The gut microbiome modulate response to immunotherapy in cancer.

Gut microbiota have been reported to play an important role in the occurrence and development of malignant tumors. Currently, clinical studies have identified specific gut microbiota and its metabolites associated with efficacy of immunotherapy in multiple types of cancers. Preclinical investigations have elucidated that gut microbiota modulate the antitumor immunity and affect the efficacy of cancer immunotherapy. Certain microbiota and its metabolites may favorably remodel the tumor microenvironment by engaging innate and/or adaptive immune cells. Understanding how the gut microbiome interacts with cancer immunotherapy opens new avenues for improving treatment strategies. Fecal microbial transplants, probiotics, dietary interventions, and other strategies targeting the microbiota have shown promise in preclinical studies to enhance the immunotherapy. Ongoing clinical trials are evaluating these approaches. This review presents the recent advancements in understanding the dynamic interplay among the host immunity, the microbiome, and cancer immunotherapy, as well as strategies for modulating the microbiome, with a view to translating into clinical applications.

Comprehensive commissioning of a cone beam CT imaging ring for treatment of HDR GYN patients.

PURPOSE: A new mobile cone beam computed tomography (CBCT) imaging ring (IRm, Elekta, v2.10.6, Veenendaal, Netherlands) has recently been proposed for brachytherapy to improve procedure efficiency. We describe the commissioning process and end-to-end tests for GYN HDR brachytherapy employing IRm CBCT imaging. MATERIALS AND METHODS: Commissioning included imaging isocenter test, 3D image quality, 2D imaging quality, image dose, and tube characteristics. CIRS HDR GYN phantom and Venezia CT/MR gynecological applicator were used to perform end-to-end (E2E) tests and optimize workflow. Venezia applicator and four interstitial needles were inserted into the phantom and IRm CBCT images were acquired. Phantom and applicator were scanned with CT scanner (Siemens SOMATOM go.Open Pro) using department's pelvis imaging protocol. MR imaging was performed using 0.35T MR Linac TRUFI pulse sequence. CBCT images were registered to CT and MR using rigid registration to assess image quality and applicator geometry fidelity. RESULTS: All physics tests passed within acceptance tolerances. Registration of CBCT images to MR and CT scans was acceptable for applicator placement. Applicator registration of CBCT images to CT demonstrated excellent agreement of most distal source dwell position (<1 mm). Slice thickness was also measured to be 1.25 mm, within 0.5 mm of its nominal value. CONCLUSION: Based on E2E and commissioning results, IRm is an appropriate tool for brachytherapy treatment planning. This study demonstrated good image quality in GYN phantom and Venezia applicator using the IRm. Distal source dwell position agreement between CBCT and CT was acceptable for clinical use.

BCAA-producing Clostridium symbiosum promotes colorectal tumorigenesis through the modulation of host cholesterol metabolism.

Identification of potential bacterial players in colorectal tumorigenesis has been a focus of intense research. Herein, we find that Clostridium symbiosum (C. symbiosum) is selectively enriched in tumor tissues of patients with colorectal cancer (CRC) and associated with higher colorectal adenoma recurrence after endoscopic polypectomy. The tumorigenic effect of C. symbiosum is observed in multiple murine models. Single-cell transcriptome profiling along with functional assays demonstrates that C. symbiosum promotes the proliferation of colonic stem cells and enhances cancer stemness. Mechanistically, C. symbiosum intensifies cellular cholesterol synthesis by producing branched-chain amino acids (BCAAs), which sequentially activates Sonic hedgehog signaling. Low dietary BCAA intake or blockade of cholesterol synthesis by statins could partially abrogate the C. symbiosum-induced cell proliferation in vivo and in vitro. Collectively, we reveal C. symbiosum as a bacterial driver of colorectal tumorigenesis, thus identifying a potential target in CRC prediction, prevention, and treatment.

The effects of air and transportation noise pollution-related altered blood gene expression, DNA methylation, and protein abundance levels on gastrointestinal diseases risk.

