tbuckley/cabot-search huggingface dataset:
A Novel Small-Molecule Inhibitor of Transforming Growth Factor β Type I Receptor Kinase (SM16) Inhibits Murine Mesothelioma Tumor Growth <i>In vivo</i> and Prevents Tumor Recurrence after Surgical Resection
Authors: Eiji Suzuki, Samuel Kim, H.-Kam Cheung, Michael J. Corbley, Xiamei Zhang, Lihong Sun, Feng Shan, Juswinder Singh, Wen-Cherng Lee, Steven M. Albelda, Leona E. Ling
Journal: Cancer Research (2007)

Abstract Malignant mesothelioma is an aggressive and lethal pleural cancer that overexpresses transforming growth factor β (TGFβ). We investigated the efficacy of a novel small-molecule TGFβ type I receptor (ALK5) kinase inhibitor, SM16, in the AB12 syngeneic model of malignant mesothelioma. SM16 inhibited TGFβ signaling seen as decreased phosphorylated Smad2/3 levels in cultured AB12 cells (IC50, ∼200 nmol/L). SM16 penetrated tumor cells in vivo, suppressing tumor phosphorylated Smad2/3 levels for at least 3 h following treatment of tumor-bearing mice with a single i.p. bolus of 20 mg/kg SM16. The growth of established AB12 tumors was significantly inhibited by 5 mg/kg/d SM16 (P &amp;lt; 0.001) delivered via s.c. miniosmotic pumps over 28 days. The efficacy of SM16 was a result of a CD8+ antitumor response because (a) the antitumor effects were markedly diminished in severe combined immunodeficient mice and (b) CD8+ T cells isolated from spleens of mice treated with SM16 showed strong antitumor cytolytic effects whereas CD8+ T cells isolated from spleens of tumor-bearing mice treated with control vehicle showed minimal activity. Treatment of mice bearing large tumors with 5 mg/kg/d SM16 after debulking surgery reduced the extent of tumor recurrence from 80% to &amp;lt;20% (P &amp;lt; 0.05). SM16 was also highly effective in blocking and regressing tumors when given p.o. at doses of 0.45 or 0.65 g/kg in mouse chow. Thus, SM16 shows potent activity against established AB12 malignant mesothelioma tumors using an immune-mediated mechanism and can significantly prevent tumor recurrence after resection of bulky AB12 malignant mesothelioma tumors. These data suggest that ALK5 inhibitors, such as SM16, offer significant potential for the treatment of malignant mesothelioma and possibly other cancers. [Cancer Res 2007;67(5):2351–9]
Eradication of Large Tumors in Mice by a Tritherapy Targeting the Innate, Adaptive, and Regulatory Components of the Immune System
Authors: Pedro Berraondo, Clémence Nouzé, Xavier Préville, Daniel Ladant, Claude Leclerc
Journal: Cancer Research (2007)

Abstract Targeting the human papillomavirus (HPV) E7 antigen to dendritic cells with the adenylate cyclase (CyaA) of Bordetella pertussis as a vaccine vector led to potent therapeutic immune responses against TC-1 tumors in a murine model of cervical carcinoma induced by HPV. However, as the time between tumor graft and vaccination increased, the antitumor efficacy of the CyaA-E7 vaccine gradually decreased. The vaccine had no effect if the tumor diameter was &amp;gt;8 mm. Analyses of regulatory cells recruited during TC-1 tumor growth revealed a high number of splenic MDSCs and a large percentage of regulatory T cells, particularly in the tumor. Administration of a tritherapy including CpG complexed with a cationic lipid, low-dose cyclophosphamide, and the CyaA-E7 vaccine completely overcame tumor-associated immunosuppression and eradicated large, established tumors in almost all treated animals. This strong antitumor response was followed by a large expansion of regulatory T cells in tumor, spleen, and tumor-draining lymph nodes and of splenic neutrophils. These findings indicate that immunotherapeutic strategies that simultaneously target innate, adaptive, and regulatory components of the immune system are effective in the eradication of large tumors. [Cancer Res 2007;67(18):8847–55]
Regulation of Experimental Autoimmune Encephalomyelitis by Natural Killer (NK) Cells
Authors: Ben-ning Zhang, Takashi Yamamura, Takayuki Kondo, Michio Fujiwara, Takeshi Tabira
Journal: The Journal of Experimental Medicine (1997)

