Rs1884444 variant in IL23R gene is associated with a decreased risk in esophageal cancer in Chinese population.

Single nucleotide polymorphisms (SNPs) in interleukin-23 receptor (IL23R) are involved in the pathogenesis of many cancers and autoimmune diseases. IL23R gene is still controversial in the study of esophageal cancer. The aim of this research is to investigate the influence of IL23R SNPs on the risk of esophageal cancer. Five hundred six esophageal cancer and 507 controls frequency matched by age and gender were conducted, and the genotypes were determined by the Agena MassARRAY. Logistic regression analysis was used to evaluate the odd ratios (ORs) and 95% confidence intervals (CIs) of rs1884444 and rs6682925 with susceptibility of esophageal cancer. A total of 30 articles are eligible. Pooled ORs and the 95% CI were calculated using the random-effect model. Database predicts the expression of IL23R gene in esophageal cancer. IL23R rs1884444 allele G decreased the risk of esophageal cancer under allele, genotype, and additive models (allele model: OR = 0.82, 95% CI: 0.68-0.98, P = .032; genotype model: OR = 0.65, 95% CI: 0.44-0.97, P = .035; additive model: OR = 0.82, 95% CI: 0.68-0.98, P = .031). Meta-analysis shown that IL23R rs1884444 increased the risk of overall disease in allele model (OR = 1.16, 95% CI: 1.08-1.25, P < .001), and also increased the risk of gastrointestinal tumor (OR = 1.18, 95% CI: 1.05-1.31, P = .005). The database analysis showed that the expression of IL23R gene was upregulated in esophageal cancer tissues. IL23R rs1884444 may play an important role in the susceptibility of esophageal cancer.

Association between TIMP-2 gene polymorphism and breast cancer in Han Chinese women.

BACKGROUND: TIMP-2 gene plays an important role in the development of breast cancer. The present study was conducted to evaluate whether TIMP-2 gene polymorphisms are associated with breast cancer risk in a Han Chinese cohort. METHODS: Six single nucleotide polymorphisms (SNPs) within the TIMP-2 gene in 571 breast cancer and 578 healthy control subjects were genotyped through the Agena MassARRAY. Logistic regression analysis was used to assess the influence of TIMP-2 polymorphisms on breast cancer. Functional annotation of TIMP-2 variants and TIMP-2 expression were analyzed by bioinformatics. RESULTS: Bioinformatics analysis found that rs4789936 was likely to affect transcription factor binding, motifs, DNase footprint, and DNase peaks; and TIMP-2 was under-expressed in breast cancer, the risk allele of rs4789936 was associated with increased expression of TIMP-2 in peripheral blood samples. Importantly, individuals carrying TIMP-2 rs2277698 T allele have a 19% lower risk of breast cancer than individuals with allele C, providing protection (OR = 0.81, 95%CI = 0.67-0.99, p = 0.041). In the breast cancer patients with c-erb positive and PR positive, when the CC genotype was used as a reference, individuals carrying the TT genotype increased the risk of breast cancer. Haplotype analysis showed "TCC" was associated with a reduced risk of breast cancer (OR = 0.79, 95%CI = 0.63-0.97, p = 0.028). CONCLUSION: Our study indicated that TIMP-2 rs2277698 was associated with breast cancer susceptibility.

Ribosome display and selection of single-chain variable fragments effectively inhibit growth and progression of microspheres in vitro and in vivo.

