tbuckley/cabot-search huggingface dataset:
Single-chain polymer nanoparticles in controlled drug delivery and targeted imaging
Authors: A. Pia P. Kröger, Jos M.J. Paulusse
Journal: Journal of Controlled Release (2018)

As a relatively new class of materials, single-chain polymer nanoparticles (SCNPs) just entered the field of (biomedical) applications, with recent advances in polymer science enabling the formation of bio-inspired nanosized architectures. Exclusive intramolecular collapse of individual polymer chains results in individual nanoparticles. With sizes an order of magnitude smaller than conventional polymer nanoparticles, SCNPs are in the size regime of many proteins and viruses (1-20 nm). Multifaceted syntheses and design strategies give access to a wide set of highly modular SCNP materials. This review describes how SCNPs have been rendered water-soluble and highlights ongoing research efforts towards biocompatible SCNPs with tunable properties for controlled drug delivery, targeted imaging and protein mimicry.
Abstract 2626: Combination of chemotherapy and cytokine facilitates adoptive transferred effector T cells homing to the core of metastatic tumors
Authors: Jiemiao Hu, Qingnan Zhao, Xueqing Xia, Richard Gorlick, Shulin Li
Journal: Cancer Research (2018)

Abstract Metastatic disease accounts for most cases of cancer mortality, due to its systemic nature and resistance to existing therapeutics for primary tumors. Immune therapy has become a viable alternative for treating drug-resistant tumors. In fact, increased immune density in metastasis lesions is associated with beneficial clinical outcomes. Notably, tumor infiltrating lymphocyte (TIL) infusions extended the overall survival of refractory melanoma patients. However, whether or not T cell therapy could be used to successfully limit the metastatic progression largely depends on the complexity of T cell penetration and tumor-immune cell interaction in distant sites. During the past years, our group has identified a simple combination of an immune stimulatory signal (interleukin-12) and chemotherapy (doxorubicin) that persistently induces NKG2D ligand on tumor cells in vivo across tumor types and developed a novel CD28 stimulation based approach for fast induction of NKG2D receptor on CD8+ T cells. We found in breast carcinoma model (4T-1) and pediatric osteosarcoma models (K7M3 and LM8), adoptive transfer of NKG2D+CD8+ T cells after the combination of IL-12 plus doxorubicin treatment dramatically reduced the numbers and sizes of metastatic nodules, leading to significantly prolonged survival time. Mechanically, the treatment of IL-12 plus doxorubicin widely upregulated the expression of NKG2D ligands exclusively on tumor cells in metastatic lesions, and allowed high density of NKG2D+CD8+ T cell accumulation at both the core and invasive margin areas of metastatic tumors. Furthermore, this combination therapeutic led to reduced regulatory T cell infiltration, resulting in increased CD8+ T cell to regulatory T cell ratios in metastatic tumors. Collectively, here we reported that a simple combination treatment of IL-12 plus doxorubicin with subsequent NKG2D+ CD8+T cell adoptive transfer may transform the metastatic tumor microenvironment to enable the influx of NKG2D+CD8+ T cells which effectively kill tumor cells via NKG2D-NKG2D ligand interaction. This promising therapeutic approach greatly improved the effectiveness and potential of adoptive T cell therapy in treating cancer patients with metastatic diseases. Citation Format: Jiemiao Hu, Qingnan Zhao, Xueqing Xia, Richard Gorlick, Shulin Li. Combination of chemotherapy and cytokine facilitates adoptive transferred effector T cells homing to the core of metastatic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2626.
Heart Rate–Independent Vagal Effect on End-Systolic Elastance of the Canine Left Ventricle Under Various Levels of Sympathetic Tone
Authors: YasunoriNakayama, HiroshiMiyano, ToshiakiShishido, MasashiInagaki, ToruKawada, MasaruSugimachi, KenjiSunagawa
Journal: Circulation (2001)

