Exosome-Transmitted lncRNA H19 Inhibits the Growth of Pituitary Adenoma.

CONTEXT: Our previous study demonstrated that the expression of long noncoding RNA (lncRNA) H19 was frequently downregulated in human primary pituitary adenomas and negatively correlated with tumor progression. However, the role of exosomal lncRNA H19 in the inhibition of pituitary tumor growth remains unclear. OBJECTIVE: To investigate whether exosomal H19 could be transported across the cell membrane to exert its inhibitory effect on pituitary tumor growth. DESIGN: Empty lentivirus GH3 cells with or without H19 overexpression were used to establish a xenograft model. Isolated exosomes were identified by transmission electron microscopy, nanoparticle tracking, and Western blotting. The expression levels of serum exosomal H19 from 200 healthy subjects and 206 patients with various subtypes of pituitary tumors were detected by ultracentrifugation and quantitative real-time PCR. RESULTS: The growth of distal tumor cells was inhibited by transferring exosomal H19, which could be transported through cell membrane and exert its inhibitory effect. Cabergoline increased H19 expression and played a synergic therapeutic effect with exosomal H19. Exosomal H19 inhibited phosphorylation of the mTORC1 substrate 4E-BP1. Of note, the expression level of exosomal H19 in the patients with all subtypes of pituitary tumors was significantly lower than that in the healthy subjects. The change of plasma exosomal H19 level may be correlated with the prognosis or drug response of the patients. CONCLUSION: Exosomal H19 inhibits the growth of distal pituitary tumors through inhibiting 4E-BP1 phosphorylation. Plasma exosomal H19 may serve as an important biomarker for predicting medical responses of patients with prolactinomas.

Multidisciplinary team efforts improve the surgical outcomes of sellar region lesions during pregnancy.

PURPOSE: Treatment of space-occupying lesions (SOLs) in the sellar region is a clinical challenge, especially in pregnant women because many treatment decisions are restrained due to pregnancy. We attempt to discuss the surgical indications and timing for pregnant patients and highlight the importance of multidisciplinary team (MDT) treatment. METHODS: From August 2017 to February 2018, four pregnant women were admitted to our hospital with severe visual impairment due to sellar region SOLs, including two cases of tuberculum sellae meningioma, one case of giant pituitary adenoma and one case of a pituitary abscess. All four patients were safely treated by surgery during the second and third trimesters of pregnancy through concerted efforts of the MDT, including a neurosurgeon as the team leader in combination with experts in obstetrics, ophthalmology and endocrinology. RESULTS: The SOLs were removed completely from all four patients, resulting in significantly improved vision without operation-related complications. Pregnancy continued postoperatively to full-term delivery in three of the four patients. The other patient with a pituitary abscess selected to terminate the pregnancy at a gestational age of 20 weeks because of her own concerns. The four babies (including a pair of twins) were born healthy and had developed normally at the 6-week postpartum follow-up. CONCLUSIONS: With the MDT guiding the decision-making process, surgical resection of sellar region SOLs in pregnant women with severe visual impairment is practical to improve the prognosis without affecting the outcomes of pregnancy for either the mother or the infant.

DEPTOR inhibits cell proliferation and confers sensitivity to dopamine agonist in pituitary adenoma.

DEP domain-containing mechanistic target of rapamycin (mTOR)-interacting protein (DEPTOR) is an important modulator of mTOR, a highly conserved kinase whose hyperactivation is critically involved in a variety of human tumors. The role of DEPTOR playing in pituitary adenoma (PA) is largely unknown. Here, we reported that DEPTOR was downregulated in PA tissues, especially dopamine-resistant prolactinomas. Consistently, overexpression of DEPTOR inhibited pituitary tumor GH3 and MMQ cells proliferation in vitro and in vivo, and sensitized GH3 and MMQ cells to cabergoline (CAB), a dopamine agonist (DA). Conversely, knockdown of DEPTOR promoted GH3 and MMQ cells proliferation, and conferred cells resistance to CAB. Mechanistically, DEPTOR inhibited both mTOR Complex 1 (mTORC1) and 2 (mTORC2) activities in PA cells. In addition, DEPTOR expression level was increased to suppress mTOR kinase activity via decreasing E3 ubiquitin ligase, ßTrCP1, in response to CAB. Furthermore, DEPTOR enhanced autophagy-dependent cell death to confer cells sensitivity to CAB. Taken together, our results suggest that DEPTOR may be a potential target for the treatment of PAs.

