tbuckley/cabot-search huggingface dataset:
Dose and Schedule Study of Panitumumab Monotherapy in Patients with Advanced Solid Malignancies
Authors: Louis M. Weiner, Arie S. Belldegrun, Jeffrey Crawford, Anthony W. Tolcher, Pamela Lockbaum, Rosalin H. Arends, Lynn Navale, Rafael G. Amado, Gisela Schwab, Robert A. Figlin
Journal: Clinical Cancer Research (2008)

Abstract Purpose: This phase 1 study evaluated the safety, pharmacokinetics, and activity of panitumumab, a fully human, IgG2 monoclonal antibody that targets the epidermal growth factor receptor in patients with previously treated epidermal growth factor receptor–expressing advanced solid tumors. Experimental Design: Sequential cohorts were enrolled to receive four i.v. infusions of panitumumab monotherapy at various doses and schedules. Safety was continuously monitored. Serum samples for pharmacokinetic, immunogenicity, and chemistry assessments were drawn at preset intervals. Tumor response was assessed at week 8. Results: Ninety-six patients received panitumumab. Median (range) age was 61 years (32-79 years), and 72 (75%) patients were male. Tumor types were 41% colorectal cancer, 22% prostate, 16% renal, 15% non–small cell lung, 3% pancreatic, 3% esophageal/gastroesophageal, and 1% anal. The overall incidence of grade 3 or 4 adverse events was 32% and 7%, respectively. The incidence of skin-related toxicities was dose dependent. No maximum tolerated dose was reached. No human anti-panitumumab antibodies were detected. No investigator-determined panitumumab infusion-related reactions were reported. Serum panitumumab concentrations were similar in the 2.5 mg/kg weekly, 6.0 mg/kg every 2 weeks, and 9.0 mg/kg every 3 weeks dose cohorts. Five of 39 patients (13%) with colorectal cancer had a confirmed partial response, and 9 of 39 patients (23%) with colorectal cancer had stable disease. Conclusions: Panitumumab was well tolerated with comparable exposure and safety profiles for the weekly, every 2 weeks, and every 3 weeks administration schedules. Rash and dry skin occurred more frequently in the dose cohorts receiving ≥2.5 mg/kg weekly dose. Panitumumab has single-agent antitumor activity, most notably in patients with advanced colorectal cancer.
Molecular Analysis of the SGLT2 Gene in Patients with Renal Glucosuria
Authors: René Santer, Martina Kinner, Christoph L. Lassen, Reinhard Schneppenheim, Paul Eggert, Martin Bald, Johannes Brodehl, Markus Daschner, Jochen H.H. Ehrich, Markus Kemper, Salvatore Li Volti, Thomas Neuhaus, Flemming Skovby, Peter G.F. Swift, Jürgen Schaub, Dan Klaerke
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. The role of SGLT2 (the gene for a renal sodium-dependent glucose transporter) in renal glucosuria was evaluated. Therefore, its genomic sequence and its intron-exon organization were determined, and 23 families with index cases were analyzed for mutations. In 21 families, 21 different SGLT2 mutations were detected. Most of them were private; only a splice mutation was found in 5 families of different ethnic backgrounds, and a 12-bp deletion was found in two German families. Fourteen individuals (including the original patient with ’renal glucosuria type 0′) were homozygous or compound heterozygous for an SGLT2 mutation resulting in glucosuria in the range of 14.6 to 202 g/1.73 m 2 /d (81 - 1120 mmol/1.73 m 2 /d). Some, but not all, of their heterozygous family members had an increased glucose excretion of up to 4.4 g/1.73 m 2 /d (24 mmol/1.73 m 2 /d). Likewise, in index cases with glucosuria below 10 g/1.73 m 2 /d (55 mmol/1.73 m 2 /d) an SGLT2 mutation, if present, was always detected in the heterozygous state. We conclude that SGLT2 plays an important role in renal tubular glucose reabsorption. Inheritance of renal glucosuria shows characteristics of a codominant trait with variable penetrance. E-mail: r.santer@uke.uni-hamburg.de
The cellular prion protein counteracts cardiac oxidative stress
Authors: Filippo Zanetti, Andrea Carpi, Roberta Menabò, Marco Giorgio, Rainer Schulz, Guro Valen, Anton Baysa, Maria Lina Massimino, Maria Catia Sorgato, Alessandro Bertoli, Fabio Di Lisa
Journal: Cardiovascular Research (2014)

