tbuckley/cabot-search huggingface dataset:
Directions of Drug Discovery in Osteoporosis
Authors: Gregory R. Mundy
Journal: Annual Review of Medicine (2002)

▪ Abstract Osteoporosis is a condition of increasing importance and prevalence in all parts of the world and particularly in Asia. Recent advances have led to the introduction of effective drugs that decrease bone resorption and stabilize bone mass. However, these drugs have been identified by serendipity rather than rational drug design and are not ideal because of limited bioavailability, mode of administration, or other unwanted effects. There is still a place for even more suitable and effective resorption inhibitors than those currently available. The more compelling need in this field is an acceptable drug that is anabolic for bone, that safely and acceptably increases bone mass and improves the disturbances in bone microarchitecture that characterize established and advanced osteoporosis. Possible approaches to identifying more effective resorption inhibitors and new anabolic agents are discussed.
Riociguat for the treatment of inoperable CTEPH or persistent/recurrent PH after pulmonary endarterectomy (PEA): A responder analysis from the phase III CHEST-1 study
Authors: Andrea M. D'Armini, Hossein-Ardeschir Ghofrani, Nick H. Kim, Eckhard Mayer, Gerald Simonneau, Martin R. Wilkins, Tomás Pulido, Arno Fritsch, Neil Davie, Marius M. Hoeper
Journal: European Respiratory Journal (2013)

Background   PEA is the treatment of choice for CTEPH, but a proportion of patients (pts) are ineligible or have persistent/recurrent PH after PEA. CHEST-1 showed that riociguat is a promising therapy for such pts, as it improved 6-min walking distance (6MWD), hemodynamics, WHO functional class (FC), and NT-proBNP.   Aims   To determine the proportion of pts in CHEST-1 who achieved responder thresholds shown previously to correlate with improved outcome in pts with other forms of PH, at baseline (BL) and after targeted therapy.   Methods   In this randomized, double-blind, Phase III study, pts received placebo (pbo) or individually titrated riociguat (up to 2.5 mg tid) for 16 wks. The criteria of a positive response were: 6MWD increase ≥30 m and ≥40 m, 6MWD ≥380 m, cardiac index (CI) ≥2.5 L/min/m 2 , PVR  -5 , SvO 2  ≥65%, FC I/II, and NT-proBNP    Results   The proportion of pts meeting these criteria at BL and Wk 16 is shown below. At BL, the proportions were similar in the pbo and riociguat arms. Riociguat increased the proportion of pts achieving these criteria at Wk 16; minimal improvements or decreases were seen in the pbo arm for most parameters.   Conclusions   Riociguat increased the proportion of CTEPH pts achieving criteria defining a positive response to therapy.
Cellular and humoral autoimmunity directed at bile duct epithelia in murine biliary atresia
Authors: Cara L. Mack, Rebecca M. Tucker, Brandy R. Lu, Ronald J. Sokol, Andrew P. Fontenot, Yoshiyuki Ueno, Ronald G. Gill
Journal: Hepatology (2006)

Biliary atresia is an inflammatory fibrosclerosing lesion of the bile ducts that leads to biliary cirrhosis and is the most frequent indication for liver transplantation in children. The pathogenesis of biliary atresia is not known; one theory is that of a virus-induced, subsequent autoimmune-mediated injury of bile ducts. The aim of this study was to determine whether autoreactive T cells and autoantibodies specific to bile duct epithelia are present in the rotavirus (RRV)- induced murine model of biliary atresia and whether the T cells are sufficient to result in bile duct inflammation. In vitro analyses showed significant increases in IFN-γ–producing T cells from RRV-diseased mice in response to bile duct epithelial autoantigen. Adoptive transfer of the T cells from RRV-diseased mice into naïve syngeneic SCID recipients resulted in bile duct–specific inflammation. This induction of bile duct pathology occurred in the absence of detectable virus, indicating a definite response to bile duct autoantigens. Furthermore, periductal immunoglobulin deposits and serum antibodies reactive to bile duct epithelial protein were detected in RRV-diseased mice. In conclusion, both cellular and humoral components of autoimmunity exist in murine biliary atresia, and the progressive bile duct injury is due in part to a bile duct epithelia–specific T cell–mediated immune response. The role of cellular and humoral autoimmunity in human biliary atresia and possible interventional strategies therefore should be the focus of future research.
Translational Activation of Snail1 and Other Developmentally Regulated Transcription Factors by YB-1 Promotes an Epithelial-Mesenchymal Transition
Authors: Valentina Evdokimova, Cristina Tognon, Tony Ng, Peter Ruzanov, Natalya Melnyk, Dieter Fink, Alexey Sorokin, Lev P. Ovchinnikov, Elai Davicioni, Timothy J. Triche, Poul H.B. Sorensen
Journal: Cancer Cell (2009)
Sequential expression of antigens on sexual stages of Plasmodium falciparum accessible to transmission-blocking antibodies in the mosquito.
Authors: A N Vermeulen, T Ponnudurai, P J Beckers, J P Verhave, M A Smits, J H Meuwissen
Journal: The Journal of Experimental Medicine (1985)