In this report, we establish a regulatory role of natural killer (NK) cells in experimental autoimmune encephalomyelitis (EAE), a prototype T helper cell type 1 (Th1)-mediated disease. Active sensitization of C57BL/6 (B6) mice with the myelin oligodendrocyte glycoprotein (MOG)35-55 peptide induces a mild form of monophasic EAE. When mice were deprived of NK cells by antibody treatment before immunization, they developed a more serious form of EAE associated with relapse. Aggravation of EAE by NK cell deletion was also seen in beta 2-microglobulin-/- (beta 2m-/-) mice, indicating that NK cells can play a regulatory role in a manner independent of CD8+ T cells or NK1.1+ T cells (NK-T cells). The disease enhancement was associated with augmentation of T cell proliferation and production of Th1 cytokines in response to MOG35-55. EAE passively induced by the MOG35-55-specific T cell line was also enhanced by NK cell deletion in B6, beta 2m-/-, and recombination activation gene 2 (RAG-2)-/- mice, indicating that the regulation by NK cells can be independent of T, B, or NK-T cells. We further showed that NK cells inhibit T cell proliferation triggered by antigen or cytokine stimulation. Taken together, we conclude that NK cells are an important regulator for EAE in both induction and effector phases.
A randomised controlled trial on the efficacy and tolerability with dose escalation of allopurinol 300-600 mg/day versus benzbromarone 100-200 mg/day in patients with gout
Authors: M K Reinders, C Haagsma, T L T. A Jansen, E N van Roon, J Delsing, M A F J van de Laar, J R B J Brouwers
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objectives:</h3> To compare the efficacy and tolerability of allopurinol 300–600 mg/day versus benzbromarone 100–200 mg/day used to attain a target serum urate concentration (sUr) ⩽0.30 mmol/l (5 mg/dl). <h3>Methods:</h3> A randomised, controlled, open-label, multicentre trial in gout patients with renal function defined as a calculated creatinine clearance ⩾50 ml/min. Patients were treated with 300 mg allopurinol or 100 mg benzbromarone once a day (stage 1). If sUr ⩽0.30 mmol/l was not attained after 2 months, the dose was doubled to allopurinol 300 mg twice a day or benzbromarone 200 mg once a day (stage 2). The primary end point was treatment success in either of the two stages, defined as clinical tolerability and attainment of biochemical target sUr. <h3>Results:</h3> Sixty-five patients were enrolled in stage 1; 36 received allopurinol and 29 received benzbromarone. Fifty-five patients (85%) were analysed at stage 1: the success rates were 8/31 (26%) and 13/25 (52%), respectively, and the difference was −0.26 (95% CI from −0.486 to −0.005), p = 0.049. At stage 2, the success rates were 21/27 (78%) and 18/23 (78%), respectively, and the difference was −0.005 (95% CI from −0.223 to 0.220), p = 1.00. Two patients stopped receiving allopurinol and three stopped receiving benzbromarone because of adverse drug reactions. <h3>Conclusions:</h3> Increasing the allopurinol dose from 300 to 600 mg/day and the benzbromarone dose from 100 to 200 mg/day according to the target sUr produced significantly higher success rates (both 78% successful in attaining sUr ⩽0.30 mmol/l). No significant differences in treatment success between benzbromarone and allopurinol were found after dose escalation. <h3>Trial registration number:</h3> ISRCTN49563848).
ABCB5-Mediated Doxorubicin Transport and Chemoresistance in Human Malignant Melanoma
Authors: Natasha Y. Frank, Armen Margaryan, Ying Huang, Tobias Schatton, Ana Maria Waaga-Gasser, Martin Gasser, Mohamed H. Sayegh, Wolfgang Sadee, Markus H. Frank
Journal: Cancer Research (2005)

