We have recently demonstrated that the iv administration of 0.6-60 micrograms/kg.day of acidic fibroblast growth factor (acidic FGF) increases thyroid weight in male and female rats. Interestingly, ...measurement of serum TSH and thyroid hormones in rats treated with 6 micrograms/kg.day acidic FGF for 30 days revealed only a slight increase in serum T4 and reverse T3 concentrations. Since thyroid function was only examined 24 h after the 30th daily treatment, we performed a series of experiments to evaluate the effects of acidic FGF on thyroid function following single and 6 multiple injections of acidic FGF. There was a small increase in the serum TSH concentrations at 2, 4, 8, and 24 h after a single high dose iv injection of acidic FGF (60 micrograms/kg). In contrast, serum T3 concentrations were slightly decreased at 2, 4, and 8 h after acidic FGF administration. There was no effect of a single injection of acidic FGF on serum T4, reverse T3, or thyroglobulin concentrations. After 6 days of treatment, there was a 34% increase in the thyroid weights of rats treated with acidic FGF. Analysis of serum hormones revealed a slight increase in serum TSH, T3, and T4 concentrations in acidic FGF-treated rats, but no change in serum reverse T3 or thyroglobulin concentrations. There was no effect of acidic FGF administration on thyroid radioiodine uptake, the intrathyroidal metabolism of radioiodine, or the relative amounts of thyroidal thyroglobulin or peroxidase messenger RNAs, or on liver 5'-deiodinase activity. In hypophysectomized rats, with no detectable levels of serum TSH, acidic FGF failed to increase thyroid weight. These data suggest that FGFs may participate with TSH in the regulation of thyroid weight and colloid accumulation, and that autocrine or paracrine growth factors may be involved in the pathogenesis of colloid goiter.
We have recently demonstrated that the iv administration of acidic fibroblast growth factor (a-FGF) to rats for 6 days results in a marked increase in thyroid weight with colloid accumulation and ...flat, quiescent follicular cells. Whereas a-FGF administration consistently increases thyroid weight, there are only minor alterations in serum TSH and thyroid hormones, and no change in intrathyroidal metabolism of 125I metabolism. In the present work, we studied the effects of 1 or 6 daily injections of a-FGF (60 micrograms/kg BW) or vehicle on the mRNA levels for histone, c-fos, actin, type I 5' deiodinase (5'D-I), thyroid peroxidase, and thyroglobulin and cathepsin D in the thyroid, liver and bone. Rats were sacrificed 0.5, 2, 4, 8 and 24 h after the 1st or the 6th a-FGF injection and thyroid, liver, and calvarium were removed. The relative amounts of mRNAs were determined by slot blot analysis. There was a 43% increase in thyroid weight in rats treated with a-FGF for 6 days compared to vehicle-treated rats. We observed an increase in c-fos mRNA content in the thyroid gland 0.5 to 4 h after 1 or 6 injections of a-FGF. In contrast, treatment with a-FGF for 1 or 6 days did not affect histone mRNA content, a marker of proliferative activity or actin mRNA levels. Treatment with a-FGF caused a marked decrease in thyroid 5' D-I mRNA content in the thyroid. The decrease was present 2 h after the first injection and reached a nadir 8 h later.
Osteocalcin, a bone-specific protein and marker of the mature osteoblast, is expressed only in nonproliferating osteoblasts in a mineralizing extracellular matrix, while type I collagen is expressed ...in proliferating cells. The nuclear proteins encoded by the c-fos and c-jun protooncogenes are expressed during the proliferation period of osteoblast phenotype development. We present evidence that AP-1 (HeLa cell-activating protein 1) sites residing within two promoter elements of the osteocalcin gene bind the Fos-Jun protein complex: the osteocalcin box (OC box; nucleotides -99 to -76), which contains a CCAAT motif as a central element and influences tissue-specific basal levels of osteocalcin gene transcription, and the vitamin D-responsive element (VDRE; nucleotides -462 to -440), which mediates enhancement of osteocalcin gene transcription. Gel electrophoretic mobility-shift analysis demonstrated high AP-1 binding activity in proliferating osteoblasts and dramatic changes in this activity after the down-regulation of proliferation and the initiation of extracellular-matrix mineralization in primary cultures of normal diploid osteoblasts. Methylation interference analysis established at single nucleotide resolution that purified recombinant Fos and Jun proteins bind in a sequence-specific manner to the AP-1 sites within the VDRE and OC box. Similarly, an AP-1 motif within a putative VDRE of the alkaline phosphatase gene, which is also expressed after the completion of proliferation, binds the Fos-Jun complex. These results support a model in which coordinate occupancy of the AP-1 sites in the VDRE and OC box in proliferating osteoblasts may suppress both basal level and vitamin D-enhanced osteocalcin gene transcription as well as transcription of other genes associated with osteoblast differentiation--a phenomenon we describe as phenotype suppression. This model is further supported by binding of the Fos-Jun complex at an AP-1 site in the type αI collagen promoter that is contiguous with, but not overlapping, the VDRE. Such a sequence organization in the collagen VDRE motif is compatible with vitamin D modulation of collagen but not with osteocalcin and alkaline phosphatase expression in proliferating osteoblasts.
Abstract
Background
In solid organ transplant (SOT) recipients, the primary vaccination series against Coronavirus Disease 2019 is 3 doses followed by boosters. We determined whether a fourth dose ...booster induced Omicron BA.4/5 neutralizing antibodies (nAbs) and T cells in a large multicenter cohort study.
Methods
Serum was collected 4–6 weeks post-third and post-fourth doses of messenger RNA vaccine in 222 SOT recipients. nAbs were measured using a pseudovirus neutralization assay that targeted the Omicron BA.4/5 spike protein. A subset underwent T-cell testing.
Results
The median age of the cohort was 63 years (interquartile range IQR, 50–68) with 61.7% men. BA.4/5 nAb detection increased from 26.6% (59 of 222) post-third dose to 53.6% (119 of 222) post-fourth dose (P < .0001). In patients with breakthrough infection prior to the fourth dose (n = 27), nAbs were detected in 77.8% and median nAb titers were significantly higher compared with those with 4 vaccine doses alone (P < .0001). Factors associated with a low BA.4/5 neutralization response after the fourth dose were older age (odds ratio OR, 0.96; 95% confidence interval CI, .94–.99), mycophenolate use (OR, 0.39; 95% CI, .20–.77) and prednisone use (OR, 0.34; 95% CI, .18–.63), and vaccine type (OR, 0.72; 95% CI, .51–.99), while breakthrough infection prior to the fourth dose (OR, 3.6; 95% CI, 1.3–9.9) was associated with a greater nAb response. Polyfunctional BA.4/5-specific CD4+ T cells significantly increased after 4 doses and were identified in 76.9% of patients at a median frequency of 213/106 cells (IQR, 98–650).
Conclusions
In summary, a booster significantly increases BA.4/5-specific neutralization and polyfunctional CD4+ T-cell responses, suggesting protection from severe disease even with new Omicron variants. However, SOT recipients who are older and on mycophenolate and prednisone need additional preventative strategies.
This prospective, multicenter cohort study of organ transplant recipients showed suboptimal neutralization to booster vaccine against BA.4/5, which is especially impacted by age and mycophenolate and prednisone use. Vaccination produced T-cell responses in the majority of patients.
