tbuckley/cabot-search huggingface dataset:
Mutant LKB1 Confers Enhanced Radiosensitization in Combination with Trametinib in KRAS-Mutant Non–Small Cell Lung Cancer
Authors: Yifan Wang, Nan Li, Wen Jiang, Weiye Deng, Rui Ye, Cai Xu, Yawei Qiao, Amrish Sharma, Ming Zhang, Mien-Chie Hung, Steven H. Lin
Journal: Clinical Cancer Research (2018)

Purpose: The MEK inhibitor trametinib radiosensitizes KRAS-mutant non-small cell lung cancer (NSCLC) and is being tested clinically with chemoradiation. However, variability in response to trametinib suggests that additional pathways are involved. The mechanism of resistance to trametinib radiosensitization is still unknown.Experimental Design: We used a panel of KRAS-mutant NSCLC cells and tested the radiosensitization effects of trametinib by clonogenic survival assay. Then, we investigated the mechanisms underlying the resistance to the combination therapy through several knockout and overexpression systems. Finally, we validated our findings in syngeneic mouse models in a treatment setting that mimicked the standard of care in the clinic.Results: Radiosensitization by trametinib was effective only in KRAS-LKB1-mutated cells with wild-type (WT) p53, and we found that restoring LKB1 expression in those cells blocked that sensitization. Trametinib and radiotherapy both induced senescence in a p53-dependent manner, but in WT LKB1 cells, the combination also activated the AMPK-autophagy pathway to rescue damaged cells from senescence. LKB1-knockout or autophagy inhibition in WT LKB1 cells potentiated trametinib radiosensitization. In syngeneic animal models of Kras-mutant lung tumors, Lkb1-knockout tumors were resistant to trametinib and chemoradiation given separately, but the combination greatly controlled tumor growth and prolonged survival.Conclusions: The LKB1 mutation in KRAS-mutant NSCLC conferred enhanced radiosensitization in combination with trametinib. The WT LKB1 could activate autophagy through AMPK pathway to induce resistance to the combination of trametinib and radiation. The KRAS-LKB1 mutation could potentially be a biomarker to select patients for trametinib and radiotherapy combination therapy. Clin Cancer Res; 24(22); 5744-56. ©2018 AACR.
Engineered T Cells in Synovial Sarcoma: Persistence Pays Off!
Authors: Emily Z. Keung, Hussein A. Tawbi
Journal: Cancer Discovery (2018)

Abstract Summary: Synovial sarcoma (SS) is an aggressive malignancy that typically affects adolescents and young adults and is associated with poor prognosis. Although SS has failed to respond to immune checkpoint blockade, other strategies designed to generate an immune response, including adoptive cell therapies targeting the cancer testis antigen NY-ESO-1, have shown encouraging results. In this issue, D'Angelo and colleagues confirm the safety and feasibility of adoptive T-cell therapy with autologous T cells engineered to express NY-ESO-1c259, an affinity-enhanced T-cell receptor recognizing an HLA-A2–restricted NY-ESO-1–derived peptide, and demonstrate encouraging antitumor responses in 50% of treated patients, particularly in the setting of persistence of polyfunctional NY-ESO-1c259–expressing T cells in circulation for at least 6 months. Cancer Discov; 8(8); 914–7. ©2018 AACR. See related article by D'Angelo et al., p. 944.
Abstract 2387: The oncogenic role and therapeutic potential of PTPN11 in melanoma
Authors: Kristen Suzanne Hill, Evan Roberts, Ellen Marin, Xue Wang, Jamie Teer, Jane Messina, Jerry Wu, Minjung Kim
Journal: Cancer Research (2018)

