Project description:Recent evidence suggests that the descending modulatory pathways from the brainstem rostral ventromedial medulla (RVM) are important for bladder inflammatory pain. This study aimed to identify the long-term molecular changes in RVM neurons due to early life cystitis during neuronal development and the effect of reexposure later in adulthood. RVM tissues from two treatment protocols were used: (1) neonatal zymosan exposures with acute adult rechallenge (RC) and (2) only neonatal zymosan exposures (NRC). RNAseq analysis showed upregulation of several genes associated with synaptic plasticity (Grin1, Grip2, Notch1, Arc, and Scn2b) in the cystitis groups compared to controls in both protocols. The RC protocol exhibited a stronger treatment effect with significantly higher fold differences between the groups compared to the NRC protocol (p<0.001, fold differences RC vs NRC). In microarrays, miR-34a-5p showed cystitis-induced downregulation in both protocols. Bioinformatics analysis identified multiple 3’UTRs complementary binding sites for miR-34a-5p on Grin2b, Notch1, Grip2, Scn2b, and Arc genes. The enhanced response in the RC protocol indicates a possible priming effect of early life cystitis on rechallenge in adulthood. These long-term molecular alterations may play a critical role in the development of chronic bladder pain conditions as seen in patients with Interstitial Cystitis/Bladder pain syndrome
Project description:Cystitis is a bacterial infection of the bladder that occurs in about half of women at least once in their lifetime. Antibiotics such as nitrofurantoin are used to treat cystitis but antibiotic resistance is a concern, especially for recurrent infections. Here we report an open label, randomized, single-center, phase 2 study to analyze the acute and long-term safety and efficacy of the IL-1 receptor antagonist anakinra, compared to nitrofurantoin, in recurrent cystitis. Thirty adult female patients with a documented history of recurrent cystitis and a current acute cystitis episode were randomized in a 2:1 ratio to treatment with anakinra (n=20) or nitrofurantoin (n=10) for five days. Primary and secondary efficacy end points were reached, defined as the reduction in typical symptoms, measured by the acute cystitis symptom score (ACSS, day 5), longitudinal symptom scores, recurrence rates, quality of life gene, expression analysis and microbiology at follow-up on days 15, 30 and at six months. Symptom scores were decreased in the anakinra (P<0.001), and nitrofurantoin (P<0.001) arms after five days and remained low after 15, 30 days and 6 months. Recurrences were less frequent after 6 months in both treatment groups compared to the 6-month pre-enrolment history (P<0.001 for anakinra and P=0.004 for nitrofurantoin) and the quality of life was increased, without adverse effects. Immune gene expression was rapidly inhibited in the anakinra treated patients but not in the nitrofurantoin group. Targeted innate immune inhibition therapy shows non-inferiority to nitrofurantoin in patients with recurrent acute cystitis (German Clinical Trials Register, DRKS00025964; EudraCT, 2019-004209-28).
Project description:We compared the chnages in urinary bladder and iliac lymph nodes microRNAs in the control and experimental autoimmune cystitis in mice. A set of urinary bladder microRNAs (miRNAs) shows profound upregulation or downregulation in the expression profiles of the experimental IC as compared to control.
Project description:Melanoma accounts for the majority of all skin cancer-related deaths and only 1/3rd of melanoma patients with distal metastasis survive beyond five years. However, current therapies including BRAF/MEK targeted therapies or immunotherapies only benefit a subset of melanoma patients due to the emergence of intrinsic or extrinsic resistance mechanisms. Effective treatment of melanoma will thus require new and more effective therapeutic agents. Towards the goal of identifying new therapeutic agents, we conducted an unbiased, druggable epigenetic drug screen using a library of 32 epigenetic inhibitors obtained from the Structural Genome Consortium that targets proteins encoding for epigenetic regulators. This chemical genetic screening identified TP-472, which targets bromodomain-7/9, as the strongest inhibitor of melanoma growth in both short- and long-term survival assays and in mouse models of melanoma tumor growth. Mechanistically, using a transcriptome-wide mRNA sequencing profile we identified TP-472 treatment downregulates genes encoding various extracellular matrix (ECM) proteins, including integrins, collagens, and fibronectins. Reactome-based functional pathway analyses revealed that many of the ECM proteins are involved in extracellular matrix interactions required for cancer cell growth and proliferation. TP-472 treatment also upregulated several pro-apoptotic genes that can inhibit melanoma growth. Collectively, our results identify BRD7/9 inhibitor TP-472 as a potentially useful therapeutic agent for melanoma therapy.