tbuckley/cabot-search huggingface dataset:
N-cadherin, E-cadherin, ERCC1, and c-kit expression in small cell lung cancer (SCLC) and potential for new therapeutic targets
Authors: M. Batus, R. Myint, J. Coon, S. Basu, K. Kaiser, M. Fidler, P. Bonomi
Journal: Journal of Clinical Oncology (2009)

e22157 Background: Minimal advances have been made in the treatment of SCLC. Molecular markers may allow us to better stratify patients (pts) for new treatment options and drug combinations. The objective of our study was to determine the frequency and potential prognostic significance of N-cadherin (N-cad), E-cadherin (E-cad), ERCC1, and c-kit (CD117) expression in SCLC. Methods: Tissue from 132 pts with SCLC was retrospectively stained for N-cad, E-cad, ERCC1, and c-kit. Frequency of expression (% of tumor cells staining positive) was measured on a scale of 0–4 (freq 0=no expression (&lt;1%), freq 1=1–10%, freq 2=11–35%, freq 3=36–70%, freq 4=71–100%). Charts were reviewed for stage, performance status, date of diagnosis/death, survival, and treatment (type, dates, response). The frequency of molecular markers was correlated with clinical data and overall survival. Results: Age range 42 to 97 years, 65 male:67 female, and 64 had limited and 68 had extensive stage. Of the 132 pts, 75% had tumors that expressed (frequency ≥ 1) N-cad, 58% E-cad, 70% ERCC1, and 55% c-kit. Comparing tumor marker expression with survival using either the Log-Rank Test or the Wilcoxon Test, there was no significant association for N-cad, E-cad, or ERCC1. However, tumors that expressed c-kit with frequency ≥ 3 had a trend toward superior survival compared with frequency &lt; 3. Median survival for c-kit frequency ≥ 3 was 496 days compared to 312 days for frequency &lt; 3 (p = 0.09, Log-Rank Test). Conclusions: In our retrospective study of 132 SCLC pts, we found that all 4 markers were expressed in greater than 50% of specimens, and that higher c-kit expression was associated with marginally significant increase in overall survival. Though previous experience with imatinib alone or with chemotherapy showed limited clinical activity in unselected SCLC pts, given preclinical synergy with cisplatin, it seems reasonable to consider combination therapy with cisplatin/etoposide and imatinib in pts selected for high c-kit expression. [Table: see text] No significant financial relationships to disclose.
Results of the Phase 1 Trial of RG7112, a Small-Molecule MDM2 Antagonist, in Acute Leukemia
Authors: Michael Andreeff, Kevin R. Kelly, Karen Yee, Sarit Assouline, Roger Strair, Leslie Popplewell, David Bowen, Giovanni Martinelli, Mark W. Drummond, Paresh Vyas, Mark Kirschbaum, Swaminathan Padmanabhan Iyer, Kensuke Kojima, David Geho, Steven Blotner, Suzanne Cheng, Lyubomir Vassilev, Meichun Ding, Jianguo Zhi, Steven Middleton, Gwen Nichols
Journal: Blood (2012)
Abstract 286: Preclinical study: HDAC inhibition combined with gemcitabine for the treatment of leiomyosarcoma
Authors: Gonzalo Lopez, Edwin Choy, Shreyaskumar Patel, Hemant Bid, Danielle Braggio, Dina Lev, Raphael Pollock
Journal: Cancer Research (2016)

