Mendelian randomization combined with multi-omics explores the relationship between heart failure and cancer.

Background: Whether there is an association between HF (HF) and cancer has not been conclusively established, and it is not clear whether patients with cancer can share similar hospitalization strategies and outcomes with patients with HF. Methods: Genome-wide association summary statistics were performed using a two-sample Mendelian randomization (MR) method for HF patients and cancer patients from the GWAS directory, with co-localization and Summary Data-Based Mendelian Randomization (SMR) analyses to identify HF-associated genes, and transcriptomic analyses to analyze the roles of these genes in the clinical diagnosis and targeted therapies of multiple cancer types. Results: Two-sample MR analysis showed that increased risk of HF was associated with decreased risk of cervical, brain, breast, colorectal, lung, and skin cancers, and co-localization combined with SMR analysis identified ABO and SURF1 as HF-associated genes, and transcriptomic analyses showed that ABO is a risk factor for HF and a protective factor against cancer, whereas SURF1 is a protective factor against HF and a protective factor against cancer. Conclusion: There was no causal relationship between heart failure and cancers (Cervical, brain, breast, colorectal, lung and skin cancers) risk factors, however there was a trend toward a negative causal relationship between heart failure and cancers (Cervical, brain, breast, colorectal, lung and skin cancers) occurrence.

IQGAP3 promotes the progression of glioma as an immune and prognostic marker.

Background: IQGAP3 plays a crucial role in regulating cell proliferation, division, and cytoskeletal organization. Abnormal expression of IQGAP3 has been linked to various tumors, but its function in glioma is not well understood. Methods: Various methods, including genetic differential analysis, single-cell analysis, ROC curve analysis, Cox regression, Kaplan-Meier analysis, and enrichment analysis, were employed to analyze the expression patterns, diagnostic potential, prognostic implications, and biological processes involving IQGAP3 in normal and tumor tissues. The impact of IQGAP3 on immune infiltration and the immune microenvironment in gliomas was evaluated using immunofluorescence. Additionally, the cBioPortal database was used to analyze copy number variations and mutation sites of IQGAP3. Experimental validation was also performed to assess the effects of IQGAP3 on glioma cells and explore underlying mechanisms. Results: High IQGAP3 expression in gliomas is associated with an unfavorable prognosis, particularly in wild-type IDH and 1p/19q non-codeleted gliomas. Enrichment analysis revealed that IQGAP3 is involved in regulating the cell cycle, PI3K/AKT signaling, p53 signaling, and PLK1-related pathways. Furthermore, IQGAP3 expression may be closely related to the immunosuppressive microenvironment of glioblastoma. BRD-K88742110 and LY-303511 are potential drugs for targeting IQGAP3 in anti-glioma therapy. In vitro experiments showed that downregulation of IQGAP3 inhibits the proliferation and migration of glioma cells, with the PLK1/PI3K/AKT pathway potentially playing a crucial role in IQGAP3-mediated glioma progression. Conclusion: IQGAP3 shows promise as a valuable biomarker for diagnosis, prognosis, and immunotherapeutic strategies in gliomas.

Dapagliflozin prevents kidney podocytes pyroptosis via miR-155-5p/HO-1/NLRP3 axis modulation.

