tbuckley/cabot-search huggingface dataset:
Recombinant LCMV Vectors Induce Protective Immunity following Homologous and Heterologous Vaccinations
Authors: Jessica Wingerath, Dmitrij Ostroumov, Norman Woller, Michael P. Manns, Daniel D. Pinschewer, Klaus Orlinger, Ursula Berka, Florian Kühnel, Thomas C. Wirth
Journal: Molecular Therapy (2017)

Successful vaccination against cancer and infectious diseases relies on the induction of adaptive immune responses that induce high-titer antibodies or potent cytoxic T cell responses. In contrast to humoral vaccines, the amplification of cellular immune responses is often hampered by anti-vector immunity that either pre-exists or develops after repeated homologous vaccination. Replication-defective lymphocytic choriomeningitis virus (LCMV) vectors represent a novel generation of vaccination vectors that induce potent immune responses while escaping recognition by neutralizing antibodies. Here, we characterize the CD8 T cell immune response induced by replication-defective recombinant LCMV (rLCMV) vectors with regard to expansion kinetics, trafficking, phenotype, and function and we perform head-to-head comparisons of the novel rLCMV vectors with established vectors derived from adenovirus, vaccinia virus, or Listeria monocytogenes. Our results demonstrate that replication-deficient rLCMV vectors are safe and ideally suited for both homologous and heterologous vaccination regimens to achieve optimal amplification of CD8 T cell immune responses in vivo. Successful vaccination against cancer and infectious diseases relies on the induction of adaptive immune responses that induce high-titer antibodies or potent cytoxic T cell responses. In contrast to humoral vaccines, the amplification of cellular immune responses is often hampered by anti-vector immunity that either pre-exists or develops after repeated homologous vaccination. Replication-defective lymphocytic choriomeningitis virus (LCMV) vectors represent a novel generation of vaccination vectors that induce potent immune responses while escaping recognition by neutralizing antibodies. Here, we characterize the CD8 T cell immune response induced by replication-defective recombinant LCMV (rLCMV) vectors with regard to expansion kinetics, trafficking, phenotype, and function and we perform head-to-head comparisons of the novel rLCMV vectors with established vectors derived from adenovirus, vaccinia virus, or Listeria monocytogenes. Our results demonstrate that replication-deficient rLCMV vectors are safe and ideally suited for both homologous and heterologous vaccination regimens to achieve optimal amplification of CD8 T cell immune responses in vivo.
Combinations of HER2, estrogen receptor (ER) and IGF-I receptor (IGF1R) inhibitors induce apoptosis in breast cancer cells: Dramatic effects of HER2 inhibitors on non-overexpressing cells
Authors: Michael P. Digiovanna, Ashok Chakraborty
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

1226 

The ER, HER2 and IGF1R display important signaling interactions in breast cancer. We examined the effect of combinations of antagonists of these receptors in 2 human breast cancer cell lines: BT474 (ER+, HER2+, IGF1R low) and MCF7 (ER+, HER2 low, IGF1R high). In BT474 cells, growth is inhibited by HER2 and ER antagonists, but not by IGF1R antagonists; however, IGF1R antagonists enhance the effect of the former agents. IGF1R antagonists only minimally augment the effects of HER2 antagonists on cell cycle pertubation. While HER2 and ER antagonists do not cause apoptosis, they dramatically enhanced apoptosis induced by IGF1R antagonists. In MCF7 cells, growth is inhibited by IGF1R and ER antagonists (and more so by their combination), but not by HER2 antagonists; however, HER2 antagonism enhances the effect of the former agents. While HER2 and IGF1R antagonists individually do not perturb cell cycle, their combination gives a small degree of cell cycle perturbation. ER antagonists alter cell cycle, an effect enhanced by IGF1R or HER2 antagonists. While these agents produce a small amount of apoptosis individually, their combination causes a dramatic degree of apoptosis, most striking for the IGF1R/HER2 antagonist combination. A dual HER2/EGFR inhibitor has more dramatic effects than HER2 antagonists. Hence such drug combinations may be useful treatments for breast cancer patients, and combinations may be beneficial even in tumors in which single drugs are inactive.
Abstract 192: Roles of Phosphodiesterases 2 and 3 at the T-tubules of Adult Mouse Cardiomyocytes
Authors: Ruwan K Perera, Viacheslav O Nikolaev
Journal: Circulation Research (2013)

