tbuckley/cabot-search huggingface dataset:
Mechanisms of Activity of the TORC1 Inhibitor Everolimus in Waldenstrom Macroglobulinemia
Authors: Aldo M. Roccaro, Antonio Sacco, Xiaojing Jia, Ranjit Banwait, Patricia Maiso, Feda Azab, Ludmila Flores, Salomon Manier, Abdel Kareem Azab, Irene M. Ghobrial
Journal: Clinical Cancer Research (2012)

Abstract Purpose: The TORC1 inhibitor everolimus has previously shown significant activity as a single agent in hematologic malignancies, with reported responses of 30% to 70% in Waldenstrom macroglobulinemia. However, the specific mechanisms by which this class of mTOR inhibitors exerts anti–Waldenstrom macroglobulinemia activity have not been fully investigated. We therefore sought to dissect the mechanisms of everolimus-dependent modulation of Waldenstrom macroglobulinemia cell survival. Experimental Design: We confirmed that everolimus targets mTOR in patients treated with everolimus and responding to therapy. We evaluated the effect of everolimus on proliferation and survival of primary Waldenstrom macroglobulinemia cells, as well as of other IgM-secreting lymphoma cell lines. Everolimus-dependent mechanisms of induced apoptosis and its effect on Waldenstrom macroglobulinemia cells in the context of bone marrow microenvironment have been also evaluated. miRNA-155 loss-of-function studies were conducted. Moreover, the combinatory effect of bortezomib and rituximab has been tested. Results: We showed that everolimus targeted mTOR downstream signaling pathways, ex vivo, in patients responding to everolimus treatment. Everolimus induced toxicity in primary Waldenstrom macroglobulinemia cells, as well as in other IgM-secreting lymphoma cells, supported by cell-cycle arrest and caspase-dependent and -independent induction of apoptosis. Importantly, everolimus targeted Waldenstrom macroglobulinemia cells even in the context of bone marrow milieu, where it affected migration, adhesion, and angiogenesis. Everolimus-dependent anti–Waldenstrom macroglobulinemia activity was partially driven by miRNA-155. Moreover, everolimus synergized with bortezomib and rituximab in targeting Waldenstrom macroglobulinemia cells, as shown by synergistic inhibition of p65/ and p50/NF-κB activities. Conclusions: These findings provide a better understanding of the mechanisms that are responsible for everolimus-induced anti–Waldenstrom macroglobulinemia activity. Clin Cancer Res; 18(24); 6609–22. ©2012 AACR.
The aortic bodies supplied by coronary arteries in the dog. Their contribution to the hypertensive response that follows serotonin injection.
Authors: R W Eckstein
Journal: Circulation Research (1977)

I assessed the role of the chemoreceptors (aortic bodies) supplied by the coronary arteries in the hypertensive response induced by left atrial injection of (200 microgram serotonin) in adult anesthetized dogs. I compared the pressor response induced by serotonin during normal coronary circulation with that during exclusion of the central coronary segments from which the coronary blood supply to the aortic bodies arises. Exclusion of the central segments reduced the pressor response significantly from the control responses. Exclusion of the coronary blood supply of the aortic bodies resulted in a reduction of the control response of more than 50% in only two of the 21 dogs. I conclude that although the aortic bodies supplied by the coronary arteries play a significant role in the total hypertensive response to injected serotonin, their role usually is not predominant.
Symptoms of Posttraumatic Stress in Young Adult Survivors of Childhood Cancer
Authors: Wendy L. Hobbie, Margaret Stuber, Kathleen Meeske, Kathryn Wissler, Mary T. Rourke, Kathy Ruccione, Andrea Hinkle, Anne E. Kazak
Journal: Journal of Clinical Oncology (2000)