Abstract Enhanced drug efflux mediated by ABCB1 P-glycoprotein and related ATP-binding cassette transporters is one of several mechanisms of multidrug resistance thought to impair chemotherapeutic success in human cancers. In malignant melanoma, its potential contribution to chemoresistance is uncertain. Here, we show that ABCB5, which functions as a determinant of membrane potential and regulator of cell fusion in physiologic skin progenitor cells, is expressed in clinical malignant melanoma tumors and preferentially marks a subset of hyperpolarized, CD133+ stem cell phenotype-expressing tumor cells in malignant melanoma cultures and clinical melanomas. We found that ABCB5 blockade significantly reversed resistance of G3361 melanoma cells to doxorubicin, an agent to which clinical melanomas have been found refractory, resulting in a 43% reduction in the LD50 from 4 to 2.3 μmol/L doxorubicin (P &amp;lt; 0.05). Our results identified ABCB5-mediated doxorubicin efflux transport as the underlying mechanism of resistance, because ABCB5 blockade significantly enhanced intracellular drug accumulation. Consistent with this novel ABCB5 function and mechanism in doxorubicin resistance, gene expression levels of the transporter across a panel of human cancer cell lines used by the National Cancer Institute for drug screening correlated significantly with tumor resistance to doxorubicin (r = 0.44; P = 0.016). Our results identify ABCB5 as a novel drug transporter and chemoresistance mediator in human malignant melanoma. Moreover, our findings show that ABCB5 is a novel molecular marker for a distinct subset of chemoresistant, stem cell phenotype-expressing tumor cells among melanoma bulk populations and indicate that these chemoresistant cells can be specifically targeted via ABCB5 to enhance cytotoxic efficacy.
Bone Fractures and Hypoglycemic Treatment in Type 2 Diabetic Patients
Authors: Matteo Monami, Barbara Cresci, Angela Colombini, Laura Pala, Daniela Balzi, Francesca Gori, Veronica Chiasserini, Niccolò Marchionni, Carlo Maria Rotella, Edoardo Mannucci
Journal: Diabetes Care (2008)

Hypoglycemic treatments could modulate the risk for fractures in many ways. Most studies have not explored the effect on the incidence of bone fractures of individual oral hypoglycemic agents, rather all oral treatments as a whole. The aim of this case-control study, nested within a retrospective cohort, is the assessment of the risk for bone fractures associated with exposure to insulin or different oral hypoglycemic agents.A case-control study nested within a cohort of 1,945 diabetic outpatients with a follow-up of 4.1 +/- 2.3 years was performed, comparing 83 case subjects of bone fractures and 249 control subjects matched for age, sex, duration of diabetes, BMI, A1C, comorbidity, smoking, and alcohol abuse. Exposure to hypoglycemic drugs during the 10 years preceding the event (or matching index date) was assessed.In a model including treatment with insulin secretagogues metformin and insulin for at least 36 months during the previous 10 years, no significant association was observed between bone fractures and medications. In an alternative model considering treatments at the time of fracture, insulin treatment was significantly associated with bone fractures in men (OR 3.20 [95% CI 1.32-7.74]) but not in women (1.41 [0.73-2.73]).Insulin-sensitizing treatment with metformin is not associated with a higher incidence of bone fractures, suggesting that the negative effect of thiazolidinediones is due to a specific action on bone metabolism rather a reduction of insulinemia. Conversely, current treatment with insulin increases the risk of fractures; at the same time, exposure to this agent in the longer term does not appear to affect bone frailty.
The Impact of a Consortium of Fermented Milk Strains on the Gut Microbiome of Gnotobiotic Mice and Monozygotic Twins
Authors: Nathan P. McNulty, Tanya Yatsunenko, Ansel Hsiao, Jeremiah J. Faith, Brian D. Muegge, Andrew L. Goodman, Bernard Henrissat, Raish Oozeer, Stéphanie Cools-Portier, Guillaume Gobert, Christian Chervaux, Dan Knights, Catherine A. Lozupone, Rob Knight, Alexis E. Duncan, James R. Bain, Michael J. Muehlbauer, Christopher B. Newgard, Andrew C. Heath, Jeffrey I. Gordon
Journal: Science Translational Medicine (2011)

