bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of neoadjuvant chemoradiotherapy with S-1 plus biweekly cisplatin for advanced gastric cancer patients with lymph node metastasis: -KOGC04-
Authors: Matsuda Satoru , Takahashi Tsunehiro , Fukada Junichi , Fukuda Kazumasa , Kawakubo Hirofumi , Saikawa Yoshiro , Kawaguchi Osamu , Takeuchi Hiroya , Shigematsu Naoyuki , Kitagawa Yuko 
Published: January 2014

Abstract

Background
In patients with highly advanced gastric cancer, the recurrence rate remains high and the prognosis disappointing. We previously reported a phase I study of a neoadjuvant chemoradiotherapy of S-1 plus weekly cisplatin. Although adequate safety and efficacy were reported, myelosuppression was frequently observed, leading to treatment delay in several cases. To decrease toxicity and improve efficacy, we planned a phase I study with a modified chemotherapy regimen with biweekly cisplatin.

Methods
Patients with advanced gastric cancer and lymph node metastasis who were treated by our institution between 2011 and 2012 were eligible for inclusion. The initial chemoradiotherapy schedule consisted of 6 weeks of S-1 orally administered on days 1–15 with an escalating dose of cisplatin administered on days 1 and 15. The starting dose (level 1) of cisplatin was 15 mg/m2, the second dose (level 2) was 20 mg/m2, and the third dose (level 3) was 25 mg/m2. Radiation of 40 Gy was administered in 20 fractions. After initial chemoradiotherapy, one cycle of combination chemotherapy with S-1 plus cisplatin was delivered. The second cycle was 42 days in duration and included S-1 administered on days 1–29 plus biweekly cisplatin administered on days 1, 15, and 29. After neoadjuvant treatment, a curative gastrectomy with extended (D2) lymph node dissection was planned.

Results
Nine patients were enrolled. At level 3, one patient had dose-limiting grade 3 diarrhea. Another patient experienced grade 3 nausea and intended to discontinue the treatment. Overall, because 2 of 3 patients experienced dose-limiting toxicity at level 3, we confirmed level 3 (Cisplatin 25 mg/m2) as the maximum tolerated dose and level 2 (Cisplatin 20 mg/m2) as the recommended dose (RD). The response rate was 78%, and 8 patients underwent curative gastrectomy. Resected specimens showed a histological response in 6 patients (75%), including one with a pathological complete response.

Conclusions
In this phase I trial, RD of cisplatin was identified as 20 mg/m2. Generally, S-1 plus biweekly cisplatin can be given safely with concurrent radiation. We have initiated a multicenter phase II trial to further confirm the efficacy and safety of this approach.

Trial registration

UMIN000008941
Recombinant human mannose-binding lectin dampens human alveolar macrophage inflammatory responses to influenza A virus in vitro
Authors: Nelson Benjamin , Zhou Xiuqin , White Mitchell , Hartshorn Kevan , Takahashi Kazue , Kinane T Bernard , Anandaiah Asha , Koziel Henry 
Published: January 2014

ABSTRACTIAV pneumonia remains a serious global health problem, and preventative and therapeutic strategies remain limited. AM are critical effector cells in the control of influenza, impairing IAV replication, promoting IAV clearance, and promoting efferocytosis and resolution of lung inflammation. MBL, an innate immune pattern recognition molecule, present in the lungs, binds IAV, and plasma MBL deficiency is associated with increased susceptibility to IAV, although the mechanism remains incompletely understood, and the influence of MBL on the IAV-AM interaction has not been established. In the current study, focusing on human macrophages (U937 cell line and clinically relevant human AM), data demonstrated that unopsonized IAV is readily internalized, induced release of TNF and ROS, and promoted macrophage apoptosis. In contrast, IAV, opsonized with rhMBL, reduced IAV uptake and macrophage apoptosis and dramatically reduced TNF release and ROS. Macrophage host-defense responses were reduced further in the presence of MASPs. Taken together, these data support the concept that rhMBL may serve a protective innate host response and a critical biological response modifier function by limiting AM inflammation, oxidative injury, and AM apoptosis, which may allow effective IAV clearance while limiting collateral damage to vital organs, such as the lungs.
Rac1 and Rac2 control distinct events during antigen-stimulated mast cell exocytosis
Authors: Baier Alicia , Ndoh Vivian N E , Lacy Paige , Eitzen Gary 
Published: January 2014

