The Tautomerase Activity of Tumor Exosomal MIF Promotes Pancreatic Cancer Progression by Modulating MDSC Differentiation.

Pancreatic cancer is a deadly disease that is largely resistant to immunotherapy, in part because of the accumulation of immunosuppressive cells in the tumor microenvironment (TME). Much evidence suggests that tumor-derived exosomes (TDE) contribute to the immunosuppressive activity mediated by myeloid-derived suppressor cells (MDSC) within the pancreatic cancer TME. However, the underlying mechanisms remain elusive. Herein, we report that macrophage migration inhibitory factor (MIF) in TDEs has a key role in inducing MDSC formation in pancreatic cancer. We identified MIF in both human and murine pancreatic cancer-derived exosomes. Upon specific shRNA-mediated knockdown of MIF, the ability of pancreatic cancer-derived exosomes to promote MDSC differentiation was abrogated. This phenotype was rescued by reexpression of the wild-type form of MIF rather than a tautomerase-null mutant or a thiol-protein oxidoreductase-null mutant, indicating that both MIF enzyme activity sites play a role in exosome-induced MDSC formation in pancreatic cancer. RNA sequencing data indicated that MIF tautomerase regulated the expression of genes required for MDSC differentiation, recruitment, and activation. We therefore developed a MIF tautomerase inhibitor, IPG1576. The inhibitor effectively inhibited exosome-induced MDSC differentiation in vitro and reduced tumor growth in an orthotopic pancreatic cancer model, which was associated with decreased numbers of MDSCs and increased infiltration of CD8+ T cells in the TME. Collectively, our findings highlight a pivotal role for MIF in exosome-induced MDSC differentiation in pancreatic cancer and underscore the potential of MIF tautomerase inhibitors to reverse the immunosuppressive pancreatic cancer microenvironment, thereby augmenting anticancer immune responses.

Inhibition of GPR30 sensitized gefitinib to NSCLC cells via regulation of epithelial-mesenchymal transition.

Introduction: G-protein coupled receptor 30 (GPR30) is associated with cell metastasis and drug resistance in many different cancer cells. The present study aimed to reveal the sensitivity of GPR30 to gefitinib in non-small cell lung cancer (NSCLC) cells.Methods: Cell viability and proliferation were detected using cell counting kit 8 and 5-ethynyl-2'-deoxyuridine assays, respectively. Western blotting and quantitative real-time reverse transcription PCR were used to detect GPR30 or epithelial-mesenchyme transition (EMT)-related mRNA and protein expression.Results: The results showed that GPR30 expression is associated with gefitinib sensitivity. G15, as a GPR30 antagonist, reduced GPR30 expression. We chose the maximum concentration of G15 with minimal cytotoxicity to detect cell viability after combined treatment with gefitinib in NSCLC cells, which indicated that G15 could increase sensitivity to gefitinib. However, the effect of G15 on gefitinib sensitivity disappeared after treatment with a small interfering RNA targeting GPR30. Further research showed that G15 or GPR30 siRNA treatment could upregulate E-cadherin and downregulate vimentin levels.Conclusion: Taken together, these data suggested that G15 could enhance NSCLC sensitivity to gefitinib by inhibition of GPR30 and EMT.

Persulfate-based remediation of organic-contaminated soil: Insight into the impacts of natural iron ions and humic acids with complexation/redox functionality.

The use of persulfate (PDS) for in-situ chemical oxidation of organic contaminants in soils has garnered significant interest. However, the presence of naturally occurring iron-containing substances and humic acid (HA) in environmental compartments can potentially influence the effectiveness of soil remediation. Thus, this study aimed to investigate the role of key functional groups (adjacent phenolic hydroxyl (Ar-OH) and carboxyl groups (-COOH)) in HA that interact with iron. Modified HAs were used to confirm the significance of these moieties in iron interaction. Additionally, the mechanism by which specific functional groups affect Fe complexation and redox was explored through contaminant degradation experiments, pH-dependent investigations, HA by-products analysis, and theoretical calculations using six specific hydroxybenzoic acids as HA model compounds. The results showed a strong positive correlation between accessible Ar-OH and -COOH groups and Fe3+/Fe2+ redox. This was attributed to HA undergoing a conversion process to a semiquinone-containing radical form, followed by a quinone-containing intermediate, while Fe3+ acted as an electron shuttle between HA and PDS, with Fe3+ leaching facilitated by generated H+ ions. Although the stability of HA-Fe3+ complexes with -COOH as the primary binding sites was slightly higher at neutral/alkaline conditions compared to acidic conditions, the buffering properties of the soil and acidification of the PDS solution played a greater role in determining the Ar-OH groups as the primary binding site in most cases. Therefore, the availability of Ar-OH groups on HA created a trade-off between accelerated Fe3+/Fe2+ redox and quenching reactions. Appropriate HA and iron contents were found to favor PDS activation, while excessive HA could lead to intense competition for reactive oxygen species (ROS), inhibiting pollutant degradation in soil. The findings provide valuable insights into the interaction of HA and Fe-containing substances in persulfate oxidation, offering useful information for the development of in-situ remediation strategies for organic-contaminated soil.

