tbuckley/cabot-search huggingface dataset:
Abstract 4510: RG7787 - a novel de-immunized PE based fusion protein for therapy of mesothelin-positive solid tumors
Authors: Gerhard Niederfellner, Frieder Bauss, Sabine Imhof-Jung, Friederike Hesse, Sven Kronenberg, Roland Staak, Martin Lechmann, Ben Krippendorff, Wolfgang Richter, Rita Mateus, Gwendlyn Kollmorgen, Ulli Brinkmann, Masanori Onda, Ira Pastan, Klaus Bosslet
Journal: Cancer Research (2014)

Abstract Attaching toxic payloads to antibodies has recently been established as a breakthrough in cancer therapy. Most of the currently developed antibody drug conjugate programs represent targeted chemotherapy with microtubule polymerization inhibiting drugs and hence share resistance mechanisms and side effects with classical chemotherapeutics like Taxol. Inhibition of protein synthesis by Pseudomonas Exotoxin (PE) is a more powerful mode of action that interferes with all hallmarks of cancer cells, not just with proliferation. However, its clinical use has been limited by immunogenicity as shown for SS1P, a mesothelin targeted immunotoxin. We have developed a novel de-immunized PE fusion protein (RG7787) for treatment of mesothelin-positive tumors. In order to de-immunize PE, point mutations have been introduced into domain III and the entire domain II has been deleted reducing the size of the effector moiety to approximately 24 kD. PE24 fusions with a disulfide-stabilized Fv fragment have previously been shown to be much better tolerated in rodents, but this could, at least in part, also be attributed to a much reduced serum half-life and exposure. In order to also de-immunize the targeting moiety of RG7787 and restore PK parameters similar to those of SS1P, we substituted the mouse dsFv moiety by a humanized Fab fragment. We show that RG7787 has indeed similar PK properties to SS1P in mouse and cyno. Cell viability assays show that RG7787 has similar cytotoxic potency as SS1P on different cell lines. In-vivo equipotency to SS1P in different xenograft models has been achieved at ∼3 fold higher doses indicating that tumor penetration of SS1P might be slightly better. However, RG7787 is up to tenfold better tolerated in rodents and cynomolgus monkeys, indicating that the therapeutic window is improved. RG7787 achieves potent tumor growth inhibition and even tumor regressions in several xenograft models. We also observed clearly synergistic efficacy with Taxol treatment in different tumor models making this a promising combination for clinical trials. Citation Format: Gerhard Niederfellner, Frieder Bauss, Sabine Imhof-Jung, Friederike Hesse, Sven Kronenberg, Roland Staak, Martin Lechmann, Ben Krippendorff, Wolfgang Richter, Rita Mateus, Gwendlyn Kollmorgen, Ulli Brinkmann, Masanori Onda, Ira Pastan, Klaus Bosslet. RG7787 - a novel de-immunized PE based fusion protein for therapy of mesothelin-positive solid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4510. doi:10.1158/1538-7445.AM2014-4510
Reduced Skeletal Muscle Oxygen Uptake and Reduced β-Cell Function
Authors: Claus Thamer, Michael Stumvoll, Andreas Niess, Otto Tschritter, Michael Haap, Regine Becker, Fatemeh Shirkavand, Oliver Bachmann, Kristian Rett, Annette Volk, Hans Häring, Andreas Fritsche
Journal: Diabetes Care (2003)