Diabetic nephropathy (DN) is a significant clinical microvascular complication associated with diabetes mellitus (DM), and end-stage diabetes giving rise to kidney failure is developing into the major etiological factor of chronic kidney failure. Dapagliflozin is reported to limit podocyte damage in DM, which has proven to protect against renal failure. Mounting evidence has demonstrated that pyroptosis is associated with DM progression. Nevertheless, whether pyroptosis causes DN and the underlying molecular pathways remain obscure. In this study, we aimed to explore the antipyroptotic attributes of dapagliflozin and elucidate the underlying mechanisms of kidney damage in diabetes. In vivo, experiments were conducted in streptozotocin (STZ)-induced type 2 diabetic mice, which were administered dapagliflozin via gavage for 6 weeks. Subsequently, the specific organizational characteristics and expression of pyroptosis-related genes were evaluated. Intragastric dapagliflozin administration markedly reduced renal tissue injury. Meanwhile, dapagliflozin also attenuated the expression level of pyroptosis associated genes, including ASC, cleaved Caspase-1, GSDMD N-termini, NLRP3, IL-18, and IL-1ß in renal tissue of dapagliflozin-treated animals. Similar antipyroptotic effects were observed in palmitic acid (PA)-treated mouse podocytes. We also found that heme oxygenase 1 (HO-1) enhanced the protection of mouse podocyte clone 5 cells (MPC5). Moreover, miR-155-5p inhibition increased pyroptosis in PA-treated MPC5 cells, suggesting that miR-155-5p acts as an endogenous stimulator that increases HO-1 expression and reduces pyroptosis. Hence, our findings imply that dapagliflozin inhibits podocyte pyroptosis via the miR-155-5p/HO-1/NLRP3 axis in DM. Furthermore, dapagliflozin substitution may be regarded as an effective strategy for preventing pyroptosis in the kidney, including a therapeutic option for treating pyroptosis-related DN.

Observation of the Effects of Different Enzyme Digestion Time and Enzyme Digestion Methods on the Extraction of Primary Renal Tubular Epithelial Cells from Sprague-Dawley Suckling Mice.

Renal tubular epithelial cells are one of the essential functional cells in the kidney. Optimizing the isolation and culture method of primary renal tubular epithelial cells from SD mammary rats provides better experimental materials for renal tubule-related studies, which is essential for studying the pathogenesis of renal diseases, especially diabetic nephropathy and drug screening. SD rat renal tubular epithelial cells were isolated and purified by 2.5-mg/ml collagenase II or 2 mg/ml trypsin + 2.5 mg/ml collagenase II enzymatic digestion. The isolation and purification were observed at different time points (15 min, 30 min, 45 min, and 60 min) to determine the optimal extraction time for the enzymatic digestion method. After comparing the two enzymatic methods, it was determined that the trypsin + collagenase II enzymatic method was more effective. The primary renal tubular epithelial cells extracted by the trypsin + collagenase II digestion method were identified by the marker Cytokeratin 18 of renal tubular epithelial cells at 45 min of digestion with high purity. We established a simple, efficient, and reproducible method for isolation and culture of renal tubular epithelial cells in SD mammary gland rats.

Mesenchymal stem cells overexpressing XIST induce macrophage M2 polarization and improve neural stem cell homeostatic microenvironment, alleviating spinal cord injury.

Spinal cord injury (SCI) is a significant cause of disability worldwide, with limited treatment options. This study investigated the potential of bone marrow-derived mesenchymal stem cells (BMSCs) modified with XIST lentiviral vector to modulate macrophage polarization and affect neural stem cell (NSC) microenvironment reconstruction following SCI. Bioinformatics analysis revealed that MID1 might be crucial for BMSCs' treatment of SCI. XIST overexpression enriched Zmynd8 to the promoter region of MID1 and inhibited MID1 transcription, which promoted macrophage M2 polarization. In vitro experiments showed that BMSCs-XIST promoted NSC proliferation, migration, differentiation, and axonal growth by inducing macrophage M2 polarization, suppressing inflammation, and accelerating the re-establishment of the homeostatic microenvironment of NSCs. In vivo, animal experiments confirmed that BMSCs-XIST significantly alleviated SCI by promoting NSC differentiation and axon formation in the injured area. The study demonstrated the potential of XIST-overexpressing BMSCs for treating SCI by regulating macrophage polarization and homeostasis of the NSC microenvironment. These findings provide new insights into the development of stem cell-based therapies for SCI.

A Comprehensive Analysis of the Prognostic, Immunological and Diagnostic Role of CCNF in Pan-cancer.