P-glycoprotein antibody-conjugated paclitaxel liposomes targeted for multidrug-resistant lung cancer.

Aims: To overcome the resistance of lung cancer to paclitaxel. Methods: P-glycoprotein antibody-conjugated paclitaxel PEG-coated immunoliposomes (Pab-PTX-L) were prepared, and a series of quality evaluations, in vitro cell evaluation and assessment of their in vivo antitumor effect in mice were conducted. Results: The results showed that Pab-PTX-L was nano-sized with high encapsulation efficiency of paclitaxel. For the paclitaxel-resistant lung cancer A549/T cells, the cellular uptake and cell viability inhibition and apoptosis of Pab-PTX-L-treated cells were higher than those of the control groups. More importantly, Pab-PTX-L showed a good targeting and antitumor effect on tumor tissue in mouse experiments. Conclusion: This study will provide a new insight on enhanced paclitaxel delivery into paclitaxel-resistant cancer cells.

Corrigendum: Validation of the GALAD model and establishment of a new model for HCC detection in Chinese patients.

[This corrects the article DOI: 10.3389/fonc.2022.1037742.].

Autoimmunity associates with severity of illness in elderly patients with drug-induced liver injury.

Background: Drug-induced liver injury (DILI) is a potentially serious adverse drug reaction. Due to the lack of definite etiology, specific clinical manifestations, and diagnostic methods, its prediction and diagnosis are challenging. Elderly individuals are deemed to be at high risk for DILI due to abnormal pharmacokinetics, aging tissue repair function, comorbidities, and taking multiple drugs. This study aimed to identify the clinical characteristics and explore the risk factors associated with the severity of illness in elderly patients with DILI. Methods: In the present study, the clinical characteristics at the time of liver biopsy of consecutive patients with biopsy-proven DILI who presented at our hospital from June 2005 to September 2022 were evaluated. Hepatic inflammation and fibrosis were assessed according to the Scheuer scoring system. The presence of autoimmunity was considered if IgG level >1.1 × ULN (1826 mg/dL), or high titer (>1:80) of ANA, or SMA. Results: In total, 441 patients were enrolled, and the median age was 63.3 years (IQR, 61.0-66.0); 122 (27.7%), 195 (44.2%), or 124 (28.1%) were classified as having minor, moderate, or severe hepatic inflammation, respectively; and 188 (42.6%), 210 (47.6%) or 43 (9.8%) patients presented minor, significant fibrosis or cirrhosis, respectively. Female sex (73.5%) and the cholestatic pattern (47.6%) were dominant in elderly DILI patients. Autoimmunity existed in 201 patients (45.6%). Comorbidities were not directly associated with the severity of DILI. PLT (OR: 0.994, 95% CI: 0.991-0.997; p < 0.001), AST (OR: 1.001, 95% CI: 1.000-1.003, p = 0.012), TBIL (OR: 1.006, 95% CI: 1.003-1.010, p < 0.001), and autoimmunity (OR: 1.831, 95% CI: 1.258-2.672, p = 0.002) were associated with the degree of hepatic inflammation. Meanwhile, PLT (OR: 0.990, 95% CI: 0.986-0.993, p < 0.001), TBIL (OR: 1.004, 95% CI: 1.000-1.007, p = 0.028), age (OR: 1.123, 95% CI: 1.067-1.183, p < 0.001), and autoimmunity (OR: 1.760, 95% CI: 1.191-2.608, p = 0.005) were associated with the stage of hepatic fibrosis. Conclusion: This study revealed that the presence of autoimmunity represents a more serious illness state of DILI, deserving more intensive monitoring and progressive treatment.

