SRY-Box transcription factor 9 triggers YAP nuclear entry via direct interaction in tumors.

The translocation of YAP from the cytoplasm to the nucleus is critical for its activation and plays a key role in tumor progression. However, the precise molecular mechanisms governing the nuclear import of YAP are not fully understood. In this study, we have uncovered a crucial role of SOX9 in the activation of YAP. SOX9 promotes the nuclear translocation of YAP by direct interaction. Importantly, we have identified that the binding between Asp-125 of SOX9 and Arg-124 of YAP is essential for SOX9-YAP interaction and subsequent nuclear entry of YAP. Additionally, we have discovered a novel asymmetrical dimethylation of YAP at Arg-124 (YAP-R124me2a) catalyzed by PRMT1. YAP-R124me2a enhances the interaction between YAP and SOX9 and is associated with poor prognosis in multiple cancers. Furthermore, we disrupted the interaction between SOX9 and YAP using a competitive peptide, S-A1, which mimics an α-helix of SOX9 containing Asp-125. S-A1 significantly inhibits YAP nuclear translocation and effectively suppresses tumor growth. This study provides the first evidence of SOX9 as a pivotal regulator driving YAP nuclear translocation and presents a potential therapeutic strategy for YAP-driven human cancers by targeting SOX9-YAP interaction.

Rifaximin treatment shapes a unique metagenome-metabolism network in patients with decompensated cirrhosis.

BACKGROUND: Patients with decompensated cirrhosis face poor prognosis and increased mortality risk. Rifaximin, a non-absorbable antibiotic, has been shown to have beneficial effects in preventing complications and improving survival in these patients. However, the underlying mechanisms of rifaximin's effects remain unclear. METHODS: We obtained fecal samples from decompensated cirrhotic patients undergoing rifaximin treatment and controls, both at baseline and after 6 months of treatment. Shotgun metagenome sequencing profiled the gut microbiome, and untargeted metabolomics analyzed fecal metabolites. Linear discriminant and partial least squares discrimination analyses were used to identify differing species and metabolites between rifaximin-treated patients and controls. RESULTS: Forty-two patients were enrolled and divided into two groups (26 patients in the rifaximin group and 16 patients in the control group). The gut microbiome's beta diversity changed in the rifaximin group but remained unaffected in the control group. We observed 44 species with reduced abundance in the rifaximin group, including Streptococcus_salivarius, Streptococcus_vestibularis, Haemophilus_parainfluenzae, etc. compared to only four in the control group. Additionally, six species were enriched in the rifaximin group, including Eubacterium_sp._CAG:248, Prevotella_sp._CAG:604, etc., and 14 in the control group. Furthermore, rifaximin modulated different microbial functions compared to the control. Seventeen microbiome-related metabolites were altered due to rifaximin, while six were altered in the control group. CONCLUSION: Our study revealed distinct microbiome-metabolite networks regulated by rifaximin intervention in patients with decompensated cirrhosis. These findings suggest that targeting these specific metabolites or related bacteria might be a potential therapeutic strategy for decompensated cirrhosis.

Metformin abrogates Fusobacterium nucleatum-induced chemoresistance in colorectal cancer by inhibiting miR-361-5p/sonic hedgehog signaling-regulated stemness.

BACKGROUND: Chemotherapy resistance is the major cause of recurrence in patients with colorectal cancer (CRC). A previous study found that Fusobacterium (F.) nucleatum promoted CRC chemoresistance. Additionally, metformin rescued F. nucleatum-induced tumorigenicity of CRC. Here, we aimed to investigate whether metformin could revert F. nucleatum-induced chemoresistance and explore the mechanism. METHODS: The role of metformin in F. nucleatum-infected CRC cells was confirmed using cell counting kit 8 assays and CRC xenograft mice. Stemness was identified by tumorsphere formation. Bioinformatic analyses were used to explore the regulatory molecules involved in metformin and F. nucleatum-mediated regulation of the sonic hedgehog pathway. RESULTS: We found that metformin abrogated F. nucleatum-promoted CRC resistance to chemotherapy. Furthermore, metformin attenuated F. nucleatum-stimulated stemness by inhibiting sonic hedgehog signaling. Mechanistically, metformin diminished sonic hedgehog signaling proteins by targeting the MYC/miR-361-5p cascade to reverse F. nucleatum-induced stemness, thereby rescuing F. nucleatum-triggered chemoresistance in CRC. CONCLUSIONS: Metformin acts on F. nucleatum-infected CRC via the MYC/miR-361-5p/sonic hedgehog pathway cascade, subsequently reversing stemness and abolishing F. nucleatum-triggered chemoresistance. Our results identified metformin intervention as a potential clinical treatment for patients with chemoresistant CRC with high amounts of F. nucleatum.

Fusobacterium nucleatum exacerbates colitis by damaging epithelial barriers and inducing aberrant inflammation.

