tbuckley/cabot-search huggingface dataset:
Chimeric antigen receptor-engineered T cells for cancer immunotherapy: progress and challenges
Authors: Ethan Q Han, Xiu-ling Li, Chun-rong Wang, Tian-fang Li, Shuang-yin Han
Journal: Journal of Hematology & Oncology (2013)

Recent years have witnessed much progress in both basic research and clinical trials regarding cancer immunotherapy with chimeric antigen receptor (CAR)-engineered T cells. The unique structure of CAR endows T cell tumor specific cytotoxicity and resistance to immunosuppressive microenvironment in cancers, which helps patients to better tackle the issue of immunological tolerance. Adoptive immunotherapy (AIT) using this supernatural T cell have gained momentum after decades of intense debates because of the promising results obtained from preclinical models and clinical trials. However, it is very important for us to evaluate thoroughly the challenges/obstacles before widespread clinical application, which clearly warrants more studies to improve our understanding of the mechanism underlying AIT. In this review, we focus on the critical issues related to the clinical outcomes of CAR-based adoptive immunotherapy and discuss the rationales to refine this new cancer therapeutic modality.
Functional Dissection of the CCBE1 Protein
Authors: M. Guy Roukens, Josi Peterson-Maduro, Yvonne Padberg, Michael Jeltsch, Veli-Matti Leppänen, Frank L. Bos, Kari Alitalo, Stefan Schulte-Merker, Dörte Schulte
Journal: Circulation Research (2015)

Rationale : Collagen- and calcium-binding EGF domain–containing protein 1 (CCBE1) is essential for lymphangiogenesis in vertebrates and has been associated with Hennekam syndrome. Recently, CCBE1 has emerged as a crucial regulator of vascular endothelial growth factor-C (VEGFC) signaling. Objective : CCBE1 is a secreted protein characterized by 2 EGF domains and 2 collagen repeats. The functional role of the different CCBE1 protein domains is completely unknown. Here, we analyzed the functional role of the different CCBE1 domains in vivo and in vitro. Methods and Results : We analyzed the functionality of several CCBE1 deletion mutants by generating knock-in mice expressing these mutants, by analyzing their ability to enhance Vegfc signaling in vivo in zebrafish, and by testing their ability to induce VEGFC processing in vitro. We found that deleting the collagen domains of CCBE1 has a much stronger effect on CCBE1 activity than deleting the EGF domains. First, although CCBE1ΔCollagen mice fully phenocopy CCBE1 knock-out mice, CCBE1ΔEGF knock-in embryos still form rudimentary lymphatics. Second, Ccbe1ΔEGF, but not Ccbe1ΔCollagen, could partially substitute for Ccbe1 to enhance Vegfc signaling in zebrafish. Third, CCBE1ΔEGF, similarly to CCBE1, but not CCBE1ΔCollagen could activate VEGFC processing in vitro. Furthermore, a Hennekam syndrome mutation within the collagen domain has a stronger effect than a Hennekam syndrome mutation within the EGF domain. Conclusions: We propose that the collagen domains of CCBE1 are crucial for the activation of VEGFC in vitro and in vivo. The EGF domains of CCBE1 are dispensable for regulation of VEGFC processing in vitro, however, they are necessary for full lymphangiogenic activity of CCBE1 in vivo.
Autoregulation of blood flow within individual arterioles in the rat cremaster muscle.
Authors: R J Morff, H J Granger
Journal: Circulation Research (1982)

