THE JEREMIAH METZGER LECTURE: A BRIEF HISTORY OF EUGENICS IN AMERICA: IMPLICATIONS FOR MEDICINE IN THE 21 CENTURY.

In the first half of the 20 century, the US was swept up in a multifaceted movement to enhance the genetic makeup of the country's population. This eugenics movement, based on flawed scientific principles promulgated by Galton in the UK and Davenport in the US included legally mandated compulsory sterilization in 27 states in the US and sharply restricted immigration from many parts of the world. Compulsory sterilization legislation was upheld by the Supreme Court in 1927.

A double negative: inhibition of hepatic Gi signaling improves glucose homeostasis.

Hepatic glucose production (HGP) is a key determinant of glucose homeostasis. Glucagon binding to its cognate seven-transmembrane Gs-coupled receptor in hepatocytes stimulates cAMP production, resulting in increased HGP. In this issue of the JCI, Rossi and colleagues tested the hypothesis that activation of hepatic Gi-coupled receptors, which should inhibit cAMP production, would oppose the cAMP-inducing action of glucagon and thereby decrease HGP.

Allosteric Modulation of the Calcium-sensing Receptor Rectifies Signaling Abnormalities Associated with G-protein α-11 Mutations Causing Hypercalcemic and Hypocalcemic Disorders.

Germline loss- and gain-of-function mutations of G-protein α-11 (Gα11), which couples the calcium-sensing receptor (CaSR) to intracellular calcium (Ca(2+) i) signaling, lead to familial hypocalciuric hypercalcemia type 2 (FHH2) and autosomal dominant hypocalcemia type 2 (ADH2), respectively, whereas somatic Gα11 mutations mediate uveal melanoma development by constitutively up-regulating MAPK signaling. Cinacalcet and NPS-2143 are allosteric CaSR activators and inactivators, respectively, that ameliorate signaling disturbances associated with CaSR mutations, but their potential to modulate abnormalities of the downstream Gα11 protein is unknown. This study investigated whether cinacalcet and NPS-2143 may rectify Ca(2+) i alterations associated with FHH2- and ADH2-causing Gα11 mutations, and evaluated the influence of germline gain-of-function Gα11 mutations on MAPK signaling by measuring ERK phosphorylation, and assessed the effect of NPS-2143 on a uveal melanoma Gα11 mutant.

The Calcilytic Agent NPS 2143 Rectifies Hypocalcemia in a Mouse Model With an Activating Calcium-Sensing Receptor (CaSR) Mutation: Relevance to Autosomal Dominant Hypocalcemia Type 1 (ADH1).

Autosomal dominant hypocalcemia type 1 (ADH1) is caused by germline gain-of-function mutations of the calcium-sensing receptor (CaSR) and may lead to symptomatic hypocalcemia, inappropriately low serum PTH concentrations and hypercalciuria. Negative allosteric CaSR modulators, known as calcilytics, have been shown to normalize the gain-of-function associated with ADH-causing CaSR mutations in vitro and represent a potential targeted therapy for ADH1. However, the effectiveness of calcilytic drugs for the treatment of ADH1-associated hypocalcemia remains to be established.

Research in academic medical centers: two threats to sustainable support.

Reductions in federal support and clinical revenue jeopardize biomedical research and, in turn, clinical medicine.

The stem cell wars: a dispatch from the front.

The development of human embryonic stem cell (hESC) lines in 1998 offered the prospect of a new era of regenerative medicine in which cell therapy might cure intractable diseases such as type 1 diabetes, Parkinson's disease, and spinal cord injury. The Bush Administration decision in 2001 to restrict federal funding of hESC research touched off a controversy that continues to the present. One response to the Bush policy was establishment of state stem cell research funding programs, notably the California Institute of Regenerative Medicine (CIRM).

'Personalized medicine' to identify genetic risks for type 2 diabetes and focus prevention: can it fulfill its promise?

