bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent Progress in Relaxin‐3‐Related Research
Authors: LIU CHANGLU , BONAVENTURE PASCAL , SUTTON STEVEN W. , CHEN JINGCAI , KUEI CHESTER , NEPOMUCENO DIANE , LOVENBERG TIMOTHY W.
Published: June 2005

Abstract: Relaxin‐3 (R3) is the latest member of the insulin (INSL) superfamily, which is composed of peptides with diverse sequences held together by characteristic disulfide links connecting A and B peptide chains. R3 has nearly exclusive expression in the brainstem and was demonstrated to be an additional ligand for LGR7. We recently identified R3 as a ligand for two orphan G‐protein coupled receptors, GPCR135 and GPCR142. The predominant brain expression for both R3 and GPCR135, coupled with their high affinity interaction, strongly suggests that R3 is the endogenous ligand for GPCR135. Both R3 and GPCR135 from different species are highly conserved from genetic sequences to in vitro pharmacology. By contrast, GPCR142 is a pseudogene in the rat, and the mouse gene is less conserved with human GPCR142, suggesting that GPCR142 may have a diminished role as a receptor for R3 in the rodent. In addition, the tissue expression pattern of GPCR142, which is primarily in peripheral tissue, is drastically different from that of R3, suggesting that GPCR142 may have an endogenous ligand other than R3. Sequence analysis among INSL/relaxin family members shows that INSL5 is the closest member of R3. We were able to demonstrate that INSL‐5 is an agonist for GPCR142 but not for GPCR135. We also showed that the mRNA expression pattern of INSL‐5 overlaps with that of GPCR142. By substituting the A chain of R3 with the A chain of INSL‐5, we devised a chimeric peptide (R3/I5) that is about 1000‐fold selective for GPCR135 and GPCR142 over LGR7. Autoradiographic distribution of GPCR135 binding sites using [125I]R3/I5 in rat brain shows that GPCR135 receptor is most prominent in areas known for the processing of sensory signals.
Relaxin Modulates Fibroblast Function, Collagen Production, and Matrix Metalloproteinase‐2 Expression by Cardiac Fibroblasts
Authors: MOOKERJEE ISHANEE , UNEMORI ELAINE N. , DU XIAO‐JUN , TREGEAR GEOFFREY W. , SAMUEL CHRISHAN S.
Published: June 2005

Abstract: Cardiac fibrosis is a hallmark of heart disease and involves recruitment, proliferation, and differentiation of extracellular matrix‐producing fibroblasts, leading to overproduction of collagen within the myocardium. In this study, the effects of relaxin in inhibiting these processes were investigated. We used neonatal rat atrial and ventricular fibroblasts, which respond to pro‐fibrotic stimuli (i.e., transforming growth factor‐β and angiotensin II) and naturally express the relaxin receptor LGR7. Relaxin significantly inhibited TGF‐β‐ and angiotensin II‐mediated fibroblast function and collagen production over a 72‐h period, while increasing MMP‐2 expression and activity in the presence of both profibrotic factors (all P <.05). These studies demonstrate that relaxin may have therapeutic potential in diseased states characterized by cardiac fibrosis.
Central Effects of Long‐Term Relaxin Expression in the Rat
Authors: SILVERTOWN JOSH D. , FRASER RUSSELL , POTERSKI ROMAN S. , GEDDES BRAD , SUMMERLEE ALASTAIR J.S.
Published: June 2005

Abstract: A recombinant adenovirus containing the human H2 preprorelaxin (hH2) cDNA and a reporter gene was coinjected with a transactivator virus (Ad‐tTA) into the lateral cerebral ventricles of female rats. Cardiovascular effects were measured over a 21‐day period. Circulating vasopressin in the periphery was significantly greater (P <.0001) in the relaxin‐treated group throughout the experimental period, compared with controls. There was a significant decrease in plasma osmolality (P <.05) by approximately 10 mmol/L in the treated group by day 14. Immunofluorescence for hH2 present in cryosections showed rAd transduction and hH2 expression from ependymal cells of the ventricular system. Adenovirus‐mediated delivery of hH2 to the brain is capable of producing bioactive relaxin that affects cardiovascular parameters.
Pathways Used by Relaxin to Regulate Myometrial Phospholipase C
Authors: ZHONG MIAO , KU CHUN‐YING , SANBORN BARBARA M.
Published: June 2005

Abstract: Relaxin exhibits pleiotropic effects on reproductive and nonreproductive tissues; the signaling mechanisms underlying these functions are still not well understood. Activation of protein kinase A and several other signal‐regulated protein kinases results in the phosphorylation of phospholipase C (PLC)‐β3 and inhibit Gαq‐stimulated PLC activity. Therefore, PLCβ3 may be targeted by both contractant and relaxant signaling pathways in myometrium and play a critical role in the balance between them. PHM1 cells express mRNA for relaxin receptor LGR7, and relaxin inhibits oxytocin‐stimulated PLC activity in these cells. Thus, this model system may be useful in delineating signaling pathways used by relaxin. Here, we present evidence that relaxin stimulates phosphorylation of PLCβ3 in PHM1 cells.
Effects of Relaxin on Vascular Smooth Muscle and Endothelial Cells in Normotensive and Hypertensive Rats
Authors: FAILLI PAOLA , NISTRI SILVIA , MAZZETTI LUCA , CHIAPPINI LAURA , BANI DANIELE
Published: June 2005

