Biomedical subjects

W Y Chan

Publications and source records attributed to W Y Chan.

At least 37 records · Page 2Linked to original sources

PubMed2001

Design of oxytocin antagonists, which are more selective than atosiban.

We report the solid phase synthesis of four pairs of L- and D-thienylalanine (Thi/D-Thi) position two modified analogues of the following four oxytocin (OT) antagonists: des-9-glycinamide [1-(beta-mercapto-beta,beta-pentamethylene propionic acid), 2-O-methyltyrosine, 4-threonine]ornithine-vasotocin (desGly(NH2)9,d (CH2)5[Tyr(Me)2,Thr4]OVT) (A); the Tyr-(NH2)9 analogue of (A), d(CH2)5[Tyr(Me)2,Thr4,Tyr-(NH2)9]OVT (B); the Eda9 analogue (where Eda = ethylenediamine) of (A), d(CH2)5[Tyr(Me)2, Thr4, Eda9]OVT (C); and the retro Tyr10 modified analogue of (C), d(CH2)5[Tyr(Me)2, Thr4, Eda9<--Tyr10]OVT (D). The eight new analogues of A-D are (1) desGly(NH2),d(CH2)5[Thi2,Thr4]OVT, (2) desGly(NH2),d(CH2)5[D-Thi2,Thr4]OVT, (3) d(CH2)5[Thi2, Thr4,Tyr-(NH2)9]OVT, (4) d(CH2)5[D-Thi2,Thr4,Tyr-(NH2)9]OVT (5) d(CH2)5[Thi2,Thr4Eda9]OVT, (6) d(CH2)5[D-Thi2,Thr4,Eda9]OVT, (7) d(CH2) [Thi2,Thr4,Eda9<--Tyr10]OVT, (8) d(CH2),[D-Thi2,Thr4,Eda9<--Tyr10]OVT. We also report the synthesis of (C). Peptides 1-8 and C were evaluated for agonistic and antagonistic activities in in vitro and in vivo OT assays, in in vivo vasopressor (V1a receptor) assays and in in vivo antidiuretic (V2 receptor) assays. None of the eight peptides nor C exhibit oxytocic or vasopressor agonism. Peptides 1-8 are extremely weak V2 agonists (antidiuretic activities range from < 0.0005 to 0.20 U/mg). Peptide C is a weak mixed V2 agonist/antagonist. Peptides 1-8 and C exhibit potent in intro (no Mg2+) OT antagonism (anti-OT pA2 values range from 7.76 to 8.05). Peptides 1-8 are all OT antagonists in vivo (estimated in vivo anti-OT pA2 values range from 6.54-7.19). With anti-V1a pA2 values of approximately 5-5.80, peptides 1-8 exhibit marked reductions in anti-V1a potencies relative to those of the parent peptides A-D (anti-V1a pA2 range from 6.48 to 7.10) and to l-deamino[D-Tyr(Et)2, Thr4]OVT (Atosiban, trade name Tractocile) (anti-V1a pA2-6.14). Atosiban has recently been approved in Europe for clinical use for the prevention of premature labour (Pharm. J. 264(7-100): 871). Peptides 1-8 exhibit striking gains in in vitro anti-OT/anti-V1a selectivities with respect to the parent peptides A, B, C and D and to Atosiban. Peptides 1-8 exhibit anti-OT (in vitro)/anti-V1a selectivities of 450, 525, 550, 450, approximately 1080, 116, 355, 227 respectively. The corresponding values for A-D and Atosiban are 30, 4.2, 4.3, 2.6 and 37. With the exception of peptide 6, the remaining seven peptides exhibit 3-18-fold gains in anti-OT (in vivo)/anti-V1a selectivity with respect to Atosiban, peptides 1-8 exhibit anti-OT (in vivo)/anti-V1a selectivities of 22, approximately 82, approximately 82, 147, approximately 83, 11, 31 and 42. By comparison, Atosiban exhibits an anti-OT (in vivo)/anti-V1a selectivity = 8. With an estimated in vivo anti-OT pA2 value = 7.19+/-0.06, peptide 4 is equipotent with Atosiban (pA2 = 7.05+/-0.05). However, with its significantly reduced anti-vasopressor potency, pA2 = approximately 5, it is approximately 18 times more selective for OT receptors with respect to VP V1a receptors than Atosiban. Since we have shown that V1a antagonism could be an unwanted side-effect in tocolytics, peptide 4 and some of the OT antagonists reported here have advantages over Atosiban and thus may be suitable candidates for evaluation as potential tocolytic agents for the treatment of preterm labour.

