tbuckley/cabot-search huggingface dataset:
H-2 effects on cell-cell interactions in the response to single non-H-2 alloantigens. II. H-2 D region control of H-7.1-specific stimulator function in mixed lymphocyte culture and susceptibility to lysis by H-7.1- specific cytotoxic cells
Authors: PJ Wettstein, JA Frelinger
Journal: The Journal of Experimental Medicine (1977)

The relative immunogenicity of the H-7.1 alloantigen has been shown in a previous communication to be regulated by a gene in the D region of the mouse major histocompatibility (H-2) complex. The level of relative immunogenicity was inferred from survival times of H-7.1-incompatible skin grafts donated by donors with different H-2 haplotype origins of H-2D region genes. In this communication we report the results of an extension of these previous investigations into the possible role of H-2D region genes in controlling the capacity of H-7.1-incompatible lymphocytes to stimulate H-7.1-speciflc mixed lymphocyte culture proliferation and generation of cytotoxic effector cells. The results reported herein demonstrate that the H-2D genotype of H-7.1-incompatible stimulator cells determines the relative H-7.1-specific capacity of those lymphocytes to stimulate H-7.1-specific proliferation of in vivo primed responder T cells in secondary mixed lymphocyte culture. H-2D(b)-bearing, H-7.l-incompatible stimulators were significantly more effective in stimulating H-7.1-specific proliferation than H-2D(d)-bearing stimulators. As expected, H-2D(b), H-7.1-in-compatible stimulators were also more effective than H-2D(d) a stimulators in generating H-7.1- specific cytotoxic effector cells. Further, the susceptibility of (51)Cr- labeled, H-7.1-incompatible lymphoblast targets to H-7.1-specific lysis was similarly regulated by an H-2D gene. Reciprocal H-2 restriction (F(1) cells are capable of killing only the cells bearing the immunizing cell parental H-2 haplotype) observed by other investigators for cytolysis of non-H-2-incompatible targets was not observed. H-2D a-bearing, H-7.1- incompatible stimulators stimulated generation of cytotoxic effectors capable of detectably lysing H-2D(b) but not H-2D(a)-bearing, H-7.1- incompatible targets. The impact of these observations on the proposed models for H-2 restriction of non-H-2 histocompatibility antigen-specific cytolysis is discussed.
Cisplatin Plus Gemcitabine Versus a Cisplatin-Based Triplet Versus Nonplatinum Sequential Doublets in Advanced Non–Small-Cell Lung Cancer: A Spanish Lung Cancer Group Phase III Randomized Trial
Authors: V. Alberola, C. Camps, M. Provencio, D. Isla, R. Rosell, C. Vadell, I. Bover, A. Ruiz-Casado, P. Azagra, U. Jiménez, J.L. González-Larriba, P. Diz, F. Cardenal, A. Artal, A. Carrato, S. Morales, J.J. Sánchez, R. de las Peñas, E. Felip, G. López-Vivanco
Journal: Journal of Clinical Oncology (2003)

To compare the survival benefit obtained with cisplatin plus gemcitabine, a cisplatin-based triplet, and nonplatinum sequential doublets in advanced non-small-cell lung cancer (NSCLC).Stage IIIB to IV NSCLC patients were randomly assigned to receive cisplatin 100 mg/m2 day 1 plus gemcitabine 1,250 mg/m2 days 1 and 8, every 3 weeks for six cycles (CG); cisplatin 100 mg/m2 day 1 plus gemcitabine 1,000 mg/m2 and vinorelbine 25 mg/m2 days 1 and 8, every 3 weeks for six cycles (CGV); or gemcitabine 1,000 mg/m2 plus vinorelbine 30 mg/m2 days 1 and 8, every 3 weeks for three cycles, followed by vinorelbine 30 mg/m2 days 1 and 8 plus ifosfamide 3 g/m2 day 1, every 3 weeks for three cycles (GV-VI).Five hundred fifty-seven patients were assigned to treatment (182 CG, 188 CGV, 187 GV-VI). Response rates were significantly inferior for the nonplatinum sequential doublet (CG, 42%; CGV, 41%; GV-VI, 27%; CG v GV-VI, P =.003). No differences in median survival or time to progression were observed. Toxicity was higher for the triplet: grade 3 to 4 neutropenia (GC, 32%; CGV, 57%; GV-VI, 27%; P <.05); neutropenic fever (CG, 4%; CGV, 19%; GV-VI, 5%; P <.0001); grade 3 to 4 thrombocytopenia (CG, 19%; CGV, 23%; GV-VI, 3%; P =.0001); and grade 3 to 4 emesis (GC, 22%; GCV, 32%; GV-VI, 6%; P <.0001).On the basis of these results, CG remains a standard regimen for first-line treatment of advanced NSCLC.
Inhibition of MMP-9 expression by PPAR activators in human bronchial epithelial cells
Authors: M Hetzel
Journal: Thorax (2003)

