tbuckley/cabot-search huggingface dataset:
Phylogenomics of C4 Photosynthesis in Sedges (Cyperaceae): Multiple Appearances and Genetic Convergence
Authors: G. Besnard, A. M. Muasya, F. Russier, E. H. Roalson, N. Salamin, P.-A. Christin
Journal: Molecular Biology and Evolution (2009)

C4 photosynthesis is an adaptive trait conferring an advantage in warm and open habitats. It originated multiple times and is currently reported in 18 plant families. It has been recently shown that phosphoenolpyruvate carboxylase (PEPC), a key enzyme of the C4 pathway, evolved through numerous independent but convergent genetic changes in grasses (Poaceae). To compare the genetics of multiple C4 origins on a broader scale, we reconstructed the evolutionary history of the C4 pathway in sedges (Cyperaceae), the second most species-rich C4 family. A sedge phylogeny based on two plastome genes (rbcL and ndhF) has previously identified six fully C4 clades. Here, a relaxed molecular clock was used to calibrate this tree and showed that the first C4 acquisition occurred in this family between 19.6 and 10.1 Ma. According to analyses of PEPC-encoding genes (ppc), at least five distinct C4 origins are present in sedges. Two C4Eleocharis species, which were unrelated in the plastid phylogeny, acquired their C4-specific PEPC genes from a single source, probably through reticulate evolution or a horizontal transfer event. Acquisitions of C4 PEPC in sedges have been driven by positive selection on at least 16 codons (3.5% of the studied gene segment). These sites underwent parallel genetic changes across the five sedge C4 origins. Five of these sites underwent identical changes also in grass and eudicot C4 lineages, indicating that genetic convergence is most important within families but that identical genetic changes occurred even among distantly related taxa. These lines of evidence give new insights into the constraints that govern molecular evolution.
Safety and Clinical Effect of Subcutaneous Human Interleukin-21 in Patients with Metastatic Melanoma or Renal Cell Carcinoma: A Phase I Trial
Authors: Henrik Schmidt, Janet Brown, Ulrik Mouritzen, Peter Selby, Kirsten Fode, Inge Marie Svane, Graham P. Cook, David Hal Mollerup, Poul F. Geertsen
Journal: Clinical Cancer Research (2010)

Abstract Purpose: This phase I study in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC) evaluated the safety and maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of s.c. treatment of human recombinant interleukin 21 (IL-21). Experimental Design: Phase I dose-escalation trial with treatment of three to six patients at each dose level, escalating from 3 to 300 μg/kg. Treatment was administered s.c. on an outpatient basis 3 days per week for 8 or 16 weeks. Results: Twenty-six patients entered the study. Recombinant IL-21 was generally well tolerated, and dose-limiting toxicities (DLT) were first seen at dose levels of 200 and 300 μg/kg. The following four DLTs were observed in three patients: increased transaminases, increased hyperbilirubinemia, hypersensitivity reaction, and lethargy. The MTD was declared to be 200 μg/kg, although five of seven patients at the 300 μg/kg dose level experienced no DLTs. A treatment-related effect on soluble CD25 was observed at all dose levels and increased with dose level. Furthermore, higher doses induced interferon-γ, perforin, and granzyme B mRNA expression in peripheral blood, and granzyme B protein expression in both CD8+ T cells and natural killer cells, consistent with the activation of cytotoxic lymphocytes. Three patients, one patient with MM and two with RCC, obtained a partial response. Conclusion: Outpatient treatment with s.c. administered IL-21 was tolerated and had dose-dependent pharmacodynamics. rIL-21 showed antitumor activity in patients with MM and RCC. Clin Cancer Res; 16(21); 5312–9. ©2010 AACR.
Dissecting Molecular Mechanisms of Synergy Between IL-13 and IL-17A in Severe Asthma
Authors: Sara L. Stoffers, Stephane Lajoie, Adelaide G. van Lier, Xue Zhang, Umasundari Sivaprasad, Melinda Butsch Kovacic, Marsha Wills-Karp, Ian P. Lewkowich
Journal: Journal of Allergy and Clinical Immunology (2015)
Piecing together the problems in diagnosing low-level chromosomal mosaicism
Authors: Caroline Robberecht, Jean-Pierre Fryns, Joris Robert Vermeesch
Journal: Genome Medicine (2010)

Low-level somatic chromosomal mosaicism, which usually arises from post-zygotic errors, is a known cause of several well defined genetic syndromes and has been implicated in various multifactorial diseases. It is, however, not easy to diagnose, as various physical and technical factors complicate its identification.
Use of investigations in lower respiratory tract infection in the community: a European survey
Authors: M Woodhead, G Gialdroni Grassi, GJ Huchon, P Leophonte, F Manresa, T Schaberg
Journal: European Respiratory Journal (1996)

