tbuckley/cabot-search huggingface dataset:
Second-line treatment in exon 11-mutated GIST patients: Imatinib dose escalation or sunitinib? Retrospective analysis of a multi-institutional experience.
Authors: Bruno Vincenzi, Margherita Nannini, Elena Fumagalli, Giuseppina Maltese, Anna Maria Frezza, Daniele Santini, Mariella Spalato Ceruso, Giuseppe Badalamenti, Maria A. Pantaleo, Paolo Giovanni Casali, Giuseppe Tonini
Journal: Journal of Clinical Oncology (2014)

10515 Background: Data from metastatic GIST patients harbouring exon 11 mutation who received a second line treatment with sunitinib or imatinib dose escalation were retrospectively analysed to compare survival. Methods: 123 exon 11 mutated advanced GIST patients were included. All patients progressed on imatinib 400 mg/die and received, on discretion of physician, a second line treatment with either imatinib (800 mg/die) or sunitinib (50 mg/die 4 weeks on/2 weeks of or 37.5 mg/day continuous daily dose). The type of exon 11 mutation was recorded (deletion versus others) and correlated with survival and response according to RECIST or CHOI criteria Results: 79 patients (64%) received a second line treatment with imatinib, 44 (36%) sunitinib. For 94 patients the exact mutation was available: exon 11 mutation was represented by a deletion in 42 cases (45%), by other gene aberrations in 52 (55%). Median follow-up was 61 months. The median time to progression (TTP) in patients receiving sunitinib and imatinib was 10 (95% CI 9.7-10.9) and 5 months (95% CI 3.6-6.7) respectively (P=0.012). No significant difference was found in overall survival (OS) (58 versus 62 respectively, P=0.883). Interestingly, the impact of deletion in exon 11 was statistically significant longer in patients treated with imatinib (TTP 24 versus 6 months, P=0.02), while it was irrelevant in patients treated with sunitinb (P=0.683). A border line statistically significant difference was identified also in terms of OS in the group of patients treated with imatinib as second line (71 months in not deletes exon 11 patients vs 54 months in deleted ones, P=0.063). No difference was detected in the group of patients treated with sunitinb according to the mutation status in the exon 11 (P=0.370). Conclusions: In exon 11 mutated GIST patients progressing on a first line treatment with imatinib 400 mg/die, a second line treatment with sunitinib is associated with an improvement in TTP without any impact on survival. Deletion in exon 11 seems to be relevant for sensitivity to imatinib-based therapy as second line in terms of TTP, while the impact of mutation was not identified in patients treated with sunitinib.
Abstract 142: Role of CK2α in Heart Tube Proliferation
Authors: Isabel Dominguez, Irene Roman Degano, Laura Macias Alvarez, Jesus Revuelta-Cervantes
Journal: Circulation Research (2012)

Congenital heart disease (CHD) groups a number of structural malformations of the heart and associated blood vessels present at birth. CHD is the most common birth defect, arise from defective cardiogenesis, and can be due to genetic and/or environmental factors that affect cellular processes such as proliferation during heart formation. The highly conserved serine-threonine kinase, CK2α, has been implicated in proliferative processes, including cancer, and it is a target of environmental toxins. To test whether CK2α plays a role in cardiogenesis, we used a CK2α deficient mouse. CK2α-/- mice die around embryonic day (E)11 and showed dysmorphic outflow tracts (OFT), hypoplastic right ventricles (RV) and poorly developed ventricular trabeculations. These defects, the probable cause of the lethality, could be due to deficient proliferation. Thus, we tested whether reduced CK2α expression leads to proliferative signal defects during cardiogenesis. We used three or more pairs of somite-matched wild-type and CK2α-/- embryos for the analysis of proteins by immunofluorescence and immunoblot, and of transcript expression by RT-qPCR and in situ hybridization. At E9.5 and E10.5, the number of Isl1+ cells in the OFT and the levels of Isl1 transcript in the heart of CK2α-/- embryos was no different from wild-type. These data suggest that the mechanism underlying the OFT and RV defects is different from progenitor incorporation defects. CK2α deficient hearts expressed pan-cardiac gene and protein markers normally at E9.5 and E10.5; and apoptosis was not affected, indicating that the heart malformations may be due to proliferative defects. Indeed, mitotic rates were decreased throughout the heart in CK2α mutants compared to wild-type embryos at E9.5 and E10.5; but a mitotic defect was not apparent at E8.5. The observed decrease in proliferation correlated with decreased expression of cardiac proliferative markers such as n-myc and decrease in proliferative signal pathways in the heart tube. In conclusion, these data show that, from E9.5 on, CK2α is necessary for proliferation and proliferative signal pathway activation in the heart tube; and that cellular mechanisms other than progenitor incorporation may play a key role in OFT and RV defects.
Therapeutic Effect of Astroglia-like Mesenchymal Stem Cells Expressing Glutamate Transporter in a Genetic Rat Model of Depression
Authors: Amit Shwartz, Oshra Betzer, Noam Kronfeld, Gila Kazimirsky, Simona Cazacu, Susan Finniss, Hae Kyung Lee, Menachem Motiei, Shani Yael Dagan, Rachela Popovtzer, Chaya Brodie, Gal Yadid
Journal: Theranostics (2017)