PURPOSE: This study assessed the prevalence of posttraumatic stress symptoms in young adult survivors of childhood cancer and the association of posttraumatic stress with anxiety, adjustment, perceptions of illness and treatment, and medical data extracted from oncology records. PATIENTS AND METHODS: Seventy-eight young adults (ages 18 to 40 years) who had been treated for childhood cancer completed questionnaires and psychiatric interviews assessing posttraumatic stress, anxiety, perceptions of their illness and treatment, and symptoms of psychologic distress. Data on treatment intensity and severity of medical late effects were collected via chart review. RESULTS: Of the patient sample, 20.5% met American Psychiatric Association Diagnostic and Statistical Manual criteria for posttraumatic stress disorder (PTSD) at some point since the end of their treatment. Clinically significant levels of intrusive (9%) and avoidant (16.7%) symptoms were reported. Participants also reported elevated state and trait anxiety. Participants with PTSD reported higher perceived current life threat, more intense treatment histories, and higher (and clinically significant) levels of psychologic distress than those who did not have PTSD. CONCLUSION: One-fifth of this sample of young adult survivors of childhood cancer met criteria for a diagnosis of PTSD, with clinically significant symptoms of intrusion and avoidance reported. As in other samples, PTSD in young adult survivors was associated with anxiety and other psychologic distress. Survivors’ perceptions of treatment and its effects were more highly associated with posttraumatic stress than were more objective medical data. The data suggest that cancer-related posttraumatic stress may emerge in young adulthood and may affect the achievement of developmental milestones and orientation toward health care.
TV: Broadcasters block Asian health soap opera
Authors: R. Coombes
Journal: BMJ (2003)

£340 000 drama sought to tackle heart disease and diabetes

Television companies in the United Kingdom are refusing to broadcast a multicultural soap opera that promotes public health issues—even though government funding means it won't cost them a penny.

The makers of Kismet Road , who admit that the show “isn't exactly ER ,” remain convinced that the mix of kitchen-sink drama and health information could win huge audiences among the UK's south Asian population.

The soap, a 13 part saga in English, Urdu, and Punjabi, whose largely inexperienced cast includes former Big Brother contestant Narinder Kaur, was filmed in Yorkshire and the Midlands on a shoestring budget.

Storylines tackle health issues such as coronary heart disease and diabetes, found at a higher than average rate in Asian communities, but also traditionally off-limits subjects, such as contraception, impotency, and alcohol misuse.

The main characters include Raana Haq, a practice nurse, and Dr McWaverley, an amiable but hapless consultant who offends his Asian patients by referring to “you people” and warning them to stay off the “fatty curries.”

In one plot …
Morphological and molecular characteristics of living human fetuses between Carnegie stages 7 and 23: developmental stages in the post-implantation embryo
Authors: LM Harkness, DT Baird
Journal: Human Reproduction Update (1997)

Determination of embryonic age groups or stages has been based on the Carnegie Institute collection started in 1887. Improved technology has enabled the building of a new collection of embryos of < 9 weeks gestation; these were then used to compare with the original Carnegie collection. The results suggest that in providing definitive stages that are rigidly bound by developmental events, limitations are placed on categorizing the embryo. Allocation of embryos to a specific stage can assist in identifying post-ovulatory age but overlaps between stages could lead to classification into an incorrect stage.
Understanding Cancer Treatment and Outcomes: The Cancer Care Outcomes Research and Surveillance Consortium
Authors: John Z. Ayanian, Elizabeth A. Chrischilles, Robert B. Wallace, Robert H. Fletcher, Mona N. Fouad, Catarina I. Kiefe, David P. Harrington, Jane C. Weeks, Katherine L. Kahn, Jennifer L. Malin, Joseph Lipscomb, Arnold L. Potosky, Dawn T. Provenzale, Robert S. Sandler, Michelle van Ryn, Dee W. West
Journal: Journal of Clinical Oncology (2004)

The National Cancer Institute (NCI) has funded the Cancer Care Outcomes Research and Surveillance (CanCORS) Consortium as the centerpiece of the NCI's ongoing initiative to improve cancer care. This commentary provides an introduction to the goals and methods of the CanCORS Consortium to the broader community of cancer researchers and clinicians, many of whom are caring for patients participating in this study.
A phase III randomized study comparing concomitant standard cisplatin (P) - etoposide (E) and chest irradiation to concomitant etoposide plus daily cisplatin and chest irradiation as induction therapy for limited (LD) small-cell lung cancer (SCLC)
Authors: T. Berghmans, P. Van Houtte, J. Lafitte, A. Efremidis, M. Florin, M. Paesmans, N. Leclercq, J. Sculier
Journal: Journal of Clinical Oncology (2008)