A questionnaire survey was performed on the use of investigations and their impact on treatment of adult lower respiratory tract infection in the community. Data on the management of 2,056 such infections were obtained simultaneously from general practitioners in France, Germany, Italy, Spain and the UK. Diagnostic tests were only performed in 29% of cases. Chest radiographs were performed most frequently (22%), followed by peripheral blood white cell count (15%) and microbiological examination of sputum (7%), with major differences being found in the frequency of these tests both by clinical diagnosis and country. A change in initial antibiotic therapy was made in 12% of cases, with use of investigation being significantly linked to such changes. Second- and third-line antibiotics were significantly different to first-line therapy, with macrolides the most frequently prescribed second-line and quinolones the most frequently prescribed third-line antibiotics.
Phase I and pharmacologic study of 9-aminocamptothecin colloidal dispersion formulation in patients with refractory or relapsed acute leukemia
Authors: N. Vey, H. Kantarjian, H. Tran, M. Beran, S. O'Brien, C. Bivins, F. Giles, J. Cortes, B. Cheson, S. Arbuck, E. Estey
Journal: Annals of Oncology (1999)
Pleuropulmonary complications of pancreatitis
Authors: M. D. Kaye
Journal: Thorax (1968)

Pancreatitis, in common with many other upper abdominal diseases, often leads to pleuropulmonary complications. Radiological evidence of pleuropulmonary abnormality was found in 55% of 58 cases examined retrospectively. The majority of such abnormalities are not specific for pancreatitis; but a particular category of pleural effusions, rich in pancreatic enzymes, is a notable exception. A patient with this type of effusion, complicated by a spontaneous bronchopleural fistula and then by an empyema, is reported. The literature relating to pancreatic enzyme-rich pleural effusions (pathognomonic of pancreatitis) is reviewed. Of several possible mechanisms involved in pathogenesis, transdiaphragmatic lymphatic transfer of pancreatic enzymes, intrapleural rupture of mediastinal extensions of pseudocysts, and diaphragmatic perforation are the most important. The measurement of pleural fluid amylase, at present little employed in this country, has considerable diagnostic value. Enzyme-rich effusions are more commonly left-sided, are often blood-stained, are frequently associated with pancreatic pseudocysts, and—if long standing—may be complicated by a bronchopleural fistula.
A prospective coagulation study including resistance to activated protein C and mutations in factors V and II in venous leg ulcers
Authors: None Ribeaudeau, None Senet, None Cayuela, None Fund, None Paul, None Robert, None Scrobohaci, None Dubertret
Journal: British Journal of Dermatology (1999)

Hypercoagulable states have been reported to be associated with venous leg ulcers. In an attempt to investigate the prevalence of hypercoagulable states in patients with venous leg ulcers, we performed a prospective case-control study for the presence of coagulation defects in such patients, including resistance to activated protein C (APC), factor V Leiden mutation and a newly described mutation in factor II. Results were compared with those obtained in a control group. APC resistance was found in four of 33 patients tested, but only one was found to be heterozygous for the factor V Leiden mutation. Factor II mutation was found in two of 30 patients tested. Our findings show that the prevalence of coagulation abnormalities is not different in patients with venous leg ulcers from controls in our study, suggesting that only selected patients with venous ulcers and a history of recurrent deep venous thrombosis should be investigated for the presence of coagulation defects.
Broadly targeted human cytomegalovirus-specific CD4<b>+</b> and CD8<b>+</b> T cells dominate the memory compartments of exposed subjects
Authors: Andrew W. Sylwester, Bridget L. Mitchell, John B. Edgar, Cara Taormina, Christian Pelte, Franziska Ruchti, Paul R. Sleath, Kenneth H. Grabstein, Nancy A. Hosken, Florian Kern, Jay A. Nelson, Louis J. Picker
Journal: The Journal of Experimental Medicine (2005)