Background: Cyclin F (CCNF) represents a pivotal constituent within the family of cell cycle proteins, which also belongs to the F-box protein family and acts as a critical regulatory factor in cell cycle transition. Its heightened expression has been consistently identified across various cancer types, including breast, pancreatic, and colorectal cancer. Nonetheless, a comprehensive exploration of CCNF's involvement in pan-cancer remains lacking. Methods: This study collected transcriptomic data and clinical information from several databases, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and BioGPS detabase. Employing bioinformatics methods, we investigated the potential oncogenic role of CCNF, utilizing various databases such as cBioPortal, Human Protein Atlas (HPA), TIMER2, UALCAN, GEPIA, GSCALite, and CTD detabase. These analyses focused on exploring CCNF expression, prognosis, gene mutations, immune cell infiltration, DNA methylation levels, and targeted chemical drugs across different tumor types. Additionally, we obtained CCNF-related genes from GeneMANIA and GEPIA databases and conducted GO and KEGG enrichment analyses to gain deeper insights into the biological processes associated with CCNF. Furthermore, we validated the differential expression of CCNF in normal human breast cancer and breast cancer cell lines using experimental verification. Results: CCNF exhibited upregulation in the majority of cancer types, demonstrating early diagnostic potential in 15 cancers and prognostic implications for adverse outcomes across numerous malignancies. Furthermore, CCNF was found to be linked with markers of the tumor immune microenvironment in various cancers. Additionally, CCNF expression influenced genetic alterations in pan-cancer. Enrichment analysis revealed that CCNF primarily participates in crucial biological pathways such as the cell cycle, p53 signaling pathway, and cellular senescence pathways. RT-qpcr and WB assays further confirmed that CCNF expression was higher in human cancer cell lines than in normal cell lines. Conclusion: The underlying role and mechanism of CCNF in pan-cancer were elucidated through comprehensive bioinformatics analysis and experimental validation. CCNF holds promise as an invaluable early detection indicator and tumor biomarker, offering potential targets for tumor treatment and prevention.

Role of transcription factor FOXM1 in diabetes and its complications (Review).

Diabetes mellitus is a chronic metabolic disease commonly associated with complications such as cardiovascular disease, nephropathy and neuropathy, the incidence of which is increasing yearly. Transcription factor forkhead box M1 (FOXM1) serves an important role in development of diabetes and its complications. The present study aimed to review the association between FOXM1 with pathogenesis of diabetes and its complications. FOXM1 may be involved in development and progression of diabetes and its complications by regulating cell biological processes such as cell cycle, DNA damage repair, cell differentiation and epithelial­mesenchymal transition. FOXM1 is involved in regulation of insulin secretion and insulin resistance, and FOXM1 affects insulin secretion by regulating expression of insulin­related genes and signaling pathways; FOXM1 is involved in the inflammatory response in diabetes, and FOXM1 can regulate key genes associated with inflammatory response and immune cells, which in turn affects occurrence and development of the inflammatory response; finally, FOXM1 is involved in the regulation of diabetic complications such as cardiovascular disease, nephropathy and neuropathy. In summary, the transcription factor FOXM1 serves an important role in development of diabetes and its complications. Future studies should explore the mechanism of FOXM1 in diabetes and find new targets of FOXM1 as a potential treatment for diabetes and its complications.

Dapagliflozin alleviates renal podocyte pyroptosis via regulation of the HO­1/NLRP3 axis.

Diabetic nephropathy is one of the most significant complications of diabetes, resulting in increased patient mortality. Dapagliflozin is an inhibitor of sodium­glucose cotransporter 2 that has an important protective effect on the kidney. Recent studies showed that pyroptosis is involved in the advancement of diabetic nephropathy (DN). However, the potential molecular mechanisms underlying the association between pyroptosis and renal podocyte injury in DN remain unclear. Thus, the present study investigated the anti­pyroptotic function of dapagliflozin in podocytes and further clarified the potential mechanisms. In this study, a model of lipid metabolism disturbance was established through palmitic acid (PA) induction in a mouse podocyte clone 5 (MPC5) cell line. MPC5 PA­induced pyroptosis was measured by ELISA, western blotting, quantitative PCR and Hoechst 33342/propidium iodide double­fluorescence staining. The protective role of HO­1 was measured using knockdown and overexpression experiments. It was found that dapagliflozin attenuated the expression of pyroptosis­related proteins, including nucleotide oligomerization domain­like receptor thermal protein domain associated protein 3, apoptosis­associated speck­like protein containing a caspase activation and recruitment domain, caspase­1, IL­18 and IL­1ß in the PA group. Meanwhile, the heme oxygenase 1 (HO­1) expression level decreased within PA, an effect that was reversed by dapagliflozin. Furthermore, the expression of pyroptosis­related proteins and inflammatory cytokines was reduced following HO­1 overexpression. Therefore, these results suggested that dapagliflozin ameliorates MPC5 pyroptosis by mediating HO­1, which has a protective effect on diabetic nephropathy.