Background Although we have shown that in rabbits the direct (heart rate [HR]–independent) vagal effect on left ventricular end-systolic elastance (Ees) was negligible under minimal sympathetic tone, how underlying sympathetic tone modulates the inotropic response to vagal stimulation remains unknown. Methods and Results We used an isolated canine heart preparation with functioning autonomic nerves. We examined the direct vagal inotropic effect by measuring Ees under fixed-rate atrial pacing with or without concomitant sympathetic nerve stimulation. Right and left vagal stimulation at 20 Hz decreased HR by 27±3% and 14±2%, respectively, and decreased Ees by 11±2% and 6±2%, respectively. When we fixed HR by atrial pacing, right and left vagal stimulation at 20 Hz did not decrease Ees (0.01±0.3% and 0.3±0.4%; NS). Concomitant left sympathetic nerve stimulation at 4 Hz enhanced direct vagal negative inotropism to −19±3% and −34±5% for 20-Hz right and left vagal stimulation (interaction, P<0.01). Conclusions ...
Cardiovascular Stress Hyperreactivity in Babies of Smokers and in Babies Born Preterm
Authors: GaryCohen, SilvanoVella, HeatherJeffery, HugoLagercrantz, MiriamKatz-Salamon
Journal: Circulation (2008)

Background— Being born preterm, small, and to a mother who smokes are common perinatal complications with major public health implications. Evidence suggests that each affects the body’s structure and function in ways that could increase susceptibility to cardiovascular dysfunction later in life. Here, we used 2 routine stress reactivity tests to identify incipient “silent” programming of cardiovascular dysfunction associated with adverse perinatal events. Methods and Results— We studied 29 control babies born at term to nonsmokers, 18 term-born babies of mothers who smoked throughout pregnancy (mean, 15 cigarettes a day), and 31 babies born preterm to nonsmokers. All infants were compared at the same age after conception (ie, at 40 to 42 weeks), during sleep. We analyzed blood pressure (BP) and heart rate responses to breathing 4% CO2 for 4 minutes or to passive head-up tilt to 60°. BP was measured continuously from a wrist cuff. CO2 exposure raised heart rate and BP in controls by 10%, and tilt increase...
Abstract 5836: Activation Induced Cytosine Deamination, AICDA, is induced after EGFR TKI exposure leading to secondary resistant mutations in lung adenocarcinoma
Authors: Najwa El Kadi, April Davis, Alexander Cooke, Luo Wang, Hasan Korkaya, Gregory Kalemkerian, Khaled Hassan
Journal: Cancer Research (2018)

Abstract Background: Epidermal growth factor receptor (EGFR) activation mutations occur in 10-50% of lung adenocarcinomas. This leads to constitutive activation of EGFR, which triggers multiple downstream survival and proliferation pathways. EGFR tyrosine kinase inhibitors (TKIs) are the mainstay of treatment for stage IV non-small cell lung cancer (NSCLC) patients with EGFR mutations. Acquired EGFR mutations are the main mechanism of on-target resistance to TKIs. T790M mutation that occurs after first line TKI treatment, is a cytosine to thymine (C&amp;gt;T) single nucleotide transition leading to a threonine to methionine amino acid change at position 790 (i.e. T790M). Interestingly, treatment with Osimertinib, that overcomes the T790M mutation, leads to other acquired resistant mutations, C797S, G796S/R and L792F/H. Our data suggest that resistant mutations are acquired events secondary to cytosine deamination through Activation Induced Cytosine Deamination enzyme (AICDA). Results: Sub clones of the lung adenocarcinoma cell line PC9 with no evidence of T790M mutation by droplet digital PCR (ddPCR) at baseline, were treated with EGFR TKI. After serially increasing the treatment dose, T790M mutation was detected by ddPCR associated with a significant increase in AICDA expression. Knocking down AICDA by shRNA, decreases the development of T790M in PC9 cell lines after TKI exposure. Similarly, when the resistant T790M PC9 clones were treated with Osimertinib, the expression of AICDA was also induced. Using mass spectrometry, we established that cytosine at codon 790 is methylated; thus, deamination of 5-methylcytosine leads to thymine directly, explaining the T790M C&amp;gt;T mutation. In addition, using ChIP assay and pharmacological inhibition we confirm that upon TKI exposure, NFĸB binds AICDA promoter and induces its expression. In a mouse xenograft model, the induction of NFĸB and AICDA after EGFR TKI exposure is abrogated by concurrent use of an NFĸB inhibitor. Finally, patients treated with EFR TKI had an increased expression of AICDA upon progression. Conclusion: In EGFR driven lung adenocarcinoma, NFĸB pathway is activated upon exposure to EGFR TKIs which induces AICDA expression. AICDA deaminates cytosine into other nucleotides leading to treatment resistance. Citation Format: Najwa El Kadi, April Davis, Alexander Cooke, Luo Wang, Hasan Korkaya, Gregory Kalemkerian, Khaled Hassan. Activation Induced Cytosine Deamination, AICDA, is induced after EGFR TKI exposure leading to secondary resistant mutations in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5836.
Abstract 20628: Multivitamin/Mineral Use and Risk of Cardiovascular Disease: Meta-Analysis of Prospective Cohort Studies
Authors: Joonseok Kim, Jaehyoung Choi, Dorothy E Jung, Soo Young Kwon
Journal: Circulation (2016)

