Hereditary Neuroendocrine Tumors: Providing Comprehensive Care for Individuals Who Have a Germline Pathogenic Variant Associated With Paragangliomas and Pheochromocytomas.

Both paragangliomas and pheochromocytomas can be associated with germline pathogenic variants. Although these neuroendocrine tumors are relatively rare, the identification of patients and families with germline risk enables the implementation of surveillance programs to decrease the morbidity and mortality associated with these tumors. Individuals with germline risk require lifelong screening, which is implemented as early as age 5 years. In addition to ensuring that surveillance protocols are implemented, nurses provide education about symptoms that require prompt evaluation.

Assessment of the potential activity of major dietary compounds as selective estrogen receptor modulators in two distinct cell models for proliferation and differentiation.

Estrogen receptors (ERs) α and ß are distributed in most tissues of women and men. ERs are bound by estradiol (E2), a natural hormone, and mediate the pleiotropic and tissue-specific effects of E2, such as proliferation of breast epithelial cells or protection and differentiation of neuronal cells. Numerous environmental molecules, called endocrine disrupting compounds, also interact with ERs. Phytoestrogens belong to this large family and are considered potent therapeutic molecules that act through their selective estrogen receptor modulator (SERM) activity. Using breast cancer cell lines as a model of estrogen-dependent proliferation and a stably ER-expressing PC12 cell line as a model of neuronal differentiating cells, we studied the SERM activity of major dietary compounds, such as apigenin, liquiritigenin, daidzein, genistein, coumestrol, resveratrol and zearalenone. The ability of these compounds to induce ER-transactivation and breast cancer cell proliferation and enhance Nerve Growth Factor (NGF) -induced neuritogenesis was assessed. Surprisingly, although all compounds were able to activate the ER through an estrogen responsive element reporter gene, they showed differential activity toward proliferation or differentiation. Apigenin and resveratrol showed a partial or no proliferative effect on breast cancer cells but fully contributed to the neuritogenesis effect of NGF. However, daidzein and zearalenone showed full effects on cellular proliferation but did not induce cellular differentiation. In summary, our results suggest that the therapeutic potential of phytoestrogens can diverge depending on the molecule and the phenotype considered. Hence, apigenin and resveratrol might be used in the development of therapeutics for breast cancer and brain diseases.

A rare case of juvenile hypertension: coexistence of type 2 multiple endocrine neoplasia -related bilateral pheochromocytoma and reninoma in a young patient with ACE gene polymorphism.

BACKGROUND: Pheochromocytoma and reninoma represent two rare diseases causing hypertension. We here reported a rare case of association between type 2 multiple endocrine neoplasia related bilateral pheochromocytoma and reninoma. Moreover, polymorphism of ACE gene, which is known to be related to an increase of cardiovascular risk, has been found in the same patient. CASE PRESENTATION: A 24 year old Caucasian man came to our attention for severe hypertension, resistant to anti-hypertensive polytherapy. At the age of twenty he had undergone total thyroidectomy with lymphadenectomy for medullary carcinoma. Genetic testing showed a RET mutation of codon 918 (exon 16) not documented in other family members. During the follow-up, a progressive increase of urinary metanephrines and catecholamines was recorded. Our evaluation confirmed the presence of severe hypertension (220/140 mmHg) and a severe increase of urinary catecholamines and metanephrines. Due to the presence of hypokalemia, other causes of hypertension were researched leading to the discovery of hyperreninemia (236 µUI/ml) with mild hyperaldosteronism, and a mild increase of the renal artery resistance at ultrasound. An abdominal MRI showed multiple adrenal masses and a right kidney nodular lesion of about 2 cm. The patient underwent bilateral adrenalectomy and right nephrectomy, and histology confirmed the presence of bilateral pheochromocytoma and right reninoma. The post-surgery laboratory evaluation showed a rapid reduction of the urinary metanephrines while plasma renin level remained low in spite of the bilateral adrenalectomy without any mineralocorticoid supplementation. To further investigate these unusual feature, we performed genetic testing for the ACE gene, which revealed the presence of ACE I/D polymorphism. CONCLUSION: This unique report describes the association between two rare causes of hypertension in the same patient. Furthermore, the absence of requirement of mineralocorticoid supplementation in spite of bilateral adrenalectomy, represent an uncommon and interest finding.

