tbuckley/cabot-search huggingface dataset:
Paclitaxel induces the apoptosis in MCF10AT series of human breast epithelial cells: A model for proliferative breast disease and carcinoma
Authors: So Hee Kim, Seong-Hee Ko, Min Jeong Kang, Raymond Novak
Journal: Cancer Research (2008)

3217  Human proliferative breast disease (PBD) refers to a sequence of progressive morphologic changes, including hyperplasia that occurs in the breast tissue prior to breast cancer development. MCF10AT cell series of human breast epithelial cell includes normal MCF10A (10A), premalignant MCF10AT (10AT) and MCF10ATG3B (10ATG3B), and fully malignant MCF10CA1a (10CA1a) cells and serves as a unique model system for development of PBD and carcinoma. The effects of paclitaxel (PTX), anti-microtubule agent, in MCF10AT cell lineage were examined. PTX inhibited the proliferation of MCF10AT cell lineage in a time-dependent (24, 48 and 72 h) and a concentration-dependent (0~10 nM) manners. PTX (10 nM) inhibited the proliferation of 10A, 10AT, 10ATG3B and 10CA1a cells by 65, 56, 43 and 52%, respectively, at 48 h. Treatment of cells with PTX (10 nM) for 24 h induced the apoptosis with the percentage of cells in sub-G1 phase being 23.6, 26.1, 25.2 and 10.2% in 10A, 10AT, 10ATG3B, and 10CA1a cells, respectively, showing less sensitiveness to 10CA1a tumor cells. However, further treatment of cells with PTX for 48 h resulted in G1-phase arrest. Treatment of cells with PTX (0~10 nM) for 24 h showed the appearance of DNA fragmentation (a hallmark of apoptosis) with less sensitiveness to 10CA1a tumor cells. PTX increased the protein expression of p53 by 87, 102, 812 and 84% in 10A, 10AT, 10ATG3B and 10CA1a cells, respectively, and induced cleaved poly(ADP-ribose) polymerase (PARP) fragmentation. These results correlated well to PTX-mediated induction of apoptosis with the decreased sensitivity of 10CA1a cells. In accordance with the G1-phase arrest, retinoblastoma (Rb), phospho-Rb and cyclin-dependent kinase (cdk)-2 proteins significantly decreased after PTX treatment. PTX increased the protein expression of cdk inhibitor, p21Waf1, by 2.57, 1.53 and 2.48 fold in 10A, 10AT and 10ATG3B cells, respectively, with the negligible detection in 10CA1a cells. The protein expression of p27Kip1, another cdk inhibitor, also significantly increased by 2.73, 2.22, 2.40 and 1.71 fold for 10A, 10AT, 10ATG3B and 10CA1a cells, respectively, after the treatment of PTX. Collectively, these data show that PTX inhibited cell proliferation by G1 cell cycle arrest in MCF10AT cell lineage. PTX also induced the apoptosis of 10A, 10AT and 10ATG3B cells, whereas 10CA1a tumor cells were less inducible to PTX effects. The effects of PTX on DNA fragmentation, p53 protein expression and PARP cleavage contributed to the induction of apoptosis in 10A, 10AT and 10AT3B cells, with a lesser effect noted for 10CA1a tumor cells.  Supported by Research Fund by Kangnung National University and Regional Technology Innovation (RTI 05-01-02) Program of the Ministry of Commerce, Industry and Energy (MOCIE)  Keywords: MCF 10AT cells; paclitaxel; apoptosis; DNA fragmentation; p53; PARP
Enhanced glioma-targeting and stability of L GICP peptide coupled with stabilized peptide D A7R
Authors: Mingfei Zhang, Weiyue Lu
Journal: Acta Pharmaceutica Sinica B (2018)

Malignant glioma is usually accompanied by vigorous angiogenesis to provide essential nutrients. An effective glioma targeting moiety should include excellent tumor-cell homing ability as well as good neovasculature-targeting efficiency, and should be highly resistant to enzyme degradation in the bloodstream. The phage display-selected heptapeptide, the glioma-initiating cell peptide (GICP), was previously reported as a ligand for the VAV3 protein (a Rho-GTPase guanine nucleotide exchange factor), which is mainly expressed on glioma cells; the stabilized heptapeptide DA7R has been shown to be the ligand of both vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1), and has demonstrated good neovasculature-targeting ability. By linking DA7R and GICP, a multi-receptor targeting molecule was obtained. The stability of these three peptides was evaluated and their targeting efficiency on tumor-related cells and models was compared. The ability of these peptides to cross the blood--tumor barrier (BTB) was also determined. The results indicate that the coupled Y-shaped peptide DA7R–GICP exhibited improved tumor and neovasculature targeting ability and had higher efficiency in crossing the BTB than either individual peptide.