Introduction: Multiple prospective studies have attempted to identify the association between multivitamin/mineral (MVM) supplementation and cardiovascular outcomes, but the benefit of MVM remains ...
Abstract 13306: Combined Assessment of Acute Kidney Injury and Increased Plasma Concentration of D-dimer Is Useful for Evaluating 1-year Mortality in Patients Hospitalized to Coronary Care Units
Authors: Shigeru Matsui, Junichi Ishii, Ryuunosuke Okuyama, Hiroshi Takahashi, Hideki Kawai, Takashi Muramatsu, Akira Yamada, Sadako Motoyama, Hiroyuki Naruse, Mutsuharu Hayashi, Hideki Izawa, Yukio Ozaki
Journal: Circulation (2015)

Background: Acute kidney injury (AKI) detected after admission to coronary care unit (CCU) is associated with very poor outcomes. We prospectively investigated the prognostic value of a combination of AKI and high plasma D-dimer levels for 1-year mortality in patients hospitalized to CCUs. Methods: D-dimer, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitive C-reactive protein (hsCRP) levels were measured in 1228 patients on admission to CCUs, of whom 56% had decompensated heart failure and 38% had acute coronary syndrome. AKI was defined as an increase of &gt;25% in creatinine from baseline or an absolute increase of ≥0.5 mg/dL within 48 h after admission. Left ventricular ejection fraction (LVEF) and E/e’ ratio were estimated using echocardiography with tissue Doppler imaging. Results: AKI was detected in 163 (13%) patients. During 1-year follow-up period, there were 149 (12%) deaths. The patients who died were older (median: 77 vs. 73 years; p &lt; 0.0001) and exhibited higher D-dimer (2.7 vs. 1.3 μg/mL; p &lt; 0.0001), NT-proBNP (5495 vs. 1525 pg/mL; p &lt; 0.0001), and hsCRP levels (0.92 vs, 0.26 mg/L; p &lt; 0.0001) and E/e’ ratio (15.0 vs. 13.2; p = 0.006). They also had a higher incidence of AKI (26% vs. 12%; p &lt; 0.0001) and lower LVEF (39% vs. 49%; p &lt; 0.0001) and estimated glomerular filtration rate (45 vs. 62 mL/min/1.73 m 2 ; p &lt; 0.0001) than patients who survived. Multivariate Cox regression analysis, including 12 clinical, biochemical, and echocardiographic variables, identified AKI (relative risk: 1.79; p = 0.008) and increased D-dimer level (relative risk: 1.83 per 10-fold increment; p = 0.002) as independent predictors of 1-yeart mortality. The combined assessment of AKI and D-dimer quartiles was significantly associated with 1-year mortality rates (Figure). Conclusions: The combined assessment of AKI and high D-dimer levels may be useful for evaluating the risk of 1-year mortality in patients admitted to CCUs.
Apoptosis Resistance and NOTCH1 Mutations Impair Clinical Outcome in Chronic Lymphocytic Leukemia (CLL) Patients Treated with Ibrutinib
Authors: Giovanni Del Poeta, Maria Ilaria Del Principe, Massimiliano Postorino, Riccardo Bomben, Emilia Iannella, Francesco Buccisano, Maria Francesca Rossi, Adriano Venditti, Enrico Santinelli, Paolo de Fabritiis, Maria Cantonetti, Sergio Amadori, Valter Gattei, William Arcese
Journal: Blood (2017)
Abstract 552: PEPD is an essential regulator of p53 tumor suppressor
Authors: Lu Yang, Yun Li, Arup Bhattacharya, Yuesheng Zhang
Journal: Cancer Research (2018)