Abstract: We tested the effects of relaxin on [Ca2+]i response to angiotensin II in smooth muscle (vSMC) and endothelial cells isolated from hypertensive (SHR) and normotensive (WKY) rats. Relaxin markedly reduced the [Ca2+]i response of vSMCs from WKY, but not from SHR rats. Western blots showed that cGMP‐dependent protein kinase G was reduced in vSMCs from SHR as compared with WKY rats. Relaxin also blunted the [Ca2+]i response in endothelial cells from WKY, but not from SHR rats. However, in endothelial cells from SHR and WKY rats, protein kinase G was nearly unexpressed, thus accounting for an alternative pathway of the intracellular response to nitric oxide and relaxin. Hence, vSMCs and endothelial cells in SHR rats show a deficiency response to nitric oxide that may render them insensitive to relaxin.
Is Relaxin a Calcium Transporter/Buffer?
Authors: FIELDS PHILLIP A.
Published: June 2005

Abstract: Relaxin inhibits smooth muscle contractions by binding Ca2+ and making it unavailable to the contractile elements. Rat uterus sarcoplasmic reticulum (SR) was isolated, incubated with 45Ca in the presence and absence of porcine relaxin, and filtered. In the presence of relaxin, only 4% of the 45Ca was on the filter with the SR as compared to that measured on the filter with SR alone or in the presence of proteins of similar isoelectric point (cytochrome C) and size (insulin). A Sephadex G‐25 column was equilibrated with buffer containing 45Ca, and 0.5 mL fractions were collected. Each fraction contained 240‐250K cpm. Relaxin was diluted in the buffer, added to the top of the column, and eluted. A peak of 45Ca (>600K cpm) was found with the eluted relaxin. No peak of 45Ca was associated with cytochrome C or insulin under the same conditions. The eluted fractions containing 45Ca and relaxin were combined. A sample was incubated with rabbit anti‐porcine relaxin serum and goat anti‐rabbit serum and centrifuged, and 45Ca in the pellet and supernatant was determined. Ninety‐eight percent of the 45Ca was found in the supernatant. Thus, 45Ca was not tightly bound to relaxin or the antibodies knocked the 45Ca off. Is relaxin a calcium transporter or buffer?
Human Decidual Relaxin and Preterm Birth
Authors: BRYANT‐GREENWOOD GILLIAN D. , YAMAMOTO SANDRA Y. , LOWNDES KIMBERLY M. , WEBSTER LISA E. , PARG SIMONE S. , AMANO AARON , BULLESBACH ERIKA E. , SCHWABE CHRISTIAN , MILLAR LYNNAE K.
Published: June 2005

Abstract: Relaxin in human pregnancy is both a systemic hormone from the corpus luteum and an autocrine/paracrine hormone at the maternal‐fetal interface formed by the decidua/placenta and fetal membranes. We have focused our studies on the autocrine/paracrine roles of relaxin, especially in the preterm premature rupture of the fetal membranes, which causes 30‐40% of preterm births. By using different techniques and different tissue collections, our laboratory has shown that expression of the relaxin genes and proteins in the decidua and placenta is increased in patients with preterm premature rupture of the fetal membranes. Relaxin binding and the expression of LGR7 are primarily in the chorion and decidua and are downregulated after spontaneous labor and delivery both at term and preterm. However, expression of LGR7 in the fetal membranes is significantly greater in all clinical situations at preterm than term, suggesting an important role for relaxin in these tissues at that time. The roles of the relaxin system in three potential causes of preterm birth are discussed: in the growth and proliferation of the membranes important for fetal membrane accommodation to fetal and placental growth, in acute infection, and in the inflammatory response leading to the initiation of labor.
Does Human Relaxin Accelerate Orthodontic Tooth Movement in Rats?
Authors: LIU ZI JUN , KING GREGORY J. , GU GAO MAN , SHIN JA YOUNG , STEWART DENNIS R.
Published: June 2005

Abstract: Human relaxin was administered to young rats through either minipumps (group P) or subcutaneous injections (group I). Control rats received pump implants containing placebo (group C). Day 0 was the day of orthodontic appliance placement and activation to pull bilateral upper first molars forward, and day 14 was the end time point. Cephalometric radiographs (three repeated exposures) were taken at 0, 3, 5, 7, 10, and 14 days. The total length of three maxillary molar segments and the space between the first and second molars were measured under a dissecting microscope postmortem. Both groups P and I showed rapid tooth movement at day 3. Movement slowed, but it still increased gradually in group P while decreasing in group I after that. Concurrent tooth lateral drifts to the buccal side were smaller in both groups P and I. The length and space were larger in both groups P and I. Thus, administration of human relaxin may accelerate the early stages of orthodontic tooth movement in rats.
Photonic Monitoring in Real Time of Vascular Endothelial Growth Factor Receptor 2 Gene Expression under Relaxin‐Induced Conditions in a Novel Murine Wound Model
Authors: RYAN PETER L. , YOUNGBLOOD RAMEY C. , HARVILL JANE , WILLARD SCOTT T.
Published: June 2005