7521 Background: Early concomitant chemoradiotherapy is a standard of care in LD SCLC. The primary endpoint addressed by the trial was to look to a survival benefit if cisplatin was administered daily during radiotherapy compared to a standard approach. Methods: Patients with previously untreated pathologically proven LD SCLC, Karnofsky performance status ≥ 60, adequate hematologic, hepatic, renal, lung and cardiac functions were eligible. After central randomization, patients received a first course of E (100 mg/m² D1–3) plus P given either at 90 mg/m² on D1 (arm A) or at 6 mg/m² (D1–5, D8–12, D15–19) (arm B) one hour prior to chest irradiation (15 fractions of 2.66 Gy). Afterwards, all patients received P (90 mg/m² D1) plus E (100 mg/m² D1–3) up to 6 cycles. We planned to randomize 232 patients to detect a 10% increase in 2-year survival rate in the experimental arm (α 5%, β 20%). Results: From 1993 to 2006, 204 eligible patients were randomized (arm A 104, arm B 100), without any significant imbalance between both arms. Objective response rates were 84% (arm A) and 80% (arm B) (p = 0.59). Sixty-nine deaths occurred in each arm. Median, 2- and 5-years survivals were 15.5 m, 35%, 18% (arm A) and 17 m, 38%, 21% (arm B) (HR 0.89, 95% CI 0.65–1.22; p = 0.48). There was more leucopenia and nephrotoxicity during the first course in arm A and more thrombopenia and esophagitis in arm B. Conclusions: In both arms, patients with LD SCLC obtained good long-term survival with early concurrent chemoradiotherapy regardless the way cisplatin was administered during radiotherapy. No significant financial relationships to disclose.
Structure, Regulation, and Function of Mammalian Membrane Guanylyl Cyclase Receptors, With a Focus on Guanylyl Cyclase-A
Authors: Michaela Kuhn
Journal: Circulation Research (2003)

Besides soluble guanylyl cyclase (GC), the receptor for NO, there are at least seven plasma membrane enzymes that synthesize the second-messenger cGMP. All membrane GCs (GC-A through GC-G) share a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic (GC) region. Although the presence of the extracellular domain suggests that all these enzymes function as receptors, specific ligands have been identified for only three of them (GC-A through GC-C). GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure and volume homeostasis and also local antihypertrophic actions in the heart. GC-B is a specific receptor for C-type natriuretic peptide, having more of a paracrine function in vascular regeneration and endochondral ossification. GC-C mediates the effects of guanylin and uroguanylin on intestinal electrolyte and water transport and on epithelial cell growth and differentiation. GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction. Finally, the functions of GC-D (located in the olfactory neuroepithelium) and GC-G (expressed in highest amounts in lung, intestine, and skeletal muscle) are completely unknown. This review discusses the structure and functions of membrane GCs, with special emphasis on the physiological endocrine and cardiac functions of GC-A, the regulation of hormone-dependent GC-A activity, and the relevance of alterations of the atrial natriuretic peptide/GC-A system to cardiovascular diseases.
Three cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) or epirubicin, bleomycin, vinblastine, and methotrexate (EBVM) plus extended field radiation therapy in early and intermediate Hodgkin disease: 10-year results of a randomized trial
Authors: C. l. Maignan
Journal: Blood (2003)
Inhibition of Vascular Endothelial Growth Factor Receptor-1/Wnt/β-catenin Crosstalk Leads to Tumor Cell Death
Authors: Benjamin D. Zeitlin, Lee M. Ellis, Jacques E. Nör
Journal: Clinical Cancer Research (2009)

Abstract Two genes are considered synthetic lethal if mutation of either alone allows cell viability, whereas simultaneous mutation leads to cell death. A synthetic lethal screen unveiled the dependency of Wnt/β-catenin-addicted colorectal cancer cells on vascular endothelial growth factor receptor-1 kinase activity and suggested a novel therapeutic approach for this malignancy. (Clin Cancer Res 2009;15(24):7453–5)
Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation
Authors: Rubén Martínez-Barricarte, Meike Heurich, Francisco Valdes-Cañedo, Eduardo Vazquez-Martul, Eva Torreira, Tamara Montes, Agustín Tortajada, Sheila Pinto, Margarita Lopez-Trascasa, B. Paul Morgan, Oscar Llorca, Claire L. Harris, Santiago Rodríguez de Córdoba
Journal: Journal of Clinical Investigation (2010)

