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Abstract Background Isolated hypogonadotropic hypogonadism (IHH) is a clinical syndrome described by failure of gonadal function secondary to defects on the synthesis, secretion, or action of the gonadotropin‐releasing hormone (GnRH). The secreted glycoprotein SEMA3A binds its receptors NRP1 or NRP2 and PLXNA to participate in axonal projection, dendritic branching, synaptic formation, and neuronal migration. Deficiency in SEMA3A, NRP1, NRP2, and PLXNA1 have been related to abnormal GnRH neuron development in mice and IHH in humans. Methods The aim of this study was to examine the genotypic and phenotypic spectra of the NRP1, NRP2, and PLXNA1 genes in a large cohort of IHH probands from China. We screened NRP1, NRP2, and PLXNA1 variants in Chinese IHH patients by whole exome sequencing and pedigree analysis. Results We identified 10 heterozygous missense variants in PLXNA1, five heterozygous missense variants in NRP1, and two heterozygous missense variants in NRP2. NRP1 variants were found only in IHH patients with defective olfaction (i.e., Kallmann syndrome, KS). In addition, 85% (17/20) of patients harbored variants in other IHH‐associated genes. Conclusion Our study greatly enriched the genotypic and phenotypic spectra of PLXNA1, NRP1, and NRP2 in IHH. It may be conducive to the genetic counseling, diagnosis, and treatment of IHH with mutations in the PLXNA1, NRP1, and NRP2 genes. Furthermore, our results indicated that NRP1 were strongly linked to hearing loss.

AIM: To compare the efficacy of intravitreal injection of ranibizumab plus low power 532 laser versus 532 laser alone for treating retinal vein occlusion(RVO)with macular edema complication.METHODS: Retrospective study of 48 patients diagnosed RVO complicated with macular edema from June 2017 to March 2018. Group A of 31 eyes(31 patients)were treated with intravitreal injection of ranibizumab plus low power 532 laser(the power is about 2/3 of the power of group B, about 100-130mw), and group B of 17 eyes(17 patients)were treated with 532 laser(the power is 150-200mw)alone. The best corrected visual acuity(BCVA), foveal retinal thickness(CMT), FFA and fundus were observed both before and after treatment at timepoint of 1mo, 2mo and 3mo between the two groups.RESULTS: In group A, BCVA was 0.84±0.02, 0.49±0.04, 0.29±0.04, 0.26±0.04 before and the 1, 2, 3mo after treatment. In group B, BCVA was 0.85±0.04, 0.58±0.01, 0.53±0.01, 0.53±0.02. The CMT value of group A before and after treatment was 527.5±17.59, 371±17.36, 298.5±32.87, 257.75±17.30μm, respectively. Group B was 535±16.36, 425±24.44, 420.25±17.70, 427.75±17.89μm. Intra-group comparison show statistical differences, group A had lower BCVA and CMT value than group B at the same time point(PPCONCLUSION: Both methods are effective in treating RVO with macular edema, improving vision, alleviating ME, and effectively controlling the disease.However, combined treatment can significantly reduce macular edema, improve vision, and be more stable than laser treatment alone.

RNF216, encoding an E3 ubiquitin ligase, has been identified as a causative gene for Gordon Holmes syndrome, characterized by ataxia, dementia, and hypogonadotropic hypogonadism. However, it is still elusive how deficiency in RNF216 leads to hypogonadotropic hypogonadism. In this study, by using GN11 immature GnRH neuronal cell line, we demonstrated an important role of RNF216 in the GnRH neuron migration. RNA interference of RNF216 inhibited GN11 cell migration, but had no effect on the proliferation of GN11 cells or GnRH expression. Knockdown of RNF216 increased the protein levels of its targets, Arc and Beclin1. RNAi of Beclin1, but not Arc, normalized the suppressive effect caused by RNF216 knockdown. As Beclin1 plays a critical role in the autophagy regulation, we further demonstrated that RNAi of RNF216 led to increase in autophagy, and autophagy inhibitor CQ and 3-MA rescued the GN11 cell migration deficit caused by RNF216 knockdown. We further demonstrated that pharmacological increase autophagy by rapamycin could suppress the GN11 cell migration. We thus have identified that RNF216 regulates the migration of GnRH neuron by suppressing Beclin1 mediated autophagy, and indicated a potential contribution of autophagy to the hypogonadotropic hypogonadism.