Abstract: Relaxin is known to promote vascular endothelial growth factor (VEGF) expression in reproductive tissue, and successful wound healing depends on good vascularization of wound sites, a process that relaxin may facilitate. Thus, the objective of this study was to evaluate the efficacy of relaxin on the development of vascular tissue at wound sites in a novel VEGF receptor 2‐luc (VEGFR2‐luc) transgenic mouse wound model by monitoring the rate of VEGFR2‐luc‐mediated gene expression using bioluminescence and real‐time imaging. To this end, 12 FVB/N VEGFR2‐luc transgenic male mice were assigned to treatments (six per group): saline alone or relaxin (1 g/6 h/14 days) administered intraperitoneally (i.p.). On day 0, a set of full‐thickness wounds (6‐mm punch) were generated under anesthesia on the dorsal aspect of each mouse. Photonic emissions were recorded (5‐min collection of photons) from wound sites 10 min after the administration of luciferin (150 mg/kg i.p.) on day 0 and on days 1, 2, 4, 7, 9, 11, and 14 postwounding to quantify luciferase activity using an IVIS 100 biophotonic imaging system. Animals were sacrificed (three per group) on day 7 or 14, and wound tissue specimens were recovered for molecular and histologic analyses. Although photonic emission from wound sites increased (P <.001) over time with peak values obtained by day 7, no significant (P >.05) effect of relaxin treatment on VEGFR2‐luc gene expression was noted at wound sites. Whereas measuring relaxin's effect on angiogenesis indirectly via the VEGFR2 model was not successful, photonic imaging provides an exciting new tool using alternative models (i.e., VEGF‐luc mouse) to study relaxin‐induced gene expression in normal (i.e., wound healing) or tumorigenic tissues in real time.
Relaxin of Prostatic Origin Might Be Linked to Perineal Hernia Formation in Dogs
Authors: NIEBAUER GERT W. , SHIBLY SARINA , SELTENHAMMER MONIKA , PIRKER ARMIN , BRANDT SABINE
Published: June 2005

Abstract:Perineal hernia occurs spontaneously in older male dogs after idiopathic weakening of the pelvic diaphragm. Hernias invariably contain cystic paraprostatic tissues. Castration reduces incidence and recurrence after surgical repair. Although cystic prostatic hypertrophy is a consistent feature in patients with perineal hernia, an endocrine link of the disease to steroid sex hormones has not been demonstrated. Employing immunohistochemistry, we found intense relaxin immunoreactivity in dogs with perineal hernia within the epithelia of hypertrophic prostates and in periprostatic tissues. The prostate of normal dogs exhibited similar but less intense relaxin staining. In neutered dogs with prostatic atrophy, relaxin immunostaining was weak or absent. Periprostatic cysts highly expressed relaxin precursors in the fluid phase as shown by SDS‐gel electrophoresis. Relaxin of prostatic origin, therefore, is possibly a local factor in connective tissue weakening and subsequently in perineal hernia formation.
Human Recombinant Relaxin Reduces Heart Injury and Improves Ventricular Performance in a Swine Model of Acute Myocardial Infarction
Authors: PERNA AVIO‐MARIA , MASINI EMANUELA , NISTRI SILVIA , BANI SACCHI TATIANA , BIGAZZI MARIO , BANI DANIELE
Published: June 2005

Abstract: This study shows that relaxin can be effective in the treatment of acute myocardial infarction. In a swine model of heart ischemia‐reperfusion currently used to test cardiotropic drugs because of its similarities with human myocardial infarction, human recombinant relaxin (2.5 and 5 μg/kg body weight), given at reperfusion after a 30‐min ischemia, markedly reduced the main serum markers of myocardial damage (myoglobin, CK‐MB, and troponin T) and the metabolic and histopathologic parameters of myocardial inflammation and cardiomyocyte injury, resulting in overall improvement of ventricular performance (increased cardiac index) compared to the controls. These results provide a background for future clinical trials with human relaxin as adjunctive therapy to catheter‐based coronary angioplasty in patients with acute myocardial infarction.
Relaxin as an Additional Protective Substance in Preserving and Reperfusion Solution for Liver Transplantation, Shown in a Model of Isolated Perfused Rat Liver
Authors: BOEHNERT MARKUS U. , HILBIG HEIDEGARD , ARMBRUSTER FRANZ P.
Published: June 2005

Abstract: Reperfusion injury is a problem in organ transplantation. Relaxin causes vessel dilation and inhibition of platelet and mast cell activation. The study investigates the protective effect of relaxin on liver tissue against cell damage during organ preservation and reperfusion. Liver transplantation was simulated in a model of isolated perfused rat liver. Relaxin was applicated during reperfusion and/or preservation. To quantify cell damage, we examined the perfusate for malonyldialdehyde (MDA) and myeloperoxidase activity (MPO), and liver tissue underwent immunohistochemical study. Relaxin as an additional substance in preserving/reperfusion solution decreases MPO and MDA levels in the perfusate and immunohistochemical study. Relaxin seems to have a protective effect against cell damage in ischemia and reperfusion injury.
Relaxin Adenylyl Cyclase System of Pregnant Women with Diabetes: Functional Defects in Insulin and Relaxin Adenylyl Cyclase Signaling Systems in Myometrium of Pregnant Women with Type 1 Diabetes
Authors: KUZNETSOVA LUDMILA , PLESNEVA SVETLANA , SHPAKOV ALEXANDER , PERTSEVA MARIANNA
Published: June 2005

Abstract: The study was conducted to reveal the functional disturbances in two novel insulin and relaxin adenylyl cyclase signaling mechanisms (ACSMs). It was shown for the first time that in myometrium of pregnant women with insulin insufficiency the functional defects of Gs‐protein‐AC coupling in insulin‐ and relaxin H2‐regulated AC systems were developed. As a result, the sensitivity of the signaling systems to both hormones and potentiation of their AC effects by guanine nucleotides were markedly decreased compared with that in control group. These functional defects in ACSM may lead to violation of the process of insulin and relaxin signal transduction.
Evolution of the Signaling System in Relaxin‐Family Peptides
Authors: HSU SHEAU YU TEDDY , SEMYONOV JENIA , PARK JAE‐IL , CHANG CHIA LIN
Published: June 2005