AimsThe cellular prion protein, PrPC, whose aberrant isoforms are related to prion diseases of humans and animals, has a still obscure physiological function. Having observed an increased expression of PrPC in two in vivo paradigms of heart remodelling, we focused on isolated mouse hearts to ascertain the capacity of PrPC to antagonize oxidative damage induced by ischaemic and non-ischaemic protocols.
De novo expression of endothelial sialyl Lewis(a) and sialyl Lewis(x) during cardiac transplant rejection: superior capacity of a tetravalent sialyl Lewis(x) oligosaccharide in inhibiting L-selectin-dependent lymphocyte adhesion.
Authors: J P Turunen, M L Majuri, A Seppo, S Tiisala, T Paavonen, M Miyasaka, K Lemström, L Penttilä, O Renkonen, R Renkonen
Journal: The Journal of Experimental Medicine (1995)

Acute organ transplant rejection is characterized by a heavy lymphocyte infiltration. We have previously shown that alterations in the graft endothelium lead to increased lymphocyte traffic into the graft. Here, we demonstrate that lymphocytes adhere to the endothelium of rejecting cardiac transplants, but not to the endothelium of syngeneic grafts or normal hearts analyzed with the in vitro Stamper-Woodruff binding assay. Concomitant with the enhanced lymphocyte adhesion, the cardiac endothelium begins to de novo express sialyl Lewis(a) and sialyl Lewis(x) (sLea and sLex) epitopes, which have been shown to be sequences of L-selectin counterreceptors. The endothelium of allografts, but not that of syngeneic grafts or normal controls, also reacted with the L-selectin-immunoglobulin G fusion protein, giving further proof of inducible L-selectin counterreceptors. The lymphocyte adhesion to endothelium could be significantly decreased either by treating the lymphocytes with anti-L-selectin antibody HRL-1, or by treating the tissue sections with sialidase or anti-sLea or anti-sLex monoclonal antibodies. Finally, we synthetized enzymatically several members of the sLex family oligosaccharides and analyzed their ability to block lymphocyte adhesion to cardiac endothelium. The monovalent sLex (a tetramer), divalent sLex (a decamer), and tetravalent sLex (a 22-mer) could all significantly reduce lymphocyte binding, but the inhibition by the tetravalent sLex-construct was clearly superior to other members of the sLex family. The crucial control oligosaccharides, sialyl lactosamines lacking fucose but being otherwise similar to the members of sLex family, had no effect on lymphocyte binding.
Low-Voltage-Activated (T-Type) Calcium Channels Control Proliferation of Human Pulmonary Artery Myocytes
Authors: David M. Rodman, Katherine Reese, Julie Harral, Brian Fouty, Songwei Wu, James West, Marloes Hoedt-Miller, Yuji Tada, Kai-Xun Li, Carlyne Cool, Karen Fagan, Leanne Cribbs
Journal: Circulation Research (2005)