Distinguishing the surface markers of cancer stem cells (CSCs) is a useful method for early diagnosis and treatment of tumors, as CSCs may participate in tumorigenesis and metastasis by migrating into the circulatory system. However, the potential targets of CSCs are expressed at low levels in the natural state and are always changing. Thus, dynamic screening has been reported to be an effective measure for exploring CSC markers. In recent years, diverse single-chain variable fragments (scFvs) have been widely used in immunotherapy. In this study, we determined that the scFvs, screened using RD, had a high affinity to microspheres and could inhibit their progression. We also observed that the selected scFvs underwent evolution in vitro, and antitumor-associated proteins were successfully expressed. Combined with chemotherapy, the scFvs had a synergistic effect on the inhibition of the microspheres' progression in vitro and in vivo, which could be ascribed to their high affinity for stem-like cells and the inhibition of the microspheres' collective behaviors. In addition, proteins inhibiting CD44+ /CD24+ and MAPK were involved. Our data indicated that dynamic screening of the scFvs in a natural state was of great significance in the inhibition of the microspheres in vitro and in vivo.

Thymoquinone inhibits the metastasis of renal cell cancer cells by inducing autophagy via AMPK/mTOR signaling pathway.

Thymoquinone (TQ, 2-methyl-5-isopropyl-1,4-benzoquinone), a bioactive constituent extracted from the seeds of Nigella sativa, has been proved to exert anti-tumor efficiency in various cancers. Autophagy is a self-digestion phenomenon, and its role in tumor formation and progression remains controversial. In the present study, we investigated the effects of TQ on renal cell cancer (RCC) cell lines (786-O and ACHN) using wound healing assay, transwell assay and western blot analysis. We found that TQ effectively inhibited the metastatic capacity of RCC cells in vitro, which was also verified in a xenograft model. Meanwhile, we observed LC3 puncta and detected the expression of LC3 in TQ-treated RCC cells, and then found that autophagy was induced by TQ in 786-O and ACHN cell lines. In addition, TQ inhibited the migration and invasion as well as the EMT in RCC cells in an autophagy-dependent manner. To further explore the underlying mechanism, we detected the AMPK/mTOR signaling pathway. The results indicated that TQ inhibited the metastasis of RCC cells by inducing autophagy via AMPK/mTOR signaling pathway. In conclusion, our findings provide a novel therapeutic strategy that aims at TQ-induced autophagy in RCC treatment.

Celecoxib induced apoptosis against different breast cancer cell lines by down-regulated NF-κB pathway.

Inducible cyclooxgenase-2 (COX-2) is commonly overexpressed in breast tumors and is a target for cancer therapy. Here, we studied the effect of Celecoxib, a COX-2 inhibitor on two molecular breast cancer subtypes-MDA-MB-231 and SK-BR-3. Firstly, MDA-MB-231 and SK-BR-3 cells were treated with various concentration of Celecoxib for 24 and 48 h. Celecoxib-inhibition of NF-κB (p52 and p65) transcriptional activity and effect of Caspase 3 pathway were examined by western blotting. COX-2 mRNA was assessed by RT-PCR. Cell viability was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazoliumbromide (MTT) assay. Both cell cycle profiles and apoptosis were analyzed using flow cytometry. We found that Celecoxib inhibited the proliferation of the MDA-MB-231 cell line in a dose-time dependent manner versus SK-BR-3 in a dose dependent manner only (p < 0.05). Celecoxib induced apoptosis of the MDA-MB-231 and SK-BR-3 cell lines in a dose-time dependent manner (p < 0.05) with more mean apoptotic cells in MDA-MB-231 than SK-BR-3. Significant cell-cycle arrest at the G1 phase in the MDA-MB-231 versus G2 phase in SK-BR-3 cell lines. NF-κB (p52 and p65) and COX-2 expressions were downregulated in a dose dependent manner, while Caspase 3 expression was upregulated in both cell lines. In this present study, our data indicated Celecoxib might affect each breast cancer subtype independently. Therefore, when using Celecoxib in treatment of breast cancer, it is imperative to consider the subtype of breast cancer on a molecular level.

The CNGRCLLII(KLAKLAK)2 peptide shows cytotoxicity against HUVECs by inducing apoptosis: An in vitro and in vivo study.

