Explore the vast range of titles available.

Growth hormone (GH) research and its clinical application for the treatment of growth disorders span more than a century. During the first half of the 20th century, clinical observations and anatomical and biochemical studies formed the basis of the understanding of the structure of GH and its various metabolic effects in animals. The following period (1958-1985), during which pituitary-derived human GH was used, generated a wealth of information on the regulation and physiological role of GH -- in conjunction with insulin-like growth factors (IGFs) -- and its use in children with GH deficiency (GHD). The following era (1985 to present) of molecular genetics, recombinant technology and the generation of genetically modified biological systems has expanded our understanding of the regulation and role of the GH-IGF axis. Today, recombinant human GH is used for the treatment of GHD and various conditions of non-GHD short stature and catabolic states; however, safety concerns still accompany this therapeutic approach. In the future, new therapeutics based on various components of the GH-IGF axis might be developed to further improve the treatment of such disorders. In this Review, we describe the history of GH research and clinical use with a particular focus on disorders in childhood.

Key Points Thyroid hormones have a direct effect on the heart Patients with hypothyroidism or hyperthyroidism have increased risk of cardiovascular disease Treatment with thyroid hormones in patients with hypothyroidism improves cardiovascular risk factors, but the effect on cardiovascular events has not been assessed in randomized, controlled trials In experimental settings, thyroid hormones influence myocardial remodelling and function after myocardial infarction, but the utility of thyroid hormone replacement therapy in patients with acute cardiac events is yet to be elucidated Intracellular and circulating thyroid hormone concentrations (mainly T 3 ) decrease after acute myocardial infarction and in chronic heart failure, and this reduction is associated with poor outcomes Small studies showed that treatment with thyroid hormones is safe and beneficial in patients with chronic heart failure; however, larger, adequately powered trials are required to confirm safety and assess efficacy Thyroid hormones have an important role in maintaining cardiovascular homeostasis, and subtle changes in thyroid hormone concentrations adversely influence the cardiovascular system. In this Review, Jabbar et al . discuss the role of thyroid hormones in the pathogenesis and management of cardiovascular diseases such as heart failure and acute myocardial infarction, and outline the utility of therapy with thyroid hormones for the management of these conditions. Myocardial and vascular endothelial tissues have receptors for thyroid hormones and are sensitive to changes in the concentrations of circulating thyroid hormones. The importance of thyroid hormones in maintaining cardiovascular homeostasis can be deduced from clinical and experimental data showing that even subtle changes in thyroid hormone concentrations — such as those observed in subclinical hypothyroidism or hyperthyroidism, and low triiodothyronine syndrome — adversely influence the cardiovascular system. Some potential mechanisms linking the two conditions are dyslipidaemia, endothelial dysfunction, blood pressure changes, and direct effects of thyroid hormones on the myocardium. Several interventional trials showed that treatment of subclinical thyroid diseases improves cardiovascular risk factors, which implies potential benefits for reducing cardiovascular events. Over the past 2 decades, accumulating evidence supports the association between abnormal thyroid function at the time of an acute myocardial infarction (MI) and subsequent adverse cardiovascular outcomes. Furthermore, experimental studies showed that thyroid hormones can have an important therapeutic role in reducing infarct size and improving myocardial function after acute MI. In this Review, we summarize the literature on thyroid function in cardiovascular diseases, both as a risk factor as well as in the setting of cardiovascular diseases such as heart failure or acute MI, and outline the effect of thyroid hormone replacement therapy for reducing the risk of cardiovascular disease.

Prostate cancer is the second-leading cause of cancer-related mortality in men in Western societies. Androgen receptor (AR) signaling is a critical survival pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. Although a majority of patients initially respond to ADT, most will eventually develop castrate resistance, defined as disease progression despite serum testosterone levels of <20 ng/dl. The recent discovery that AR signaling persists during systemic castration via intratumoral production of androgens led to the development of novel anti-androgen therapies including abiraterone acetate and enzalutamide. Although these agents effectively palliate symptoms and prolong life, metastatic castration-resistant prostate cancer remains incurable. An increased understanding of the mechanisms that underlie the pathogenesis of castrate resistance is therefore needed to develop novel therapeutic approaches for this disease. The aim of this review is to summarize the current literature on the biology and treatment of castrate-resistant prostate cancer.