Autoregulatory responses to alterations in arterial or venous perfusion pressure were determined for individual arterioles within the rat cremaster muscle. The cremaster muscle of pentobarbital anesthetized rats (50 mg/kg, ip) was surgically exposed and maintained in a controlled tissue bath for visualization by in vitro television microscopy. Cremaster bath PO2 was controlled at either a high (approximately 70 mm Hg) or low (approximately 19 mm Hg) level. Inside diameter and red blood cell velocity were measured for individual first (1A), second (2A), or third (3A) branching order arterioles, and instantaneous blood flows within each arteriole were calculated. To measure the autoregulatory responses, we decreased arterial perfusion pressure to the microvascular bed by gradually occluding the sacral aorta. Significant autoregulation was observed in all orders of vessels, but, in general, autoregulation was more pronounced at all vessel levels when bath PO2 was low, and the autoregulatory gain was greater for the smaller vessels compared to the larger vessels. Elevation of venous pressure within the vascular bed by gradual occlusion of the inferior vena cava led to a significant vasoconstriction of the smaller vessels, suggesting that a significant myogenic component was present. The vasoconstriction response to elevated venous pressure was more pronounced when bath PO2 was high. Our data are not consistent with a purely myogenic or purely metabolic mechanism, but suggest that both mechanisms are simultaneously contributing to the local vascular regulation.
Building capacity for sustainable research programmes for cancer in Africa
Authors: Isaac Adewole, Damali N. Martin, Makeda J. Williams, Clement Adebamowo, Kishor Bhatia, Christine Berling, Corey Casper, Karima Elshamy, Ahmed Elzawawy, Rita T. Lawlor, Rosa Legood, Sam M. Mbulaiteye, Folakemi T. Odedina, Olufunmilayo I. Olopade, Christopher O. Olopade, Donald M. Parkin, Timothy R. Rebbeck, Hana Ross, Luiz A. Santini, Julie Torode, Edward L. Trimble, Christopher P. Wild, Annie M. Young, David J. Kerr
Journal: Nature Reviews Clinical Oncology (2014)
Measurement of Hemoglobin A1c
Authors: David B. Sacks
Journal: Diabetes Care (2012)

Evaluation of glycemia is used for the diagnosis and management of patients with diabetes. Glucose and hemoglobin A1c (HbA1c) provide complementary information and both are used to assess an individual’s glycemic status. The concentration of glucose in the blood indicates the subject’s glycemia at the time of blood sampling. However, blood glucose concentrations are modified by numerous factors, ranging from food ingestion and exercise to stress and medication (1). By contrast, the concentration of HbA1c in the blood reflects the average glucose over the preceding 8–12 weeks. Thus, HbA1c provides an additional criterion for assessing glucose control that is free of the wide diurnal fluctuations that occur with blood glucose. HbA1c has several additional attributes, which render it valuable in the setting of diabetes. These include, but are not limited to, the following: the subject does not need to be fasting, blood can be sampled any time of the day, the sample is stable, and there is very little biological variability (1). These factors, in conjunction with the documentation that HbA1c predicts the development of microvascular (2,3) and macrovascular (4) complications of diabetes, have led to the widespread adoption of HbA1c as integral to the management of patients with diabetes. Guidelines from several prominent clinical organizations recommend that HbA1c be measured at regular intervals in all patients with diabetes (5,6).

The quality of analytical methods for HbA1c initially lagged considerably behind the evidence of its clinical value. Early assays lacked standardization, substantially limiting the use of HbA1c in patient care. Considerable effort was invested to effect standardization, with schemes developed in the 1990s in Japan (7), Sweden (8), and the U.S. (9). All HbA1c results were reported as a percentage of hemoglobin. The subsequent …
A Novel Role for Calpain in the Endothelial Dysfunction Induced by Activation of Angiotensin II Type 1 Receptor Signaling
Authors: Rosario Scalia, Yulan Gong, Brett Berzins, Brin Freund, Danielle Feather, Gavin Landesberg, Gourav Mishra
Journal: Circulation Research (2011)

The cytosolic protease calpain has been recently implicated in the vascular remodeling of angiotensin II (Ang II) type 1 receptor (AT(1)R) signaling. The role of Ang II/AT(1)R/calpain signaling on endothelial function, an important and early determinant of vascular pathology, remains though totally unknown. Accordingly, we investigated the role of calpain in the endothelial dysfunction of Ang II.To demonstrate a mechanistic role for calpain in the endothelial dysfunction induced by Ang II/AT(1)R signaling. To establish endothelial-expressed calpains as an important target of AT(1)R signaling.Subchronic administration of nonpressor doses of Ang II to rats and mice significantly increased vascular calpain activity via AT(1)R signaling. Intravital microscopy studies revealed that activation of vascular expressed calpains causes endothelial dysfunction with increased leukocyte-endothelium interactions and albumin permeability in the microcirculation. Western blot and immunohistochemistry studies confirmed that Ang II/AT(1)R signaling preferentially activates the constitutively expressed μ-calpain isoform and demonstrated a calpain-dependent degradation of IκBα, along with upregulation of nuclear factor κB-regulated endothelial cell adhesion molecules. These physiological and biochemical parameters were nearly normalized following inhibition of AT(1)R or calpain in vivo. RNA silencing studies in microvascular endothelial cells, along with knockout and transgenic mouse studies, further confirmed the role of μ-calpain in the endothelial adhesiveness induced by Ang II.This study uncovers a novel role for calpain in the endothelial dysfunction of Ang II/AT(1)R signaling and establishes the calpain system as a novel molecular target of the vascular protective action of renin-angiotensin system inhibition. Our results may have significant clinical implications in vascular disease.
Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein
Authors: Chang Hoon Lee, Mark Melchers, Hongsheng Wang, Ted A. Torrey, Rebecca Slota, Chen-Feng Qi, Ji Young Kim, Patricia Lugar, Hee Jeong Kong, Lila Farrington, Boris van der Zouwen, Jeff X. Zhou, Vassilios Lougaris, Peter E. Lipsky, Amrie C. Grammer, Herbert C. Morse
Journal: The Journal of Experimental Medicine (2005)