PURPOSE: cAMP is a key regulator of proper heart function. Its functional effects are controlled and regulated by spatial and temporal signal segregation at the subcellular level. In cardiomyocytes, transverse (T)- tubules form a highly organized network of membrane structures which are crucial for normal cAMP signaling. Morphological changes, such as loss of T-tubules, are associated with cardiac disease. This study aimed to gain insight into localized cAMP dynamics and its regulation in the T-tubular microdomain in health and disease. Methods: Generation of a transgenic mouse expressing a targeted Förster resonance energy transfer (FRET)-based biosensor (pmE1). Confocal microscopy for co-localization of pmE1 with T-tubular structures. Histological, morphometric and ultrasound analysis for characterization of heart function. Transverse aortic constriction (TAC) surgery for hypertrophy induction. FRET-based cAMP measurements and PDE activity assay with single freshly isolated adult ventricular myocytes of healthy and diseased mice. Results: The transgene did not alter heart function per se. We performed FRET measurements in freshly isolated cardiomyocytes to compare T-tubular with cytosolic cAMP responses and their regulation by beta1- and beta2-adrenergic receptors (β-ARs) and phosphodiesterase (PDE) isoforms. As expected, T-tubular β2-AR signals were higher than cytosolic ones (&gt;2-fold). Comparison of PDE activity profiles between the two compartments showed marked differences with regard to the β2-cAMP signal. In particular, T-tubular β2-cAMP is mainly controlled by PDE3. Strikingly, in hypertrophied myocytes (8 weeks post-TAC) we could detect a switch from PDE3 to PDE2-dependent regulation of these cAMP signals. Conclusions: We could establish transgenic mice expressing a FRET-biosensor to measure local cAMP levels in the T-tubular compartment and uncover its differential regulation by β1- and β2-ARs and several PDE families, especially by PDE3. The switch from PDE3 to PDE2 regulation of β2-cAMP in diseased cardiomyocytes could represent a novel mechanism of local cAMP signaling and cGMP/cAMP cross-talk in cardiomyocytes.
Severe Plantar Warts in an Immunocompromised Patient
Authors: Gehaan F D'Souza, James E Zins
Journal: New England Journal of Medicine (2017)

A 25-year-old woman who had undergone orthotopic heart transplantation presented with a 4-year history of severe warts on both her feet. After debulking surgery, these lesions gradually disappeared during treatment with cidofovir.
Additional Chromosomal Abnormalities in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Treated with Tyrosine Kinase Inhibitors: Differential Outcomes According to Type of Chromosomal Abnormality
Authors: Nicholas J. Short, Elias J. Jabbour, Koji Sasaki, Heidi Ko, Farhad Ravandi, C. Cameron Yin, Maria R. Khouri, Jorge E. Cortes, Rebecca Garris, Susan M. O'Brien, Keyur P. Patel, Guillermo Garcia-Manero, Deborah A Thomas, Naval Daver, Kiran Naqvi, Prithviraj Bose, Nitin Jain, Marina Konopleva, Hagop M. Kantarjian
Journal: Blood (2016)
Enhancing the usability of systematic reviews by improving the consideration and description of interventions
Authors: Tammy C Hoffmann, Andrew D Oxman, John PA Ioannidis, David Moher, Toby J Lasserson, David I Tovey, Ken Stein, Katy Sutcliffe, Philippe Ravaud, Douglas G Altman, Rafael Perera, Paul Glasziou
Journal: BMJ (2017)

The importance of adequate intervention descriptions in minimising research waste and improving research usability and reproducibility has gained attention in the past few years. Nearly all focus to date has been on intervention reporting in randomised trials. Yet clinicians are encouraged to use systematic reviews, whenever available, rather than single trials to inform their practice. This article explores the problem and implications of incomplete intervention details during the planning, conduct, and reporting of systematic reviews and makes recommendations for review authors, peer reviewers, and journal editors
Letrozole suppresses plasma oestradiol (E2) levels more completely than anastrozole in postmenopausal women with breast cancer
Authors: J. M. Dixon, L. Renshaw, O. Young, J. Murray, E. J. Macaskill, M. McHugh, E. Folkerd, D. Cameron, M. Dowsett
Journal: Journal of Clinical Oncology (2006)