<h3>Abstract</h3> Single-cell RNA-seq (scRNA-seq) profiles gene expression with a resolution that empowers depiction of cell atlas in complex systems. Here, we developed a stepwise computational pipeline SCAPTURE to identify, evaluate, and quantify cleavage and polyadenylation sites (PASs) from 3' tag-based scRNA-seq. SCAPTURE detects PASs <i>de novo</i> in single cells with high sensitivity and accuracy, enabling detection of previously unannotated PASs. Quantified alternative PAS transcripts refine cell identities, enriching information extracted from scRNA-seq.
Do we need controlled clinical trials in pulmonary arterial hypertension?
Authors: N. Galiè
Journal: European Respiratory Journal (2001)

<b>Introduction:</b> congenital bronchopulmonary malformations are uncommon but potentially life-threatening. <b>Methods:</b> 73 patients were evaluated for primary or secondary bronchopulmonary abnormalities, in 2018. <b>Results:</b> 10 had static airway anomalies: congenital subglottic stenosis (n=2), left bronchial stenosis (n=4), congenital tracheal stenosis (n=4). 23 had dynamic airway abnormalities: tracheomalacia (n=21), laryngomalacia (n=2), bronchomalacia (n=3). 27 had bronchial tree and lung development anomalies: left bronchial atresia (n=2), right bronchial atresia (n=2), supernumerary bronchus (n=2), “tracheal” bronchus (n=4), bronchus rotation (n=1), cystic adenomatoid malformation (n=6), bronchogenic cyst (n=1), congenital lobar emphysema (n=2), lung hypoplasia (4), lung hypo-dysplasia (n=2). 8 patients had diaphragmatic anomalies: congenital diaphragmatic hernias (n=6) and relaxation (n=2). 35 had vascular anomalies determining trachea-bronchial tree involvement: double aortic arch (n=7), right aortic arch and arteria lusoria with or without Kommerell diverticulum (n=respectively 9 and 6) were the most frequent. 56 children had respiratory symptoms. All the woman performed a prenatal US: 18 detected a malformation, 1 was false negative. 6/7 fetal cardiac US were positive. 69 patients underwent chest CT scan, all were positive. 38 patients underwent flexible laryngo-tracheo-bronchoscopy (LTBS), 35 were positive. Surgery was performed in 31 children. <b>Conclusions:</b> we propose the description of large sample of pediatric patients with congenital bronchopulmonary malformations, followed from one Center. Chest CT and LTBS are important investigation in congenital airway anomalies.
Genomic Biomarkers Correlate with HLA-Identical Renal Transplant Tolerance
Authors: Joseph R. Leventhal, James M. Mathew, Daniel R. Salomon, Sunil M. Kurian, Manikkam Suthanthiran, Anat Tambur, John Friedewald, Lorenzo Gallon, Jane Charette, Josh Levitsky, Yashpal Kanwar, Michael Abecassis, Joshua Miller
Journal: Journal of the American Society of Nephrology (2013)