While Ca 2+ influx is essential for activation of the cell cycle machinery, the processes that regulate Ca 2+ influx in this context have not been fully elucidated. Electrophysiological and molecular studies have identified multiple Ca 2+ channel genes expressed in mammalian cells. Ca v 3.x gene family members, encoding low voltage-activated (LVA) or T-type channels, were first identified in the central nervous system and subsequently in non-neuronal tissue. Reports of a potential role for T-type Ca 2+ channels in controlling cell proliferation conflict. The present study tested the hypothesis that T-type Ca 2+ channels, encoded by Ca v 3.x genes, control pulmonary artery smooth muscle cell proliferation and cell cycle progression. Using quantitative RT/PCR, immunocytochemistry, and immunohistochemistry we found that Ca v 3.1 was the predominant Ca v 3.x channel expressed in early passage human pulmonary artery smooth muscle cells in vitro and in the media of human pulmonary arteries, in vivo. Selective blockade of Ca v 3.1 expression with small interfering RNA (siRNA) and pharmacological blockade of T-type channels completely inhibited proliferation in response to 5% serum and prevented cell cycle entry. These studies establish that T-type voltage-operated Ca 2+ channels are required for cell cycle progression and proliferation of human PA SMC.
Lichen sclerosus and atopy in boys: coincidence or correlation?
Authors: K. Becker, V. Meissner, W. Farwick, R. Bauer, M.R. Gaiser
Journal: British Journal of Dermatology (2012)

Lichen sclerosus (LS) is a sclerosing skin disease of presumably autoimmune origin affecting mainly the anogenital area. The aetiology is not completely understood. Comorbidity between genital LS and atopy in girls has been described but so far no controlled study has been performed.A prospective epidemiological case-control study was designed to clarify if there is comorbidity between genital LS and atopic skin diathesis (AD) in boys.The study included a total of 92 boys aged between 1 and 17 years. The disease group consisted of 48 boys who underwent surgery for phimosis that was histologically confirmed as LS. The control group included 44 boys who were circumcised for phimosis for other medical reasons. Both groups were examined and the parents were interviewed following the criteria of the validated Diepgen atopy score. Patients with a score > 9 were assumed to have AD.Within the LS group (median age 8·7 years) 12 boys were diagnosed with AD (25%), while there were only three boys with AD (7%) in the control group (median age 5·3 years). The difference was significant using an age-adjusted logistic regression (P < 0·05). Prior to our study nine boys of the LS group (19%) and four boys of the control group (9%) had already been diagnosed with AD.We have demonstrated a significant comorbidity between LS and AD in boys. AD seems to be a priming precondition for the development of LS in boys.
Skin wound healing in the SKH-1 female mouse following inducible nitric oxide synthase inhibition
Authors: R.R. Bell, R.W. Dunstan, N.K. Khan
Journal: British Journal of Dermatology (2007)

The inducible isoform of the nitric oxide (NO) synthase (NOS) enzyme (iNOS) is upregulated by inflammatory mediators and/or other pathological stresses, generating high, sustained levels of NO. Cumulative data suggest a role for NO in the regulation of skin wound healing, although it is not clear to what extent NO generated by iNOS, and possibly endothelial NOS (eNOS), contribute to that healing process. Because of the current lack of understanding regarding the contribution of iNOS in wound healing, as well as the lack of wound healing data available for SC-842, an iNOS inhibitor, this in vivo study was conducted to investigate the possible role of SC-842 in interfering with wound healing.This study evaluated whether inhibition of iNOS affects incisional skin wound healing.Using a cutaneous full-thickness, sutured, incisional wound model in hairless SKH-1 mice, the role of iNOS in the wound healing process was evaluated by comparing in vivo effects of the iNOS inhibitor, SC-842, at various doses that result in selective inhibition of iNOS as well as nonselective NOS inhibition (as evidenced by elevated blood pressure resulting in inhibition of eNOS and/or neuronal NOS). Dexamethasone was used as a positive control.There were no differences in wound healing at day 28 postwounding, as evaluated by tensile strength and histology, between SC-842- and vehicle-treated animals. A decrease in tensile strength was noted at day 14 postwounding in wounds from the mid- and high-dose-treated animals as compared with vehicle-treated animals, but this difference was slight and was not associated with histological differences from vehicle-treated controls.These data indicate that iNOS inhibition does not adversely affect the healing of incisional wounds in SKH-1 mice as assessed over 28 days by wound tensile strength and histology.
Asthma and atopy in overweight children
Authors: L M Schachter, J K Peat, C M Salome
Journal: Thorax (2003)