Abstract Objective Leiomyosarcoma (LMS) is a malignant soft tissue sarcoma (STS) with a dismal prognosis following metastasic disease. Chemotherapeutic intervention has demonstrated to have modest clinical efficacy with no curative potential in LMS patients. Previously, we demonstrated pan-HDAC inhibition to have a superior effect in various complex karyotypic sarcomas. In this study, our goal is to evaluate the therapeutic efficacy of pan-HDACi alone and in combination with gemcitabine in LMS. Methods Human leiomyosarcoma (LMS) cell lines were used for in vitro and in vivo studies. Compounds tested included a pan-HDAC inhibitor (HDACi) and nucleoside analog, gemcitabine (Gem). MTS and clonogenic assays were used to evaluate the effect of HDACi on LMS cell growth. Cell cycle FACS and annexin V PI/FACS analysis were used to determine the effects of HDACi on cell cycle and apoptosis, respectively. Compusyn software was used to determine in vitro synergy studies for the combination of HDACi + Gem. A LMS xenograft model in SCID mice was used to test the impact of HDACi alone, Gem alone and the combination of HDACi + Gemcitabine. Results Pan-HDAC inhibition abrogated LMS cell growth and clonogenic potential. HDACi induced G2/M cell cycle growth arrest and enhanced apoptosis in LMS cell lines. The combination of HDACi + Gem exhibited a synergistic effect in LMS cells in vitro. Similarly, HDACi combined with Gem resulted in superior anti-LMS effects in vivo. Conclusion LMS are aggressive, metastatic tumors with poor prognosis where effective therapeutic interventions are wanting. Our studies demonstrate the potential utility of pan-HDAC inhibition combined with gemcitabine for the treatment of LMS. Citation Format: Gonzalo Lopez, Edwin Choy, Shreyaskumar Patel, Hemant Bid, Danielle Braggio, Dina Lev, Raphael Pollock. Preclinical study: HDAC inhibition combined with gemcitabine for the treatment of leiomyosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 286.
Abstract 805: The molecular mechanisms of obesity driving breast cancer etiology and prognosis in post-menopausal women
Authors: Yu Jing Jan Heng, Jun Wang, Aditi Hazra, David J. Hunter, A. Heather Eliassen, Rulla M. Tamimi, Susan E. Hankinson, Andrew H. Beck
Journal: Cancer Research (2016)

Abstract This study aims to gain insights into the molecular mechanisms of obesity driving breast cancer etiology and prognosis as post-menopausal women with high body mass index (BMI) have increased breast cancer risk and poorer prognosis. We examined the differential gene expression of breast tumors from 441 post-menopausal women part of the Nurses’ Health Studies. Primary analysis was performed between women with BMI of &amp;lt;25, ≥25 to &amp;lt;30, ≥30 to 35 and ≥35 while secondary analysis was performed using BMI as a continuous variable. Analyses were adjusted for age of diagnosis, year of diagnosis, post-menopausal hormone therapy, alcohol consumption, microarray batch and ER status. In the primary analysis, differentially expressed genes associated with BMI were identified in pairwise analyses comparing women with BMI ≥35 with women in lower BMI categories (&amp;lt;25 vs. ≥35, n = 58 significant genes; ≥25 to &amp;lt;30 vs. ≥35, n = 29; ≥30 to 35 vs. ≥35, n = 12; FDR&amp;lt;0.05); no significant genes were identified in the other pairwise comparisons. In the secondary analysis which considered BMI as a continuous value, two genes, NCOA3 and PTPN1, were significantly up-regulated in breast tumors with increasing BMI (FDR&amp;lt;0.05). Gene set enrichment analyses suggested that tumors from post-menopausal women with increasing BMI have increased inflammation and decreased carcinogen/anti-cancer drug metabolism. These molecular insights have further elucidated breast cancer etiology in post-menopausal women with high BMI. Citation Format: Yu Jing Jan Heng, Jun Wang, Aditi Hazra, David J. Hunter, A. Heather Eliassen, Rulla M. Tamimi, Susan E. Hankinson, Andrew H. Beck. The molecular mechanisms of obesity driving breast cancer etiology and prognosis in post-menopausal women. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 805.
Phase I study of proteasome inhibitor bortezomib (B) concurrent with re-irradiation therapy (re-RT) for recurrent squamous cell carcinoma of the head and neck (SCCHN).
Authors: J. C. Morris, D. E. Citrin, L. Nottingham, S. F. Rudy, N. Harold, T. Cooley-Zgela, D. Goldstein, J. J. Wright, B. A. Conley, C. Van Waes
Journal: Journal of Clinical Oncology (2010)