Plasmodium falciparum gametocytes contain specific antigens, some of which (Mr 230,000, 48,000, 45,000) are expressed on the surface of the newly emerged macrogamete. A different antigen (Mr 25,000) surrounds the surface of the ookinete and, although present to some extent in the developing gametocyte, is synthesized in high quantities by the macrogamete/zygote and expressed progressively on the transforming zygote surface. These antigens are targets of transmission blocking antibodies that are effective at two distinct points after gametogenesis: fertilization of the macrogamete and ookinete to oocyst development. The antigens involved in the fertilization blockade are the Mr 48 and 45 proteins, which are expressed on the macrogamete surface. The Mr 230 K coprecipitating protein probably plays no part in transmission block. mAb directed against the Mr 25 K ookinete surface protein blocked transmission without inhibiting ookinete formation, indicating that this protein has an important role in the transformation of ookinete into oocyst. A combination of mAb recognizing different epitopes on the same protein molecule acted synergistically in inhibiting oocyst formation. Using a mixture of two blocking mAb reacting against the Mr 48/45 and 25 K proteins, respectively, an additive blocking effect could be demonstrated.
EFFICACY OF IMPLANTABLE CARDIOVERTER DEFIBRILLATORS IN ADULTS WITH CONGENITAL HEART DISEASE
Authors: Zeliha Koyak, Joris R. De Groot, Isabelle C. Van Gelder, Werner Budts, Lieselot Van Erven, Pascal F.H.M. Van Dessel, Arie Van Dijk, Joep L.R.M. Smeets, Alexander H. Maass, Arthur A.M. Wilde, Petronella G. Pieper, Barbara J.M. Mulder
Journal: Journal of the American College of Cardiology (2011)
Rate of Atherosclerotic Plaque Formation Predicts Cardiovascular Events in ESRD
Authors: Francesco Antonio Benedetto, Giovanni Tripepi, Francesca Mallamaci, Carmine Zoccali
Journal: Journal of the American Society of Nephrology (2008)

Carotid intima media thickness (IMT) is a strong, independent predictor of cardiovascular events in both the general population and among those with end-stage renal disease (ESRD), but it is unknown whether changes in IMT or other ultrasound-measured indicators of atherosclerosis over time provide additional prognostic information. The progression of atherosclerosis with carotid ultrasound was followed in a cohort of 135 ESRD patients, 103 of whom had a repeat ultrasound after 15 mo of follow-up. The number of plaques and the proportion of patients with severe atherosclerosis increased substantially during the follow-up period, but IMT, common carotid artery diameter, common carotid artery wall-to-lumen ratio, and cross-sectional area, did not change. The rate of formation of new plaques was a strong, independent predictor of incident cardiovascular events, even after adjusting for baseline plaque burden and other potential confounders. New plaque formation over time was independently predicted by background plaque burden and serum C-reactive protein (P = 0.004 and P = 0.02, respectively). Changes in IMT and the other ultrasound-measured indicators of atherosclerosis progression did not predict cardiovascular outcomes. Therefore, monitoring IMT over time is unlikely to provide additional prognostic information compared with a single measurement, but longitudinal ultrasound monitoring of plaque formation may be useful for cardiovascular risk stratification in the ESRD population.
H-2 antigens of the thymus determinelymphocyte specificity
Authors: PJ Fink, MJ Bevan
Journal: The Journal of Experimental Medicine (1978)