Abstract The RAS/RAF/MEK/ERK signaling pathway, which is intricately regulated by multiple proteins including PTPN11 (Tyrosine-Protein Phosphatase Non-Receptor Type 11, encoding SHP2), is frequently activated in melanoma. Although implicated as an oncogene in multiple cancer types, the oncogenic role of PTPN11 has not been established in melanoma. Recently, we preformed whole exome sequencing on tumors generated by a mouse model driven by loss of PTEN and CDKN2A (INK4A/ARF) and identified several conserved cross-species orthologous mutations in Kras, Erbb3, and Ptpn11. In this study, we addressed the functional roles of PTPN11 in melanoma tumorigenesis and tumor maintenance; as well as, PTPN11's effect on the RAS/RAF/MEK/ERK signaling pathway and its activation status in human melanoma. PTPN11 can be activated by receptor tyrosine kinases (RTKs) or by point mutations. We observed activating phosphorylation on Tyr 542 of PTPN11 in 40% (n=15/38) of melanoma specimens and the majority of human melanoma cell lines (n=14), supporting frequent activation of PTPN11 in human melanoma even though the mutation rate is low (1~3%). PTPN11 knock-down suppressed ERK activation in NRAS mutant and BRAF/NRAS wild-type melanoma cells, but not in BRAF mutant cells. Moreover, we have shown that expression of active PTPN11E76K mutant drives soft-agar colony growth in vitro, tumor growth in nude mice, RAS/RAF/MEK/ERK activation, and resistance to MEK inhibition. Alternatively, knock-down of Ptpn11 reduces colony growth and ERK activation. We generated a tet-inducible, melanocyte-specific, PTPN11E76K transgenic mouse model in a PTEN and CDKN2A null background and observed melanoma formation. Implantation of melanoma cells derived from this model showed doxycycline dependent tumor growth in nude mice. Doxycycline withdrawal and subsequent extinction of PTPN11E76K caused regression of established tumors, supporting the tumor maintenance role of PTPN11. Subsequently, tumor tissue from this model underwent phosphor-tyrosine proteomic analysis to identify downstream effectors of PTPN11's protein tyrosine phosphatase activity. The proteins identified in this analysis are currently being confirmed. These data support the oncogenic roles of PTPN11 in melanoma by regulating RAS/RAF/MAPK pathway activation and the value of PTPN11 as a novel and actionable therapeutic target. Citation Format: Kristen Suzanne Hill, Evan Roberts, Ellen Marin, Xue Wang, Jamie Teer, Jane Messina, Jerry Wu, Minjung Kim. The oncogenic role and therapeutic potential of PTPN11 in melanoma [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 2387.
Abstract 14016: Severity Assessment of Brain Damage With rSO2 monitoring for Extracorporeal Cardiopulmonary Resuscitation After Out-of-hospital Cardiac Arrest
Authors: Takashi Unoki, Kei Nishiyama, Noritoshi Ito, Tomohiko Orita, Hideki Arimoto, Satoru Beppu, Mitsuru Abe, Tomoyuki Endo, Hideto Yasuda, Ken Nagao
Journal: Circulation (2016)

