tbuckley/cabot-search huggingface dataset:
Abstract 270: Role of the Mitochondrial Iron in Cardiomyoblast Survival and Maturation of Cytosolic Fe/S Proteins.
Authors: Anita Thakur, Marina Bayeva, Hossein Ardehali
Journal: Circulation Research (2013)

ATP-binding cassette (ABC)-B8 is an ABC half transporter that resides in the inner mitochondrial membrane. We previously showed that ABCB8 has a role in mitochondrial iron export, and that a reduction in ABCB8 both in vitro and in vivo results in mitochondrial iron accumulation, increased reactive oxygen species (ROS) and cell death, and decreased activity of cytosolic Fe/S proteins. However, it is not known whether the cytotoxic effects of ABCB8 knockdown are due to mitochondrial iron accumulation or decreased cytosolic Fe/S protein or other processes. Furthermore, the link between mitochondrial iron and the activity of cytosolic Fe/S proteins is uncharacterized. Here, we studied whether a reduction in mitochondrial iron can reverse the effects of ABCB8 knockdown on cell survival, ROS production and the activity of Fe/S proteins. We altered the mitochondrial iron using various iron chelators and by decreasing the levels of mitochondrial iron importer, mitoferrin-2 (MFRN2). The increase in mitochondrial iron and ROS levels associated with ABCB8 knockdown was significantly reversed by iron chelators and with MFRN-2 knockdown. Furthermore, cell death was also reversed with iron chelators and MFRN-2 knockdown, suggesting that the cytotoxic effects of ABCB8 knockdown is due to mitochondrial iron accumulation. We then studied the effects of iron chelators on cytosolic Fe/S proteins. Iron chelators reversed the defect in cytosolic Fe/S proteins that is associated with ABCB8 knockdown in cell culture or knockout in mice. However, antioxidants and knockdown of MFRN-2 failed to have similar effects. These results indicated that the defect in the maturation of cytosolic Fe/S proteins due to mitochondrial iron accumulation can be reversed by chelating mitochondrial iron, and is independent of the associated oxidative stress. Thus, mitochondrial iron levels are likely sensed in the cytoplasm and determine the maturation of cytosolic Fe/S proteins. Altogether, these studies provide insights into the role of mitochondrial iron in the cytotoxic effects of ABCB8 knockdown, and suggest that mitochondrial iron is sensed in the cytoplasm and influences the maturation of cytosolic Fe/S proteins.
A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer
Authors: B.H. O'Neil, A.J. Scott, W.W. Ma, S.J. Cohen, L. Leichman, D.L. Aisner, A.R. Menter, M.A. Tejani, J.K. Cho, J. Granfortuna, L. Coveler, O.O. Olowokure, J.C. Baranda, M. Cusnir, P. Phillip, J. Boles, R. Nazemzadeh, M. Rarick, D.J. Cohen, J. Radford, L. Fehrenbacher, R. Bajaj, V. Bathini, P. Fanta, J. Berlin, A.J. McRee, R. Maguire, F. Wilhelm, M. Maniar, A. Jimeno, C.L. Gomes, W.A. Messersmith
Journal: Annals of Oncology (2015)
Tumor infiltrating lymphocytes and hydrophobic amino acid changes in HER2-positive metastatic breast cancer.
Authors: Vassiliki Kotoula, Eleni Giannoulatou, Zoi Alexopoulou, Vasilios Karavasilis, Athanasios Kotsakis, Dimitrios Dionysopoulos, Christos Christodoulou, Eleftheria Tsolaki, Mattheos Bobos, Elpida Charalambous, George E. Pentheroudakis, Thomas Makatsoris, Sofia Chrisafi, Dimitrios G. Pectasides, Amanda Psyrri, Pavlos Papakostas, Evangelia Razis, Dimitris Bafaloukos, Vasileios Georgoulias, George Fountzilas
Journal: Journal of Clinical Oncology (2016)