Recent studies have proposed that abnormal glutamatergic neurotransmission and glial pathology play an important role in the etiology and manifestation of depression. It was postulated that restoration of normal glutamatergic transmission, by enhancing glutamate uptake, may have a beneficial effect on depression. We examined this hypothesis using unique human glial-like mesenchymal stem cells (MSCs), which in addition to inherent properties of migration to regions of injury and secretion of neurotrophic factors, were differentiated to express high levels of functional glutamate transporters (excitatory amino acid transporters; EAAT). Additionally, gold nanoparticles (GNPs), which serve as contrast agents for CT imaging, were loaded into the cells for non-invasive, real-time imaging and tracking of MSC migration and final location within the brain. MSC-EAAT (2×105; 10 μl) were administered (i.c.v.) to Flinder Sensitive Line rats (FSLs), a genetic model for depression, and longitudinal behavioral and molecular changes were monitored. FSL rats treated with MSC-EAAT showed attenuated depressive-like behaviors (measured by the forced swim test, novelty exploration test and sucrose self-administration paradigm), as compared to controls. CT imaging, Flame Atomic Absorption Spectroscopy analysis and immunohistochemistry showed that the majority of MSCs homed specifically to the dentate gyrus of the hippocampus, a region showing structural brain changes in depression, including loss of glial cells. mRNA and protein levels of EAAT1 and BDNF were significantly elevated in the hippocampus of MSC-EAAT-treated FSLs. Our findings indicate that MSC-EAATs effectively improve depressive-like manifestations, possibly in part by increasing both glutamate uptake and neurotropic factor secretion in the hippocampus.
Nut consumption and survival in stage III colon cancer patients: Results from CALGB 89803 (Alliance).
Authors: Temidayo Fadelu, Donna Niedzwiecki, Sui Zhang, Xing Ye, Leonard Saltz, Robert J. Mayer, Rex B. Mowat, Renaud Whittom, Alexander Hantel, Al Bowen Benson, Daniel M. Atienza, Michael J. Messino, Hedy L. Kindler, Alan P. Venook, Shuji Ogino, Kimmie Ng, Edward L. Giovannucci, Jeffrey A. Meyerhardt, Ying Bao, Charles S. Fuchs
Journal: Journal of Clinical Oncology (2017)

3517 Background: Recent prospective cohort studies suggest states of energy excess and hyperinsulinemia, including type 2 diabetes (T2D), obesity, sedentary lifestyle, Western pattern diet, increased dietary glycemic load, high intake of sugar-sweetened beverages, and elevated plasma C-peptide are each associated with an increased risk of colon cancer (CC) recurrence and mortality. Conversely, observational studies indicate that increasing nut intake is associated with lower risk of T2D, metabolic syndrome and insulin resistance. However, the effect of nut intake on CC recurrence and survival is unknown. Methods: We conducted a prospective, observational study of 826 patients with stage III CC who reported dietary intake with food frequency questionnaires while enrolled in a randomized adjuvant chemotherapy trial. Using Cox proportional hazards regression, we assessed associations of nut intake with cancer recurrence and mortality. The primary endpoint was disease-free survival (DFS) defined as time from completion of dietary questionnaire following adjuvant therapy to cancer recurrence, death or last follow-up. Results: Compared to patients who abstained from nuts, those who consumed ≥ 2 servings of nuts per week had an adjusted hazard ratio (HR) of 0.58 (95% CI, 0.37 to 0.92; P trend = 0.03) for DFS and 0.43 (95% CI, 0.25 to 0.74; P trend = 0.01) for overall survival (OS). On subgroup analysis, the significant association was confined to tree-nut intake: HR = 0.54 (95% CI, 0.34 to 0.85; P trend = 0.04) for DFS and HR = 0.47 (95% CI, 0.27 to 0.82; P trend = 0.04) for OS. There was no significant association between intake of peanut or peanut butter and patient outcome. Association of total nut intake with improved outcomes was maintained across other known or suspected predictors of recurrence and mortality, including across common genomic alterations (microsatellite instability, KRAS mutation, BRAF mutation, and PIK3CA mutation). Conclusions: Higher consumption of nuts may be associated with significantly reduced cancer recurrence and death in patients with stage III CC. Support: U10CA180821, U10CA180882, Pfizer. Clinical trial information: NCT00003835.
Oncogenic Activation of the RNA Binding Protein NELFE and MYC Signaling in Hepatocellular Carcinoma
Authors: Hien Dang, Atsushi Takai, Marshonna Forgues, Yotsowat Pomyen, Haiwei Mou, Wen Xue, Debashish Ray, Kevin C.H. Ha, Quaid D. Morris, Timothy R. Hughes, Xin Wei Wang
Journal: Cancer Cell (2017)
Resistance Mechanisms to AZD9291 and Rociletinib—Response
Authors: Reinhard Büttner, Jürgen Wolf, Roman K. Thomas, Martin L. Sos
Journal: Clinical Cancer Research (2017)

