tbuckley/cabot-search huggingface dataset:
Inducible Apoptosis as a Safety Switch for Adoptive Cell Therapy
Authors: Antonio Di Stasi, Siok-Keen Tey, Gianpietro Dotti, Yuriko Fujita, Alana Kennedy-Nasser, Caridad Martinez, Karin Straathof, Enli Liu, April G. Durett, Bambi Grilley, Hao Liu, Conrad R. Cruz, Barbara Savoldo, Adrian P. Gee, John Schindler, Robert A. Krance, Helen E. Heslop, David M. Spencer, Cliona M. Rooney, Malcolm K. Brenner
Journal: New England Journal of Medicine (2011)

Cellular therapies could play a role in cancer treatment and regenerative medicine if it were possible to quickly eliminate the infused cells in case of adverse events. We devised an inducible T-cell safety switch that is based on the fusion of human caspase 9 to a modified human FK-binding protein, allowing conditional dimerization. When exposed to a synthetic dimerizing drug, the inducible caspase 9 (iCasp9) becomes activated and leads to the rapid death of cells expressing this construct.We tested the activity of our safety switch by introducing the gene into donor T cells given to enhance immune reconstitution in recipients of haploidentical stem-cell transplants. Patients received AP1903, an otherwise bioinert small-molecule dimerizing drug, if graft-versus-host disease (GVHD) developed. We measured the effects of AP1903 on GVHD and on the function and persistence of the cells containing the iCasp9 safety switch.Five patients between the ages of 3 and 17 years who had undergone stem-cell transplantation for relapsed acute leukemia were treated with the genetically modified T cells. The cells were detected in peripheral blood from all five patients and increased in number over time, despite their constitutive transgene expression. A single dose of dimerizing drug, given to four patients in whom GVHD developed, eliminated more than 90% of the modified T cells within 30 minutes after administration and ended the GVHD without recurrence.The iCasp9 cell-suicide system may increase the safety of cellular therapies and expand their clinical applications. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; ClinicalTrials.gov number, NCT00710892.).
Reducing Consumption of Sugar-Sweetened Beverages Is Associated With Reduced Blood Pressure
Authors: Liwei Chen, Benjamin Caballero, Diane C. Mitchell, Catherine Loria, Pao-Hwa Lin, Catherine M. Champagne, Patricia J. Elmer, Jamy D. Ard, Bryan C. Batch, Cheryl A.M. Anderson, Lawrence J. Appel
Journal: Circulation (2010)

Increased consumption of sugar-sweetened beverages (SSBs) has been associated with an elevated risk of obesity, metabolic syndrome, and type II diabetes mellitus. However, the effects of SSB consumption on blood pressure (BP) are uncertain. The objective of this study was to determine the relationship between changes in SSB consumption and changes in BP among adults.This was a prospective analysis of 810 adults who participated in the PREMIER Study (an 18-month behavioral intervention trial). BP and dietary intake (by two 24-hour recalls) were measured at baseline and at 6 and 18 months. Mixed-effects models were applied to estimate the changes in BP in responding to changes in SSB consumption. At baseline, mean SSB intake was 0.9+/-1.0 servings per day (10.5+/-11.9 fl oz/d), and mean systolic BP/diastolic BP was 134.9+/-9.6/84.8+/-4.2 mm Hg. After potential confounders were controlled for, a reduction in SSB of 1 serving per day was associated with a 1.8-mm Hg (95% confidence interval, 1.2 to 2.4) reduction in systolic BP and 1.1-mm Hg (95% confidence interval, 0.7 to 1.4) reduction in diastolic BP over 18 months. After additional adjustment for weight change over the same period, a reduction in SSB intake was still significantly associated with reductions in systolic and diastolic BPs (P<0.05). Reduced intake of sugars was also significantly associated with reduced BP. No association was found for diet beverage consumption or caffeine intake and BP. These findings suggest that sugars may be the nutrients that contribute to the observed association between SSB and BP.Reduced consumption of SSB and sugars was significantly associated with reduced BP. Reducing SSB and sugar consumption may be an important dietary strategy to lower BP.URL: http://clinicaltrials.gov. Unique identifier: NCT00000616.
Serum 25-Hydroxyvitamin D3 Concentrations and Prevalence of Cardiovascular Disease Among Type 2 Diabetic Patients
Authors: Massimo Cigolini, Maria Pina Iagulli, Valentino Miconi, Micaela Galiotto, Simonetta Lombardi, Giovanni Targher
Journal: Diabetes Care (2006)

