Vascular NRP2 triggers PNET angiogenesis by activating the SSH1-cofilin axis.

BACKGROUND: Angiogenesis is a critical step in the growth of pancreatic neuroendocrine tumors (PNETs) and may be a selective target for PNET therapy. However, PNETs are robustly resistant to current anti-angiogenic therapies that primarily target the VEGFR pathway. Thus, the mechanism of PNET angiogenesis urgently needs to be clarified. METHODS: Dataset analysis was used to identify angiogenesis-related genes in PNETs. Immunohistochemistry was performed to determine the relationship among Neuropilin 2 (NRP2), VEGFR2 and CD31. Cell proliferation, wound-healing and tube formation assays were performed to clarify the function of NRP2 in angiogenesis. The mechanism involved in NRP2-induced angiogenesis was detected by constructing plasmids with mutant variants and performing Western blot, and immunofluorescence assays. A mouse model was used to evaluate the effect of the NRP2 antibody in vivo, and clinical data were collected from patient records to verify the association between NRP2 and patient prognosis. RESULTS: NRP2, a VEGFR2 co-receptor, was positively correlated with vascularity but not with VEGFR2 in PNET tissues. NRP2 promoted the migration of human umbilical vein endothelial cells (HUVECs) cultured in the presence of conditioned medium PNET cells via a VEGF/VEGFR2-independent pathway. Moreover, NRP2 induced F-actin polymerization by activating the actin-binding protein cofilin. Cofilin phosphatase slingshot-1 (SSH1) was highly expressed in NRP2-activating cofilin, and silencing SSH1 ameliorated NRP2-activated HUVEC migration and F-actin polymerization. Furthermore, blocking NRP2 in vivo suppressed PNET angiogenesis and tumor growth. Finally, elevated NRP2 expression was associated with poor prognosis in PNET patients. CONCLUSION: Vascular NRP2 promotes PNET angiogenesis by activating the SSH1/cofilin/actin axis. Our findings demonstrate that NRP2 is an important regulator of angiogenesis and a potential therapeutic target of anti-angiogenesis therapy for PNET.

Erectile dysfunction in Fragile X patients.

AIM: To report the clinical experience during collecting sperm samples in the Fragile X syndrome (FXS) male patients. METHODS: Two different polymerase chain reaction (PCR) based methods were used for the molecular diagnosis of FXS. Sperm collection was done mostly according to the laboratory manual of the World Health Organization. RESULTS: We failed to collect sperm samples from five Fragile X subjects aged 18-60 years as a result of an unexpected erectile dysfunction (ED). Multiple examinations of the same subject at different times, and of different subjects from different provinces examined by different physicians, showed the same result consistently in all the five subjects. CONCLUSION: Erectile reflex is an instinctive response in all healthy males. The absence of erection can be caused by hormonal, physical or neuronal malfunction. As hormonal profiles were reported to be generally normal in Fragile X men, we propose that an unknown physical factor or the neuronal circuit, or both, underlying the erection is compromised. The finding of this symptom in Fragile X patients may help better understand the clinical spectrum and pathogeneses of the disease.

[Clinical characteristics and genetic analyses of familial recurrent moles].

OBJECTIVE: To probe the clinical characteristics and genetic origin of familial recurrent mole (FRM). METHODS: Two cases of FRM were reported retrospectively. Microsatellite polymorphism was used to determine the genetic origin of the two FRM and other six sporadic moles from other independent families. RESULTS: The two FRM patients came from two independent families. Both of them had more than two times of hydatidiform moles and the same condition had happened to their sisters. The last mole from each of these two patients was identified as biparental complete hydatidiform mole (BiCHM). Among the six sporadic moles, one was partial hydatidiform mole (PHM), which was identified as triploid with one haploid maternal set of chromosomes and two haploid paternal sets of chromosomes. The other five sporadic moles were all androgenetic complete hydatidiform mole (AnCHM), which lacked maternal genetic material. The two women with FRM developed into persistent trophoblastic disease (PTD) and gained complete remission (CR) after medical therapy and/or pulmonary lobectomy. CONCLUSIONS: FRM is exceedingly rare. Most of them are biparental in origin. It ought to be an important step to identify the genetic origin in evaluating the outcomes of the women with recurrent hydatidiform moles.

[Novel mutation of fibrillin 1 gene cause ectopia lentis in a Chinese family].

OBJECTIVE: To identify the mutation gene of a Chinese family with ectopia lentis. METHODS: Clinical observation and pedigree analysis were undertaken in a family with ectopia lentis. Venous blood was drawn from 7 affected and 3 unaffected subjects. Genomic DNA was extracted. Linkage to the fibrillin 1 (FBN1) locus was not excluded. Mutation of this gene was screened by PCR of FBN1 exons and direct sequencing. PCR and restrictive endonuclease digestion were applied for population study. RESULTS: A missense mutation G640A in exon six of FBN1 gene was identified in affected patients of this Chinese family. The correspond amino acid change was Gly214Ser. Restrictive endonuclease site Eag I was eliminated. This mutation was not found in unaffected family members of this family nor it was found among 50 unrelated normal controls. CONCLUSIONS: A novel mutation of FBN1 gene with Glycine to Serine change is responsible for the ectopia lentis patients in a Chinese family.