Discovery of a Potent and Selective CCR8 Small Molecular Antagonist IPG7236 for the Treatment of Cancer.

Recently, there has been increasing evidence indicating that the CC chemokine receptor 8 (CCR8) plays an important role in mediating the recruitment and immunosuppressive function of regulatory T (Treg) cells in the tumor microenvironment. Therefore, the development of a specific CCR8 antagonist presents a potential therapeutic strategy against cancer. Despite a few small molecules having been reported as CCR8 antagonists, none has progressed to the clinical stage. Herein, we described a potent and selective CCR8 antagonist (compound 1, IPG7236) as the first small molecule to advance to the clinical stage. IPG7236 demonstrated an anti-cancer effect via modulating Treg and cytotoxic T (CD8+ T) cells. IPG7236 alone or in combination with PD-1 antibody exhibited significant tumor suppression effects in the mouse xenograft model of human breast cancer. IPG7236 is a promising clinical candidate that targets CCR8 with excellent in vitro ADMET properties, pharmacokinetics, safety profiles, and in vivo efficacy.

Identification of immune subtypes and their prognosis and molecular implications in colorectal cancer.

Immune composition is commonly heterogeneous and varies among colorectal cancer (CRC) patients. A comprehensive immune classification may act as important characteristics to predict CRC prognosis. Thus, we aimed to identify novel immune specific subtypes to guide future therapies. Unsupervised clustering was used to classify CRC samples into different immune subtypes based on abundances of immune cell populations, during which TCGA and GSE17536 datasets were used as training and validation sets, respectively. The associations between the immune subtypes and patient prognosis were investigated. Further, we identified differentially expressed genes (DEGs) between immune high and low subtypes, followed by functional enrichment analyses of DEGs. The expression levels of 74 immunomodulators (IMs) across immune subtypes were analyzed. As a result, we clustered CRC samples into three distinct immune subtypes (immune high, moderate, and low). Patients with immune-high subtype showed the best prognosis, and patients with immune-low subtype had the worst survival in both TCGA and GSE17536 cohorts. A group of 2735 up-regulated DEGs were identified across immune high and low subtypes. The main DEGs were the members of complement components, chemokines, immunoglobulins, and immunosuppressive genes that are involved in immune modulation-related pathways (e.g., cytokine-cytokine receptor interaction) or GO terms (e.g., adaptive immune response and T cell activation). The expression levels of 63 IMs were significantly varied across immune subtypes. In conclusion, this study provides a conceptual framework and molecular characteristics of CRC immune subtypes, which may accurately predict prognosis and offer novel targets for personalized immunotherapy through modifying subtype-specific tumor immune microenvironment.

Effect of garlic essential oil in 97 patients hospitalized with covid-19: A multi-center experience.

To observe the synergistic effect of garlic essential oil in patients with novel coronavirus disease (COVID-19), in addition to the routine treatment, we used garlic essential oil in COVID-19 patients with mild to moderate symptoms and compared their results to those of patients who did not receive the essential oil. We conducted a quasi-experimental study with COVID-19 patients from 3 hospitals. In the experimental group, 97 patients received garlic essential oil combined with conventional treatment. In the control group, 100 patients received only the conventional treatment for COVID-19. The effectiveness and safety of the garlic essential oil were assessed. Compared to the control group, the group receiving garlic essential oil showed a shorter duration of symptoms, shorter time to negative nucleic acid testing (NAT) results and shorter time to improvement on the computed tomography (CT). In the same period, the experimental group showed an increase in the rate of the disappearance of symptoms and the improvement rates of NAT and CT. Due to its effectiveness and safety in patients with COVID-19, garlic essential oil is recommended as a preventive measure or a supportive therapy during the COVID-19 pandemic.

Flooding-induced rhizosphere Clostridium assemblage prevents root-to-shoot cadmium translocation in rice by promoting the formation of root apoplastic barriers.