Neoadjuvant nivolumab in early-stage, resectable non-small cell lung cancers.
Authors: Jamie E. Chaft, Patrick M. Forde, Kellie Nicole Smith, Valsamo Anagnostou, Tricia Cottrell, Janis M. Taube, Natasha Rekhtman, Taha Merghoub, David Randolph Jones, Matthew David Hellmann, Stephen C. Yang, Stephen Broderick, Valerie W. Rusch, Victor E. Velculescu, Suzanne Louise Topalian, Drew M. Pardoll, Julie R. Brahmer
Journal: Journal of Clinical Oncology (2017)

8508 Background: Anti-PD-1 therapy produces objective and often durable responses in ~20% of unselected patients (pts) with metastatic non-small cell lung cancer (NSCLC). However, the role of PD-1 blockade in treating resectable NSCLC is unknown. This is the first study to test nivolumab in the neoadjuvant setting. This trial design provides an opportunity to examine anti-PD-1 mechanism of action and immunologic correlates of outcomes. Methods: Patients with Stage IB - IIIA NSCLC received 2 doses of nivolumab 3mg/kg over 4 weeks before surgery. The primary endpoint was safety in 20 patients with resected NSCLC. Efficacy was explored using objective pathologic response criteria. Correlative studies of the tumor immune microenvironment, tumor mutation and predicted neoantigen loads, and changes in T cell receptor (TCR) clonality in tumor and blood pre and post treatment were conducted. Results: 22 pts were treated. Nivolumab was well-tolerated and no surgeries were delayed. 1 pt withdrew from study preop without progression or toxicity. Among the 21 attempted resections, 1 tumor was unresectable. 9/21 (43%, 95% CI 24-63%) had a major pathologic response ( &lt; 10% viable tumor cells in resection specimen). With a median postop follow-up of 9 months, 18 pts (86%) remain alive and recurrence free. Pre-treatment tumor exome sequencing showed a correlation between both tumor mutation and predicted neoantigen loads with pathologic response. Multiplex immunohistochemistry of pre- and post-treatment tumors showed an influx of PD-1+CD8+ T cells into responding tumors. TCR sequencing demonstrated that expanded peripheral T cell clones after treatment match clones found in the tumor. Conclusions: Neoadjuvant nivolumab in resectable NSCLC did not delay surgery. Major pathologic response rate was encouraging and compares favorably to outcomes with cisplatin-based neoadjuvant chemotherapy. Genomic analyses suggest that higher mutational and neoantigen burden could result in deeper pathologic response. Immunologic analyses support the detection of intra-tumoral T cell clones in the blood after treatment with nivolumab and may provide further insight into the molecular and immunologic features of response and non-response to PD-1 blockade. Clinical trial information: NCT02259621.