The ability to achieve immunologic tolerance after transplantation is a therapeutic goal. Here, we report interim results from an ongoing trial of tolerance in HLA-identical sibling renal transplantation. The immunosuppressive regimen included alemtuzumab induction, donor hematopoietic stem cells, tacrolimus/mycophenolate immunosuppression converted to sirolimus, and complete drug withdrawal by 24 months post-transplantation. Recipients were considered tolerant if they had normal biopsies and renal function after an additional 12 months without immunosuppression. Of the 20 recipients enrolled, 10 had at least 36 months of follow-up after transplantation. Five of these 10 recipients had immunosuppression successfully withdrawn for 16-36 months (tolerant), 2 had disease recurrence, and 3 had subclinical rejection in protocol biopsies (nontolerant). Microchimerism disappeared after 1 year, and CD4(+)CD25(high)CD127(-)FOXP3(+) regulatory T cells and CD19(+)IgD/M(+)CD27(-) B cells were increased through 5 years post-transplantation in both tolerant and nontolerant recipients. Immune/inflammatory gene expression pathways in the peripheral blood and urine, however, were differentially downregulated between tolerant and nontolerant recipients. In summary, interim results from this trial of tolerance in HLA-identical renal transplantation suggest that predictive genomic biomarkers, but not immunoregulatory phenotyping, may be able to discriminate tolerant from nontolerant patients.
Metabolism of formycin B by Leishmania amastigotes in vitro. Comparative metabolism in infected and uninfected human macrophages.
Authors: J D Berman, P Rainey, D V Santi
Journal: The Journal of Experimental Medicine (1983)

Formycin B is metabolized by cutaneous Leishmania amastigotes within cultured human macrophages to give formycin B 5'-monophosphate and formycin A 5'-mono-, di-, and triphosphates. Formycin A is also incorporated into RNA. The activity of formycin B against amastigotes was correlated with the levels of formycin A metabolites formed in the parasites. Uninfected macrophages also convert formycin B into the same products, but the levels are markedly lower than those seen in infected macrophages. The results suggest that a sufficient therapeutic index exists to warrant consideration of formycin B as an anti-leishmanial drug in humans.
DNA Damage Persistence as Determinant of Tumor Sensitivity to the Combination of Topo I Inhibitors and Telomere-Targeting Agents
Authors: Annamaria Biroccio, Manuela Porru, Angela Rizzo, Erica Salvati, Carmen D'Angelo, Augusto Orlandi, Daniela Passeri, Marco Franceschin, Malcolm F.G. Stevens, Eric Gilson, Giovanni Beretta, Gabriella Zupi, Claudio Pisano, Franco Zunino, Carlo Leonetti
Journal: Clinical Cancer Research (2011)

We previously reported that the G-quadruplex (G4) ligand RHPS4 potentiates the antitumor activity of camptothecins both in vitro and in tumor xenografts. The present study aims at investigating the mechanisms involved in this specific drug interaction.Combination index test was used to evaluate the interaction between G4 ligands and standard or novel Topo I inhibitors. Chromatin immunoprecipitation was performed to study the presence at telomeres of various types of topisomerase, while immunolabeling experiments were performed to measure the activation of DNA damage both in vitro and in tumor xenografts.We report that integration of the Topo I inhibitor SN-38, but not the Topo II poison doxorubicin with telomere-based therapy is strongly effective and the sequence of drug administration is critical in determining the synergistic interaction, impairing the cell ability to recover from drug-induced cytotoxicity. The synergistic effect of this combination was also observed by using novel camptothecins and, more interestingly, mice treated with ST1481/RHPS4 combination showed an inhibition and delay of tumor growth as well as an increased survival. The study of the mechanism(s) revealed that treatment with G4 ligands increased Topo I at the telomeres and the functional relevance of this observation was directly assessed by showing that standard and novel camptothecins stabilized DNA damage both in vitro and in xenografts.Our results demonstrate an outstanding efficacy of Topo I inhibitors/G4 ligands combination, which likely reflects an enhanced and persistent activation of DNA damage response as a critical determinant of the therapeutic improvement.
Endocrinology of sex steroid hormones and cell dynamics in the periodontium
Authors: Angelo Mariotti, Michael Mawhinney
Journal: Periodontology 2000 (2012)