OBJECTIVE: Fusobacterium nucleatum (F. nucleatum) has been reported to be enriched in patients with inflammatory bowel disease (IBD). This study aimed to explore the role of F. nucleatum in IBD and its pathogenic mechanism. METHODS: Several bacteria that have been reported to be associated with IBD or colorectal cancer were measured in the fecal samples of 91 patients with IBD and 43 healthy individuals. Mice with dextran sulfate sodium (DSS)-induced colitis and a Caco-2 cell line were used to explore the pathogenicity of F. nucleatum. Barrier damage was evaluated by a transmission electron microscope, the permeability of fluorescein isothiocyanate-dextran, transepithelial electrical resistance and immunofluorescence. Protein levels of the cell-cell junction and activation of the STAT3 signaling pathway were detected by immunohistochemistry and immunoblot. Cytokine secretion and T-cell differentiation were measured by quantitative real-time polymerase chain reaction and flow cytometry. RESULTS: F. nucleatum was significantly enriched in the feces of patients with IBD and its abundance correlated with disease activity. Administration of F. nucleatum markedly exacerbated colitis in a DSS mouse model. Mechanistically, F. nucleatum damaged epithelial integrity and increased permeability by regulating the expression and distribution of tight junction proteins zonula occludens-1 and occludin. Moreover, F. nucleatum promoted the secretion of cytokines (tumor necrosis factor-α, interferon-γ, interleukin [IL]-1ß, IL-6, and IL-17), activated the STAT3 signaling pathway, and induced CD4+ T cell proliferation and Th1 and Th17 subset differentiations. CONCLUSION: F. nucleatum can damage the intestinal barrier and induce aberrant inflammation, which exacerbates colitis.

Comparative Study of Transrectal Real-time Tissue Elastography and Magnetic Resonance Diffusion-Weighted Imaging in the Diagnosis and Guided Biopsy of Prostate Cancer / 中山大学学报(医学科学版)

@#【Objectives】 To comparatively analyze the diagnostic performance of transrectal real- time elastography（TRTE）and magnetic resonance diffusion- weighted imaging （DWI）in differentiating benign from malignant prostatic lesions，to evaluate the value of the two methods in guided prostate biopsy，and to investigate the correlation between the two methods and Gleason scores. 【Methods】 A total of 126 patients with suspected prostate cancer underwent prostate biopsy. Preoperative tests of TRTE and DWI were performed in all of the included patients. Combined with pathological results，the diagnostic efficacy of TRTE and DWI for prostate cancer and the effects of prostate biopsy guided by the two methods were compared ，and the relationship between the elastography score and ADC value and Gleason scores were also evaluated.【Results】 The sensitivity，specificity，accuracy of diagnosing prostate cancer by TRTE were 78.8% ，78.3% ，78.6% ，the sensitivity，specificity，accuracy of diagnosing prostate cancer by DWI were 87.9% ，90% ，88.9% ， there was no significant difference of sensitivity and specificity between the two groups（P > 0.05），and the accuracy was statistically different（P < 0.05）. The AUC of elastography score and ADC value were 0.859 and 0.906，the accuracy of the diagnosis of benign and malignant prostate lesions by ADC value method was higher than elastography score ，but there was no statistically significant difference （P > 0.05）. A significant positive correlation was found between elastography score and Gleason scores，while a significant negative correlation was found between ADC value and Gleason scores.【Conclusions】TRTE and DWI is valuable in diagnosis of prostatic lesions. Biopsy guided by the two methods can improve the detection rate of prostate cancer and can provide indicative evidence for tumor differentiation analysis.

Epidemiological study of human caliciviruses among children with acute diarrhea in Lulong county, 1999 - 2001 / 中华流行病学杂志

<p><b>OBJECTIVE</b>To investigate the epidemiological characteristus of human caliciviruses (HuCVs) among children under 5 years of age with acute diarrhea and to estimate the disease burden in Lulong county.</p><p><b>METHODS</b>HuCVs were detected by enzyme linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR). Some PCR amplicons were cloned and sequenced. Phylogenetic tree was constructed for strain characterization. The rate of HuCVs-attributed hospitalization was estimated according to the positive rate of HuCVs detection in fecal specimens collected from hospitalized diarrhea patients.</p><p><b>RESULTS</b>Between July 1999 and June 2001, 708 fecal specimens were collected, of which 393 rotavirus-negative and 5 rotavirus-positive specimens were detected for HuCVs. Thirty-one point six percentage of fecal specimens from patients with diarrhea was HuCVs positive. Among inpatients, HuCVs positive rate was 17.5%. HuCVs detection was mainly distributed in 3 - 17 mouth-old children, in winter. All 11 strains belonged to NLV GII in which 6 strains GII-3, 2 strains GII-4 and 3 strains GII-7, and they shared 55.1% - 100% nucleotide identity. NLV GII-4 and GII-7 were identified in 2000, while NLV GII-3 and GII-7 in 2001. The preliminary estimate of HuCVs-attributed hospitalization rate was 3.6 per thousand.</p><p><b>CONCLUSION</b>Human caliciviruses with different genotypes circulated among children in Lulong county with GII NLVs were the prevalent strains. The disease burden of HuCVs was second to rotavirus.</p>