ABSTRACTThe release of preformed mediators from immune cells is through a process described as exocytosis. In mast cells, exocytosis is regulated by several coordinated intracellular signaling pathways. Here, we investigated the role of the hematopoietic-specific Rho GTPase, Rac2, and the ubiquitously expressed Rac1, in controlling mast cell exocytosis. These two isoforms showed equivalent levels of expression in mouse BMMCs. Although Rac1 and Rac2 share 92% sequence identity, they were not functionally redundant, as Rac2−/− BMMCs were defective in exocytosis, even though Rac1 levels were unaffected. Antigen-stimulated WT mast cells underwent a series of morphological transitions: initial flattening, followed by actin-mediated peripheral membrane ruffling and calcium influx, which preceded exocytosis. Whereas membrane ruffling was unaffected in Rac2−/− BMMCs, calcium influx was decreased significantly. Calcium influx was studied further by examining SOCE. In Rac2−/− BMMCs, the activation of PLCγ1 and calcium release from intracellular stores occurred normally; however, activation of plasma membrane calcium channels was defective, shown by the lack of extracellular calcium influx and a reduction of YFP-STIM1 puncta at the plasma membrane. Additionally, we used the small molecule Rac inhibitor, EHT 1864, to target Rac signaling acutely in WT BMMCs. EHT 1864 blocked exocytosis and membrane ruffling completely in conjunction with exocytosis. Our findings suggest that antigen-stimulated membrane ruffling in mast cells is a Rac1-mediated process, as this persisted in the absence of Rac2. Therefore, we define distinct modes of Rac-regulated mast cell exocytosis: Rac2-mediated calcium influx and Rac1-mediated membrane ruffling.
Macrophage uptake and accumulation of folates are polarization-dependent in vitro and in vivo and are regulated by activin A
Authors: Samaniego Rafael , Palacios Blanca Soler , Domiguez-Soto Ángeles , Vidal Carlos , Salas Azucena , Matsuyama Takami , Sánchez-Torres Carmen , de la Torre Inmaculada , Miranda-Carús Maria Eugenia , Sánchez-Mateos Paloma , Puig-Kröger Amaya 
Published: January 2014

ABSTRACTVitamin B9, commonly known as folate, is an essential cofactor for one-carbon metabolism that enters cells through three major specialized transporter molecules (RFC, FR, and PCFT), which differ in expression pattern, affinity for substrate, and ligand-binding pH dependency. We now report that the expression of the folate transporters differs between macrophage subtypes and explains the higher accumulation of 5-MTHF—the major folate form found in serum—in M2 macrophages in vitro and in vivo. M1 macrophages display a higher expression of RFC, whereas FRβ and PCFT are preferentially expressed by anti-inflammatory and homeostatic M2 macrophages. These differences are also seen in macrophages from normal tissues involved in folate transit (placenta, liver, colon) and inflamed tissues (ulcerative colitis, RA), as M2-like macrophages from normal tissues express FRβ and PCFT, whereas TNF-α-expressing M1 macrophages from inflamed tissues are RFC+. Besides, we provide evidences that activin A is a critical factor controlling the set of folate transporters in macrophages, as it down-regulates FRβ, up-regulates RFC expression, and modulates 5-MTHF uptake. All of these experiments support the notion that folate handling is dependent on the stage of macrophage polarization.
Regulation of Osteoblast Differentiation Mediated by Bone Morphogenetic Proteins, Hedgehogs, and Cbfa1
Authors: Yamaguchi Akira , Komori Toshihisa , Suda Tatsuo 
Published: January 2014

AbstractOsteoblasts arise from common progenitors with chondrocytes, muscle and adipocytes, and various hormones and local factors regulate their differentiation. We review here regulation of osteoblast differentiation mediated by the local factors such as bone morphogenetic proteins (BMPs) and hedgehogs and the transcription factor, core-binding factor α-1 (Cbfa1). BMPs are the most potent regulators of osteoblast differentiation among the local factors. Sonic and Indian hedgehogs are involved in osteoblast differentiation by interacting with BMPs. Cbfa1, a member of the runt domain gene family, plays a major role in the processes of a determination of osteoblast cell lineage and maturation of osteoblasts. Cbfa1 is an essential transcription factor for osteoblast differentiation and bone formation, because Cbfa1-deficient mice completely lacked bone formation due to maturation arrest of osteoblasts. Although the regulatory mechanism of Cbfa1 expression has not been fully clarified, BMPs are an important local factor that up-regulates Cbfa1 expression. Thus, the intimate interaction between local factors such as BMPs and hedgehogs and the transcription factor, Cbfa1, is important to osteoblast differentiation and bone formation.
Premature Adrenarche—Normal Variant or Forerunner of Adult Disease?*
Authors: Ibáñez Lourdes , DiMartino-Nardi Joan , Potau Neus , Saenger Paul 
Published: January 2014