Pan-cancer analysis: SPAG5 is an immunological and prognostic biomarker for multiple cancers.

Sperm-associated antigen 5 (SPAG5) is a mitotic spindle protein that regulates the separation of sister chromatids into daughter cells. Recent studies have discovered its overexpression in various cancers, suggesting its oncogenic characteristics and functions. However, a comprehensive analysis of SPAG5 regarding its diagnostic, prognostic, and immune-related effects across different cancer types is lacking. In this study, we employed bioinformatics methods and integrated multiple public databases to explore the potential oncogenic role of SPAG5. We analyzed its expression, prognosis, related chemicals, enriched pathways, immune infiltration, and its impact on different tumor genetic alterations. The results revealed that SPAG5 is highly expressed in most cancers and significantly correlates with poor patient prognosis. Additionally, SPAG5 expression showed potential for early cancer diagnosis in 15 different cancer types. In terms of tumor immunity, high expression of SPAG5 was associated with an immunosuppressive tumor microenvironment and immune therapy efficacy indicators. SPAG5 expression exhibited a negative correlation with most immune cell infiltrates but demonstrated a significant positive correlation with Th2 cells and MDSC cells. Multicolor fluorescence immunohistochemistry demonstrated that SPAG5 activates immune cell populations within tumors, indicating its significant role in the tumor microenvironment. Enrichment analysis indicated that SPAG5-related genes are mainly involved in cell cycle, cellular senescence, P53 signaling pathway, and FoxO signaling pathway. Furthermore, we confirmed the high expression of SPAG5 in cancer cells and observed that its knockdown upregulated the expression of the p53 protein. In conclusion, SPAG5 holds value as a diagnostic, prognostic, and immune biomarker in various cancers and may provide a novel target for tumor immunotherapy.

The development of an anti-cancer peptide M1-21 targeting transcription factor FOXM1.

BACKGROUND: Transcription factor FOXM1 is a potential target for anti-cancer drug development. An interfering peptide M1-21, targeting FOXM1 and FOXM1-interacting proteins, is developed and its anti-cancer efficacy is evaluated. METHODS: FOXM1 C-terminus-binding peptides are screened by in silico protocols from the peptide library of FOXM1 (1-138aa) and confirmed by cellular experiments. The selected peptide is synthesized into its D-retro-inverso (DRI) form by fusing a TAT cell-penetrating sequence. Anti-cancer activities are evaluated in vitro and in vivo with tumor-grafted nude mice, spontaneous breast cancer mice, and wild-type metastasis-tracing mice. Anti-cancer mechanisms are analyzed. Distribution and safety profiles in mice are evaluated. RESULTS: With improved stability and cell inhibitory activity compared to the parent peptide, M1-21 binds to multiple regions of FOXM1 and interferes with protein-protein interactions between FOXM1 and its various known partner proteins, including PLK1, LIN9 and B-MYB of the MuvB complex, and ß-catenin. Consequently, M1-21 inhibits FOXM1-related transcriptional activities and FOXM1-mediated nuclear importation of ß-catenin and ß-catenin transcriptional activities. M1-21 inhibits multiple types of cancer (20 µM in vitro or 30 mg/kg in vivo) by preventing proliferation, migration, and WNT signaling. Distribution and safety profiles of M1-21 are favorable (broad distribution and > 15 h stability in mice) and the tested non-severely toxic dose reaches 200 mg/kg in mice. M1-21 also has low hemolytic toxicity and immunogenicity in mice. CONCLUSIONS: M1-21 is a promising interfering peptide targeting FOXM1 for the development of anti-cancer drugs.

Development of a method to diagnose endometrial cancer based on the AuNRs-AntiVimentin optical probe.