2603 Background: B demonstrated antitumor and radiosensitizing activity in preclinical solid tumor models. Methods: A phase I trial was designed to assess escalating doses of B 0.6, 0.9 or 1.2 mg/m2 IV twice weekly concurrent with re-RT 2Gy/5 days/wk to 60-70 Gy. Evaluations included standard measures for adverse events (CTC v3.0), tumor response (RECIST), progression-free survival (PFS) and overall survival (OS). Baroreceptor reflex testing was initiated in a subset of patients to assess the potential cause of observed orthostatic hypotension. Results: 25 patients with recurrent SCCHN were treated: 19 men, 6 women, median age 57 yrs, ECOG performance status∼1, prior surgery and chemotherapies∼1 and > 6 mos since prior RT. All were evaluable for toxicity and 19 for response. B 0.6 or 0.9 mg/m2 + re-RT given 2x/wk for 6-7 wks without breaks was associated with dose-limiting orthostatic hypotension and/or hyponatremia. Amended schedules with a mid-course 2-wk break from B and re-RT, or B alone, were better tolerated. B 0.9 mg/m2 2x/wk with a 2-wk mid- course break was established as the MTD and schedule, based on a dose-limiting neuropathy. Pre-existing and treatment-associated baroreceptor reflex dysfunction was seen in several subjects. Radiation mucositis was less than expected at doses and schedules studied. 5/5 pts given B 0.6 mg/m2 2x/wk without break had early progressive disease, while 5 PRs and 1 SD were seen in 10 subjects treated at the same dose with a 2 wk break. At 0.9 mg/m2, 3 SD and 3 PD were seen. The median PFS and OS of ∼2 + 4 mos in subjects treated without break was inferior to that of ∼4 + 11 months seen in patients treated with breaks. Conclusions: Decreased response in patients treated with B+re-RT without break or at higher doses suggests that proteasome inhibition may confer radioprotection in SCCHN. Peripheral or baroreceptor reflex neuropathy is dose-limiting in some heavily pretreated HNSCC patients. Supported by NIH Intramural Project ZIADC-000016 and a CRADA with Millennium Pharmaceuticals. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium
Impact Of ABO Incompatibility On Overall Survival After Unrelated Cord Blood Transplantation a Single Institute Experience In China
Authors: Sun Zimin, Ji Mengmeng, Yao Wen, Zheng Changcheng, Tong Juan, Liu Huilan, Geng Liangquan, Baolin Tang, Zhu Xiaoyu, Song Kaidi, Kaiyang Ding
Journal: Blood (2013)
Central ECG analysis of resminostat, a new oral histone deacetylase inhibitor (HDACi), in clinical development as anticancer compound.
Authors: B. Hauns, A. Mais, R. Jankowsky, B. Hentsch, W. Haverkamp
Journal: Journal of Clinical Oncology (2010)

e13609 Background: Resminostat (4SC-201) is a new, specific, potent, pan-HDAC inhibitor with broad anti-tumor activity in preclinical models and promising clinical characteristics. Methods: 19 patients with advanced solid tumors were treated in a first-in-human trial at increasing oral daily dose levels from 100 mg to 800 mg in repeated 14-day cycles consisting of 5 consecutive treatment days followed by a 9-day rest period. Cardiac function was monitored by pulse rate, blood pressure, troponin levels, and continuous ECG telemetry during the first treatment day. In addition, standard 12-lead rest ECGs were conducted frequently to aid in the determination of potential effects on QT interval prolongation. An intensive profile consisting of 18 single ECGs was performed from day 1 to 5 during cycle 1, and a reduced number of ECGs in the following cycles, if there were no clinically relevant findings. Subsequent to the on-site clinical assessment, ECGs were sent to a core lab for further analysis by a trained cardiologist. PR, QRS, and QT intervals and heart rate (HR) were measured in lead II across 3 consecutive beats using markers for the respective ECG intervals. Results: No signal for drug-induced prolongation of QTc was observed. A dose-dependent increase in HR with a maximum mean increase of up to 22 beats per minute and a corresponding shortening of the PR and QT interval was found. HR correction with Fridericia's formula did not reveal consistent changes in QTc. The incidence of QTcF outliers was very small. The results suggest that resminostat does not affect the duration of myocardial repolarization. At doses ≥ 400 mg, unspecific flattening of the T-wave and slight depression of the ST-segment were observed frequently. However, in some patients such findings were already observed at baseline. No dose-limiting toxicities were seen with regard to cardiac safety in all dose cohorts. Conclusions: Central analysis of phase I ECG measurements did not reveal a drug- induced prolongation of the QTc interval. Drug administration was frequently associated with moderate increases in HR. At higher doses ≥ 400 mg unspecific changes in T-wave morphology and slight ST-segment depression were observed. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration 4SC AG 4SC AG 4SC AG 4SC AG
P0212 : Identifying the trigger matters – outcome of severe acute kidney injury in patients with cirrhosis and ascites
Authors: T. Bucsics, M. Mandorfer, P. Schwabl, S. Bota, M. Trauner, W. Sieghart, A. Ferlitsch, M. Peck-Radosavljevic, T. Reiberger
Journal: Journal of Hepatology (2015)
A Multimedia E-Book— <i>A Story of Health</i> : Filling a Gap in Environmental Health Literacy for Health Professionals
Authors: Mark D. Miller, Maria Valenti, Ted Schettler, Brian Tencza
Journal: Environmental Health Perspectives (2016)