After immunization, normal H-2 heterozygous mice (for example H-2(b) × H-2(d)) generate two populations of cytotoxic effector T cells, one specific for target cells expressing H-2(b)-plus-antigen and the other specific for H- 2(d)-plus-antigen. With a multideterminant antigen, these two populations have about the same activity. We show here that the H-2 type of resident cells in the thymus determines the H-2 preference of cytotoxic T lymphocytes. F(1)(B 10 × B 10.D2) (H-2(b) × H-2 (d)) mice were thymectomized, lethally irradiated, and reconstituted with T-cell-depleted syngeneic hematopoietic cells. Groups of such ATXBM mice were grafted subcutaneously with neonatal thymus lobes from parental mice, either B10 (H-2 (b)) or B10.D2 (H-2(d)). 2-3 mo later, the mice were immunized against the minor histocompatibility antigens on F(1)(BALB/c × BALB.B) cells and assayed for cytotoxic T-cell activity. H-2(b) × H-2(d) ATXBM mice with H-2(b) thymus grafts responded to antigen-plus-H-2(b) much better than to antigen-plus-H-2(d), and vice versa for the mice with H-2(d) thymus grafts. As judged by antiserum treatment, the effector cells were of F(1) origin. To explore the possibility that the "thymus preference" may have been due to suppression of T-cell activity, nonimmune spleen and lymph node cells from normal H-2(b) × H-2(d) mice and cells from H-2(b) × H-2(d) mice bearing a homozygous thymus were mixed 1:1 and immunized in adoptive transfer. The mixture responded to antigen-plus-H-2(b) and antigen-plus-H-2(d) equally well, demonstrating that the cells that showed a "thymus preference" could not suppress a response to antigen in association with the nonthymic H-2 type. We conclude from these and other experiments that H-2 antigens present on resident cells of the thymus determine the spectrum of specificity of T cells which mature in that thymus and eventually make up the peripheral T- cell pool.
Role of Endothelin in Endotoxin-induced Sustained Pulmonary Hypertension in Sheep
Authors: JAMES R. SNAPPER, JOHN S. THABES, PETER L. LEFFERTS, WEIXUAN LU
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

BMS182874, an endothelin receptor antagonist, blocks the effects of exogenously administered endothelins in chronically instrumented awake sheep. A possible role for endothelin in endotoxin-induced pulmonary hypertension in sheep was investigated by studying animals given intravenous endotoxin with and without pretreatment with BMS182874. BMS182874 administration alone caused a reduction in pulmonary artery pressure (P[PA]) and systemic arterial pressure (P[SA]). Endotoxin alone caused an acute, nearly threefold increase in P(PA) which was followed, from 2-5 h after endotoxin, by a sustained but less severe increase in P(PA). These changes were accompanied by a threefold increase in lung lymph flow and dramatic increases in plasma and lung lymph thromboxane B2 concentrations. Pretreatment with BMS182874 significantly attenuated the early endotoxin-induced acute increase in P(PA) and completely blocked the late sustained pulmonary hypertension (p < 0.05), while having no affect on the increases in thromboxane levels. BMS182874 shifts the dose response curve for U46619, a prostaglandin H2 analogue, to the right. BMS182874, in addition to functioning as an endothelium receptor antagonist, appears to counteract the action of thromboxane at the receptor level. We theorize that BMS182874 attenuates the early endotoxin-induced pulmonary hypertension by counteracting the effects of thromboxane, since previous studies demonstrated that the early acute rise in P(PA) is caused by thromboxane. The late sustained pulmonary hypertension of endotoxemia, on the other hand, appears to be mediated by endothelin.
Ultrasound or computed tomography for the initial investigation of biliary obstruction.
Authors: D F Martin
Journal: Gut (1988)

A genetic predisposition for colorectal cancer in inflammatory bowel disease SIR,-We were very interested to read the recent article of Gyde and coworkers' suggesting that patients with ulcerative colitis having extensive disease may have a genetic predisposition for colo- rectal cancer whereas in those with more limited disease even longstanding inflammation has no major effect in promoting cancer.Our review2 of data on the occurrence of colorectal cancer in colonic Crohn's disease has led us to a similar approach to the problem.We found that the reported diversity of patterns in 'colorectal Crohn's carcinoma' strengthens the assumption of several more or less interrelated factors which can be grouped according to two main aetiopathogenic mechanisms: acquired and genetic.With the former the chronicity of the localised inflammatory process (fistula, stricture, perianal inflammation, etc) predisposes the colon to malignant changes, as in other organs.3With the latter, the development of carcinoma and Crohn's disease in the same patient results from an individual predisposition, independent of age at onset and duration of previous disease.Supporting this view are those cases in which Crohn's disease and carcinoma developed separately in the small and large intestine, or in two different parts of the colon,4 as well as the frequency of such patients with extra- intestinal cancers" and the high incidence of carcinoma of the colon among relatives of patients with Crohn's disease.7Although our findings differ somewhat from those of Gyde et al, indicating a variability in the possible manifestations of the genetic factors among patients with ulcerative colitis and those with Crohn's disease, we are in full agreement as to the importance of further studies, including a programme of typing of such patients and their relatives.7"
TNF-α Mediates Macrophage-Induced Bystander Effects through Netrin-1
Authors: Yonghong Yang, Xingmin Wang, Danny R. Moore, Stanley A. Lightfoot, Mark M. Huycke
Journal: Cancer Research (2012)

