The TRIM37 variants in Mulibrey nanism patients paralyze follicular helper T cell differentiation.

The Mulibrey (Muscle-liver-brain-eye) nanism caused by loss-of-function variants in TRIM37 gene is an autosomal recessive disorder characterized by severe growth failure and constrictive pericarditis. These patients also suffer from severe respiratory infections, co-incident with an increased mortality rate. Here, we revealed that TRIM37 variants were associated with recurrent infection. Trim37 FINmajor (a representative variant of Mulibrey nanism patients) and Trim37 knockout mice were susceptible to influenza virus infection. These mice showed defects in follicular helper T (TFH) cell development and antibody production. The effects of Trim37 on TFH cell differentiation relied on its E3 ligase activity catalyzing the K27/29-linked polyubiquitination of Bcl6 and its MATH domain-mediated interactions with Bcl6, thereby protecting Bcl6 from proteasome-mediated degradation. Collectively, these findings highlight the importance of the Trim37-Bcl6 axis in controlling the development of TFH cells and the production of high-affinity antibodies, and further unveil the immunologic mechanism underlying recurrent respiratory infection in Mulibrey nanism.

Value of pulse oximetry watch for diagnosing pediatric obstructive sleep apnea/hypopnea syndrome.

OBJECTIVE: To evaluate the clinical value of pulse oximetry watch (POW) for diagnosing pediatric Obstructive sleep apnea/hypopnea syndrome (OSAHS). METHODS: We selected 32 children (boys: 25, 4-16 years old) who came to the hospital for diagnosing OSAHS from July to October 2016. Polysomnography (PSG) and POW were used simultaneously and recorded the apnea hypopnea index (AHI), LSpO2, and ODI4. Pearson analysis, t test, and receiver-operating characteristic (ROC) were used to analyze the correlation between PSG-AHI and other indicators, the diagnosis accordance rate, and the sensitivity and specificity of POW, respectively. RESULTS: According to PSG-AHI, 32 children were divided into two groups: primary snoring (n = 5) and OSAHS (n = 27). There was no significant difference between PSG-ODI4 and POW-ODI4 (p > .05). A statistically significant correlation between PSG-AHI and POW-ODI4 was found (r = .719, p < .001). When PSG-AHI >1, 5, 10, 15, and 20 events/h, the area under the curve (AUC) was 0.685 (p > .05), 0.733, 0.798, 0.922, and 0.929 (p < .05), respectively. There were high levels of sensitivity (83.33%) and specificity (92.31%) in the OSAHS with AHI >20 events/h level, whereas the sensitivity and specificity were unacceptable (<75%) at the level of AHI >1, 5, 10, and 15 events/h. CONCLUSIONS: POW cannot replace PSG to diagnose pediatric OSAHS because of low sensitivity and specificity, but can be used for screening severe OSAHS in children.

Reduced Retinal Vessel Density in Obstructive Sleep Apnea Syndrome Patients: An Optical Coherence Tomography Angiography Study.

Purpose: To examine the retinal vasculature in patients with obstructive sleep apnea-hypopnea syndrome (OSAS) and to determine the correlation between retinal vascularity and the severity of OSAS. Design: Prospective, cross-sectional study. Methods: Sixty-nine consecutive subjects who underwent polysomnography were enrolled. Patients were divided into three groups according to the severity of OSAS, which was defined using the apnea-hypopnea index (AHI) as normal-to-mild (AHI <15), moderate (≥15 to <30), or severe (≥30). The vessel densities, and macular and retinal nerve fiber layer thicknesses were compared among the three groups. The correlations between clinical variables (age, heart rate, body mass index, ocular perfusion pressure, spherical equivalence, IOP, inner retinal thickness, and AHI) and vessel densities were also determined. Results: The full and inner parafoveal retinal thickness and the retinal nerve fiber layer thickness were similar in all three groups. The retinal vessel density decreased with greater severity of OSAS. The decrease in vessel density differed between the peripapillary and parafoveal areas. The moderate group had a significantly lower vessel density than the normal-to-mild group in the peripapillary area (P < 0.05), but similar vessel density as the normal-to-mild group in the parafoveal area (P > 0.05). The vessel densities in the parafoveal and peripapillary areas were significantly and negatively correlated with AHI (both P < 0.05); the relative reduction in vessel density was greater in the peripapillary area than in the parafoveal area. Conclusions: In OSAS patients, the vessel densities in the peripapillary and parafoveal areas decreased with greater disease severity, and the decrease was more prominent in the peripapillary area.