Abstract 13042: EP4 Signaling in Smooth Muscle Cells Attracts Inflammatory Immune Responses in the Aorta
Authors: Ryo Ishiwata, Utako Yokoyama, Yasuhiro Ichikawa, Daisuke Kurotaki, Shota Yasuda, Motohiko Goda, Shinichi Suzuki, Munetaka Masuda, Tomohiko Tamura, Yoshihiro Ishikawa
Journal: Circulation (2016)

Chronic inflammation driven by prostaglandin E 2 (PGE 2 ) is a basis for vascular diseases such as abdominal aortic aneurysm (AAA). We have reported that PGE 2 receptor, EP4, is responsible for AAA progression. However, precise molecular mechanisms are unknown. Since EP4 expression was upregulated in smooth muscle cells (SMCs) in human AAA, we hypothesized that EP4 in SMCs promotes vascular inflammatory responses in AAA. Methods and Results: EP4 transgenic mice (EP4-Tg) in which EP4 is overexpressed selectively in SMCs under SM22α promoter were generated using Cre-loxP system. Neither EP4-Tg nor littermate non-transgenic mice (Non-Tg) exhibited hypertension, hyperlipidemia, or vascular anomaly at basal condition (male, 12-16 weeks-old). Angiotensin II (AngII) infusion (1.0μg/kg/min) caused AAA rupture-related death in all the EP4-Tg around day14 of infusion, while no AAA were observed in Non-Tg until day28 ( n =6-7, P &lt;0.001). To elucidate initial events leading to AAA, the aortae were analyzed at day4 of AngII infusion, at which no AAA was observed. In EP4-Tg aortae, MMP-9 activity was induced ( n =6-7, P &lt;0.05) and IL-6 production was upregulated (5.0±1.8-fold vs. Non-Tg, n =6-7, P &lt;0.05). FACS analysis showed that infiltration of Ly6C hi inflammatory monocytes was enhanced in EP4-Tg aortae, coinciding with the emergence of MMP-9 expression in resident macrophages but not in Non-Tg counterpart (n=4, P &lt;0.01). IL-6 expression was detected primarily in SMC layer in EP4-Tg by immunohistochemistry. Administration of IL-6R antibody (MR16-1, 10mg/kg/2days) in vivo inhibited AngII-induced infiltration of Ly6C hi monocytes (0.3±0.1-fold, n =4, P &lt;0.05) and AAA rupture in EP4-Tg ( n =6, P =0.06). Administration of EP4 antagonist (ONO AE3-208, 0.1mg/kg, BID) also inhibited AngII-induced AAA in EP4-Tg ( n =8, P =0.05). In vitro , EP4 stimulation induced more abundant IL-6 production in EP4-Tg aortic SMCs than Non-Tg SMCs (33.0±4.8-fold, n =4, P &lt;0.001), which was attenuated by PKA inhibitor or TAK1 inhibitor. Immunohistochemistry showed abundant expressions of IL-6 and phosphorylated TAK1 in EP4-positive human AAA but not in non-aneurysmal aorta. Conclusion: PGE 2 -EP4 signaling in SMCs initiates inflammatory reaction and AAA formation via upregulation of IL-6.
The tyrosine kinase p56lck is essential in coxsackievirus B3-mediated heart disease
Authors: Peter Liu, Karen Aitken, Young-Yun Kong, Mary Anne Opavsky, Tammy Martino, Fayez Dawood, Wen-Hu Wen, Ivona Kozieradzki, Kurt Bachmaier, David Straus, Tak W. Mak, Josef M. Penninger
Journal: Nature Medicine (2000)
Elixir of Life
Authors: Ergin Beyret, Paloma Martinez Redondo, Aida Platero Luengo, Juan Carlos Izpisua Belmonte
Journal: Circulation Research (2018)

All living beings undergo systemic physiological decline after ontogeny, characterized as aging. Modern medicine has increased the life expectancy, yet this has created an aged society that has more predisposition to degenerative disorders. Therefore, novel interventions that aim to extend the healthspan in parallel to the life span are needed. Regeneration ability of living beings maintains their biological integrity and thus is the major leverage against aging. However, mammalian regeneration capacity is low and further declines during aging. Therefore, modalities that reinforce regeneration can antagonize aging. Recent advances in the field of regenerative medicine have shown that aging is not an irreversible process. Conversion of somatic cells to embryonic-like pluripotent cells demonstrated that the differentiated state and age of a cell is not fixed. Identification of the pluripotency-inducing factors subsequently ignited the idea that cellular features can be reprogrammed by defined factors that specify the desired outcome. The last decade consequently has witnessed a plethora of studies that modify cellular features including the hallmarks of aging in addition to cellular function and identity in a variety of cell types in vitro. Recently, some of these reprogramming strategies have been directly used in animal models in pursuit of rejuvenation and cell replacement. Here, we review these in vivo reprogramming efforts and discuss their potential use to extend the longevity by complementing or augmenting the regenerative capacity.