592 Background: In HER2-positive metastatic breast cancer (mBC), the role of tumor infiltrating lymphocytes (TILs) and mutation types remains unexplored. Herein we evaluated such parameters focusing on mutations changing chemical amino acid properties. Methods: Targeted NGS results were available for 136 primary tumors from an equal number of HER2-positive mBC patients, 96 of whom relapsed (R) following adjuvant treatment and 40 presented with metastatic disease (de novo). Coding mutations were analyzed for changed amino acid properties to hydrophobic, polar and charged. Outcome analyses (time to progression [TTP] and survival) were performed in trastuzumab-naïve patients who received this drug upon diagnosis of mBC (N = 124). Results: A total of 1194 coding mutations in 58 genes were identified in 111/136 tumors (82%). Of these, 19% had a mean of 47 mutations and 22 mutated genes. R-mBC patients were richer in mutations as compared to de novo mBC (Kruskal-Wallis, p = 0.032). TILs density (mean: 14%; median: 10%; > 50% TILs in 3.9% of tumors only), as well as mutations changing amino acid properties into hydrophobic (34%), polar (37%) and charged (35%) did not differ between R- and de novo mBC. TILs density (continuous and 10% increments) was not associated with mutation load, type of mutations and patient outcome. Hydrophobic mutations predicted for unfavorable TTP (HR = 2.82, 95% CI 1.22-6.84, Wald’s p = 0.016) and survival (HR = 2.38, 95% CI 1.12-5.08, p = 0.025) in de novo but not in R-mBC (interaction p = 0.068 for TTP). In multivariable models in the entire series, hydrophobic mutations in de novo mBC remained significant for unfavorable TTP (Wald’s p = 0.021) along with negative ER/PgR and premenopausal status; the same mutations also predicted for unfavorable survival (p = 0.064) along with negative ER/PgR and PS ≥ 1. Conclusions: Primary tumors of HER2-positive mBC patients are poor in TILs, which are not related to outcome, but rich in mutations. In this context, patients with hydrophobic mutations do not seem to benefit from trastuzumab, especially if presenting with de novo mBC. If validated, the presence of hydrophobic mutations in a failed host-immune environment may provide a rationale for immunomodulation.
Phase III adjuvant trial of concurrent epirubicin/taxane vs. sequential epirubicin/cyclophosphamide followed by taxane for node positive breast cancer
Authors: R. Lambert-Falls, M. A. Deutsch, C. Desch, K. Zhou, E. Perez
Journal: Journal of Clinical Oncology (2006)