Interferon (IFN) consensus sequence-binding protein/IFN regulatory factor 8 (IRF8) is a transcription factor that regulates the differentiation and function of macrophages, granulocytes, and dendritic cells through activation or repression of target genes. Although IRF8 is also expressed in lymphocytes, its roles in B cell and T cell maturation or function are ill defined, and few transcriptional targets are known. Gene expression profiling of human tonsillar B cells and mouse B cell lymphomas showed that IRF8 transcripts were expressed at highest levels in centroblasts, either from secondary lymphoid tissue or transformed cells. In addition, staining for IRF8 was most intense in tonsillar germinal center (GC) dark-zone centroblasts. To discover B cell genes regulated by IRF8, we transfected purified primary tonsillar B cells with enhanced green fluorescent protein–tagged IRF8, generated small interfering RNA knockdowns of IRF8 expression in a mouse B cell lymphoma cell line, and examined the effects of a null mutation of IRF8 on B cells. Each approach identified activation-induced cytidine deaminase (AICDA) and BCL6 as targets of transcriptional activation. Chromatin immunoprecipitation studies demonstrated in vivo occupancy of 5′ sequences of both genes by IRF8 protein. These results suggest previously unappreciated roles for IRF8 in the transcriptional regulation of B cell GC reactions that include direct regulation of AICDA and BCL6.
Hypoxia-Induced Vascular Endothelial Growth Factor Transcription and Protection from Apoptosis Are Dependent on α6β1 Integrin in Breast Carcinoma Cells
Authors: Jun Chung, Sangoh Yoon, Kaustubh Datta, Robin E. Bachelder, Arthur M. Mercurio
Journal: Cancer Research (2004)

The alpha6beta1 integrin has been implicated in breast carcinoma progression, but the mechanisms involved remain elusive. MDA-MB-435 cells engineered to be deficient in alpha6beta1 expression form primary tumors that are highly apoptotic and unable to metastasize, although they exhibit no increased apoptosis in vitro under standard culture conditions. Based on the hypothesis that alpha6beta1 is necessary for the survival of these cells in the tumor microenvironment, we report here that hypoxia protects these cells from apoptosis induced by serum deprivation and that hypoxia-mediated protection requires alpha6beta1 expression. We investigated the influence of alpha6beta1 on vascular endothelial growth factor (VEGF) expression because autocrine VEGF is necessary for the survival of serum-deprived cells in hypoxia. The results obtained indicate that alpha6beta1 is necessary for VEGF expression because the ability of hypoxia to activate HIF-1 and to stimulate VEGF transcription in MDA-MB-435 cells is dependent on alpha6beta1 expression by a mechanism that involves protein kinase C-alpha.
Clenbuterol-Supported Dynamic Training of Skeletal Muscle Ventricles Against Systemic Load
Authors: Norbert W. Guldner, Peter Klapproth, Martin Großherr, Matthias Stephan, Elisabeth Rumpel, Ralf Noel, Hans-H. Sievers
Journal: Circulation (2000)

