Deep learning model based on endoscopic images predicting treatment response in locally advanced rectal cancer undergo neoadjuvant chemoradiotherapy: a multicenter study.

PURPOSE: Neoadjuvant chemoradiotherapy has been the standard practice for patients with locally advanced rectal cancer. However, the treatment response varies greatly among individuals, how to select the optimal candidates for neoadjuvant chemoradiotherapy is crucial. This study aimed to develop an endoscopic image-based deep learning model for predicting the response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. METHODS: In this multicenter observational study, pre-treatment endoscopic images of patients from two Chinese medical centers were retrospectively obtained and a deep learning-based tumor regression model was constructed. Treatment response was evaluated based on the tumor regression grade and was defined as good response and non-good response. The prediction performance of the deep learning model was evaluated in the internal and external test sets. The main outcome was the accuracy of the treatment prediction model, measured by the AUC and accuracy. RESULTS: This deep learning model achieved favorable prediction performance. In the internal test set, the AUC and accuracy were 0.867 (95% CI: 0.847-0.941) and 0.836 (95% CI: 0.818-0.896), respectively. The prediction performance was fully validated in the external test set, and the model had an AUC of 0.758 (95% CI: 0.724-0.834) and an accuracy of 0.807 (95% CI: 0.774-0.843). CONCLUSION: The deep learning model based on endoscopic images demonstrated exceptional predictive power for neoadjuvant treatment response, highlighting its potential for guiding personalized therapy.

Cholestasis-induced phenotypic transformation of neutrophils contributes to immune escape of colorectal cancer liver metastasis.

BACKGROUND: Cholestasis is a common yet severe complication that occurs during the advancement of liver metastasis. However, how cholestasis impacts the development, treatment, and tumor microenvironment (TME) of liver metastasis remains to be elucidated. METHODS: Extrahepatic and intrahepatic cholestatic mouse models with liver metastasis were established to detect the differential expression levels of genes, infiltration of immune cells and change in bile acid-associated metabolites by using RNA-Sequencing, flowcytometry, and liquid chromatography and mass spectrometry. Western blot was applied to neutrophils under the stimulation of primary bile acids (BAs) in vitro to study the mechanism of phenotypic alteration. In vitro coculture of BA-treated neutrophils with CD8+ T cells were performed to study the immune-suppressive effect of phenotypic-altered neutrophils. Clinical samples collected from colorectal cancer patients with liver metastasis and cholestasis were applied to RNA-Seq. RESULTS: Compared to non-cholestatic mice, the progression of liver metastasis of cholestatic mice was significantly accelerated, which was associated with increased neutrophil infiltration and T-cell exclusion. Both neutrophils and T cells expressed higher immunosuppressive markers in the cholestatic mouse model, further indicating that an immunosuppressive tumor microenvironment was induced during cholestasis. Although neutrophils deletion via anti-Ly6G antibody partially hindered liver metastasis progression, it reduced the overall survival of mice. Tauro-ß-muricholic acid (Tß-MCA) and Glycocholic acid (GCA), the two most abundant cholestasis-associated primary BAs, remarkably promoted the expression of Arg1 and iNOS on neutrophils via p38 MAPK signaling pathway. In addition, BAs-pretreated neutrophils significantly suppressed the activation and cytotoxic effects of CD8+ T cells, indicating that the immunosuppressive phenotype of neutrophils was directly induced by BAs. Importantly, targeting BA anabolism with Obeticholic acid (OCA) under cholestasis effectively suppressed liver metastasis progression, enhanced the efficacy of immune checkpoint blockade, and prolonged survival of mice. CONCLUSIONS: Our study reveals the TME of cholestasis-associated liver metastasis and proposes a new strategy for such patients by targeting bile acid anabolism.

Insight into the mechanisms of combined toxicity of cadmium and flotation agents in luminescent bacteria: Role of micro/nano particles.

