tbuckley/cabot-search huggingface dataset:
Therapeutic Antibodies to Human L1CAM: Functional Characterization and Application in a Mouse Model for Ovarian Carcinoma
Authors: Silke Wolterink, Gerhard Moldenhauer, Mina Fogel, Helena Kiefel, Marco Pfeifer, Sandra Lüttgau, Ricardo Gouveia, Julia Costa, Jan Endell, Ulrich Moebius, Peter Altevogt
Journal: Cancer Research (2010)

Recent work has identified L1CAM (CD171) as a novel marker for human carcinoma progression. Functionally, L1CAM promotes tumor cell invasion and motility, augments tumor growth in nude mice, and facilitates experimental tumor metastasis. These functional features qualify L1 as an interesting target molecule for tumor therapy. Here, we generated a series of novel monoclonal antibodies (mAb) to the L1CAM ectodomain that were characterized by biochemical and functional means. All novel mAbs reacted specifically with L1CAM and not with the closely related molecule CHL1, whereas antibodies to the COOH terminal part of L1CAM (mAb2C2, mAb745H7, pcytL1) showed cross-reactivity. Among the novel mAbs, L1-9.3 was selected and its therapeutic potential was analyzed in various isotype variants in a model of SKOV3ip cells growing i.p. in CD1 nude mice. Only therapy with the IgG2a variant efficiently prolonged survival and reduced tumor burden. This was accompanied by an increased infiltration of F4/80-positive monocytic cells. Clodronate pretreatment of tumor-bearing animals led to the depletion of monocytes and abolished the therapeutic effect of L1-9.3/IgG2a. Expression profiling of tumor-derived mRNA revealed that L1-9.3/IgG2a therapy induced altered expression of cellular genes associated with apoptosis and tumor growth. Our results establish that anti-L1 mAb therapy acts via immunologic and nonimmunologic effector mechanism to block tumor growth. The novel antibodies to L1CAM could become helpful tools for the therapy of L1-positive human carcinomas.
Topotecan Blocks Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor Expression Induced by Insulin-Like Growth Factor-I in Neuroblastoma Cells
Authors: Kiichiro Beppu, Katsuya Nakamura, W. Marston Linehan, Annamaria Rapisarda, Carol J. Thiele
Journal: Cancer Research (2005)

The extent of angiogenesis and/or vascular endothelial growth factor (VEGF) expression in neuroblastoma tumors correlates with metastases, N-myc amplification, and poor clinical outcome. Understanding the mechanisms regulating VEGF expression in neuroblastoma cells provides additional therapeutic options to control neuroblastoma tumor growth. VEGF mRNA is controlled by growth factors and hypoxia via the transcription factor hypoxia-inducible factor (HIF-1alpha). HIF-1alpha protein levels are regulated by the von Hippel Lindau tumor suppressor gene, VHL, which targets HIF-1alpha degradation. To determine whether the levels of VEGF in neuroblastomas are due to mutations in VHL, we evaluated genomic DNA from 15 neuroblastoma cell lines using PCR. We found no mutations in exons 1, 2, or 3 of the VHL gene. VEGF mRNA levels in neuroblastoma cells cultured in serum-free medium increased after 8 to 16 hours in serum, insulin-like growth factor-I (IGF-I), epidermal growth factor, or platelet-derived growth factor. Serum/IGF-I induced increases in HIF-1alpha protein that temporally paralleled increases in VEGF mRNA, whereas HIF-1beta levels were unaffected. VEGF and HIF-1alpha levels were blocked by inhibitors of phosphatidylinositol 3-kinase and mammalian target of rapamycin. Furthermore, we confirmed that HIF-1alpha mediates approximately 40% of the growth factor activity stimulating VEGF protein expression. Topotecan blocked the IGF-I-stimulated increase in HIF-1alpha but not HIF-1beta, and this resulted in a decrease in VEGF in four neuroblastoma cell lines tested. These data indicate that growth factors in an autocrine or paracrine manner play a major role in regulating VEGF levels in neuroblastoma cells and that targeted therapies to phosphatidylinositol 3-kinase, mammalian target of rapamycin, and/or HIF-1alpha have the potential to inhibit VEGF expression and limit neuroblastoma tumor growth.
Expression of transferrin receptors on monocytes in hemochromatosis
Authors: Paul C. Adams, Luan A. Chau, Martin White, Andrew Lazarovits
Journal: American Journal of Hematology (1991)