Abstract: Recent studies have characterized two G‐protein‐coupled receptors (GPCRs), LGR7 and LGR8, as relaxin receptors. Later studies have shown that LGR7 and LGR8 also are cognate receptors for the relaxin‐family peptides, INSL7/relaxin3 and INSL3, respectively. In addition, INSL7/relaxin3 signals through two orphan GPCRs, GPCR135 and GPCR142, whereas INSL5 is a select ligand for GPCR142. These findings have greatly enhanced our understanding of the physiology and signaling of this unique group of peptide hormones. Phylogenetic analysis of relaxin‐family peptides and their co‐evolved receptors suggests that the ancestor relaxin gene duplicated multiple times in a vertebrate branch‐specific manner. Among the seven human relaxin‐family peptides (relaxin1, relaxin2, INSL3/RLF, INSL4/EPIL, INSL5/RIF2, INSL6/RIF1, and INSL7/relaxin3), INSL7 and INSL5 could represent the most ancient form. By contrast, the most widely studied family peptides, human relaxins H1 and H2, appear to be derived from recent gene duplication in mammals. Therefore, relaxin‐family peptides could be important for the evolution and adaptation to lineage‐specific physiologic processes during evolution. Duplicated relaxin‐family genes assumed regulatory roles in newly evolved reproductive processes, and relaxin/LGR signaling was harnessed for signaling in the uterus and mammary gland in addition to other tissues. Although the precise evolutionary history of relaxin ligand/receptor pairs remains to be elucidated, these findings indicate that the expansion of relaxin‐family genes and their specific regulatory functions have evolved during vertebrate evolution to allow the development of a tissue‐specific regulatory mechanism in a lineage‐specific manner and provide a revealing portrait of molecular evolution in action.
Coevolution of the Relaxin‐Like Peptides and Their Receptors
Authors: WILKINSON TRACEY N. , SPEED TERENCE P. , TREGEAR GEOFFREY W. , BATHGATE ROSS A.D.
Published: June 2005

Abstract: Currently, four relaxin peptide family receptors are known: LGR7 is the relaxin receptor, although it also interacts specifically with relaxin‐3; LGR8 is the insulin‐like factor 3 (INSL3) receptor; and GPCR135 or the somatostatin‐ and angiotensin‐like peptide receptor (SALPR) and GPCR142 are both specific relaxin‐3 receptors. Because these receptors coevolved together with their relaxin ligands, phylogenetic analysis of these sequences can provide insight into peptide‐receptor interactions and even predict interacting partners for INSL4, INSL5, and INSL6, the receptors for which are unknown.
Involvement of Proteases in Cytokine‐Induced Hematopoietic Stem Cell Mobilization
Authors: VELDERS GERJO A. , FIBBE WILLEM E.
Published: June 2005

Abstract: The number of circulating stem cells and progenitor cells can be increased by physiological stress, such as exercise, stress, and infections. The process of shifting the stem cells from the bone marrow into the peripheral blood is referred to as “mobilization” or “egress.” Cytokine‐mobilized hematopoietic progenitor cells (HPCs) are currently used for autologous or allogeneic stem cell transplantation in a variety of malignant and nonmalignant diseases. In spite of the wide‐spread use of mobilized peripheral blood stem cells for transplantation, the mechanisms underlying mobilization are still incompletely understood. Here we discuss the role of neutrophils and proteases as mediators of stem cell mobilization.
Epigenetic Regulation of Normal and Cancer Stem Cells
Authors: CLARKE MICHAEL F.
Published: June 2005

Abstract: In many tissues, a cellular hierarchy exists in which a small population of stem cells is responsible for the production of the mature cells of the organ. The stem cells maintain themselves through a process known as self‐renewal. Similarly, tumors contain a minority population of cancer stem cells that maintain the tumor. Some factors that regulate this process of self‐renewal are conserved from fruit fly to humans. Disruption of the regulation of self‐renewal results in cancer. Thus understanding the mechanisms that regulate stem cell generation has implications for normal development and disease.
Gene Expression in Stem Cell‐Supporting Stromal Cell Lines
Authors: CHARBORD PIERRE , MOORE KATERI
Published: June 2005

Abstract:Cells in the immediate microenvironment together with hematopoietic stem cells (HSCs) constitute the stem cell niche. The microenvironmental or stromal cells provide a complex molecular milieu that helps mediate and balance the self‐renewal and commitment potentials of stem cells. The molecules in this milieu are not well defined. In this study, we have intersected previous cDNA subtraction studies with array expression methodologies to define and categorize known gene products expressed by HSC‐supportive stromal cell lines. Data were curated from our previously released Stromal Cell Database (StroCDB) containing a set of gene products enriched for expression in the fetal liver stromal cell line AFT024. Global expression analyses were extended to other stem cell‐supporting and ‐nonsupporting fetal liver stromal cell lines using commercially available microarrays. Known and previously described gene products from selected categories were studied: transcription factors, cell membrane proteins, cytoskeleton and related proteins, extracellular matrix proteins, cell adhesion molecules and their corresponding signaling molecules, and cytokines and their related mediators. More than 300 known gene products were selected for expression in HSC‐supporting stromal cells compared to nonsupporting lines. Analyses of the data suggest that HSC‐supportive cells are immature, sessile, and highly reactive after binding to integrin ligands and cytokines. Therefore, they provide a dynamic space poised to respond to molecular cues elaborated within the stem cell niche. The study provides a survey of known proteins that play key roles in the support of HSCs by fetal liver stromal cells. It also provides insights into the biology of the stem cell niche by highlighting the complex network of intercellular signaling and communication involved in the organization of the niche space.
Effect of Tyrosine Kinase Inhibition Using Imatinib on Normal Lymphohematopoietic Cells
Authors: BALABANOV STEFAN , APPEL SILKE , KANZ LOTHAR , BROSSART PETER , BRÜMMENDORF TIM H.
Published: June 2005