Water managements are the most effective agricultural practices for restraining cadmium (Cd) uptake and translocation in rice, which closely correlated with rhizosphere assembly of beneficial microbiome. However, the role of the assemblage of specific microbiota in controlling root-to-shoot Cd translocation in rice remains scarcely clear. The aim of this study was to ascertain how water managements shaped rhizosphere microbiome and mediated root-to-shoot Cd translocation. To disentangle the acting mechanisms of water managements, we performed an experiment monitoring Cd uptake and transport in rice and changes in soil microbial communities in response to continuously flooding and moistening irrigation. Continuously flooding changed rhizosphere microbial communities, leading to the increased abundance of anaerobic bacteria such as Clostridium populations. Weighted gene co-expression network analysis (WGCNA) showed that a dominant OTU163, corresponding to Clostridium sp. CSP1, exhibited a strong negative correlation with root-to-shoot Cd translocation. An integrated analysis of transcriptome and metabolome further indicated that the Clostridium-secreted butyric acid was involved in the regulation of phenylpropanoid pathway in rice roots. The formation of endodermal suberized barriers and lignified xylems was remarkably enhanced in the Clostridium-treated roots, which led to more Cd retained in root cell wall and less Cd in the xylem sap. Collectively, our results indicate that the development of root apoplastic barriers can be orchestrated by beneficial Clostridium strains that are assembled by host plants grown under flooding regime, thereby inhibiting root-to-shoot Cd translocation.

Analysis of BRCA Germline Mutations in Chinese Prostate Cancer Patients.

Recent studies have indicated that prostate cancer (PCa) with BRCA2 mutations is more aggressive. However, these reports mostly focused on Caucasus populations, and large-scale studies on BRCA mutations in Chinese PCa populations remain limited. Herein, we screened, from multiple centers in China, a total of 172 patients with PCa carrying BRCA1/2 germline mutations. The variant distribution and type, associated somatic variant, and frequency of the BRCA germline variants in these patients were analyzed retrospectively. We found that Chinese patients with PCa carrying BRCA1/2 germline mutations were diagnosed at an earlier age, i.e., 67 years (range, 34-89 years), and most had metastatic castration-resistant PCa (mCRPC) (54.65%, 94/172). The top three BRCA variants were frameshift, missense, and splicing variants. The overall pathogenic rates of the BRCA1 and BRCA2 variants were 17.46% (11/63) and 56.55% (82/145), respectively. Among the somatic mutations associated with BRCA2 germline mutations, the highest frequency was for FOXA1 (circulating tumor DNA [ctDNA] sequencing, 7.4%; tissue samples, 52%) and NCOR2 mutations (ctDNA sequencing, 7.4%; tissue samples, 24%); TP53 was the dominant somatic mutation associated with BRCA1 germline mutations (ctDNA sequencing, 25%; tissue samples, 17%). Ultimately, in Chinese patients, PCa with BRCA1/2 germline mutations tends to be more aggressive. Compared with BRCA1, BRCA2 has a higher frequency of germline pathogenic mutations. FOXA1, NCOR2, and TP53 somatic mutations associated with higher BRCA1/2 germline pathogenic mutations. Our description of BRCA germline mutations in the Chinese PCa patients provides more reference data for the precise diagnosis and treatment of Chinese PCa patients.

Cytokines screening identifies MIG (CXCL9) for postoperative recurrence prediction in operated non-small cell lung cancer patients.

BACKGROUND: Exploration of reliable biomarkers most likely to identify non-small cell lung cancer (NSCLC) patients at high risk for recurrence after surgery is needed. METHODS: Quantibody® Human Cytokine Antibody 6000 was used as screening tool to measure serum levels of 280 cytokines in ten healthy individuals and nine samples from three NSCLC patients before operation, after operation and postoperative recurrence. Selected cytokines were validated in two independent sets (89 patients before surgery, 69 patients after surgery and 40 patients with postoperative recurrence for each set) using ELISA method. The association of the selected cytokine with clinicopathologic features was also evaluated. RESULTS: Thirty-six cytokines were declined after surgery and again elevated when recurrence. We selected MIG to be further assessed in 2 validation sets, the mean value of serum MIG levels in 396 NSCLC patients was 253.42 ± 274.48 pg/mL and was significantly higher than the level in 60 healthy controls (47.65 ± 33.23 pg/mL, P < 0.0001). The serum MIG levels were 366.36 ± 324.04 pg/mL pre-operation, 134.04 ± 127.52 pg/mL post-operation and 208.05 ± 239.39 pg/mL in recurrence in NSCLC patients. The serum MIG levels were significant differences among NSCLC patients of pre-operation, post-operation and recurrence and controls (P < 0.0001). Moreover, Serum MIG levels were decreased markedly after operation and notably increased when disease relapsed (P < 0.0005). Serum MIG levels trend to be higher in patients with male gender, older age, smoking habit, poor tumor differentiation, and non-adenocarcinoma histology. CONCLUSIONS: These data indicated that MIG might be an indicator of postoperative recurrence and help to identify NSCLC patient who was easy to relapse after surgery.