Abstract Macrophage-induced bystander effects have been implicated as an important mediator of chromosomal instability and colon cancer triggered by Enterococcus faecalis, a human intestinal commensal bacteria. There is little understanding about how inflammatory cytokines mediate bystander effects, but questions in this area are important because of the pivotal contributions made by inflammatory processes to cancer initiation and progression. Here, we report that the central proinflammatory cytokine TNF-α acts as a diffusible mediator of the bystander effects induced by macrophages, an effect caused by a proliferation of macrophages that trigger epithelial cell production of Netrin-1, a neuronal guidance molecule. TNF-α-mediated bystander assays used a murine coculture system of primary colonic epithelial cells and E. faecalis-infected macrophages (in vitro), with an interleukin 10 (IL-10)-deficient mouse model of colon cancer that involves long-term colonization with E. faecalis (in vivo). In cell cocultures, we observed increased expression of the TNF-α receptor Tnfrsf1b and Netrin-1. These effects were blocked by anti-TNF-α antibody or by pretreatment with an inhibitor of NF-κB signaling. RNAi-mediated attenuation of Tnfrsf1b decreased TNF-α-induced netrin-1 production and augmented epithelial cell apoptosis in culture. Extending these observations, colon biopsies from E. faecalis-colonized IL-10−/− mice exhibited crypt hyperplasia and increased staining for macrophages, TNF-α, netrin-1, NF-κB, Tnfrsf1b, and the proliferation marker proliferating cell nuclear antigen while also displaying a reduction in epithelial cell apoptosis. Together, our results define a pathway for macrophage-induced bystander effects in which TNF-α triggers TNFRSF1b receptor signaling leading to increased production of Netrin-1, crypt hyperplasia, and decreased epithelial cell apoptosis. In elucidating an important commensal-associated proinflammatory mechanism in the intestinal microenvironment, our work highlights the role of Netrin-1 and a specific TNF-α receptor as candidate targets to prevent or treat colorectal cancer. Cancer Res; 72(20); 5219–29. ©2012 AACR.
Identification of a Novel Small Molecule HIF-1α Translation Inhibitor
Authors: Takuhito Narita, Shaoman Yin, Christine F. Gelin, Carlos S. Moreno, Manuel Yepes, K.C. Nicolaou, Erwin G. Van Meir
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Hypoxia inducible factor-1 (HIF-1), the central mediator of the cellular response to low oxygen, functions as a transcription factor for a broad range of genes that provide adaptive responses to oxygen deprivation. HIF-1 is overexpressed in cancer and has become an important therapeutic target in solid tumors. In this study, a novel HIF-1α inhibitor was identified and its molecular mechanism was investigated. Experimental Design: Using a HIF-responsive reporter cell–based assay, a 10,000-member natural product–like chemical compound library was screened to identify novel HIF-1 inhibitors. This led us to discover KC7F2, a lead compound with a central structure of cystamine. The effects of KC7F2 on HIF-1 transcription, translation, and protein degradation processes were analyzed. Results: KC7F2 markedly inhibited HIF-mediated transcription in cells derived from different tumor types, including glioma, breast, and prostate cancers, and exhibited enhanced cytotoxicity under hypoxia. KC7F2 prevented the activation of HIF-target genes such as carbonic anhydrase IX, matrix metalloproteinase 2 (MMP2), endothelin 1, and enolase 1. An investigation into the mechanism of action of KC7F2 showed that it worked through the down-regulation of HIF-1α protein synthesis, an effect accompanied by the suppression of the phosphorylation of eukaryotic translation initiation factor 4E binding protein 1 and p70 S6 kinase, key regulators of HIF-1α protein synthesis. Conclusion: These results show that KC7F2 is a potent HIF-1 pathway inhibitor and its potential as a cancer therapy agent warrants further study. (Clin Cancer Res 2009;15(19):6128–36)
Subtypes of Breast Cancer Show Preferential Site of Relapse
Authors: Marcel Smid, Yixin Wang, Yi Zhang, Anieta M. Sieuwerts, Jack Yu, Jan G.M. Klijn, John A. Foekens, John W.M. Martens
Journal: Cancer Research (2008)