Key Points The use of hormone-replacement therapy (HRT) has been vigorously debated Earlier observational data showed many benefits of HRT, which include reduced coronary heart disease (CHD) and mortality Randomized trials in older women (aged >60 years) have shown no benefit and increased harm Reassessment of clinical trials in women initiating treatment close to the onset of menopause and newer studies and meta-analyses now show benefit and rare risks More studies show benefit with oestrogen alone than with oestrogen plus progestogen The effects of reduced CHD and mortality in women initiating therapy around menopause suggest a possible role for HRT in primary prevention Clinical practice regarding the use of hormone-replacement therapy (HRT) has undergone many changes since its introduction in the 1940s. Here, Roger Lobo frames the current thinking on the use of HRT in postmenopausal women, beginning with a historical perspective and then discussing how the interpretation of HRT data has changed over time. For several decades, the role of hormone-replacement therapy (HRT) has been debated. Early observational data on HRT showed many benefits, including a reduction in coronary heart disease (CHD) and mortality. More recently, randomized trials, including the Women's Health Initiative (WHI), studying mostly women many years after the the onset of menopause, showed no such benefit and, indeed, an increased risk of CHD and breast cancer, which led to an abrupt decrease in the use of HRT. Subsequent reanalyzes of data from the WHI with age stratification, newer randomized and observational data and several meta-analyses now consistently show reductions in CHD and mortality when HRT is initiated soon after menopause. HRT also significantly decreases the incidence of various symptoms of menopause and the risk of osteoporotic fractures, and improves quality of life. In younger healthy women (aged 50–60 years), the risk–benefit balance is positive for using HRT, with risks considered rare. As no validated primary prevention strategies are available for younger women (<60 years of age), other than lifestyle management, some consideration might be given to HRT as a prevention strategy as treatment can reduce CHD and all-cause mortality. Although HRT should be primarily oestrogen-based, no particular HRT regimen can be advocated.

Prostate tumors develop resistance to androgen deprivation therapy (ADT) by multiple mechanisms, one of which is to express constitutively active androgen receptor (AR) splice variants lacking the ligand-binding domain. AR splice variant 7 (AR-V7, also termed AR3) is the most abundantly expressed variant that drives prostate tumor progression under ADT conditions. However, the molecular mechanism by which AR-V7 is generated remains unclear. In this manuscript, we demonstrated that RNA splicing of AR-V7 in response to ADT was closely associated with AR gene transcription initiation and elongation rates. Enhanced AR gene transcription by ADT provides a prerequisite condition that further increases the interactions between AR pre-mRNA and splicing factors. Under ADT conditions, recruitment of several RNA splicing factors to the 3′ splicing site for AR-V7 was increased. We identified two RNA splicing enhancers and their binding proteins (U2AF65 and ASF/SF2) that had critical roles in splicing AR pre-mRNA into AR-V7. These data indicate that ADT-induced AR gene transcription rate and splicing factor recruitment to AR pre-mRNA contribute to the enhanced AR-V7 levels in prostate cancer cells.

Background: Adjuvant endocrine therapy is recommended for women with oestrogen receptor-positive breast cancer, but many women do not take the medication as directed and they stop treatment before completing the standard 5-year duration. Methods: This retrospective cohort study conducted between 1993 and 2008 of all women with incident breast cancer, who are residing in the Tayside region of Scotland, examined adherence to prescribed adjuvant tamoxifen or aromatase inhibitors (AIs). Survival analysis examined the effect of adherence on all-cause mortality, breast cancer death and recurrence, using linked prescribing, cancer registry, clinical cancer audit, hospital discharge and death records. Results: A total of 3361 women with breast cancer were followed for a median 4.47 years (interquartile range (IQR)=2.04–8.55). The median overall adherence was 90% (IQR=90–100%), but the annual adherence reduced after a longer period from diagnosis. Low adherence of <80% was associated with poorer survival (hazard ratios=1.20; 95% confidence interval=1.03–1.40, P =0.019). There was no significant difference for low adherence over the treatment period and recurrence, or breast cancer death, but patients with high annual adherence for 5 years had better outcomes than those with 3 or less. Conclusion: Low adherence to all adjuvant endocrine therapy for women with breast cancer, whether tamoxifen or AI, increases the risk of death.