Background —The profound loss of power that occurs in skeletal muscle after electrical conditioning has been the major limiting factor in its clinical application. This study investigates a 3-fold approach for chronic conditioning of skeletal muscle ventricles (SMVs) combining electrical transformation, dynamic training against systemic load, and pharmacological support with clenbuterol. Methods and Results —In 10 adult male goats, SMVs were constructed from latissimus dorsi muscle wrapped around an intrathoracic training device with windkessel characteristics. SMVs were stimulated electrically and trained dynamically by shifting volume against systemic load. Group 1 goats were controls (n=5), and group 2 goats (n=5) were supported with clenbuterol (150 μg 3 times a week). SMV dynamics were recorded weekly over 5 to 8 months: peak pressure (P max ), stroke volume (SV), volume displacement per minute (VD), stroke work per day (SW/d), and maximum rates of pressure generation, +dP/dt max , and decay, −dP/dt max . In group 1, after 149.5±2.7 days (n=4), data were P max =70.8±4.7 mm Hg, SV=3.2±1.2 mL, VD=62.3±21.1 mL/min, SW/d=0.8±0.4 kJ, +dP/dt max =64±13 mm Hg/s, and −dP/dt max =156±32 mm Hg/s. These parameters were significantly improved ( P &lt;0.007) in the clenbuterol-treated group 2 after 151±2.7 days: P max =176.2±43.8 mm Hg, SV=23.3±6.1 mL, VD=568.2±186.1 mL/min, SW/d=9.1±2.2 kJ, +dP/dt max =1134±267 mm Hg/s, and −dP/dt max =1028±92 mm Hg/s. In 2 SMVs of group 2, VD increased to 1090 and 1235 mL/min after 202 and 246 days of training, respectively. At termination, myosin heavy chains were totally transformed into myosin heavy chain-1 in all SMVs. Conclusions —This clenbuterol-supported dynamic training provides powerful SMVs that may have important clinical implications for the treatment of end-stage heart failure by muscular blood pumps.
Inhibins in female and male reproductive physiology: role in gametogenesis, conception, implantation and early pregnancy
Authors: Stefano Luisi, Pasquale Florio, Fernando M. Reis, Felice Petraglia
Journal: Human Reproduction Update (2004)

A great deal of new information has arisen in the recent years concerning inhibin physiology and clinical relevance in reproductive medicine. It is now recognized that the two inhibin isoforms, named inhibin A and inhibin B, are produced by the gonads in the course of gamete maturation and in women have a different pattern of secretion throughout the menstrual cycle. Since inhibins are also produced by placenta and fetal membranes, it has been suggested that there is an involvement in physiological adaptation of pregnancy. Evidence from several sources has underlined the clinical usefulness of the measurement of inhibin-related proteins in the diagnosis and follow-up of different fertility disturbances and early pregnancy viability. In the male, inhibin B is produced in the testis, principally by the Sertoli cells. Inhibin B expression and secretion are positively correlated with Sertoli cell function, sperm number, and spermatogenic status and are negatively correlated with FSH. This review covers the most recent advances on the role of inhibins in human reproductive function. Considerable progress in the understanding of inhibin physiology has resulted from selective measurement of the two inhibin molecular forms, named inhibin A and B. Newly recognized alterations of inhibin levels in gynaecological diseases as well as in normal and pathological pregnancy are discussed, with particular emphasis on the potential clinical usefulness of assessing inhibin levels in serum and other biological fluids.
Effect of Complete Remission and Responses Less Than Complete Remission on Survival in Acute Myeloid Leukemia: A Combined Eastern Cooperative Oncology Group, Southwest Oncology Group, and M. D. Anderson Cancer Center Study
Authors: Roland B. Walter, Hagop M. Kantarjian, Xuelin Huang, Sherry A. Pierce, Zhuoxin Sun, Holly M. Gundacker, Farhad Ravandi, Stefan H. Faderl, Martin S. Tallman, Frederick R. Appelbaum, Elihu H. Estey
Journal: Journal of Clinical Oncology (2010)

It is known that complete remission (CR) prolongs survival in acute myeloid leukemia (AML). In 2003, less stringent response categories were introduced, most notably CR with incomplete platelet recovery (CRp). Although the significance of CRp for survival remains unclear, reports of AML trials frequently combine CR with CRp rather than considering CR as a separate entity.This practice led us to retrospectively examine the effect of CR on outcome in newly diagnosed AML, by using data from 6,283 patients treated on Eastern Cooperative Oncology Group (ECOG) and Southwest Oncology Group (SWOG) protocols or at M. D. Anderson Cancer Center. This effect was then contrasted with the effect of CRp in the M. D. Anderson Cancer Center cohort.At least 94% of patients receiving cytarabine-based therapy and surviving for more than 3 or 5 years achieved a CR with either initial or salvage therapy; limited data suggest the same for patients receiving initial therapies that did not contain cytarabine. Patients with CR were more likely to live beyond 3 or 5 years than patients with CRp. The likelihood of achieving a CR rather than CRp was greater for patients with AML who had better prognosis. After adjustment for covariates, the relapse-free survival of patients achieving CR was longer than that of patients achieving CRp, whereas patients with CRp survived longer than those with resistant disease.Our data indicate that CR is of unique clinical significance and should be reported as separate response in trials of newly diagnosed AML. Nonetheless, our findings validate CRp as a clinically meaningful response.
Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial
Authors: William D Schweickert, Mark C Pohlman, Anne S Pohlman, Celerina Nigos, Amy J Pawlik, Cheryl L Esbrook, Linda Spears, Megan Miller, Mietka Franczyk, Deanna Deprizio, Gregory A Schmidt, Amy Bowman, Rhonda Barr, Kathryn E McCallister, Jesse B Hall, John P Kress
Journal: The Lancet (2009)
Malignant Transformations of C3H Mouse Cells In Vitro. Development of Transplantable Ascites Tumors From Mouse Embryo Cells Treated With 4-Nitroquinoline 1-Oxide2
Authors: Jiro Fujimoto
Journal: JNCI Journal of the National Cancer Institute (1973)