Introduction: Decisions regarding extracorporeal cardiopulmonary resuscitation (E-CPR) for patients after out-of-hospital cardiac arrest (OHCA) are difficult to make. Hypothesis: We hypothesized that regional brain oxygen saturation (rSO2) value monitoring in the emergency room was useful for speculating on brain damage severity for prognostication for E-CPR after OHCA. Methods: The J-POP registry is a prospective multicenter cohort study to test whether rSO2 predicts neurological outcomes after nontraumatic OHCA. We measured rSO2 values in OHCA patients immediately after hospital arrival with a near-infrared spectrometer placed on the forehead. The primary endpoint was neurological outcome (cerebral performance category: 1, 2) 90 days after OHCA. Results: We consecutively enrolled 1,921 OHCA patients. After 90 days, 79 (4%) patients had good neurological outcomes and a median lower rSO2 level of 15% (95% confidence interval (CI): 15-20%). Receiver operating curve analysis indicated an optimal rSO2 cutoff point was about 40% for predicting good neurological outcome (area under curve = 0.91 [95% CI: 0.90 - 0.92], P &lt; 0.01). Compared to patients without return of spontaneous circulation (ROSC) upon arrival at the hospital, those with ROSC had significantly higher rSO2 levels (56% [95% CI: 39-65%] vs. 15% [95% CI: 15-17%], respectively; P &lt; 0.01). In patients without ROSC upon arrival at the hospital (n=1773), the percentage of patients with a good 90-day neurological outcome increased significantly in proportion to their rSO2 levels upon arrival at the hospital (P &lt; 0.01, Figure). In patients with E-CPR (n=121), the percentage of patients with a good 90-day neurological outcome increased significantly if their rSO2 levels upon arrival at the hospital was &gt;40% (5/16, 31% vs 6/105, 6%, P &lt; 0.01). Conclusions: rSO2 value monitoring in the emergency room was useful for speculating on brain damage severity for prognostication for E-CPR after OHCA.
Abstract 12553: Telmisartan, a Clinically Available Anti-Hypertensive Medicine, Enhances Mitochondrial Function and Improves Endothelial Dysfunction Through the AMPK Pathway
Authors: HirofumiKurokawa, SeigoSugiyama, ToshimitsuNozaki, KoichiSugamura, KensukeToyama, JunichiMatsubara, KoichiroFujisue, KeisukeOhba, HirofumiMaeda, EiichirouYamamoto, KenichiTsujita, KoichiKaikita, SeijiHokimoto, HisaoOgawa
Journal: Circulation (2014)

Background: Mitochondrial dysfunction plays an important role in cellular senescence and impaired function of vascular endothelium, resulted in cardiovascular diseases. AMP-activated protein kinase (AMPK) plays a critical role in mitochondrial biogenesis and endothelial function. Telmisartan (TELMI) is a unique angiotensin II type I receptor blocker (ARB) that has clinically been shown to prevent cardiovascular events in high risk patients. We investigated whether TELMI could modulate mitochondrial function leads to improvement of endothelial function via AMPK, and could improve endothelial function in mice and human. Methods and Results: In cultured human coronary artery endothelial cells (HCAECs), TELMI significantly increased the phosphorylation of AMPK (1.61±0.45 fold, p<0.05) and endothelial nitric oxide synthase (eNOS) (1.39±0.23 fold, p<0.01), and enhanced mitochondrial function as assessed by both mitochondrial reductase activity (1.22±0.15 fold, p<0.01) and ATP production (1.16±0.93 fold, p<0.05)...
Antihypertensive Treatment Improves Endothelium-Dependent Hyperpolarization in the Mesenteric Artery of Spontaneously Hypertensive Rats
Authors: UranOnaka, KojiFujii, IsaoAbe, MasatoshiFujishima
Journal: Circulation (1998)

Background—The vascular endothelium releases endothelium-derived hyperpolarizing factor (EDHF). The mesenteric arteries of 6- to 8-month-old spontaneously hypertensive rats (SHRs) exhibit an impairment of the hyperpolarization induced by acetylcholine via EDHF. Methods and Results—We determined whether antihypertensive treatment can improve EDHF-mediated responses in SHRs. Beginning at age 8 to 9 months, the animals were treated with either enalapril (40 mg · kg−1 · d−1) (SHR-Es) or a combination of hydralazine (25 mg · kg−1 · d−1) and hydrochlorothiazide (7.5 mg · kg−1 · d−1) (SHR-Hs) for 3 months. The control groups were age-matched SHRs (SHR-Cs) and Wistar Kyoto rats (WKYs). The two treatments lowered the blood pressure to comparable extents. The acetylcholine-induced hyperpolarization in the mesenteric artery of treated SHRs improved to a level comparable to that in WKYs (acetylcholine 10−5 mol/L with norepinephrine 10−5 mol/L: SHR-E, −14.4±1.8; SHR-H, −12.0±1.3; SHR-C, −7.2±1.2; and WKY, −13.3±2.3 mV...
Overexpression of Inducible Nitric Oxide Synthase in Rostral Ventrolateral Medulla Causes Hypertension and Sympathoexcitation via an Increase in Oxidative Stress
Authors: YoshikuniKimura, YoshitakaHirooka, YojiSagara, KojiIto, TakuyaKishi, HiroakiShimokawa, AkiraTakeshita, KenjiSunagawa
Journal: Circulation Research (2005)