Currently, risk assessment and pollution management in mines primarily focus on toxic metals, with the flotation agents being overlooked. However, the combined effects of metals and flotation agents in mines remain largely unknown. Therefore, this study aimed to evaluate the combined effects of Cd and two organic flotation agents (ethyl xanthate (EX) and diethyldithiocarbamate (DDTC)), and the associated mechanisms. The results showed that Cd + EX and Cd + DDTC exhibited synergistic toxicity. The EC50 values for luminescent bacteria were 1.6 mg/L and 1.0 mg/L at toxicity unit ratios of 0.3 and 1, respectively. The synergistic effects were closely related with the formation of Cd(EX)2 and Cd(DDTC)2 micro/nano particles, with nano-particles exhibiting higher toxicity. We observed severe cell membrane damage and cell shrinkage of the luminescent bacteria, which were probably caused by secondary harm to cells through the released CS2 during their decomposition inside cells. In addition, these particles induced toxicity by altering cellular levels of biochemical markers and the transcriptional levels of transport proteins and lipoproteins, leading to cell membrane impairment and DNA damage. This study has demonstrated that particulates formed by Cd and flotation agents contribute to the majority of the toxicity of the binary mixture. This study helps to better understand the complex ecological risk of inorganic metals and organic flotation agents in realistic mining environments.

VEGFR2 blockade inhibits glioblastoma cell proliferation by enhancing mitochondrial biogenesis.

BACKGROUND: Glioblastoma is an aggressive brain tumor linked to significant angiogenesis and poor prognosis. Anti-angiogenic therapies with vascular endothelial growth factor receptor 2 (VEGFR2) inhibition have been investigated as an alternative glioblastoma treatment. However, little is known about the effect of VEGFR2 blockade on glioblastoma cells per se. METHODS: VEGFR2 expression data in glioma patients were retrieved from the public database TCGA. VEGFR2 intervention was implemented by using its selective inhibitor Ki8751 or shRNA. Mitochondrial biogenesis of glioblastoma cells was assessed by immunofluorescence imaging, mass spectrometry, and western blot analysis. RESULTS: VEGFR2 expression was higher in glioma patients with higher malignancy (grade III and IV). VEGFR2 inhibition hampered glioblastoma cell proliferation and induced cell apoptosis. Mass spectrometry and immunofluorescence imaging showed that the anti-glioblastoma effects of VEGFR2 blockade involved mitochondrial biogenesis, as evidenced by the increases of mitochondrial protein expression, mitochondria mass, mitochondrial oxidative phosphorylation (OXPHOS), and reactive oxygen species (ROS) production, all of which play important roles in tumor cell apoptosis, growth inhibition, cell cycle arrest and cell senescence. Furthermore, VEGFR2 inhibition exaggerated mitochondrial biogenesis by decreased phosphorylation of AKT and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which mobilized PGC1α into the nucleus, increased mitochondrial transcription factor A (TFAM) expression, and subsequently enhanced mitochondrial biogenesis. CONCLUSIONS: VEGFR2 blockade inhibits glioblastoma progression via AKT-PGC1α-TFAM-mitochondria biogenesis signaling cascade, suggesting that VEGFR2 intervention might bring additive therapeutic values to anti-glioblastoma therapy.

Iron-Nickel synergistic catalysis growth of (Fe,Ni)9S8/Ni3S2@N,S codoped carbon bridged nanowires enhanced oxygen evolution reaction performance.

Improving the conductivity of the electrocatalyst itself is essential for enhancing its performance. In this work, N, S-rich 6-thioguanine (TG) is selected as the ligand to synthesize a Fe, Ni bimetallic porous coordination polymer (PCP), which is then derived to fabricate N,S codoped carbon (NSC)-coated (Fe,Ni)9S8/Ni3S2 bridged nanowires. The (Fe,Ni)9S8/Ni3S2@NSC bridged nanowires obtained through bimetallic synergistic catalysis and self-sulfurization processes not only introduced additional electrocatalytic active sites but also significantly enhance the overall conductivity of the catalyst due to the interconnected nanowire structure. The resulting (Fe,Ni)9S8/Ni3S2@NSC demonstrates remarkable oxygen evolution reaction (OER) performance, exhibiting an overpotential as low as 252 mV at a current density of 10 mA cm-2. This work proposes a novel strategy for enhancing the overall conductivity of catalysts by growing bridged nanowires, providing valuable insights and inspiration for the design and preparation of advanced transition metal sulfide electrocatalysts.

Standardized ileal digestibility of amino acids in Chinese fermented soybean meal from different sources fed to mid and late-gestating sows.

