IgE-neutralizing UB-221 mAb, distinct from omalizumab and ligelizumab, exhibits CD23-mediated IgE downregulation and relieves urticaria symptoms.

Over the last 2 decades, omalizumab is the only anti-IgE antibody that has been approved for asthma and chronic spontaneous urticaria (CSU). Ligelizumab, a higher-affinity anti-IgE mAb and the only rival viable candidate in late-stage clinical trials, showed anti-CSU efficacy superior to that of omalizumab in phase IIb but not in phase III. This report features the antigenic-functional characteristics of UB-221, an anti-IgE mAb of a newer class that is distinct from omalizumab and ligelizumab. UB-221, in free form, bound abundantly to CD23-occupied IgE and, in oligomeric mAb-IgE complex forms, freely engaged CD23, while ligelizumab reacted limitedly and omalizumab stayed inert toward CD23; these observations are consistent with UB-221 outperforming ligelizumab and omalizumab in CD23-mediated downregulation of IgE production. UB-221 bound IgE with a strong affinity to prevent FcԑRI-mediated basophil activation and degranulation, exhibiting superior IgE-neutralizing activity to that of omalizumab. UB-221 and ligelizumab bound cellular IgE and effectively neutralized IgE in sera of patients with atopic dermatitis with equal strength, while omalizumab lagged behind. A single UB-221 dose administered to cynomolgus macaques and human IgE (ε, κ)-knockin mice could induce rapid, pronounced serum-IgE reduction. A single UB-221 dose administered to patients with CSU in a first-in-human trial exhibited durable disease symptom relief in parallel with a rapid reduction in serum free-IgE level.

Intracellular expression of Vitreoscilla hemoglobin in Aspergillus terreus to alleviate the effect of a short break in aeration during culture.

A continuous supply of O(2) is important for itaconic acid production in Aspergillus terreus. Any interruption of aeration significantly reduces itaconic acid production. To overcome this effect, A. terreus M8 was transformed with the Vitreoscilla hemoglobin gene (vgb) which, as shown by Southern hybridization, was integrated into the recipient chromosome. The activity of the expressed hemoglobin was confirmed by a CO-difference spectrum. During itaconic acid production, the effect of a break in aeration during cultivation in the transformant with the vgb gene is alleviated. Additionally, the transformant shows improved itaconic acid production.

Conversion of the cleavage specificity of subtilisin YaB on oxidized insulin chains to an elastase-like specificity by replacement of Gly124 with Ala.

Replacement of Gly124 on the S1 pocket of subtilisin YaB with Ala changed the cleavage pattern on oxidized insulin B-chain from the subtilisin type to the elastase type. The initial cleavage site in the B-chain shifted from L15-Y16 for wild-type YaB to A14-L15 for the G124A mutant. Upon complete hydrolysis with the G124A mutant, four of the six major cleavage sites on the B-chain were identical to porcine pancreatic elastase cleavage sites.

Expression of sialyltransferase family members in cervix squamous cell carcinoma correlates with lymph node metastasis.

OBJECTIVE: Altered messenger ribonucleic acid (mRNA) expression of the four sialyltransferases (STs including ST3Gal I, ST3Gal III, ST3Gal IV, and ST6Gal I) is important in squamous cell carcinoma of the cervix. This study further investigates their changes in mRNA expression of the four STs in FIGO stage IB1 squamous cell carcinoma to assess the extent of sialylation associated with lymph node metastases. METHODS: Alterations in ST mRNA expression in FIGO IB1 cervical squamous cell carcinomas (n = 79) were examined by semiquantitative reverse transcription-polymerase chain reaction. RESULTS: Both ST6Gal I mRNA and ST3Gal III mRNA expressions were significantly increased in patients with lymph node metastases compared to those without lymph node metastases (P = 0.002 and P = 0.001, respectively, Mann-Whitney U test). Using receiver operating characteristic curves of ST ratio index for accuracy comparison of lymph node metastases, ST3Gal III and ST6Gal I were observed to be fairly interchangeable (area under the curve (AUC) of 3Gal I = 0.810; AUC of 6Gal I = 0.786, significance of difference between AUC = 0.810). High ST6Gal I expression was associated with other invasive properties of cervical cancer, such as deep stromal invasion and presence of lymph-vascular space involvement. ST6Gal I expression seemed to be more enhanced in bigger tumors. CONCLUSIONS: Our results suggested that ST3Gal III and ST6Gal I were of importance for the lymph node metastases in FIGO IB1 cervical cancer patients; more specifically, overexpression of ST6Gal I was of crucial relevance for the presence of poor prognostic factors, such as deep stromal invasion and lymph-vascular space involvement and lymph node metastases.