<b>Background:</b> Obesity may be associated with an increase in asthma and atopy in children. If so, the effect could be due to an effect of obesity on lung volume and thus airway hyperresponsiveness. <b>Methods:</b> Data from 5993 caucasian children aged 7–12 years from seven epidemiological studies performed in NSW were analysed. Subjects were included if data were available for height, weight, age, skin prick test results to a common panel of aeroallergens, and a measure of airway responsiveness. History of doctor diagnosed asthma, wheeze, cough, and medication use was obtained by questionnaire. Recent asthma was defined as a doctor diagnosis of asthma ever and wheeze in the last 12 months. Body mass index (BMI) percentiles, divided into quintiles per year age, were used as a measure of standardised weight. Dose response ratio (DRR) was used as a measure of airway responsiveness. Airway hyperresponsiveness was defined as a DRR of ⩾8.1. Adjusted odds ratios were obtained by logistic regression. <b>Results:</b> After adjusting for atopy, sex, age, smoking and family history, BMI was a significant risk factor for wheeze ever (OR = 1.06, p = 0.007) and cough (OR = 1.08, p = 0.001), but not for recent asthma (OR = 1.02, p = 0.43) or airway hyperresponsiveness (OR = 0.97 p = 0.17). In girls a higher BMI was significantly associated with higher prevalence of atopy (χ<sup>2</sup> trend 7.9, p = 0.005), wheeze ever (χ<sup>2</sup> trend 10.4, p = 0.001), and cough (χ<sup>2</sup> trend 12.3, p&lt;0.001). These were not significant in boys. <b>Conclusions:</b> Higher BMI is a risk factor for atopy, wheeze ever, and cough in girls only. Higher BMI is not a risk factor for asthma or airway hyperresponsiveness in either boys or girls.
Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the <i>Rag2</i> mouse model of Omenn syndrome
Authors: Barbara Cassani, Pietro Luigi Poliani, Veronica Marrella, Francesca Schena, Aisha V. Sauer, Maria Ravanini, Dario Strina, Christian E. Busse, Stephan Regenass, Hedda Wardemann, Alberto Martini, Fabio Facchetti, Mirjam van der Burg, Antonius G. Rolink, Paolo Vezzoni, Fabio Grassi, Elisabetta Traggiai, Anna Villa
Journal: The Journal of Experimental Medicine (2010)

Hypomorphic RAG mutations, leading to limited V(D)J rearrangements, cause Omenn syndrome (OS), a peculiar severe combined immunodeficiency associated with autoimmune-like manifestations. Whether B cells play a role in OS pathogenesis is so far unexplored. Here we report the detection of plasma cells in lymphoid organs of OS patients, in which circulating B cells are undetectable. Hypomorphic Rag2R229Q knock-in mice, which recapitulate OS, revealed, beyond severe B cell developmental arrest, a normal or even enlarged compartment of immunoglobulin-secreting cells (ISC). The size of this ISC compartment correlated with increased expression of Blimp1 and Xbp1, and these ISC were sustained by elevated levels of T cell derived homeostatic and effector cytokines. The detection of high affinity pathogenic autoantibodies toward target organs indicated defaults in B cell selection and tolerance induction. We hypothesize that impaired B cell receptor (BCR) editing and a serum B cell activating factor (BAFF) abundance might contribute toward the development of a pathogenic B cell repertoire in hypomorphic Rag2R229Q knock-in mice. BAFF-R blockade reduced serum levels of nucleic acid-specific autoantibodies and significantly ameliorated inflammatory tissue damage. These findings highlight a role for B cells in OS pathogenesis.
A randomized, multicenter, phase II study of vandetanib monotherapy versus vandetanib in combination with gemcitabine versus gemcitabine plus placebo in subjects with advanced biliary tract cancer: the VanGogh study
Authors: A. Santoro, V. Gebbia, T. Pressiani, A. Testa, N. Personeni, E. Arrivas Bajardi, P. Foa, A. Buonadonna, K. Bencardino, C. Barone, D. Ferrari, A. Zaniboni, M.C. Tronconi, G. Cartenì, M. Milella, A. Comandone, S. Ferrari, L. Rimassa
Journal: Annals of Oncology (2014)
Wnt Proteins Promote Bone Regeneration
Authors: Steven Minear, Philipp Leucht, Jie Jiang, Bo Liu, Arial Zeng, Christophe Fuerer, Roel Nusse, Jill A. Helms
Journal: Science Translational Medicine (2010)