Evaluation of Primary Angle-Closure Glaucoma Susceptibility Loci in Patients with Early Stages of Angle-Closure Disease
Authors: Monisha E. Nongpiur, Ching-Yu Cheng, Roopam Duvesh, Saravanan Vijayan, Mani Baskaran, Chiea-Chuen Khor, John Allen, Srinivasan Kavitha, Rengaraj Venkatesh, David Goh, Rahat Husain, Pui Yi Boey, Desmond Quek, Ching Lin Ho, Tina T. Wong, Shamira Perera, Tien Yin Wong, Subbiah R. Krishnadas, Periasamy Sundaresan, Tin Aung, Eranga N. Vithana
Journal: Ophthalmology (2018)
Genetic basis of human congenital anomalies of the kidney and urinary tract
Authors: Simone Sanna-Cherchi, Rik Westland, Gian Marco Ghiggeri, Ali G. Gharavi
Journal: Journal of Clinical Investigation (2018)

The clinical spectrum of congenital anomalies of the kidney and urinary tract (CAKUT) encompasses a common birth defect in humans that has significant impact on long-term patient survival. Overall, data indicate that approximately 20% of patients may have a genetic disorder that is usually not detected based on standard clinical evaluation, implicating many different mutational mechanisms and pathogenic pathways. In particular, 10% to 15% of CAKUT patients harbor an unsuspected genomic disorder that increases risk of neurocognitive impairment and whose early recognition can impact clinical care. The emergence of high-throughput genomic technologies is expected to provide insight into the common and rare genetic determinants of diseases and offer opportunities for early diagnosis with genetic testing.
BRAF-V600E in Peripheral Mononuclear Cells and Microglia-like Brain Cells Suggest Hematopoietic Origin of Langerhans Cell Histiocytosis-Associated Neurodegeneration
Authors: Daniel Zinn, Jennifer Picarsic, Rikhia Chakraborty, Howard Lin, Harshal Abhyankar, Brooks Scull, Albert Shih, Karen Phaik Har Lim, Olive S. Eckstein, Tricia L. Peters, Walter Olea, Thomas Burke, Nabil Ahmed, John Hicks, Brandon Tran, Jeremy Jones, Robert Dauser, Michael R. Jeng, Robert A Baiocchi, Deborah E. Schiff, Stanton Goldman, Kenneth Matthew Heym, Harry Wilson, Benjamin Carcamo, Ashish Kumar, Carlos Rodriguez-Galindo, Nicholas Whipple, Patrick Campbell, Geoffrey Murdoch, Simon Heales, Marian Malone, Randy Woltjer, Joseph Quinn, Paul Orchard, Michael Kruer, Ronald Jaffe, Markus G Manz, Sergio Lira, Donald Will Parsons, Miriam Merad, Tsz-kwong Man, Kenneth L. McClain, Carl E. Allen
Journal: Blood (2017)
Loss of RKIP is a frequent event in myeloid sarcoma and promotes leukemic tissue infiltration
Authors: Veronica Caraffini, Bianca Perfler, Johannes Lorenz Berg, Barbara Uhl, Silvia Schauer, Karl Kashofer, Nassim Ghaffari-Tabrizi-Wizsy, Herbert Strobl, Albert Wölfler, Gerald Hoefler, Heinz Sill, Armin Zebisch
Journal: Blood (2018)
Take me to the liver: adipose tissue macrophages coordinate hepatic neutrophil recruitment
Authors: Gerard Pernes, Graeme I Lancaster, Andrew J Murphy
Journal: Gut (2018)

In the lean, healthy state, adipose tissue (AT) has critical roles in maintaining organismal homeostasis. Paramount among the various roles of AT is the regulation of whole body metabolism. While adipocytes per se are key players in metabolic homeostasis, for example, by storing nutrients and releasing soluble factors, work over the last decade has revealed that AT-resident immune cells have a profound impact on AT function. Obesity is a risk factor for numerous conditions, including cardiovascular disease, type 2 diabetes, cancer, osteoarthritis, sleep apnoea and infertility. Obesity is also a major risk factor for the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), an effect that is primarily attributable to increased hepatic lipid accumulation and inflammation. During the development of obesity, the AT expands and the AT-resident immune cell profile is dramatically altered,1 ultimately initiating AT inflammation and altered whole body metabolism. Most prominent among these changes is the marked recruitment of CD11c+ inflammatory macrophages to visceral (v)AT. By producing a range of secreted factors, obese, inflamed AT, primarily via inflammatory macrophages, has effects on multiple tissues, including initiating myelopoiesis within the bone marrow and stimulating hepatic glucose production. However, while the role of AT inflammatory macrophages in altered metabolic homeostasis is well established, whether AT macrophages (ATMs) directly cause hepatic inflammation during the development of NASH is unknown.