Fibrinogen Asn-Gly-Arg motif can specifically recognize and bind to Aminopeptidase N (CD13) on vascular endothelial cells in newly formed tumor vessels. Adipose-derived stem cells can serve as ideal vectors for gene therapy because of their ability of migrating to tumor tissues. First, this study was aimed to design a new peptide (CNGRCLLII(KLAKLAK)2) named CNAK which contains cyclic Asn-Gly-Arg motif and test its biological activity against human umbilical vein endothelial cells. Second, we aimed to construct stably transfected adipose-derived stem cells which express the CNAK peptide and investigate their anti-angiogenic activity in vivo. Adipose-derived stem cells were employed to localize CNAK on vascular endothelial cells in tumors based on their homing property. First of all, the new peptide was synthesized, which effectively entered into CD13+ human umbilical vein endothelial cells and showed cytotoxicity against human umbilical vein endothelial cells. The peptide induced apoptosis of human umbilical vein endothelial cells in a time- and dose-dependent manner, inhibited the expression of Bcl-2, and promoted the expression of Caspase-3 in human umbilical vein endothelial cells. Furthermore, the migration and tube formation of human umbilical vein endothelial cells were inhibited by CNAK. Primary adipose-derived stem cells were then isolated and identified. Stably transfected adipose-derived stem cells which express CNAK peptide (CNAK-ASCs) were successfully established, and the migration of CNAK-ASCs was assessed. In vivo, CNAK-ASCs were found to inhibit the growth and angiogenesis of breast cancer xenografts. This effect may be through inhibiting the secretion of matrix metalloproteinase-2 and membrane type 1-matrix metalloproteinase in vivo. It was also found that CNAK-ASCs reduced the quantity of breast cancer stem cells in tumor tissues. Our data suggested that the new peptide CNAK containing Asn-Gly-Arg motif had anti-angiogenic activity in vitro and in vivo.

[Construction and Identification of the cDNA Expression Library for Human Esophageal Cancer Cells].

OBJECTIVES: To construct a cDNA phage expression library for human esophageal cancer cells. METHODS: After the total RNA were obtained from esophageal cancer cells, the mRNA were separated with magnetic beads adsorption method, and the single-strand and double-strand cDNA were synthesized through reverse transcription. With the undesirable cDNA fragments removed, the remaining cDNA (linked withEcoR1 aptamer and phosphorylated its 5'end) combined with the carrier of T7 Select10-3b. The recombinant phage were packaged in vitro for preliminary cDNA library. PCR was used to identify the size of inserted cDNA. RESULTS: The constructed original cDNA phage expression library for human esophageal cancer cells was consisted of 2.01×106 pfu/mL bacteriophages with a recombination rate of 100%. The length of the inserted cDNA fragments were range from 300 bp to 1 500 bp. CONCLUSIONS: The cDNA phage expression library of human esophageal cell is successfully constructed to meet the currently recognized standards, and can be well used to screen cDNA-cloned genes of human esophageal cancer antigens by serological analysis of recombinantly expressed cDNA clone (SEREX).

Notch1 signaling regulates the epithelial-mesenchymal transition and invasion of breast cancer in a Slug-dependent manner.