Abstract: Imatinib is a selective tyrosine kinase inhibitor used for the treatment of Philadelphia chromosome‐positive leukemias and other malignancies. An important clinical observation is that imatinib can affect the function of normal nonmalignant cells resulting in myelosuppression in treated patients. This observation is supported by the recent findings suggesting that imatinib might affect mobilization, proliferation, and differentiation of hematopoietic progenitor cells while leaving hematopoietic stem cells unaffected. Furthermore, the induction of a specific T cell response seems to be impaired in chronic myeloid leukemia (CML) patients treated with imatinib in contrast to patients receiving interferon‐α. Recent studies demonstrate that in vitro exposure of mobilized human CD34+ progenitors to imatinib inhibits their differentiation into dendritic cells. This is of importance as some of the therapeutic effects in the treatment of patients with CML are mediated by the induction of leukemia‐specific T cell responses. Studies investigating the effects of imatinib on normal hematopoiesis are of interest because they might help us better understand the side effects observed clinically and might lead to the identification of novel therapeutic applications of the drug (e.g., in Bcr‐Abl− myeloproliferative disorders and potentially as an immunomodulatory agent).
Clonal Multilineage Differentiation of Murine Common Pluripotent Stem Cells Isolated from Skeletal Muscle and Adipose Stromal Cells
Authors: CASE JAMIE , HORVATH TAMARA L. , HOWELL JONATHAN C. , YODER MERVIN C. , MARCH KEITH L. , SROUR EDWARD F.
Published: June 2005

Abstract: Pluripotent stem cells (PSCs) with transdifferentiation capacity may provide useful therapeutic modalities in the areas of cellular restoration and regenerative medicine. The utility of PSCs depends on their ability to respond to different stimuli and to adapt to tissue‐specific differentiation conditions. Given that a number of cells possessing characteristics of PSCs have been identified and isolated from several adult murine tissues, we hypothesized that a common PSC may exist in multiple murine tissues and that these cells may either reside permanently in specific sites or continue to circulate and colonize tissues as needed. Previous data from our laboratory suggest that PSCs exhibiting an immunophenotype of CD45−Sca‐1+c‐kit−Thy‐1+ can be isolated from multiple murine tissues and may represent putative common PSCs (CoPSCs). To investigate whether the multiple tissue differentiation potential observed with these cells resulted from the presence of different tissue‐restricted progenitors within CD45−Sca‐1+c‐kit−Thy‐1+ cells or was the product of clonal differentiation of CoPSCs, clonality studies were performed. Single skeletal muscle (SM)‐derived CoPSCs were expanded for 10 days, and progeny cells were split into three culture conditions designed to stimulate myogenic, adipogenic, and neurogenic differentiation. Analysis of 600 clones indicated that 2.16%, 0.83%, and 0.33% of the total number of plated single cells were capable of unipotent, bipotent, and tripotent differentiation, respectively, into combinations of myocytes, adipocytes, and neuronal cells. Given that SM‐derived CoPSCs represent 4.78% of the total cells analyzed, tripotent CoPSCs made up 0.016% of the total muscle cells. Similar results were obtained in clonal analyses using adipose stromal cell (ASC)‐derived CoPSCs, suggesting that both SM‐ and ASC‐derived CoPSCs may be phenotypically and functionally identical. Taken together, these data demonstrate that a common PSC can be identified in different murine tissues and suggest that a small fraction of these cells are capable of clonal differentiation into multiple cell types.
Human Adaptive Immune System Rag2−/−γc−/− Mice
Authors: CHICHA LAURIE , TUSSIWAND ROXANE , TRAGGIAI ELISABETTA , MAZZUCCHELLI LUCA , BRONZ LUCIO , PIFFARETTI JEAN‐CLAUDE , LANZAVECCHIA ANTONIO , MANZ MARKUS G.
Published: June 2005

Abstract: Although many biologic principles are conserved in mice and humans, species‐specific differences exist, for example, in susceptibility and response to pathogens, that often do not allow direct implementation of findings in experimental mice to humans. Research in humans, however, for ethical and practical reasons, is largely restricted to in vitro assays that lack components and the complexity of a living organism. To nevertheless study the human hematopoietic and immune system in vivo, xenotransplantation assays have been developed that substitute human components to small animals. Here, we summarize our recent findings that transplantation of human cord blood CD34+ cells to newborn Rag2−/−γc−/− mice leads to de novo development of major functional components of the human adaptive immune system. These human adaptive immune system Rag2−/−γc−/− (huAIS‐RG) mice can now be used as a technically straightforward preclinical model to evaluate in vivo human adaptive immune system development as well as immune responses, for example, to vaccines or live infectious pathogens.
Hodgkin's Lymphoma in Elderly Patients: A Comprehensive Retrospective Analysis From the German Hodgkin's Study Group
Authors: Engert Andreas , Ballova Veronika , Haverkamp Heinz , Pfistner Beate , Josting Andreas , Dühmke Eckhart , Müller-Hermelink Konrad , Diehl Volker
Published: June 2005

Purpose

With improved prognosis for patients with Hodgkin's lymphoma (HL), interest increasingly focuses on high-risk groups such as elderly patients. We thus performed a retrospective analysis using the German Hodgkin's Study Group (GHSG) database to determine clinical risk factors, course of treatment, and outcome in elderly HL patients in comparison with younger adults.