OBJECTIVE—Studies on insulin sensitivity and insulin secretion in subjects with a familial predisposition for type 2 diabetes mellitus (T2DM) traditionally produce inconsistent results. This may be due to small sample size, subject selection, matching procedures, and perhaps lack of a measure of physical fitness. RESEARCH DESIGN AND METHODS—In the present study, we specifically tested the hypothesis that a family history of T2DM is associated with reduced Vo2max, measured by incremental bicycle ergometry, independent of insulin sensitivity estimated from an oral glucose tolerance test (OGTT; n = 424) and measured by a euglycemic-hyperinsulinemic clamp (n = 185). Subjects included in the study were young (34 ± 10 years), healthy, and normal glucose tolerant with either a first-degree relative (FDR) with T2DM (n = 183), a second-degree relative with T2DM (n = 94), or no family history of T2DM (control subjects, n = 147). BMI, percent body fat, waist-to-hip ratio (WHR), and habitual physical activity (HPA; standard questionnaire) were comparable among groups. FDRs had significantly lower Vo2max than control subjects: 40.5 ± 0.6 vs. 45.2 ± 0.9 ml O2/kg lean body mass, P = 0.01 after adjusting for sex, age, BMI, HPA, and insulin sensitivity (euglycemic-hyperinsulinemic clamp). RESULTS—BMI, percent body fat, waist-to-hip ratio (WHR), and habitual physical activity (HPA; standard questionnaire) were comparable among groups. FDRs had significantly lower Vo2max than control subjects: 40.5 ± 0.6 vs. 45.2 ± 0.9 ml O2/kg lean body mass, P = 0.01 after adjusting for sex, age, BMI, HPA, and insulin sensitivity (euglycemic-hyperinsulinemic clamp). Insulin sensitivity per se was not affected by family history of T2DM after adjusting for age, sex, BMI, and percent body fat (P = 0.76). The appropriateness of β-cell function for the individual insulin sensitivity (disposition index: product of a validated secretion parameter [OGTT] and sensitivity [clamp]) was significantly lower in FDRs (87 ± 4 units) versus control subjects (104 ± 6 units, P = 0.02 after adjusting for sex, age, and BMI). Analyses of the larger OGTT group produced essentially the same results. CONCLUSIONS—In conclusion, these data are compatible with the hypothesis that familial predisposition for T2DM impairs maximal oxygen consumption in skeletal muscle. Because habitual physical activity was not different, genetic factors may be involved. Conceivably, reduced Vo2max precedes skeletal muscle insulin resistance, providing a partial explanation for discrepancies in the literature.
INHIBITORY AND STIMULATORY EFFECTS OF CONCANAVALIN A ON THE RESPONSE OF MOUSE SPLEEN CELL SUSPENSIONS TO ANTIGEN
Authors: Richard W. Dutton
Journal: The Journal of Experimental Medicine (1973)

The addition of concanavalin A to mouse spleen cell suspensions can either inhibit or stimulate the immune response to heterologous erythrocytes according to the experimental conditions. Evidence is presented which is incompatible with the hypothesis that these two effects are mediated by a single cell and which favors the hypothesis of separate inhibitor and stimulatory cells.
Lysosomal Fusion Is Essential for the Retention of <i>Trypanosoma cruzi</i> Inside Host Cells
Authors: Luciana O. Andrade, Norma W. Andrews
Journal: The Journal of Experimental Medicine (2004)

Trypomastigotes, the highly motile infective forms of Trypanosoma cruzi, are capable of infecting several cell types. Invasion occurs either by direct recruitment and fusion of lysosomes at the plasma membrane, or through invagination of the plasma membrane followed by intracellular fusion with lysosomes. The lysosome-like parasitophorous vacuole is subsequently disrupted, releasing the parasites for replication in the cytosol. The role of this early residence within lysosomes in the intracellular cycle of T. cruzi has remained unclear. For several other cytosolic pathogens, survival inside host cells depends on an early escape from phagosomes before lysosomal fusion. Here, we show that when lysosome-mediated T. cruzi invasion is blocked through phosophoinositide 3-kinase inhibition, a significant fraction of the internalized parasites are not subsequently retained inside host cells for a productive infection. A direct correlation was observed between the lysosomal fusion rates after invasion and the intracellular retention of trypomastigotes. Thus, formation of a parasitophorous vacuole with lysosomal properties is essential for preventing these highly motile parasites from exiting host cells and for allowing completion of the intracellular life cycle.
The Silent Clap
Authors: A. Eugene Washington
Journal: JAMA (1981)

