Dimerization among the EGFR family of tyrosine kinase receptors leads to allosteric activation of the kinase domains of the partners. Unlike other members in the family, the kinase domain of HER3 lacks key amino acid residues for catalytic activity. As a result, HER3 is suggested to serve as an allosteric activator of other EGFR family members which include EGFR, HER2 and HER4. To study the role of intracellular domains in HER3 dimerization and activation of downstream signaling pathways, we constructed HER3/HER2 chimeric receptors by replacing the HER3 kinase domain (HER3-2-3) or both the kinase domain and the C-terminal tail (HER3-2-2) with the HER2 counterparts and expressed the chimeric receptors in Chinese hamster ovary (CHO) cells. While over expression of the intact human HER3 transformed CHO cells with oncogenic properties such as AKT/ERK activation and increased proliferation and migration, CHO cells expressing the HER3-2-3 chimeric receptor showed significantly reduced HER3/HER2 dimerization and decreased phosphorylation of both AKT and ERK1/2 in the presence of neuregulin-1 (NRG-1). In contrast, CHO cells expressing the HER3-2-2 chimeric receptor resulted in a total loss of downstream AKT activation in response to NRG-1, but maintained partial activation of ERK1/2. The results demonstrate that the intracellular domains play a crucial role in HER3's function as an allosteric activator and its role in downstream signaling.
Amino Acid Sequence ; Animals ; CHO Cells ; Cell Movement ; Cell Proliferation ; Cricetinae ; Cricetulus ; Extracellular Signal-Regulated MAP Kinases ; metabolism ; Humans ; Intracellular Space ; enzymology ; MAP Kinase Signaling System ; Models, Molecular ; Molecular Sequence Data ; Phosphatidylinositol 3-Kinases ; metabolism ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Proto-Oncogene Proteins c-akt ; metabolism ; Receptor, ErbB-2 ; chemistry ; Receptor, ErbB-3 ; chemistry ; genetics ; metabolism ; Recombinant Fusion Proteins ; chemistry ; genetics ; metabolism ; Signal Transduction

Objective:To investigate the incidence of and risk factors for osteoporosis in patients with pemphigus treated with systemic glucocorticoids, and to analyze the current status of prevention and treatment of osteoporosis.Methods:Clinical data were collected from 101 inpatients with pemphigus treated in Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College from January 2014 to January 2019, and these patients were divided into osteoporosis group ( n= 21) and non-osteoporosis group ( n= 80) according to their bone mineral density (BMD) values. Correlations of osteoporosis with patients′ general information, treatment duration and cumulative dose of glucocorticoids, application of immunosuppressive agents, diabetes mellitus, hypertension, hyperlipidemia, smoking, outdoor activity and other factors were analyzed, and the application status of calcium supplements, vitamin D and bisphosphonates was also analyzed. Enumeration data were compared by using chi-square test, measurement data were compared by using t test, and multiple factors influencing osteoporosis were analyzed by using non-conditional Logistic regression analysis. Results:Logistic regression analysis showed that age ( P= 0.001, OR= 1.08, 95% CI: 1.03- 1.14) and cumulative dose of glucocorticoids ( P<0.001, OR= 1.72, 95% CI: 1.18- 2.52) were risk factors for the occurrence of osteoporosis, while outdoor activity ( P<0.001, OR= 0.04, 95% CI: 0.01- 0.21) was a protective factor. Moreover, 13 (61.9%) patients in the osteoporosis group and 16 (21.6%) patients in the non-osteoporosis group received combination treatment with calcium supplements, vitamin D and bisphosphonates. Conclusions:Pemphigus patients treated with systemic glucocorticoids are prone to develop osteoporosis. Older age, cumulative dose of glucocorticoids may be risk factors for osteoporosis in patients with pemphigus, while outdoor activity may be a protective factor. The prevention and treatment of osteoporosis in pemphigus patients are still not standardized.