Validation of the GALAD model and establishment of a new model for HCC detection in Chinese patients.

Background: GALAD model is a statistical model used to estimate the possibility of hepatocellular carcinoma (HCC) in patients with chronic liver disease. Many studies with other ethnic populations have shown that it has high sensitivity and specificity. However, whether this model can be used for Chinese patients remains to be determined. Our study was conducted to verify the performance of GALAD model in a Chinese cohort and construct a new model that is more appropriately for Chinese populations. Methods: There are total 512 patients enrolled in the study, which can be divided into training set and validation set. 80 patients with primary liver cancer, 139 patients with chronic liver disease and 87 healthy people were included in the training set. Through the ROC(receiver operating characteristic) curve analysis, the recognition performance of GALAD model for liver cancer was evaluated, and the GAADPB model was established by logistic regression, including gender, age, AFP, DCP, total protein, and total bilirubin. The validation set (75 HCC patients and 130 CLD patients) was used to evaluate the performance of the GAADPB model. Result: The GALAD and GAADPB achieved excellent performance (area under the receiver operating characteristic curve [AUC], 0.925, 0.945), and were better than GAAP, Doylestown, BALAD-2, aMAP, AFP, AFP-L3%, DCP and combined detection of AFP, AFP-L3 and DCP (AUCs: 0.894, 0.870, 0.648, 0.545, 0.879, 0.782, 0.820 and 0.911) for detecting HCC from CLD in the training set. As for early stage of HCC (BCLC 0/A), GAADPB had the best sensitivity compared to GALAD, ADP and DCP (56.3%, 53.1%, 40.6%, 50.0%). GAADPB had better performance than GALAD in the test set, AUC (0.896 vs 0.888). Conclusions: The new GAADPB model was powerful and stable, with better performance than the GALAD and other models, and it also was promising in the area of HCC prognosis prediction. Further study on the real-world HCC patients in China are needed.

SEPT6_TRIM33 Gene Fusion and Mutated TP53 Pathway Associate With Unfavorable Prognosis in Patients With B-Cell Lymphomas.

BACKGROUND: Mounting studies have sought to identify novel mutation biomarkers having diagnostic and prognostic potentials. Nevertheless, the understanding of the mutated pathways related to development and prognosis of B-cell lymphoma is still lacking. We aimed to comprehensively analyze the mutation alterations in genes of canonical signaling pathways and their impacts on the clinic outcomes of patients with B-cell lymphoma. METHODS: Circulating cell-free DNA (cfDNA) samples from 79 patients with B-cell lymphomas were used for targeted sequencing with a 560-gene panel for depicting mutation landscapes and identifying gene fusion events. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses of mutated genes were performed. The associations of mutation status of genes and seven canonical oncogenic pathways with progression-free survival (PFS) were assessed using Kaplan-Meier test and multivariate Cox analysis. The variant allele frequencies (VAFs) of genes in TP53 and Hippo pathways in paired baseline and post-treatment samples from 18 B-cell lymphoma patients were compared. Finally, the associations of identified fusion genes, mutated genes, and pathways with treatment response were evaluated based on objective response rates (ORRs) comparisons of groups. RESULTS: We identified 666 mutations from 262 genes in baseline cfDNAs from 79 B-cell lymphoma patients, and found some genes were preferentially mutated in our cohort such as GNAQ, GNAS, H3F3A, DNMT3A, HLA-A, and HLA-B. These frequently mutated genes were significantly associated with negative "regulation of gene expression, epigenetic" and virus infections such as cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus 1 infections. We detected five fusion genes in at least two patients with B-cell lymphoma, and among them, TCF7L2_WT1 gene fusion was most frequently detected in 30.4% of patients (24 of 79 cases). SEPT6_TRIM33 gene fusion, mutated TP53 and Hippo pathways were significantly associated with poor PFS, and SEPT6_TRIM33 fusion gene and mutated TP53 pathway were independent prognostic factors for B-cell lymphoma. A decreased VAF of TP53 p.Y88C and LATS2 p.F972L was detected in patients with complete response to treatments. Moreover, a significant difference in ORR was observed in patients with NPM1_NR4A3 and SEPT6_TRIM33 fusions. CONCLUSIONS: SEPT6_TRIM33 gene fusion and mutated TP53 and Hippo pathways may serve as prognostic makers for B-cell lymphoma patients.