AbstractAdrenarche is the puberty of the adrenal gland. The descriptive term pubarche indicates the appearance of pubic hair, which may be accompanied by axillary hair. This process is considered premature if it occurs before age 8 yr in girls and 9 yr in boys.The chief hormonal product of adrenarche is dehydroepiandrosterone (DHEA) and its sulfated product DHEA-S. The well documented evolution of adrenarche in primates and man is incompatible with either a neutral or harmful role for DHEA and implies most likely a positive role for some aspect of young adult pubertal maturation and developmental maturation. Premature adrenarche has no adverse effects on the onset and progression of gonadarche in final height.Both extra- and intraadrenal factors regulate adrenal androgen secretion. Recent studies have shown that premature adrenarche in childhood may have consequences such as functional ovarian hyperandrogenism, polycystic ovarian syndrome, and insulin resistance in later life, sometimes already recognizable in childhood or adolescence. Premature adrenarche may thus be a forerunner of syndrome X in some children. The association of these endocrine-metabolic abnormalities with reduced fetal growth and their genetic basis remain to be elucidated.
The Somatomedin Hypothesis: 2001
Authors: Le Roith Derek , Bondy Carolyn , Yakar Shoshana , Liu Jun-Li , Butler Andrew 
Published: January 2014

AbstractSince the original somatomedin hypothesis was conceived, a number of important discoveries have allowed investigators to modify the concept. Originally somatic growth was thought to be controlled by pituitary GH and mediated by circulating insulin-like growth factor-I (IGF-I, somatomedin C) expressed exclusively by the liver. With the discovery that IGF-I is produced by most, if not all, tissues, the role of autocrine/paracrine IGF-I vs. the circulating form has been hotly debated. Recent experiments using transgenic and gene-deletion technologies have attempted to answer these questions. In the liver-specific igf-1 gene-deleted mouse model, postnatal growth and development are normal despite the marked reduction in circulating IGF-I and IGF-binding protein levels; free IGF-I levels are normal. Thus, the normal postnatal growth and development in these animals may be due to normal free IGF-I levels (from as yet unidentified sources), although the role of autocrine/paracrine IGF-I has yet to be determined.
Signal Transducer and Activator of Transcription (STAT)-A and STAT5B Differentially Regulate Human Mammary Carcinoma Cell Behavior
Authors: Tang Jian-Zhong , Zuo Ze-Hua , Kong Xiang-Jun , Steiner Michael , Yin Zhinan , Perry Jo K. , Zhu Tao , Liu Dong-Xu , Lobie Peter E. 
Published: January 2014

Abstract
Increased signal transducer and activator of transcription (STAT)-5 activation has been reported in various malignancies including mammary carcinoma. However, it is only recently that potentially distinct roles of STAT5A and STAT5B in neoplasia have begun to emerge. Herein we systematically delineate the functions of STAT5A and STAT5B in human mammary carcinoma cells. Forced expression of constitutively active (CA) STAT5A enhanced both survival and anchorage-independent growth of human mammary carcinoma cells but concordantly suppressed cell motility as revealed in colony scattering, cell migration, and invasion assays. In contrast, forced expression of CA STAT5B exhibited lower potency than CA STAT5A in enhancing survival and anchorage-independent growth of mammary carcinoma cells and exerted no effects on cell motility. Differential expression of genes that regulate cellular survival and motility was concomitantly observed on forced expression of CA STAT5A or CA STAT5B. We also observed that functions of STAT5A and STAT5B were similarly differential in T47D cells. Small interfering RNA-mediated depletion of STAT5A significantly impaired anchorage-independent growth of MCF-7 cells, whereas a smaller reduction was observed upon small interfering RNA-mediated depletion of STAT5B. Depletion of endogenous STAT5A also significantly enhanced cell motility, whereas depletion of endogenous STAT5B exhibited no effect. Xenograft studies provided data concordant with the in vitro effects of the two STAT5 isoforms. We therefore demonstrate that STAT5A and STAT5B differentially regulate behavior of human mammary carcinoma cells.
The Central Regulation of Bone Mass, the First Link between Bone Remodeling and Energy Metabolism
Authors: Karsenty Gerard , Oury Franck 
Published: January 2014