Numerous scientific studies assert the existence of hormone-sensitive periodontal tissues. Tissue specificity of hormone localization, identification of hormone receptors and the metabolism of hormones are evidence that periodontal tissues are targets for sex steroid hormones. Although the etiologies of periodontal endocrinopathies are diverse, periodontal pathologies are primarily the consequence of the actions and interactions of sex steroid hormones on specific cells found in the periodontium. This review provides a broad overview of steroid hormone physiology, evidence for the periodontium being a target tissue for sex steroid hormones and theories regarding the roles of sex steroid hormones in periodontal pathogenesis. Using this information, a teleological argument for the actions of steroid hormones in the periodontium is assessed.
Latency of the Human Herpesviruses
Authors: Kenneth D. Croen
Journal: Annual Review of Medicine (1991)

The herpesviruses are ubiquitous pathogens that establish latent infections and can reactivate to produce recurrent disease. The fact that clinical recurrences are infrequent in most healthy individuals indicates that potent regulatory mechanisms must exist to ensure viral latency. Rapid progress is being made toward understanding the pathogenesis of latency and reactivation and is the subject of this review.
Misidentification of ampicillin–sulbactam heteroresistance in Acinetobacter baumannii strains from ICU patients
Authors: Vincenzo Savini, Chiara Catavitello, Marzia Talia, Fabio Febbo, Andrea Balbinot, Arianna Pompilio, Giovanni Di Bonaventura, Raffaele Piccolomini, Domenico D'Antonio
Journal: Journal of Infection (2009)
A rare cause of dysphagia in a young Caucasian man
Authors: Paolo Cecinato, Ramona Zecchini, Maurizio Cavina, Moira Ragazzi, Romano Sassatelli
Journal: Gut (2014)

A 23-years-old Caucasian man was admitted to our institution for progressive weight loss and dysphagia. His past medical history was apparently unremarkable, including his laboratory tests, except for the presence of uninvestigated episodes of dysphagia he had since childhood.

The patient performed a barium oesophagogram which showed oesophageal dysmotility (figure 1A) followed by an oesophagogastroduodenoscopy, demonstrating the presence of multiple tubular duplications of the middle and distal third of the oesophagus, with a contextual stricture of the lumen crossable only with ultrathin endoscope (GIF XP160; Olympus, Tokyo, Japan) (figure 2 and see online supplementary video 1). The gastroduodenal mucosa appeared regular. Multiple biopsies of the proximal two-thirds of the oesophagus were performed. A thoracic CT …
Mutations and Deletions of the <i>TP53</i> Gene Predict Nonresponse to Treatment and Poor Outcome in First Relapse of Childhood Acute Lymphoblastic Leukemia
Authors: Jana Hof, Stefanie Krentz, Claudia van Schewick, Gabriele Körner, Shabnam Shalapour, Peter Rhein, Leonid Karawajew, Wolf-Dieter Ludwig, Karl Seeger, Günter Henze, Arend von Stackelberg, Christian Hagemeier, Cornelia Eckert, Renate Kirschner-Schwabe
Journal: Journal of Clinical Oncology (2011)