Metagenomic analyses of gnotobiotic mice and monozygotic twins reveal the effects of eating a popular fermented milk product on their microbiomes.
Characterization of GD2 Peptide Mimotope DNA Vaccines Effective against Spontaneous Neuroblastoma Metastases
Authors: Stefan Fest, Nicole Huebener, Silke Weixler, Matthias Bleeke, Yan Zeng, Anne Strandsby, Rudolf Volkmer-Engert, Christiane Landgraf, Gerhard Gaedicke, Angelika B. Riemer, Elke Michalsky, Ines S. Jaeger, Robert Preissner, Elisabeth Förster-Wald, Erika Jensen-Jarolim, Holger N. Lode
Journal: Cancer Research (2006)

Abstract Disialoganglioside GD2 is an established target for immunotherapy in neuroblastoma. We tested the hypothesis that active immunization against the glycolipid GD2 using DNA vaccines encoding for cyclic GD2-mimicking decapeptides (i.e., GD2 mimotopes) is effective against neuroblastoma. For this purpose, two GD2 peptide mimotopes (MA and MD) were selected based on docking experiments to anti-GD2 antibody ch14.18 (binding free energy: −41.23 kJ/mol for MA and −48.06 kJ/mol for MD) and Biacore analysis (Kd = 12.3 × 10−5 mol/L for MA and 5.3 × 10−5 mol/L for MD), showing a higher affinity of MD over MA. These sequences were selected for DNA vaccine design based on pSecTag2-A (pSA) also including a T-cell helper epitope. GD2 mimicry was shown following transfection of CHO-1 cells with pSA-MA and pSA-MD DNA vaccines, with twice-higher signal intensity for cells expressing MD over MA. Finally, these DNA vaccines were tested for induction of tumor protective immunity in a syngeneic neuroblastoma model following oral DNA vaccine delivery with attenuated Salmonella typhimurium (SL 7207). Only mice receiving the DNA vaccines revealed a reduction of spontaneous liver metastases. The highest anti-GD2 humoral immune response and natural killer cell activation was observed in mice immunized with the pSA-MD, a finding consistent with superior calculated binding free energy, dissociation constant, and GD2 mimicry potential for GD2 mimotope MD over MA. In summary, we show that DNA immunization with pSA-MD may provide a useful strategy for active immunization against neuroblastoma. (Cancer Res 2006; 66(21): 10567-75)
Risk factors for community-acquired pneumonia in adults in Europe: a literature review
Authors: Antoni Torres, Willy E Peetermans, Giovanni Viegi, Francesco Blasi
Journal: Thorax (2013)

<h3>Background</h3> Community-acquired pneumonia (CAP) causes considerable morbidity and mortality in adults, particularly in the elderly. <h3>Methods</h3> Structured searches of PubMed were conducted to identify up-to-date information on the incidence of CAP in adults in Europe, as well as data on lifestyle and medical risk factors for CAP. <h3>Results</h3> The overall annual incidence of CAP in adults ranged between 1.07 to 1.2 per 1000 person-years and 1.54 to 1.7 per 1000 population and increased with age (14 per 1000 person-years in adults aged ≥65 years). Incidence was also higher in men than in women and in patients with chronic respiratory disease or HIV infection. Lifestyle factors associated with an increased risk of CAP included smoking, alcohol abuse, being underweight, having regular contact with children and poor dental hygiene. The presence of comorbid conditions, including chronic respiratory and cardiovascular diseases, cerebrovascular disease, Parkinson9s disease, epilepsy, dementia, dysphagia, HIV or chronic renal or liver disease all increased the risk of CAP by twofold to fourfold. <h3>Conclusion</h3> A range of lifestyle factors and underlying medical conditions are associated with an increased risk of CAP in European adults. Understanding of the types of individual at greatest risk of CAP can help to ensure that interventions to reduce the risk of infection and burden of disease are targeted appropriately.
Endogenous Interleukin-4 Promotes Tumor Development by Increasing Tumor Cell Resistance to Apoptosis
Authors: Zhiguang Li, Jing Jiang, Zibing Wang, Jinhua Zhang, Mingjie Xiao, Chunhui Wang, Yu Lu, Zhihai Qin
Journal: Cancer Research (2008)