A bibliometric analysis of the research on hematological tumor microenvironment.

BACKGROUND: In recent years, the incidence of hematological tumors has increased. The tumor microenvironment (TME) is the local biological environment in the process of tumor occurrence and development and is closely related to hematological malignancies, including lymphoma and leukemia. This study aims to conduct a bibliometric analysis of the research on the hematological TME, reflect the general situation of the research in this field, and remind the focus of future research. METHODS: Search the Science Citation Index Expanded (SCI-E) database on the Web of Science Core Collection (WOSCC). Use subject terms to search tumor microenvironment; the limited search subject is Hematology, and the time range is from 1990 to July 18, 2021. Use CiteSpace software to analyze the number of annual papers published, the number of citations, the distribution of disciplines, the distribution of countries/institutions, the distribution of authors, the distribution of journals, and the frequency of use of keywords and its trend of change. RESULTS: There were 1,992 related research articles cited 77,213 times. The top 5 countries with the number of published papers in this field are: the United States, Italy, China, Germany, and the United Kingdom; the top 5 centrally ranked countries are the United States, Italy, Spain, France, and Japan. Literature and cooperation are mainly from the United States. The top three researchers with several published papers are Anderson KC, Ansell SM, and Gascoyne RD. Their centrality scores are all low, with only 5 researchers reaching above 0.01, and there is less collaboration between the authors. High-quality papers are from Blood, Cancer Res, P Natl Acad Sci USA, and Nature. Keyword analysis shows that immunotherapy is the current focus of research in this field. CONCLUSIONS: The research on the microenvironment of hematological malignancies is rapidly developing. At present, the main research focus is on targeted immunotherapy.

A Muscle-Invasive Bladder Cancer Patient With High Tumor Mutational Burden and RB1 Mutation Achieved Bladder Preservation Following Chemotherapy Combined With Immunotherapy: A Case Report.

Neoadjuvant chemotherapy followed by radical cystectomy is the standard of care for patients diagnosed with muscle-invasive bladder cancer (MIBC). However, urinary diversion following radical cystectomy significantly reduces patient quality of life. In addition, patients who significantly respond to neoadjuvant chemotherapy have a strong will to preserve the bladder. Bladder-sparing therapy has become a research focus worldwide. Although the bladder-sparing regimen, referred to as trimodality therapy (TMT), has been accepted, the efficacy of immunotherapy combined with chemotherapy for bladder preservation in patients with MIBC has not yet been published. We describe the case of a 50-year-old male presented intermittent macrohematuria and was diagnosed with bladder urothelial carcinoma by diagnostic transurethral resection of bladder tumor (TURBt) with clinical stage IIIA (cT3bN0M0). A complete response was achieved after four courses of neoadjuvant chemotherapy combined with pembrolizumab. Then, we performed a second TURBt plus randomized biopsy by cystoscopy. The pathology indicated no tumor in the bladder. Adjuvant chemoradiotherapy and immunotherapy were subsequently performed. Imaging examinations, cystoscopy and urine tumor DNA (utDNA) levels were used for surveillance after treatment. Finally, the patient achieved bladder preservation and had remained cancer-free for 19 months at the last follow-up on February 20, 2021. This is the first published case study to describe neoadjuvant chemotherapy plus pembrolizumab followed by concurrent chemoradiotherapy as a novel bladder-sparing regimen and successfully achieved a promising outcome.

SLF1 polymorphism predicts response to oxaliplatin-based adjuvant chemotherapy in patients with colon cancer.