Asymptomatic gonorrhea, once considered the exclusive domain of women, is increasingly being recognized among men. Confirming earlier studies,<sup>1</sup>investigators in the 1970s have documented asymptomatic prevalence rates as high as 60% among infected men who are sexual partners of high-risk women,<sup>2-4</sup>ie, repeaters and women with gonococcal pelvic inflammatory disease (PID). Such reports highlight new opportunities for an improved strategy of control and for the physician's role in preventing cases. Potterat and King in this issue ofThe JOURNAL(p 578) argue that case interview resources should be redirected toward selected women, away from symptomatic men, with the intent of discovering more asymptomatic men. They attribute a reduction in gonorrhea incidence rates in their community to this new approach. The new approach began in El Paso County (Colorado) in late 1975. It is interesting to examine their comparative data for the period before their new program was initiated
Body-Methylated Genes in Arabidopsis thaliana Are Functionally Important and Evolve Slowly
Authors: S. Takuno, B. S. Gaut
Journal: Molecular Biology and Evolution (2011)

DNA methylation of coding regions, known as gene body methylation, is conserved across eukaryotic lineages. The function of body methylation is not known, but it may either prevent aberrant expression from intragenic promoters or enhance the accuracy of splicing. Given these putative functions, we hypothesized that body-methylated genes would be both longer and more functionally important than unmethylated genes. To test these hypotheses, we reanalyzed single-base resolution bisulfite sequence data from Arabidopsis thaliana to differentiate body-methylated genes from unmethylated genes using a probabilistic approach. Contrasting genic characteristics between the two groups, we found that body-methylated genes tend to be longer and to be more functionally important, as measured by phenotypic effects of insertional mutants and by gene expression, than unmethylated genes. We also found that methylated genes evolve more slowly than unmethylated genes, despite the potential for increased mutation rates in methylated CpG dinucleotides. We propose that slower rates in body-methylated genes are a function of higher selective constraint, lower nucleosome occupancy, and a lower proportion of CpG dinucleotides.
Role of the p38 Mitogen-Activated Protein Kinase Pathway in Cytokine-Mediated Hematopoietic Suppression in Myelodysplastic Syndromes
Authors: Efstratios Katsoulidis, Yongzhong Li, Patrick Yoon, Antonella Sassano, Jessica Altman, Padma Kannan-Thulasiraman, Lakshmi Balasubramanian, Simrit Parmar, John Varga, Martin S. Tallman, Amit Verma, Leonidas C. Platanias
Journal: Cancer Research (2005)

Abstract The p38 mitogen-activated protein kinase (MAPK) pathway is activated by IFNs and other cytokines to mediate signals for important cellular functions, including transcriptional regulation and apoptosis. We examined the role of the p38 pathway in the generation of the effects of myelosuppressive cytokines on human hematopoiesis. Pharmacologic inhibition of p38 using BIX-01208 resulted in reversal of IFN-, tumor necrosis factor-α (TNF-α)–, and transforming growth factor-β (TGF-β)–mediated suppression of human erythroid (blast-forming unit-erythroid) and myeloid (granulocyte-macrophage colony-forming unit) colony formation, consistent with a key role for p38 in the generation of myelosuppressive signals by different cytokines. Similarly, the myelosuppressive effects of TNF-α and TGF-β were reversed by small interfering RNAs targeting p38α expression, further establishing the requirement of this kinase in the induction of myelosuppressive responses. As TNF overproduction has been implicated in the pathophysiology of bone marrow failure states, we determined whether pharmacologic inhibition of p38 reverses the hematopoietic defects seen in bone marrows from patients with myelodysplastic syndromes (MDS) and the anemia of chronic disease. Addition of pharmacologic inhibitors of p38 on such bone marrows resulted in increased numbers of erythroid and myeloid progenitors. Similarly, inhibition of the activity of the downstream effectors of p38, MAPK activated protein kinase-2, and mitogen and stress activated kinase 1 partially restored the hematopoietic defect seen in these bone marrows. Taken altogether, our data implicate the p38 MAPK in the pathophysiology of myelodysplasias and suggest that p38 pharmacologic inhibitors may have therapeutic applications in the treatment of MDS.
The Role of Innate Immunity in Autoimmunity
Authors: Jean-François Bach, Albert Bendelac, Michael B. Brenner, Harvey Cantor, Gennaro De Libero, Mitchell Kronenberg, Lewis L. Lanier, David H. Raulet, Mark J. Shlomchik, Matthias G. von Herrath
Journal: The Journal of Experimental Medicine (2004)