573 Background: This study evaluates whether concurrent epirubicin/taxane (ET) improves disease-free survival (DFS) at 3 yrs compared to the sequential combination of epirubicin/cyclophosphamide followed by a taxane (EC&gt;T) in pts with operable node (+) breast cancer. Methods: Eligible pts were randomized to receive either ET (E 75 mg/m 2 ) for 8 cycles q21 days or EC&gt;T (E 90 mg/m 2 , C 600 mg/m 2 ) for 4 cycles, followed by 4 cycles of a taxane q21 days. Choice of T (paclitaxel 175 mg/m 2 or docetaxel 75 mg/m 2 ) was at the physician’s discretion. The primary endpoint is DFS. A 0.10 increase in the probability of DFS at 3 yrs for the ET arm would be considered clinically relevant. To detect 82 events, 300 subjects per arm are required to provide 90% power at 5% significance level. Results: 617 pts were enrolled from Nov 2000 to June 2003; 308 pts received ET and 309 pts received EC&gt;T. Both treatment arms were well balanced with respect to age, nodal+, ER status, Her-2+ and PS; median age 52.5 (42%&lt;50 years old); 70% ER+; 61% LN (1–3); 16% Her-2+; 87% PS 0. Total of 2206 cycles of treatment were given to ET compared 2314 cycles of treatment to EC&gt;T. At 30 months of median follow-up there were DFS 102 events occurred; 47 events in ET arm (16%) and 55 events in EC&gt;T arm (18%); 63 total deaths; 29 deaths in ET arm and 34 deaths in EC&gt;T arm. The most common toxicities include alopecia (50%), fatigue (31%), nausea and vomiting (30%), dyspepsia (27%), febrile neutropenia (15%), constipation (12%), diarrhea (10%), arthralgia (11%), stomatitis (10%). In cardiac safety f/u, only one pt in ET arm remained LVEF drop &gt;15. Conclusions: Epirubicin can be combined with taxanes in both sequential and concurrent therapies and both regimens are effective and well tolerated. The study is sponsored by Pfizer Inc. No significant financial relationships to disclose.
Predictors of stopping chemotherapy early and short survival in patients with potentially platinum sensitive (PPS) recurrent ovarian cancer (ROC) who have had ≥3 lines of prior chemotherapy: The GCIG symptom benefit study (SBS).
Authors: Felicia Roncolato, Florence Joly, Rachel O'Connell, Anne Lanceley, Florian Heitz, Luke Buizen, Aikou Okamoto, Eriko Aotani, Vanda Salutari, Paul P. Donnellan, Amit M. Oza, Elisabeth Avall-Lundqvist, Jonathan S. Berek, Felix Hilpert, Amanda Feeney, Celia Roemer-Becuwe, Martin R. Stockler, Madeleine Trudy King, Michael Friedlander
Journal: Journal of Clinical Oncology (2017)

5575 Background: PPS ROC is defined by a platinum free interval &gt; 6 months. Women starting ≥3 lines of chemotherapy for PPS ROC are however a heterogeneous group with variable response to chemotherapy and OS. We sought to identify baseline characteristics (health related quality of life [HRQL] and clinical features) that were associated with stopping chemotherapy early and shorter OS to improve patient selection for palliative chemotherapy. Methods: 378 women with PPS ROC starting ≥3 lines chemotherapy enrolled in GCIG SBS. HRQL was assessed with EORTC QLQ-C30/QLQ-OV28. Associations with stopping chemotherapy early (by 8 weeks) were assessed with logistic regression. Associations with OS were assessed with Cox proportional hazards regression. Variables significant in univariable analysis (p &lt; 0.05) were included as candidates for multivariable analyses using backward elimination to select those independently significant at p &lt; 0.05. Results: Median age was 64 years. The line of chemotherapy was third in 40%, fourth in 29%, and ≥ fifth in 31%. Chemotherapy was stopped early in 45/378 (12%) and their median OS was 3.4 months. Poor physical function (PF) and global health status (GHS) at baseline were significant univariable predictors of stopping chemotherapy early (p &lt; 0.008); PF remained significant in a multivariable model adjusting for clinical factors (haemoglobin [Hb], ascites, abdominal cramps, neutrophil: lymphocyte≥5, platelets, log CA125); p = 0.03. Median OS in the whole group was 16.6 months. PF, role function, GHS and abdominal/GI symptoms were significant univariable predictors of OS (p &lt; 0.001); PF and GHS remained significant predictors of OS in multivariable models including Hb, ascites, neutrophil: lymphocyte≥5, platelets, log CA125, ECOG and BMI (p &lt; 0.007). Conclusions: In women with PPS ROC ≥3 lines chemotherapy, baseline PF and GHS are independent significant predictors of stopping chemotherapy early and short OS. HRQOL is easily measured, prognostic and may improve clinical trial stratification, patient-doctor communication and support clinical decision making. Clinical trial information: 12607000603415.
Demethylation Therapy as a Targeted Treatment for Human Papillomavirus–Associated Head and Neck Cancer
Authors: Asel Biktasova, Michael Hajek, Andrew Sewell, Cyril Gary, Gary Bellinger, Hari A. Deshpande, Aarti Bhatia, Barbara Burtness, Benjamin Judson, Saral Mehra, Wendell G. Yarbrough, Natalia Issaeva
Journal: Clinical Cancer Research (2017)