Endometrial cancer is one of the common gynecological malignancies, and its incidence has been increasing year by year in recent years, raising higher requirements for its rapid diagnosis. In this article, gold nanorods (AuNRs) with localized surface plasmon resonance properties (LSPR) has used to prepare AuNRs-antibody to waveform protein (AuNRs-AntiVimentin) optical probes, and a new method has been constructed that could rapidly detect and identify endometrial cancer tissue sections by polarized light microscopy. AuNRs were prepared by seed growth method using gold chloride as raw material, and the morphology of AuNRs and the optical characteristics of AuNRs-AntiVimentin has characterized by transmission electron microscopy (TEM), ultraviolet-visible spectroscopy (UV-Vis), and zeta potential; immunohistochemistry (IHC) and AuNRs-AntiVimentin optical probes have used to detect clinical endometrial cancer, respectively. The AuNRs-AntiVimentin optical probe has been used to detect endometrial cancer tissue sections and found to have good bio-specificity, with no significant difference in the detection of AuNRs-AntiVimentin compared with conventional IHC techniques (p > .05). An optical probe generated by coupling AuNRs with Vimentin antibodies has been obtained to detect and identify endometrial cancer with simple operation and comparable effect to conventional IHC, providing a new method and idea for the rapid detection of endometrial cancer.

FOXM1: Functional Roles of FOXM1 in Non-Malignant Diseases.

Forkhead box (FOX) proteins are a wing-like helix family of transcription factors in the DNA-binding region. By mediating the activation and inhibition of transcription and interactions with all kinds of transcriptional co-regulators (MuvB complexes, STAT3, ß-catenin, etc.), they play significant roles in carbohydrate and fat metabolism, biological aging and immune regulation, development, and diseases in mammals. Recent studies have focused on translating these essential findings into clinical applications in order to improve quality of life, investigating areas such as diabetes, inflammation, and pulmonary fibrosis, and increase human lifespan. Early studies have shown that forkhead box M1 (FOXM1) functions as a key gene in pathological processes in multiple diseases by regulating genes related to proliferation, the cell cycle, migration, and apoptosis and genes related to diagnosis, therapy, and injury repair. Although FOXM1 has long been studied in relation to human diseases, its role needs to be elaborated on. FOXM1 expression is involved in the development or repair of multiple diseases, including pulmonary fibrosis, pneumonia, diabetes, liver injury repair, adrenal lesions, vascular diseases, brain diseases, arthritis, myasthenia gravis, and psoriasis. The complex mechanisms involve multiple signaling pathways, such as WNT/ß-catenin, STAT3/FOXM1/GLUT1, c-Myc/FOXM1, FOXM1/SIRT4/NF-κB, and FOXM1/SEMA3C/NRP2/Hedgehog. This paper reviews the key roles and functions of FOXM1 in kidney, vascular, lung, brain, bone, heart, skin, and blood vessel diseases to elucidate the role of FOXM1 in the development and progression of human non-malignant diseases and makes suggestions for further research.

USP39 facilitates breast cancer cell proliferation through stabilization of FOXM1.

Deubiquitinating enzyme dysregulation has been linked to the development of a variety of human malignancies, including breast cancer. However, the exact involvement of the deubiquitinating enzyme USP39 in the progression of breast cancer is yet unknown. Cell viability and colony formation analysis was used to assess the effects of USP39 knockdown on breast cancer cells in this study. The interaction between USP39 and FOXM1 was investigated using co-immunoprecipitation (co-IP) and in vitro deubiquitination analysis. The expression of USP39 and FOXM1 in breast cancer tissues was studied using the TCGA database. According to our findings, USP39 deubiquitinates and stabilizes FOXM1, promoting breast cancer cell proliferation, colony formation, and tumor growth in vivo. Furthermore, elevated USP39 expression lowers FOXM1 ubiquitination, resulting in increased transcriptional activity. In addition, the high expression of USP39 reduces the ubiquitination of FOXM1, thereby enhancing the transcriptional activity of FOXM1 and regulating the expression of downstream genes Cdc25b and Plk1. USP39 is positively correlated with the expression level of FOXM1 in breast cancer cells. In general, our research revealed the USP39-FOXM1 axis as a critical driver of breast cancer cell proliferation and provided a theoretical foundation for targeting the USP39-FOXM1 axis for pancreatic cancer treatment.

