followed up for one year after surgery. Remission of irregular menstruation was defined as a spontaneous consecutive six-month menstrual cycle in one year. Subgroup analysis was conducted using tertiles of preoperative BMI and postoperative total weight loss (TWL)% to determine their correlation with the remission of irregular menstruation after SG. Results: 79.03% (181/229) patients achieved remission of irregular menstruation one year after SG with a TWL% of 33.25 ± 0.46%. No significant difference was detected in the remission rate among the subgroups with different BMI (P=0.908). TWL% was correlated with the remission of irregular menstruation (OR 1.78, 95% CI 1.18-2.69, P<0.05). Conclusions: SG had a significant effect on the remission of irregular menstruation in patients with obesity and PCOS. Preoperative BMI did not emerge as a decisive factor correlated with remission; instead, TWL% showed potential as a key factor.

Cyclin-dependent kinase inhibitor 1A inhibits pyroptosis to enhance human lung adenocarcinoma cell radioresistance by promoting DNA repair.

Purpose: One of the best anticancer treatments available is radiotherapy, which can be used either alone or in conjunction with other forms of treatment including chemotherapy and surgery. Nevertheless, a number of biochemical and physiological processes that react to ionizing radiation might provide tumor cells radioresistance, which makes radiotherapy ineffective. It has been found that CDKN1A regulates DNA damage repair, which contributes to tumor radioresistance. However, the precise mechanism is still unknown. Therefore, this study aimed to explore the mechanisms underlying CDKN1A-enhanced radioresistance in tumor cells. Methods: Cells were irradiated with 4 Gy after CDKN1A overexpression or knockdown. CDKN1A expression was measured using real-time PCR, cell viability was evaluated using cell counting kit-8 and colony formation assays, and cytotoxicity was assessed using a lactate dehydrogenase assay. Pyroptosis in cells was analyzed using caspase-1 activity assay, enzyme-linked immunosorbent assay, and flow cytometry. Inflammation activation was detected through a co-immunoprecipitation assay. Activation of pyroptosis-related proteins was analyzed using immunohistochemistry, Western blot, and immunofluorescence. Tumor radioresistance in vivo was evaluated in a mouse xenograft model. Results: Radiotherapy upregulated CDKN1A expression, which promoted lung adenocarcinoma cell survival. CDKN1A influenced radiation-induced pyroptosis in A549, which mainly depended on inhibiting the activation of the AIM2 inflammasome by promoting DNA repair. Additionally, CDKN1A upregulation enhanced A549 xenograft tumor radioresistance by inhibiting radiation-induced pyroptosis in vivo. Conclusions: CDKN1A inhibits pyroptosis to enhance the radioresistance of lung adenocarcinoma cells by promoting DNA repair. This study may serve as a reference for developing novel targeted therapies against cancer.

Establishment and Characterization of an Epstein-Barr Virus-positive Cell Line from a Non-keratinizing Differentiated Primary Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC), a cancer that is etiologically associated with the Epstein-Barr virus (EBV), is endemic in Southern China and Southeast Asia. The scarcity of representative NPC cell lines owing to the frequent loss of EBV episomes following prolonged propagation and compromised authenticity of previous models underscores the critical need for new EBV-positive NPC models. Herein, we describe the establishment of a new EBV-positive NPC cell line, designated NPC268 from a primary non-keratinizing, differentiated NPC tissue. NPC268 can undergo productive lytic reactivation of EBV and is highly tumorigenic in immunodeficient mice. Whole-genome sequencing revealed close similarities with the tissue of origin, including large chromosomal rearrangements, while whole-genome bisulfite sequencing and RNA sequencing demonstrated a hypomethylated genome and enrichment in immune-related pathways, respectively. Drug screening of NPC268 together with six other NPC cell lines using 339 compounds, representing the largest high-throughput drug testing in NPC, revealed biomarkers associated with specific drug classes. NPC268 represents the first and only available EBV-positive non-keratinizing differentiated NPC model, and extensive genomic, methylomic, transcriptomic, and drug response data should facilitate research in EBV and NPC, where current models are limited. SIGNIFICANCE: NPC268 is the first and only EBV-positive cell line derived from a primary non-keratinizing, differentiated nasopharyngeal carcinoma, an understudied but important subtype in Southeast Asian countries. This model adds to the limited number of authentic EBV-positive lines globally that will facilitate mechanistic studies and drug development for NPC.