We determined apparent ileal digestibility (AID) and standardized ileal digestibility (SID) values of crude protein (CP) and amino acids (AA) in fermented soybean meal from five different sources (FSBM 1 to 5) in China when fed to mid and late-gestating sows. Twenty-four parity four sows (12 at 30 d in gestation and 12 at 80 d in gestation) were fitted with a T-cannula in the distal ileum and used in this experiment. Sows were randomly assigned to a replicated 6 × 3 Youden square design including six diets and three periods. Six diets were provided for sows in mid and late gestation, including a nitrogen-free diet and five test diets containing 26% FSBM from different sources. Results showed that there were differences in AID and SID of CP among the different FSBM samples, but no differences between sow physiological stages were observed. Specifically, when mid-gestating sows were fed FSBM 2, the AID of CP was the lowest, whereas FSBM 3 exhibited a greater AID of CP when compared to the other FSBM samples (P < 0.01). Furthermore, during late gestation, FSBM 3 consistently had greater SID of CP when compared to other FSBM samples (P < 0.01). The ileal digestibility of most AA varied with different FSBM samples. In both mid and late gestation, differences (P < 0.05) were observed for AID of lysine, tryptophan, histidine, and arginine across different FSBM samples. Similarly, the AID of dispensable AA (cysteine, glutamine, and serine) also exhibited differences (P < 0.05) across different FSBM samples in both mid and late-gestating sows. For mid-gestating sows, SID differences relating to lysine, phenylalanine, tryptophan, threonine, and arginine were observed among different diets (P < 0.05). In late-gestating sows, SID values for lysine, tryptophan, leucine, and arginine differed across diets (P < 0.05). Furthermore, the ileal digestibility of some dispensable AA was influenced by physiological stage, as evidenced by greater AID and SID values for glycine, glutamine, cysteine, and serine in late-gestating sows when compared to mid-gestating sows (P < 0.01). In summary, our study determined AA ileal digestibility of different FSBM fed to mid and late-gestating sows. We observed that the AA ileal digestibility differed among five FSBM samples, but the physiological stage of sows did not affect the ileal digestibility of CP and most AA. Additionally, when formulating diets for sows, it is crucial to consider the nutritional value differences of FSBM.

Fermented soybean meal (FSBM) is obtained from the microbial fermentation of soybean meal, which reduces anti-nutritional factor levels and enhances other nutrient content. Substituting soybean meal with FSBM in piglet and growing pig diets improves nutrient digestibility. However, its nutritional value for sows remains unclear. Therefore, five sources of FSBM were fed to sows in mid and late gestation to evaluate apparent ileal digestibility (AID) and standardized ileal digestibility (SID) values of amino acids (AA). We found that different FSBM samples impacted the SID value of AA when fed to gestating sows. Additionally, sow physiological stage influenced the SID of some dispensable AA. These findings provide valuable insights into the incorporation of FSBM into sow diets.

Immune reactions following intestinal transplantation: Mechanisms and prevention.

For patients with intestinal failure, small bowel transplantation remains one of the most effective treatments despite continuous advancements in parenteral nutrition techniques. Long-term use of parenteral nutrition can result in serious complications that lead to metabolic dysfunction and organ failure. However, the small intestine is a highly immunogenic organ with a large amount of mucosa-associated lymphoid tissue and histocompatibility antigens; therefore, the small intestine is highly susceptible to severe immune rejection. This article discusses the mechanisms underlying immune rejection after small bowel transplantation and presents various options for prevention and treatment. Our findings offer new insights into the development of small bowel transplantation.

Chemotherapy-induced pneumatosis intestinalis followed by hepatic portal venous gas. A case report.

Pneumatosis intestinalis (PI) is a rare disease, and there are many theories about its pathogenesis. Hepatic portal venous gas (HPVG), is thought to occur secondary to intramural intestinal gas emboli migrating through the portal venous system via the mesenteric veins. PI accompanied by HPVG is usually a sign of bowel ischaemia and is associated with a high mortality rate. We report here, a patient with liver metastases from colorectal cancer who developed PI followed by HPVG after treatment with 5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6). Timely attention and management of gastrointestinal symptoms following chemotherapy are essential in the treatment of this type of patient.

Red blood cell membrane-coated functionalized Cu-doped metal organic framework nanoformulations as a biomimetic platform for improved chemo-/chemodynamic/photothermal synergistic therapy.