Response to oxaliplatin-based adjuvant chemotherapy varies among patients with stage II and III colon cancer; however, genetic alterations associated with this response remain incompletely characterized. A three-stage analytical framework, including the discovery, validation, and replication stages, was designed to explore genetic alterations modulating response to oxaliplatin-based chemotherapy in adjuvant setting among patients with stage II and III colon cancer receiving complete resection of tumor. Except for several somatic mutated genes, such as ARSD and ACE, showing less definitive associations with response to oxaliplatin-based adjuvant chemotherapy, we found stable associations of rs6891545C > A polymorphism in SLF1 gene, a key component of DNA damage response system, with the response across all three stages. Patients with rs6891545 A allele had significantly lower risk of poor responsiveness to oxaliplatin-based adjuvant chemotherapy at both discovery and validation stages, compared with ones possessing wild homozygous genotype CC (discovery stage: odds ratio, 0; 95% CI, 0-0.48; P = .005; validation stage: odds ratio, 0.33; 95% CI, 0.11-0.99; P = .048). In the replication cohort, rs6891545 A allele was confirmed to be strongly associated with improved DFS (hazard ratio, 0.43; 95% CI, 0.23-0.81; P = .007). Notably, the improvement persisted after controlling for sex, age, tumor location, differentiation, and stage (hazard ratio, 0.42; 95% CI, 0.22-0.80; P = .009). Moreover, in silico analysis unraveled strong impact of rs6891545 A allele on local secondary structure of SLF1 mRNA, possibly leading to low SLF1 protein expression. We conclude that the rs6891545C > A polymorphism may serve as an independent marker of response to oxaliplatin-based adjuvant chemotherapy in patients with stage II and III colon cancer, with improved clinical benefit observed in patients with the A allele possibly attributable to low expression of SLF1 protein resulting in deficient DNA repair capacity.

ATR and BRCA2 Simultaneous Mutation in a ccRCC With Sarcomatoid Differentiation and Extensive Metastases: A Case Report.

The genomic landscape and driver-gene mutations differ significantly among diverse histological subtypes of clear cell renal cell carcinoma (ccRCC) due to the intratumoral heterogeneity. Frequent mutations in canonical DNA damage response genes, such as BRCA1/2 or ATR serine/threonine kinase (ATR) haven't been reported even in large-scale genomic profiling of ccRCC researches. Herein, we reported a rare ccRCC harboring ATR and BRCA2 simultaneous mutation with complicated morphologies and extensive metastases. Our case indicates that the deleterious alteration of DNA damage response genes, increasing CD8+ TILs, high PD1/PD-L1 expression and high TMB might contribute to this patient's tumor metastasis and aggressive biological behavior.

Robust Prediction of Immune Checkpoint Inhibition Therapy for Non-Small Cell Lung Cancer.

Background: The development of immune checkpoint inhibitors (ICIs) is a revolutionary milestone in the field of immune-oncology. However, the low response rate is the major problem of ICI treatment. The recent studies showed that response rate to single-agent programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibition in unselected non-small cell lung cancer (NSCLC) patients is 25% so that researchers defined several biomarkers to predict the response of immunotherapy in ICIs treatment. Common biomarkers like tumor mutational burden (TMB) and PD-L1 expression have several limitations, such as low accuracy and inadequately validated cutoff value. Methods: Two published and an unpublished ICIs treatment NSCLC cohorts with 129 patients were collected and divided into a training cohort (n = 53), a validation cohort (n = 22), and two independent test cohorts (n = 34 and n = 20). We identified six immune-related pathways whose mutational status was significantly associated with overall survival after ICIs treatment. Then these pathways mutational status combined with TMB, PD-L1 expression and intratumor heterogeneity were incorporated to build a Bayesian-regularization neural networks (BRNN) model to predict the ICIs treatment response. Results: We firstly proved that TMB, PD-L1, and mutant-allele tumor heterogeneity (MATH) were independent biomarkers. The survival analysis of six immune-related pathways revealed the mutational status could distinguish overall survival after ICIs treatment. When predicting immunotherapy efficacy, the overall accuracy of area under curve (AUC) in validation cohort reaches 0.85, outperforming previous predictors in either sensitivity or specificity. And the AUC in two independent test cohorts reach 0.74 and 0.80. Conclusion: We developed a pathway-model that could predict the efficacy of ICIs in NSCLC patients. Our study made a significant contribution to solving the low prediction accuracy of immunotherapy of single biomarker. With the accumulation of larger data sets, further studies are warranted to refine the predictive performance of the approach.