Abstract To assess whether an abnormality in transferrin receptor expression or regulation could represent an underlying metabolic defect in the reticuloendothelial (RE) system in hemochromatosis, monocytes were analyzed for the expression of the transferrin receptor using a monoclonal antibody (Act II) to the transferrin receptor (CD71) and flow cytometric analysis. Hemochromatosis patients (n = 14), and normal volunteers with no clinical evidence of iron overload (n = 14) were studied. A significant inverse relationship was observed for the relationship between the expression of transferrin receptor on monocytes and log(hepatic iron concentration) in hemochromatosis patients (r = −0.59, P &lt; 02) and also for the relationship between the expression of transferrin receptor and log(serum ferritin) in normal volunteers (r = −0.90, P &lt;.001). There was no significant difference in the mean expression of monocyte transferrin receptor between hemochromatosis patients and normal volunteers. However, the expression of the transferrin receptor in hemochromatosis patients was disproportionately higher than would be predicted from the relationship between serum ferritin and transferrin receptor expression in normal volunteers. The inverse relationship of the monocyte transferrin receptor relative to body iron stores in hemochromatosis is consistent with observations in other tissues, and suggests that non‐transferrin iron metabolism, including ferritin, requires further investigation in the RE cell in hemochromatosis.
INDELible: A Flexible Simulator of Biological Sequence Evolution
Authors: W. Fletcher, Z. Yang
Journal: Molecular Biology and Evolution (2009)

Many methods exist for reconstructing phylogenies from molecular sequence data, but few phylogenies are known and can be used to check their efficacy. Simulation remains the most important approach to testing the accuracy and robustness of phylogenetic inference methods. However, current simulation programs are limited, especially concerning realistic models for simulating insertions and deletions. We implement a portable and flexible application, named INDELible, for generating nucleotide, amino acid and codon sequence data by simulating insertions and deletions (indels) as well as substitutions. Indels are simulated under several models of indel-length distribution. The program implements a rich repertoire of substitution models, including the general unrestricted model and nonstationary nonhomogeneous models of nucleotide substitution, mixture, and partition models that account for heterogeneity among sites, and codon models that allow the nonsynonymous/synonymous substitution rate ratio to vary among sites and branches. With its many unique features, INDELible should be useful for evaluating the performance of many inference methods, including those for multiple sequence alignment, phylogenetic tree inference, and ancestral sequence, or genome reconstruction.
Lone atrial fibrillation in vigorously exercising middle aged men: case-control study
Authors: J. Karjalainen, U. M Kujala, J. Kaprio, S. Sarna, M. Viitasalo
Journal: BMJ (1998)

Regular physical exercise reduces cardiovascular morbidity.1 2 However, our clinical impression is that atrial fibrillation is quite common in otherwise healthy middle aged men engaged in long term vigorous endurance sports. We therefore compared the prevalence of atrial fibrillation in middle aged men doing intense endurance training and men from the general population.

We chose top level veteran orienteers to represent subjects doing long term vigorous exercise. A high position in the veteran ranking list is an indicator of years of intense training. We enrolled the 60 top ranked orienteers in 1984 from the race classes age 35-39 years, 40-44 years, 45-49 years, and 55-59 years, a total of 300 runners. The 495 controls comprised all men aged 35-59 enrolled for an earlier study.2 At 20 years old these subjects had been completely healthy (fully fit for military …
Cyclosporin‐a for the treatment of pure red cell aplasia in a patient with chronic lymphocytic leukemia
Authors: G. Chikkappa, D. Pasquale, P. G. Phillips, K. F. Mangan, M. F. Tsan
Journal: American Journal of Hematology (1987)

Abstract A 62‐year‐old man with B‐cell chronic lymphocytic leukemia had three separate episodes of pure red cell aplasia (PRCA). The last episode was treated with cyclosporin‐A (CyA) and prednisone. After the patient was on the therapy for 2 weeks, erythropoietic recovery was observed and with continued therapy the hematocrit (Hct) became normal. The PRCA remission was associated with a fall in the blood lymphocyte count, and a reduction in the spleen and lymph node size and bone marrow lymphocyte density. At diagnosis of PRCA the blood T‐cells bearing IgG Fc receptors (T gamma cells) were increased, and the marrow contained very few or no late‐stage erythroid progenitors. After remission of PRCA the T gamma cell fraction decreased, and the marrow erythroid progenitor's number became normal. We speculate that therapy with CyA and prednisone inhibited the production of interleukins‐1 and ‐2 from monocytes and T‐cells, respectively, and was responsible for the reduction of the T gamma cell fraction and B‐cell leukemic mass in this patient. Further, we believe that normalization of T gamma cells in association with the therapy was responsible for the PRCA remission.
Macular Ganglion Cell Layer Imaging in Preperimetric Glaucoma with Speckle Noise–Reduced Spectral Domain Optical Coherence Tomography
Authors: Noriko Nakano, Masanori Hangai, Hideo Nakanishi, Satoshi Mori, Masayuki Nukada, Yuriko Kotera, Hanako Ohashi Ikeda, Hajime Nakamura, Atsushi Nonaka, Nagahisa Yoshimura
Journal: Ophthalmology (2011)
Evidence for central hypertyraminemia in hepatic encephalopathy.
Authors: B A Faraj, V M Camp, J D Ansley, J Scott, F M Ali, E J Malveaux
Journal: Journal of Clinical Investigation (1981)