Nanoformulations for combining chemotherapy, chemodynamic therapy, and photothermal therapy have enormous potential in tumor treatment. Coating nanoformulations with cell membranes endows them with homologous cellular mimicry, enabling nanoformulations to acquire new functions and properties, including homologous targeting and long circulation in vivo, and can enhance internalization by homologous cancer cells. Herein, we fused multifunctional biomimetic nanoformulations based on Cu-doped zeolitic imidazolate framework-8 (ZIF-8). Hydroxycamptothecin (HCPT), a clinical anti-tumor drug, was encapsulated into ZIF-8, which was subsequently coated with polydopamine (PDA) and red blood cell membrane. The as-fabricated biomimetic nanoformulations showed an enhanced cell uptake in vitro and the potential to prolong blood circulation in vivo, producing effective synergistic chemotherapy, chemodynamic therapy, and photothermal therapy under the 808 nm laser irradiation. Together, the biomimetic nanoformulations showed a prolonged blood circulation and evasion of immune recognition in vivo to provide a bio-inspired strategy which may have the potential for the multi-synergistic therapy of breast cancer.

Red Blood Cell Membrane-Camouflaged Polydopamine and Bioactive Glass Composite Nanoformulation for Combined Chemo/Chemodynamic/Photothermal Therapy.

Combinations of different therapeutic strategies, including chemotherapy (CT), chemodynamic therapy (CDT), and photothermal therapy (PTT), are needed to effectively address evolving drug resistance and the adverse effects of traditional cancer treatment. Herein, a camouflage composite nanoformulation (TCBG@PR), an antitumor agent (tubercidin, Tub) loaded into Cu-doped bioactive glasses (CBGs) and subsequently camouflaged by polydopamine (PDA), and red blood cell membranes (RBCm), was successfully constructed for targeted and synergetic antitumor therapies by combining CT of Tub, CDT of doped copper ions, and PTT of PDA. In addition, the TCBG@PRs composite nanoformulation was camouflaged with a red blood cell membrane (RBCm) to improve biocompatibility, longer blood retention times, and excellent cellular uptake properties. It integrated with long circulation and multimodal synergistic treatment (CT, CDT, and PTT) with the benefit of RBCms to avoid immune clearance for efficient targeted delivery to tumor locations, producing an "all-in-one" nanoplatform. In vivo results showed that the TCBG@PRs composite nanoformulation prolonged blood circulation and improved tumor accumulation. The combination of CT, CDT, and PTT therapies enhanced the antitumor therapeutic activity, and light-triggered drug release reduced systematic toxicity and increased synergistic antitumor effects.

Dual blockade of EGFR and PI3K signaling pathways offers a therapeutic strategy for glioblastoma.

BACKGROUND: Glioblastoma multiforme (GBM) is a devastating disease that lacks effective drugs for targeted therapy. Previously, we found that the third-generation epidermal growth factor receptor (EGFR) inhibitor AZD-9291 persistently blocked the activation of the ERK pathway but had no inhibitory effect on the phosphoinositide 3-kinase (PI3K)/Akt pathway. Given that the PI3K inhibitor GDC-0084 is being evaluated in phase I/II clinical trials of GBM treatment, we hypothesized that combined inhibition of the EGFR/ERK and PI3K/Akt pathways may have a synergistic effect in the treatment of GBM. METHODS: The synergistic effects of cotreatment with AZD-9291 and GDC-0084 were validated using cell viability assays in GBM and primary GBM cell lines. Moreover, the underlying inhibitory mechanisms were assessed through colony formation, EdU proliferation, and cell cycle assays, as well as RNA-seq analyses and western blot. The therapeutic effects of the drug combination on tumor growth and survival were investigated in mice bearing tumors using subcutaneously or intracranially injected LN229 xenografts. RESULTS: Combined treatment with AZD-9291 and GDC-0084 synergistically inhibited the proliferation and clonogenic survival, as well as induced cell cycle arrest of GBM cells and primary GBM cells, compared to monotherapy. Moreover, AZD-9291 plus GDC-0084 combination therapy significantly inhibited the growth of subcutaneous tumors and orthotopic brain tumor xenografts, thus prolonging the survival of tumor-bearing mice. More importantly, the combination of AZD-9291 and GDC-0084 simultaneously blocked the activation of the EGFR/MEK/ERK and PI3K/AKT/mTOR signaling pathways, thereby exerting significant antitumor activity. CONCLUSION: Our findings demonstrate that the combined blockade of the EGFR/MEK/ERK and PI3K/AKT/mTOR pathways is more effective against GBM than inhibition of each pathway alone, both in vitro and in vivo. Our results suggest that AZD-9291 combined with GDC-0084 may be considered as a potential treatment strategy in future clinical trials. Video Abstract.

