Serum TG level may be a useful marker of tumor burden and response to treatment for soft tissue sarcoma. Anti-GD1a and anti-GT1b IgM titers predicted survival and may be of therapeutic and prognostic value in the management of soft tissue sarcoma.
BACKGROUND. Pancreatic adenocarcinoma cells express gangliosides and sialylLewis (sLe) antigens. It is not known whether these carbohydrate antigens can be targeted by immunotherapy. The authors measured the expression of GM 2 and sLe antigens on the surface of pancreatic carcinoma cells and the serum levels of total gangliosides, GM 2 , and antiganglioside antibodies in patients with pancreatic carcinoma.
METHODS.Cell surface GM 2 and sLe antigens were measured by cell suspension enzyme linked immunoadsorbent assay (ELISA) in four pancreatic carcinoma cell lines. Sera from 20 pancreatic carcinoma patients and 20 age-and gender-matched healthy volunteers were analyzed for antiganglioside and anti-sLe immunoglobulin (Ig) M titers by ELISA. Serum levels of total gangliosides and GM 2 also were measured.
RESULTS.All cell lines expressed GM 2 and sLe antigens. When compared with ageand gender-matched volunteers, patients had significantly higher serum levels of total gangliosides (25.6 Ϯ 9.0 mg/dL vs. 15.6 Ϯ 2.7 mg/dL; P Ͻ 0.001), GM 2 (0.278 Ϯ 0.415 mg/dL vs. 0.013 Ϯ 0.018 mg/dL; P ϭ 0.02), ELISA units of anti-GM 2 IgM antibody (368 Ϯ 95 vs. 155 Ϯ 25; P ϭ 0.04) and anti-GD 1b IgM antibody (351 Ϯ 91 vs. 138 Ϯ 26; P ϭ 0.03), but not anti-sLe x IgM (1389 Ϯ 345 vs. 1081 Ϯ 224; P ϭ 0.46) or anti-sLe a IgM antibody (1097 Ϯ 253 vs. 1200 Ϯ 315; P ϭ 0.80). Patients with unresectable tumors had higher serum levels of total gangliosides compared with patients with resectable tumors, and a serum level Ͼ 25 mg/dL was found to correlate significantly with poor overall survival (P Ͻ 0.02).
CONCLUSIONS.Increased serum levels of total gangliosides and GM 2 may reflect shedding or release of gangliosides from the surface of tumor cells. Production of IgM antibody against GM 2 and GD 1b indicates that these gangliosides are immunogenic antigens that may be potential targets for effective active immunotherapy.
Adenylyl cyclases (ACs) are enzymes that catalyze the synthesis of cAMP from ATP. The cAMP signaling cascade is involved in a number of physiological processes spanning from breathing to memory and cardiac function. Among the nine different membranous AC isoforms, a role for adenylyl cyclase 1 (AC1) has been suggested in learning, memory, pain, and opioid dependence. AC1 is one of the calcium/calmodulin‐stimulated ACs and previous studies suggest that inhibition AC1 could relieve inflammatory pain and reduce signs of opioid dependence. However, non‐selective inhibition of AC1 and closely related AC8 could lead to learning and memory impairments. We previously identified ST034307 as a selective inhibitor of AC1 and revealed anti‐allodynic activity in the mouse CFA inflammatory pain model. As part of our ongoing studies to identify selective AC inhibitors we developed a novel cellular model that used CRISPR/Cas 9 editing to remove 95% of the forskolin‐stimulated cAMP signal from wild type HEK293 cells (Soto‐Velasquez et al., 2018). We have now used this cellular model to re‐evaluate the AC isoform selectivity of ST034307. The results confirmed unprecedented selective inhibition of AC1 vs the closely related AC8. The development of AC1‐selective inhibitors like ST034307 now provides an opportunity to better study this protein and determine the physiological effects of inhibiting AC1 in additional animal models. The present work represents a comprehensive pre‐clinical study with the selective AC1 inhibitor ST034307. We have determined ST034307’s biodistribution to mouse blood and brain at different time points after injection. In addition, we have shown that the compound is effective and comparable to ketoprofen to relieve visceral and inflammatory pain in mice, and that it does not disrupt mouse innate behavior (nesting) at analgesic doses. In fear extinction experiments with rats ST034307 had no effects on extinction learning. However, the compound disrupted the consolidation of fear extinction compared to vehicle‐treated rats. These data support previous studies suggesting that AC1 inhibitors may be useful to treat pain and also indicates that normal innate behavior is not disrupted at analgesic doses. Moreover, the effect on consolidation of fear extinction may suggest a novel use for these compounds in anxiety disorders, such as post‐traumatic stress disorders (PTSD).
Support or Funding Information
This work was supported by the American Association of Colleges of Pharmacy (New Investigator Award), Palm Beach Atlantic University (Quality Initiative Grant), Lloyd L. Gregory School of Pharmacy (Integra Connect Grant), Purdue College of Pharmacy, and Richard and Anne Borch Award.
Circulating immune complexes in sera from sickle cell anemia (SCA) patients were investigated using inhibition of complement-dependent lymphocyte rosette formation (EAC rosette inhibition) and the anticomplementary assay. A significant inhibition of EAC rosette formation was seen in seven (77%) sera from SCA patients with hepatic crisis. Four (44%) sera from these patients showed slightly increased anticomplementary activity. These preliminary results provide evidence for the presence of circulating immune complexes in some SCA patients with hepatic crisis.
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