Translational research : the journal of laboratory and clinical medicine
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Multicenter Study
Expression and function of α4β7 integrin predict the success of vedolizumab treatment in inflammatory bowel disease.
Inflammatory bowel diseases are medically intractable and require constant therapy in many cases. While a growing number of biologicals and small molecules is available for treatment, a substantial portion of patients experiences primary non-response to these compounds and head-to-head evidence for therapy selection is scarce. Thus, approaches to predict treatment success in individual patients are a huge unmet need. ⋯ Moreover, high dynamic adhesion of CD4+ T cells to MAdCAM-1 and high reduction of adhesion by vedolizumab in vitro at baseline were associated with clinical remission. These data substantiate the potential of α4β7 integrin function and expression to forecast outcomes of vedolizumab therapy. Further translational efforts are necessary to improve the performance of the assays and to implement the concept in clinical practice.
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Long-read sequencing reveals oncogenic mechanism of HPV-human fusion transcripts in cervical cancer.
Integration of high-risk human papillomavirus (HPV) into the host genome is a crucial event for the development of cervical cancer, however, the underlying mechanism of HPV integration-driven carcinogenesis remains unknown. Here, we performed long-read RNA sequencing on 12 high-grade squamous intraepithelial lesions (HSIL) and cervical cancer patients, including 3 pairs of cervical cancer and corresponding para-cancerous tissue samples to investigate the full-length landscape of cross-species genome integrations. In addition to massive unannotated isoforms, transcriptional regulatory events, and gene chimerism, more importantly, we found that HPV-human fusion events were prevalent in HPV-associated cervical cancers. ⋯ Highly expressed HPV-human fusion transcripts, eg, HPV16 E6*I-E7-E1SD880-human gene, were the key driver of cervical carcinogenesis, which could trigger overexpression of E6*I and E7, and destroy the transcription of tumor suppressor genes CMAHP, TP63 and P3H2. Finally, evidence from in vitro and in vivo experiments demonstrates that the novel read-through fusion gene mRNA, E1-CMAHP (E1C, formed by the integration of HPV58 E1 with CMAHP), existed in the fusion transcript can promote malignant transformation of cervical epithelial cells via regulating downstream oncogenes to participate in various biological processes. Taken together, we reveal a previously unknown mechanism of HPV integration-driven carcinogenesis and provide a novel target for the diagnosis and treatment of cervical cancer.
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Human body fluids have become an indispensable resource for clinical research, diagnosis and prognosis. Urine is widely used to discover disease-specific glycoprotein biomarkers because of its recurrently non-invasive collection and disease-indicating properties. While urine is an unstable fluid in that its composition changes with ingested nutrients and further as it is excreted through micturition, urinary proteins are more stable and their abnormal glycosylation is associated with diseases. ⋯ In this article, we evaluate the clinical applications of urine, introduce methods for urine glycosylation analysis, and discuss urine glycoprotein biomarkers. We emphasize the importance of mining urinary glycoproteins and searching for disease-specific glycosylation in various diseases (including cancer, neurodegenerative diseases, diabetes, and viral infections). With advances in mass spectrometry-based glycomics/glycoproteomics/glycopeptidomics, characterization of disease-specific glycosylation will optimistically lead to the discovery of disease-related urinary biomarkers with better sensitivity and specificity in the near future.
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Prostate cancer (PCa) is one of the leading causes of cancer-related deaths among men. Consequently, the identification of novel molecular targets for treatment is urgently needed to improve patients' outcomes. Our group recently reported that some elements of the cellular machinery controlling alternative-splicing might be useful as potential novel therapeutic tools against advanced PCa. ⋯ Notably, RBM22 overexpression decreased aggressiveness features in vitro, and in vivo. These actions were associated with the splicing dysregulation of numerous genes and to the downregulation of critical upstream regulators of cell-cycle (i.e., CDK1/CCND1/EPAS1). Altogether, our data demonstrate that RBM22 plays a critical pathophysiological role in PCa and invites to suggest that targeting negative regulators of RBM22 expression/activity could represent a novel therapeutic strategy to tackle this disease.
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The third leading cause of cancer-related deaths in the United States is pancreatic cancer, more than 95% of which is pancreatic ductal adenocarcinoma (PDA). The incidence rate of PDA nearly matches its mortality rate and the best treatment till date is surgical resection for which only 25% are eligible. Tumor recurrence and metastasis are the main causes of cancer-related mortality. ⋯ This reduction in oncogenic signaling triggered anoikis as indicated by reduced expression of antiapoptotic proteins, PTRH2 and BCL2. TAB004 treatment slowed the growth of PDA xenograft compared to IgG control and enhanced survival of mice when combined with 5-FU. Since TAB004 significantly reduced colony forming potential and triggered anoikis in the PDA cells, we suggest that it could be used as a potential prophylactic agent to curb tumor relapse after surgery, prevent metastasis and help increase the efficacy of chemotherapeutic agents.