We would like to take the opportunity and respond to the letter of Dr. Nele Van der Steen and her colleagues that discusses our recent publication in which we describe heterogenic patterns or resistance to third-generation EGFR inhibitors. It is correct that we primarily focused on the description
Clinical characteristics associated with postoperative seizure control in adult low-grade gliomas: a systematic review and meta-analysis
Authors: Xia Shan, Xing Fan, Xing Liu, Zheng Zhao, Yinyan Wang, Tao Jiang
Journal: Neuro-Oncology (2017)

Epilepsy is the most common symptom in patients with supratentorial low-grade gliomas (LGGs), which adversely affects the patient's quality of life. Poor seizure control with anti-epileptic therapy is an indication for surgery in these patients. Recent studies have sought to identify predictors of postoperative seizure control after surgical resection of LGG; gross total resection was shown to be a significant predictor in this respect. However, the prognostic value of other factors is not clear.We performed a systematic review and meta-analysis of 23 studies with a combined study population of 2641 patients with LGG, in order to identify potential factors associated with favorable postoperative seizure control. Data were extracted on age and sex of patient, tumor location, tumor histology, type of seizure, seizure duration, extent of resection, and imaging characteristics.Patients ≥45 years of age achieved better postoperative seizure control (risk ratio [RR], 0.89; 95% CI, 0.81-0.99). Focal seizures were associated with poor seizure control (RR, 1.32; 95% CI, 1.18-1.49) compared with generalized seizures (RR, 0.77; 95% CI, 0.68-0.87). Prolonged history of seizures (≥1 y) had a negative impact on postoperative seizure control (RR, 1.22; 95% CI, 1.10-1.34). Gross total resection was superior to subtotal resection with respect to postoperative seizure control (RR, 0.68; 95% CI, 0.63-0.73).This systematic review and meta-analysis identified predictors of postoperative seizure control in patients undergoing surgical resection of LGGs. Our results provide a reference for clinical treatment of LGG-related epilepsy.
Mycobacterial Infections in Adult Recipients of Allogeneic Hematopoietic Stem Cell Transplantation: A Cohort Study in a High Endemic Area
Authors: Liu Yao-Chung, Chi-Jung Wu, Sheng-Hsuan Chien, Nai-Wen Fan, Ming-Hung Hu, Jyh-Pyng Gau, Chia-Jen Liu, Yuan-Bin Yu, Liang-Tsai Hsiao, Tzeon-Jye Chiou, Jin-Hwang Liu
Journal: Blood (2016)
Prognotic Impact of Mutations in Systemic Mastocytosis
Authors: Lisa Pieri, Giada Rotunno, Francesca Gesullo, Tiziana Fanelli, Giuditta Corbizi Fattori, Annalisa Pacilli, Federica Scarfì, Maria Loredana Iorno, Fabio Almerigogna, Roberto Salerno, Paola Guglielmelli, Roberta Zanotti, Alessandro M. Vannucchi
Journal: Blood (2016)
Chemical Studies on the Components of Normal and Neoplastic Tissues. II. The Nucleoprotein Fraction of Normal Animal Liver
Authors: Jesse P. Greenstein, Wendell V. Jenrette
Journal: JNCI Journal of the National Cancer Institute (1940)