Journal Article Malignant Transformations of C3H Mouse Cells In Vitro. Development of Transplantable Ascites Tumors From Mouse Embryo Cells Treated With 4-Nitroquinoline 1-Oxide Get access Jiro Fujimoto Jiro Fujimoto City of Hope National Medical Center, Duarte, California 91010 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 50, Issue 1, January 1973, Pages 79–85, https://doi.org/10.1093/jnci/50.1.79 Published: 01 January 1973 Article history Received: 10 April 1972 Revision received: 18 September 1972 Accepted: 27 September 1972 Published: 01 January 1973
Imaging research results from the Osteoarthritis Initiative (OAI): a review and lessons learned 10 years after start of enrolment
Authors: Felix Eckstein, C Kent Kwoh, Thomas M Link
Journal: Annals of the Rheumatic Diseases (2014)

The Osteoarthritis Initiative (OAI) is a multicentre, prospective, observational, cohort study of knee osteoarthritis (OA) that began recruitment in 2004. The OAI provides public access to clinical and image data, enabling researchers to examine risk factors/predictors and the natural history of knee OA incidence and progression, and the qualification of imaging and other biomarkers. In this narrative review, we report imaging findings and lessons learned 10 years after enrolment has started. A literature search for full text articles published from the OAI was performed up to 31 December 2013 using Pubmed and the OAI web page. We summarise the rationale, design and imaging protocol of the OAI, and the history of OAI publications. We review studies from early partial, and later full OAI public data releases. The latter are structured by imaging method and tissue, reviewing radiography and then MRI findings on cartilage morphology, cartilage lesions and composition (T2), bone, meniscus, muscle and adipose tissue. Finally, analyses directly comparing findings from MRI and radiography are summarised. Ten years after the first participants were enrolled and first papers published, the OAI has become an invaluable resource to the OA research community. It has fuelled novel methodological approaches of analysing images, and has provided a wealth of information on OA pathophysiology. Continued collection and public release of long-term observations will help imaging measures to gain scientific and regulatory acceptance as 'prognostic' or 'efficacy of intervention' biomarkers, potentially enabling shorter and more efficient clinical trials that can test structure-modifying therapeutic interventions (NCT00080171).
Effects of prostaglandin E2 inhalation on hypercapnic response in normal subjects.
Authors: J Midorikawa, Y Kikuchi, O Taguchi, W Hida, S Okabe, T Takishima, K Shirato
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

It is known that the ventilatory response to carbon dioxide (CO2) is increased in asthmatics with airway obstruction. Increased vagal afferent activity as well as increased airway resistance have been postulated as the causative mechanisms. However, whether increased vagal afferent activity without bronchoconstriction increases the ventilatory response to CO2 has not been investigated in humans. We examined the effects of prostaglandin E2 (PGE2) inhalation, which is known to stimulate vagal afferent receptors in the lung without an increase in airway resistance, on the respiratory response to CO2 in seven healthy male subjects. Either physiologic saline or PGE2 (100 micrograms/ml) was inhaled through a Bird nebulizer for 3 min. Twenty minutes after each inhalation, the responses of minute ventilation (VE) and occlusion pressure (P0.1) to hyperoxic hypercapnia were measured. Both the relationships between VE and P0.1 to an increase in tension of end-tidal CO2 (PETCO2) were analyzed by linear regression. Although the mean value of respiratory resistance after PGE2 (3.0 cm H2O/L/s +/- 0.4) did not differ significantly from that after saline (3.1 cm H2O/L/s +/- 0.4), inhaled PGE2 significantly increased the hypercapnic response. This result suggests that the increased vagal afferent activity per se plays an important role in increasing the hypercapnic ventilatory response in humans.