Dense deposit disease (DDD) is a severe renal disease characterized by accumulation of electron-dense material in the mesangium and glomerular basement membrane. Previously, DDD has been associated with deficiency of factor H (fH), a plasma regulator of the alternative pathway (AP) of complement activation, and studies in animal models have linked pathogenesis to the massive complement factor 3 (C3) activation caused by this deficiency. Here, we identified a unique DDD pedigree that associates disease with a mutation in the C3 gene. Mutant C(3923ΔDG), which lacks 2 amino acids, could not be cleaved to C3b by the AP C3-convertase and was therefore the predominant circulating C3 protein in the patients. However, upon activation to C3b by proteases, or to C3(H₂O) by spontaneous thioester hydrolysis, C(3923ΔDG) generated an active AP C3-convertase that was regulated normally by decay accelerating factor (DAF) but was resistant to decay by fH. Moreover, activated C(3b923ΔDG) and C3(H₂O)(923ΔDG) were resistant to proteolysis by factor I (fI) in the presence of fH, but were efficiently inactivated in the presence of membrane cofactor protein (MCP). These characteristics cause a fluid phase-restricted AP dysregulation in the patients that continuously activated and consumed C3 produced by the normal C3 allele. These findings expose structural requirements in C3 that are critical for recognition of the substrate C3 by the AP C3-convertase and for the regulatory activities of fH, DAF, and MCP, all of which have implications for therapeutic developments.
Interleukin-2 enhances CD4+ T cell memory by promoting the generation of IL-7Rα–expressing cells
Authors: Hans Dooms, Kristen Wolslegel, Patricia Lin, Abul K. Abbas
Journal: The Journal of Experimental Medicine (2007)

The common γ chain cytokines interleukin (IL)-2 and IL-7 are important regulators of T cell homeostasis. Although IL-2 is implicated in the acute phase of the T cell response, IL-7 is important for memory T cell survival. We asked whether regulated responsiveness to these growth factors is determined by temporal expression of the cytokine-specific IL-2 receptor (R) α and IL-7Rα chains. We demonstrate that IL-2Rα is expressed early after priming in T cell receptor–transgenic CD4+ T cells, whereas IL-7Rα expression is lost. In the later stage of the response, IL-7Rα is reexpressed while IL-2Rα expression is silenced. This reciprocal pattern of IL-2Rα/IL-7Rα expression is disturbed when CD4+ T cells are primed in the absence of IL-2 signals. Primed IL-2−/− or CD25−/− (IL-2Rα−/−) CD4+ T cells, despite showing normal induction of activation markers and cell division, fail to reexpress IL-7Rα late in the response. Because the generation of CD4+ memory T cells is dependent on IL-7–IL-7Rα interactions, primed IL-2−/− or CD25−/− CD4+ T cells develop poorly into long-lived memory cells. Retrovirus-mediated expression of IL-7Rα in IL-2−/− T cells restores their capacity for long-term survival. These results identify IL-2 as a factor regulating IL-7Rα expression and, consequently, memory T cell homeostasis in vivo.
An Outbreak of Escherichia coli 0157:H7 Infections Traced to Jerky Made From Deer Meat
Authors: William E. Keene
Journal: JAMA (1997)

<h3>Objective.</h3> —To investigate a 1995 outbreak of Escherichia coli O157:H7 infections and to assess the safety of meat dehydration methods. <h3>Design.</h3> —Survey subsequent to routine surveillance report, environmental investigations, and laboratory experimentation. <h3>Setting.</h3> —Oregon community. <h3>Participants.</h3> —Members of an extended household and their social contacts with confirmed or presumptive<i>E coli</i>O157:H7 infections. <h3>Results.</h3> —A total of 6 confirmed and 5 presumptive cases were identified. Homemade venison jerky was implicated as the source of transmission.<i>E coli</i>0157:H7 with the same distinctive, pulsed-field gel electrophoresis pattern seen in the case isolates was recovered from leftover jerky, uncooked meat from the same deer, a saw used to dismember the carcass, and fragments of the deer hide. In a subsequent survey,<i>E coli</i>O157:H7 was recovered from 3 (9%) of 32 deer fecal pellets collected in nearby forest land. In the laboratory, inoculated venison was dried at several time and temperature combinations, ranging up to 10 hours at 62.8°C. Viable organisms were recovered under all conditions tested. <h3>Conclusions.</h3> —Deer can be colonized by<i>E coli</i>O157:H7 and can be a source of human infections. Conditions necessary to ensure the safety of dried meat deserve further review. Game should be handled with the same caution indicated for commercially slaughtered meat.
Demonstration of a Left Atrial Input to the Atrioventricular Node in Humans
Authors: Mario D. Gonzalez, Leonardo J. Contreras, Francisco Cardona, Christopher J. Klugewicz, Jamie B. Conti, Anne B. Curtis, Timothy E. Morey, Donn M. Dennis
Journal: Circulation (2002)