Purpose: DNA methylation in human papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) may have importance for continuous expression of HPV oncogenes, tumor cell proliferation, and survival. Here, we determined activity of a global DNA-demethylating agent, 5-azacytidine (5-aza), against HPV+ HNSCC in preclinical models and explored it as a targeted therapy in a window trial enrolling patients with HPV+ HNSCC.Experimental Design: Sensitivity of HNSCC cells to 5-aza treatment was determined, and then 5-aza activity was tested in vivo using xenografted tumors in a mouse model. Finally, tumor samples from patients enrolled in a window clinical trial were analyzed to identify activity of 5-aza therapy in patients with HPV+ HNSCC.Results: Clinical trial and experimental data show that 5-aza induced growth inhibition and cell death in HPV+ HNSCC. 5-aza reduced expression of HPV genes, stabilized p53, and induced p53-dependent apoptosis in HNSCC cells and tumors. 5-aza repressed expression and activity of matrix metalloproteinases (MMP) in HPV+ HNSCC, activated IFN response in some HPV+ head and neck cancer cells, and inhibited the ability of HPV+ xenografted tumors to invade mouse blood vessels.Conclusions: 5-aza may provide effective therapy for HPV-associated HNSCC as an alternative or complement to standard cytotoxic therapy. Clin Cancer Res; 23(23); 7276-87. ©2017 AACR.
Evaluation of the feasibility of expression microarray analysis in endoscopically obtained biopsies of gastric carcinoma and their clinical applicability
Authors: Minaxi Jhawer, Li-Xuan Qin, Hans Gerdes, David Klimstra, Mark Schattner, Agnes Viale, David Kelsen, Manish Shah
Journal: Clinical Cancer Research (2007)

A48    Background:  The feasibility of extracting high quality RNA for expression microarray analysis from endoscopic biopsy in gastric carcinoma has not been previously established.   Methods:  Patients with histologically confirmed locally advanced gastric or gastroesophageal junction adenocarcinoma were screened for enrollment in an NCI-sponsored trial of neoadjuvant irinotecan and cisplatin chemotherapy (NC1-5917). All patients underwent a repeat endoscopic biopsy for the procurement of fresh tumor tissue. Gross microdissection was performed to enrich the sample to at least 80% malignancy. RNA was isolated from the tumor specimens using RNeasy columns (Qiagen) and its quality verified by RNA 6000 NanoAssay and Bioanalyzer 2100 (Agilent). Gene expression profiling was performed on Human Genome U133A GeneChip (Affymetrix) which contained 22,215 oligonucleotide-base probe-sets. Differential gene expression profiles for Lauren’s classification were assessed using empirical Bayes  t  test, a threshold  p      Results:  Of 36 patients with previous biopsy confirmed gastric cancer, repeat endoscopic biopsy identified carcinoma in 28 patients (78%, 95%CI 61-90%). Adequate RNA for microarray analysis was obtained from 21 patients-representing 58% of those who presented for the procedure and 75% in whom endoscopic biopsies confirmed malignancy. This yield improved with increasing number of samples taken.  Lauren’s classification was available on 26 patients who underwent resection. From the total 54,613 gene probe-sets on the arrays, comparison of the expression profiles of diffuse-type and intestinal-type identified 167 genes that were differentially expressed.   Conclusions:  Endoscopic biopsy for expression analysis of gastric and gastroesophageal cancer is feasible. We demonstrate in a proof of principal experiment that expression analysis at the time of endoscopic biopsy can differentiate Lauren’s histology. This histologic characteristic is not routinely evaluable by pathologic review. We plan to extend these studies to evaluate gene expression profiles that could predict response to chemotherapy and additional identify key oncogenic pathways for future development of therapeutic agents. (Supported by ASCO Career Development Award 2003 (MAS) and the NCI grant N01-CM17105 (DKP)).
The development of Ceflatonin® for use in solid tumors
Authors: Shawnya Michaels, Dennis Brown
Journal: Cancer Research (2006)