INTRODUCTION: Air pollution and transportation noise pollution has been linked to gastrointestinal (GI) diseases, but their relationship remains unclear. METHODS: We extracted the significantly modulated genes and CpG sites related to air pollution (PM2.5, PM10, and NOx) and transportation noise pollution (aircraft, railway, and traffic road noise) from previous published studies. Genome-wide methylation analysis and colocalization analysis with these CpG sites and GWAS data of GI diseases were performed to disentangle the relationship between pollution-related blood DNA methylation (DNAm) alterations and GI diseases risk. Summary-based Mendelian randomization (SMR) analysis assessed the impact of pollution-related genes on GI diseases risk across methylation, gene expression, and protein levels. Enrichment analysis investigated the implicated biological pathways and immune cell types. RESULTS: DNAm at cg00227781 [CD300A] (modulated by NOx exposure) and cg19215199 [ZMIZ1] (modulated by PM2.5 exposure) was significantly linked to increased noninfective enteritis and colitis risk, while cg08500171 [BAT2] (modulated by NOx exposure) is significantly associated with an increased gastroesophageal reflux disease (GERD) risk. Colocalization analysis provides strong evidence supporting a shared causal variant between these associations. Multi-omics levels SMR analysis revealed that pollution-modulated lower DNAm at 5 specific CpG sites were associated with increased expression of 4 genes (IL21R, EVPL, SYNGR1, and WDR46), subsequently increasing the risk of GERD, ulcerative colitis, and gastric ulcer. 7 circulating proteins coded by pollution-modulated genes were observed to be associated with 6 GI diseases risk. Enrichment analysis implicates immune and inflammatory responses, MAPK signaling, and telomere maintenance in these pollution-induced effects. CONCLUSION: We identified potential links between air and transportation noise pollution-related gene methylation, expression, and protein abundance with GI diseases risk, possibly revealing new therapeutic targets.

The adhesin RadD enhances Fusobacterium nucleatum tumour colonization and colorectal carcinogenesis.

Fusobacterium nucleatum can bind to host cells and potentiate intestinal tumorigenesis. Here we used a genome-wide screen to identify an adhesin, RadD, which facilitates the attachment of F. nucleatum to colorectal cancer (CRC) cells in vitro. RadD directly binds to CD147, a receptor overexpressed on CRC cell surfaces, which initiated a PI3K-AKT-NF-κB-MMP9 cascade, subsequently enhancing tumorigenesis in mice. Clinical specimen analysis showed that elevated radD gene levels in CRC tissues correlated positively with activated oncogenic signalling and poor patient outcomes. Finally, blockade of the interaction between RadD and CD147 in mice effectively impaired F. nucleatum attachment and attenuated F. nucleatum-induced oncogenic response. Together, our study provides insights into an oncogenic mechanism driven by F. nucleatum RadD and suggests that the RadD-CD147 interaction could be a potential therapeutic target for CRC.

Novel frameless LINAC radiosurgery solution for uveal melanoma.

Introduction: Radiation treatment has replaced enucleation as an organ-preservation treatment for patients with uveal melanoma (UM). We developed a novel non-invasive, frameless LINAC based solution for fractionated stereotactic radiosurgery (fSRS) treatment. Methods: We designed and constructed the a stereotactic ocular localization box that can be attached and indexed to a stereotactic LINAC tabletop. It contains adjustable LED lights as a gaze focus point and CCD camera for monitoring of the patient's eye position. The device also has 6 infrared spheres compatible with the ExacTRAC IGRT system. Treatment plans were developed using iPLAN Dose version 4.5, with conformal dynamic arcs and 6MV photon beam in flattening filter free mode, dosed to 50Gy in 5 fractions. During treatment, patients were instructed to stare at the light when a radiation beam is prepared and ready for delivery. Eye movement was tracked throughout treatment. Residual setup errors were recorded for evaluation. Results: The stereotactic ocular localization box was 3D-printed with polylactic acid material and attached to the stereotactic LINAC tabletop. 10 patients were treated to evaluate the feasibility, tolerability and setup accuracy. Median treatment time for each arc is 17.3 ± 2.4 seconds (range: 13.8-23.4). After ExacTRAC setup, the residual setup errors are -0.1 ± 0.3 mm laterally, -0.1 ± 0.3 mm longitudinally, and 0 ± 0.2 mm vertically. The residue rotational errors are -0.1 ± 0.3 degree pitch, 0.1 ± 0.2 degree roll, and 0 ± 0.2 degree couch rotation. All patients received treatment successfully. Conclusion: We successfully developed a novel non-invasive frameless mask-based LINAC solution for SRS for uveal melanoma, or other ocular tumors. It is well tolerated with high set up accuracy. Future directions for this localization box would include a multi-center trial to assess the efficacy and reproducibility in the fabrication and execution of such a solution for UM therapy.