The Wnt signaling pathway plays a central role in bone development and homeostasis. In most cases, Wnt ligands promote bone growth, which has led to speculation that Wnt factors could be used to stimulate bone healing. We gained insights into the mechanism by which Wnt signaling regulates adult bone repair through the use of the mouse strain Axin2(LacZ/LacZ) in which the cellular response to Wnt is increased. We found that bone healing after injury is accelerated in Axin2(LacZ/LacZ) mice, a consequence of more robust proliferation and earlier differentiation of skeletal stem and progenitor cells. In parallel, we devised a biochemical strategy to increase the duration and strength of Wnt signaling at the sites of skeletal injury. Purified Wnt3a was packaged in liposomal vesicles and delivered to skeletal defects, where it stimulated the proliferation of skeletal progenitor cells and accelerated their differentiation into osteoblasts, cells responsible for bone growth. The end result was faster bone regeneration. Because Wnt signaling is conserved in mammalian tissue repair, this protein-based approach may have widespread applications in regenerative medicine.
CROSS-REACTIONS OF ANTITYPHOID AND ANTIPARATYPHOID B HORSE SERA WITH VARIOUS POLYSACCHARIDES
Authors: Michael Heidelberger, Felix Cordoba
Journal: The Journal of Experimental Medicine (1956)

A study was made of cross-reactions of synthetic polyglucose and of numerous plant and bacterial gums in an antityphoid and an antiparatyphoid B horse serum. The observed differences permit conclusions to be drawn regarding certain of the linkages likely to be found in the fine structures of each of the corresponding Salmonella polysaccharides:- 1. Cross-reactions of the antityphoid serum with the specific polysaccharide of Type II pneumococcus and with tamarind seed polysaccharide, glycogen and synthetic polyglucose indicate that the acetic acid-degraded O-polysaccharide of S. typhi, strain O 901, may contain part, at least, of its glucose as 1,4,6-branch points or in 1,6-linkage, perhaps adjacent to a terminal, non-reducing, galactopyranose unit. 2. Cross-reactions of both antisera with arabogalactans point to the existence of (probably beta-) 1,3-, 1,6-, and/or 1,3,6-linkages of galactose in both the typhoid and paratyphoid B polysaccharides. 3. The differential reactivities of the galactomannans and yeast mannan suggest that the mannose in the typhoid polysaccharide is linked 1,2- or 1,3- with possible non-reducing mannopyranose end groups attached 1,6-. In the paratyphoid B polysaccharide the linkages are probably galacto-oligomannose 1,4-, or 1,4,6-, or the corresponding linkages of mannose alone.
Adiponectin actions in the cardiovascular system
Authors: T HOPKINS, N OUCHI, R SHIBATA, K WALSH
Journal: Cardiovascular Research (2006)

Obesity is strongly associated with the pathogenesis of type 2 diabetes, hypertension, and cardiovascular disease. Levels of the hormone adiponectin are downregulated in obese individuals, and several experimental studies show that adiponectin protects against the development of various obesity-related metabolic and cardiovascular diseases. Adiponectin exhibits favorable effects on atherogenesis, endothelial function, and vascular remodeling by modulation of signaling cascades in cells of the vasculature. More recent findings have shown that adiponectin directly affects signaling in cardiac cells and is beneficial in the setting of pathological cardiac remodeling and acute cardiac injury. Several of these effects of adiponectin have been attributed to the activation of the 5′ AMP-activated protein kinase signaling cascade and other signaling proteins. This review will discuss the epidemiological and experimental studies that have elucidated the role of adiponectin in a variety of cardiovascular diseases.
Effects of corticosteroids on bronchodilator action in chronic obstructive lung disease.
Authors: J B Wempe, D S Postma, N Breederveld, E Kort, T W van der Mark, G H Koeter
Journal: Thorax (1992)