The present study examined the role of inducible nitric oxide synthase (iNOS) in the rostral ventrolateral medulla (RVLM) of the brain stem, where the vasomotor center is located, in the control of blood pressure and sympathetic nerve activity. Adenovirus vectors encoding iNOS (AdiNOS) or β-galactosidase (Adβgal) were transfected into the RVLM in Wistar-Kyoto (WKY) rats. Blood pressure and heart rate were monitored using a radiotelemetry system. iNOS expression in the RVLM was confirmed by immunohistochemical staining or Western blot analysis. Mean arterial pressure significantly increased from day 6 to day 11 after AdiNOS transfection, but did not change after Adβgal transfection. Urinary norepinephrine excretion was significantly higher in AdiNOS-transfected rats than in Adβgal-transfected rats. Microinjection of aminoguanidine or S-methylisothiourea, iNOS inhibitors, or tempol, an antioxidant, significantly attenuated the pressor response evoked by iNOS gene transfer. The levels of thiobarbituric acid-...
Overall survival and risk of second malignancies with cancer chemotherapy and G-CSF support
Authors: G.H. Lyman, L. Yau, R. Nakov, A. Krendyukov
Journal: Annals of Oncology (2018)

BackgroundThe use of supportive granulocyte colony-stimulating factor (G-CSF) to reduce the risk of neutropenic complications in high-risk cancer patients is consistently recommended by several clinical practice guidelines. However, in a previous meta-analysis, G-CSF prophylaxis was associated with an increased risk of secondary malignancies while reducing long-term mortality. We present here an updated systematic review and meta-analysis.Materials and methodsA systematic literature search was carried out to identify randomized controlled trials of cancer patients receiving conventional-dose chemotherapy, assigned to primary G-CSF support or a control group without initial G-CSF, with at least 2 years of follow-up. Studies were categorized into one of the four groups, based on the chemotherapy regimen and study design. An updated meta-analysis was carried out; relative risk (RR) and 95% confidence intervals (CIs) for all-cause mortality and secondary malignancies were calculated.ResultsOf 2604 articles screened, 14 eligible studies were identified and combined with studies identified in the previous systematic literature searches. The updated meta-analysis included a total of 68 studies presenting 71 separate comparisons. Survival was significantly improved in patients receiving primary G-CSF support, compared with patients without primary G-CSF support (mortality RR=0.92; 95% CI 0.90–0.95; ARD=−3.3%; 95% CI −4.2–−2.4; P< 0.0001). The largest improvement in survival was observed with dose-dense chemotherapy regimens with G-CSF support, compared with controls receiving no G-CSF support (mortality RR=0.86; 95% CI 0.80–0.92; P< 0.0001). Patients who received primary G-CSF support experienced a significantly higher risk of secondary malignancies, compared with controls (RR=1.85; 95% CI 1.19–2.88; ARD=0.47; 95% CI 0.21–0.73; P< 0.01).ConclusionsOur findings demonstrate that overall survival is improved in patients receiving intensified chemotherapy with primary G-CSF support, compared with those receiving standard chemotherapy. Primary G-CSF support was also associated with a higher risk of developing secondary malignancies, including secondary acute myeloid leukemia and myelodysplastic syndrome.
Dominant Negative Suppression of Rad Leads to QT Prolongation and Causes Ventricular Arrhythmias via Modulation of L-type Ca2+ Channels in the Heart
Authors: HirotakaYada, MitsushigeMurata, KoujiShimoda, ShinsukeYuasa, HarukoKawaguchi, MasakiIeda, TakeshiAdachi, MitsuruMurata, SatoshiOgawa, KeiichiFukuda
Journal: Circulation Research (2007)