Modulating Coordination of Iron Atom Clusters on N,P,S Triply-Doped Hollow Carbon Support towards Enhanced Electrocatalytic Oxygen Reduction.

Constructing atom-clusters (ACs) with in situ modulation of coordination environment and simultaneously hollowing carbon support are critical yet challenging for improving electrocatalytic efficiency of atomically dispersed catalysts (ADCs). Herein, a general diffusion-controlled strategy based on spatial confining and Kirkendall effect is proposed to construct metallic ACs in N,P,S triply-doped hollow carbon matrix (MACs /NPS-HC, M=Mn, Fe, Co, Ni, Cu). Thereinto, FeACs /NPS-HC with the best catalytic activity for oxygen reduction reaction (ORR) is thoroughly investigated. Unlike the benchmark sample of symmetrical N-surrounded iron single-atoms in N-doped carbon (FeSAs /N-C), FeACs /NPS-HC comprises bi-/tri-atomic Fe centers with engineered S/N coordination. Theoretical calculation reveals that proper Fe gathering and coordination modulation could mildly delocalize the electron distribution and optimize the free energy pathways of ORR. In addition, the triple doping and hollow structure of carbon matrix could further regulate the local environment and allow sufficient exposure of active sites, resulting in more enhanced ORR kinetics on FeACs /NPS-HC. The zinc-air battery assembled with FeACs /NPS-HC as cathodic catalyst exhibits all-round superiority to Pt/C and most Fe-based ADCs. This work provides an exemplary method for establishing atomic-cluster catalysts with engineered S-dominated coordination and hollowed carbon matrix, which paves a new avenue for the fabrication and optimization of advanced ADCs.

Preclinical evaluation of Mito-LND, a targeting mitochondrial metabolism inhibitor, for glioblastoma treatment.

BACKGROUND: Glioblastoma (GBM) is a brain tumor with the highest level of malignancy and the worst prognosis in the central nervous system. Mitochondrial metabolism plays a vital role in the occurrence and development of cancer, which provides critical substances to support tumor anabolism. Mito-LND is a novel small-molecule inhibitor that can selectively inhibit the energy metabolism of tumor cells. However, the therapeutic effect of Mito-LND on GBM remains unclear. METHODS: The present study evaluated the inhibitory effect of Mito-LND on the growth of GBM cells and elucidated its potential mechanism. RESULTS: The results showed that Mito-LND could inhibit the survival, proliferation and colony formation of GBM cells. Moreover, Mito-LND induced cell cycle arrest and apoptosis. Mechanistically, Mito-LND inhibited the activity of mitochondrial respiratory chain complex I and reduced mitochondrial membrane potential, thus promoting ROS generation. Importantly, Mito-LND could inhibit the malignant proliferation of GBM by blocking the Raf/MEK/ERK signaling pathway. In vivo experiments showed that Mito-LND inhibited the growth of GBM xenografts in mice and significantly prolonged the survival time of tumor-bearing mice. CONCLUSION: Taken together, the current findings support that targeting mitochondrial metabolism may be as a potential and promising strategy for GBM therapy, which will lay the theoretical foundation for further clinical trials on Mito-LND in the future.

Alcohol reshapes a liver premetastatic niche for cancer by extra- and intrahepatic crosstalk-mediated immune evasion.