Lymphotoxin's role in prostate cancer progression In the early stages of prostate cancer, cancerous cell growth is dependent on androgens, hence the success of prostatectomy, radiation and androgen-ablating drug therapies. With time, the cancer often develops into an androgen-insensitive, therapy-resistant form with high mortality rates. Work in mouse models of prostate cancer raises the possibility that androgen-ablating therapies may indirectly promote the development of metastatic secondary tumours. Ammirante et al . report that in mice with transgene-induced spontaneous prostate cancer, B-cell infiltration, a component of the natural inflammatory response, activates lymphotoxin release, which stimulates metastasis. In the second model, involving subcutaneous transplantation of an androgen-dependent prostate cancer cell line, it is shown that regression of androgen-deprived primary tumours results in an inflammatory response — and lymphotoxin production. Interfering with the lymphotoxin pathway may therefore offer therapeutic strategies for androgen-independent prostate cancer. In a mouse model of prostate cancer it is shown that infiltrating B cells promote tumorigenesis by secreting lymphotoxin. Lymphotoxin accelerates the emergence of castration-resistant prostate tumours in this model. Interfering with this pathway may offer therapeutic strategies for androgen-independent prostate cancer. Prostate cancer (CaP) progresses from prostatic intraepithelial neoplasia through locally invasive adenocarcinoma to castration-resistant metastatic carcinoma 1 . Although radical prostatectomy, radiation and androgen ablation are effective therapies for androgen-dependent CaP, metastatic castration-resistant CaP is a major complication with high mortality 2 . Androgens stimulate growth and survival of prostate epithelium and early CaP. Although most patients initially respond to androgen ablation, many develop castration-resistant CaP within 12–18 months 2 . Despite extensive studies, the mechanisms underlying the emergence of castration-resistant CaP remain poorly understood and their elucidation is critical for developing improved therapies. Curiously, castration-resistant CaP remains androgen-receptor dependent, and potent androgen-receptor antagonists induce tumour regression in castrated mice 3 . The role of inflammation in castration-resistant CaP has not been addressed, although it was reported that intrinsic NF-κB activation supports its growth 4 . Inflammation is a localized protective reaction to injury or infection, but it also has a pathogenic role in many diseases, including cancer 5 . Whereas acute inflammation is critical for host defence, chronic inflammation contributes to tumorigenesis and metastatic progression. The inflammation-responsive IκB kinase (IKK)-β and its target NF-κB have important tumour-promoting functions within malignant cells and inflammatory cells 6 . The latter, including macrophages and lymphocytes, are important elements of the tumour microenvironment 7 , 8 , 9 , but the mechanisms underlying their recruitment remain obscure, although they are thought to depend on chemokine and cytokine production 10 . We found that CaP progression is associated with inflammatory infiltration and activation of IKK-α, which stimulates metastasis by an NF-κB-independent, cell autonomous mechanism 11 . Here we show that androgen ablation causes infiltration of regressing androgen-dependent tumours with leukocytes, including B cells, in which IKK-β activation results in production of cytokines that activate IKK-α and STAT3 in CaP cells to enhance hormone-free survival.

Key Points Approximately 10% of cancers in women occur in those <45 years old, and in the USA, the number of new cases of invasive cancer diagnosed in women during 2012 was almost 800,000 Chemotherapy, radiotherapy, surgery and bone marrow transplantation have led to a considerable improvement in survival rates, but these treatments can result in premature ovarian failure (POF) The risk of POF depends on the follicular reserve, the age of the patient and the type and dose of drugs used Different options exist to preserve fertility in women at risk of POF, including ovarian transposition, embryo and oocyte cryopreservation, and ovarian tissue cryopreservation In prepubertal girls or patients requiring immediate chemotherapy, ovarian tissue cryopreservation is the only method currently available Medical therapy (with a gonadotropin-releasing hormone agonist) before chemotherapy is still controversial Advances in cancer therapy over the past two decades have resulted in more patients surviving for longer after treatment. As many therapies can cause premature ovarian failure (POF), infertility in female cancer patients now needs to be addressed. This Review analyses the options that are currently available to preserve fertility in female patients with cancer and in women at risk of POF. In women, ∼10% of cancers occur in those <45 years old. Chemotherapy, radiotherapy and bone marrow transplantation can cure >90% of girls and young women with diseases that require such treatments. However, these treatments can result in premature ovarian failure, depending on the follicular reserve, the age of the patient and the type and dose of drugs used. This article discusses the different fertility preservation strategies: medical therapy before chemotherapy; ovarian transposition; embryo cryopreservation; oocyte vitrification; and ovarian tissue cryopreservation. The indications, results and risks of these options are discussed. Whether medical therapy should be used to protect the gonads during chemotherapy remains a source of debate. Fertility preservation needs to be completed before chemotherapy and/or irradiation is started and might take 2–3 weeks with established techniques such as embryo or oocyte cryopreservation. Further studies are needed in patients with cancer to confirm the excellent outcomes obtained in patients without cancer or in egg donation programmes. For prepubertal girls or cases where immediate therapy is required, cryopreservation of ovarian tissue is the only available option. Finally, possible future approaches are reviewed, including in vitro maturation of nonantral follicles, the artificial ovary, oogonial stem cells and drugs to prevent follicle loss.