Human cytomegalovirus (HCMV) infections of immunocompetent hosts are characterized by a dynamic, life-long interaction in which host immune responses, particularly of T cells, restrain viral replication and prevent disease but do not eliminate the virus or preclude transmission. Because HCMV is among the largest and most complex of known viruses, the T cell resources committed to maintaining this balance have never been characterized completely. Here, using cytokine flow cytometry and 13,687 overlapping 15mer peptides comprising 213 HCMV open reading frames (ORFs), we found that 151 HCMV ORFs were immunogenic for CD4+ and/or CD8+ T cells, and that ORF immunogenicity was influenced only modestly by ORF expression kinetics and function. We further documented that total HCMV-specific T cell responses in seropositive subjects were enormous, comprising on average ∼10% of both the CD4+ and CD8+ memory compartments in blood, whereas cross-reactive recognition of HCMV proteins in seronegative individuals was limited to CD8+ T cells and was rare. These data provide the first glimpse of the total human T cell response to a complex infectious agent and will provide insight into the rules governing immunodominance and cross-reactivity in complex viral infections of humans.
Response: Re: Hypertension as a Biomarker of Efficacy in Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib
Authors: B. I. Rini, D. P. Cohen, D. R. Lu, I. Chen, S. Hariharan, M. E. Gore, R. A. Figlin, M. S. Baum, R. J. Motzer
Journal: JNCI Journal of the National Cancer Institute (2011)
An Overview of Schizophrenia from a Predominantly Psychological Approach
Authors: SILVANO ARIETI
Journal: American Journal of Psychiatry (1974)

The author reviews the psychological approach to the study and treatment of schizophrenia—its psychogenesis, psychodynamics, psychological structures and mechanisms, and psychotherapy. He notes the areas in which changes of position or emphasis are called for, particularly the formation of the maternal image and the self-image, and discusses the new conceptions of schizophrenia that view it as simply a variety of human existence rather than as a disease.
Targeting the NF-κB and mTOR Pathways with a Quinoxaline Urea Analog That Inhibits IKKβ for Pancreas Cancer Therapy
Authors: Prakash Radhakrishnan, Vashti C. Bryant, Elizabeth C. Blowers, Rajkumar N. Rajule, Nagsen Gautam, Muhammad M. Anwar, Ashley M. Mohr, Paul M. Grandgenett, Stephanie K. Bunt, Jamie L. Arnst, Subodh M. Lele, Yazen Alnouti, Michael A. Hollingsworth, Amarnath Natarajan
Journal: Clinical Cancer Research (2013)

The presence of TNF-α in approximately 50% of surgically resected tumors suggests that the canonical NF-κB and the mTOR pathways are activated. Inhibitor of IκB kinase β (IKKβ) acts as the signaling node that regulates transcription via the p-IκBα/NF-κB axis and regulates translation via the mTOR/p-S6K/p-eIF4EBP axis. A kinome screen identified a quinoxaline urea analog 13-197 as an IKKβ inhibitor. We hypothesized that targeting the NF-κB and mTOR pathways with 13-197 will be effective in malignancies driven by these pathways.Retrospective clinical and preclinical studies in pancreas cancers have implicated NF-κB. We examined the effects of 13-197 on the downstream targets of the NF-κB and mTOR pathways in pancreatic cancer cells, pharmacokinetics, toxicity and tumor growth, and metastases in vivo.13-197 inhibited the kinase activity of IKKβ in vitro and TNF-α-mediated NF-κB transcription in cells with low-μmol/L potency. 13-197 inhibited the phosphorylation of IκBα, S6K, and eIF4EBP, induced G1 arrest, and downregulated the expression of antiapoptotic proteins in pancreatic cancer cells. Prolonged administration of 13-197 did not induce granulocytosis and protected mice from lipopolysaccharide (LPS)-induced death. Results also show that 13-197 is orally available with extensive distribution to peripheral tissues and inhibited tumor growth and metastasis in an orthotopic pancreatic cancer model without any detectable toxicity.These results suggest that 13-197 targets IKKβ and thereby inhibits mTOR and NF-κB pathways. Oral availability along with in vivo efficacy without obvious toxicities makes this quinoxaline urea chemotype a viable cancer therapeutic.
Understanding Parents’ Approaches to Care and Treatment of Children With Cancer When Standard Therapy Has Failed
Authors: Myra Bluebond-Langner, Jean Bello Belasco, Ann Goldman, Carmen Belasco
Journal: Journal of Clinical Oncology (2007)