Osthole attenuates doxorubicin-induced apoptosis in PC12 cells through inhibition of mitochondrial dysfunction and ROS production.

Doxorubicin (DOX) is a potent, broad-spectrum chemotherapeutic drug used for treatment of several types of cancers. Despite its effectiveness, it has a wide range of toxic side effects, many of which most likely result from its inherent prooxidant activity. It has been reported that DOX has toxic effects on normal tissues, including brain tissue. In the current study, we investigated the protective effect of osthole isolated from Prangos ferulacea (L.) Lindl. on oxidative stress and apoptosis induced by DOX in PC12 as a neuronal model cell line. PC12 cells were pretreated with osthole 2 h after treatment with different concentrations of DOX. 24 h later, the cell viability, mitochondrial membrane potential (MMP), the activity of caspase-3, the expression ratio of Bax/Bcl-2, and the generation of intracellular ROS were detected. We found that pretreatment with osthole on PC12 cells significantly reduced the loss of cell viability, the activity of caspase-3, the increase in Bax/Bcl-2 ratio, and the generation of intracellular ROS induced by DOX. Moreover, pretreatment with osthole led to an increase in MMP in PC12 cells. In conclusion, our results indicated that pretreatment with nontoxic concentrations of osthole protected PC12 cells from DOX-mediated apoptosis by inhibition of ROS production.

NID67, a small putative membrane protein, is preferentially induced by NGF in PC12 pheochromocytoma cells.

In an effort to identify genes involved in neuronal differentiation, we have used representational difference analysis (RDA) to clone cDNAs that are preferentially induced by nerve growth factor (NGF) vs. epidermal growth factor (EGF) in PC12 pheochromocytoma cells. We now report the cloning of a previously unknown primary response gene, NID67. In addition to a robust induction by NGF and FGF, both of which cause PC12 cells to differentiate, NID67 is strongly induced by forskolin, A23187 and ATP. EGF, TPA and KCl induce NID67 only weakly. NID67 mRNA is most abundant in heart, ovary and adrenal. Modest levels are present in most brain regions, testis, thyroid, thymus, pituitary, kidney and intestine; little NID67 is present in skeletal muscle and cerebellum. The NID67 cDNA contains a 180 bp open reading frame (ORF) that encodes a 60 amino acid protein. The central 29 amino acids are very hydrophobic and very likely comprise a transmembrane domain. Mouse and human NID67 cDNAs contain an ORF similar to NID67; the rat and human protein sequences are 85% identical whereas the rat and mouse sequences are 92% identical. In vitro transcription and translation reactions confirmed that the ORF we identified produces a 6000 Da protein product. Several small membrane proteins are similar to NID67; they contain a transmembrane domain and little more. All of these proteins participate in forming or regulating ion channels. NID67 may play a similar role in cellular physiology.

Cloning and characterization of cDNAs for novel proteins with glutamic acid-proline dipeptide tandem repeats.

cDNAs with identical 3' sequences containing a hexanucleotide repeat -(GAGCCG)9- were isolated from rat pheochromocytoma and brain cDNA libraries. The cDNA with the longest open reading frame codes for a protein of 24.6 kDa containing a 16-fold -(Glu-Pro)- dipeptide repeat within a glutamate and proline rich region at its deduced C-terminus. cDNAs with the identical 3' sequence and a divergent 5' sequence were isolated from a rat skeletal muscle cDNA library. The latter are predicted to code for a protein of 15.5 kDa with a C-terminal repetitive domain identical to that in the pheochromocytoma and brain cDNAs. The cDNAs recognize a 1.8 kb mRNA species present in a variety of tissues, being particularly abundant in cardiac and skeletal muscle.