Journal Article Chemical Studies on the Components of Normal and Neoplastic Tissues. II. The Nucleoprotein Fraction of Normal Animal Liver Get access Jesse P. Greenstein, Jesse P. Greenstein research fellow National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Wendell V. Jenrette Wendell V. Jenrette technical assistance National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 1, Issue 1, 1940-1941, Pages 91–104, https://doi.org/10.1093/jnci/1.1.91 Published: 01 August 1940
Constitutive ubiquitination of ERBB3 does not require tyrosine phosphorylation
Authors: Carmen Warren, Ralf Landgraf
Journal: Cancer Research (2007)

3768   Ubiquitination of ERBB receptor tyrosine kinases, specifically EGFR and ERBB2, serves as a signal for receptor downregulation following ligand-induced activation. Deregulation of ubiquitination control can contribute to cellular transformation. While the mechanisms for EGFR and ERBB2 downregulation have been extensively studied, little is known about the components involved in the degradation of ERBB3. Following ligand stimulation and the formation of activated ERBB2/ERBB3 heterodimers, ERBB3 is rapidly degraded at rates similar to activated EGFR. However, ERBB3 also displays a high level of constitutive turnover relative to the other ERBB receptors. Here we evaluate the role of ERBB3 ubiquitination in the constitutive turnover and ligand-induced downregulation of ERBB3. We show that ERBB3 is ubiquitinated both in the absence and presence of its ligand, neuregulin. However, the degree of ERBB3 ubiquitination increases upon ligand-induced activation. Furthermore, tyrosine phosphorylation of ERBB3 is required for ligand-induced ubiquitination, but is not necessary for the ligand-independent ubiquitination of ERBB3. Kinase inhibitors that decrease ERBB3 tyrosine phosphorylation reduce ligand-induced ubiquitination of ERBB3, but have no effect on ligand-independent ubiquitination. Our data suggest that alternate mechanisms regulate the ubiquitination of ERBB3 during constitutive turnover and ligand-induced downregulation.
Aneurysmal Subarachnoid Hemorrhage
Authors: Koen de Gans, Mervyn D Vergouwen, Yvo B Roos
Journal: New England Journal of Medicine (2006)

In this editorial, the issues of hypocapnia and its relation to symptomatic vasospasm, prognosis, and outcome among patients with aneurysmal subarachnoid hemorrhage is discussed. Potential directions for future studies are provided.
Prognostic impact of trisomy 8 cytogenetic abnormality in acute myelogenous leukemia: Analysis of a large cohort (N=2187) of newly diagnosed patients.
Authors: Gautam Borthakur, Cecilia Ysabel Arana Yi, Jorge E. Cortes, Wei Qiao, Tapan M. Kadia, Farhad Ravandi, Stefan Faderl, Guillermo Garcia-Manero, Mark Brandt, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2013)

7089 Background: Trisomy 8 is grouped as intermediate risk in cytogenetic (CG) classifications of acute myelogenous leukemia (AML). In a multi-variate analysis of MRC data, trisomy 8 was associated with worse overall survival (OS). Methods: Between years 1993-2012, 2,187 patients (pts) with newly diagnosed AML presented at MD Anderson Cancer Center and 21 (10%) were with a trisomy 8 CG abnormality. The median age of trisomy 8 pts was 63 years (range, 17-89 years) and 59% were males. Sixty four (30%) had isolated trisomy 8, 45 (21%) had trisomy 8 +≤2 additional cytogenetic abnormalities and 102 (49%) had trisomy 8 + ≥3 additional abnormalities. Thirty three percent of pts with trisomy 8+≤2 additional abnormalities, had secondary AML compared to 21% of diploid CG (p=.007). Mutations in the FLT3 gene was seen in 9% and N or KRAS gene in 8%. Results: The overall remission rate (RR) was 47%, 53% and 43% among pts with trisomy 8 alone, trisomy 8+≤2 and trisomy 8+≥3 abnormalities respectively. Among pts &lt;60 years of age and with trisomy 8 + ≤2 abnormalities, RR was 71% and the same was 77% for pts with diploid CG. For pts ≥ 60 years, the RRs were 26% and 57% respectively. Among pts ≥ 60 years and trisomy 8 with complex CG (≥3 additional abnormalities) the RR was 38% and that for patients with complex (non-trisomy 8) CG was 41%. Patients with trisomy 8 either alone or ≤2 additional abnormalities had a shorter OS (p= .04 and .05 respectively, median 10.8 and 8.6 months vs 16.5 months) compared to those with diploid CG. Event free survival was also shorter among patient with isolated trisomy 8 versus those with diploid CG (p=.008, median 2.9 versus 7.5 months). On the other hand, patients with trisomy 8+≥3 abnormalities had outcomes comparable to non-trisomy 8 CG group. Conclusions: Non-complex CG trisomy 8 is associated with worse clinical outcome in patients with AML than those with diploid CG and its inclusion in intermediate risk group may need reconsideration. The most adverse impact appears to be from lower RR among patients with trisomy 8+≤2 additional abnormalities and ≥60 years of age.
Interval dosing with the HDAC inhibitor vorinostat effectively reverses HIV latency
Authors: Nancie M. Archin, Jennifer L. Kirchherr, Julia A.M. Sung, Genevieve Clutton, Katherine Sholtis, Yinyan Xu, Brigitte Allard, Erin Stuelke, Angela D. Kashuba, Joann D. Kuruc, Joseph Eron, Cynthia L. Gay, Nilu Goonetilleke, David M. Margolis
Journal: Journal of Clinical Investigation (2017)