Disorders of L-type Ca2+ channels can cause severe cardiac arrhythmias. A subclass of small GTP-binding proteins, the RGK family, regulates L-type Ca2+ current (ICa,L) in heterologous expression systems. Among these proteins, Rad (Ras associated with diabetes) is highly expressed in the heart, although its role in the heart remains unknown. Here we show that overexpression of dominant negative mutant Rad (S105N) led to an increase in ICa,L and action potential prolongation via upregulation of L-type Ca2+ channel expression in the plasma membrane of guinea pig ventricular cardiomyocytes. To verify the in vivo physiological role of Rad in the heart, a mouse model of cardiac-specific Rad suppression was created by overexpressing S105N Rad, using the α-myosin heavy chain promoter. Microelectrode studies revealed that action potential duration was significantly prolonged with visible identification of a small plateau phase in S105N Rad transgenic mice, when compared with wild-type littermate mice. Telemetric e...
Abstract 5022: Precision medicine: High-throughput 3D bioprinting of embedded multicellular cancer spheroids
Authors: Lakmali Atapattu, Robert Utama, Aiden O'Mahony, Christopher Fife, Jongho Baek, Théophile Allard, Kieran O'Mahony, Julio Ribeiro, Katharina Gaus, Justin Gooding, Maria Kavallaris
Journal: Cancer Research (2018)

Abstract Three-dimensional (3D) cancer cell models, such as 3D multicellular spheroids, are superior models of in vivo systems than the more popular two-dimensional (2D) cell culture. 3D cancer spheroids provide a closer reflection of tumor gene expression and biology than 2D cultures. This is particularly relevant for drug development and precision medicine programs were cell culture conditions that better reflect the 3D tumor environments, including matrix stiffness, would be highly advantageous. A key challenge for the routine application of embedded 3D cancer spheroids in precision and drug programs is the lack of high throughput and uniform production of spheroids in a biocompatible matrix. To address this, we have developed a high-throughput method of producing 3D multicellular cancer spheroids embedded inside a tissue-like matrix using a custom-built drop-on-demand 3D bioprinter. The 3D bioprinter is capable of printing a cell-suspension ink with up to 300 million cells/mL and a cell viability greater than 95%. We have validated the 3D bioprinting using glioblastoma, neuroblastoma and lung cancer cells. The 3D bioprinted spheroids were confirmed to maintain all the biological characteristics typically found in a cancer spheroid. In particular, the 3D bioprinted cancer spheroids were shown to be viable and proliferating, preserved the apoptotic and cancer-stemness characteristics and using super-resolution lattice-light sheet microscopy, we showed the spheroids maintained the same structural integrity as manually formed spheroids. The potential application of the 3D bioprinted spheroids for high-throughput drug screening in 3D environments was demonstrated using doxorubicin as the model drug. 3D-bioprinting of patient-derived cancer cells for precision medicine applications is now underway. High-throughput embedded 3D bioprinting has enormous potential to accelerate precision medicine, drug discovery and cancer biology. Citation Format: Lakmali Atapattu, Robert Utama, Aiden O'Mahony, Christopher Fife, Jongho Baek, Théophile Allard, Kieran O'Mahony, Julio Ribeiro, Katharina Gaus, Justin Gooding, Maria Kavallaris. Precision medicine: High-throughput 3D bioprinting of embedded multicellular cancer spheroids [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 5022.
Abstract 17379: The Incidence and Risk Associated with a Serum Potassium <4.0 Mmol/l in Patients with Heart Failure and a Reduced Left Ventricular Ejection Fraction (HF-REF): Results from the Emphasis-HF Trial
Authors: BertramPitt, John JMcMurray, KarlSwedberg, StuartPocock, HenryKrum, Dirk Jvan Veldhuisen, HarryShi, JohnVincent, FaiezZannad
Journal: Circulation (2012)