Accumulating research suggests that low 25-hydroxyvitamin D3 [25(OH)D] concentrations may be inversely associated with type 2 diabetes (1,2,3), metabolic syndrome (4,5), insulin resistance (6), and cardiovascular disease (CVD) (7).

Much remains to be learned, however, about the relationships between vitamin D status, metabolic syndrome, and CVD. Furthermore, the published data in humans arguing that hypovitaminosis D is a CVD risk factor remain conflicting (8,9).

Because this topic has received scant attention and the available information on associations between vitamin D status and CVD among type 2 diabetic adults was lacking, we examined the relationships between serum 25(OH)D concentrations and prevalent CVD in type 2 diabetic adults.

We studied 459 consecutive type 2 diabetic outpatients attending our clinic after exclusion of those with recent acute illness or advanced chronic liver or renal disease and those who were taking medications known to alter vitamin D metabolism. The control group consisted of 459 (64% men, age 61 ± 6 years) age- and sex-matched nondiabetic volunteers.

Biochemical blood measurements were determined by standard laboratory procedures. Serum 25(OH)D concentrations were measured during winter months using an automated chemiluminescence immunoassay (DiaSorin Liaison). Metabolic syndrome was defined according to the Adult Treatment Panel III criteria (10). Presence of coronary (myocardial infarction, angina, or …
Detection of bcl-2 protein and bcl-2 messenger RNA in normal and neoplastic lymphoid tissues by immunohistochemistry and in situ hybridization
Authors: E Kondo, S Nakamura, H Onoue, Y Matsuo, T Yoshino, H Aoki, K Hayashi, K Takahashi, J Minowada, S Nomura
Journal: Blood (1992)
Short-term Course of Intraocular Pressure after Intravitreal Injection of Triamcinolone Acetonide
Authors: Matthew S. Benz, Thomas A. Albini, Eric R. Holz, Rohit R. Lakhanpal, Andrew C. Westfall, Mohan N. Iyer, Petros E. Carvounis
Journal: Ophthalmology (2006)
Biosimilar G-CSF Based Mobilization of Peripheral Blood Hematopoietic Stem Cells for Autologous and Allogeneic Stem Cell Transplantation
Authors: Michael Schmitt, Amy Publicover, Kim H Orchard, Matthias Görlach, Lei Wang, Anita Schmitt, Jiju Mani, Panagiotis Tsirigotis, Reeba Kuriakose, Arnon Nagler
Journal: Theranostics (2014)

The use of granulocyte colony stimulating factor (G-CSF) biosimilars for peripheral blood hematopoietic stem cell (PBSC) mobilization has stimulated an ongoing debate regarding their efficacy and safety. However, the use of biosimilar G-CSF was approved by the European Medicines Agency (EMA) for all the registered indications of the originator G-CSF (Neupogen (®) ) including mobilization of stem cells. Here, we performed a comprehensive review of published reports on the use of biosimilar G-CSF covering patients with hematological malignancies as well as healthy donors that underwent stem cell mobilization at multiple centers using site-specific non-randomized regimens with a biosimilar G-CSF in the autologous and allogeneic setting. A total of 904 patients mostly with hematological malignancies as well as healthy donors underwent successful autologous or allogeneic stem cell mobilization, respectively, using a biosimilar G-CSF (520 with Ratiograstim®/Tevagrastim, 384 with Zarzio®). The indication for stem cell mobilization in hematology patients included 326 patients with multiple myeloma, 273 with Non-Hodgkin's lymphoma (NHL), 79 with Hodgkin's lymphoma (HL), and other disease. 156 sibling or volunteer unrelated donors were mobilized using biosimilar G-CSF. Mobilization resulted in good mobilization of CD34+ stem cells with side effects similar to originator G-CSF. Post transplantation engraftment did not significantly differ from results previously documented with the originator G-CSF. The side effects experienced by the patients or donors mobilized by biosimilar G-CSF were minimal and were comparable to those of originator G-CSF. In summary, the efficacy of biosimilar G-CSFs in terms of PBSC yield as well as their toxicity profile are equivalent to historical data with the reference G-CSF.
MACROGLOBULINEMIA
Authors: Leonhard Korngold, Gerda Van Leeuwen
Journal: The Journal of Experimental Medicine (1957)