During right atrial stimulation, the anterior and posterior approaches provide inputs to the atrioventricular (AV) node. The purpose of the present study was to determine how activation proceeding from the left atrium reaches the AV node.We studied AV nodal conduction during right and left atrial (coronary sinus) stimulation in 46 patients (27 women and 19 men; mean age, 46+/-4 years) who had structurally normal hearts. At an identical cycle length (600 ms), left atrial stimulation resulted in shorter A-H intervals than right atrial stimulation (73+/-3 ms versus 99+/-3 ms; P<0.05). In addition, atrial electrograms recorded close to the His bundle changed from near to far field potentials when stimulation was shifted to the left atrium. The A-H interval prolonged as the site of pacing was progressively moved from the distal to the proximal coronary sinus. During constant pacing from the distal coronary sinus, atrial activation close to the His bundle could be advanced by late extrastimuli delivered at the anterior and posterior approaches (up to 11+/-2 ms and 9+/-1 ms, respectively), without altering His bundle activation time. In contrast, late extrastimuli delivered at the inferoparaseptal mitral annulus advanced both the A and H electrograms in 19 of 20 patients, which is consistent with a left-sided input to the AV node. Right and left atrial stimulation resulted in similar AV nodal function.The mitral annulus provides a left atrial input to the human AV node.
Neutrophils promote Alzheimer's disease–like pathology and cognitive decline via LFA-1 integrin
Authors: Elena Zenaro, Enrica Pietronigro, Vittorina Della Bianca, Gennj Piacentino, Laura Marongiu, Simona Budui, Ermanna Turano, Barbara Rossi, Stefano Angiari, Silvia Dusi, Alessio Montresor, Tommaso Carlucci, Sara Nanì, Gabriele Tosadori, Lucia Calciano, Daniele Catalucci, Giorgio Berton, Bruno Bonetti, Gabriela Constantin
Journal: Nature Medicine (2015)
Patients with stage III/IV Hodgkin's disease in partial remission after MOPP/ABV chemotherapy have excellent prognosis after additional involved-field radiotherapy: Interim results from the ongoing EORTC-LCG and GPMC phase III trial
Authors: J. Raemaekers, M. Burgers, M. Henry-Amar, A. Pinna, A. Mandard, S. Monfardini, A. Hagenbeek, W. Breed, P. Carde, M. Vovk, A. van Hoof, J. Thomas, E. Noordijk
Journal: Annals of Oncology (1997)
Female Gender and Carcinoma In Situ in the Prostatic Urethra Are Prognostic Factors for Recurrence, Progression, and Disease-Specific Mortality in T1G3 Bladder Cancer Patients Treated With Bacillus Calmette-Guérin
Authors: Joan Palou, Richard J. Sylvester, Oscar Rodríguez Faba, Rubén Parada, Juan A. Peña, Ferran Algaba, Humberto Villavicencio
Journal: European Urology (2011)
Roles of Sildenafil in Enhancing Drug Sensitivity in Cancer
Authors: Zhi Shi, Amit K. Tiwari, Atish S. Patel, Li-Wu Fu, Zhe-Sheng Chen
Journal: Cancer Research (2011)

Abstract The phenomenon of multidrug resistance (MDR) has decreased the hope for successful cancer chemotherapy. The ATP-binding cassette (ABC) transporter superfamily is the largest transmembrane family. The overexpression of ABC transporters is a major determinant of MDR in cancer cells both in vitro and in vivo. Unfortunately, until recently, most of the strategies used to surmount ABC-transporter–mediated MDR have had limited success. An ideal modulator of MDR would be one that has a low liability to induce toxicity and alter the pharmacokinetic profile of antineoplastic drugs. Sildenafil, an inhibitor of cGMP-specific phosphodiesterase type 5, was found to significantly reverse ABC-transporter–mediated MDR. Our results indicate that sildenafil has differential inhibitory effects on ABC transporters: It significantly decreases the efflux activity of ABCB1 and ABCG2, but has no significant effects on ABCC1. Emerging evidence indicates that sildenafil and other phosphodiesterase type 5 inhibitors may enhance the sensitivity of certain types of cancer to standard chemotherapeutic drugs. Cancer Res; 71(11); 3735–8. ©2011 AACR.