Pharmacokinetics, pharmacodynamics and safety of 15 mg-tolvaptan administered orally for 7 consecutive days to Chinese patients with child-Pugh B cirrhosis.

Background: Tolvaptan, a selective vasopressin V2-receptor antagonist, can elicit a diuretic effect without significant electrolyte loss. The aims were to evaluate multiple-dose pharmacokinetics, pharmacodynamics and safety of daily administration of 15 mg tolvaptan in Chinese adult patients with confirmed Child-Pugh Class B cirrhosis accompanied by ascites. Methods: This was an open-label, single-center, single- and multiple-dose study. All patients received a daily 15 mg dose of tolvaptan for 7 consecutive days. The plasma concentrations of tolvaptan and its two metabolites (DM-4103, DM-4107) were measured using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). In addition, various pharmacokinetics parameters were calculated. The pharmacodynamic outcomes evaluated changes in serum sodium and potassium concentrations, daily urine volume, daily water consumption, fluid balance and body weight. Safety profiles, including the incidence of treatment-emergent adverse events (TEAEs), were carefully recorded. Results: Eleven patients with Child-Pugh B cirrhosis were eventually enrolled in the study. Plasma concentrations of tolvaptan and DM-4107 reached steady-states after 7 days of consecutive oral administration. No accumulation of tolvaptan or DM-4107 was found, but DM-4103 accumulated 18.2-fold after multiple-dosing. The daily urine volume and daily water consumption were statistically significantly increased after administration of tolvaptan from Day 1 to Day 7 (all p < 0.05), accompanied by an increased serum sodium concentration. Of 11 patients, 9 (81.8%) reported 20 TEAEs, with the majority being mild to moderate in severity. The most commonly occurring TEAEs were thirst (45.5%), pollakiuria (36.4%) and dry mouth (27.3%). Conclusion: Tolvaptan at a daily dose of 15 mg had a diuretic effect but did not increase serum sodium excretion or lead to tolvaptan accumulation. It is therefore can be safely used for short-term treatment of Chinese adult patients with confirmed Child-Pugh B cirrhosis. Clinical Trial Registration: https://clinicaltrials.gov/search?term=NCT01359462, identifier NCT01359462.

Metabolic syndrome, its components, and gastrointestinal cancer risk: a meta-analysis of 31 prospective cohorts and Mendelian randomization study.