Public health measures are required to address the worldwide increase in type 2 diabetes. Proponents of personalized medicine predict a future in which disease treatment and, more important, prevention will be tailored to high-risk individuals rather than populations and will be based on genetic and other new biomarker tests. Accurate biomarker tests to identify people at risk for diabetes could allow more-targeted and perhaps individualized prevention efforts.

Future diagnostic and therapeutic trends in endocrine cancers.

Current treatment of endocrine cancers relies primarily on surgical resection, which is generally effective only for localized disease. Radioactive iodine treatment is an important modality for those thyroid cancers that maintain the ability to take up iodine. For endocrine cancers that are no longer localized, current modes of therapy, including various combinations of chemotherapy and radiation, are inadequate, posing a major challenge to ongoing research to develop more effective methods for diagnosis and treatment.

Commentary: new guidelines for NIH peer review: improving the system or undermining it?

The National Institutes of Health (NIH) peer review system has been viewed as the best way to guarantee the scientific independence of biomedical research in the United States, and it has been emulated internationally. The system, however, is subject to a variety of stresses, and these have always been exacerbated at times of flat NIH funding, as in the past five years. To address several of these stresses, NIH first conducted a "diagnostic self-study" of the peer review system and then implemented a number of changes.

Recapitulation of pancreatic neuroendocrine tumors in human multiple endocrine neoplasia type I syndrome via Pdx1-directed inactivation of Men1.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal syndrome caused by mutations in the MEN1 tumor suppressor gene. Whereas the protein product of MEN1, menin, is ubiquitously expressed, somatic loss of the remaining wild-type MEN1 allele results in tumors primarily in parathyroid, pituitary, and endocrine pancreas. To understand the endocrine specificity of the MEN1 syndrome, we evaluated biallelic loss of Men1 by inactivating Men1 in pancreatic progenitor cells using the Cre-lox system.

Parathyroid tumor development involves deregulation of homeobox genes.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome caused by mutations in the MEN1 tumor suppressor gene. Loss of the functional second copy of the MEN1 gene causes individuals to develop multiple endocrine tumors, primarily affecting the parathyroid, pituitary, and pancreas. While it is clear that the protein encoded by MEN1, menin, suppresses endocrine tumors, its biochemical functions and direct downstream targets remain unclear.

Inherited endocrine diseases involving G proteins and G protein-coupled receptors.

Naturally occurring mutations in the G protein Gs-alpha subunit and in a number of G protein-coupled receptors (GPCRs) have been identified in human diseases. Loss-of-function mutations in GPCRs for various hormones lead to hormone resistance manifest as hypofunction of the gland expressing the affected GPCR. Conversely, GPCR gain-of-function mutations lead to hormone-independent activation and hyperfunction of the involved gland.

Structure and function of the human calcium-sensing receptor: insights from natural and engineered mutations and allosteric modulators.

The human extracellular Ca(2+)-sensing receptor (CaR), a member of the G protein-coupled receptor family 3, plays a key role in the regulation of extracellular calcium homeostasis. It is one of just a few G protein-coupled receptors with a large number of naturally occurring mutations identified in patients. In contrast to the small sizes of its agonists, this large dimeric receptor consists of domains with topologically distinctive orthosteric and allosteric sites.

Distribution of menin-occupied regions in chromatin specifies a broad role of menin in transcriptional regulation.

Menin is the protein product of the MEN1 tumor-suppressor gene; one allele of MEN1 is inactivated in the germ line of patients with "multiple endocrine neoplasia type 1" (MEN1) cancer syndrome. Menin interacts with several proteins involved in transcriptional regulation. RNA expression analyses have identified several menin-regulated genes that could represent proximal or distal interaction sites for menin.

The parathyroid/pituitary variant of multiple endocrine neoplasia type 1 usually has causes other than p27Kip1 mutations.

Context: One variant of multiple endocrine neoplasia type 1 (MEN1) is defined by sporadic tumors of both the parathyroids and pituitary. The prevalence of identified MEN1 mutations in this variant is lower than in familial MEN1 (7% vs. 90%), suggesting different causes.