BACKGROUND: The epithelial-mesenchymal transition (EMT) is crucial for the invasion and metastasis of breast cancer. However, how Notch signaling regulates the EMT process and invasion in breast cancer remains largely unknown. METHODS: The impact of Notch1 silencing by specific shRNAs on the EMT and invasion of human breast cancer MCF-7 and MDA-MB-231 cells as well as xenografts was tested by western blot, real-time polymerase chain reaction (RT-PCR), immunofluorescence, transwell, and immunohistochemistry assays. The effect of Slug silencing or upregulation on the EMT and invasion of breast cancer cells was analyzed, and the effect of Notch1 signaling on Slug expression was determined by the luciferase reporter assay. RESULTS: The Notch1 intracellular domain (N1ICD) and Jagged1 were expressed in breast cancer cells. Notch1 silencing reversed the spontaneous EMT process and inhibited the migration and invasion of breast cancer cells and the growth of xenograft breast cancers. The expression of N1ICD was upregulated significantly by Jagged1-mediated Notch signaling activation. Moreover, Jagged1-mediated Notch signaling promoted the EMT process, migration, and invasion of breast cancer cells, which were abrogated by Notch silencing. Furthermore, the N1ICD positively regulated the Slug expression by inducing Slug promoter activation. Importantly, the knockdown of Slug weakened the invasion ability of breast cancer cells and reversed the Jagged1-induced EMT process with significantly decreased expression of vimentin and increased expression of E-cadherin. In addition, Slug overexpression restored the Notch1 knockdown-suppressed EMT process. CONCLUSIONS: Our novel data indicate that Notch signaling positively regulates the EMT, invasion, and growth of breast cancer cells by inducing Slug expression. The Notch1-Slug signaling axis may represent a potential therapeutic target for breast cancer therapy.

An antimicrobial peptide containing NGR motif has potent antitumor activity against CD13+ and CD13- tumor cells.

Antimicrobial peptides (AMPs) with Asn-Gly-Arg (NGR) motif have potent cytotoxicity, preferably against tumor cells due to their binding to CD13 on tumor cells. However, the importance of αvß3 expression for antitumor activity of AMPs containing NGR has not been clarified. This study was aimed at designing a new AMP containing NGR and testing their biological activity against different types of tumor cells with varying CD13 and αvß3 expression. We first synthesized the new AMP containing NGR motif (CK21), which effectively entered into CD13+ HT-1080, but less into CD13- αvß3+ MDA-MB-435 and further less into stable αvß3-silencing MDA-MB-435 cells. Furthermore, CK21 displayed dose-dependent antiproliferation against these tumor cells and induced cell cycling arrest at G2/M phases and apoptosis of these tumor cells. In addition, CK21 inhibited the invasion of these tumor cells in vitro and inhibited the growth of implanted tumor cells in vivo. Particularly, the antitumor effect of CK21 in CD13+ HT-1080 was stronger than that of CD13- αvß3+ MDA-MB-435 and much stronger than that of stable αvß3-silencing MDA-MB-435. Our data indicated that the new AMPs containing NGR had potent antitumor activity against CD13+ or αvß3+ tumor cells, preferably against CD13+ tumor cells, possibly through binding to CD13 or αvß3 on tumor cells.

[Combination of phage display and SEREX for screening early lung cancer associated antigens].

OBJECTIVE: To screen out effective lung cancer associated antigens for early diagnosis in order to improve the level of early diagnosis. METHODS: A T7 phage display cDNA library of human early lung cancer was developed. And then differential phage clones were picked out to be sequenced and bioinformatically analyzed. With the 8 screened differential phage clones a lung cancer associated antigen microarray was established to evaluate the single or combined roles of all the selected antigens in the diagnosis of lung cancer by the reaction of the antigens plus serum from normal subjects and patients with lung cancer, respectively. RESULTS: The titer of the constructed cDNA library was 3.71×10 (6); pfu/ml and the number of phage was 1.11×10 (6); pfu, with a recombination rate of cDNA library over 90%. Nine differential phage clones were initially screened out, but the genes of two antigens (A42 and A83) were found the same. Bioinformatics analyses showed that the genes of the 8 antigens were known before and they were all proven to be related with tumor except A64. The positive reaction rates of the 8 antigens with serum from lung cancer patients were significantly higher than that with serum from normal subjects (Ps<0.05). When keeping specificity no less than 60%, the sensitivity of each antigen in predicting lung cancer alone was under 70% and the areas under curve (AUC) of the antigens were all under 0.8. However, when all the antigens were combined to detect lung cancer, the sensitivity and specificity was 90.8% and 94.1%, respectively, and AUC reached up to 0.969. CONCLUSION: A T7 phage display cDNA library with a good quality of capacity, recombination rate and representativeness of human early lung cancer was successfully developed, and 8 lung cancer associated antigens were screened out. A combination of the 8 antigens can greatly improve their value to diagnose lung cancer with a higher sensitivity and specificity (both above 90%)．

Unveiling the immune symphony: decoding colorectal cancer metastasis through immune interactions.