Biological Assay↗

PubMed2001

T cell receptor Vbeta repertoire expression reflects gastric carcinoma progression.

Analysis of TCR beta-chain complementarity-determining region size gives an indication of the T cell immune response. We examined CD4+ and CD8+ subgroups of T cells in the peripheral blood (PBL), benign gastric mucosa, and tumor (TIL) lymphocytes of 12 patients with primary gastric carcinomas of both intestinal and diffuse types. The average number of expanded clones in each compartment, expressed by the 24 families of the TCRVbeta repertoire, was analyzed according to tumor histological type, maximal invasive depth, and lymph node metastases. Fewer clones were expressed by the PBL in the cases with lymph node metastases than in those without (CD4+ P = 0.00017, CD8+ P = 0.016). Fewer CD8+ clones were expressed by the PBL in the cases with full thickness tumor infiltration than in those involving only the mucosa and submucosa (P = 0.05). The CD8+ TIL showed significantly fewer clones in the diffuse-type carcinoma than in the intestinal type (P = 0.046).

Adenocarcinoma↗

PubMed2001

Molecular determinants of metabotropic glutamate receptor 1B trafficking.

The metabotropic glutamate receptor mGluR1 undergoes alternative splicing to generate isoforms differing in C-terminal sequence. The mechanism by which these isoforms give different functional responses to agonists in vitro is so far unclear. Using the native mGluR1 and CD2-mGluR1 chimeric molecules, as well as their C-terminal truncations and mutants, we identified an endoplasmic reticulum (ER) retention signal Arg-Arg-Lys-Lys within the C-terminal sequence of mGluR1b. Its presence results in a much reduced cell surface expression of the receptor and chimeric molecules in cell lines and their restricted trafficking in neurones. This motif is also present in the C-terminus of mGluR1a, but its effect is overcome by a region of the mGluR1a-specific C-terminal sequence (amino acids 975-1098). Our results indicate that these splice variants of mGluR1 utilize different targeting pathways and suggest that this may be a general phenomenon in the metabotropic glutamate receptor gene family.

Amino Acid Sequence↗

PubMed2001

SPARC (secreted protein acidic and rich in cysteine) induces apoptosis in ovarian cancer cells.

Secreted protein acidic and rich in cysteine (SPARC) is an extracellular Ca(2+)-binding matricellular glycoprotein that associates with cell populations undergoing migration, morphogenesis, and differentiation. Studies on endothelial cells have established that its principal functions in vitro are counteradhesion and antiproliferation. The mechanism(s) underlying these antitumor effects is unknown. In this study, we showed that SPARC expression in ovarian cancer cells is inversely correlated with the degree of malignancy. The immunohistochemical data presented here confirmed the importance of diminished SPARC expression in ovarian cancer development. Treating human ovarian surface epithelial cells and ovarian cancer cells with SPARC revealed that as SPARC inhibits the proliferation of both normal and cancer cells, it induces apoptosis only in cancer cells. This observation indicates that down-regulation of SPARC is essential for ovarian carcinogenesis as cancer cells become sensitized to the apoptotic activity of SPARC during malignant transformation. We also showed here the first direct evidence that putative SPARC receptors are present on ovarian epithelial cells. Their levels are higher in human ovarian surface epithelial cells than cancer cells. Binding of SPARC to its receptor is likely to trigger tissue-specific signaling pathways that mediate its tumor suppressing functions. Decrease in ligand-receptor interaction by the down-regulation of SPARC and/or its receptor is essential for ovarian carcinogenesis.