Rabbits were immunized with three highly purified macroglobulins, from patients with macroglobulinemia. The antisera reacted with two macroglobulins with sedimentation constants of 19S and 26S of homologous antigen, and cross-reacted with the 7S and 19S globulins of normal gamma(1)-globulin and the heterologous pathological 19S macroglobulins. Exhaustive absorption of these antisera with normal gamma-globulins rendered them specific for the homologous macroglobulins. The antigenic properties of the pathological macroglobulins indicate that these proteins are abnormal.
Identification of the highest dose of docetaxel associable with active doses of epirubicin. Results from a dose-finding study in advanced breast cancer patients
Authors: M. Venturini, A. Michelotti, P. Papaldo, L. Del Mastro, M. Bergaglio, R. Lionetto, G. Lunardi, C. Sguotti, L. Frevola, S. Donati, R. Rosso, F. Cognetti
Journal: Annals of Oncology (2001)
CELL-MEDIATED LYMPHOLYSIS
Authors: Barbara J. Alter, Dolores J. Schendel, Marilyn L. Bach, Fritz H. Bach, Jan Klein, Jack H. Stimpfling
Journal: The Journal of Experimental Medicine (1973)

The cell-mediated lympholytic capability of mouse spleen cells stimulated in mixed lymphocyte culture is related to the major histocompatibility complex genotype on target lymphocytes. The strain combinations AQR-B10. T(6R) and B10.A(4R)-B10.A(2R) that result in significant mixed lymphocyte culture activation do not mediate cell-mediated lympholysis on sensitizing target lymphocytes; serologically defined regions (H-2K and H-2D) are identical within each combination. H-2K or H-2D region disparity alone does not cause cell-mediated lympholysis. However after mixed lymphocyte culture activation as seen with B10.A-B10.T(6R), a target cell bearing only an H-2K region difference from the effector cell is sensitive to cell-mediated lympholysis. Likewise an H-2D region difference is an adequate target after mixed lymphocyte culture activation of the effector cell in the combination B10.A(2R)-B10.D2.
Analysing chronic spinal changes in ankylosing spondylitis: a systematic comparison of conventional x rays with magnetic resonance imaging using established and new scoring systems
Authors: J Braun
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objectives:</b> To compare conventional radiography and magnetic resonance imaging (MRI) for detection of chronic changes in the spine of patients with ankylosing spondylitis (AS). <b>Methods:</b> Assessment of chronic lesions in conventional <i>x</i> rays and T<sub>1</sub> weighted MRI turbo spin echo sequences was performed with the established <i>x</i> ray scores BASRI and SASSS, the new Berlin score, and the MRI scoring system ASspiMRI-c All images were read twice and "blindly" by two readers. One vertebral unit (VU) was defined as the region between two virtual lines drawn through the middle of each vertebra. Definite involvement was defined as a score ⩾2 in a spinal segment. <b>Results:</b> Thirty nine patients with AS were examined (25 (64%) male, mean age 40.9 years, 33/36 (92%) HLA-B27 positive). The Berlin score correlated with the BASRI (<i>r</i> = 0.73, p = 0.01). The ASspiMRI-c correlated well with the BASRI and the Berlin score (<i>r</i> = 0.66 and <i>r</i> = 0.51, respectively, p = 0.01). The Berlin <i>x</i> ray score showed that 12/35 (34.3%), 13/35 (37.1%), and 12/28 (31.6%) patients had definite involvement of the cervical spine (CS), thoracic spine (TS), and lumbar spine (LS), respectively. The ASspiMRI-c showed that 10/36 (27.8%), 21/36 (58.3%), and 9/35 (25.7%) patients had definite involvement of the CS, TS, and LS, respectively. Syndesmophytes were found in 14.4% of all VUs with 90% agreement between the SASSS and Berlin score. <b>Conclusions:</b> T<sub>1</sub> weighted MRI can detect chronic lesions in AS. The two new scoring systems proved valid in comparison with established scoring systems and based on aspects of the OMERACT filter. The thoracic spine is most commonly affected in AS. This part of the spine is best assessed by MRI.
Characterizing Extravascular Fluid Transport of Macromolecules in the Tumor Interstitium by Magnetic Resonance Imaging
Authors: Arvind P. Pathak, Dmitri Artemov, B. Douglas Ward, David G. Jackson, Michal Neeman, Zaver M. Bhujwalla
Journal: Cancer Research (2005)