9-Hydroxypheophorbide α-mediated photodynamic therapy induces matrix metalloproteinase-2 (MMP-2) and MMP-9 down-regulation in Hep-2 cells via ROS-mediated suppression of the ERK pathway.

BACKGROUND: Photodynamic therapy (PDT) is a promising treatment modality for malignant diseases through the generation of reactive oxygen species (ROS). In this study, we assessed the change of migration and invasion of HEp-2 cells after sublethal doses of 9-hydroxypheophorbide α (9-HPbD)-mediated PDT in vitro, and explored the role of ROS in 9-HPbD-PDT-induced anti-metastatic effects in HEp-2 cells. METHODS: Following PDT, ROS were measured by a fluorescence microscope in both the presence and absence of glutathione (GSH) pretreatment. Wound healing assay, cell migration assay, and matrigel invasion assay were used to evaluate the cellular migration and invasion. Western blot was performed to investigate the signaling pathways that may have been involved. RESULTS: ROS were rapidly generated in 9-HPbD-loaded HEp-2 laryngeal cancer cells by the activation of a diode laser and were significantly inhibited by a 6-h GSH pretreatment. Wound healing assay, cell migration assay, and matrigel invasion assay showed that sublethal PDT significantly suppressed the migration and invasion of HEp-2 cells. GSH decreased the ability of PDT to inhibit the invasion of HEp-2 cells. Western blot analysis showed that PDT significantly inhibited the phosphorylation of MEK1/2 and ERK1/2, and significantly suppressed the expression of MMP-2 and MMP-9 after 24h following the implementation of sublethal PDT, and these efficacies of PDT could be abrogated by GSH pretreatment. CONCLUSIONS: 9-HPbD-PDT attenuated the migration and invasion of HEp-2 cells in vitro, which may be related to the down-regulated expression of MMP-2 and MMP-9 via ROS-mediated-inhibition of phosphorylation in the ERK/MEK signaling pathway.

[Clinical significance of lymph vessel density marked by lymphatic vessel endothelial hyaluronic acid receptor-1 in laryngeal squamous cell carcinomas].

OBJECTIVE: To study the relationship between density, location, proliferation of lymph vessels and clinicopathological features of laryngeal squamous carcinoma. METHOD: Tumor lymph vessels were quantitated and located in archival specimens of laryngeal carcinoma by LSAB immunostaining for the recently described lymphatic endothelial marker LYVE-1. The Ki67 proliferation marker was used to evaluate the proliferating conditions of LYVE-1(+) vessels with EnVision immunohistochemical methods. RESULT: (1) The density of intratumoral LYVE-1(+) vessels was higher in the cases of neck lymph nodal metastasis group than that of no neck lymph nodal metastasis group (P = 0.000). There was a significant difference of the density of intratumoral LYVE-1(+) vessels in the cases of T1, T2 and T(3-4) group. There was no significant difference of the density of intratumoral LYVE-1(+) vessels between supraglottic group and glottic group, squamous cell histological types I group and types II group (P = 0.125, 0.146, respectively). (2) The density of peritumoral LYVE-1(+) vessels was higher in the cases of neck lymph nodal metastasis group than that of no neck lymph nodal metastasis group. However,there was no statistic significance (P = 0.253). (3) Ki67(+) immunostaining occurs in some of the intratumoral LYVE-1(+) vessels, interestingly, there was no this phenomenon in the peritumoral LYVE-1(+) vessels. CONCLUSION: Intratumoral lymph vessel density marked by LYVE-1 in laryngeal carcinoma was significantly correlated with tumor infiltration and metastasis. Our results provide potent evidence that proliferating lymphatics exists in intratumoral areas of laryngeal carcinoma mainly which maybe contribute to lymph node metastasis in some cases.