Treatment of L5-S1 Floating Calcified Lumbar Disc Herniation with Percutaneous Endoscopic Interlaminar Discectomy.

OBJECTIVE: The floating calcified tissue in floating calcified lumbar disc herniation (FCLDH) is hard and often adheres to the dura mater, which can easily cause nerve root damage during surgery, making the operation challenging. We proposed the classification of FCLDH and a new technique for removing floating calcified tissue and reported the clinical efficacy and safety of this new technique in clinical practice. METHODS: From January 2019 to October 2021, 24 patients (13 males and 11 females, 46.4 ± 7.72 years) with L5-S1 floating calcified lumbar disc herniation were treated with percutaneous endoscopic interlaminar discectomy (PEID). According to FCLDH classification, a total of Type Ia: nine cases, Type Ib: five cases, Type IIa: four cases, and Type IIa: six cases were included. The visual analogue scale (VAS) and Oswestry disability index (ODI) were recorded pre-operatively and 3 days postoperatively, 6 months postoperatively, and at the last follow-up. The postoperative curative effect was evaluated according to the modified MacNab criteria. Computed tomography (CT) and magnetic resonance imaging (MRI) of the lumbar spine were performed 3 days after surgery to evaluate the efficacy of the surgery. RESULTS: All patients successfully underwent PEID. The VAS and ODI scores at 3 days postoperatively, 6 months postoperatively, and at the last follow-up were significantly improved and statistically significant compared to those of the preoperative period (p < 0.05). All the patients were followed up for 12-24 months (mean, 16.6 ± 4.6 months). At the last follow-up, according to the modified MacNab criteria, 15 cases were excellent, eight were good, and one was fair. The combined excellent and good rate was 95.83% (23/24). Postoperative review revealed that all floating calcified tissues were effectively removed and the nerve roots were adequately decompressed without complications such as cerebrospinal fluid leakage and lumbar spine infection. CONCLUSION: The classification of FCLDH we proposed can well guide the selection of surgical plans. PEID combined with floating calcified tissue removal technology has good efficacy in the treatment of L5-S1 FCLDH, ensuring accurate removal of calcified tissue, reducing complications and improving the quality of life of affected individuals.

Corylifol A suppresses osteoclastogenesis and alleviates ovariectomy-induced bone loss via attenuating ROS production and impairing mitochondrial function.

Osteoporosis is a systemic disease characterized by an imbalance in bone homeostasis, where osteoblasts fail to fully compensate for the bone resorption induced by osteoclasts. Corylifol A, a flavonoid extracted from Fructus psoraleae, has been identified as a potential treatment for this condition. Predictions from network pharmacology and molecular docking studies suggest that Corylifol A exhibits strong binding affinity with NFATc1, Nrf2, PI3K, and AKT1. Empirical evidence from in vivo experiments indicates that Corylifol A significantly mitigates systemic bone loss induced by ovariectomy by suppressing both the generation and activation of osteoclasts. In vitro studies further showed that Corylifol A inhibited the activation of PI3K-AKT and MAPK pathways and calcium channels induced by RANKL in a time gradient manner, and specifically inhibited the phosphorylation of PI3K, AKT, GSK3 ß, ERK, CaMKII, CaMKIV, and Calmodulin. It also diminishes ROS production through Nrf2 activation, leading to a decrease in the expression of key regulators such as NFATcl, C-Fos, Acp5, Mmp9, and CTSK that are involved in osteoclastogenesis. Notably, our RNA-seq analysis suggests that Corylifol A primarily impacts mitochondrial energy metabolism by suppressing oxidative phosphorylation. Collectively, these findings demonstrate that Corylifol A is a novel inhibitor of osteoclastogenesis, offering potential therapeutic applications for diseases associated with excessive bone resorption.

Exploring the formation pathway and antioxidant properties of the sugar-smoking pigment 5-GGMF.

The present study aimed to elucidate the pathway of pigment formation and identify the source of antioxidant activity during sugar smoking. Building upon previous research, this investigation replicated the sucrose cleavage process involved in sugar-smoking through model reactions to obtain distinct model reaction products. The products were analyzed using various techniques such as ultraviolet-visible spectrometry, Fourier-transform infrared spectroscopy, high-performance liquid chromatography, and high-performance liquid chromatography-tandem mass spectrometry. The findings revealed that the pyrolysis of sucrose at 330 °C yielded glucose and fructose, with fructose pyrolysis producing significantly more 5-HMF than glucose. Moreover, the antioxidant capacity of 5-HMF was found to make a substantial contribution. The primary source of 5-HMF was identified as fructose resulting from the cleavage of sucrose at 330 °C, while the primary pathway for the formation of the sugar-smoking pigment 5-GGMF was attributed to the intermolecular dehydration of 5-HMF and glucose at 150 °C.