Abstract Noninvasive imaging techniques to image and characterize delivery and transport of macromolecules through the extracellular matrix (ECM) and supporting stroma of a tumor are necessary to develop treatments that alter the porosity and integrity of the ECM for improved delivery of therapeutic agents and to understand factors which influence and control delivery, movement, and clearance of macromolecules. In this study, a noninvasive imaging technique was developed to characterize the delivery as well as interstitial transport of a macromolecular agent, albumin-GdDTPA, in the MCF-7 human breast cancer model in vivo, using magnetic resonance imaging. The transport parameters derived included vascular volume, permeability surface area product, macromolecular fluid exudate volume, and drainage and pooling rates. Immunohistochemical staining for the lymphatic endothelial marker LYVE-1 was done to determine the contribution of lymphatics to the macromolecular drainage. Distinct pooling and draining regions were detected in the tumors using magnetic resonance imaging. A few lymphatic vessels positively stained for LYVE-1 were also detected although these were primarily collapsed and tenuous suggesting that lymphatic drainage played a minimal role, and that the bulk of drainage was due to convective transport through the ECM in this tumor model.
Functional Analysis of c-Met/Hepatocyte Growth Factor Pathway in Malignant Pleural Mesothelioma
Authors: Ramasamy Jagadeeswaran, Patrick C. Ma, Tanguy Y. Seiwert, Sujatha Jagadeeswaran, Osvaldo Zumba, Vidya Nallasura, Salman Ahmed, Rosangela Filiberti, Michela Paganuzzi, Riccardo Puntoni, Robert A. Kratzke, Gavin J. Gordon, David J. Sugarbaker, Raphael Bueno, Varalakshmi Janamanchi, Vytas P. Bindokas, Hedy L. Kindler, Ravi Salgia
Journal: Cancer Research (2006)