Summary:Narrative approaches and storytelling are emerging as powerful health promotion tools that can spark interest, increase understanding of determinants of health, and translate complex science. A Story of Health, a multimedia e-book with continuing education credits was designed to harness the power of storytelling to increase environmental health literacy. Health professionals are a key audience. They recognize that patients may be suffering from preventable illnesses of environmental origin but often feel ill-equipped to educate individuals and families about risks associated with common exposures. A Story of Health seeks to fill this gap and help readers develop the competencies they need in order to help patients make informed choices, reduce health risks, improve quality of life, and protect the environment. Americans rate nurses and medical doctors as having the highest honesty and ethical standards of all professions. These medical professionals can play a key role in changing patterns of patient behavior and influencing public policies. The e-book provides an easily accessible method of developing environmental health competency. The multimedia format with graphical interpretations allows for quick reviews of topics or for more in-depth analysis via links to additional resources. The CE evaluations have been overwhelmingly positive.
Phase II study of figitumumab in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: GORTEC 2008-02.
Authors: S. Schmitz, M. Kaminsky-Forrett, S. Henry, S. Zanetta, L. Geoffrois, E. Bompas, A. Moxhon, J. Guigay, J. H. Machiels
Journal: Journal of Clinical Oncology (2010)

5500 Background: Insulin-like growth factor-1 receptor (IGF-1R) plays an important role in the growth and apoptosis of cancer cells, and is overexpressed in squamous cell carcinoma of the head and neck (HNSCC). In xenograft murine models, antitumor activity against HNSCC tumors has been observed with monoclonal antibodies against IGF-1R. Figitumumab is a fully human monoclonal antibody IgG2 subtype that specifically binds to the IGF-IR. We investigated figitumumab monotherapy in palliative HNSCC. Methods: Palliative HNSCC progressing after platinum-based therapy were eligible. Patients received figitumumab IV 20 mg/kg, every 3 weeks. Tumor evaluation was performed every 6-8 weeks. The primary endpoint was disease control rate (SD, PR, CR) at 6-8 weeks. A Simon two-stage design was used (a=0.15, b=0.10, H0=10%, H1=25%), with at least 2 out of the first 17 patients with SD to continue accrual in the second stage. Results: 17 pts (M/F:13/4; ECOG 0- 1/2/unknown: 9/7/1) were included. 7 pts had been previously treated with anti-EGFR treatment. According to RECIST, 3 pts achieved a SD and 14 were in PD at the first tumor evaluation performed at 6 weeks. However, the 3 pts with SD had all an increase in their tumor size at 6 weeks (% increase in sum of the largest diameters: + 6%, +7%, and +19%) and all were in RECIST PD at 3 months. After central imaging review, it was decided to stop the trial due to low efficacy. The main relevant Gr3-4 toxicities were hyperglycemia (4 pts), asthenia (1pt), anorexia (1 pt), infection (1pt), anemia (1pt), and gastro-intestinal bleeding (1 pt). One grade 5 tumor bleeding was observed in the context of disease progression. Conclusions: Figitumumab monotherapy has no clinically significant activity in unselected palliative HNSCC pts. Further investigation with IGF-1R inhibitors in HNSCC should be pursued in combination with chemotherapy or targeted therapies to study potential synergies and/or overcome treatment resistance. No significant financial relationships to disclose.
B-cell-specific depletion of tumour necrosis factor alpha inhibits atherosclerosis development and plaque vulnerability to rupture by reducing cell death and inflammation
Authors: Christopher Tay, Yu-Han Liu, Hamid Hosseini, Peter Kanellakis, Anh Cao, Karlheinz Peter, Peter Tipping, Alex Bobik, Ban-Hock Toh, Tin Kyaw
Journal: Cardiovascular Research (2016)