Colorectal cancer (CRC), known for its high metastatic potential, remains a leading cause of cancer-related death. This review emphasizes the critical role of immune responses in CRC metastasis, focusing on the interaction between immune cells and tumor microenvironment. We explore how immune cells, through cytokines, chemokines, and growth factors, contribute to the CRC metastasis cascade, underlining the tumor microenvironment's role in shaping immune responses. The review addresses CRC's immune evasion tactics, especially the upregulation of checkpoint inhibitors like PD-1 and CTLA-4, highlighting their potential as therapeutic targets. We also examine advanced immunotherapies, including checkpoint inhibitors and immune cell transplantation, to modify immune responses and enhance treatment outcomes in CRC metastasis. Overall, our analysis offers insights into the interplay between immune molecules and the tumor environment, crucial for developing new treatments to control CRC metastasis and improve patient prognosis, with a specific focus on overcoming immune evasion, a key aspect of this special issue.

Therapeutic efficacy of acupuncture point stimulation for stomach cancer pain: a systematic review and meta-analysis.

Purpose: In recent years, traditional Chinese medicine has received widespread attention in the field of cancer pain treatment. This meta-analysis is the first to evaluate the effectiveness and safety of acupuncture point stimulation in the treatment of stomach cancer pain. Methods: For this systematic review and meta-analysis, we searched PubMed, Web of Science, Cochrane Library, Embase, WANFANG, China National Knowledge Infrastructure (CNKI), and Chinese Journal of Science and Technology (VIP) databases as well as forward and backward citations to studies published between database creation to July 27, 2023. All randomized controlled trials (RCTs) on acupuncture point stimulation for the treatment of patients with stomach cancer pain were included without language restrictions. We assessed all outcome indicators of the included trials. The evidence from the randomized controlled trials was synthesized as the standardized mean difference (SMD) of symptom change. The quality of the evidence was assessed using the Cochrane Risk of Bias tool. This study is registered on PROSPERO under the number CRD42023457341. Results: Eleven RCTs were included. The study included 768 patients, split into 2 groups: acupuncture point stimulation treatment group (n = 406), medication control group (n = 372). The results showed that treatment was more effective in the acupuncture point stimulation treatment group than in the medication control group (efficacy rate, RR = 1.63, 95% CI 1.37 to 1.94, p < 0.00001), decreasing in NRS score was greater in acupuncture point stimulation treatment group than in the medication control group (SMD = -1.30, 95% CI -1.96 to -0.63, p < 0.001). Systematic Review Registration: https://clinicaltrials.gov/, identifier CRD42023457341.

Circadian rhythms and breast cancer: unraveling the biological clock's role in tumor microenvironment and ageing.

Breast cancer (BC) is one of the most common and fatal malignancies among women worldwide. Circadian rhythms have emerged in recent studies as being involved in the pathogenesis of breast cancer. In this paper, we reviewed the molecular mechanisms by which the dysregulation of the circadian genes impacts the development of BC, focusing on the critical clock genes, brain and muscle ARNT-like protein 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK). We discussed how the circadian rhythm disruption (CRD) changes the tumor microenvironment (TME), immune responses, inflammation, and angiogenesis. The CRD compromises immune surveillance and features and activities of immune effectors, including CD8+ T cells and tumor-associated macrophages, that are important in an effective anti-tumor response. Meanwhile, in this review, we discuss bidirectional interactions: age and circadian rhythms, aging further increases the risk of breast cancer through reduced vasoactive intestinal polypeptide (VIP), affecting suprachiasmatic nucleus (SCN) synchronization, reduced ability to repair damaged DNA, and weakened immunity. These complex interplays open new avenues toward targeted therapies by the combination of clock drugs with chronotherapy to potentiate the immune response while reducing tumor progression for better breast cancer outcomes. This review tries to cover the broad area of emerging knowledge on the tumor-immune nexus affected by the circadian rhythm in breast cancer.