Apoptosis↗

PubMed2001

Analysis of gene expression following sciatic nerve crush and spinal cord hemisection in the mouse by microarray expression profiling.

1. The responses of periphery (PNS) and central nervous systems (CNS) towards nerve injury are different: while injured mammalian periphery nerons can successfully undergo regeneration, axons in the central nervous system are usually not able to regenerate. 2. In the present study, the genes which were differentially expressed in the PNS and CNS following nerve injury were identified and compared by microarray profiling techniques. 3. Sciatic nerve crush and hemisection of the spinal cord of adult mice were used as the models for nerve injury in PNS and CNS respectivey. 4. It was found that of all the genes examined, 14% (80/588) showed changes in expression following either PNS or CNS injury, and only 3% (18/588) showed changes in both types of injuries. 5. Among all the differentially expressed genes, only 8% (6/80) exhibited similar changes in gene expression (either up- or down-regulation) following injury in both PNS and CNS nerve injuries. 6. Our results indicated that microarray expression profiling is an efficient and useful method to identify genes that are involved in the regeneration process following nerve injuries, and several genes which are differentially expressed in the PNS and/or CNS following nerve injuries were identified in the present study.

Animals↗

PubMed2001

Effect of Helicobacter pylori eradication on expression of cyclin D2 and p27 in gastric intestinal metaplasia.

BACKGROUND AND AIMS: Cyclins and cyclin-dependent kinase inhibitors play a crucial role in the control of cell cycle transitions. Enhanced expression of cyclin D2 and reduced expression of p27kip1 (p27) have been implicated in the pathogenesis of cancer. Because intestinal metaplasia has been regarded as a pre-malignant lesion, we investigated the expression of cyclin D2 and p27 in Helicobacter pylori-associated chronic gastritis with and without intestinal metaplasia, and followed the changes after H. pylori eradication. METHODS: Expression of cyclin D2 and p27 was studied by immunohistochemistry in 59 patients (including 35 patients with intestinal metaplasia) and in 10 gastric cancer patients. Among them, 29 H. pylori-infected patients had serial gastric biopsies taken before and at 1-year after eradication of H. pylori. RESULTS: Expression of cyclin D2 was significantly higher in gastric cancers when compared to their adjacent non-tumour tissues (median score 3 vs. 1, P=0.015). Over-expression of cyclin D2 was detected in H. pylori-associated chronic gastritis and intestinal metaplasia, which was reduced after eradication of the organism (median score 2 vs. 1, P=0.037 in chronic gastritis; median score 2 vs. 0, P=0.008 in intestinal metaplasia). While the normal gastric mucosa showed strong p27 expression, five of the 10 gastric cancer tissues exhibited reduced p27 expression (P=0.039). Diminished p27 expression was also seen in intestinal metaplasia, which was restored 1-year after H. pylori eradication (eight out of 16 vs. one out of 16, P=0.018). Reduced expression of p27 was frequently associated with increased cyclin D2 expression in H. pylori-associated intestinal metaplasia (P=0.02). CONCLUSION: Over-expression of cyclin D2 and reduced expression of p27 are closely linked to H. pylori-associated intestinal metaplasia. Eradication of H. pylori infection reverses the aberrant expression of cyclin D2 and p27 in intestinal metaplasia.

Cyclin D2↗

PubMed2001

Nodular Leydig cell hyperplasia in a boy with familial male-limited precocious puberty.

In boys with familial male-limited precocious puberty, an activating mutation of the luteinizing hormone receptor causes Leydig cell hyperplasia, resulting in excess testosterone production. There are no reports of Leydig cell masses in boys with familial male-limited precocious puberty. We describe a 10-year-old boy with familial male-limited precocious puberty who developed Leydig cell nodules.

Child↗

PubMed2001

Epstein-Barr virus-associated gastric lymphomas are distinct from mucosa-associated lymphoid tissue-type lymphomas: genetic abnormalities of p53 gene.