552 Background: Letrozole (L) is a more potent aromatase inhibitor in vitro than anastrozole (A). One study in 12 patients showed that in patients L provides more complete inhibition of whole body aromatase and suppression of estrone sulphate levels than A but L did not significantly suppress E2 levels more than A possibly because of the small size of the study and the difficulty of measuring E2 in postmenopausal women (Geisler et al, JCO, 20, 751, 2002). The current aim was to conduct a much larger study to determine whether 2.5mg L suppresses E2 significantly more than 1mg A and if so in what proportion of patients this is the case. Methods: 54 postmenopausal women with invasive estrogen receptor positive breast cancer were randomised as part of their adjuvant hormone therapy to receive either: 12 weeks of L followed by 12 weeks of A (L→A) or 12 weeks of A followed by 12 weeks of L (A→L). Blood for hormones were taken at the same time of the day before and after 12 weeks of each drug. E2 was measured by a highly sensitive radioimmunoassay (Dowsett et al, Cancer Res 1987;47:1957–61) with a formal detection limit of 3pmol/l. In this study we also quantified values by extrapolation below this limit. Results: 27 patients had L→A and 27 A→L. Baseline E2 levels varied from 3 to 91 pmol/l with a median of 26 pmol/l. Only 1of 54 (2%) patients had an E2 value ≥ 3pmol/l after L compared with 20 of 54 (37%) after A(p &lt;0.000005). After extrapolation, mean E2 level after A was 2.91 (SEM 0.18) pmol/l with a median of 2.70 pmol/l and after L was 1.76 (SEM 0.10) pmol/l with a median of 1.70 pmol/l (p&lt;0.0001). Mean residual estradiol was 9.2% of baseline with A and 5.6% with L. Conclusions: This study has demonstrated unequivocally that the more complete inhibition of aromatase achieved by 2.5mg of letrozole than 1mg of anastrozole results in a greater degree of suppression of E2, the most bioactive oestrogen. [Table: see text]
Cholangiocytes and the environment in primary sclerosing cholangitis: where is the link?
Authors: Steven P O’Hara, Tom H Karlsen, Nicholas F LaRusso
Journal: Gut (2017)

In primary sclerosing cholangitis (PSC), annular fibrosis around intrahepatic and extrahepatic bile ducts leads to progressive liver disease for which there is no effective therapy except liver transplantation.1 The concentric accumulation of connective tissue around bile ducts suggests that the cholangiocyte plays an integral role in PSC pathogenesis. However, what initiates changes in cholangiocyte phenotype and how cholangiocytes interact with cells in the peribiliary extracellular matrix like immune cells and stromal components is largely unknown. Over the last 10 years, genome-wide association studies in PSC have revealed >20 risk genes.2–5 A significant observation that can be derived from these data, which also applies to other non-Mendelian phenotypes, is that the predominant risk contribution is likely to come from one or more environmental sources, rather than the genetic aberrations. Indeed, in PSC, we estimate that <10% of the overall liability is accounted for by the genetic findings; with extrapolations into hypothetical, larger study populations, it is unlikely to exceed 30%–40%.6 7 Research dissecting the remaining environmental contribution to PSC and other complex diseases is methodologically challenging. The exposures of an organism throughout life as a whole have recently been referred to as the exposome8 and include a myriad of components of both the external (eg, xenobiotics) and internal (eg, gut microbes) milieu.

There is a long tradition and effective means for detecting infectious exposures in medicine. Robert Koch in the late 19th century proposed criteria to identify a disease as infectious.9 These included (i) the organism is regularly associated with the disease, (ii) the organism can be isolated from the diseased host and grown in culture and (iii) the disease can be reproduced when the organism is introduced into a healthy susceptible host. With the development of nucleic acid sequence-based identification of microbes, as well as the …
Nilotinib As Second-Line Therapy in Patients with Chronic Myeloid Leukemia in Chronic Phase: Thailand Experience
Authors: Kanchana Chansung, Chittima Sirijerachai, Arnuparp Lekhakula, Pongtep Viboonjuntra, Pimjai Niparuck, Teeraya Pauvilai, Tontanai Numbenjapon, Udomsak Bunworasate, Weerasak Nawarawong, Adisak Tantiworawit, Tawatchai Suwanban, Saengsuree Jootar
Journal: Blood (2016)
The Fluid Mechanics of Transcatheter Heart Valve Leaflet Thrombosis in the Neosinus
Authors: Prem A. Midha, Vrishank Raghav, Rahul Sharma, Jose F. Condado, Ikechukwu U. Okafor, Tanya Rami, Gautam Kumar, Vinod H. Thourani, Hasan Jilaihawi, Vasilis Babaliaros, Raj R. Makkar, Ajit P. Yoganathan
Journal: Circulation (2017)