Key Points In addition to phenotypic differences, recently discovered differences in genetic mutations between metastatic and early stage breast cancer mean the advanced state can be considered a different disease New mutations in genes, such as ESR1 , provide direct evidence of an evolving disease that likely confers treatment resistance and represent targets for future therapies Other molecular adaptations that can occur in advanced disease also offer promising therapeutic targets using agents such as mTOR, CD4/6 and PI3K inhibitors During metastasis, a switch to oestrogen receptor (ER) or HER2 positive disease is a recognized phenomenon, but the value of altering therapy on the basis of such changes is unclear No biomarkers exist to guide endocrine or biological therapy choices in metastatic disease; however, an appreciation of the clinical evidence of resistance may help Everolimus plus exemestane may be preferable after all lines of single agent endocrine therapy have been employed, and possibly following single-agent chemotherapy Hormone-receptor-positive breast cancer accounts for the majority of all breast cancers. The evolution of this disease from early stage to the metastatic setting leads to increased heterogeneity and the development of treatment resistance representing a great challenge for management decisions. In this Review, we examine the current evidence that can guide treatment decisions in patients with advanced-stage ER+ breast cancer, discuss how to tackle these therapeutic challenges and provide suggestions for the optimal management of this patient population. Hormone-receptor-positive breast cancer accounts for the majority—up to 80%—of all breast cancers. The evolution of breast cancer from early stage to the metastatic setting leads to increased heterogeneity, the occurrence of new mutations, and the development of treatment resistance representing a great challenge for management decisions. Unfortunately, little data exist to offer guidance in this context, and a reliance on traditional clinical parameters remains when deciding on optimal treatment. In advanced-stage oestrogen receptor-positive (ER+) disease, ongoing issues include the choice between endocrine therapy and chemotherapy, the appropriate sequence of treatment agents, and the incorporation of biological agents, such as everolimus, into the treatment armamentarium. In metastatic disease, repeated biopsies can help to reassess the receptor or genetic mutational status; however, the evidence to support this approach is limited. In this Review, we examine the current evidence that can guide treatment decisions in patients with advanced-stage ER+ breast cancer, discuss how to tackle these therapeutic challenges and provide suggestions for the optimal management of this patient population.

Background: Hepatocellular carcinoma (HCC) growth relies on angiogenesis via vascular endothelial growth factor (VEGF) release. Hypoxia within tumour environment leads to intracellular stabilisation of hypoxia inducible factor 1 alpha (Hif1 α ) and signal transducer and activator of transcription (STAT3). Melatonin induces apoptosis in HCC, and shows anti-angiogenic features in several tumours. In this study, we used human HepG2 liver cancer cells as an in vitro model to investigate the anti-angiogenic effects of melatonin. Methods: HepG2 cells were treated with melatonin under normoxic or CoCl 2 -induced hypoxia. Gene expression was analysed by RT–qPCR and western blot. Melatonin-induced anti-angiogenic activity was confirmed by in vivo human umbilical vein endothelial cells (HUVECs) tube formation assay. Secreted VEGF was measured by ELISA. Immunofluorescence was performed to analyse Hif1 α cellular localisation. Physical interaction between Hif1 α and its co-activators was analysed by immunoprecipitation and chromatin immunoprecipitation (ChIP). Results: Melatonin at a pharmacological concentration (1 m M ) decreases cellular and secreted VEGF levels, and prevents HUVECs tube formation under hypoxia, associated with a reduction in Hif1 α protein expression, nuclear localisation, and transcriptional activity. While hypoxia increases phospho-STAT3, Hif1 α , and CBP/p300 recruitment as a transcriptional complex within the VEGF promoter, melatonin 1 m M decreases their physical interaction. Melatonin and the selective STAT3 inhibitor Stattic show a synergic effect on Hif1 α , STAT3, and VEGF expression. Conclusion: Melatonin exerts an anti-angiogenic activity in HepG2 cells by interfering with the transcriptional activation of VEGF, via Hif1 α and STAT3. Our results provide evidence to consider this indole as a powerful anti-angiogenic agent for HCC treatment.