Cancer metastatic organotropism is still a mystery. The liver is known to be susceptible to cancer metastasis and alcoholic injury. However, it is unclear whether and how alcohol facilitates liver metastasis and how to intervene. Here, we show that alcohol preferentially promotes liver metastasis in colon-cancer-bearing mice and post-surgery pancreatic cancer patients. The mechanism is that alcohol triggers an extra- and intrahepatic crosstalk to reshape an immunosuppressive liver microenvironment. In detail, alcohol upregulates extrahepatic IL-6 and hepatocellular IL-6 receptor expression, resulting in hepatocyte STAT3 signaling activation and downstream lipocalin-2 (Lcn2) upregulation. Furthermore, LCN2 promotes T cell-exhaustion neutrophil recruitment and cancer cell epithelial plasticity. In contrast, knocking out hepatocellular Stat3 or systemic Il6 in alcohol-treated mice preserves the liver microenvironment and suppresses liver metastasis. This mechanism is reflected in hepatocellular carcinoma patients, in that alcohol-associated signaling elevation in noncancerous liver tissue indicates adverse prognosis. Accordingly, we discover a novel application for BBI608, a small molecular STAT3 inhibitor that can prevent liver metastasis. BBI608 pretreatment protects the liver and suppresses alcohol-triggered premetastatic niche formation. In conclusion, under extra- and intrahepatic crosstalk, the alcoholic injured liver forms a favorable niche for cancer cell metastasis, while BBI608 is a promising anti-metastatic agent targeting such microenvironments.

[Treatment of rheumatoid arthritis by injection of sinomenine solid lipid nanoparticles under a fluorescence endoscopic laser confocal microscope].

A fluorescence endoscopic laser confocal microscope(FELCM) was used to direct the injection of sinomenine solid lipid nanoparticles(Sin-SLN) into the joint, and the in vitro effectiveness of Sin-SLN in the treatment of rheumatoid arthritis(RA) was evaluated. Sin-SLN was prepared with the emulsion evaporation-low temperature curing method. The Sin-SLN prepared under the optimal conditions showed the encapsulation efficiency of 64.79%±3.12%, the drug loading of 3.84%±0.28%, the average particle size of(215.27±4.21) nm, and the Zeta potential of(-32.67±0.84) mV. Moreover, the Sin-SLN demonstrated good stability after sto-rage for 30 days. The rabbit model of RA was established by the subcutaneous injection of ovalbumin and complete Freund's adjuvant. Five groups were designed, including a control group, a model group, a Sin(1.5 mg·kg~(-1)) group, a Sin-SLN(1.5 mg·kg~(-1)) group, and a dexamethasone(positive drug, 1.0 mg·kg~(-1), ig) group. The control group and the model group only received puncture treatment without drug injection. After drug administration, the local skin temperature and knee joint diameter were monitored every day. The knee joint diameter and the local skin temperature were lower in the drug administration groups than in the model group(P<0.05, P<0.01). FELCM recorded the morphological alterations of the cartilage of knee joint. The Sin-SLN group showed compact tissue structure and smooth surface of the cartilage. Enzyme-linked immunosorbent assay(ELISA) was employed to determine the serum le-vels of interleukin-1(IL-1) and tumor necrosis factor-α(TNF-α). The findings revealed that the Sin-SLN group had lower IL-1 and TNF-α levels than the model group(P<0.05, P<0.01). Hematoxylin-eosin(HE) staining was employed to reveal the pathological changes of the synovial tissue, which were significantly mitigated in the Sin-SLN group. The prepared Sin-SLN had uniform particle size and high stability. Through joint injection administration, a drug reservoir was formed. Sin-SLN effectively alleviate joint swelling and cartilage damage of rabbit, down-regulated the expression of inflammatory cytokines, and inhibited the epithelial proliferation and inflammatory cell infiltration of the synovial tissue, demonstrating the efficacy in treating RA.

Prognostic value of systemic immune inflammation index and geriatric nutrition risk index in early-onset colorectal cancer.

Background: Systemic nutritional and inflammatory markers, which are easy to measure are associated with the progression and prognosis of many cancers. Nevertheless, among the various available indicators, optimal prognostic indicators for patients with early-onset colorectal cancer have not been identified. Therefore, the aim of this study was to identify optimal nutritional and inflammatory markers for early-onset colorectal cancer and examine the relationship between systemic nutritional and inflammatory markers before treatment and survival in patients with early-onset colorectal cancer. Methods: We retrospectively collected data from 236 eligible patients with early-onset colorectal cancer. Area under the prognostic curve (AUC) and concordance index (C-index) were used to compare seven systemic nutritional and inflammatory markers to identify the optimal inflammatory immune markers. Univariate and multivariate COX regression analyses were used to evaluate the prognostic value of indicators in the total study population and different subgroups. Results: The AUC and C-index showed that the systemic immune inflammation index (SII) and geriatric nutrition risk index (GNRI) had higher prognostic values than other systemic nutritional and inflammatory indicators. Compared with patients in the low SII group, those in the high SII group had lower overall survival (HR, 4.42, 95% CI, 2.36-8.27, p = 0.000). Compared with patients in the high GNRI group, those in the low GNRI group had lower overall survival (HR, 0.33, 95% CI, 0.19-0.56, p = 0.000). SII was negatively associated with GNRI (R = -0.3, p < 0.001), and both were correlated with the tumor stage. Conclusion: SII and GNRI are suitable nutritional and inflammatory factors for predicting OS in patients with early-onset colorectal cancer; high SII and low GNRI were correlated with worse prognoses. Identifying the high inflammatory state and low nutritional state of patients before surgery and conducting active and timely therapeutic interventions could improve patient prognosis.