Diagnostic performance and clinical impacts of metagenomic sequencing after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Metagenomic Next-Generation Sequencing (mNGS) is a rapid, non-culture-based, high-throughput technique for pathogen diagnosis. Despite its numerous advantages, only a few studies have investigated its use in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: We conducted a retrospective analysis of 404 mNGS tests performed on 264 patients after allo-HSCT. The tests were divided into three groups (Phase A, B, C) based on the time spent hospitalized post-transplantation, and we evaluated the analytical performance of mNGS in comparison with conventional microbiological tests (CMT), while also analyzing its clinical utility for clinical impacts. RESULTS: Metagenomic sequencing demonstrated a significantly higher rate of positive microbiological findings as compared to CMT (334/404 (82.7 %) vs. 159/404 (39.4 %), respectively, P < 0.001). The detection rates by both mNGS and CMT varied across the three-phase (mNGS: A-60/89 (67.4 %), B-147/158 (93.0 %), C-125/157 (79.6 %), respectively, P < 0.001; CMT: A-21/89 (23.6 %), B-79/158 (50.0 %), C-59/157 (37.6 %), respectively, P < 0.001). The infection sites and types of pathogens were also different across the three phases. Compared to non-GVHD cases, mNGS detected more Aspergillus spp. and Mucorales in GVHD patients (Aspergillus: 12/102 (11.8 %) vs. 8/158 (5.1 %), respectively, P = 0.048; Mucorales: 6/102 (5.9 %) vs. 2/158 (1.3 %), respectively, P = 0.035). Forty-five (181/404) percent of mNGS tests yielded a positive impact on the clinical diagnosis, while 24.3 % (98/404) of tests benefited the patients in antimicrobial treatment. CONCLUSION: mNGS is an indispensable diagnostic tool in identifying pathogens and optimizing antibiotic therapy for hematological patients receiving allo-HSCT.

ß-Cell Function and Insulin Dynamics in Obese Patients With and Without Diabetes After Sleeve Gastrectomy.

Improved ß-cell function seems to be essential for better glucose homeostasis after Roux-en-Y gastric bypass but is less studied after sleeve gastrectomy (SG). We evaluated the effects of SG on ß-cell function in obese patients with diabetes (DM group) and without (control group) in response to both oral and intravenous glucose stimulation. The DM group demonstrated impaired insulin sensitivity and insulin response to glucose before surgery. The insulin sensitivity index of both groups significantly improved after SG. In addition, the insulin response to glucose (early insulinogenic index in oral glucose tolerance test and acute insulin response to glucose in an intravenous glucose tolerance test) increased in the DM group but decreased in the control group. As a result, ß-cell function improved significantly in both groups after SG since the disposition index (DI) increased in both. However, the DI of the DM group was not restored to the level of control group up to 1 year after SG. Our results support that obese patients, with and without diabetes, could benefit from SG in ß-cell function. For obese patients at risk for or who have been diagnosed with diabetes, interventions should be recommended early to preserve or restore ß-cell function, and SG could be an effective choice. Further studies are needed for long-term effects.

A Polymeric Hydrogel to Eliminate Programmed Death-Ligand 1 for Enhanced Tumor Radio-Immunotherapy.

Programmed death-ligand 1 (PD-L1) is a specialized shield on tumor cells that evades the immune system. Even inhibited by PD-L1 antibodies, a cycling process constantly transports PD-L1 from inside to outside of cells, facilitating the renewal and replenishment of PD-L1 on the cancer cell membrane. Herein, we develop a sodium alginate hydrogel consisting of elesclomol-Cu and galactose to induce persistent cuproptosis, leading to the reduction of PD-L1 for radio-immunotherapy of colon tumors. First, a prefabricated hydrogel is synthesized by immobilizing elesclomol onto a sodium alginate saccharide chain through the coordination with bivalent copper ions (Cu2+), followed by incorporation of galactose. After implantation into the tumors, this prefabricated hydrogel can be further cross-linked in the presence of physiological calcium ions (Ca2+), resulting in the formation of a hydrogel with controlled release of elesclomol-Cu2+ (ES-Cu) and galactose. The hydrogel effectively induces the oligomerization of DLAT and cuproptosis in colorectal cancer cells. Interestingly, radiation-induced PD-L1 upregulation is abrogated in the presence of the hydrogel, releasing ES-Cu and galactose. Consequently, the sensitization of tumor to radiotherapy and immunotherapy is significantly improved, further prolonging the survival of tumor-bearing mice in both local and metastatic tumors. Our study introduces an approach that combines cuproptosis with immunotherapy and radiotherapy.