Deciphering the role of tryptophan metabolism-associated genes ECHS1 and ALDH2 in gastric cancer: implications for tumor immunity and personalized therapy.

Background: Tryptophan Metabolism-associated Genes (TMGs), such as ECHS1 and ALDH2, are crucial in cancer progression through immunosuppressive mechanisms, particularly in Gastric Cancer (GC). This study explores their effects on the Tumor Microenvironment (TME). Additionally, it examines their potential as novel immunotherapy targets. Methods: We utilized single-cell and bulk transcriptomic technologies to analyze the heterogeneity of GC. Non-negative Matrix Factorization (NMF) clustering identified key TMGs, and extensive RNA-seq analyses were performed to pinpoint prognostic genes and potential immunotherapy targets. Furthermore, through PCR analyses we found that ECHS1 and ALDH2 gene expression plays a regulatory role in the migration, invasion and inflammatory factor in AGS and SNU-1 cell lines. The interference effect of si-ECHS1 and ad-ALDH2 was validated using cell scratch assay in AGS and SNU-1 cell line. Results: We observed a statistically significant correlation between ECHS1 and ALDH2 expression and increased TME heterogeneity. Our findings also revealed that ECHS1 down-regulation and ALDH2 up-regulation contribute to reduced TME heterogeneity, decreased inflammation, and inhibited AGS and SNU-1 tumor cells migration and proliferation. GSVA enrichment analysis highlighted the NF-kappa B(NF-κB) signaling pathway as specifically regulated by TMGs. Furthermore,ECHS1 and ALDH2 modulated CD8+ and CD4+ T cell activities, impacting GC progression. In vitro experiments further solidified our conclusions by showcasing the inhibitory effects of Si-ECHS1 and ad-ALDH2 on the invasive and proliferative capabilities of AGS and SNU-1 cells. Moreover, Si-ECHS1 and ad-ALDH2 gene expression effectively reduced the expression of inflammatory factors IL-10,IL-7,CXCL8 and IL-6, leading to a remarkable alleviation of chronic inflammation and the heterogeneous nature of the TME. Conclusion: This research highlights the importance of ECHS1 and ALDH2 in GC progression and immune modulation, suggesting that targeted therapies focusing on these genes offer promising avenues for personalized immunotherapy in GC. These findings hold potential for improving patient survival and quality of life. Future studies on the NF-κB signaling pathway's role in this context are warranted to further elucidate the mechanisms underlying TMG-mediated immune modulation in GC.

Advancing immunotherapy for melanoma: the critical role of single-cell analysis in identifying predictive biomarkers.

Melanoma, a malignant skin cancer arising from melanocytes, exhibits rapid metastasis and a high mortality rate, especially in advanced stages. Current treatment modalities, including surgery, radiation, and immunotherapy, offer limited success, with immunotherapy using immune checkpoint inhibitors (ICIs) being the most promising. However, the high mortality rate underscores the urgent need for robust, non-invasive biomarkers to predict patient response to adjuvant therapies. The immune microenvironment of melanoma comprises various immune cells, which influence tumor growth and immune response. Melanoma cells employ multiple mechanisms for immune escape, including defects in immune recognition and epithelial-mesenchymal transition (EMT), which collectively impact treatment efficacy. Single-cell analysis technologies, such as single-cell RNA sequencing (scRNA-seq), have revolutionized the understanding of tumor heterogeneity and immune microenvironment dynamics. These technologies facilitate the identification of rare cell populations, co-expression patterns, and regulatory networks, offering deep insights into tumor progression, immune response, and therapy resistance. In the realm of biomarker discovery for melanoma, single-cell analysis has demonstrated significant potential. It aids in uncovering cellular composition, gene profiles, and novel markers, thus advancing diagnosis, treatment, and prognosis. Additionally, tumor-associated antibodies and specific genetic and cellular markers identified through single-cell analysis hold promise as predictive biomarkers. Despite these advancements, challenges such as RNA-protein expression discrepancies and tumor heterogeneity persist, necessitating further research. Nonetheless, single-cell analysis remains a powerful tool in elucidating the mechanisms underlying therapy response and resistance, ultimately contributing to the development of personalized melanoma therapies and improved patient outcomes.