The histone deacetylase (HDAC) inhibitor vorinostat (VOR) can increase HIV RNA expression in vivo within resting CD4+ T cells of aviremic HIV+ individuals. However, while studies of VOR or other HDAC inhibitors have reported reversal of latency, none has demonstrated clearance of latent infection. We sought to identify the optimal dosing of VOR for effective serial reversal of HIV latency.In a study of 16 HIV-infected, aviremic individuals, we measured resting CD4+ T cell-associated HIV RNA ex vivo and in vivo following a single exposure to VOR, and then in vivo after a pair of doses separated by 48 or 72 hours, and finally following a series of 10 doses given at 72-hour intervals.Serial VOR exposures separated by 72 hours most often resulted in an increase in cell-associated HIV RNA within circulating resting CD4+ T cells. VOR was well tolerated by all participants. However, despite serial reversal of latency over 1 month of VOR dosing, we did not observe a measurable decrease (>0.3 log10) in the frequency of latent infection within resting CD4+ T cells.These findings outline parameters for the experimental use of VOR to clear latent infection. Latency reversal can be achieved by VOR safely and repeatedly, but effective depletion of persistent HIV infection will require additional advances. In addition to improvements in latency reversal, these advances may include the sustained induction of potent antiviral immune responses capable of recognizing and clearing the rare cells in which HIV latency has been reversed.Clinicaltrials.gov NCT01319383.NIH grants U01 AI095052, AI50410, and P30 CA016086 and National Center for Advancing Translational Sciences grant KL2 TR001109.
Asymptomatic Dysprothrombinemia (Prothtombin Himi) with p.M380T and p.R431H Shows Severely Reduced Clotting Activity, Moderate Antithrombin Resistance and Severe Thrombomodulin Binding Defect
Authors: Eriko Morishita, Mao Takata, Fumina Taniguchi, Masashi Akiyama, Akiko Sekiya, Akira Takagi, Toshiyuki Miyata, Tetsuhito Kojima
Journal: Blood (2016)
Co-Activation of PKC-δ by CRIF1 Modulates Oxidative Stress in Bone Marrow Multipotent Mesenchymal Stromal Cells after Irradiation by Phosphorylating NRF2 Ser40
Authors: Lili Chen, Qian Ran, Yang Xiang, Lixin Xiang, Li Chen, Fengjie Li, Jiang Wu, Chun Wu, Zhongjun Li
Journal: Theranostics (2017)

The high mortality associated with pancytopenia and multi-organ failure resulting from hematopoietic disorders of acute radiation syndrome (h-ARS) creates an urgent need for developing more effective treatment strategies.Here, we showed that bone marrow multipotent mesenchymal stromal cells (BMMSCs) effectively regulate oxidative stress following radiative injury, which might be on account of irradiation-induced elevation of protein levels of CR6-interacting factor 1(CRIF1) and nuclear factor E2-related factor 2(NRF2).Crif1-knockdown BMMSCs presented increased oxidative stress and apoptosis after irradiation, which were partially due to a suppressed antioxidant response mediated by decreased NRF2 nuclear translocation.Co-immunoprecipitation (Co-IP) experiments indicated that CRIF1 interacted with protein kinase C-δ (PKC-δ).NRF2 Ser40 phosphorylation was inhibited in Crif1-deficient BMMSCs even in the presence of three kinds of PKC agonists, suggesting that CRIF1 might co-activate PKC-δ to phosphorylate NRF2 Ser40.After radiative injury, the supporting effect of BMMSCs for the colony forming ability of HSCs in vitro was reduced, and the deficiency of CRIF1 aggravated such damage.Thus, CRIF1 plays an essential role in PKC-δ/NRF2 pathway modulation to alleviate oxidative stress in BMMSCs after irradiative injury, and at some level it may maintain the HSCs-supporting effect of BMMSCs after radiative injuries.