<h3>Objective.</h3> To evaluate the comparative effectiveness of nonbiologic disease-modifying antirheumatic drugs (DMARD) versus biologic DMARD (bDMARD) for treatment of rheumatoid arthritis (RA), using 2 common analytic approaches. <h3>Methods.</h3> We analyzed change in Clinical Disease Activity Index (CDAI) scores in patients with RA enrolled in a US-based observational registry from 2001 to 2008 using multivariable (MV) regression and propensity score (PS) matching. Among patients who initiated treatment with a nonbiologic DMARD (n = 1729), we compared patients who switched to, or added, another nonbiologic (n = 182) or a bDMARD (n = 342) at 5, 9, and 24 months after treatment change. <h3>Results.</h3> Both analytic approaches showed that patients switching to or adding another nonbiologic DMARD demonstrated improvement across 9 and 24 months (both p &lt; 0.001). Both approaches also demonstrated greater improvement in CDAI among recipients of bDMARD relative to a second nonbiologic DMARD at 5 months (p &lt; 0.02). The MV regression approach upheld these results at 9 and 24 months (p &lt; 0.03). In contrast, the PS-matching approach did not show a sustained advantage with bDMARD at these later timepoints, possibly because of lower statistical power and/or lower baseline disease activity in the PS-matched cohort. <h3>Conclusion.</h3> Patients in both treatment groups generally experienced lower CDAI scores across time. Patients switching to bDMARD demonstrated greater improvement than patients switching to nonbiologic DMARD with both analytic approaches at 5 months. Relative advantages with bDMARD were observed at 9 and 24 months only with MV regression. These analyses provide a practical example of how findings in comparative effectiveness research can diverge with different methodological approaches.
Association of Caveolin-1 Gene Polymorphism With Kidney Transplant Fibrosis and Allograft Failure
Authors: Jason Moore
Journal: JAMA (2010)

Caveolin-1 (CAV1) is an inhibitor of tissue fibrosis.To study the association of CAV1 gene variation with kidney transplant outcome, using kidney transplantation as a model of accelerated fibrosis.Candidate gene association and validation study. Genomic DNA from 785 white kidney transplant donors and their respective recipients (transplantations in Birmingham, England, between 1996 and 2006; median follow-up, 81 months) were analyzed for common variation in CAV1 using a single-nucleotide polymorphism (SNP) tagging approach. Validation of positive findings was sought in an independent kidney transplant donor-recipient cohort (transplantations in Belfast, Northern Ireland, between 1986 and 2005; n = 697; median follow-up, 69 months). Association between genotype and allograft failure was initially assessed by Kaplan-Meier analysis, then in an adjusted Cox model.Death-censored allograft failure, defined as a return to dialysis or retransplantation.The presence of donor AA genotype for the CAV1 rs4730751 SNP was associated with increased risk of allograft failure in the Birmingham group (donor AA vs non-AA genotype in adjusted Cox model, hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.29-3.16; P = .002). No other tag SNPs showed a significant association. This finding was validated in the Belfast cohort (in adjusted Cox model, HR, 1.56; 95% CI, 1.07-2.27; P = .02). Overall graft failure rates were as follows: for the Birmingham cohort, donor genotype AA, 22 of 57 (38.6%); genotype CC, 96 of 431 (22.3%); and genotype AC, 66 of 297 (22.2%); and for the Belfast cohort, donor genotype AA, 32 of 48 (67%); genotype CC, 150 of 358 (42%); and genotype AC, 119 of 273 (44%).Among kidney transplant donors, the CAV1 rs4730751 SNP was significantly associated with allograft failure in 2 independent cohorts.