Mitochondrial inhibitors: a new horizon in breast cancer therapy.

Breast cancer, due to resistance to standard therapies such as endocrine therapy, anti-HER2 therapy and chemotherapy, continues to pose a major health challenge. A growing body of research emphasizes the heterogeneity and plasticity of metabolism in breast cancer. Because differences in subtypes exhibit a bias toward metabolic pathways, targeting mitochondrial inhibitors shows great potential as stand-alone or adjuvant cancer therapies. Multiple therapeutic candidates are currently in various stages of preclinical studies and clinical openings. However, specific inhibitors have been shown to face multiple challenges (e.g., single metabolic therapies, mitochondrial structure and enzymes, etc.), and combining with standard therapies or targeting multiple metabolic pathways may be necessary. In this paper, we review the critical role of mitochondrial metabolic functions, including oxidative phosphorylation (OXPHOS), the tricarboxylic acid cycle, and fatty acid and amino acid metabolism, in metabolic reprogramming of breast cancer cells. In addition, we outline the impact of mitochondrial dysfunction on metabolic pathways in different subtypes of breast cancer and mitochondrial inhibitors targeting different metabolic pathways, aiming to provide additional ideas for the development of mitochondrial inhibitors and to improve the efficacy of existing therapies for breast cancer.

Revealing the association between East Asian oral microbiome and colorectal cancer through Mendelian randomization and multi-omics analysis.

Background: Colorectal cancer (CRC) poses a global health threat, with the oral microbiome increasingly implicated in its pathogenesis. This study leverages Mendelian Randomization (MR) to explore causal links between oral microbiota and CRC using data from the China National GeneBank and Biobank Japan. By integrating multi-omics approaches, we aim to uncover mechanisms by which the microbiome influences cellular metabolism and cancer development. Methods: We analyzed microbiome profiles from 2017 tongue and 1915 saliva samples, and GWAS data for 6692 CRC cases and 27178 controls. Significant bacterial taxa were identified via MR analysis. Single-cell RNA sequencing and enrichment analyses elucidated underlying pathways, and drug predictions identified potential therapeutics. Results: MR identified 19 bacterial taxa significantly associated with CRC. Protective effects were observed in taxa like RUG343 and Streptococcus_umgs_2425, while HOT-345_umgs_976 and W5053_sp000467935_mgs_712 increased CRC risk. Single-cell RNA sequencing revealed key pathways, including JAK-STAT signaling and tyrosine metabolism. Drug prediction highlighted potential therapeutics like Menadione Sodium Bisulfite and Raloxifene. Conclusion: This study establishes the critical role of the oral microbiome in colorectal cancer development, identifying specific microbial taxa linked to CRC risk. Single-cell RNA sequencing and drug prediction analyses further elucidate key pathways and potential therapeutics, providing novel insights and personalized treatment strategies for CRC.

Efficacy and safety of PD-1/PD-L1 plus CTLA-4 antibodies ± other therapies in lung cancer: a systematic review and meta-analysis.