In mongrel dogs, the effect of end-to-side portacaval shunt on plasma, cerebrospinal fluid (CSF) and brain tyramine, tyrosine, dopamine, norepinephrine, and epinephrine were studied. It was found that the level of tyramine in plasma, CSF, and selected brain regions increased steadily after the construction of the shunts. These elevations became more pronounced when the dogs manifested symptoms of hepatic encephalopathy. In postshunted dogs with stage II and III hepatic encephalopathy, tyramine concentration in corpus striatum (1,312 +/- 371), hypothalamus (400 +/- 67.0), and midbrain (660 +/- 78.7 ng/g) was significantly (P less than 0.05) higher than the level in dogs with stage 0 and I hepatic encephalopathy and sham-operated dogs serving as controls (corpus striatum, 831 +/- 140; hypothalamus, 167 +/- 40.0; and midbrain, 132 +/- 37.4 ng/g). This was followed by a concomitant depletion of dopamine and norepinephrine in these brain regions (postshunt: dopamine 104 +/- 20.0, 3,697 +/- 977, and 105 +/- 14.1; norepinephrine 521 +/- 71.6, 81.6 +/- 13.7, and 218 +/- 31.7 ng/g; vs. sham group: dopamine 532 +/- 83.1, 8,210 +/- 1,126, and 192 +/- 35.0; norepinephrine 1,338 +/- 425, 124 +/- 21.3, and 449 +/- 89.7 ng/g) of encephalopathic dogs with portacaval shunt. Furthermore, tyramine, tyrosine, dopamine, and norepinephrine levels in plasma and CSF increased markedly as clinical features in the dogs' behavior characteristic of hepatic encephalopathy occurred, including hypersalivation, ataxia, flapping tremor, somnolence, and coma. Cerebral hypertyraminemia and a defect in sympathetic neurotransmission may contribute to the development of hepatic encephalopathy of liver disease.
The presence of circulating tumor cells (CTCs) correlates with lymph node metastasis in nonresectable squamous cell carcinoma of the head and neck region (SCCHN)
Authors: T. Hristozova, R. Konschak, C. Stromberger, A. Fusi, Z. Liu, W. Weichert, A. Stenzinger, V. Budach, U. Keilholz, I. Tinhofer
Journal: Annals of Oncology (2011)
Diversity of the class II (I-Ak/I-Ek)-restricted T cell repertoire for influenza hemagglutinin and antigenic drift. Six nonoverlapping epitopes on the HA1 subunit are defined by synthetic peptides.
Authors: D S Burt, K H Mills, J J Skehel, D B Thomas
Journal: The Journal of Experimental Medicine (1989)

H-2k-restricted T cell clones derived from CBA mice infected with X31 (H3N2) influenza virus, were shown to recognize distinct, nonoverlapping sequences within the HA1 subunit of the viral hemagglutinin (HA) using synthetic peptides. Three I-Ak-restricted T cell sequences were identified within HA1 68-83, 120-139, and 269-288, and two recognition sites presented in the context of the I-Ek molecule were mapped to HA1 sequences 226-245 and 246-265. T cell clones specific for these regions of HA1 demonstrated varying abilities to differentiate between natural variant viruses that had accumulated substitutions within their HA molecules as a result of antigenic drift. Clones that recognized sequences HA1 226-245 and HA1 246-265 failed to discriminate between natural variants and focused on conserved sequences within these epitopes. A majority of T cell clones were sensitive to amino acid substitutions that have featured in antigenic drift occurring within three major antigenic sites of the HA1 subunit; substitutions at HA1 residues 78 (V)/83(K) and 275(D)/278(I) within the HA1 subunit of mutant viruses correlated with a 75% reduction in the proliferative response for T cell clones specific for sequences HA1 68-83 and HA1 269-288, respectively. Furthermore, a clone that recognized HA1 120-139 was nonresponsive to a mutant virus HK/71, implicating amino acids at HA1 position 129(G) and/or 132(Q) within this sequence as crucial for recognition. Our data, together with the previous finding that sequence HA1 53-63 is also a major I-Ak-restricted T cell recognition site, demonstrate a level of diversity in the T cell recognition of influenza HA, within a single mouse haplotype hitherto unrecognized, and imply that the T cell repertoire diversity against foreign antigens may be greater than previously assumed. Furthermore, the frequency at which HA-specific T cells have been identified that focus on amino acids within the HA1 subunit of HA also featuring in antigenic drift, suggests that a failure of MHC class II-restricted T cells to recognize specific epitopes within mutant HA molecules may contribute significantly to the capacity of variant influenza viruses to evade immune recognition.
Dr Solbert Permutt, 1925–2012
Authors: Wayne Mitzner, J.T. Sylvester
Journal: European Respiratory Journal (2012)