Abstract Peptidase D (PEPD), also known as prolidase among other names, is an enzyme that hydrolyzes dipeptides with proline or hydroxyproline at the carboxy terminus and is believed to be important for collagen metabolism, as proline and hydroxyproline are very abundant in collagen. Interestingly, we recently found that eliminating cellular PEPD causes cell death and tumor regression due to p53 activation. Here, we show that PEPD binds to and suppresses over half of nuclear and cytoplasmic p53 under normal conditions, independent of its enzymatic activity. PEPD binds to the proline-rich domain in p53, which inhibits phosphorylation of nuclear p53 and MDM2-mediated mitochondrial translocation of nuclear and cytoplasmic p53. Indeed, PEPD competes with MDM2 for p53 binding. However, the PEPD-p53 complex is critical for p53 response to stress, as stress signals doxorubicin (DOX) and hydrogen peroxide each must free p53 from PEPD in order to achieve robust p53 activation, which is mediated by reactive oxygen species. Thus, PEPD stores p53 for stress response, but this also renders cells dependent on PEPD for survival as it suppresses p53. Our results reveal a major p53 regulatory mechanism and a critical physiological function of PEPD. The p53-PEPD system likely operates in most if not all cells, since both p53 and PEPD are expressed ubiquitously. Disrupting PEPD suppression of p53 may be an important therapeutic strategy in cancer, as our data show that PEPD knockdown by RNA interference in tumors in mice causes p53 activation in the tumor tissues and tumor regression. Our study also reveals a previously unrecognized anticancer mechanism of DOX. We show that the key step in DOX-induced p53 activation is the disruption of p53 association with PEPD via reactive oxygen species. This finding also raises the intriguing question of whether other stress-inducing anticancer agents also disrupt the PEPD-p53 complex for p53 activation and suggests that antioxidants may inhibit the anticancer activity of DOX and other agents by inhibiting p53 separation from PEPD. This work is supported by NCI grants and Roswell Park Alliance Foundation Grants. Citation Format: Lu Yang, Yun Li, Arup Bhattacharya, Yuesheng Zhang. PEPD is an essential regulator of p53 tumor suppressor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 552.
Positive Association of the Endothelial Nitric Oxide Synthase Gene Polymorphisms With High-Altitude Pulmonary Edema
Authors: YundenDroma, MasayukiHanaoka, MasaoOta, YoshihikoKatsuyama, TomonobuKoizumi, KeisakuFujimoto, ToshioKobayashi, KeishiKubo
Journal: Circulation (2002)

Background— A defect of nitric oxide (NO) synthesis in the lung of high-altitude pulmonary edema (HAPE) has been suggested to contribute to its exaggerated pulmonary hypertension. Several polymorphisms have been identified in the gene encoding endothelial nitric oxide synthase (eNOS), which is a key enzyme responsible for NO synthesis, some of which were reported to be associated with vascular disorders. Methods and Results— We studied 41 HAPE-susceptible subjects (HAPE-s) and 51 healthy climbers (control group) in a Japanese population. We examined 2 polymorphisms of the eNOS gene, including the Glu298Asp variant and 27-base pair (bp) variable numbers of tandem repeats using polymerase chain reaction followed by restriction fragment length polymorphism. The Asp allelic frequency of the Glu298Asp variant was 25.6% in the HAPE-s and 9.8% in the controls, which was significantly different between the two groups (P=0.0044). The eNOS4a allelic frequency of 27-bp variable numbers of tandem repeats was 23.2% in...
Paclitaxel Reduces Tumor Growth by Reprogramming Tumor-Associated Macrophages to an M1 Profile in a TLR4-Dependent Manner
Authors: Carlos W. Wanderley, David F. Colón, João Paulo M. Luiz, Francisco F. Oliveira, Paula R. Viacava, Caio A. Leite, Janaina A. Pereira, Camila M. Silva, Cassia R. Silva, Rangel L. Silva, Cesar A. Speck-Hernandez, José M. Mota, José C. Alves-Filho, Roberto C. Lima-Junior, Thiago M. Cunha, Fernando Q. Cunha
Journal: Cancer Research (2018)