During the 2004 International Congress of Immunology in Montreal, a panel of experts gathered for an “Ideashop” discussion on the potential role of innate immunity in autoimmunity and the ways in which this might be targeted in future therapies.
Integrity of SOS1/EPS8/ABI1 Tri-Complex Determines Ovarian Cancer Metastasis
Authors: Huijun Chen, Xufeng Wu, Zhixing K. Pan, Shuang Huang
Journal: Cancer Research (2010)

Abstract Ovarian cancer is mainly confined in peritoneal cavity and its metastasis is often associated with the formation of malignant ascites. As lysophosphatidic acid (LPA) is present at high levels in ascites of ovarian cancer patients and potently stimulates cell migration, we reason that LPA-stimulated cell migration may play an important role in ovarian cancer metastasis. Here, we show that only ovarian cancer cell lines with LPA migratory response undergo peritoneal metastatic colonization. LPA-stimulated cell migration is required for metastatic colonization because knockdown of LPA receptor subtype 1 (LPAR1) abolishes this event. However, the difference in metastatic potentials is not caused by the absence of LPAR1 because both metastatic and nonmetastatic lines express similar levels of LPAR1. Instead, we find that LPA can activate Rac only in metastatic cells and that metastatic colonization of ovarian cancer cells necessitates Rac activity. These results thus suggest that LPA-induced Rac activation is a prerequisite for ovarian cancer metastasis. In metastatic cells, Rac activation is facilitated by SOS1/EPS8/ABI1 tri-complex and the integrity of this tri-complex is essential for LPA-stimulated cell migration and metastatic colonization. We show that at least 1 member of SOS1/EPS8/ABI1 tri-complex is absent in nonmetastatic ovarian cancer cells and reexpressing the missing one conferred them with metastatic capability. Importantly, coexpression of SOS1, EPS8, and ABI1, but not of any individual member of SOS1/EPS8/ABI1 tri-complex, correlates with advanced stages and shorter survival of ovarian cancer patients. Our study implicates that the integrity of SOS1/EPS8/ABI1 tri-complex is a determinant of ovarian cancer metastasis. Cancer Res; 70(23); 9979–90. ©2010 AACR.
Colonic H+-K+-ATPase is induced and mediates increased <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" altimg="si5.gif" overflow="scroll"><mml:mrow><mml:msubsup><mml:mrow><mml:mi mathvariant="normal">HCO</mml:mi></mml:mrow><mml:mn>3</mml:mn><mml:mo>−</mml:mo></mml:msubsup></mml:mrow></mml:math> reabsorption in inner medullary collecting duct in potassium depletion
Authors: Suguru Nakamura, Hassane Amlal, John H. Galla, Manoocher Soleimani
Journal: Kidney International (1998)
Workplace Allergenicity of a Psyllium‐Containing Bulk Laxative
Authors: W. F. GAUSS, J. P. ALAREE, M. H. KAROL
Journal: Allergy (1985)

IgE antibodies specific to psyllium were demonstrated by RAST in a patient with workplace‐related asthmatic and dermatological reactions. Antibodies were not cross‐reactive with the related plant, English plantain.
Diagnosis and Treatment of Chronic Arterial Insufficiency of the Lower Extremities: A Critical Review
Authors: Jeffrey I. Weitz, John Byrne, G. Patrick Clagett, Michael E. Farkouh, John M. Porter, David L. Sackett, D. Eugene Strandness, Lloyd M. Taylor
Journal: Circulation (1996)