UBA1 inhibition contributes radiosensitization of glioblastoma cells via blocking DNA damage repair.

Glioblastoma multiforme (GBM) is a brain tumor with high mortality and recurrence rate. Radiotherapy and chemotherapy after surgery are the main treatment options available for GBM. However, patients with glioblastoma have a grave prognosis. The major reason is that most GBM patients are resistant to radiotherapy. UBA1 is considered an attractive potential anti-tumor therapeutic target and a key regulator of DNA double-strand break repair and genome replication in human cells. Therefore, we hypothesized that TAK-243, the first-in-class UBA1 inhibitor, might increase GBM sensitivity to radiation. The combined effect of TAK-243 and ionizing radiation on GBM cell proliferation, and colony formation ability was detected using CCK-8, colony formation, and EdU assays. The efficacy of TAK-243 combined with ionizing radiation for GBM was further evaluated in vivo, and the mechanism of TAK-243 sensitizing radiotherapy was preliminarily discussed. The results showed that TAK-243, in combination with ionizing radiation, significantly inhibited GBM cell proliferation, colony formation, cell cycle arrest in the G2/M phase, and increased the proportion of apoptosis. In addition, UBA1 inhibition by TAK-243 substantially increased the radiation-induced γ-H2AX expression and impaired the recruitment of the downstream effector molecule 53BP1. Therefore, TAK-243 inhibited the radiation-induced DNA double-strand break repair and thus inhibited the growth of GBM cells. Our results provided a new therapeutic strategy for improving the radiation sensitivity of GBM and laid a theoretical foundation and experimental basis for further clinical trials.

Gold nanoparticles inhibit tumor growth via targeting the Warburg effect in a c-Myc-dependent way.

Gold nanoparticles (AuNPs) are prospective tools for nano-based medicine that can directly target cellular biological processes to influence cell fate and function. Studies have revealed the essential role of AuNPs in metabolic remodeling for macrophage polarization. Nevertheless, as a hallmark of cancer cells, metabolic changes in tumor cells in response to AuNPs have not yet been reported. In the present study, polymer- and folate-conjugated AuNPs with satisfactory biocompatibility and tumor-targeting activity were synthesized to investigate their underlying roles in tumor metabolism. Tumor cells were significantly suppressed by AuNPs in vitro and in vivo, with little cytotoxicity in non-tumor cells. Subcellular localization showed that AuNPs localized in the mitochondria of tumor cells and impaired their structure and function, leading to excessive oxidative stress and mitochondrial apoptosis. Metabolic stress, with decreased glycolysis and insufficient nutrients, was also caused by AuNPs exposure in tumor cells. Mechanistically, the key enzymes (GLUT1 and HK2) for glycolysis modulation were remarkably reduced by AuNPs in a c-Myc-dependent manner. The present study demonstrated a new mechanism for AuNPs in the inhibition of tumor growth, that is, via directly targeting glycolysis and depriving energy. These findings provide new strategies for the design of nano-based medicines and anti-glycolytic therapeutics to inhibit the development of malignant tumors. STATEMENT OF SIGNIFICANCE: Gold nanoparticles (AuNPs) have acquired ever-increasing interest for applications in cancer treatment and diagnosis due to their high biosafety and facile surface modification. Recent studies have shown that AuNPs can work as active agents to directly target the cellular processes and harbor antitumor properties, while the underlying mechanisms remain largely unknown. From the present findings, the stabilized AuNPs showed direct inhibition effects on tumor growth by glycolysis inhibition and energy deprivation. These results provide new insights of AuNPs for tumor treatments, which will further contribute to the development of promising nano-based medicines and anti-glycolytic therapies.