Patients and Methods

A total of 4,251 patients included in the GHSG studies HD5 to HD9 were analyzed, of whom 372 (8.8%) were 60 years or older and 3,879 (91.2%) were younger than 60 years. Patient characteristics, treatment results, toxicity, freedom from treatment failure (FFTF), and overall survival (OS) were compared.

Results

Elderly patients more often had mixed cellularity subtype, “B” symptoms, elevated erythrocyte sedimentation rate, and poorer performance status. Less frequently observed were nodular sclerosis subtype, large mediastinal mass, and bulky disease. Acute toxicity during chemotherapy was generally higher in elderly patients. This was most obvious for severe infections (grade 3 or 4; 15% v 6%) correlating with more severe leukopenia in elderly patients (grade 4; 38% v 23%). As a result, significantly fewer elderly patients received the intended full chemotherapy dose (75% v 91%). The survival analysis showed a significantly poorer treatment outcome for elderly patients in terms of 5-year OS (65% v 90%), FFTF (60% v 80%), and HL-specific FFTF (73% v 82%).

Conclusion

Elderly patients have a poorer risk profile compared with younger HL patients and experience more severe treatment-associated toxicity. Higher mortality during treatment as well as lower dose-intensity are the major factors explaining the poorer overall outcome of elderly HL patients.
Phase I Safety, Pharmacokinetics, and Clinical Activity Study of Lapatinib (GW572016), a Reversible Dual Inhibitor of Epidermal Growth Factor Receptor Tyrosine Kinases, in Heavily Pretreated Patients With Metastatic Carcinomas
Authors: Burris Howard A. , Hurwitz Herbert I. , Dees E. Claire , Dowlati Afshin , Blackwell Kimberly L. , O'Neil Bert , Marcom Paul K. , Ellis Matthew J. , Overmoyer Beth , Jones Suzanne F. , Harris Jennifer L. , Smith Deborah A. , Koch Kevin M. , Stead Andrew , Mangum Steve , Spector Neil L.
Published: June 2005

Purpose

This study ( EGF10004 ) assessed the safety/tolerability, pharmacokinetics, and clinical activity of daily oral dosing with lapatinib ( GW572016 ) in patients with ErbB1-expressing and/or ErbB2-overexpressing advanced-stage refractory solid tumors.

Patients and Methods

Heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers were randomly assigned to one of five dose cohorts of lapatinib administered once daily. Pharmacokinetic samples were obtained on days 1 and 20. Clinical response was assessed every 8 weeks.

Results

Sixty-seven patients with metastatic solid tumors were treated with lapatinib. The most frequently reported drug-related adverse events were diarrhea (42%) and rash (31%). No grade 4 drug-related adverse events were reported. Five grade 3 drug-related toxicities (gastrointestinal events and rash) were experienced by four patients. Drug-related interstitial pneumonitis or cardiac dysfunction associated with other ErbB-targeted therapies was not reported. Four patients with trastuzumab-resistant metastatic breast cancer—two of whom were classified as having inflammatory breast cancer—had partial responses (PRs). Twenty-four patients with various other carcinomas experienced stable disease, of whom 10 received lapatinib for ≥ 6 months. The relationships between lapatinib dose or serum concentration and clinical response could not be adequately characterized due to the limited response data. The incidence of diarrhea increased with increasing dose, whereas the incidence of rash was not related to dose.

Conclusion

Lapatinib was well tolerated at doses ranging from 500 to 1,600 mg once daily. Clinical activity was observed in heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers, including four PRs in patients with trastuzumab-resistant breast cancers and prolonged stable disease in 10 patients.
Gaussian polytopes: variances and limit theorems
Authors: Hug Daniel , Reitzner Matthias
Published: June 2005

The convex hull of n independent random points in ℝd, chosen according to the normal distribution, is called a Gaussian polytope. Estimates for the variance of the number of i-faces and for the variance of the ith intrinsic volume of a Gaussian polytope in ℝd, d∈ℕ, are established by means of the Efron-Stein jackknife inequality and a new formula of Blaschke-Petkantschin type. These estimates imply laws of large numbers for the number of i-faces and for the ith intrinsic volume of a Gaussian polytope as n→∞.
Student processes
Authors: Heyde C. C. , Leonenko N. N.
Published: June 2005

Stochastic processes with Student marginals and various types of dependence structure, allowing for both short- and long-range dependence, are discussed in this paper. A particular motivation is the modelling of risky asset time series.
Hidden regular variation and the rank transform
Authors: Heffernan Janet , Resnick Sidney
Published: June 2005

Random vectors in the positive orthant whose distributions possess hidden regular variation are a subclass of those whose distributions are multivariate regularly varying with asymptotic independence. The concept is an elaboration of the coefficient of tail dependence of Ledford and Tawn. We show that the rank transform that brings unequal marginals to the standard case also preserves the hidden regular variation. We discuss applications of the results to two examples, one involving flood risk and the other Internet data.
Heavy-tailed asymptotics of stationary probability vectors of Markov chains of gi/g/1 type
Authors: Li Quan-Lin , Zhao Yiqiang Q.
Published: June 2005

In this paper, we provide a novel approach to studying the heavy-tailed asymptotics of the stationary probability vector of a Markov chain of GI/G/1 type, whose transition matrix is constructed from two matrix sequences referred to as a boundary matrix sequence and a repeating matrix sequence, respectively. We first provide a necessary and sufficient condition under which the stationary probability vector is heavy tailed. Then we derive the long-tailed asymptotics of the R-measure in terms of the RG-factorization of the repeating matrix sequence, and a Wiener-Hopf equation for the boundary matrix sequence. Based on this, we are able to provide a detailed analysis of the subexponential asymptotics of the stationary probability vector.
Fluctuation limit of branching processes with immigration and estimation of the means
Authors: Ispány M. , Pap G. , van Zuijlen M. C. A.
Published: June 2005