To examine US and United Kingdom (UK) parents' approaches to care and treatment when standard therapy has failed and consider implications for clinical practice.We conducted a prospective, ethnographic study of parents, patients, and staff, including participant-observation; open-ended, semistructured interviews; and review of medical records at a US and UK pediatric oncology center. Thirty-four children (n = 17 US, 17 UK), whose disease had recurred with less than 30% chance of cure, were enrolled between March 2001 and June 2002 and followed until death (n = 11 US, 14 UK) or close of study in December 2005 (n = 6 US, 3 UK).There were no major differences between parents' approaches in the US and UK despite differences in health care systems, institutions, and parents' religion or ethnicity. All parents continued to have or request meetings with the oncologist and investigative procedures. No parent initiated discontinuation of cancer- or symptom-directed interventions. In 28 of 34 cases (13 US, 15 UK), parents continued to pursue cancer-directed therapies; in 16 of 28 cases (seven US, nine UK), parents initiated inquires beyond what was offered.Understanding parents' behavior requires attention to the reason and emotion they bring to decision making and their children's care, their unique responsibilities as parents, and what they learn throughout the illness. Parents do not see cancer-directed therapy and symptom-directed care as mutually exclusive, alternative approaches. Parents will not be constrained by what the oncologist offers. Physicians and parents discuss and negotiate care and treatment throughout the illness. Our findings suggest developing integrative care models incorporating cancer-directed, symptom-directed, and supportive care throughout the illness; they are most consistent with parents' approaches and advances in pediatric oncology.
Short-course FAC-M versus 1 year of CMFVP in node-positive, hormone receptor-negative breast cancer: an intergroup study.
Authors: G T Budd, S Green, R M O'Bryan, S Martino, M D Abeloff, J J Rinehart, R Hahn, J Harris, D Tormey, J O'Sullivan
Journal: Journal of Clinical Oncology (1995)

PURPOSE To compare 1 year of therapy with continuous cyclophosphamide, methotrexate, fluorouracil (5-FU), vincristine, and prednisone (CMFVP) with a short course of treatment with a doxorubicin-based regimen in the postsurgical adjuvant treatment of patients with hormone receptor-negative, node-positive breast cancer. PATIENTS AND METHODS Five-hundred thirty-one eligible women with hormone receptor-negative, node-positive breast cancer were randomized to receive either 1 year of therapy with CMFVP or 20 weeks of therapy with four 5-week courses of treatment with 5-FU, doxorubicin, cyclophosphamide, and methotrexate (FAC-M). RESULTS At a median follow-up time of 4.9 years, the two treatment arms cannot be demonstrated to be different with respect to overall survival (stratified log-rank, P = .27). The 5-year survival rate is 64% on the CMFVP arm and 61% on the FAC-M arm. CMFVP produces marginally superior disease-free survival (P = .06). The estimated 5-year disease-free survival rate is 55% for patients treated with CMFVP as opposed to 50% for patients treated with FAC-M. CONCLUSION Neither regimen was shown to be superior in terms of overall survival. Because the disease-free survival produced by CMFVP is marginally superior to that produced by FAC-M, we do not recommend FAC-M for further investigation or for routine use. Possible implications of this study are discussed in the context of other adjuvant chemotherapy trials.
Nonreversible airflow obstruction in life‐long nonsmokers with moderate to severe asthma
Authors: C.S. Ulrik, V. Backer
Journal: European Respiratory Journal (1999)

The aim of this longitudinal study was to assess the frequency of nonreversible airflow obstruction (NRAO) among adults with moderate to severe asthma, and to compare the decline of forced expiratory volume in one second (FEV1) in asthmatics with reversible and nonreversible airflow obstruction. Ninety-two (31 males) life-long nonsmokers with asthma participated in a 10-yr follow-up study; mean age 37 yrs (range 18-64) and duration of asthma 16 yrs (range 2-60) at enrolment. Case history, including use of asthma medication, was obtained, and pulmonary function, including diffusion capacity, was measured using standard techniques. At enrolment, all patients had typical symptoms and reversible airflow obstruction. (NRAO) was defined as FEV1 <80% predicted and change in deltaFEV1 after 5 mg salbutamol <9% pred. A total of 21 (23%) patients (mean age at enrolment 32 yrs) fulfilled the criteria for NRAO at the time of follow-up; current therapy was inhaled steroids (n=21, mean daily dose 1.5 mg), oral steroids (n=14), theophylline (n=20), oral beta2-agonist (n=6) and inhaled beta2-agonist. The patients with NRAO (n=21) had a steeper decline in FEV1 than the remaining patients (n=71, reversible airflow obstruction (RAO)), mean+/-SD 53+/-23 mL x yr(-1) and 36+/-21 mL x yr(-1), respectively (p<0.003). Increasing degree of bronchodilator reversibility (deltaFEV1% pred) at enrolment (p=0.002) and long-term treatment with oral corticosteroids (p=0.009) were associated with an increased risk for the presence of NRAO at follow-up. The comparison of data for NRAO and RAO patients (at follow-up) revealed no significant differences in mean values for total diffusion capacity (TL,CO), diffusion constant (KCO), or total lung capacity. The findings suggest that a subgroup of asthmatics may experience very steep rates of decline in forced expiratory volume in one second leading to severe nonreversible airflow obstruction, whereas no indication was found that long-standing asthma may lead to the development of emphysema.
Autologous Ectopic Grafting of Cryopreserved Testicular Tissue Preserves the Fertility of Prepubescent Monkeys That Receive Sterilizing Cytotoxic Therapy
Authors: Kirsi Jahnukainen, Jens Ehmcke, Mirja Nurmio, Stefan Schlatt
Journal: Cancer Research (2012)