Abstract The increase of interleukin-4 (IL-4) level in tumor environment and the up-regulation of IL-4 receptor (IL-4R) on tumor cells have been long observed. However, their significance for tumor development has not been investigated. Here, we found that endogenous IL-4 promotes tumor growth because neutralizing IL-4 by 11B11 monoclonal antibody (mAb) significantly delayed the growth of MCA205 fibrosarcoma. We also observed that tumor cells with higher IL-4R expression have more chances to survive in immunocompetent mice. To investigate how endogenous IL-4 influences tumor growth, we established a pair of tumor cells with or without IL-4R expression from the common parental cells. IL-4R–competent tumors exhibit increased growth compared with its IL-4R–deficient counterparts when inoculated into syngeneic mice. This growth advantage was still kept in IL-4R knockout mice but was abrogated in mice given i.p. with IL-4 neutralizing mAb. In vitro analyses indicate that IL-4 neither affects the proliferation of tumor cells nor changes the expression of several immune-related molecules, such as MHC-I, Fas, and B7-H3. Nonetheless, IL-4 up-regulates antiapoptotic gene expression in tumor cells and reduces apoptosis of tumor cells in vivo, as evidenced by real-time PCR, immunoblotting, and TUNEL staining. These findings were helpful to understand the long clinical observation and revealed that endogenous IL-4, the product of host immune response, can be used by tumor cells to facilitate their growth. [Cancer Res 2008;68(21):8687–94]
Endothelial Akt Signaling Is Rate-Limiting for Rapamycin Inhibition of Mouse Mammary Tumor Progression
Authors: Thuy L. Phung, Godfred Eyiah-Mensah, Rebekah K. O'Donnell, Radoslaw Bieniek, Sharon Shechter, Kenneth Walsh, Charlotte Kuperwasser, Laura E. Benjamin
Journal: Cancer Research (2007)

Chronic activation of Akt signaling in the endothelium recapitulates the salient features of a tumor vasculature and can be inhibited by rapamycin, an inhibitor of mammalian target of rapamycin. This led to the hypothesis that the antitumor efficacy of rapamycin may be partially dependent on its ability to inhibit endothelial Akt signaling, making rapamycin an antiangiogenic agent and endothelial Akt pathway inhibitor. Dose-response studies with rapamycin showed that primary human endothelial cells and fibroblasts had a bimodal Akt response with effective reductions in phosphorylated Akt (pAkt) achieved at 10 ng/mL. In contrast, rapamycin increased pAkt levels in tumor cell lines. When tumor-bearing mice were treated with rapamycin doses comparable to those used clinically in transplant patients, we observed strong inhibition of mammary tumor growth. To test whether Akt activation in the endothelium was rate-limiting for this antitumor response, we engineered mouse mammary tumor virus-polyoma virus middle T antigen mice with endothelial cell-specific expression of constitutively activated Akt. We observed that the antitumor efficacy of rapamycin was reduced in the presence of elevated endothelial Akt activation. Just as we observed in MCF7 cells in vitro, rapamycin doses that were antiangiogenic resulted in increased pAkt levels in total mouse mammary tumor virus-polyoma virus middle T antigen tumor lysates, suggesting that tumor cells had an opposite Akt response following mammalian target of rapamycin inhibition compared with tumor endothelial cells. Together, these data support the hypothesis that endothelial Akt signaling in the tumor vasculature is an important target of the novel anticancer drug rapamycin.
Effects of a leukotriene receptor antagonist on exhaled leukotriene E4 and prostanoids in children with asthma
Authors: Paolo Montuschi, Chiara Mondino, Pierluigi Koch, Peter J. Barnes, Giovanni Ciabattoni
Journal: Journal of Allergy and Clinical Immunology (2006)