Computation and molecular pharmacology to trace the anti-rheumatoid activity of Angelicae Pubescentis Radix.

BACKGROUND: The mechanism of action of Angelicae Pubescentis Radix in rheumatoid arthritis treatment is complex; the pathways and protein targets involved remain unclear. This study predicted the targets and signaling pathways of Angelicae Pubescentis Radix for rheumatoid arthritis treatment using network pharmacology and molecular docking technology and clarified its mechanism of action using in vitro cellular experiments. METHODS: Angelicae Pubescentis Radix active components and related targets were retrieved from the traditional Chinese medicine systems pharmacology database. All human proteins were mined from the global protein database, and the network of active components and targets of Angelicae Pubescentis Radix was drawn using Cytoscape 3.7.1. GeneCard, Online Mendelian Inheritance in Man, and DrugBank databases were used to mine rheumatoid arthritis-related genes. Metascape was used for Gene Ontology function analysis and Kyoto Encyclopedia of Genes and Genomes enrichment pathways. ß-sitosterol's molecular docking was determined using AutoDock Tools; pathway verification was performed in the Kyoto Encyclopedia of Genes and Genomes database, and the verified genes were input into the Human Protein Atlas database to observe the expression levels in various human body tissues. RESULTS: Eight main active components were screened out of Angelicae Pubescentis Radix from the traditional Chinese medicine systems pharmacology database, and 60 targets related to major active ingredients were obtained. Forty-two core pathogenic rheumatoid arthritis-related genes were screened from GeneCard and other related databases. The enrichment of the Kyoto Encyclopedia of Genes and Genomes pathway included the vascular endothelial growth factor signaling pathway that proved to be the decisive pathway for rheumatoid arthritis treatment by a high degree value. In vitro experiments confirmed that Angelicae Pubescentis Radix mainly regulated cell proliferation and survival through the vascular endothelial growth factor signaling pathway and showed significant therapeutic effects on rheumatoid arthritis. The prostaglandin endoperoxide synthase 2 gene was associated with rheumatoid arthritis via pathway verification and monitoring of human gene expression levels. CONCLUSIONS: The mechanism of the multi-component, multi-target, and multi-channel treatment of rheumatoid arthritis via Angelicae Pubescentis Radix was explored using network pharmacology and molecular docking technology, providing new thinking and research directions for future rheumatoid arthritis treatment using Angelicae Pubescentis Radix.

[Mechanism of Linderae Radix against gastric cancer based on network pharmacology and in vitro experimental validation].

The present study explored the main active ingredients and the underlying mechanism of Linderae Radix the treatment of gastric cancer by network pharmacology, molecular docking, and in vitro cell experiments. TCMSP, OMIM and GeneCards database were used to obtain the active ingredients of Linderae Radix to predict the related targets of both Linderae Radix and gastric cancer. After screening the common potential action targets, the STRING database was used to construct the PPI network for protein interaction of the two common targets. Enrichment analysis of GO and KEGG by DAVID database. Based on STRING and DAVID platform data, Cytoscape software was used to construct an "active ingredient-target" network and an "active ingredient-target-pathway" network. Molecular docking was performed using the AutoDock Vina to predict the binding of the active components to the key action targets, and finally the key targets and pathways were verified in vitro. According to the prediction results, there were 9 active components, 179 related targets of Radix Linderae, 107 common targets of Linderae Radix and gastric cancer, 693 biological processes, 57 cell compositions, and 129 molecular functions involved in the targets, and 161 signaling pathways involved in tumor antigen p53, hypoxia-indu-cible factor 1, etc. Molecular docking results showed that the core component, jimadone, had high binding activity with TP53. Finally, in an in vitro experiment, the screened radix linderae active ingredient gemmadone is used for preliminarily verifying the core targets and pathways of the human gastric cancer cell SGC-7901, The results showed that germacrone could significantly inhibit the proliferation of gastric cancer cells and induce the apoptosis of SGC-7901 by regulating the expression of p53, Bax, Bcl-2 and other key proteins. In summary, Radix Linderae can control the occurrence and development of gastric cancer through multi-components, multi-targets and multi-pathways, which will provide theoretical basis for further clinical discussion on the mechanism of Radix Linderae in treating gastric cancer.