BACKGROUND AND AIM: Cohort studies have linked metabolic syndrome (MetS) to gastrointestinal (GI) cancer risk. We aimed to evaluate the associations between MetS, its components, and combinations of MetS components with eight GI cancers risk. METHODS: We conducted a systematic search of prospective cohort studies and performed a meta-analysis. Subgroup analyses regarding diagnostic criteria, sex, cancer sites, histological subtypes, ethnic groups, and studies adjusted for alcohol consumption were carried out. Mendelian randomization (MR) was employed to evaluate the causality between 17 MetS-related traits and eight GI cancers among Europeans and Asians separately. RESULTS: Meta-analyses of 31 prospective studies indicated that MetS was significantly associated with an increased risk of colorectal cancer (CRC) (RR [95% CI] = 1.13 [1.12-1.15]), esophageal cancer (EC) (RR [95% CI] = 1.17 [1.03-1.32]), gallbladder cancer (GBC) (RR [95% CI] = 1.37[1.10-1.71]), liver cancer (LC) (RR [95% CI] = 1.46 [1.29-1.64]), and pancreatic cancer (PaC) (RR [95% CI] = 1.25 [1.20-1.30]), but not gastric cancer (GC) (RR [95% CI] = 1.11 [0.96-1.28]). Regarding the associations between MetS components and GI cancers risk, the following associations showed statistical significance: obesity-CRC/LC/EC/, hypertriglyceridemia-LC/PaC, reduced high-density lipoprotein (HDL)-CRC/LC/GC/PaC, hyperglycemia-CRC/LC/PaC, and hypertension-CRC/LC/EC/PaC. Sex-specific associations were observed between individual MetS components on GI cancers risk. Among the top three common combinations in both sexes, obesity + HTN + hyperglycemia had the strongest association with CRC risk (RR [95% CI] = 1.54 [1.49-1.61] for males and 1.27 [1.21-1.33] for females). MR analyses revealed causality in 16 exposure-outcome pairs: waist-to-hip ratio/BMI/HbA1c-CRC; BMI/childhood obesity/waist circumference/T2DM/glucose-EC; BMI/waist circumference/cholesterol-LC; cholesterol/childhood obesity/waist circumference/HbA1c-PaC; and HbA1c-GBC. These results were robust against sensitivity analyses. CONCLUSIONS: Since MetS is reversible, lifestyle changes or medical interventions targeting MetS patients might be potential prevention strategies for GI cancers.

Deficiency of BCAT2-mediated branched-chain amino acid catabolism promotes colorectal cancer development.

OBJECTIVE: Branched-chain amino acid (BCAA) metabolism is involved in the development of colorectal cancer (CRC); however, the underlying mechanism remains unclear. Therefore, this study investigates the role of BCAA metabolism in CRC progression. METHODS: Dietary BCAA was administered to both azoxymethane-induced and azoxymethane/dextran sodium sulfate-induced CRC mouse models. The expression of genes related to BCAA metabolism was determined using RNA sequencing. Adjacent tissue samples, obtained from 58 patients with CRC, were subjected to quantitative real-time PCR and immunohistochemical analysis. Moreover, the suppressive role of branched-chain aminotransferase 2 (BCAT2) in cell proliferation, apoptosis, and xenograft mouse models was investigated. Alterations in BCAAs and activation of downstream pathways were also assessed using metabolic analysis and western blotting. RESULTS: High levels of dietary BCAA intake promoted CRC tumorigenesis in chemical-induced CRC and xenograft mouse models. Both the mRNA and protein levels of BCAT2 were decreased in tumor tissues of patients with CRC compared to those in normal tissues. Proliferation assays and xenograft models confirmed the suppressive role of BCAT2 in CRC progression. Furthermore, the accumulation of BCAAs caused by BCAT2 deficiency facilitated the chronic activation of mTORC1, thereby mediating the oncogenic effect of BCAAs. CONCLUSION: BCAT2 deficiency promotes CRC progression through inhibition of BCAAs metabolism and chronic activation of mTORC1.

Systematic Evaluation of the Impact of Lung Segmentation Methods on 4-Dimensional Computed Tomography Ventilation Imaging Using a Large Patient Database.