Case report: Novel DGUOK variants associated with idiopathic non-cirrhotic portal hypertension in a Han Chinese child.

DGUOK deficiency has primarily been associated with lethal hepatic failure with or without hypotonia, nystagmus, and psychomotor retardation, features typical of mitochondrial disease. A study in 3 Turkish children identified homozygosity for a variant in DGUOK as associated with idiopathic non-cirrhotic portal hypertension (INCPH). However, no further instances of INCPH associated with DGUOK variants have been reported. We here describe a fourth patient with DGUOK variants and childhood-onset INCPH, a 12-year-old Han Chinese boy, reporting clinical manifestations, histopathologic findings, and results of genetic studies. The child presented with hepatosplenomegaly; portal hypertension and hypersplenism were found. Vascular changes with hepatic fibrosis (Scheuer score 3) were observed on liver biopsy. Whole-exome sequencing and family analyses revealed compound heterozygosity for the DGUOK (NM_080916.3) variants c.778_781dup, (p.Thr261Serfs*28) and c.831_832del, (p.*278Thrfs*9) in the proband. These observations support ascription of instances of INCPH in children to variation in DGUOK.

Regulation of Ion Homeostasis for Enhanced Tumor Radio-Immunotherapy.

Intra/extracellular ion content affects the growth and metastasis of tumor cells, as well as the efficacy of various antitumor therapies. Herein, a carbonic anhydrase inhibitor (CAI) is loaded onto pH-responsive calcium carbonate (CaCO3 ) nanoparticles and then modify theses nanoparticles with liposomes to obtain biocompatible CaCO3 /CAI@Lipsome (CCL) for enhance tumor radio-immunotherapy. CCL can specially decompose in tumor microenvironment, releasing calcium ion (Ca2+ ) and CAI, as well as increasing the pH value of extracellular fluid. CAI restrains the flow of hydrogen ion (H+ ) inside and outside the tumor cells, resulting in the reversal of tumor acidic microenvironment and the increase of intracellular H+ , both of which can improve the sensitivity of tumor to radiotherapy. Afterward, the increased intracellular H+ together with radiotherapy-causes reactive oxygen species promotes calcium influx, leading to cellular calcium overload. Moreover, the CCL-tailored content of H+ and Ca2+ strengthens radiotherapy-induced immunogenic cell death and dendritic cell maturation, amplifying systemic anti-tumor adaptive immunity. Meanwhile, macrophages in the CCL-treated tumors are polarized from pro-tumor M2 to anti-tumor M1 under X-ray exposure, owing to the neutralization of tumor acidic microenvironment and enhances Ca2+ content. Therefore, multi-directional regulation of the intra/extra tumor cell pH/calcium by simple nano-preparation would provide a powerful way to improve the efficacy of radio-immunotherapy.

Appraising causal risk and protective factors for rheumatoid arthritis.

Aims: Mendelian randomization (MR) is considered to overcome the bias of observational studies, but there is no current meta-analysis of MR studies on rheumatoid arthritis (RA). The purpose of this study was to summarize the relationship between potential pathogenic factors and RA risk based on existing MR studies. Methods: PubMed, Web of Science, and Embase were searched for MR studies on influencing factors in relation to RA up to October 2022. Meta-analyses of MR studies assessing correlations between various potential pathogenic factors and RA were conducted. Random-effect and fixed-effect models were used to synthesize the odds ratios of various pathogenic factors and RA. The quality of the study was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization (STROBE-MR) guidelines. Results: A total of 517 potentially relevant articles were screened, 35 studies were included in the systematic review, and 19 studies were eligible to be included in the meta-analysis. Pooled estimates of 19 included studies (causality between 15 different risk factors and RA) revealed that obesity, smoking, coffee intake, lower education attainment, and Graves' disease (GD) were related to the increased risk of RA. In contrast, the causality contribution from serum mineral levels (calcium, iron, copper, zinc, magnesium, selenium), alcohol intake, and chronic periodontitis to RA is not significant. Conclusion: Obesity, smoking, education attainment, and GD have real causal effects on the occurrence and development of RA. These results may provide insights into the genetic susceptibility and potential biological pathways of RA.