The authors studied 46 primary gastric lymphomas for expression of the p53 gene by immunohistochemistry and screened for mutations in p53 exon 5-8 by polymerase chain reaction-single strand conformation polymorphism. Twenty-five specimens cases were also analyzed for loss of heterozygosity (LOH) of chromosomal region 17p12-13.1. In 36 lymphomas negative for Epstein-Barr virus (EBV) infection, of which 29 were of mucosa-associated lymphoid tissue (MALT) type, p53 genetic changes were found in 47.2% but correlated poorly with overexpression. Only 20% of the mutations involved exon 7. There were recurrent mutations of intron 7, intron 6, and exon 6. In contrast, the 10 EBV-positive cases, none of MALT type, had a much higher rate of mutation, and all showed both p53 overexpression and p53 mutation and/or LOH, and 87.5% had mutations involving exon 7. Four of these involved codon 242, not seen in the EBV-negative group. Splicing mutations of intron 8 were seen in three specimens, two involving the same nucleotide position. In four of five specimens, LOH analysis identified microsatellite instability, allelic loss, or both. The Helicobacter pylori infection rate in the EBV-positive group (20%) was much lower than in the EBV-negative group (91.7%). These differences between the two groups suggest involvement of different carcinogens. Mutation of codon 242 has not been specifically associated with other tumors and may represent a mutational hot spot in the EBV-positive lymphomas.

Adult↗

PubMed2001

Gastric choriocarcinoma shows characteristics of adenocarcinoma and gestational choriocarcinoma: a comparative genomic hybridization and fluorescence in situ hybridization study.

The authors report two cases of the rare primary gastric choriocarcinoma. These tumors showed an overwhelming predominance of cytotrophoblast- and syncytiotrophoblast-like tumor cells that were positive for beta-human chorionic gonadotrophin, with small foci of glandular differentiation. Beta-human chorionic gonadotrophin was also detected serologically in one patient. Comparative genomic hybridization study was performed on one specimen. Copy number gains of chromosomes 12, 17, 20, 22, and X, together with losses on 18q, were the major findings. Except for the gain of chromosome 12, which is known to be uncommon in primary gastric adenocarcinoma but frequently associated with choriocarcinoma, the remaining genomic imbalances were among the most common comparative genomic hybridization findings reported in primary gastric adenocarcinoma. Fluorescence in situ hybridization on paraffin sections of both specimens confirmed the presence of polysomy 17 and trisomy 12. These results suggest that primary gastric choriocarcinoma genetically possesses characteristics of both adenocarcinoma and gestational choriocarcinoma. The authors believe this is the first interphase cytogenetics study on this rare tumor, and that the results support the theory that gastric choriocarcinoma arises from alternate differentiation pathways of adenocarcinoma.

Adenocarcinoma↗

PubMed2001

Chromosome 11 copy number gains and Epstein-Barr virus-associated malignancies.

Epstein-Barr virus (EBV) genome can be found in many malignant tumors in China. Previous data of interphase cytogenetics, by comparative genomic hybridization and/or fluorescence in situ hybridization, on nasopharyngeal carcinomas and natural killer cell-type non-Hodgkin lymphomas in Hong Kong have noted gains in chromosome 11. This study compares the frequency of chromosome 11 copy number gains in three different types of EBV-associated tumors in Hong Kong. Using alpha-satellite probes, the authors studied by fluorescence in situ hybridization 31 EBV-positive tumors comprising 10 EBV-positive gastric carcinomas, 8 lung lymphoepithelioma-like carcinomas, and 13 non-Hodgkin lymphomas. Trisomy or polysomy 11 was detected in 10 of 10 (100%) EBV-positive gastric carcinomas, 6 of 8 (75%) lung lymphoepithelioma-like carcinomas, and 4 of 13 (30.8%) non-Hodgkin lymphomas. Compared with the EBV-positive gastric carcinomas, the 10 EBV-negative gastric carcinomas that were also studied showed chromosome 11 copy number gains in 3 of 10 (30%), a significantly lower frequency. The authors conclude that gains in chromosome 11 are common in EBV-associated malignancies in Hong Kong, with the strongest association found in gastric carcinoma. There seems to be differences between EBV-associated tumors of different locations, and between gastric carcinomas with and without EBV.