PURPOSE: A novel form of lung functional imaging applied for functional avoidance radiation therapy has been developed that uses 4-dimensional computed tomography (4DCT) data and image processing techniques to calculate lung ventilation (4DCT-ventilation). Lung segmentation is a common step to define a region of interest for 4DCT-ventilation generation. The purpose of this study was to quantitatively evaluate the sensitivity of 4DCT-ventilation imaging using different lung segmentation methods. METHODS AND MATERIALS: The 4DCT data of 350 patients from 2 institutions were used. Lung contours were generated using 3 methods: (1) reference segmentations that removed airways and pulmonary vasculature manually (Lung-Manual), (2) standard lung contours used for planning (Lung-RadOnc), and (3) artificial intelligence (AI)-based contours that removed the airways and pulmonary vasculature (Lung-AI). The AI model was based on a residual 3-dimensional U-Net and was trained using the Lung-Manual contours of 279 patients. We compared the Lung-RadOnc or Lung-AI with Lung-Manual contours for the entire 4DCT-ventilation functional avoidance process including lung segmentation (surface Dice similarity coefficient [Surface DSC]), 4DCT-ventilation generation (correlation), and subanalysis of 10 patients on a dosimetric endpoint (percentage of high functional volume of lung receiving ≥20 Gy [fV20{%}]). RESULTS: Surface DSC comparing Lung-Manual/Lung-RadOnc and Lung-Manual/Lung-AI contours was 0.40 ± 0.06 and 0.86 ± 0.04, respectively. The correlation between 4DCT-ventilation images generated with Lung-Manual/Lung-RadOnc and Lung-Manual/Lung-AI were 0.48 ± 0.14 and 0.85 ± 0.14, respectively. The difference in fV20[%] between 4DCT-ventilation generated with Lung-Manual/Lung-RadOnc and Lung-Manual/Lung-AI was 2.5% ± 4.1% and 0.3% ± 0.5%, respectively. CONCLUSIONS: Our work showed that using standard planning lung contours can result in significantly variable 4DCT-ventilation images. The study demonstrated that AI-based segmentations generate lung contours and 4DCT-ventilation images that are similar to those generated using manual methods. The significance of the study is that it characterizes the lung segmentation sensitivity of the 4DCT-ventilation process and develops methods that can facilitate the integration of this novel imaging in busy clinics.

CHEK2 deficiency increase the response to PD-1 inhibitors by affecting the tumor immune microenvironment.

Immune checkpoint blockade (ICB) therapy has improved treatment effects in multiple cancers. Gene mutations in the DNA damage repair pathway (DDR) may cause genomic instability and may relate to the efficacy of ICB. Checkpoint kinase 2 (CHEK2) and polymerase epsilon (POLE) are important genes in the DDR. In this study, we aimed to study the impact of CHEK2 deficiency mutations on the response to ICB. We found that tumors with CHEK2 mutations had a significantly higher tumor mutational burden (TMB) compared to those with CHEK2-WT in a pancancer database. We noted that CHEK2 deficiency mutations potentiated the anti-tumor effect of anti-PD-1 therapy in MC38 and B16 tumor-bearing mice with the decrease of tumor volume and tumor weight after anti-PD-1 treatment. Mechanistically, CHEK2 deficiency tumors were with the increased cytotoxic CD8+ T-cell infiltration, especially cytotoxic CD8+ T cells, and modulated the tumor-immune microenvironment with an upregulated immune inflammatory pathway and antigen presentation pathway after anti-PD-1 treatment. Furthermore, murine models with POLE mutations confirmed that CHEK2 deficiency shaped similar mutational and immune landscapes as POLE mutations after anti-PD-1 treatment. Taken together, our results demonstrated that CHEK2 deficiency mutations may increase the response to ICB (eg. anti-PD-1) by influencing the tumor immune microenvironment. This indicated that CHEK2 deficiency mutations were a potentially predictive biomarker and CHEK2 deficiency may potentiate response to immunotherapy.

Protein-centric omics integration analysis identifies candidate plasma proteins for multiple autoimmune diseases.