It is with great sadness that we report to readers of the European Respiratory Journal and members of the European Respiratory Society the passing of Dr Solbert Permutt (fig. 1), who died at the age of 87 years on May 23, 2012, after a protracted battle with oesophageal cancer. As many already appreciate, Sol was one of the giants of respiratory medicine and physiology, and his passing is an immense loss to our community. He was a remarkable individual with an unbounded level of enthusiasm, creativity and inspiration. Those who had the good fortune to know him had their lives influenced in many positive ways.



Figure 1– 
Solbert Permutt, 1925–2012.



Sol entered this world on March 6, 1925, in Birmingham, AL, 9 years after his mother had a tubal ligation. At the time, his mother confided that learning of this unwanted pregnancy seemed worse than finding out she had cancer; however, Sol soon became a treasured child, in no small part because of his clearly superior intelligence. In elementary and high school, he was a brilliant but undisciplined student, who cut school to spend time at the local library and earned some spending money by teaching calculus to undergraduates at the University of Alabama. In 1942, after the onset of World War II and a single year as a student at this university, Sol was drafted into the US Army. His high scores on a medical aptitude test caused him to be assigned to the army's medical school programme, where he completed one year of premed at the …
Reactive Oxygen Species Production in Energized Cardiac Mitochondria During Hypoxia/Reoxygenation
Authors: Paavo Korge, Peipei Ping, James N. Weiss
Journal: Circulation Research (2008)

Mitochondria are an important source of reactive oxygen species (ROS), implicated in ischemia/reperfusion injury. When isolated from ischemic myocardium, mitochondria demonstrate increased ROS production as a result of damage to electron transport complexes. To investigate the mechanisms, we studied effects of hypoxia/reoxygenation on ROS production by isolated energized heart mitochondria. ROS production, tracked using Fe(2+)-catalyzed, H(2)O(2)-dependent H(2)DCF oxidation or Amplex Red, was similar during normoxia and hypoxia but markedly increased during reoxygenation, in proportion to the duration of hypoxia. In contrast, if mitochondria were rapidly converted from normoxia to near-anoxia ([O(2)], <1 micromol/L), the increase in H(2)DCF oxidation rate during reoxygenation was markedly blunted. To elicit the robust increase in H(2)DCF oxidation rate during reoxygenation, hypoxia had to be severe enough to cause partial, but not complete, respiratory chain inhibition (as shown by partial dissipation of membrane potential and increased NADH autofluorescence). Consistent with its cardioprotective actions, nitric oxide ( O) abrogated increased H(2)DCF oxidation under these conditions, as well as attenuating ROS-induced increases in matrix [Fe(2+)] and aconitase inhibition caused by antimycin. Collectively, these results suggest that (1) hypoxia that is sufficient to cause partial respiratory inhibition is more damaging to mitochondria than near-anoxia; and (2) O suppresses ROS-induced damage to electron transport complexes, probably by forming O-Fe(2+) complexes in the presence of glutathione, which inhibit hydroxyl radical formation.
Tuberculosis in contacts need not indicate disease transmission
Authors: U R Dahle
Journal: Thorax (2005)