Abstract
Evolutionary consideration and clinical observations led us to hypothesize 10 yr ago that there may be a coordinated regulation, endocrine in nature, of bone remodeling and energy metabolism. The existence of this coordinated regulation is motivated by the energetic needs of the skeleton; therefore, this regulation relies on hormones that appear during evolution with the skeleton, not with energy metabolism. Leptin is such a hormone, and it is a critical regulator of bone mass as well as of appetite and energy expenditure. This review goes over the anatomical route and molecular pathways used by leptin to inhibit both bone mass accrual and appetite through its signaling in the brain.
Does a Short Loop Feedback Mechanism for the Control of Luteinizing Hormone Secretion Exist in the Ewe?*
Authors: Skinner Donal C. , Evans Neil P. , Malpaux BenoÎt 
Published: January 2014

Abstract
It is not known whether a short loop feedback mechanism for the regulation of LH exists in sheep. This study on ovariectomized ewes investigated whether a bolus injection (10, 1, and 0.1 μg LH or 1μ g BSA; n = 4) or a 3-h continuous infusion of exogenous LH (100 or 1 ng/min; n = 7) into the third ventricle through a permanent indwelling cannula could influence the activity of the GnRH pulse generator, as determined by measurement of endogenous LH secretion. To assess the potential for involvement in a LH short loop feedback system and to estimate the level of LH in the hypothalamic milieu, the concentrations of LH in the peripheral circulation, portal circulation, and third ventricle were measured during an estradiol-induced preovulatory LH surge (n = 4).
Neither the bolus nor continuous administration of LH into the third ventricle had any effect on the mean interpulse interval, nadir, pulse amplitude, or circulating level of systemic LH. Furthermore, despite portal LH concentrations being more than 20-fold higher than jugular LH concentrations, LH levels in third ventricular cerebrospinal fluid remained barely detectable and did not reflect dynamic secretory events in the peripheral or hypothalamo-hypophyseal portal blood. These data demonstrate that in ewes, little pituitary LH reaches the third ventricle, and the small amount that does is unable to affect peripheral gonadotropin release. Our study suggests, therefore, that a short loop feedback system for LH does not exist in the ewe.
Preputial Sebocyte 5α-Reductase Isoform Specificity*
Authors: Deplewski Dianne , Liao Shutsung , Rosenfield Robert L. 
Published: January 2014

AbstractWe determined whether the 5α-reductase (5α-R) isozyme specificity in rat preputial sebocytes is in accordance with that of sebaceous glands (type 1 isoform) or with that of other genital tract androgen-dependent organs (type 2). Immunostaining indicated expression of type 1 5α-R in preputial epithelial cells in the gland as well as in culture. Northern blots and ribonuclease protection assays both showed the presence of the type 1 isozyme in preputial sebocytes, with little if any expression of the type 2 messenger RNA. Ribonuclease protection assay demonstrated that both homogenized preputial gland and freshly dispersed preputial cells express 2-fold more 5α-R type 1 messenger RNA than does skin and 7-fold more than cultured preputial cells. Since cultured preputial cells do not fully differentiate in monolayer culture, these findings suggest that 5α-R is increasingly expressed as sebaceous cells differentiate. The predominance of the type 1 isoform in preputial sebocytes is important because it indicates programming by a skin- and sebocyte-specific signal in the midst of the genital tract where the type 2 isoform otherwise predominates.
Human Thyroid Fibroblasts Exhibit a Distinctive Phenotype in Culture: Characteristic Ganglioside Profile and Functional CD40 Expression*
Authors: Smith Terry J. , Sempowski Gregory D. , Berenson Charles S. , Cao H. James , Wang Hwai-Shi , Phipps Richard P. 
Published: January 2014

AbstractFibroblasts from different regions of the human body exhibit substantial phenotypic diversity, some of which relates to the capacity for cross-talk with cells of the immune system. We examine, for the first time, thyroid fibroblast biology in culture. Thyroid explants were placed in culture, and fibroblasts were outgrown and serially passaged. These fibroblasts take on a morphology in culture resembling cells from other anatomic regions. When treated with PGE2, they assume a stellate morphology similar to that of prostanoid-treated orbital fibroblasts. The ganglioside profile exhibited by these cells is distinct from that observed previously in orbital and dermal fibroblasts. They uniformly express Thy-1, a surface glycoprotein. Messenger RNA encoding CD40, a surface receptor found on bone marrow-derived cells, and CD40 protein were expressed constitutively at low levels. Interferon-γ (500 U/ml) treatment for 48–72 h resulted in high levels of surface HLA-DR and CD40 display. When CD40 is engaged with CD40 ligand (CD40L), nuclear factor-κB binding activity is up-regulated as is interleukin (IL)-6 and IL-8 expression. IL-1β treatment up-regulates the expression of IL-1α, IL-1β, and PGE2. These observations suggest that thyroid fibroblasts possess the molecular machinery necessary for cross-talk with immunocompetent cells such as lymphocytes and mast cells through the CD40/CD40L complex, as well as through classic cytokine networks, and to participate potentially in the inflammatory response of the thyroid gland.
Gonadal Steroids Target AMPA Glutamate Receptor-Containing Neurons in the Rat Hypothalamus, Septum and Amygdala: A Morphological and Biochemical Study*
Authors: Diano Sabrina , Naftolin Frederick , Horvath Tamas L. 
Published: January 2014