Abstract We explored whether the five previously reported molecular subtypes in breast cancer show a preference for organ-specific relapse and searched for molecular pathways involved. The “intrinsic” gene list describing the subtypes was used to classify 344 primary breast tumors of lymph node–negative patients. Fisher exact tests were used to determine the association between a tumor subtype and a particular site of distant relapse in these patients who only received local treatment. Modulated genes and pathways were identified in the various groups using Significance Analysis of Microarrays and Global Testing. Bone relapse patients were most abundant in the luminal subtypes but were found less than expected in the basal subtype. The reverse was true for lung and brain relapse patients with the remark that absence of lung relapse was luminal A specific. Finally, a pleura relapse, although rare, was found almost exclusively in both luminal subtypes. Many differentially expressed genes were identified, of which several were in common in a subtype and the site to which the subtype preferentially relapsed. WNT signaling was up-regulated in the basal subtype and in brain-specific relapse, and down-modulated in the luminal B subtype and in bone-specific relapse. Focal adhesion was found up-regulated in the luminal A subtype but down-regulated in lung relapse. The five major molecular subtypes in breast cancer are evidently different with regard to their ability to metastasize to distant organ(s), and share biological features and pathways with their preferred distant metastatic site. [Cancer Res 2008;68(9):3108–14]
Changes in HBsAg carrier rate in Goto Islands, Nagasaki Prefecture, Japan
Authors: A. Matsuo, Y. Kusumoto, E. Ohtsuka, A. Ohtsuru, Y. Nakamura, H. Tajima, M. Shima, K. Nakata, T. Muro, A. Satoh, S. Nagataki, N. Ishii, T. Kohji
Journal: The Lancet (1990)
Are Oppositional Defiant and Conduct Disorder Symptoms Normative Behaviors in Preschoolers? A Comparison of Referred and Nonreferred Children
Authors: Kate Keenan, Lauren S Wakschlag
Journal: American Journal of Psychiatry (2004)

The authors' goal was to test the hypothesis that DSM-IV symptoms of oppositional defiant disorder and conduct disorder can be validly applied to preschoolers.Using a semistructured diagnostic interview, they assessed rates of symptoms of DSM-IV oppositional defiant and conduct disorders in 2.5-5.5-year-old children who were referred to a psychiatry clinic and a comparison group of nonreferred children.Clinically referred preschool children had significantly higher rates of oppositional defiant and conduct disorder symptoms than nonreferred children. Among nonreferred preschoolers, rates of all oppositional defiant and conduct disorder symptoms were at or below 8%.DSM-IV symptoms of oppositional defiant and conduct disorders distinguish referred from nonreferred preschool children in a pattern consistent with that seen in older children. Preschool children who are not seeking mental health services do not have high rates of disruptive behavior problems. The DSM-IV nosology appears to be a valid diagnostic system for discriminating between typical and atypical disruptive behaviors in preschool children.
The preoperatively normal bile duct does not dilate after cholecystectomy: results of a five year study
Authors: A W Majeed, B Ross, A G Johnson
Journal: Gut (1999)

The common hepatic duct (CHD) is commonly believed to dilate after cholecystectomy but previous studies have either not measured CHD diameter preoperatively or the follow up period is short.To measure CHD diameter before and after cholecystectomy.Patients undergoing (open) cholecystectomy and operative cholangiography had ultrasonographic measurement of CHD diameter before, and three and six months, and one and five years after cholecystectomy. The normal duct diameter was considered to be 5 mm or less, with an observer error of +/-1 mm.Fifty nine patients with normal diameter ducts were studied. The majority (more than 95%) of patients did not have a dilatation of the CHD beyond 6 mm after cholecystectomy. The CHD appeared to increase as well as decrease with an overall trend towards a minor increase at five years. This was not statistically significant if the margin of error of 1 mm was taken into account.A preoperatively normal CHD does not dilate after cholecystectomy and may require further investigation in symptomatic patients.