It remains challenging to translate the findings from genome-wide association studies (GWAS) of autoimmune diseases (AIDs) into interventional targets, presumably due to the lack of knowledge on how the GWAS risk variants contribute to AIDs. In addition, current immunomodulatory drugs for AIDs are broad in action rather than disease-specific. We performed a comprehensive protein-centric omics integration analysis to identify AIDs-associated plasma proteins through integrating protein quantitative trait loci datasets of plasma protein (1348 proteins and 7213 individuals) and totally ten large-scale GWAS summary statistics of AIDs under a cutting-edge systematic analytic framework. Specifically, we initially screened out the protein-AID associations using proteome-wide association study (PWAS), followed by enrichment analysis to reveal the underlying biological processes and pathways. Then, we performed both Mendelian randomization (MR) and colocalization analyses to further identify protein-AID pairs with putatively causal relationships. We finally prioritized the potential drug targets for AIDs. A total of 174 protein-AID associations were identified by PWAS. AIDs-associated plasma proteins were significantly enriched in immune-related biological process and pathways, such as inflammatory response (P = 3.96 × 10-10). MR analysis further identified 97 protein-AID pairs with potential causal relationships, among which 21 pairs were highly supported by colocalization analysis (PP.H4 > 0.75), 10 of 21 were the newly discovered pairs and not reported in previous GWAS analyses. Further explorations showed that four proteins (TLR3, FCGR2A, IL23R, TCN1) have corresponding drugs, and 17 proteins have druggability. These findings will help us to further understand the biological mechanism of AIDs and highlight the potential of these proteins to develop as therapeutic targets for AIDs.

Efficacy of scalp-sparing volumetric-modulated arc therapy approach in reducing scalp radiation dose for patients with glioblastoma: a cross-sectional study.

BACKGROUND: Radiation is integral to the treatment of glioblastoma (GBM). However, radiation-induced scalp toxicity can negatively impact patients' quality of life. Volumetric modulated arc therapy (VMAT) optimizes the dose to organs at risk (OARs). We hypothesize that a scalp-sparing VMAT (SSV) approach can significantly reduce undesirable doses to the scalp without compromising the target dose. METHODS: This is a retrospective cross-sectional study of GBM patients who originally received radiation with non-SSV. We contoured the scalp as a 5 mm rind-like structure beneath the skin above the level of the foramen magnum. We replanned our patients using SSV techniques. We compared dosimetric data for the scalp, planning target volume (PTV), and select critical normal structures between non-SSV and SSV plans. RESULTS: Nineteen patients with newly diagnosed GBMs were included in our study. All patients received 60 Gy in 30 fractions. 9 patients received it in a single course. The rest received 46 Gy in 23 fractions to an initial volume followed by 14 Gy in 7 fractions to a cone-down volume (split course). New VMAT plans were generated after adding the scalp as an OAR. The median scalp volume was 416 cm3 (363-468 cm3). The median reductions in scalp Dmin, Dmax, and Dmean were 43.5% (-100% to 0%), 2.8% (+13.4% to -24.9%), and 15.7% (+2.1% to -39.9%) respectively. Median reductions in scalp D20cc and D30 cc were 19.5% (-2.7% to -54.5%), and 19.0% (-5.3% to -39.5%) respectively. The median volumes of the scalp receiving 30 Gy, 40 Gy, and 50 Gy were reduced by 42.3% (-70.6% to -12.5%), 72% (-100% to -2.3%), and 92.4% (-100% to +5.4%) respectively. There were no significant differences in the doses delivered to the PTV, brainstem, optic nerves, and optic chiasm between SSV and non-SSV plans. CONCLUSIONS: SSV can significantly reduce scalp radiation dose without compromising target coverage or critical normal structure doses. This may translate into reduced acute and late radiation toxicity to the scalp. A prospective trial evaluating the clinical benefits of SSV is ongoing (NCT03251027).

Faecalibacterium prausnitzii Abrogates Intestinal Toxicity and Promotes Tumor Immunity to Increase the Efficacy of Dual CTLA4 and PD-1 Checkpoint Blockade.

Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy; however, their application is limited by the occurrence of immune-related adverse events. The gut microbiota plays important roles in the response to and toxicity of immunotherapy and Faecalibacterium prausnitzii (F. prausnitzii) has been shown to possess immunomodulatory potential. Here, we found that patients receiving ICIs who developed colitis had a lower abundance of F. prausnitzii. In vivo, immunocompetent mice administered with dextran sodium sulfate and immunodeficient NSG mice with human peripheral blood mononuclear cell transfer were treated with ICIs to study ICI-induced colitis. Dual CTLA4 and PD-1 blockade exacerbated autoimmune colitis, activated an inflammatory response, and promoted myeloid cell infiltration, with higher percentages of macrophages, dendritic cells, monocytes, and neutrophils. F. prausnitzii administration mitigated the exacerbated colitis induced by ICIs. Concomitantly, F. prausnitzii enhanced the antitumor immunity elicited by ICIs in tumor-bearing mice while abrogating colitis. In addition, administration of F. prausnitzii increased gut microbial alpha diversity and modulated the microbial composition, increasing a subset of gut probiotics and decreasing potential gut pathogens. F. prausnitzii abundance was reduced in mice that developed ICI-associated colitis. Together, this study shows that F. prausnitzii administration ameliorates ICI-induced colitis, reshapes the gut microbial composition, and enhances the antitumor activity of immunotherapy. SIGNIFICANCE: F. prausnitzii alleviates colitis while enhancing the tumor-suppressive effects of immune checkpoint blockade, indicating that supplementation with F. prausnitzii could be a treatment strategy to mitigate immunotherapy toxicity in patients with cancer.

Berberine might block colorectal carcinogenesis by inhibiting the regulation of B-cell function by Veillonella parvula.

BACKGROUND: Colorectal carcinogenesis and progression are related to the gut microbiota and the tumor immune microenvironment. Our previous clinical trial demonstrated that berberine (BBR) hydrochloride might reduce the recurrence and canceration of colorectal adenoma (CRA). The present study aimed to further explore the mechanism of BBR in preventing colorectal cancer (CRC). METHODS: We performed metagenomics sequencing on fecal specimens obtained from the BBR intervention trial, and the differential bacteria before and after medication were validated using quantitative polymerase chain reaction. We further performed ApcMin/+ animal intervention tests, RNA sequencing, flow cytometry, immunohistochemistry, and enzyme-linked immunosorbent assays. RESULTS: The abundance of fecal Veillonella parvula ( V . parvula ) decreased significantly after BBR administration ( P = 0.0016) and increased through the development from CRA to CRC. Patients with CRC with a higher V. parvula abundance had worse tumor staging and a higher lymph node metastasis rate. The intestinal immune pathway of Immunoglobulin A production was activated, and the expression of TNFSF13B (Tumor necrosis factor superfamily 13b, encoding B lymphocyte stimulator [BLyS]), the representative gene of this pathway, and the genes encoding its receptors (interleukin-10 and transforming growth factor beta) were significantly upregulated. Animal experiments revealed that V. parvula promoted colorectal carcinogenesis and increased BLyS levels, while BBR reversed this effect. CONCLUSION: BBR might inhibit V. parvula and further weaken the immunomodulatory effect of B cells induced by V. parvula , thereby blocking the development of colorectal tumors. TRIAL REGISTRAION: ClinicalTrials.gov, No. NCT02226185.

Exosome-mediated delivery of superoxide dismutase for anti-aging studies in Caenorhabditis elegans.

Aging is a dynamic and progressive process mediated by reactive oxygen species (ROS), and the antioxidant enzyme superoxide dismutase (SOD) can effectively scavenge ROS to extend longevity. However, the instability and impermeability of native enzyme limit its in vivo biomedical application. Currently, exosome as protein carriers attracts considerable attention in the disease treatment owing to low immunogenicity and high stability. Herein, SOD was encapsulated into exosomes via mechanical extrusion with saponin permeabilization to obtain SOD-loaded EXO (SOD@EXO). SOD@EXO with a hydrodynamic diameter of 101.7 ± 5.6 nm could scavenge excessive ROS and protect the cells from oxidative damage induced by 1-methyl-4-phenylpyridine. Compared with native SOD, SOD@EXO significantly extended the lifespan of N2 wild-type Caenorhabditis elegans under normal conditions. Moreover, SOD@EXO improved the resistance against heat and oxidative stress, leading to notable survival ratio under these hostile conditions. Overall, the exosome-mediated delivery of SOD could reduce ROS level and delay aging in C. elegans model, thereby providing potential strategies to treat ROS-related diseases in future.

