Mitochondrial-derived peptide humanin as therapeutic target in cancer and degenerative diseases

Introduction: Mitochondrial-derived peptides (MDPs) are encoded within the mitochondrial genome. They signal within the cell or are released to act as autocrine/paracrine/endocrine cytoprotective factors playing a key role in the cellular stress response. The first reported and better characterized MDP is humanin (HN), which exerts robust protective effects against a myriad of cytotoxic stimuli in many cell types. These effects have led to the evaluation of HN and its analogs as therapeutic targets for several chronic diseases.

Areas covered: We describe the latest findings on the mechanism of action of HN and discuss the role of HN as therapeutic target for neurodegenerative and cardiovascular diseases, diabetes, male infertility, and cancer. Since HN can be detected in circulation, we also depict its value as a biomarker for these diseases.

Expert opinion: HN analogs and peptide mimetics have been developed over the last decade and show promising results in preclinical models of degenerative diseases. Local administration of gene therapy vectors that overexpress or silence endogenous HN could also hold therapeutic potential. Controversy on the role of HN in cancer progression and chemoresistance should be addressed before the translation of these therapeutic approaches.     

ORIGINAL ARTICLE: Leuprolide stimulation testing for the evaluation of early female sexual maturation

Context Low concentrations of serum LH and/or oestradiol (E₂) in girls with early physical signs of precocious puberty pose a diagnostic challenge. Objective To assess the diagnostic value of the leuprolide stimulation test in female precocious puberty. Design Retrospective Chart Review. Setting Outpatient clinic. Patients and intervention Thirty‐nine girls, 6·9 (1·4) years, with premature stage II–III breast development, with or without pubarche, underwent stimulation testing with subcutaneous leuprolide (20 μg/kg) with the following hormonal measurements in serum: FSH, LH, oestradiol at baseline; FSH and LH at 1 and 2 h; oestradiol at 24 h. Twelve girls with isolated pubarche were also tested with leuprolide. Main outcome measure A pubertal hormonal pattern was defined as at least one of the following: a baseline serum level of LH ≥ 0·3 U/l, a baseline oestradiol ≥ 37 pmol/l (10 ng/l), a stimulated (peak) LH ≥ 5·0 U/l, a stimulated oestradiol ≥ 184 pmol/l (50 ng/l) to leuprolide. The hormonal response was related to the clinical course during a period of observation of at least 6 months. Results Following leuprolide stimulation, the hormonal response was concordant with pubertal progression (n = 23) or lack thereof (n = 16) in all children. At baseline, pubertal serum concentrations of LH and/or oestradiol were associated with pubertal progression in all, while serum prepubertal LH and/or oestradiol concentrations were associated with pubertal progression in approximately 50% of the patients. Conclusions In girls with early clinical signs of precocious puberty and low serum concentrations of LH and oestradiol in random samples, the LH and oestradiol responses to leuprolide stimulation accurately predict pubertal progression.     

Irs2 Inactivation Suppresses Tumor Progression in Pten+/− Mice

Mutations in the phosphatase and tensin homologue (PTEN)/phosphatidylinositol-3 kinase-α (PI3K) signaling pathway are frequently found in human cancer. In addition, Pten^+/− mice develop tumors in multiple organs because of the activation of the PI3K signaling cascade. Because activation of PI3K signaling leads to feedback inhibition of insulin receptor substrate-2 (IRS2) expression, an upstream activator of PI3K, we therefore anticipated that IRS2 expression would be low in tumors that lack PTEN. Surprisingly, however, an elevation of IRS2 was often detected in tumor samples in which PTEN levels were compromised. To determine the potential contribution of Irs2 to tumor progression, Pten^+/− mice were crossed with Irs2^+/− mice. Deletion of Irs2 did not affect the initiation of neoplasia found in Pten^+/− mice but suppressed cancer cell growth, proliferation, and invasion through the basement membrane. Deletion of Irs2 also attenuated the expression of Myc in prostatic intraepithelial neoplasia in Pten^+/− mice. In addition, the expression levels of IRS2 and MYC were highly correlated in human prostate cancer, and IRS2 could stimulate MYC expression in cultured cells. Our findings provide evidence that the PI3K-activating adaptor Irs2 contributes to tumor progression in Pten^+/− mice by stimulating both Myc and DNA synthesis.     

Orthodeoxia without platypnea from interatrial defect associated with persistent left superior vena cava in the absence of pulmonary hypertension

Orthodeoxia-platypnea is a rare but increasingly recognized syndrome of upright hypoxemia usually associated to breathlessness relieved by recumbency. We report the case of isolated orthodeoxia discovered in a military recruit who referred only fatigability as the clinical symptom after a forced march. Transesophageal echocardiography demonstrated the presence of interatrial defect ostium secundum type with the persistence of left superior vena cava draining into coronary sinus. Right-to-left shunt was visualized by peripheral saline contrast infusion, despite normal right hemodynamics at heart catheterization. Hypoxemia recovered after the percutaneous closure of the interatrial defect. Orthodeoxia and platypnea could occur as separate disease manifestations, the latter probably being a rarer acute event, whereas orthodeoxia was underestimated and potentially earlier screenable.