Abstract c-Met receptor tyrosine kinase (RTK) has not been extensively studied in malignant pleural mesothelioma (MPM). In this study, c-Met was overexpressed and activated in most of the mesothelioma cell lines tested. Expression in MPM tissues by immunohistochemistry was increased (82%) in MPM in general compared with normal. c-Met was internalized with its ligand hepatocyte growth factor (HGF) in H28 MPM cells, with robust expression of c-Met. Serum circulating HGF was twice as high in mesothelioma patients as in healthy controls. There was a differential growth response and activation of AKT and extracellular signal–regulated kinase 1/2 in response to HGF for the various cell lines. Dose-dependent inhibition (IC50 &amp;lt; 2.5 μmol/L) of cell growth in mesothelioma cell lines, but not in H2052, H2452, and nonmalignant MeT-5A (IC50 &amp;gt;10 μmol/L), was observed with the small-molecule c-Met inhibitor SU11274. Furthermore, migration of H28 cells was blocked with both SU11274 and c-Met small interfering RNA. Abrogation of HGF-induced c-Met and downstream signaling was seen in mesothelioma cells. Of the 43 MPM tissues and 7 cell lines, we have identified mutations within the semaphorin domain (N375S, M431V, and N454I), the juxtamembrane domain (T1010I and G1085X), and an alternative spliced product with deletion of the exon 10 of c-Met in some of the samples. Interestingly, we observed that the cell lines H513 and H2596 harboring the T1010I mutation exhibited the most dramatic reduction of cell growth with SU11274 when compared with wild-type H28 and nonmalignant MeT-5A cells. Ultimately, c-Met would be an important target for therapy against MPM. (Cancer Res 2006; 66(1): 352-61
Prevalence of small-bowel neoplasia in Lynch syndrome assessed by video capsule endoscopy
Authors: Jasmijn F Haanstra, Abdul Al-Toma, Evelien Dekker, Steven A L W Vanhoutvin, Fokko M Nagengast, Elisabeth M Mathus-Vliegen, Monique E van Leerdam, Wouter H de Vos tot Nederveen Cappel, Silvia Sanduleanu, Roeland A Veenendaal, Annemieke Cats, Hans F A Vasen, Jan H Kleibeuker, Jan J Koornstra
Journal: Gut (2014)

<h3>Objective</h3> The aim was to determine the prevalence of small-bowel neoplasia in asymptomatic patients with Lynch syndrome (LS) by video capsule endoscopy (VCE). <h3>Design</h3> After obtaining informed consent, asymptomatic proven gene mutation carriers aged 35–70 years were included in this prospective multicentre study in the Netherlands. Patients with previous small-bowel surgery were excluded. After bowel preparation, VCE was performed. The videos were read by two independent investigators. If significant lesions were detected, an endoscopic procedure was subsequently performed to obtain histology and, if possible, remove the lesion. <h3>Results</h3> In total, 200 patients (mean age 50 years (range 35–69), M/F 88/112), with proven mutations were included. These concerned MLH1 (n=50), MSH2 (n=68), MSH6 (n=76), PMS2 (n=3) and Epcam (n=3) mutation carriers. In 95% of the procedures, caecal visualisation was achieved. Small-bowel neoplasia was detected in two patients: one adenocarcinoma (TisN0Mx) and one adenoma, both located in the duodenum. In another patient, a duodenal cancer (T2N0Mx) was diagnosed 7 months after a negative VCE. This was considered a lesion missed by VCE. All three neoplastic lesions were within reach of a conventional gastroduodenoscope. All patients with neoplasia were men, over 50 years of age and without a family history of small-bowel cancer. <h3>Conclusions</h3> The prevalence of small-bowel neoplasia in asymptomatic patients with LS was 1.5%. All neoplastic lesions were located in the duodenum and within reach of conventional gastroduodenoscopy. Although VCE has the potential to detect these neoplastic lesions, small-bowel neoplasia may be missed. <h3>Trial registration number</h3> NCT00898768.
Reversibility of Trastuzumab-Related Cardiotoxicity: New Insights Based on Clinical Course and Response to Medical Treatment
Authors: Michael S. Ewer, Mary T. Vooletich, Jean-Bernard Durand, Myrshia L. Woods, Joseph R. Davis, Vicente Valero, Daniel J. Lenihan
Journal: Journal of Clinical Oncology (2005)