Inhibition of mTORC1 by lncRNA H19 via disrupting 4E-BP1/Raptor interaction in pituitary tumours.

Aberrant expression of long noncoding RNA H19 has been associated with tumour progression, but the underlying molecular tumourigenesis mechanisms remain largely unknown. Here, we report that H19 expression is frequently downregulated in human primary pituitary adenomas and is negatively correlated with tumour progression. Consistently, upregulation of H19 expression inhibits pituitary tumour cell proliferation in vitro and tumour growth in vivo. Importantly, we uncover a function of H19, which controls cell/tumour growth through inhibiting function of mTORC1 but not mTORC2. Mechanistically, we show that H19 could block mTORC1-mediated 4E-BP1 phosphorylation without affecting S6K1 activation. At the molecular level, H19 interacted with 4E-BP1 at the TOS motif and competitively inhibited 4E-BP1 binding to Raptor. Finally, we demonstrate that H19 is more effective than cabergoline treatment in the suppression of pituitary tumours. Together, our study uncovered the role of H19-mTOR-4E-BP1 axis in pituitary tumour growth regulation that may be a potential therapeutic target for human pituitary tumours.

Long-Term Clinical Outcomes of Invasive Giant Prolactinomas after a Mean Ten-Year Followup.

Objective. The aim of this study is to observe clinical outcomes after more than ten years of followup in a group of patients with invasive giant prolactinomas (IGPs) treated with dopamine agonists (DAs). Methods. Twenty-five patients met the criteria of IGPs, among which 16 patients primarily received bromocriptine (BRC) and the other nine had undergone unsuccessful microsurgery prior to BRC treatment. Results. After a mean follow-up period of 135.5 ± 4.7 months, the clinical symptoms in all patients improved by different degrees. Tumor volume was decreased by a mean of 98.6%, and the tumors of 19 patients had almost completely disappeared. The mean duration of treatment at maximal doses of BRC was 48.5 months. At the last follow-up visit, nineteen patients had normal PRL levels, and 14 of these patients had received the low-dose BRC treatment (at an average of 2.9 ± 0.3 mg/d). Younger patients < 25 years had a significantly higher rate of persistent hyperprolactinemia after long-term BRC treatment (p = 0.043). Conclusion. DAs are a first-line therapy for IGPs because they can effectively achieve long-term control in both shrinking tumor volume and normalizing the PRL level, and majority of patients need low-dose DA maintenance. Younger patients are prone to persistent hyperprolactinemia despite long-term DA treatment.

Pathologic changes caused by highly pathogenic H5N1 avian influenza virus: postmortem study of a case / 中华病理学杂志

<p><b>OBJECTIVE</b>To report the postmortem findings of a case of highly pathogenic H5N1 avian influenza virus occurring in human beings.</p><p><b>METHODS</b>Postmortem examination was carried out in a deceased caused by highly pathogenic H5N1 avian influenza virus. Detailed light microscopy of major organs, including heart, lungs, liver, spleen, kidneys and brain, was performed. The lung tissue was further investigated by histochemistry, immunohistochemistry and electron microscopy.</p><p><b>RESULTS</b>Major histopathologic changes in lungs secondary to highly pathogenic H5N1 avian influenza virus included diffuse alveolar damage, hyaline membrane formation and focal hemorrhage. Some of the alveolar spaces contained lightly eosinophilic liquid, lymphocytes, macrophages, plasma cells and small number of neutrophils. Congested capillaries were commonly seen in the alveolar septa which were focally rimmed by hyaline membrane. Immunohistochemical study showed that the lymphocytes were mainly of T lineage and macrophages were also demonstrated.</p><p><b>CONCLUSIONS</b>Highly pathogenic H5N1 avian influenza virus causes pathologic changes mostly in lungs, including diffuse alveolar damage and acute exudative changes (involving mainly T lymphocytes and macrophages). The resulting parenchymal destruction, consolidation, pulmonary edema and hemorrhage eventually lead to respiratory distress and death.</p>