In Gut , Bijnen and colleagues show that macrophages recruited to obese vAT contribute to innate immune cell recruitment in the liver, …
The Bcl-2 BH4 Antagonist Bda-366 Induces Apoptosis in CLL and DLBCL Cells through a Bcl-2 Independent Mechanism
Authors: Binu K Sasi, Tamara Vervloessem, Stefania Gobessi, Idanna Innocenti, Luca Laurenti, Geert Bultynck, Dimitar G Efremov
Journal: Blood (2016)
Sustained Long-Lasting Responses after Lenalidomide Discontinuation in Patients with Chronic Lymphocytic Leukemia
Authors: Paolo Strati, Alessandra Ferrajoli, William G Wierda, Nitin Jain, Philip A Thompson, Susan M. O'Brien, Katy Rezvani, Hagop M. Kantarjian, Jan A. Burger, Christina Hinojosa, Michael J. Keating, Zeev Estrov
Journal: Blood (2017)
Establishing a Preclinical Multidisciplinary Board for Brain Tumors
Authors: Birgit V. Nimmervoll, Nidal Boulos, Brandon Bianski, Jason Dapper, Michael DeCuypere, Anang Shelat, Sabrina Terranova, Hope E. Terhune, Amar Gajjar, Yogesh T. Patel, Burgess B. Freeman, Arzu Onar-Thomas, Clinton F. Stewart, Martine F. Roussel, R. Kipling Guy, Thomas E. Merchant, Christopher Calabrese, Karen D. Wright, Richard J. Gilbertson
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Curing all children with brain tumors will require an understanding of how each subtype responds to conventional treatments and how best to combine existing and novel therapies. It is extremely challenging to acquire this knowledge in the clinic alone, especially among patients with rare tumors. Therefore, we developed a preclinical brain tumor platform to test combinations of conventional and novel therapies in a manner that closely recapitulates clinic trials. Experimental Design: A multidisciplinary team was established to design and conduct neurosurgical, fractionated radiotherapy and chemotherapy studies, alone or in combination, in accurate mouse models of supratentorial ependymoma (SEP) subtypes and choroid plexus carcinoma (CPC). Extensive drug repurposing screens, pharmacokinetic, pharmacodynamic, and efficacy studies were used to triage active compounds for combination preclinical trials with “standard-of-care” surgery and radiotherapy. Results: Mouse models displayed distinct patterns of response to surgery, irradiation, and chemotherapy that varied with tumor subtype. Repurposing screens identified 3-hour infusions of gemcitabine as a relatively nontoxic and efficacious treatment of SEP and CPC. Combination neurosurgery, fractionated irradiation, and gemcitabine proved significantly more effective than surgery and irradiation alone, curing one half of all animals with aggressive forms of SEP. Conclusions: We report a comprehensive preclinical trial platform to assess the therapeutic activity of conventional and novel treatments among rare brain tumor subtypes. It also enables the development of complex, combination treatment regimens that should deliver optimal trial designs for clinical testing. Postirradiation gemcitabine infusion should be tested as new treatments of SEP and CPC. Clin Cancer Res; 24(7); 1654–66. ©2018 AACR.