Functional effects of monoclonal antibodies to the purified amino-terminal extracellular domain of the human Ca(2+) receptor.

Unlabelled: We generated three functionally unique monoclonal antibodies to the purified human CaR extracellular domain. Flow cytometry studies of chimeric receptors localized their epitopes to lobe 2 of the VFT domain. These results lead us to propose a mechanism for the functional effects of these antibodies.

Parathyroid-specific double knockout of Gq and G11 alpha-subunits leads to a phenotype resembling germline knockout of the extracellular Ca2+ -sensing receptor.

Germline knockout of the extracellular Ca2+ -sensing receptor (CaR) leads to a phenotype that includes severe hypercalcemia, hyperparathyroidism, relative hypocalciuria, skeletal abnormalities, retarded growth, and early postnatal death. To investigate the role of heterotrimeric G proteins in CaR signaling, we used cre/lox technology to delete the respective alpha-subunits of Gq and G11 selectively in parathyroid cells. Mice that were PTH-Cre(+/-); Gnaq(flox/flox); Gna11(-/-) (PTH-Galphaq/Galpha11 -double knockouts) were viable, but showed all the features of germline knockout of the CaR except hypocalcuria.

A missense mutation in the seven-transmembrane domain of the human Ca2+ receptor converts a negative allosteric modulator into a positive allosteric modulator.

G protein-coupled receptors (GPCRs) are the most common targets of drug action. Allosteric modulators bind to the seven-transmembrane domain of family 3 GPCRs and offer enhanced selectivity over orthosteric ligands that bind to the large extracellular N terminus. We characterize a novel negative allosteric modulator of the human Ca(2+) receptor, Compound 1, that retains activity against the E837A mutant that lacks a response to previously described positive and negative modulators.

Genome-wide analysis of menin binding provides insights into MEN1 tumorigenesis.

Multiple endocrine neoplasia type I (MEN1) is a familial cancer syndrome characterized primarily by tumors of multiple endocrine glands. The gene for MEN1 encodes a ubiquitously expressed tumor suppressor protein called menin. Menin was recently shown to interact with several components of a trithorax family histone methyltransferase complex including ASH2, Rbbp5, WDR5, and the leukemia proto-oncoprotein MLL.

Executive summary of the Strategic Plan for National Institutes of Health Obesity Research.

The Strategic Plan for National Institutes of Health (NIH) Obesity Research is intended to serve as a guide for coordinating obesity research activities across the NIH and for enhancing the development of new efforts based on identification of areas of greatest scientific opportunity and challenge. Developed by the NIH Obesity Research Task Force with critical input from external scientists and the public, the Strategic Plan reflects a dynamic planning process and presents a multidimensional research agenda, with an interrelated set of goals and strategies for achieving the goals. The major scientific themes around which the Strategic Plan is framed include the following: preventing and treating obesity through lifestyle modification; preventing and treating obesity through pharmacologic, surgical, or other medical approaches; breaking the link between obesity and its associated health conditions; and cross-cutting topics, including health disparities, technology, fostering of interdisciplinary research teams, investigator training, translational research, and education/outreach efforts.

Gland size is associated with changes in gene expression profiles in sporadic parathyroid adenomas.

Background: Sporadic parathyroid adenomas (SPAs) are benign neoplasms responsible for most cases of primary hyperparathyroidism (pHPT). The molecular pathways responsible for the variations in clinical severity of pHPT are unknown. We studied gene expression profiles in patients with SPAs and pHPT to determine associations between these changes and clinical parameters.

Homozygous loss of menin is well tolerated in liver, a tissue not affected in MEN1.

Most tumor suppressor genes show a widespread pattern of expression, yet individuals with germline, heterozygous loss of function of such genes develop tumors in a restricted set of tissues. This paradox has generated a multitude of speculative hypotheses. The gene for multiple endocrine neoplasia type I (MEN1) encodes a ubiquitously expressed tumor suppressor of unknown function called menin.