HomeCirculationVol. 94, No. 11Diagnosis and Treatment of Chronic Arterial Insufficiency of the Lower Extremities: A Critical Review
Regulation of Colorectal Carcinoma Stemness, Growth, and Metastasis by an <i>miR-200c</i>-Sox2–Negative Feedback Loop Mechanism
Authors: Yan-Xia Lu, Li Yuan, Xiao-Lei Xue, Min Zhou, Yan Liu, Chao Zhang, Jing-Ping Li, Lin Zheng, Min Hong, Xue-Nong Li
Journal: Clinical Cancer Research (2014)

Abstract Purpose: To elucidate a novel mechanism of miR-200c in the regulation of stemness, growth, and metastasis in colorectal carcinoma (CRC). Experimental Design: Quantitative reverse transcription PCR was used to quantify miR-200c expression in CRC cell lines and tissues. A luciferase assay was adopted for the target evaluation. The functional effects of miR-200c in CRC cells were assessed by its forced or inhibited expression using lentiviruses. Results: MiR-200c was statistically lower in CRC clinical specimens and highly metastatic CRC cell lines compared with their counterparts. Sox2 was validated as a target for miR-200c. The knockdown of miR-200c significantly enhanced proliferation, migration, and invasion in CRC cell lines, whereas the upregulation of miR-200c exhibited an inverse effect. Moreover, rescue of Sox2 expression could abolish the effect of the upregulation of miR-200c. In addition, the reduction of miR-200c increased the expression of CRC stem cell markers and the sphere-forming capacity of CRC cell lines. Further study has shown that miR-200c and Sox2 reciprocally control their expression through a feedback loop. MiR-200c suppresses the expression of Sox2 to block the activity of the phosphoinositide 3-kinase (PI3K)–AKT pathway. Conclusion: Our findings indicate that miR-200c regulates Sox2 expression through a feedback loop and is associated with CRC stemness, growth, and metastasis. Clin Cancer Res; 20(10); 2631–42. ©2014 AACR.
Muscle Length Directs Sympathetic Nerve Activity and Vasomotor Tone in Resistance Vessels of Hamster Retractor
Authors: Donald G. Welsh, Steven S. Segal
Journal: Circulation Research (1996)

Increased resistance to blood flow with muscle extension has been explained by the deformation of vessels within the muscle. In the present study, we developed a novel preparation of the hamster retractor muscle to investigate whether passive changes in skeletal muscle length elicit active vasomotor responses through a range of motion (85% to 130% of in vivo length; sarcomere length, 2.69±0.02 to 4.05±0.01 μm) encompassing the classic length-tension relationship. Arterioles (diameter, 32±3 μm) and feed arteries (diameter, 75±4 μm) were observed to progressively constrict (by 8±1 and 17±2 μm, respectively) with muscle lengthening, reducing blood flow by &gt;50%; reciprocal changes occurred with passive shortening. Sodium nitroprusside (10 μmol/L) dilated vessels (to 47±2 and 98±4 μm, respectively) and abolished vasomotor responses to changing muscle length. The coordination of vasomotor responses between arterioles and feed arteries maintained wall shear rate (control, 1764±200 s −1 ) and perfusion pressure (60±5 mm Hg) into the arteriolar network. Tetrodotoxin (TTX, 1 μmol/L), phentolamine (1 μmol/L), prazosin (0.1 μmol/L), or 6-hydroxydopamine (1 mmol/L) inhibited vasoconstrictor responses, indicating that action potentials initiated by muscle lengthening give rise to norepinephrine release from sympathetic nerves. As shown with glyoxylic acid staining, sympathetic nerves formed a plexus encompassing arterioles and feed arteries. To test for a reflexive response initiated by intramuscular mechanoreceptors, TTX was applied with micropipettes to proximal segments of feed arteries, thereby neurally “isolating” the muscle from the hamster. Whereas lengthening-induced vasoconstriction persisted in arterioles and in feed artery segments distal to TTX, there was no vasomotor response central to the block. We conclude that passive lengthening stimulates the activity of periarteriolar sympathetic nerves; this activity propagates antidromically along nerve fibers into the feed arteries. These findings identify a mechanotransduction sequence by which the length of skeletal muscle actively governs vasomotor tone and the supply of oxygen to muscle fibers.
Basis of hematopoietic defects in platelet-derived growth factor (PDGF)-B and PDGF β-receptor null mice
Authors: Wolfgang E. Kaminski, Per Lindahl, Nancy L. Lin, Virginia C. Broudy, Jeffrey R. Crosby, Mats Hellström, Birgitta Swolin, Daniel F. Bowen-Pope, Paul J. Martin, Russell Ross, Christer Betsholtz, Elaine W. Raines
Journal: Blood (2001)
Randomized Phase II Study of Gemcitabine Plus Cisplatin or Carboplatin, With or Without Cetuximab, As First-Line Therapy for Patients With Advanced or Metastatic Non–Small-Cell Lung Cancer
Authors: Charles A. Butts, David Bodkin, Edward L. Middleman, Craig W. Englund, David Ellison, Yasmin Alam, Harvey Kreisman, Peter Graze, James Maher, Helen J. Ross, Peter M. Ellis, William McNulty, Edward Kaplan, Virginie Pautret, Martin R. Weber, Frances A. Shepherd
Journal: Journal of Clinical Oncology (2007)