Mechanistic insights into the amelioration effects of lipopolysaccharide-induced acute lung injury by baicalein: An integrated systems pharmacology study and experimental validation.

BACKGROUND: Acute lung injury is an acute progressive respiratory failure caused by several of non-cardiogenic factors which involves in excessive amplification or uncontrolled inflammatory response. OBJECTIVES: In this study, we investigated the protective effect of baicalein against acute lung injury induced by LPS and explored the underlying mechanisms. METHODS: Forty-eight SPF male C57BL/6 mice were randomly divided into normal group, model group, dexamethasone group and baicalein low-dose, medium-dose and high-dose groups. After 5 days of adaptive feeding, the mice were intraperitoneally injected with LPS and dissected after 12 h. Hematoxylin-eosin staining, ELISA assay, immunofluorescence assay and Western-Blot were applied to appraise microstructural changes and protein expressions of lung tissues. Systems pharmacology study was used to evaluate the protection of baicalein on acute lung injury. FINDINGS: The results showed that baicalein administration could significantly inhibit LPS-induced lung morphological changes, inhibit inflammatory response and pyroptosis. A total of forty-three potential targets of baicalein and acute lung injury were obtained. And PI3K-Akt, TNF and NF-κB were mainly signaling pathways. It is worth mentioning that this experiment also confirmed that NLRP3, caspase-1 and other inflammasome are involved in pyroptosis. CONCLUSION: Baicalein has protected against LPS-induced lung tissues injury via inhibiting inflammatory response and pyroptosis.

Aqueous Organic Zinc-Ion Hybrid Supercapacitors Prepared by 3D Vertically Aligned Graphene-Polydopamine Composite Electrode.

A three-dimensional vertical-aligned graphene-polydopamine electrode (PDA@3DVAG) composite with vertical channels and conductive network is prepared by a method of unidirectional freezing and subsequent self-polymerization. When the prepared PDA@3DVAG is constructed as the positive electrode of zinc-ion hybrid supercapacitors (ZHSCs), excellent electrochemical performances are obtained. Compared with the conventional electrolyte, PDA@3DVAG composite electrode in highly concentrated salt electrolyte exhibits better multiplicity performance (48.92% at a current density of 3 A g-1), wider voltage window (-0.8~0.8 V), better cycle performance with specific capacitance from 96.7 to 59.8 F g-1, and higher energy density (46.14 Wh kg-1).

Preparation and Electrochemical Performance of Three-Dimensional Vertically Aligned Graphene by Unidirectional Freezing Method.

Three-dimensional vertically aligned graphene (3DVAG) was prepared by a unidirectional freezing method, and its electrochemical performances were evaluated as electrode materials for zinc-ion hybrid supercapacitors (ZHSCs). The prepared 3DVAG has a vertically ordered channel structure with a diameter of about 20-30 µm and a length stretching about hundreds of microns. Compared with the random structure of reduced graphene oxide (3DrGO), the vertical structure of 3DVAG in a three-electrode system showed higher specific capacitance, faster ion diffusion, and better rate performance. The specific capacitance of 3DVAG reached 66.6 F·g-1 and the rate performance reached 92.2%. The constructed 3DVAG zinc-ion hybrid supercapacitor also showed excellent electrochemical performance. It showed good capacitance retention up to 94.6% after 3000 cycles at the current density of 2 A·g-1.

The snogI Gene is Necessary for the Proper Functioning of the Nogalamycin Biosynthesis Pathway.