Adult↗

PubMed2001

Circulating cell-free Epstein-Barr virus DNA levels in patients with EBV-associated lymphoid malignancies.

Epstein-Barr virus (EBV) is a human lymphotrophic herpesvirus implicated in the development of several lymphoid malignancies. Recently, detection of cell-free EBV DNA in sera or plasma from patients with EBV-associated malignancies has been reported. However, most published studies are qualitative in nature, with only a few providing quantitative data. We have described the temporal changes of plasma EBV DNA levels in patients with EBV-associated lymphoid malignancies during therapy using quantitative real-time PCR. A close correlation between plasma EBV DNA levels and therapeutic response was observed. Our aim was to update our results and to assess the role of the plasma EBV DNA levels as a molecular marker for disease monitoring in patients with EBV-associated lymphoid malignancies.

DNA, Viral↗

PubMed2001

Spectrum of mutations of the AAAS gene in Allgrove syndrome: lack of mutations in six kindreds with isolated resistance to corticotropin.

Familial glucocorticoid deficiency due to corticotropin (ACTH) resistance consists of two distinct genetic syndromes that are both inherited as autosomal recessive traits: isolated ACTH resistance (iACTHR), which may be caused by inactivating mutations of the ACTH receptor (the MC2R gene) or mutations in an as yet unknown gene(s), and Allgrove syndrome (AS). The latter is also known as triple-A syndrome (MIM 231550). In three large cohorts of AS kindreds, the disease has been mapped to chromosome 12; most recently, mutations in the AAAS gene on 12q13 were found in these AS families. AAAS codes for the WD-repeat containing ALADIN (for alacrima-achalasia-adrenal insufficiency-neurologic disorder) protein. We investigated families with iACTHR (n = 4) and AS (n = 6) and a Bedouin family with ACTHR and a known defect of the TSH receptor. Four AS families were of mixed extraction from Puerto Rico (PR); most of the remaining six families were Caucasian families from North America (NA). Sequencing analysis found no MC2R genetic defects in any of the kindreds. No iACTHR kindreds, but all of AS families, had AAAS mutations. The previously reported IVS14+1G-->A splice donor mutation was found in all PR families, apparently due to a founder effect; one NA kindred was heterozygous for this mutation. In the latter family, long-range PCR failed to identify a deletion or other rearrangements of the AAAS gene. No other heterozygote or transmitting parent had any phenotype that could be considered part of AS. The IVS14+1G-->A mutation results in a premature termination of the predicted protein; although it was present in all PR families (in the homozygote state in three of them), there was substantial clinical variation between them. One PR family also carried a novel splice donor mutation of the AAAS gene in exon 11, IVS11+1G-->A; the proband was a compound heterozygote. A novel point mutation, 43C-->A(Gln15Lys), in exon 1 of the AAAS gene was identified in the homozygote state in a Canadian AS kindred with a milder AS phenotype. The predicted amino acid substitution in this family is located in a sequence that may participate in the preservation of stability of ALADIN beta-strands, whereas the splicing mutation in exon 11 may interfere with the formation of WD repeats in this molecule. We conclude that 1) AAAS does not appear to be frequently mutated in families with iACTHR; 2) AAAS is mutated in AS families from PR (that had previously been mapped to 12q13) and NA; and, 3) there is significant clinical variability between patients with the same AAAS defect.

Adrenocorticotropic Hormone↗

PubMed2001

Differential expression of calcium-binding proteins in the red nucleus of the developing and adult human brain.