Abstract Paclitaxel is an antineoplastic agent widely used to treat several solid tumor types. The primary mechanism of action of paclitaxel is based on microtubule stabilization inducing cell-cycle arrest. Here, we use several tumor models to show that paclitaxel not only induces tumor cell-cycle arrest, but also promotes antitumor immunity. In vitro, paclitaxel reprogrammed M2-polarized macrophages to the M1-like phenotype in a TLR4-dependent manner, similarly to LPS. Paclitaxel also modulated the tumor-associated macrophage (TAM) profile in mouse models of breast and melanoma tumors; gene expression analysis showed that paclitaxel altered the M2-like signature of TAMs toward an M1-like profile. In mice selectively lacking TLR4 on myeloid cells, for example, macrophages (LysM-Cre+/−/TLR4fl/fl), the antitumor effect of paclitaxel was attenuated. Gene expression analysis of tumor samples from patients with ovarian cancer before and after treatment with paclitaxel detected an enrichment of genes linked to the M1 macrophage activation profile (IFNγ-stimulated macrophages). These findings indicate that paclitaxel skews TAMs toward an immunocompetent profile via TLR4, which might contribute to the antitumor effect of paclitaxel and provide a rationale for new combination regimens comprising paclitaxel and immunotherapies as an anticancer treatment. Significance: This study provides new evidence that the antitumor effect of paclitaxel occurs in part via reactivation of the immune response against cancer, guiding tumor-associated macrophages toward the M1-like antitumor phenotype. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/20/5891/F1.large.jpg. Cancer Res; 78(20); 5891–900. ©2018 AACR. See related commentary by Garassino et al., p. 5729
Hypertension and Ischemic Heart Disease in Hiroshima, Japan
Authors: Samswitzer
Journal: Circulation (1963)

A random sampling of Hiroshima residents, comprising 1,051 males and 1,872 females, has been studied with respect to the interrelations of hypertension, ischemic heart disease, blood lipid levels, and ionizing irradiation experienced during the atom bombing of 1945. No significant effect of ionizing irradiation upon the cardiovascular system has been detected. No major difference in age-sex specific mean blood pressures between Hiroshima residents and a suitable white American comparison group was found. Dissimilarities noted with other groups compared are considered due to the sum of sampling bias, varying technics, and coincidental environmental factors rather than a true racial difference. Blood pressure levels, stable from puberty through young adulthood, begin to rise early in middle age and continue to rise into old age. As a result, hypertension as clinically defined (140/90), is common in middle-aged and elderly Japanese. In 94.4 per cent of instances, or more, a demonstrable etiology for hyperten...
Abstract 14848: Can a Quick-Look Exam Improve Echo Referral? Implications for Appropriate and Competent Use of Ultrasound Stethoscopes
Authors: Paul J Han, James N Phan, Kristin L Halvorsen, Tanya Wolfson, Stan A Amundson, Bruce J Kimura
Journal: Circulation (2013)

Background: As few data exist on how to cost-effectively and competently apply ultrasound stethoscopes, we examined whether a threshold accuracy of any quick-look imaging protocol could potentially...
Abstract 1792: Upregulation of INSR/IGF1Rby C-myc promotes TSCC tumorigenesis and metastasis through the NF-κB pathway
Authors: Anxun Wang, Jingjing Sun, Mei Yu, Zhiyuan Lu, Wei Wang
Journal: Cancer Research (2018)

Abstract INSR/IGF1R has been detected to be involved in tumorigenesis and metastasis in various malignancies. The aim of our study was to compare the function role and mechanism of INSR/IGF1R in the progression of tongue squamous cell carcinoma (TSCC). We found that INSR had the same up-regulated expression pattern as IGF1R in TSCC tissues. Up-regulation of INSR/IGF1R was correlated each other and associated with lymph node metastasis and poor prognosis. Functional studies established that INSR/IGF1R knockdown dramatically impeded TSCC in vitro cell growth, migration, invasion and in vivo tumorigenesis and tumor metastasis, whereas ectopic overexpression of INSR/IGF1R enhanced these parameters. INSR/IGF1R promoted TSCC tumorigenesis and metastasis by positively modulating the NF-κB pathway. Furthermore, the up-regulation of INSR and IGF1R in TSCC resulted directly from the binding of C-myc to their promoters. Collectively, our current data demonstrate that the INSR/IGF1R axis, directly targeted by C-myc, plays an important role in the development and progression of TSCC, through NF-κB pathway, and that INSR and IGF1R are potential prognostic factors for TSCC. Citation Format: Anxun Wang, Jingjing Sun, Mei Yu, Zhiyuan Lu, Wei Wang. Upregulation of INSR/IGF1Rby C-myc promotes TSCC tumorigenesis and metastasis through the NF-κB pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1792.