Fluorescence Lifetime of Chlorophyll α in Oxidized Edible Vegetable Oil.

To promote the application of time-resolved fluorescence in oxidation determination of edible vegetable oil, fluorescence lifetime of chlorophyll α in oxidized edible vegetable oils was recorded and analyzed by simulated microenvironment experiments and spectral methods. It was showed that fluorescence lifetime of chlorophyll α decreased with the increase of polarity in the early stage of oxidation, and increased with the increase of viscosity in the later stage of oxidation. Conjugation effect and hydrogen bonding existed in the microenvironment of oxidized edible vegetable oil were considered to be the factors leading to the increase of fluorescence lifetime. The change mechanism of fluorescence lifetime in oxidized edible vegetable oil was supplied, which was considered to be strong support for the application of time-resolved fluorescence.

Dipeptidase­2 is a prognostic marker in lung adenocarcinoma that is correlated with its sensitivity to cisplatin.

Lung cancer accounts for the highest percentage of cancer morbidity and mortality worldwide, and lung adenocarcinoma (LUAD) is the most prevalent subtype. Although numerous therapies have been developed for lung cancer, patient prognosis is limited by tumor metastasis and more effective treatment targets are urgently required. In the present study, gene expression profiles were extracted from the Gene Expression Omnibus database and mRNA expression data were downloaded from The Cancer Genome Atlas database. In addition, TIMER 2.0 database was used to analyze the expression of genes in normal and multiple tumor tissues. Protein expression was confirmed using the Human Protein Atlas database and LUAD cell lines, sphere formation assay, western blotting, and a xenograft mouse model were used to confirm the bioinformatics analysis. Dipeptidase­2 (DPEP2) expression was significantly decreased in LUAD and was negatively associated with prognosis. DPEP2 overexpression substantially inhibited epithelial­mesenchymal transition (EMT) as well as LUAD cell metastasis, and limited the expression of the cancer stem cell transformation markers, CD44 and CD133. In addition, DPEP2 improved LUAD sensitivity to cisplatin by inhibiting EMT; this was verified in vitro and in vivo. These data indicated that DPEP2 upregulates E­cadherin, thereby regulating cell migration, cancer stem cell transformation, and cisplatin resistance, ultimately affecting the survival of patients with LUAD. Overall, the findings of the present suggest that DPEP2 is important in the development of LUAD and can be used both as a prognostic marker and a target for future therapeutic research.

Tumor Vascular Destruction and cGAS-STING Activation Induced by Single Drug-Loaded Nano-Micelles for Multiple Synergistic Therapies of Cancer.

Cancer and its metastasis/recurrence still threaten human health, despite various advanced treatments being employed. It is of great significance to develop simple drug formulations to enhance the efficacy and synergistic integration of various monotherapies. Herein, DMXAA, a vasodestructive agent with cGAS-STING stimulation capacity, is integrated with polyethylene glycol grafted poly (lactic-co-glycolic) acid co-polymer (PLGA-PEG), obtaining PLGA-PEG/DMXAA (PPD) nanoparticles to induce the tumor-specific vascular destruction for multiple synergistic therapies of cancer. PPD could induce the formation of blood clots in the tumor after intravenous injection, which subsequently mediate photothermal therapy and further promote the release of oxygen for enhanced radiotherapy. Meanwhile, the enhanced vascular injury can induce perfect starvation therapy of tumor. More importantly, PPD-mediated therapies could trigger potent systemic anti-tumor immunity via inducing the immunogenic death of tumor cells and activating the cGAS-STING pathway. Together with anti-PD-L1, PPD-mediated therapies could not only remove the primary tumors, but also effectively eliminate the distant tumors, metastasis, and recurrence. Therefore, the modulation of tumor composition induced by a single drug-loaded nano-micelle could be utilized to enhance the therapeutic effect of multiple treatments for synergistic and systemic antitumor response, providing a practical strategy for cancer therapy.