Detecting cytokeratin 19 mRNA in the peripheral blood cells of cervical cancer patients and its clinical-pathological correlation.

OBJECTIVE: The aim of this study was to study the presence of cytokeratin 19 (CK19)-expressing cancer cells in the blood of preoperative patients with FIGO stage Ib and IIb cervical cancers who received radical hysterectomy and to investigate the cells' clinical significance. METHODS: CK19 mRNA in the blood cells of the patients was detected preoperatively by a newly designed nested reverse transcriptase-polymerase chain reaction, which excluded pseudogenes a and b, performed on 84 patients with stage Ib and IIb cervical carcinoma. Possible correlations between clinicopathological factors were then analyzed. RESULTS: The sensitivity of this assay was 1 CK19-mRNA-positive cell per 10(6) peripheral blood mononuclear cells. Results showed that 21.4% of the 84 patients with cervical carcinoma had CK19-mRNA-positive cells in the blood, in comparison with 5.7% of the 35 patients with benign gynecological tumors and 0% of the 28 healthy controls (P = 0.037 and 0.006, respectively). The positive tests in the cervical cancer patients were not associated with prognostic factors including stage, pelvic lymph node metastasis, pathological types, bulky tumor size (> or =4 cm), differentiation, parametrial extension, lymphovascular space involvement, deep stromal invasion, or age. CONCLUSIONS: This study revealed the presence of circulating CK19-expressing cancer cells in the blood of patients with untreated early-stage cervical carcinomas, indicating that cervical cancer disseminated early. The survival effect of this phenomenon must be clarified. This detection assay provides an early checkpoint in the multistep process for developing metastasis in cervical cancer patients.

Analysis of genetic aberrations in uterine adenomyosis using comparative genomic hybridization.

OBJECTIVE: To use comparative genomic hybridization (CGH) to analyzefrozen tissuesfrom adenomyosis cases to discover and map genomic regions for chromosomal gains and losses. STUDY DESIGN: In a retrospective study, upper and lower threshold values of 1.20 and 0.80, respectively, were used to define positive findings. RESULTS: No positive recurrent gene copy number alterations were detected in the 25 cases of pathologically proven adenomyosis. CONCLUSION: Although CGH is extremely useful in investigating candidate genes in the development of adenomyosis, CGH was not useful in this study. Genetic changes might be indeed extremely rare in adenomyosis, or CGH was not sensitive enough to detect candidate genes.

The concentration of serum transforming growth factor beta-1 (TGF-beta1) is decreased in cervical carcinoma patients.

Transforming growth factor beta-1 (TGF-beta1) is a multifunctional growth factor and known to inhibit the proliferation of epithelial cell. The relationship between serum TGF-beta1 level and the presence of cervical cancer was investigated in this study. The patients with cervical squamous cell carcinoma (SCC) had significantly lower level of serum TGF-beta1 (39.14 +/- 9.03 ng/mL; mean +/- SD) than those with myoma (49.17 +/- 9.38 ng/mL) and normal subjects (49.13 +/- 8.81 ng/mL), (p < 0.007 and p < 0.001, respectively). TGF-beta1 level was also lower in the patients with cervical intraepithelial neoplasia (CIN3) (42.07 +/- 9.38 ng/mL) than in normal controls (49.13 +/- 8.81 ng/mL) (p < 0.04). It suggested that diminution of the production of TGF-beta1 has close association with the neoplastic transformation of cervical epithelium.