The adult human red nucleus consists of two parts: (1) the parvocellular part, which is clearly separated from (2) the magnocellular part. The latter and its rubrospinal projection is known to be rudimentary in the adult human brain. Information concerning the fetal or neonatal features of the red nucleus is sparse. This study is aimed at providing a detailed account of the distribution of three calcium-binding proteins: calretinin (CR), calbindin (CB), and parvalbumin (PV), which are known to be expressed in distinct neuronal populations. Special attention has been paid to transient phenomena. CB was the most abundant protein in the magnocellular part in fetal and perinatal brains; immunoreactive (ir) neurons appeared numerous and densely packed. In the adult only few and widely spaced ir nerve cells were present. CR-expression largely corresponds to that of CB, except that fewer neurons were immunolabelled. In double-labellings the majority of neurons expressed both CB and CR; a moderate number of nerve cells solely expressing CR was present in the magnocellular part. PV-ir fibers and a moderate number of small cells were observed in the fetal, perinatal as well as the adult parvocellular part. A few PV-ir neurons were seen in the magnocellular part of the fetal and perinatal brains. Our results indicated that: (1) the magnocellular and parvocellular parts of the red nucleus were well-demarcated portions from fetal life onwards, thus a dominance of the parvocellular part over the magnocellular occurred during development; (2) the magnocellular part was more prominent in the fetal period than in adulthood; (3) neurons in the red nucleus were heterogeneous with respect to the immunoreactivities towards the three calcium-binding proteins examined; (4) the transient prominence of the magnocellular part might be a substrate for a specific transitory pattern of motor behaviour.

Brain↗

PubMed2001

Circulating Epstein-Barr virus DNA in the serum of patients with gastric carcinoma.

PURPOSE: We investigated the detectability of EBV DNA in the serum of gastric carcinoma patients in Hong Kong. Previous data have shown that approximately 10% of gastric carcinomas in Hong Kong are associated with EBV. EXPERIMENTAL DESIGN: We recruited 51 patients with gastric carcinoma, 30 patients with gastritis, and 197 apparently healthy controls. For gastric carcinoma patients, blood samples were obtained before surgery. After surgery, the resected tumor samples from the cancer cases were subjected to in situ hybridization for small EBV-encoded RNA (EBER). Serum EBV DNA in all cases was measured by real-time quantitative PCR. RESULTS: Serum EBV DNA was detectable in 5 of 5 (100%) EBER-positive gastric carcinoma cases (median concentration, 1063 copies/ml), in 13 of 14 (93%) EBER-negative gastric carcinoma cases with EBER-positive infiltrating lymphocytes (median concentration, 50 copies/ml), and in 0 of 32 (0%) EBER-negative cases. In the nontumor controls, serum EBV DNA was detectable in 7 of 30 (23%) gastritis cases (median concentration, 0 copies/ml) and in 7 of 197 (3.6%) apparently healthy individuals (median concentration, 0 copy/ml). CONCLUSIONS: Our data indicate that serum EBV DNA reflects tumoral EBER status and opens up the possibility that circulating EBV DNA may be used as a tumor marker for the EBER-positive gastric carcinomas. The biological and clinical significance of the presence of low levels of circulating EBV DNA in the minority of gastritis patients and healthy individuals remains to be elucidated.

DNA, Viral↗

PubMed2001

Comparison of the embryotoxic effects of saporin, agrostin (type 1 ribosome-inactivating proteins) and ricin (a type 2 ribosome-inactivating protein).

The effects of two type I ribosome-inactivating proteins, saporin and agrostin, and the type 2 ribosome-inactivating protein ricin and its constituent A and B chains, on the development of cultured mouse embryos, were investigated. Saporin and agrostin had similar embryotoxicity which was approximately 10(5) times weaker than that of ricin and its A and B chains, and the embryotoxicity of saporin and agrostin increased gradually with the dosage. In contrast, there was an abrupt rise in embryotoxictiy of ricin-A chain and B chain as the dose was raised from 10 to 20 ng x ml(-1). Saporin and agrostin did not affect the heart-beat and otic placode, but at 10 ng x ml(-1) ricin and 40 ng x ml(-1) ricin-A chain and B chain, all of the treated embryos exhibited abnormalities in heart-beat, yolk sac circulation, body axis, optic placode, otic placode, forelimb buds, branchial apparatus and cranial neural tube.