AbstractInteractions between glutamate and gonadal steroids are involved in the regulation of limbic and hypothalamic functions. We hypothesized that hormonal signals affect excitatory neurotransmission by regulating the expression of glutamate receptors (GluR) in limbic and hypothalamic regions. To test this hypothesis, first, the coexpression of dl-α-amino-3-hydroxy-5-methyl-4-isoxazone-propionate (AMPA) GluR1, GluR2/3, and androgen receptors or estrogen receptors was revealed in the same cells of septal, amygdaloid, and hypothalamic areas by double immunocytochemistry. The highest incidence of colocalization was detected in hypothalamic regions. To demonstrate a regulatory role of testosterone or estradiol on AMPA receptor expression, the hormonal milieu of male and female rats was manipulated by gonadectomy and hormonal treatment. GluR1 and GluR2/3 expression was assessed by Western blots. Statistical analysis demonstrated that testosterone and estradiol have a stimulatory influence on the expression of AMPA receptors in the hypothalamus. The regulatory effect of estradiol on AMPA receptors was found to be site and gender specific: after estradiol treatment, samples taken from the hypothalamus contained increased levels of GluR1 and GluR2/3, whereas in the septum, bed nucleus and amygdala, no changes could be detected. Furthermore, the increase in hypothalamic GluR 2/3 levels was two times higher in females, compared with males, whereas the changes in hypothalamic GluR 1 levels showed no sex differences.Our results support the hypothesis that the interaction between gonadal steroids and glutamate involves hormone regulation of GluR. This mechanism seems to be gender and site specific, suggesting that excitatory neurotransmission and related physiological mechanisms also may be distinctly different in males and females.
Comparison of the Ligand Binding Specificity and Transcript Tissue Distribution of Estrogen Receptors α and β
Authors: Kuiper George G. J. M. , Carlsson Bo , Grandien Kaj , Enmark Eva , Häggblad Johan , Nilsson Stefan , Gustafsson Jan-Åke 
Published: January 2014

Abstract
The rat estrogen receptor (ER) exists as two subtypes, ERα and ERβ, which differ in the C-terminal ligand binding domain and in the N-terminal transactivation domain. In this study we investigated the messenger RNA expression of both ER subtypes in rat tissues by RT-PCR and compared the ligand binding specificity of the ER subtypes.
Saturation ligand binding analysis of in vitro synthesized human ERα and rat ERβ protein revealed a single binding component for 16α-iodo-17β-estradiol with high affinity[ dissociation constant (Kd) = 0.1 nm for ERα protein and 0.4 nm for ERβ protein]. Most estrogenic substances or estrogenic antagonists compete with 16α-[125I]iodo-17β-estradiol for binding to both ER subtypes in a very similar preference and degree; that is, diethylstilbestrol &gt; hexestrol &gt; dienestrol &gt; 4-OH-tamoxifen &gt; 17β-estradiol &gt; coumestrol, ICI-164384 &gt; estrone, 17α-estradiol &gt; nafoxidine, moxestrol &gt; clomifene &gt; estriol, 4-OH-estradiol &gt; tamoxifen, 2-OH-estradiol, 5-androstene-3β,17β-diol, genistein for the ERα protein and dienestrol &gt; 4-OH-tamoxifen &gt; diethylstilbestrol &gt; hexestrol &gt; coumestrol, ICI-164384 &gt; 17β-estradiol &gt; estrone, genistein &gt; estriol &gt; nafoxidine, 5-androstene-3β,17β-diol &gt; 17α-estradiol, clomifene, 2-OH-estradiol &gt; 4-OH-estradiol, tamoxifen, moxestrol for the ERβ protein. The rat tissue distribution and/or the relative level of ERα and ERβ expression seems to be quite different, i.e. moderate to high expression in uterus, testis, pituitary, ovary, kidney, epididymis, and adrenal for ERα and prostate, ovary, lung, bladder, brain, uterus, and testis for ERβ. The described differences between the ER subtypes in relative ligand binding affinity and tissue distribution could contribute to the selective action of ER agonists and antagonists in different tissues.