Anthracycline drugs have multifunctional molecular structures, and small changes in the structure of the glycosyls around the chromophore affect their mechanism of action, pharmacokinetics, toxicity, anti-tumor activity, and many other significant parameters. DnrJ has a similar function to snogI but inverse stereoselectivity. SnogI encoding amino transferase was substituted for DnrJ for the purpose of obtaining nogalamycin analogues. We inactivated the snogI gene encoding an aminotransferase responsible for the formation of nogalamine and introduced the dnrJ gene encoding an aminotransferase responsible for the formation of daunosamine. We obtained the recombinant strain mLMX-3-100, in which the production of nogalamycin was disrupted. Interestingly, contrary to our predictions, no epi-nogalamycin was produced; nevertheless, the present study shows that the snogI gene is necessary for the proper functioning of the nogalamycin biosynthesis pathway. These data may provide a reference for further illustration of nogalamycin biosynthesis and its modification by way of combinatorial biosynthesis.biosynthesis and its modification by way of combinatorial biosynthesis.

Correction to: The snogI Gene is Necessary for the Proper Functioning of the Nogalamycin Biosynthesis Pathway.

[This corrects the article DOI: 10.1007/s12088-021-00941-7.].

The cell-penetrating FOXM1 N-terminus (M1-138) demonstrates potent inhibitory effects on cancer cells by targeting FOXM1 and FOXM1-interacting factor SMAD3.

Transcription factor FOXM1 is involved in stimulating cell proliferation, enhancing DNA damage repair, promoting metastasis of cancer cells, and the inhibition of FOXM1 has been shown to prevent the initiation and progression of multiple cancers and FOXM1 is considered to be an effective target for tumor therapeutic drug development. The N-terminus of FOXM1 has been found to prevent transcriptional activities of FOXM1 and to mediate the interaction between FOXM1 and SMAD3. METHODS: A recombinant FOXM1 N-terminal domain (1-138aa) fused with a nine arginine cell-penetrating peptide is produced with an E. coli expression system and named as M1-138. The effects of M1-138 on the proliferation, migration, and tumorigenic ability of cancer cells are analyzed in vitro with cell counting, transwell assays, and colony formation assays. Electrophoretic mobility shift assays (EMSAs) and Luciferase activity assays are used to test the DNA binding ability and transcriptional activity of transcription factors. The levels of mRNAs and proteins are measured by quantitative-PCR, Western blotting or Immunohistochemistry. The interactions among proteins are analyzed with Pull-down and Co-immunoprecipitation (Co-IP) assays. The nude mouse engrafted tumor models are used to test the inhibitory effects of M1-138 in vivo. RESULTS: M1-138 diminishes the proliferation and migration abilities of cancer cells through binding to FOXM1 and FOXM1-interacting factor SMAD3, and consequently attenuating FOXM1 transcriptional activities from both direct and indirect FOXM1-promoter binding mechanisms and interfering with the interaction between FOXM1 and SMAD3. Treatment of M1-138 prevents tumorigenicity of cancer cells and inhibits tumor growth in nude mouse xenograft models with no obvious signs of toxicity. CONCLUSION: M1-138 is a promising drug candidate for the development of anti-cancer therapeutics targeting FOXM1 and SMAD3.

Contralateral ureteral metastasis 4 years after radical nephrectomy.

INTRODUCTION: Metastasis of renal cell carcinoma to the contralateral ureter is extremely rare. To date, only 50 cases of metastatic RCC to the ureter have been reported, among whom 6 cases occur at the contralateral site. We herein report a rare case of metastatic RCC in the contralateral ureter 4 years after radical nephrectomy. PRESENTATION OF CASE: A 74-year-old man presented with gross, painless hematuria for one month. Computed tomography scan confirmed that a 1.5 cm × 0.5 cm tumor occurred in the contralateral distal ureter. A 3.5 cm segment of ureter was resected and a uretero-vesical anastomosis with psoas hitch was accomplished. DISCUSSION: The reappearance of hematuria after radical nephrectomy is the most common manifestation of the metastasis to the bladder or ureter. The mechanism of metastasis is not clear. In pathology, vimentin and cytokeratins might help to differentiate between metastatic clear cell renal cell carcinoma and clear cell transitional cell carcinoma. CONCLUSION: Metastasis of renal cell carcinoma to the contralateral ureter is rare. Early recognition is extremely important in protecting the remaining renal function and prolonging life-expectancy for post-nephrectomy patients. Complete metastectomy suitable anastomosis have been shown to improve survival.