To evaluate the efficacy of cetuximab added to first-line gemcitabine/platinum in chemotherapy-naïve patients with advanced non-small-cell lung cancer (NSCLC).In this noncomparative, randomized trial, chemotherapy-naïve patients with recurrent/metastatic NSCLC (stage IV or stage IIIB with malignant pleural effusion) were eligible. Patients received cisplatin (75 mg/m2 i.v., every 3 weeks) or carboplatin (area under the concentration-versus-time curve of 5 intravenously [i.v.], every 3 weeks), and gemcitabine (1,250 or 1,000 mg/m2 i.v., days 1 and 8) plus cetuximab (400 mg/m2 i.v. day 1, followed by 250 mg/m2 weekly), in arm A, or chemotherapy alone, in arm B. Response rate was the primary end point; safety, progression-free survival, and overall survival were secondary end points.Sixty-five patients were randomly assigned to arm A and 66 to arm B. Partial responses were observed in 18 patients (27.7%; 95% CI, 17.3 to 40.2) in arm A and 12 (18.2%; 95% CI, 9.8 to 29.6) in arm B. Median progression-free survival was 5.09 months for arm A (95% CI, 4.17 to 5.98) and 4.21 months (95% CI, 3.81 to 5.49) in arm B. Median overall survival was 11.99 months (95% CI, 8.80 to 15.18) and 9.26 months (95% CI, 7.43 to 11.79) in arms A and B, respectively. Overall toxicity was acceptable and consistent with the profiles of the individual agents.First-line treatment with cetuximab plus gemcitabine/platinum is well tolerated and can be administered safely in patients with advanced NSCLC. Differences in response rate, progression-free survival, and overall survival suggest that the addition of cetuximab to platinum/gemcitabine may improve clinical outcomes. Larger studies are in progress to address this hypothesis.
Pathprinting: An integrative approach to understand the functional basis of disease
Authors: Gabriel M Altschuler, Oliver Hofmann, Irina Kalatskaya, Rebecca Payne, Shannan J Ho Sui, Uma Saxena, Andrei V Krivtsov, Scott A Armstrong, Tianxi Cai, Lincoln Stein, Winston A Hide
Journal: Genome Medicine (2013)

New strategies to combat complex human disease require systems approaches to biology that integrate experiments from cell lines, primary tissues and model organisms. We have developed Pathprint, a functional approach that compares gene expression profiles in a set of pathways, networks and transcriptionally regulated targets. It can be applied universally to gene expression profiles across species. Integration of large-scale profiling methods and curation of the public repository overcomes platform, species and batch effects to yield a standard measure of functional distance between experiments. We show that pathprints combine mouse and human blood developmental lineage, and can be used to identify new prognostic indicators in acute myeloid leukemia. The code and resources are available at http://compbio.sph.harvard.edu/hidelab/pathprint.