Trastuzumab is an important biologic agent with significant activity in breast cancers that overexpress the HER2/neu marker. However, trastuzumab is associated with cardiotoxicity that has not yet been fully explored. We present our experience with patients who developed trastuzumab-related cardiotoxicity.Over a 4-year period, 38 patients with HER2/neu-positive breast cancer were referred for suspected trastuzumab-related cardiotoxicity. All patients had previously received anthracycline-based chemotherapy. Results After doxorubicin but before trastuzumab, the mean (+/- standard deviation) left ventricular ejection fraction (LVEF) was 0.61 +/- 0.13, and the LVEF decreased to 0.43 +/- 0.16 after trastuzumab (P < .0001). After withdrawal of trastuzumab, the LVEF increased to 0.56 +/- 0.11. Mean time to recovery of LVEF was 1.5 months and was temporally associated with medical treatment in 32 (84%) of the 38 patients but occurred without treatment in six patients (16%). Increases in LVEF were noted in 37 of the 38 patients. Twenty-five of these patients were re-treated with trastuzumab; three patients had recurrent left ventricular dysfunction, but 22 patients (88%) did not. All re-treatment patients continued on their therapeutic regimen for heart failure when rechallenged with trastuzumab. Nine patients underwent endomyocardial biopsy. Ultrastructural changes were not seen.Patients who develop cardiotoxicity while receiving trastuzumab therapy generally improve on removal of the agent. The mechanism of trastuzumab-related cardiac dysfunction is different from that of anthracycline cardiotoxicity, in part, demonstrated by the absence of anthracycline-like ultrastructural changes. Reintroducing trastuzumab may be appropriate for some individuals who previously have experienced trastuzumab-related cardiac dysfunction.
Targeting YB-1 in HER-2 Overexpressing Breast Cancer Cells Induces Apoptosis via the mTOR/STAT3 Pathway and Suppresses Tumor Growth in Mice
Authors: Cathy Lee, Jaspreet Dhillon, Michelle Y.C. Wang, Yuanyuan Gao, Kaiji Hu, Eugene Park, Arezoo Astanehe, Mien-Chie Hung, Peter Eirew, Connie J. Eaves, Sandra E. Dunn
Journal: Cancer Research (2008)

Abstract The Y-box binding protein-1 (YB-1) is a transcription/translation factor that is highly expressed in primary breast tumors where it is consistently associated with poor survival. It induces human epidermal growth factor receptor (her-2) along with its dimerization partner egfr by directly binding to their promoters. In addition to promoting growth by inducing receptor tyrosine kinases, YB-1 also protects cells against apoptosis through mechanisms that have not been fully revealed. Given this, we addressed whether YB-1 might be an eventual therapeutic target for breast cancer by inhibiting it with small interfering RNAs in vitro and in vivo. Inhibiting YB-1 suppressed the growth of six of seven breast cancer cell lines that had amplified her-2 or were triple negative. Importantly, targeting YB-1 induced apoptosis in BT474-m1 and Au565 breast cancer cells known to have her-2 amplifications. The potential role of signal transducers and activators of transcription 3 (STAT3) was pursued to address the underlying mechanism for YB-1–mediated survival. Inhibition of YB-1 decreased P-STAT3S727 but not P-STAT3Y705 or total STAT3. This was accompanied by decreased P-ERK1/2T202/Y204, P-mTORS2448, and total mammalian target of rapamycin mTOR. Furthering the role of STAT3 in these cells, we show that knocking it down recapitulated the induction of apoptosis. Alternatively, constitutively active P-STAT3 rescued YB-1–induced apoptosis. Finally, targeting YB-1 with 2 different siRNAs remarkably suppressed tumor cell growth in soft agar by &amp;gt;90% and delayed tumorigenesis in nude mice. We conclude that HER-2 overexpressing as well as triple-negative breast cancer cells are YB-1 dependent, suggesting it may be a good therapeutic target for these exceptionally aggressive tumors. [Cancer Res 2008;68(21):8661–6]
Imitation and cultural transmission in apes and cetaceans
Authors: Andrew Whiten
Journal: Behavioral and Brain Sciences (2001)

Recent evidence suggests imitation is more developed in some cetaceans than the authors imply. Apart from apes, only dolphins have so far shown a grasp of what it is to imitate; moreover dolphins ape humans more clearly than do apes. Why have such abilities not been associated with the kind of progressive cultural complexity characteristic of humans?