We investigate a sequence of Galton-Watson branching processes with immigration, where the offspring mean tends to its critical value 1 and the offspring variance tends to 0. It is shown that the fluctuation limit is an Ornstein-Uhlenbeck-type process. As a consequence, in contrast to the case in which the offspring variance tends to a positive limit, it transpires that the conditional least-squares estimator of the offspring mean is asymptotically normal. The norming factor is n3/2, in contrast to both the subcritical case, in which it is n1/2, and the nearly critical case with positive limiting offspring variance, in which it is n.
On asymptotically efficient simulation of large deviation probabilities
Authors: Dieker A. B. , Mandjes M.
Published: June 2005

Let {νε, ε>0} be a family of probabilities for which the decay is governed by a large deviation principle, and consider the simulation of νε0(A) for some fixed measurable set A and some ε0>0. We investigate the circumstances under which an exponentially twisted importance sampling distribution yields an asymptotically efficient estimator. Varadhan's lemma yields necessary and sufficient conditions, and these are shown to improve on certain conditions of Sadowsky. This is illustrated by an example to which Sadowsky's conditions do not apply, yet for which an efficient twist exists.
Fragmentation energy
Authors: Bertoin Jean , Martínez Servet
Published: June 2005

Motivated by a problem arising in the mining industry, we estimate the energy ε(η) that is needed to reduce a unit mass to fragments of size at most η in a fragmentation process, when η→0. We assume that the energy used in the instantaneous dislocation of a block of size s into a set of fragments (s1,s2,…) is sβφ(s1/s,s2/s,…), where φ is some cost function and β a positive parameter. Roughly, our main result shows that if α>0 is the Malthusian parameter of an underlying Crump-Mode-Jagers branching process (with α = 1 when the fragmentation is mass-conservative), then there exists a c∈(0,∞) such that ε(η)∼cηβ-α when β<α. We also obtain a limit theorem for the empirical distribution of fragments of size less than η that result from the process. In the discrete setting, the approach relies on results of Nerman for general branching processes; the continuous approach follows by considering discrete skeletons. In the continuous setting, we also provide a direct approach that circumvents restrictions induced by the discretization.
Nonzero-sum games for continuous-time Markov chains with unbounded discounted payoffs
Authors: Guo Xianping , Hernández-Lerma Onésimo
Published: June 2005

In this paper, we study two-person nonzero-sum games for continuous-time Markov chains with discounted payoff criteria and Borel action spaces. The transition rates are possibly unbounded, and the payoff functions might have neither upper nor lower bounds. We give conditions that ensure the existence of Nash equilibria in stationary strategies. For the zero-sum case, we prove the existence of the value of the game, and also provide arecursiveway to compute it, or at least to approximate it. Our results are applied to a controlled queueing system. We also show that if the transition rates areuniformly bounded, then a continuous-time game is equivalent, in a suitable sense, to a discrete-time Markov game.
Compound Poisson limits for household epidemics
Authors: Neal Peter
Published: June 2005

We consider epidemics in populations that are partitioned into small groups known as households. Whilst infectious, a typical infective makes global and local contact with individuals chosen independently and uniformly from the whole population or their own household, as appropriate. Previously, the classical Poisson approximation for the number of survivors of a severe epidemic has been extended to the household model. However, in the current work we exploit a Sellke-type construction of the epidemic process, which enables the derivation of sufficient conditions for the existence of a compound Poisson limit theorem for the survivors of the epidemic. The results are specialised to the Reed-Frost and general stochastic epidemic models.
Heterogeneous population dynamical model: a filtering problem
Authors: Gerardi A. , Tardelli P.
Published: June 2005

We consider a heterogeneous population of identical particles divided into a finite number of classes according to their level of health. The partition can change over time, and a suitable exchangeability assumption is made to allow for having identical items of different types. The partition is not observed; we only observe the cardinality of a particular class. We discuss the problem of finding the conditional distribution of particle lifetimes, given such observations, using stochastic filtering techniques. In particular, a discrete-time approximation is given.
Rarity and exponentiality: an extension of Keilson's theorem, with applications
Authors: Grübel Rudolf , Reich Marcus
Published: June 2005

We generalize a theorem due to Keilson on the approximate exponentiality of waiting times for rare events in regenerative processes. We use the result to investigate the limit distribution for a family of first entrance times in a sequence of Ehrenfest urn models. As a second application, we consider approximate pattern matching, a problem arising in molecular biology and other areas.
Burgers' turbulence problem with linear or quadratic external potential
Authors: Barndorff-Nielsen O. E. , Leonenko N. N.
Published: June 2005

We consider solutions of Burgers' equation with linear or quadratic external potential and stationary random initial conditions of Ornstein-Uhlenbeck type. We study a class of limit laws that correspond to a scale renormalization of the solutions.
The lifetime of a random set
Authors: Kiessler Peter C. , Nimitkiatklai Kanoktip
Published: June 2005

We consider the lifetimes of systems that can be modeled as particles that move within a bounded region in ℝn. Particles move within the set according to a random walk, and particles that leave the set are lost. We divide the set into equal cells and define the lifetime of the set as the time required for the number of particles in one of the cells to fall below a predetermined threshold. We show that the lifetime of the system, given a sufficiently large number of particles, is Weibull distributed.
B-stability
Authors: Mallows Colin , Shepp Larry
Published: June 2005