Noninvasive predictive models based on lifestyle analysis and risk factors for early-onset colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) incidence has increased among patients aged <50 years. Exploring high-risk factors and screening high-risk populations may help lower early-onset CRC (EO-CRC) incidence. We developed noninvasive predictive models for EO-CRC and investigated its risk factors. METHODS: This retrospective multicenter study collected information on 1756 patients (811 patients with EO-CRC and 945 healthy controls) from two medical centers in China. Sociodemographic features, clinical symptoms, medical and family history, lifestyle, and dietary factors were measured. Patients from one cohort were randomly assigned (8:2) to two groups for model establishment and internal validation, and another independent cohort was used for external validation. Multivariable logistic regression, random forest, and eXtreme Gradient Boosting (XGBoost) were performed to establish noninvasive predictive models for EO-CRC. Some variables in the model influenced EO-CRC occurrence and were further analyzed. Multivariable logistic regression analysis yielded adjusted odd ratios (ORs) and 95% confidence intervals (CIs). RESULTS: All three models showed good performance, with areas under the receiver operator characteristic curves (AUCs) of 0.82, 0.84, and 0.82 in the internal and 0.78, 0.79, and 0.78 in the external validation cohorts, respectively. Consumption of sweet (OR 2.70, 95% CI 1.89-3.86, P < 0.001) and fried (OR 2.16, 95% CI 1.29-3.62, P < 0.001) foods ≥3 times per week was significantly associated with EO-CRC occurrence. CONCLUSION: We established noninvasive predictive models for EO-CRC and identified multiple nongenetic risk factors, especially sweet and fried foods. The model has good performance and can help predict the occurrence of EO-CRC in the Chinese population.

tRNA modifications: insights into their role in human cancers.

Transfer RNA (tRNA) plays a central role in translation by functioning as a biological link between messenger RNA (mRNA) and proteins. One prominent feature of the tRNA molecule is its heavily modified status, which greatly affects its biogenesis and function. Modifications within the anticodon loop are crucial for translation efficiency and accuracy, whereas other modifications in the body region affect tRNA structure and stability. Recent research has revealed that these diverse modifications are critical regulators of gene expression. They are involved in many important physiological and pathological processes, including cancers. In this review we focus on six different tRNA modifications to delineate their functions and mechanisms in tumorigenesis and tumor progression, providing insights into their clinical potential as biomarkers and therapeutic targets.

Fusobacterium nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer.

Immune checkpoint blockade therapy with anti-PD-1 monoclonal antibody (mAb) is a treatment for colorectal cancer (CRC). However, some patients remain unresponsive to PD-1 blockade. The gut microbiota has been linked to immunotherapy resistance through unclear mechanisms. We found that patients with metastatic CRC who fail to respond to immunotherapy had a greater abundance of Fusobacterium nucleatum and increased succinic acid. Fecal microbiota transfer from responders with low F. nucleatum, but not F. nucleatum-high non-responders, conferred sensitivity to anti-PD-1 mAb in mice. Mechanistically, F. nucleatum-derived succinic acid suppressed the cGAS-interferon-ß pathway, consequently dampening the antitumor response by limiting CD8+ T cell trafficking to the tumor microenvironment (TME) in vivo. Treatment with the antibiotic metronidazole reduced intestinal F. nucleatum abundance, thereby decreasing serum succinic acid levels and resensitizing tumors to immunotherapy in vivo. These findings indicate that F. nucleatum and succinic acid induce tumor resistance to immunotherapy, offering insights into microbiota-metabolite-immune crosstalk in CRC.