CCL2 (MCP-1) Mediates Chronic Pelvic Pain Through Mast Cells in Experimental Autoimmune Cystitis

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic inflammatory bladder condition with unknown pathophysiology. Chronic pelvic pain is one of the most important and disturbing symptoms of IC/PBS, beside urinary frequency, urgency, and nocturia. Increased amounts of mast cells (MCs) and CCL2 have been found in bladder tissue and urine, respectively. Whether or not there is a causal relationship between CCL2, MCs, and pelvic pain in IC/PBS is unknown. Methods: Female BALB/c mice were immunized with a peptide consisting of residues 65-84 of the bladder urothelium-specific protein uroplakin 3A to induce experimental autoimmune cystitis (EAC), a model for human IC/PBS. Referred visceral pelvic pain was measured using von Frey monofilaments at different times after immunization. Lidocaine was instilled into the bladder, colon and uterus to locate the source of the pelvic pain. CCL2 expression in tissues was measured by qRT-PCR and ELISA, and MCs in the bladder were quantified by toluidine blue staining. An MC stabilizer (cromolyn sodium), histamine H1 receptor blocker (cetirizine), and histamine H2 receptor blocker (ranitidine) were administered orally to show the relation of MCs with the pain. CCL2-/- and CCR2-/- mice, and CCR2 (CCL2 receptor) antagonist treatment were used to delineate the causative effect of CCL2 on MC accumulation and chronic pelvic pain.Results: All mice immunized with the uroplakin 3A peptide developed pelvic pain within 5 days and up to 40 days after immunization. Lidocaine alleviated the pain only when it was installed into the bladder of EAC mice, confirming the bladder origin of the pain. The amounts of CCL2 mRNA and protein, and the numbers of MCs were markedly increased in bladder tissue up to 40 days after immunization with peptide compared with controls. Administrations of cromolyn sodium and ranitidine significantly decreased pelvic pain in the model. Moreover, immunization did not establish chronic pelvic pain or accumulation of MCs in MCP-1-/- or CCR2-/- mice, compa

CCL2 (MCP-1) Mediates Chronic Pelvic Pain Through Mast Cells in Experimental Autoimmune Cystitis

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic inflammatory bladder condition with unknown pathophysiology. Chronic pelvic pain is one of the most important and disturbing symptoms of IC/PBS, beside urinary frequency, urgency, and nocturia. Increased amounts of mast cells (MCs) and CCL2 have been found in bladder tissue and urine, respectively. Whether or not there is a causal relationship between CCL2, MCs, and pelvic pain in IC/PBS is unknown. Methods: Female BALB/c mice were immunized with a peptide consisting of residues 65-84 of the bladder urothelium-specific protein uroplakin 3A to induce experimental autoimmune cystitis (EAC), a model for human IC/PBS. Referred visceral pelvic pain was measured using von Frey monofilaments at different times after immunization. Lidocaine was instilled into the bladder, colon and uterus to locate the source of the pelvic pain. CCL2 expression in tissues was measured by qRT-PCR and ELISA, and MCs in the bladder were quantified by toluidine blue staining. An MC stabilizer (cromolyn sodium), histamine H1 receptor blocker (cetirizine), and histamine H2 receptor blocker (ranitidine) were administered orally to show the relation of MCs with the pain. CCL2-/- and CCR2-/- mice, and CCR2 (CCL2 receptor) antagonist treatment were used to delineate the causative effect of CCL2 on MC accumulation and chronic pelvic pain.Results: All mice immunized with the uroplakin 3A peptide developed pelvic pain within 5 days and up to 40 days after immunization. Lidocaine alleviated the pain only when it was installed into the bladder of EAC mice, confirming the bladder origin of the pain. The amounts of CCL2 mRNA and protein, and the numbers of MCs were markedly increased in bladder tissue up to 40 days after immunization with peptide compared with controls. Administrations of cromolyn sodium and ranitidine significantly decreased pelvic pain in the model. Moreover, immunization did not establish chronic pelvic pain or accumulation of MCs in MCP-1-/- or CCR2-/- mice, compa

CCL2 (MCP-1) Mediates Chronic Pelvic Pain Through Mast Cells in Experimental Autoimmune Cystitis

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic inflammatory bladder condition with unknown pathophysiology. Chronic pelvic pain is one of the most important and disturbing symptoms of IC/PBS, beside urinary frequency, urgency, and nocturia. Increased amounts of mast cells (MCs) and CCL2 have been found in bladder tissue and urine, respectively. Whether or not there is a causal relationship between CCL2, MCs, and pelvic pain in IC/PBS is unknown. Methods: Female BALB/c mice were immunized with a peptide consisting of residues 65-84 of the bladder urothelium-specific protein uroplakin 3A to induce experimental autoimmune cystitis (EAC), a model for human IC/PBS. Referred visceral pelvic pain was measured using von Frey monofilaments at different times after immunization. Lidocaine was instilled into the bladder, colon and uterus to locate the source of the pelvic pain. CCL2 expression in tissues was measured by qRT-PCR and ELISA, and MCs in the bladder were quantified by toluidine blue staining. An MC stabilizer (cromolyn sodium), histamine H1 receptor blocker (cetirizine), and histamine H2 receptor blocker (ranitidine) were administered orally to show the relation of MCs with the pain. CCL2-/- and CCR2-/- mice, and CCR2 (CCL2 receptor) antagonist treatment were used to delineate the causative effect of CCL2 on MC accumulation and chronic pelvic pain.Results: All mice immunized with the uroplakin 3A peptide developed pelvic pain within 5 days and up to 40 days after immunization. Lidocaine alleviated the pain only when it was installed into the bladder of EAC mice, confirming the bladder origin of the pain. The amounts of CCL2 mRNA and protein, and the numbers of MCs were markedly increased in bladder tissue up to 40 days after immunization with peptide compared with controls. Administrations of cromolyn sodium and ranitidine significantly decreased pelvic pain in the model. Moreover, immunization did not establish chronic pelvic pain or accumulation of MCs in MCP-1-/- or CCR2-/- mice, compa

Advances in Immunotherapy for Hepatocellular Carcinoma (HCC)

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related deaths in the world. More than half of patients with HCC present with advanced stage, and highly active systemic therapies are crucial for improving outcomes. Immune checkpoint inhibitor (ICI)-based therapies have emerged as novel therapy options for advanced HCC. Only one third of patients achieve an objective response with ICI-based therapies due to primary resistance or acquired resistance. The liver tumor microenvironment is naturally immunosuppressive, and specific mutations in cell signaling pathways allow the tumor to evade the immune response. Next, gene sequencing of the tumor tissue or circulating tumor DNA may delineate resistance mechanisms to ICI-based therapy and provide a rationale for novel combination therapies. In this review, we discuss the results of key clinical trials that have led to approval of ICI-based therapy options in advanced HCC and summarize the ongoing clinical trials. We review resistance mechanisms to ICIs and discuss how immunotherapies may be optimized based on the emerging research of tumor biomarkers and genomic alterations