Leukotriene (LT) E(4) and 8-isoprostane concentrations are elevated in exhaled breath condensate in children with asthma. The effects of leukotriene receptor antagonists (LTRAs) on exhaled leukotriene and prostanoids in children with asthma are unknown.(1) To study the effect of montelukast, a LTRA, on exhaled LTE(4), 8-isoprostane, and prostaglandin E(2) in children with asthma and atopic children; (2) to measure exhaled nitric oxide.An open-label study with oral montelukast (5 mg once daily for 4 weeks) was undertaken in 17 atopic children with asthma and 16 atopic children without asthma.Pretreatment exhaled LTE(4) (P < .0001) and 8-isoprostane (P < .0001) values were higher in atopic children with asthma than in atopic children without asthma. In atopic children with asthma, montelukast reduced exhaled LTE(4) by 33% (P < .001), and this reduction was correlated with pretreatment LTE(4) values (r = -0.90; P = .0001). Posttreatment exhaled LTE(4) levels in children with asthma were higher than pretreatment LTE(4) values in atopic children without asthma (P < .004). Montelukast had no effect on exhaled LTE(4) in atopic children without asthma (P = .74), or on exhaled 8-isoprostane (atopic children with asthma, P = .94; atopic children without asthma, P = .55) and PGE(2) (atopic children with asthma, P = .56; atopic children without asthma, P = .93) in both groups. In atopic children with asthma, exhaled nitric oxide concentrations were reduced by 27% (P < .05) after montelukast.Leukotriene receptor antagonists decrease exhaled LTE(4) in atopic children with asthma. This reduction is dependent on baseline exhaled LTE(4) values.Measurement of exhaled LTE(4) might help identify children with asthma most likely to benefit from LTRAs.
Elevated thymosin alpha I levels in Brazilian pemphigus foliaceus
Authors: J.T. ROSCOE, P.H. NAYLOR, L.A. DIAZ, R.S. LABIB, H.P. PATEL, A.L. GOLDSTEIN, S.A.P. SAMPAIO, G.J. ANHALT
Journal: British Journal of Dermatology (1986)

Levels of thymosin alpha I in the sera of 37 patients with Brazilian pemphigus foliaceus (BPF) were measured using a competitive binding radioimmunoassay. The values were compared with 19 patients with other forms of pemphigus, 13 relatives of patients with BPF, 18 patients with other dermatological diseases, and 265 normal controls. We found that 27 (73%) of the patients with BPF had thymosin alpha I serum levels that were at least two standard deviations above the mean for normal individuals. The mean value for patients with BPF was significantly greater than any other groups studied. The thymosin elevation is similar to alterations seen in certain viral diseases and suggests that BPF is aetiopathogenically distinct from the other forms of pemphigus.
Fatal polyarteritis presenting as asymmetrical peripheral gangrene.
Authors: M K Keech, H E Puro
Journal: Annals of the Rheumatic Diseases (1965)

before admission over the distal segments of the first second, and third fingers of the left hand; 2 days before admission the left testicle became tender and swollen.Examination.-He was a thin, anxious, white male with a rapid pulse.An electrocardiogram showed supraventri- cular tachycardia of 180-190.This did not respond to carotid massage, Valsalva's manoeuvre, gagging, eyeball pressure or vasoxyl, so he was admitted to the ward, given aramine, and slowly digitalized.Physical Examination.-Bloodpressure 122/80; tem- perature 1010 F.; lungs clear.No cardiomegaly, murmurs, or friction rubs were found.The right testicle measured I x 2 cm. and not tender, and the left 4 x 4 cm.and very tender.There was atrophy of the right arm, shoulder-girdle muscles, and pectoralis major, and a blotchy, purpleblack rash on the distal segments of the left first, second, and third fingers (Fig. 1).r ... ..w . . .Fig. I.-Gangrenous lesions of left thumb, index, and middle fingers on April 29.The left leg was atrophied with some purple dis- coloration over the left lateral malleolus and toes.The right foot showed discolorations over the first and second toes with pes cavus deformity (Fig. 2a, overleaf).549