Insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), and insulin are believed to be important in the regulation of fetal and neonatal growth. We previously reported that the profiles of IGFBPs in fetal cord serum (FCS) were dependent on the growth/metabolic status of the fetus. The goals of the current study were to examine the IGF system in FCS from term fetuses with normal growth, those with intrauterine growth retardation (IUGR), and those who were large for gestational age (LGA) and in FCS from normal weight preterm (25-37 weeks) and term fetuses in the neonatal period from the day of birth (day 0) until 7 days of age (day 7). Western ligand blotting (WLB) of term FCS revealed IGFBPs with mol wt of 43 and 38 kilodaltons (kDa; IGFBP-3), 34 kDa (IGFBP-2), 28 kDa (IGFBP-1 and glycosylated IGFBP-4), and 24 kDa (IGFBP-4). In IUGR FCS, there was a 50% decrease in IGFBP-3 detected by WLB, which was shown not to be due to an IGFBP-3 protease in IUGR sera. In LGA FCS, IGFBP-3 levels were elevated 2-fold by densitometric analysis of ligand blots. In normal term FCS, the following levels (+/- SE) were present: IGF-I, 76 +/- 16; IGF-II, 401 +/- 38; IGFBP-3, 700 +/- 112; IGFBP-1, 77 +/- 10 ng/mL; and insulin, 3.8 +/- 1.6 microU/mL. In IUGR FCS, IGF-I, IGF-II, and IGFBP-3 were significantly reduced, and IGFBP-1 was 7-fold higher than in FCS from normal weight fetuses. In LGA FCS, IGF-I, insulin, and IGFBP-3 were significantly increased, whereas IGFBP-1 was significantly decreased. During the neonatal period, IGF-I levels on day 0 were 4-fold higher in FCS from term (38-40 weeks) compared to preterm (25-31 weeks) newborns. FCS IGF-II levels did not change significantly on day 0 between 25-40 weeks gestation. In the first 7 days of postnatal life, IGF-I levels were unchanged in preterm newborns, whereas in term neonates, IGF-I levels decreased precipitously on day 1, remained low during the first 3 days of life, and returned to birth levels by the end of the first week. In contrast, IGF-II and IGFBP-3 levels did not significantly change during the first week of life in preterm or term newborns.(ABSTRACT TRUNCATED AT 400 WORDS)
Mucin 1 (MUC1 [CD227]) is a high-molecular weight (>400 kDa), type I membrane-tethered glycoprotein that is expressed on epithelial cells and extends far above the glycocalyx. MUC1 is overexpressed and aberrantly glycosylated in adenocarcinomas and in hematological malignancies. As a result, MUC1 has been a target for tumor immunotherapeutic studies in mice and in humans. MUC1 has been shown to have anti-adhesive and immunosuppressive properties, protects against infections, and is involved in the oncogenic process as well as in cell signaling. In addition, MUC1 plays a key role in the reproductive tract, in the immune system (affecting dendritic cells, monocytes, T cells, and B cells), and in chronic inflammatory diseases. Evidence for all of these roles for MUC1 is discussed herein and demonstrates that MUC1 is truly a multitasked molecule.
Background: Interleukin 12 (IL-12) is a pivotal regulator of innate and adaptive immunity. We conducted a prospective open-label, phase II clinical trial of electroporated plasmid IL-12 in advanced melanoma patients (NCT 01502293). Patients and methods: Patients with stage III/IV melanoma were treated intratumorally with plasmid encoding IL-12 (tavokinogene telseplasmid; tavo), 0.5 mg/ml followed by electroporation (six pulses, 1500 V/cm) on days 1, 5, and 8 every 90 days in the main study and additional patients were treated in two alternative schedule exploration cohorts. Correlative analyses for programmed death-ligand 1 (PD-L1), flow cytometry to assess changes in immune cell subsets, and analysis of immune-related gene expression were carried out on pre-and post-treatment samples from study patients, as well as from additional patients treated during exploration of additional dosing schedules beyond the pre-specified protocol dosing schedule. Response was measured by study-specific criteria to maximize detection of latent and potentially transient immune responses in patients with multiple skin lesions and toxicities were graded by the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Results: The objective overall response rate was 35.7% in the main study (29.8% in all cohorts), with a complete response rate of 17.9% (10.6% in all cohorts). The median progression-free survival in the main study was 3.7 months while the median overall survival was not reached at a median follow up of 29.7 months. A total of 46% of patients in all cohorts with uninjected lesions experienced regression of at least one of these lesions and 25% had a net regression of all untreated lesions. Transcriptomic and immunohistochemistry analysis showed that immune activation and co-stimulatory transcripts were up-regulated but there was also increased adaptive immune resistance. Conclusions: Intratumoral Tavo was well tolerated and led to systemic immune responses in advanced melanoma patients. While tumor regression and increased immune infiltration were observed in treated as well as untreated/ distal lesions, adaptive immune resistance limited the response.
Background: Interleukin 12 (IL-12) is a pivotal regulator of innate and adaptive immunity. We conducted a prospective open-label, phase II clinical trial of electroporated plasmid IL-12 in advanced melanoma patients (NCT 01502293). Patients and methods: Patients with stage III/IV melanoma were treated intratumorally with plasmid encoding IL-12 (tavokinogene telseplasmid; tavo), 0.5 mg/ml followed by electroporation (six pulses, 1500 V/cm) on days 1, 5, and 8 every 90 days in the main study and additional patients were treated in two alternative schedule exploration cohorts. Correlative analyses for programmed death-ligand 1 (PD-L1), flow cytometry to assess changes in immune cell subsets, and analysis of immune-related gene expression were carried out on pre-and post-treatment samples from study patients, as well as from additional patients treated during exploration of additional dosing schedules beyond the pre-specified protocol dosing schedule. Response was measured by study-specific criteria to maximize detection of latent and potentially transient immune responses in patients with multiple skin lesions and toxicities were graded by the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Results: The objective overall response rate was 35.7% in the main study (29.8% in all cohorts), with a complete response rate of 17.9% (10.6% in all cohorts). The median progression-free survival in the main study was 3.7 months while the median overall survival was not reached at a median follow up of 29.7 months. A total of 46% of patients in all cohorts with uninjected lesions experienced regression of at least one of these lesions and 25% had a net regression of all untreated lesions. Transcriptomic and immunohistochemistry analysis showed that immune activation and co-stimulatory transcripts were up-regulated but there was also increased adaptive immune resistance. Conclusions: Intratumoral Tavo was well tolerated and led to systemic immune responses in advanced melanoma patients. While tumor regression and increased immune infiltration were observed in treated as well as untreated/ distal lesions, adaptive immune resistance limited the response.
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