PURPOSE: To investigate the efficacy and safety of programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) plus cytotoxic T lymphocyte antigen-4 (CTLA-4) antibodies ± other therapies in patients with advanced lung cancer. METHODS: In accordance with the retrieval strategy, we searched electronic databases for randomised controlled trials testing PD-1/PD-L1 plus CTLA-4 antibodies in patients with lung cancer; RR (for objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and immune-related adverse events (irAEs)) from individual studies were calculated and pooled by using random-effects models or fixed-effects models; heterogeneity and publication bias analyses were also performed, using Review Manager 5.3 and Stata 15.1 for statistical analysis. RESULTS: We included six studies. Four different immune checkpoint inhibitors (nivolumab, pembrolizumab, durvalumab, tremelimumab) were used. Dual checkpoint inhibitors ± other therapies for advanced lung cancer showed significant improvements in ORR (RR 1.49, 95% CI 1.11 to 1.98; p=0.007), OS (HR 0.72, 95% CI 0.63 to 0.83; p<0.00001), and PFS (HR 0.72, 95% CI 0.63 to 0.82; p<0.00001). The subgroup analyses were consistent with the pooled results. The PD-L1 ≥1% (HR 0.67, 95% CI 0.54 to 0.82; p<0.0001) subgroup differences indicated a statistically significant subgroup effect, but the PD-L1 <1% subgroup (HR 0.88, 95% CI 0.75 to 1.05; p=0.15) was not statistically significant. The incidence of adverse events (grade ≥3) was lower than that of the control group (RR 0.90, 95% CI 0.80 to 1.02; p=0.09), but was not significant. CONCLUSIONS: PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors ± other therapies can improve the ORR, OS and PFS of patients with advanced or metastatic lung cancer, but the incidence of adverse reactions is high although generally tolerable. PROSPERO REGISTRATION: CRD42020149216.

Case report: Interstitial implantation radiotherapy combined with immunotherapy and GM-CSF in oligometastatic platinum-resistant ovarian cancer.

Background: Treatment for platinum-resistant ovarian cancer is challenging. Currently, platinum-resistant ovarian cancer is typically treated with non-platinum single-agent chemotherapy ± bevacizumab, but the prognosis is often extremely poor. In the treatment of platinum-resistant ovarian cancer patients, reports of triple therapy with interstitial implantation radiotherapy combined with immunotherapy and granulocyte-macrophage colony-stimulating factor (GM-CSF) (PRaG for short) are relatively rare. Case description: Here, we report a patient with oligometastatic platinum-resistant ovarian cancer. The patient achieved partial response (PR) of the lesion and sustained benefit for more than six months after receiving interstitial implantation radiotherapy combined with immunotherapy along with GM-CSF. Conclusion: This triple therapy may provide additional options for these patients.

Effects of miR­93 on epithelial­to­mesenchymal transition and vasculogenic mimicry in triple­negative breast cancer cells.

Triple­negative breast cancer (TNBC) is characterized by strong invasiveness, frequent local recurrence and distant metastasis, with poor prognosis. According to tumor angiogenesis theory, tumor cells can obtain blood supply not only by fusing with host blood vessels, but also by constructing a new vascular system through angiogenesis, so as to continuously obtain nutrients and oxygen supply; this is called vasculogenic mimicry (VM). In our previous study, differential expression profiles of miRNAs were examined with gene chip in TNBC and corresponding paracancer tissues, which demonstrated significant up­regulation of microRNA (miR)­93. Bioinformatics found that the target genes of miR­93 were associated with cell proliferation, invasion and migration. The present study investigated the association between miR­93, epithelial­to­mesenchymal transition (EMT) and VM formation in TNBC cell lines. The results indicated that miR­93 depletion suppressed MDA­MB­231 cell viability, invasion and migration (P<0.001). In addition, knockdown of miR­93 significantly upregulated the expression levels of EMT­associated genes such as E­cadherin and occludin, but downregulated the expression levels of vimentin and N­cadherin in MDA­MB­231 cells. VM formation assay showed a significant decrease in microtubule­forming ability of cells following miR­93 knockdown, which was associated with the occurrence of EMT, suggesting that miR­93 may promote the formation of VM via EMT and may be a therapeutic target for the treatment of TNBC.