Background: Transcatheter heart valve (THV) thrombosis has been increasingly reported. In these studies, thrombus quantification has been based on a 2-dimensional assessment of a 3-dimensional phenomenon. Methods: Postprocedural, 4-dimensional, volume-rendered CT data of patients with CoreValve, Evolut R, and SAPIEN 3 transcatheter aortic valve replacement enrolled in the RESOLVE study (Assessment of Transcatheter and Surgical Aortic Bioprosthetic Valve Dysfunction With Multimodality Imaging and Its Treatment with Anticoagulation) were included in this analysis. Patients on anticoagulation were excluded. SAPIEN 3 and CoreValve/Evolut R patients with and without hypoattenuated leaflet thickening were included to study differences between groups. Patients were classified as having THV thrombosis if there was any evidence of hypoattenuated leaflet thickening. Anatomic and THV deployment geometries were analyzed, and thrombus volumes were computed through manual 3-dimensional reconstruction. We aimed to identify and evaluate risk factors that contribute to THV thrombosis through the combination of retrospective clinical data analysis and in vitro imaging in the space between the native and THV leaflets (neosinus). Results: SAPIEN 3 valves with leaflet thrombosis were on average 10% further expanded (by diameter) than those without (95.5±5.2% versus 85.4±3.9%; P &lt;0.001). However, this relationship was not evident with the CoreValve/Evolut R. In CoreValve/Evolut Rs with thrombosis, the thrombus volume increased linearly with implant depth ( R 2 =0.7, P &lt;0.001). This finding was not seen in the SAPIEN 3. The in vitro analysis showed that a supraannular THV deployment resulted in a nearly 7-fold decrease in stagnation zone size (velocities &lt;0.1 m/s) when compared with an intraannular deployment. In addition, the in vitro model indicated that the size of the stagnation zone increased as cardiac output decreased. Conclusions: Although transcatheter aortic valve replacement thrombosis is a multifactorial process involving foreign materials, patient-specific blood chemistry, and complex flow patterns, our study indicates that deployed THV geometry may have implications on the occurrence of thrombosis. In addition, a supraannular neosinus may reduce thrombosis risk because of reduced flow stasis. Although additional prospective studies are needed to further develop strategies for minimizing thrombus burden, these results may help identify patients at higher thrombosis risk and aid in the development of next-generation devices with reduced thrombosis risk.
Percutaneous endoscopic necrosectomy
Authors: Lionel D’Souza, Andrew Korman, David Carr-Locke, Petros Benias
Journal: Endoscopy (2017)

A 32-year-old man presented to our institution with abdominal pain, anorexia, fevers, and leukocytosis from a large walled-off necrosis. Prior to this presentation he had been admitted to a local hospital 6 weeks previously with acute severe alcohol-related pancreatitis, which entailed a prolonged stay in the intensive care unit due to multiorgan failure. He was found to have an abdominal fluid collection during this admission for which a percutaneous drain had been placed.
Phase II study of GM-CSF secreting allogeneic pancreatic cancer vaccine (GVAX) with PD-1 blockade antibody and stereotactic body radiation therapy (SBRT) for locally advanced pancreas cancer (LAPC).
Authors: Valerie Lee, Christina Rodriguez, Ella-Mae Shupe, Linda Chen, Rose Parkinson, Jennifer N. Durham, Elizabeth Sugar, Cara Wilt, Keith R. McIntyre, Amy Hacker-Prietz, Matthew J. Weiss, Jin He, Christopher Lee Wolfgang, Ana De Jesus-Acosta, Dung T. Le, Joseph M. Herman, Daniel A. Laheru, Amol Narang, Elizabeth M. Jaffee, Lei Zheng
Journal: Journal of Clinical Oncology (2017)