564   Ceflatonin® (Homoharringtonine, HHT) is in clinical development for the treatment of a number of leukemia indications including CML resistant to Gleevec therapy. We have previously shown that HHT displays a unique pattern of angiogenic inhibition in the chorioallantoic membrane (CAM) assay, suggesting its utility in solid tumors. However, HHT has shown limited clinical activity in solid cancers as a single agent. Many topoisomerase inhibitors, including camptothecin (topo I), mitoxantrone (topo II) and etoposide (topo II), have also shown antiangiogenic activity in experimental models. Combining HHT with topoisomerase inhibitors may result in enhanced tumor control via angiogenic inhibition. Quinamed® (amonafide dihydrochloride, AMF) also targets topoisomerase II and is in Phase II trials as a single agent for prostate and other solid tumors. Using the RIF-1 murine tumor growth delay model, HHT was given in combination with either camptothecin, etoposide, mitoxantrone or amonafide. Enhanced tumor growth delay resulted from treatment combinations. In particular, the T/C ratio of HHT (4mg/Kg) and AMF (30mg/Kg), alone were 1.3 and 1.2, respectively, but in combination, the T/C rose to 1.6. Additionally, morphological tumor changes characterized by a blackened and necrotic tumor center indicate that angiogenesis may be a target for the combinations. These results suggest that HHT may be of value for the treatment of solid tumors in combination with other angiogenesis inhibitors.
Adult T-Cell Leukemia-Lymphoma: Role of a Human Retrovirus&lt;xref ref-type="fn" rid="FN1"&gt;1&lt;/xref&gt;
Authors: Max Essex
Journal: JNCI Journal of the National Cancer Institute (1982)

Adult T-Cell Leukemia-Lymphoma: Role of a Human Retrovirus Get access Max Essex Max Essex Department of Microbiology Harvard University School of Public HealthBoston, Massachusetts 02115 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 69, Issue 4, October 1982, Pages 981–985, https://doi.org/10.1093/jnci/69.4.981 Published: 01 October 1982
HIF activation causes synthetic lethality between the <i>VHL</i> tumor suppressor and the <i>EZH1</i> histone methyltransferase
Authors: Abhishek A. Chakraborty, Eijiro Nakamura, Jun Qi, Amanda Creech, Jacob D. Jaffe, Joshiawa Paulk, Jesse S. Novak, Kshithija Nagulapalli, Samuel K. McBrayer, Glenn S. Cowley, Javier Pineda, Jiaxi Song, Yaoyu E. Wang, Steven A. Carr, David E. Root, Sabina Signoretti, James E. Bradner, William G. Kaelin
Journal: Science Translational Medicine (2017)

Dysregulated H3K27 demethylase activity in pVHL-deficient cells increases dependence on the EZH1 H3K27 methyltransferase.
Predicting treatment response for non-Hodgkin's lymphoma: A multi-institutional MR spectroscopy study
Authors: Fernando Arias-Mendoza, Truman Brown
Journal: Clinical Cancer Research (2007)