Boys faced with future sterility as a result of the need of a sterilizing cancer therapy might avoid this fate by engraftment of cryopreserved immature testicular tissue after therapy is completed. Efforts to address this important survivorship issue have been encouraged by reports of the long-term survival and proliferation of human spermatogonia after xenotransplant of cryopreserved immature testicular tissue into immunocompromised murine hosts. However, spermatogenic arrest at the pachytene spermatocyte stage that occurs in this situation has been associated with a failure in sperm production. In this study, we used a prepubescent simian model to address the possibility that testicular tissue engraftment is insufficiently supported in the model to allow suitable maturation of germ cells. Briefly, we carried out autologous orthotopic grafting of cryopreserved testicular tissue from four prepubescent monkeys and one pubescent rhesus monkey after testicular irradiation and castration of the host animal. Five months after implantation of scrotal grafts, we determined that 3% to 7% of the autografts could be recovered with spermatogenesis proceeding through spermatozoa formation in 13% to 17% of the seminiferous tubules formed in the grafts. In contrast, Sertoli cell-only tubules were detected in parallel xenografts transplanted into immunocompromised mice. Our results show that cryopreservation of testicular tissue from prepubescent primates can maintain the fully functional capacity of spermatogonia to produce sperm, but that host conditions are critical for spermatogenic maturation. Furthermore, our results establish an initial perspective on the quantity of cryopreserved material needed to ensure success in preserving fertility through testicular tissue grafts.
Cyclic neutropenia in mammals
Authors: Jorge M. Pacheco, Arne Traulsen, Tibor Antal, David Dingli
Journal: American Journal of Hematology (2008)

Cyclic neutropenia (CN) has been well documented in humans and the gray collie. A recent model of the architecture and dynamics of hematopoiesis has been used to provide insights into the mechanism of cycling of this disorder. It provides a link between the cycling period and the cells where the mutated ELA2 is expressed. Assuming that the biologic defect in CN is the same in dogs, and the observation that the structure of hematopoiesis is invariant across mammals, we use allometric scaling techniques to correctly predict the period of cycling in the gray collie and extend it to other mammals from mice to elephants. This work provides additional support for the relevance of animal models to understand disease but cautions that disease dynamics in model animals are different and this has to be taken into consideration when planning experiments.
Calcitonin gene–related peptide inhibits Langerhans cell–mediated HIV-1 transmission
Authors: Yonatan Ganor, Anne-Sophie Drillet-Dangeard, Lucia Lopalco, Daniela Tudor, Giuseppe Tambussi, Nicolas Barry Delongchamps, Marc Zerbib, Morgane Bomsel
Journal: The Journal of Experimental Medicine (2013)

Upon its mucosal entry, human immunodeficiency virus type 1 (HIV-1) is internalized by Langerhans cells (LCs) in stratified epithelia and transferred locally to T cells. In such epithelia, LCs are in direct contact with peripheral neurons secreting calcitonin gene–related peptide (CGRP). Although CGRP has immunomodulatory effects on LC functions, its potential influence on the interactions between LCs and HIV-1 is unknown. We show that CGRP acts via its receptor expressed by LCs and interferes with multiple steps of LC-mediated HIV-1 transmission. CGRP increases langerin expression, decreases selected integrins, and activates NF-κB, resulting in decreased HIV-1 intracellular content, limited formation of LC–T cell conjugates, and elevated secretion of the CCR5-binding chemokine CCL3/MIP-1α. These mechanisms cooperate to efficiently inhibit HIV-1 transfer from LCs to T cells and T cell infection. In vivo, HIV-1 infection decreases CGRP plasma levels in both vaginally SHIV-challenged macaques and HIV-1–infected individuals. CGRP plasma levels return to baseline after highly active antiretroviral therapy. Our results reveal a novel path by which a peripheral neuropeptide acts at the molecular and cellular levels to limit mucosal HIV-1 transmission and suggest that CGRP receptor agonists might be used therapeutically against HIV-1.