In the clinical management of children with relapsed acute lymphoblastic leukemia (ALL), treatment resistance remains a major challenge. Alterations of the TP53 gene are frequently associated with resistance to chemotherapy, but their significance in relapsed childhood ALL has remained controversial because of small studies.Therefore, we systematically studied 265 first-relapse patients enrolled in the German Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Mü nster 2002 (ALL-REZ BFM 2002) trial for sequence and copy number alterations of the TP53 gene by using direct sequencing and multiplex ligation-dependent probe amplification.We observed copy number and sequence alterations of TP53 in 12.4% (27 of 218) of patients with B-cell precursor ALL and 6.4% (three of 47) of patients with T-cell ALL relapse. Backtracking to initial ALL in 23 matched samples revealed that 54% of all TP53 alterations were gained at relapse. Within B-cell precursor ALL, TP53 alterations were consistently associated with nonresponse to chemotherapy (P < .001) and poor event-free survival (P < .001) and overall survival rates (P = .002). TP53 alterations also had a significant impact on survival within intermediate-risk (S2) and high-risk (S3/S4) relapse patients (P = .007 and P = .019, respectively). This prognostic significance of TP53 alterations was confirmed in multivariate analysis. Besides their clinical impact, TP53 alterations were associated with a higher fraction of leukemic cells in S/G(2)-M phase of the cell cycle at relapse diagnosis.Alterations of the TP53 gene are of particular importance in the relapse stage of childhood ALL, in which they independently predict high risk of treatment failure in a significant number of patients. Therefore, they will aid in future risk assessment of children with ALL relapse.
Antitumor Activity of Immunotoxins with T-Cell Receptor–like Specificity against Human Melanoma Xenografts
Authors: Eynav Klechevsky, Michael Gallegos, Galit Denkberg, Karolina Palucka, Jacques Banchereau, Cyril Cohen, Yoram Reiter
Journal: Cancer Research (2008)

Abstract In this study, we have explored the use of Fab-toxin proteins (immunotoxin) to target antigen-specific MHC-peptide complexes of in vitro and in vivo cancer cells. A human phage display library was used to screen for T-cell receptor (TCR)–like antibodies that are highly specific for the peptide melanoma-associated antigen MART-126-35 presented by HLA-A201. We also used previously selected TCR-like antibodies specific for the peptide melanoma-associated antigen gp100280-288 presented by HLA-A201. The recombinant immunotoxin constructs were generated by fusing the targeting Fab fragment to a truncated form of Pseudomonas exotoxin, PE38KDEL. These immunotoxins bound with high affinity to the EBV-transformed JY cell line pulsed with the aforementioned peptides and internalized within 30 min. A significant inhibition of protein synthesis, which resulted in cell death, was detected at 24 h. MART-1–specific and gp100-specific immunotoxins bound and killed HLA-A201 melanoma MART-1+ and gp100+ cell lines that were presented at natural levels but do not bind to HLA-A201− or to HLA-A201+ MART-1− and gp100− cell lines. In severe combined immunodeficient mice, MART-1 and gp100 immunotoxins significantly and discriminately inhibited human melanoma growth. These results show that MHC class I/peptide complexes can serve as a specific target for passive immunotherapy of cancer. [Cancer Res 2008;68(15):6360–7]
Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1
Authors: Marion G Ott, Manfred Schmidt, Kerstin Schwarzwaelder, Stefan Stein, Ulrich Siler, Ulrike Koehl, Hanno Glimm, Klaus Kühlcke, Andrea Schilz, Hana Kunkel, Sonja Naundorf, Andrea Brinkmann, Annette Deichmann, Marlene Fischer, Claudia Ball, Ingo Pilz, Cynthia Dunbar, Yang Du, Nancy A Jenkins, Neal G Copeland, Ursula Lüthi, Moustapha Hassan, Adrian J Thrasher, Dieter Hoelzer, Christof von Kalle, Reinhard Seger, Manuel Grez
Journal: Nature Medicine (2006)
Activation of the Steroid and Xenobiotic Receptor (Human Pregnane X Receptor) by Nontaxane Microtubule-Stabilizing Agents
Authors: Sridhar Mani, Haiyan Huang, Sumathy Sundarababu, Wenjing Liu, Ganjam Kalpana, Amos B. Smith, Susan B. Horwitz
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Because induction of drug efflux transporters is one of the major underlying mechanisms of drug resistance in cancer chemotherapy, and human pregnane X receptor (hPXR) is one of the principal “xenobiotic” receptors whose activation induces transporter and drug-metabolizing enzyme gene transcription, it would be ideal to develop chemotherapy drugs that do not activate hPXR. This report describes studies undertaken to explore the characteristics of hPXR stimulation and mechanisms of drug-receptor interactions in vitro with new anti-tubulin drugs. Experimental Design: In vitro transient transcription, glutathione S-transferase pull-down assays, and mammalian one-hybrid and two-hybrid systems were used to explore drug-receptor interactions. Loss of righting reflex was used to assess effects of drugs on PXR activity in vivo. Results: The current study showed that paclitaxel, discodermolide, and an analogue of epothilone B, BMS-247550, induced CYP3A4 protein expression in HepG2 hepatoma cells. Transient transcription assays of a luciferase reporter in the presence and absence of a GAL4-steroid and xenobiotic receptor (SXR) plasmid in HepG2 cells showed that these drugs activate hPXR. This was not true for the inactive analogue of paclitaxel, baccatin III, or for an analogue of epothilone A, analogue 5, none of which stabilizes microtubules. To determine the mechanisms by which paclitaxel, discodermolide, and BMS-247550 activate hPXR, a mammalian two-hybrid assay was done using VP16SRC-1 (coactivator) and GAL4-SXR. SRC-1 preferentially augmented the effects of these drugs on hPXR. Expression of SMRT (corepressor) but not NCoR suppressed the drug-induced activation of SXR by ∼50%, indicating a selectivity in corepressor interaction with hPXR. These drugs resulted in shortened duration of loss of righting reflex in vivo, indicating drug-induced activation of PXR in mice. Conclusion: These findings suggest that activation of hPXR with selective displacement of corepressors is an important mechanism by which microtubule-stabilizing drugs induce drug-metabolizing enzymes both in vitro and in vivo.
Paclitaxel Decreases the Interstitial Fluid Pressure and Improves Oxygenation in Breast Cancers in Patients Treated With Neoadjuvant Chemotherapy: Clinical Implications
Authors: Alphonse G. Taghian, Rita Abi-Raad, Sherif I. Assaad, Adrian Casty, Marek Ancukiewicz, Eren Yeh, Peryhan Molokhia, Khaled Attia, Timothy Sullivan, Irene Kuter, Yves Boucher, Simon N. Powell
Journal: Journal of Clinical Oncology (2005)