Traditional contact investigation is an important tool for controlling tuberculosis. It may also help to indicate drug susceptibility patterns when Mycobacterium tuberculosis cultures are not available. Such investigations often underestimate the degree of transmission found by genotyping, but overestimation may also occur. This report is the result of a routine successive DNA restriction fragment length polymorphism (RFLP) analysis of M tuberculosis isolated in Norway.Fifteen immigrants belonging to the same community were notified with tuberculosis during February to September 2003. The mycobacterial isolates were analysed by RFLP.All 15 patients had social contact with each other and 13 belonged to the same church community. A total of 14 cultures were positive for M tuberculosis. Among these isolates, six different genotypes were found. Five patients had not acquired the infection from the putative source.Reactivation of tuberculosis may occur in contacts during the development of an outbreak. In such situations, traditional contact investigations may overestimate the rate of transmission found by genotyping of M tuberculosis. When cultures are unavailable and presumed drug susceptibility patterns are based on that of contacts, such overestimation may lead to incorrect treatment of a patient. Contact investigations must be combined with genotyping of M tuberculosis to conclude how tuberculosis is transmitted. This is especially important in persons with several risk factors for infection.
The Expansion of mtDNA Haplogroup L3 within and out of Africa
Authors: P. Soares, F. Alshamali, J. B. Pereira, V. Fernandes, N. M. Silva, C. Afonso, M. D. Costa, E. Musilova, V. Macaulay, M. B. Richards, V. Cerny, L. Pereira
Journal: Molecular Biology and Evolution (2011)

Although fossil remains show that anatomically modern humans dispersed out of Africa into the Near East ∼100 to 130 ka, genetic evidence from extant populations has suggested that non-Africans descend primarily from a single successful later migration. Within the human mitochondrial DNA (mtDNA) tree, haplogroup L3 encompasses not only many sub-Saharan Africans but also all ancient non-African lineages, and its age therefore provides an upper bound for the dispersal out of Africa. An analysis of 369 complete African L3 sequences places this maximum at ∼70 ka, virtually ruling out a successful exit before 74 ka, the date of the Toba volcanic supereruption in Sumatra. The similarity of the age of L3 to its two non-African daughter haplogroups, M and N, suggests that the same process was likely responsible for both the L3 expansion in Eastern Africa and the dispersal of a small group of modern humans out of Africa to settle the rest of the world. The timing of the expansion of L3 suggests a link to improved climatic conditions after ∼70 ka in Eastern and Central Africa rather than to symbolically mediated behavior, which evidently arose considerably earlier. The L3 mtDNA pool within Africa suggests a migration from Eastern Africa to Central Africa ∼60 to 35 ka and major migrations in the immediate postglacial again linked to climate. The largest population size increase seen in the L3 data is 3–4 ka in Central Africa, corresponding to Bantu expansions, leading diverse L3 lineages to spread into Eastern and Southern Africa in the last 3–2 ka.
Acquired Ultrafiltration Dysfunction in Peritoneal Dialysis Patients
Authors: Peter J. Margetts, David N. Churchill
Journal: Journal of the American Society of Nephrology (2002)

Eberhard Ritz 

Peritoneal dialysis (PD) is used by over 100,000 end-stage renal disease (ESRD) patients worldwide, accounting for approximately 15% of the dialysis population ([1][1]). The relative value of PD is still uncertain and contested due to a lack of randomized clinical trials comparing
Loss of the Pro-Apoptotic BH3-only Bcl-2 Family Member Bim Inhibits BCR Stimulation–induced Apoptosis and Deletion of Autoreactive B Cells
Authors: Anselm Enders, Philippe Bouillet, Hamsa Puthalakath, Yuekang Xu, David M. Tarlinton, Andreas Strasser
Journal: The Journal of Experimental Medicine (2003)

During development, the stochastic process assembling the genes encoding antigen receptors invariably generates B and T lymphocytes that can recognize self-antigens. Several mechanisms have evolved to prevent the activation of these cells and the concomitant development of autoimmune disease. One such mechanism is the induction of apoptosis in developing or mature B cells by engagement of the B cell antigen receptor (BCR) in the absence of T cell help. Here we report that B lymphocytes lacking the pro-apoptotic Bcl-2 family member Bim are refractory to apoptosis induced by BCR ligation in vitro. The loss of Bim also inhibited deletion of autoreactive B cells in vivo in two transgenic systems of B cell tolerance. Bim loss prevented deletion of autoreactive B cells induced by soluble self-antigen and promoted accumulation of self-reactive B cells developing in the presence of membrane-bound self-antigen, although their numbers were considerably lower compared with antigen-free mice. Mechanistically, we determined that BCR ligation promoted interaction of Bim with Bcl-2, inhibiting its survival function. These findings demonstrate that Bim is a critical player in BCR-mediated apoptosis and in B lymphocyte deletion.