Animals↗

PubMed2000

The GABAB receptor interacts directly with the related transcription factors CREB2 and ATFx.

gamma-Aminobutyric acid type B (GABA(B)) receptors mediate the metabotropic actions of the inhibitory neurotransmitter GABA. These seven-transmembrane receptors are known to signal primarily through activation of G proteins to modulate the action of ion channels or second messengers. The functional GABA(B) receptor is made up of a heterodimer consisting of two subunits, GABA(B)-R1 and GABA(B)-R2, which interact via coiled-coil domains in their C-terminal tails. By using a yeast two-hybrid approach, we have identified direct interactions between the C-terminal tails of GABA(B)-R1 and GABA(B)-R2 with two related transcription factors, CREB2 (ATF4) and ATFx. In primary neuronal cultures as well in recombinant Chinese hamster ovary cells expressing GABA(B) receptors, CREB2 is localized within the cytoplasm as well as the nucleus. Activation of the GABA(B) receptor by the specific agonist baclofen leads to a marked translocation and accumulation of CREB2 from the cytoplasm into the nucleus. We demonstrate that receptor stimulation results in activation of transcription from a CREB2 responsive reporter gene. Such a signaling mechanism is unique among Family C G protein-coupled receptors and, in the case of the GABA(B) receptor and CREB2, may play a role in long-term changes in the nervous system.

Amino Acid Sequence↗

PubMed2000

Retinoic acid receptor-beta: an endogenous inhibitor of the perinatal formation of pulmonary alveoli.

Pulmonary alveoli are formed, in part, by subdivision (septation) of the gas-exchange saccules of the immature lung. Septation is developmentally regulated, and failure to septate at the appropriate time is not followed by delayed spontaneous septation. We report retinoic acid receptor (RAR) beta knockout mice exhibit premature septation; in addition, they form alveoli twice as fast as wild-type mice during the period of septation but at the same rate as wild-type mice thereafter. Consistent with the perinatal effect of RARbeta knockout, RARbeta agonist treatment of newborn rats impairs septation. These results 1) identify RARbeta as the first recognized endogenous signaling that inhibits septation, 2) demonstrate premature onset of septation may be induced, and 3) show the molecular signaling regulating alveolus formation differs during and after the period of septation. Suppressing perinatal RARbeta signaling by RARbeta antagonists may offer a novel, nonsurgical, means of preventing, or remediating, failed septation in prematurely born children.

Animals↗

PubMed2000

Luteinizing hormone receptor mutations in disorders of sexual development and cancer.

Human male sexual development is regulated by chorionic gonadotropin (CG) and luteinizing hormone (LH). Aberrant sexual development caused by both activating and inactivating mutations of the human luteinizing hormone receptor (LHR) have been described. All known activating mutations of the LHR are missense mutations caused by single base substitution. The most common activating mutation is the replacement of Asp-578 by Gly due to the substitution of A by G at nucleotide position 1733. All activating mutations are present in exon 11 which encodes the transmembrane domain of the receptor. Constitutive activity of the LHR causes LH releasing hormone-independent precocious puberty in boys and the autosomal dominant disorder familial male-limited precocious puberty (FMPP). Both germline and somatic activating mutations of the LHR have been found in patients with testicular tumors. Activating mutations have no effect on females. The molecular genetics of the inactivating mutations of the LHR are more variable and include single base substitution, partial gene deletion, and insertion. These mutations are not localized and are present in both the extracellular and transmembrane domain of the receptor. Inactivation of the LHR gives rise to the autosomal recessive disorder Leydig cell hypoplasia (LCH) and male hypogonadism or male pseudohermaphroditism. Severity of the clinical phenotype in LCH patients correlates with the amount of residual activity of the mutated receptor. Females are less affected by inactivating mutation of the LHR. Symptoms caused by homozygous inactivating mutation of the LHR include polycystic ovaries and primary amenorrhea.

Disorders of Sex Development↗