Abstract 12677: Serum FGF23 Level is Associated With Cardiac Abnormality Among Patients Without Chronic Kidney Disease Stages
Authors: Suguru Tanaka, Hideaki Morita, Yoshihiro Takeda, Shu-ichi Fujita, Koichi Sohmiya, Masaaki Hoshiga, Nobukazu Ishizaka
Journal: Circulation (2016)

Background: Several experimental studies have demonstrated that fibroblast growth factor 23 (FGF23) may induce myocardial hypertrophy. On the other hand, few studies have clearly demonstrated the relationship between FGF23 level and left ventricular hypertrophy among subjects without chronic kidney disease (CKD; i.e., CKD stage G1 or G2). We investigate the association between FGF23 and cardiac parameters among 903 patients with various degrees of renal function, including 234 patients with CKD stage G1/G2. Methods and Results: Serum levels of full-length FGF23 were determined by enzyme immunoassay. After adjustment for sex, age, and estimated glomerular filtration rate (eGFR), the highest FGF23 tertile was significantly associated with left ventricular hypertrophy among patients with CKD stage G1/G2 as compared with the lowest FGF23 tertile as well as among those with CKD stage G3a/G3b/G4. This association retained significance after further adjustment for serum levels of corrected calcium, inorganic phosphate, and C-reactive protein. FGF23 was also associated with left ventricular ejection fraction (LVEF) &lt;50% among patients with CKD stage G1/G after multivariate analysis. By the ROC curve analysis among these no-CKD patients, compared with model 1 (combination of age, sex, and eGFR), area under the curve of model 2 (model 1+FGF23) was significantly greater for the prediction of left ventricular hypertrophy. Conclusions: An association between FGF23 and cardiac hypertrophy and systolic dysfunction was observed among patients without CKD as well as those with CKD, suggesting FGF23 per se may have direct effect on the cardiac geometry and performance.
How accurate is clinical assessment of neck veins in the estimation of central venous pressure in acute heart failure? Insights from a prospective study
Authors: Tobias Breidthardt, Zoraida Moreno‐Weidmann, Heiko Uthoff, Zaid Sabti, Sven Aeppli, Christian Puelacher, Fabio Stallone, Raphael Twerenbold, Karin Wildi, Nikola Kozhuharov, Desiree Wussler, Dayana Flores, Samyut Shrestha, Patrick Badertscher, Jasper Boeddinghaus, Thomas Nestelberger, Maria Rubini Gimenez, Daniel Staub, Markus Aschwanden, Jens Lohrmann, Otmar Pfister, Stefan Osswald, Christian Mueller
Journal: European Journal of Heart Failure (2018)
Endoplasmic reticulum stress in the pathogenesis of fibrotic disease
Authors: Jonathan A. Kropski, Timothy S. Blackwell
Journal: Journal of Clinical Investigation (2018)

Eukaryotic cells contain an elegant protein quality control system that is crucial in maintaining cellular homeostasis; however, dysfunction of this system results in endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). Severe or prolonged ER stress is associated with the development of degenerative and fibrotic disorders in multiple organs, as evidenced by the identification of disease-causing mutations in epithelial-restricted genes that lead to protein misfolding or mistrafficking in familial fibrotic diseases. Emerging evidence implicates ER stress and UPR signaling in a variety of profibrotic mechanisms in individual cell types. In epithelial cells, ER stress can induce apoptosis, inflammatory signaling, and epithelial-mesenchymal transition. In other cell types, ER stress is linked to myofibroblast activation, macrophage polarization, and T cell differentiation. ER stress–targeted therapies have begun to emerge using approaches that range from global enhancement of chaperone function to selective targeting of activated ER stress sensors and other downstream mediators. As the complex regulatory mechanisms of this system are further clarified, there are opportunities to develop new disease-modifying therapeutic strategies in a wide range of chronic fibrotic diseases.