TPS4154 Background: Optimal treatment strategy beyond systemic chemotherapy for LAPC remains undefined. SBRT improves local control, but distant metastasis free survival (DMFS) is only 7.7 months. Checkpoint inhibitors are poor monotherapies in pancreas cancer, but may be primed by SBRT via absocopal effect and GVAX, which induces novel lymphoid infiltrates and increased effector T-cells in tumor microenvironment. Methods: This is a single-arm, single-institution, open-label study for pts with LAPC. Eligibility: surgically unresectable LAPC, predominant adenocarcinoma at diagnosis, with ECOG 0-1, who remain metastases free after 4-8 cycles of FOLFIRINOX or gemcitabine/abraxane based-chemotherapy. Exclusion: those off chemotherapy &gt; 49 days prior to study treatment, prior immunotherapy, active immunosuppressive use, autoimmune disease, HIV, HBV, or HCV infection, and non-oncology vaccines within 28 days of study treatment. Pts receive cyclophosphamide (200mg/m2 IV) and pembrolizumab (200mg IV) on day 1, followed by GVAX (six intradermal injections) on day 2 every three weeks for two cycles, with cycle 2 initiating concurrently with five days of SBRT. If non-metastatic, pts undergo surgical resection, nano-knife, or EUS guided biopsy (if non-surgical). Pts receive two further cycles of chemotherapy, and if remain free of metastases, receive q3 week cyclophosphamide, pembrolizumab, and GVAX for six cycles, then are monitored for two years. The primary endpoint is DMFS. Secondary endpoints include overall survival, surgical resectability, pathologic response, quality of life, and toxicity. Exploratory objectives of peripheral antigen specific t-cell responses, and changes in immune parameters of tumor microenvironment. 11 of 54 pts have been enrolled since July 2016. Clinical trial information: NCT02648282.
p19INK4d Modulates Human Terminal Erythroid Differentiation By Post-Transcriptionally Regulating GATA1 Expression
Authors: Xu Han, Jieying Zhang, Yuanliang Peng, Huiyong Chen, Xiao Chen, Yibin Zhang, Xiao Hu, Narla Mohandas, Xiuli An, Jing Liu
Journal: Blood (2016)
Abstract #5132: The eIF4E/eIF4G interaction inhibitor 4EGI-1 augments TRAIL-induced apoptosis through DR5 induction and c-FLIP downregulation independent of inhibition of cap-dependent protein translation
Authors: Songqing Fan, Yikun Li, Ping Yue, Fadlo Khuri, Shi-Yong Sun
Journal: Cancer Research (2009)

Cap-dependent protein translation plays an important role in regulation of oncogenesis primarily through regulation of the expression of certain oncogenic proteins (e.g., cyclin D1 and HIF1\#945;,). Thus inhibition of cap-dependent protein translation has emerged as an attractive therapeutic strategy. The small molecule 4EGI-1 was identified as an inhibitor of cap-dependent translation initiation by disrupting eIF4E/eIF4G association through binding to eIF4E and exhibits growth-inhibitory and apoptosis-inducing activity in cancer cells. We were interested in its therapeutic effects in human lung cancer cells. 4EGI-1 as a single agent inhibited the growth and induced apoptosis of human lung cancer cells. When combined with the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), enhanced apoptosis-induced activity was observed. In lung cancer cells, 4EGI-1 inhibited eIF4E/eIF4G interaction, reduced the levels of cyclin D1 and HIF1\#945;, both of which are regulated by a cap-dependent translation mechanism. Moreover, 4EGI-1 upregulated DR5 expression and downregulated c-FLIP levels. Small interfering RNA (siRNA)-mediated blockade of DR5 induction or enforced expression of c-FLIP abrogated 4EGI-1\#8217;s ability to enhance TRAIL-induced apoptosis, indicating that both DR5 induction and c-FLIP downregulation contribute to enhancement of TRAIL-induced apoptosis by 4EGI-1. However, inhibition of eIF4E/eIF4G interaction by eIF4E siRNA-mediated knockdown of eIF4E effectively reduced the levels of cyclin D1 and HIF1\#945;, but failed to induce DR5 expression, downregulate c-FLIP levels, and augment TRAIL-induced apoptosis. As well, the mTOR inhibitor rapamycin, which inhibits cap-dependent translation initiation, did not enhance TRAIL-induced apoptosis. Collectively, we conclude that 4EGI-1 augments TRAIL-induced apoptosis through induction of DR5 and downregulation of c-FLIP independent of inhibition of cap-dependent protein translation. (S. Fan. and Y. Li share first authorship; this work was supported by the Georgia Cancer Coalition Distinguished Cancer Scholar award, DOD grant W81XWH-04-1-0142-VITAL, NIH RO1 CA118450-01 and NIH SPORE P50 grant CA128613-01; SY Sun, and FR Khuri are Georgia Cancer Coalition Distinguished Cancer Scholars)   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5132.