A random variable Y is branching stable (B-stable) for a nonnegative integer-valued random variable J with E(J)>1 if Y*J∿cY for some scalar c, where Y*J is the sum of J independent copies of Y. We explore some aspects of this notion of stability and show that, for any Y0 with finite nonzero mean, if we define Yn+1=Yn*J/E(J) then the sequence Yn converges in law to a random variable Y∞ that is B-stable for J. Also Y∞ is the unique B-stable law with mean E(Y0). We also present results relating to random variables Y0 with zero means and infinite means. The notion of B-stability arose in a scheme for cataloguing a large network of computers.
Optimization under the PMλ,τ policy of a finite dam with both continuous and jumpwise inputs
Authors: Lim Kyung Eun , Baek Jee Seon , Lee Eui Yong
Published: June 2005

We consider a finite dam under the policy, where the input of water is formed by a Wiener process subject to random jumps arriving according to a Poisson process. The long-run average cost per unit time is obtained after assigning costs to the changes of release rate, a reward to each unit of output, and a penalty that is a function of the level of water in the reservoir.
Competition and Incentives with Motivated Agents
Authors: Besley Timothy , Ghatak Maitreesh
Published: June 2005

A unifying theme in the literature on organizations such as public bureaucracies and private nonprofits is the importance of mission, as opposed to profit, as an organizational goal. Such mission-oriented organizations are frequently staffed by motivated agents who subscribe to the mission. This paper studies incentives in such contexts and emphasizes the role of matching the mission preferences of principals and agents in increasing organizational efficiency. Matching economizes on the need for high-powered incentives. It can also, however, entrench bureaucratic conservatism and resistance to innovations. The framework developed in this paper is applied to school competition, incentives in the public sector and in private nonprofits, and the interdependence of incentives and productivity between the private for-profit sector and the mission-oriented sector through occupational choice.
Equilibrium Investment and Asset Prices under Imperfect Corporate Control
Authors: Dow James , Gorton Gary , Krishnamurthy Arvind
Published: June 2005

We integrate a widely accepted version of the separation of ownership and control—Michael Jensen's (1986) free cash flow theory—into a dynamic equilibrium model, and study the effect of imperfect corporate control on asset prices and investment. Aggregate free cash flow of the corporate sector is an important state variable in explaining asset prices, investment, and the cyclical behavior of interest rates and the yield curve. The financial friction causes cash-flow shocks to affect investment, and causes otherwise i.i.d. shocks to be transmitted from period to period. The shocks propagate through large firms and during booms.
FDA Policy on Unapproved Drug Products: Past, Present, and Future
Authors: Chhabra Renu , Kremzner Mary E , Kiliany Brenda J
Published: June 2005

OBJECTIVE

To review the history of drug regulation by the Food and Drug Administration (FDA) as it relates to unapproved drugs and FDA policy, along with the FDA's efforts to avoid future incidents by amending and enforcing those policies that are already in place.

DATA SOURCES

Data from FDA history documents, FDA guidances, Code of Federal Regulations Title 21, and presentations by the FDA's Office of Compliance were gathered.

STUDY SELECTION AND DATA EXTRACTION

All information identified from the data sources was evaluated, and all information deemed relevant was included for this review.

DATA SYNTHESIS

Contrary to popular belief, there are drugs on the market that have not been evaluated for safety or efficacy by the FDA. For almost a century, the FDA has taken action against public health threats posed by unapproved drug products, and today's drugs and vaccines are required to demonstrate both safety and efficacy prior to marketing. The FDA has taken great strides to ensure the welfare of Americans by reacting to disasters that have occurred in the past and being proactive by setting regulations that will prevent such catastrophes from occurring in the future.

CONCLUSIONS

The FDA recognizes that drug regulation is an ongoing process and that, although we have come a long way, there is still much to be done.
Intentional and Unintentional Nonadherence to Antihypertensive Medication
Authors: Lowry Kathryn P , Dudley Tara K , Oddone Eugene Z , Bosworth Hayden B
Published: June 2005

BACKGROUND

Hypertension is poorly controlled in the US due to medication nonadherence. Recent evidence suggests that nonadherence can be classified as intentional or unintentional and different patient characteristics, such as the experience of adverse effects, may be associated with each.

OBJECTIVE

To examine associations between patient characteristics, including reported adverse effects, and both intentional and unintentional nonadherence among 588 hypertensive patients.

METHODS

Baseline data from a clinical trial, the Veterans' Study To Improve the Control of Hypertension, were examined. Intentional and unintentional nonadherence were assessed using a self-report measure. Participants were presented with a list of adverse effects commonly associated with antihypertensive medication and asked to indicate which symptoms they had experienced. Logistic regression analyses were used to examine adjusted associations between patient characteristics and type of nonadherence.

RESULTS

Approximately 31% of patients reported unintentional nonadherence and 9% reported intentional nonadherence. Non-white participants, individuals without diabetes mellitus, and individuals reporting ≥5 adverse effects were more likely to report intentional nonadherence than their counterparts. Individuals with less than a 10th-grade education and non-white participants were more likely to report unintentional nonadherence than their counterparts. When symptoms of increased urination and wheezing/shortness of breath were reported, patients were more likely to report intentional and unintentional nonadherence compared with those who were adherent. Unintentional nonadherence was also associated with reports of dizziness and rapid pulse.

CONCLUSIONS

Both intentional and unintentional nonadherence are common and related to perceived adverse effects. Furthermore, different interventions may be necessary to improve adherence in unintentionally and intentionally nonadherent patients.