A20   Numerous studies have shown that the sum of the levels of phospholipid-related metabolites  phosphoethanolamine  plus  phosphocholine  (Etn-P + Cho-P) is increased in tumor masses suggesting that phospholipid metabolism is an intrinsic part of the cancer process. Preliminary work on the pre-treatment non-invasive measurement of Etn-P + Cho-P normalized by the Pβ signal of nucleotide triphosphates ([Etn-P + Cho-P]/NTP) in  31 P-MR spectra of the tumor masses of patients with non-Hodgkin’s lymphomas (NHL) has shown that this measurement can be used as a predictive prognostic factor. In order to demonstrate reproducibility and validate the predictive prognostic results of [Etn-P + Cho-P]/NTP and its combination with IPI, a cohort of NHL patients from six research institutions under a cooperative agreement have been studied. This cooperative agreement has entailed the acquisition of non-contaminated  31 P spectra from human tumors  in situ . For this, stringent standardization and data inclusion have been set up.  To correlate the [Etn-P + Cho-P]/NTP value with clinical data, the patients were divided into four risk groups using the IPI. In order to classify a patient as having a complete response to treatment (CR), this response should have been maintained for six or more months post-treatment following the WHO criteria. All those patients that failed treatment on or before the 6-month mark were included in the not-complete response group (NCR). The CR cases of the 59 selected studies were evenly distributed between the low and low-intermediate risk groups, with just two CR cases in the high-intermediate group and none in the high group. The [Etn-P + Cho-P]/NTP ratios were significantly different between the CR and NCR for both the low risk (1.58 ± 0.1, mean ± standard error, n = 6  vs . 2.30 ± 0.24, n = 8; p  vs . 1.96 ± 0.15, n = 10; p
Blood Droplet-Based Cancer Diagnosis via Proteolytic Activity Measurement in Cancer Progression
Authors: Jin Woo Choi, Hyungbeen Lee, Gyudo Lee, Yi Rang Kim, Myung-Ju Ahn, Heung Jae Park, Kilho Eom, Taeyun Kwon
Journal: Theranostics (2017)

Matrix metalloproteinase (MMP) is a key marker and target molecule for cancer diagnosis, as MMP is able to cleave peptide chains resulting in degradation of extracellular matrix (ECM), a necessary step for cancer development. In particular, MMP2 has recently been recognized as an important biomarker for lung cancer. Despite the important role of detecting MMP molecules in cancer diagnosis, it is a daunting task to quantitatively understand a correlation between the status of cancer development and the secretion level of MMP in a blood droplet. Here, we demonstrate a nanoscale cancer diagnosis by nanomechanical quantitation of MMP2 molecules under cancer progression with using a blood droplet of lung cancer patients. Specifically, we measured the frequency dynamics of nanomechanical biosensor functionalized with peptide chains mimicking ECM in response to MMP2 secreted from tumors in lung with different metastasis level. It is shown that the frequency shift of the biosensor, which exhibits the detection sensitivity below 1 nM, enables the quantitation of the secretion level of MMP2 molecules during the progression of cancer cells or tumor growth. More importantly, using a blood droplet of lung cancer patients, nanomechanical biosensor is shown to be capable of depicting the correlation between the secretion level of MMP2 molecules and the level of cancer metastasis, which highlights the cantilever-based MMP2 detection for diagnosis of lung cancer. Our finding will broaden the understanding of cancer development activated by MMP and allow for a fast and point-of-care cancer diagnostics.
Wish-Qol Study - Assessment of Health-Related Quality of Life (HRQoL) and Health-Economic Aspects in Patients with Von Willebrand Disease (VWD) in France: Results of the Women Cohort
Authors: Annie Borel-Derlon, Jenny Goudemand, Dominique Desprez, Fabienne Volot, Yves Gruel, Sophie Bayard, Catherine Chatelanaz, Catherine Doriat-Robin, Agnes Veyradier, Edith Fressinaud, Sylvia von Mackensen
Journal: Blood (2016)
Interleukin-4 receptor-targeted delivery of Bcl-xL siRNA sensitizes tumors to chemotherapy and inhibits tumor growth
Authors: Padmanaban Guruprasath, Jihoon Kim, Gowri Rangaswamy Gunassekaran, Lianhua Chi, Soyoun Kim, Rang-Woon Park, Sang-Hyun Kim, Moon-Chang Baek, Sang Mun Bae, Sang-Yeob Kim, Dong-Kyu Kim, In-Kyu Park, Won-Jong Kim, Byungheon Lee
Journal: Biomaterials (2017)
Improving Care in an Accountable Care Organization
Authors: William B. Borden
Journal: JAMA Cardiology (2017)

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