Toll-like receptors (TLRs) regulate the balance between the innate and adaptive immune responses. Missense single nucleotide polymorphisms (SNPs) in TLRs might be functional and thus influence the risks of chronic infection and cancer development. Here, we investigated the association of two missense SNPs, rs3775291 (c.1234G>A) in the TLR3 gene and rs4833095 (c.743T>C) in the TLR1 gene, with relapse-free survival (RFS) in a cohort of prospectively observed breast cancer patients.In this prospective observational study, rs3775291 in TLR3 and rs4833095 in TLR1 were genotyped in 715 patients with primary breast cancer in a Chinese population.Univariate analysis revealed that the patients with the AA genotype of rs3775291 had a shorter RFS compared with those carrying the G allele in the recessive model (P

Objective: To identify CCDC141 variants in a large Chinese cohort with congenital hypogonadot ropic hypogonadism (CHH) and to assess the contribution of CCDC141 to CHH. Design: Detailed phenotyping was conducted in CHH patients with CCDC141 variants and co-segregation analysis was performed, when possible. Methods: Whole-exome sequencing was performed in 177 CHH patients and 4 50 unrelated, ethnically matched controls from China. Results: Seven novel CCDC141 rare sequencing variants (RSVs) were identified in 12 CHH pedig rees. Four of the variants were private mutations; however, p.Q409X, p.Q871X and p.G1488S were identified in more than one patient. Up to 75% (9/12) of patients had mutations in other CHH-associated ge nes, which is significantly higher than CHH patients without CCDC141 RSVs. The co-segregation analysis for eight CHH families showe d that 75% (6/8) CCDC141 RSVs were inherited from their fertile parents. Over half (58.3%, 8/18) of the patients exhibited other clinical deformities in addition to hypogonadism. One patient harbouring a CCDC141 RSV showed a reversal of CHH after sex-steroid replacement. Conclusions: Our results broaden the genotypic spectrum of CCDC141 in CHH, as CCDC141 RSVs alone do not appear sufficient to cause CHH. The phenotypic spectrum in patien ts with CCDC141 RSVs is much wider than originally believed. [ABSTRACT FROM AUTHOR]

Mutations in the G protein-coupled prokineticin receptor 2 (PKR2) are known to cause Kallmann syndrome and idiopathic hypogonadotropic hypogonadism manifesting with delayed puberty and infertility. Some of the mutant receptors are not routed to the cell surface; instead, they are trapped in the cellular secretory pathway. The cell-permeant agonists/antagonists have been used to rescue some membrane receptors that are not targeted onto the cell membrane. Here, we chose three disease-associated mutations (W178S, G234D, and P290S), which all resulted in retention of PKR2 intracellularly. We show that a small molecule PKR2 antagonist (A457) dramatically increased cell surface expression and rescued the function of P290S PKR2, but had no effect on W178S and G234D PKR2. Furthermore, we also tested chemical chaperone glycerol on the cell surface expression and function of PKR2 mutants. Treatment with 10% glycerol significantly increased the cell surface expression and signaling of P290S and W178S PKR2. These data demonstrate that some Kallmann syndrome-associated, intracellularly retained mutant PKR2 receptors can be functionally rescued, suggesting a potential treatment strategy for patients bearing such mutations. [ABSTRACT FROM AUTHOR]

There has been little study of how the evolution of chemoresistance in cancer affects other aspects of disease pathogenesis. Here, we show that an important chemoresistance axis driven by cytidine deaminase (CDA) also acts to suppress cell-cycle progression by regulating cyclin E-CDK2 signaling. We found that CDA was regulated by miR-484 in a gemcitabine-resistant model of breast cancer. Elevating miR-484 expression reversed the CDA effects, thereby enhancing gemcitabine sensitivity, accelerating cell proliferation, and redistributing cell-cycle progression. Conversely, elevating CDA to restore its expression counteracted the chemosensitization and cell proliferative effects of miR-484. In clinical specimens of breast cancer, CDA expression was frequently downregulated and inversely correlated with miR-484 expression. Moreover, high expression of CDA was associated with prolonged disease-free survival in studied cohorts. Collectively, our findings established that miR-484-modulated CDA has a dual impact in promoting chemoresistance and suppressing cell proliferation in breast cancer, illustrating the pathogenic tradeoffs associated with the evolution of chemoresistance in this malignant disease. [ABSTRACT FROM AUTHOR]