Introduction and Methods: Hypokalemia, defined as a serum potassium (K+) <3.5 mmol/l, is recognized as an important risk factor for cardiovascular death (CVD) in patients with HF-REF. The incidence of K+ <4.0 mmol/l and any associated risk is less certain. We analyzed the results of the EMPHASIS-HF trial in patients (n=2737) with HF-REF and mild symptoms, randomized to placebo or eplerenone with regard to the incidence of a K+ <4.0 mmol/l and the risk of the primary endpoint of CVD or hospitalization for heart failure (HFH) during the randomized trial with a median follow up of 21 months. Results: At baseline, 536/2737 (19.6%) patients had a K+ <4.0 mmol/L and 2201 (80.4%) a K+ ≥4.0 mmol/L. During treatment, 393 (73.3%) of the former and 774 (35.2%) of the latter had a K+ <4.0 mmol/L (P<0.001). At baseline, 268/1364 (19.7%) eplerenone-treated and 268/1373 (19.5%) placebo-treated patients had a K+ <4.0 mmol/L (P=0.932). During treatment, these proportions were 519/1364 (38.1%) and 648/1373 (47.2%), respect...
Abstract PR09: Modeling the tumor microenvironment in sarcoma: The impact on MPNST biology and chemotherapeutic response
Authors: Rebecca Dodd, Chang-Lung Lee, Mary Overton, Wesley Huang, William Eward, Davis Ingram, Diana Cordona, Alexander Lazar, David Kirsch
Journal: Clinical Cancer Research (2018)

Abstract NF1 haploinsufficiency is a hallmark of neurofibromatosis Type 1 and is critical for neurofibroma development. The role of the supporting stroma (endothelial cells, immune cells, fibroblasts, etc.) in the development of patient neurofibromas is well established. However, the impact of NF1 haploinsufficiency on MPNST biology is less clear. Sporadic MPNSTs arise in patients with NF1 wild-type stroma (NF1 +/+), while NF1-associated MPNSTs arise in neurofibromatosis patients with NF1 haploinsufficient stroma (NF1 -/+). Patients with NF1-associated MPNSTs have worse outcome than patients with sporadic MPNSTs, but the cause of this difference is under debate. To define the impact of stromal genetics on tumor biology, we have developed unique mouse models that reflect the genetics of patient-associated MPNSTs. Using paired littermate mice, we model the genetic status of NF1 in the tumor microenvironment of different MPNST patient populations. We use Adenovirus-Cre injections to generate MPNSTs in NF1 Flox/Flox; CDKN2A Flox/Flox and NF1 Null/Flox; CDKN2A Flox/Flox paired littermate mice to model tumors from NF1 wild-type and NF1-assoicated patients, respectively. We find that NF1 haploinsufficiency (NF1 +/- stroma) accelerates tumor onset, which is accompanied by an increase in immune cells comprising CD11B+ cells, monocytes, and mast cells. Furthermore, mast cells are also enriched in human NF1-associated MPNSTs. We used these mouse models in a preclinical trial to examine how the tumor microenvironment influences response to multiagent chemotherapy and found that the stromal NF1 status does not impact the response of MPNSTs to chemotherapy. Taken together, these studies help clarify the role of the NF1 haploinsufficient tumor microenvironment in MPNSTs. This abstract is also being presented as Poster B15. Citation Format: Rebecca Dodd, Chang-Lung Lee, Mary Overton, Wesley Huang, William Eward, Davis Ingram, Diana Cordona, Alexander Lazar, David Kirsch. Modeling the tumor microenvironment in sarcoma: The impact on MPNST biology and chemotherapeutic response [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr PR09.