It has been hypothesized that tumors with high interstitial fluid pressure (IFP) and/or hypoxia respond poorly to chemotherapy (CT) because of poor drug delivery. Preclinical studies have shown that paclitaxel reduces the IFP and improves the oxygenation (pO(2)) of tumors. Our aim is to evaluate the IFP and pO(2) before and after neoadjuvant CT using sequential paclitaxel and doxorubicin in patients with breast cancer tumors of >/= 3 cm.Patients were randomly assigned, according to an institutional review board-approved phase II protocol, to receive neoadjuvant sequential CT consisting of either four cycles of dose-dense doxorubicin at 60 mg/m(2) every 2 weeks followed by nine cycles of weekly paclitaxel at 80 mg/m(2) (group 1) or vice versa, with paclitaxel administered before doxorubicin (group 2). Patients were re-evaluated clinically and radiologically. The IFP (wick-in-needle technique) and pO(2) (Eppendorf) were measured in tumors at baseline and after completing the administration of the first and second drug.IFP and pO(2) were measured in 54 patients at baseline and after the first CT. Twenty-nine and 25 patients were randomly assigned to groups 1 and 2, respectively. Paclitaxel, when administered first, decreased the mean IFP by 36% (P = .02) and improved the tumor pO(2) by almost 100% (P = .003). In contrast, doxorubicin did not have a significant effect on either parameter. This difference was independent of the tumor size or response measured by ultrasound.Paclitaxel significantly decreased the IFP and increased the pO(2), whereas doxorubicin did not cause any significant changes. Tumor physiology could potentially be used to optimize the sequence of neoadjuvant CT in breast cancer.
Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions
Authors: David Lawrence, Zahra Shahrokh, Scot Marsters, Kirsten Achilles, Danny Shih, Barbara Mounho, Kenneth Hillan, Klara Totpal, Laura DeForge, Peter Schow, Jeffrey Hooley, Steve Sherwood, Roger Pai, Susan Leung, Lolo Khan, Brian Gliniak, Jeanine Bussiere, Craig A. Smith, Stephen S. Strom, Sean Kelley, Judith A. Fox, Deborah Thomas, Avi Ashkenazi
Journal: Nature Medicine (2001)