Objective:To evaluate the clinical efficacy and safety of omalizumab in the treatment of chronic spontaneous urticaria (CSU) .Methods:Clinical data were collected from 60 patients, who were diagnosed with CSU and received subcutaneous injections of omalizumab at a dose of 300 mg once every 4 weeks for 3 sessions in Hospital of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College from March 2020 to September 2020, and retrospectively analyzed. At weeks 0, 2, 4, 6, 8, 10 and 12, urticaria activity score over 7 days (UAS7) and chronic urticaria quality of life (CU-Q2oL) score were used to evaluate clinical symptoms and quality of life of patients. Changes in the use of other drugs were evaluated before and after the treatment with omalizumab. Paired t test was used to compare UAS7 or CU-Q2oL score before and after treatment. Results:All the 60 CSU patients received 12 weeks of omalizumab treatment. The baseline UAS7 score was 22.37 ± 8.88 points; after one session of the treatment, the UAS7 score dropped to 2.01 ± 5.13 points, reaching the treatment plateau; at week 12, it dropped to 0.6 ± 2.63 points, and 0 point (complete control) in 93.3% of the patients, 1-6 points (favorable control) in 3.3%; the time required for UAS7 score to decrease to 0 point was 22.4 ± 3.2 days. The baseline CU-Q2oL score was 34.10 ± 15.01 points; after one session of the treatment, the CU-Q2oL score dropped to 2.41 ± 7.18 points, reaching the treatment plateau; at week 12, it was 0.56 ± 2.90 points; the time required for CU-Q2oL score to drop to 0 point was 21.15 ± 16.02 days. After the combination treatment with omalizumab, a gradual decrease in dosage or withdrawal of previous therapeutic drugs was realized. At week 12, 39 patients (65%) achieved complete control, and withdrew all therapeutic drugs except omalizumab. During the treatment and follow-up, omalizumab showed good safety, and no adverse reactions were observed.Conclusion:Omalizumab at a dose of 300 mg once every 4 weeks is markedly effective and safe for the treatment of CSU, providing a new treatment option for CSU patients with poor response to traditional therapy.

Autologous submandibular gland (SMG) transplantation has been proved to ameliorate the discomforts in patients with severe keratoconjunctivitis sicca. The transplanted glands underwent a hypofunctional period and then restored secretion spontaneously. This study aims to investigate whether autonomic nerves reinnervate the grafts and contribute to the functional recovery, and further determine the origin of these nerves. Parts of the transplanted SMGs were collected from the epiphora patients, and a rabbit SMG transplantation model was established to fulfill the serial observation on the transplanted glands with time. The results showed that autonomic nerves distributed in the transplanted SMGs and parasympathetic ganglionic cells were observed in the stroma of the glands. Low-dense and unevenly distributed cholinergic axons, severe acinar atrophy and fibrosis were visible in the patients' glands 4-6 months post-transplantation, whereas the cholinergic axon density and acinar area were increased with time. The acinar area or the secretory flow rate of the transplanted glands was statistically correlated with the cholinergic axon density in the rabbit model, respectively. Meanwhile, large cholinergic nerve trunks were found to locate in the temporal fascia lower to the gland, and sympathetic plexus concomitant with the arteries was observed both in the adjacent fascia and in the stroma of the glands. In summary, the transplanted SMGs are reinnervated by autonomic nerves and the cholinergic nerves play a role in the morphological and functional restoration of the glands. Moreover, these autonomic nerves might originate from the auriculotemporal nerve and the sympathetic plexus around the supplying arteries.
Animals ; Autonomic Pathways ; growth & development ; Fascia ; innervation ; Female ; Humans ; Keratoconjunctivitis Sicca ; surgery ; Male ; Models, Animal ; Rabbits ; Recovery of Function ; Secretory Rate ; Submandibular Gland ; innervation ; transplantation ; Transplantation, Autologous