Aims B2 lymphocytes promote atherosclerosis development but their mechanisms of action are unknown. Here, we investigated the role of tumour necrosis factor alpha (TNF-α) produced by B2 cells in atherogenesis. Methods and results We found that 50% of TNF-α-producing spleen lymphocytes were B2 cells and ∼20% of spleen and aortic B cells produced TNF-α in hyperlipidemic ApoE−/− mice. We generated mixed bone marrow (80% μMT/20% TNF-α−/−) chimeric LDLR−/− mice where only B cells did not express TNF-α. Atherosclerosis was reduced in chimeric LDLR−/− mice with TNF-α-deficient B cells. TNF-α expression in atherosclerotic lesions and in macrophages were also reduced accompanied by fewer apoptotic cells, reduced necrotic cores, and reduced lesion Fas, interleukin-1β and MCP-1 in mice with TNF-α-deficient B cells compared to mice with TNF-α-sufficient B cells. To confirm that the reduced atherosclerosis is attributable to B2 cells, we transferred wild-type and TNF-α-deficient B2 cells into ApoE−/− mice deficient in B cells or in lymphocytes. After 8 weeks of high fat diet, we found that atherosclerosis was increased by wild-type but not TNF-α-deficient B2 cells. Lesions of mice with wild-type B2 cells but not TNF-α-deficient B2 cells also had increased apoptotic cells and necrotic cores. Transferred B2 cells were found in lesions of recipient mice, suggesting that TNF-α-producing B2 cells promote atherosclerosis within lesions. Conclusion We conclude that TNF-α produced by B2 cells is a key mechanism by which B2 cells promote atherogenesis through augmenting macrophage TNF-α production to induce cell death and inflammation that promote plaque vulnerability.
Rivaroxaban Limits Complement Activation Compared to Warfarin in Antiphospholipid Syndrome Patients with Venous Thromboembolism
Authors: Deepa Jayakody Arachchillage, Ian J Mackie, Maria Efthymiou, Andrew Chitolie, Beverley J Hunt, David Isenberg, Munther Khamashta, Samuel Machin, Hannah Cohen
Journal: Blood (2015)
Stand up for the NHS: Margaret McCartney joins Phil Hammond on stage in Edinburgh
Authors: Bryan Christie
Journal: BMJ (2016)

Margaret McCartney, the Glasgow GP and columnist for The BMJ , made her Edinburgh Fringe Festival debut last week. She joined the doctor and comedian Phil Hammond in an hour long show urging the audience to form a popular movement to save the NHS from market mayhem.

Dr Phil’s NHS Revolution is a verbal Punch and Judy act. The villains are dishonest politicians, profiteering corporations, and market solutions. The heroes are striking junior doctors, Britain’s army of carers, and evidence based decision making.

McCartney heads the revolution’s Anti Bollocksology Unit, providing facts that people need to know about today’s NHS.

It is not an hour …
Abstract 4807: Triphenylmethanol conjugates of triptorelin as anti-cancer prodrugs
Authors: Ryan Beni, William Boadi, Jawzah Alnakhli
Journal: Cancer Research (2016)

Abstract Triptorelin (TRP) is an anti-cancer agent used for the treatment of a wide variety of hormone-responsive cancers, such as prostate cancer. The surge of testosterone, known as a flare effect, is the major side-effect of cancer chemotherapy using TRP in a combination regiment. Improving the biological activity of TRP by increasing the cellular uptake and retention is a remedy to this end. In this study, the hydrophobicity of TRP was optimized by using an appropriate hydrophobic linker attached to tris(4-methoxyphenyl)methanol (TPM) derivatives with the expectation to improve the cellular uptake. In this regard, a number of TRP conjugates of TPM derivatives with optimized hydrophobicity were synthesized by the reaction of 2-substituted methoxy benzenes (e.g. methyl 2-methoxybenzoate, 1,2-dimethoxybenzene, methoxy-2-methylbenzene, methoxy-2-nitrobenzene, chloro-2-methxyenzene), and 1,3,5-trioxane, followed by the conjugation with TRP and decanedioic acid in the presence of HBTU/DIPEA/DIC in moderate yields. Comparative antiproliferative assays between TPM-TRP conjugates and the corresponding non-covalent physical mixtures of the TPM derivatives and TRP were performed against human acute lymphoblastic leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3), and mouse pre adipocytes (3T3-L1) cells. TPM-TRP conjugates inhibited the cell proliferation of CCRF-CEM, SK-OV-3 and 3T3-L1 cells by 55-92%, 24-73%, 37-56%, respectively, at a concentration of 10-50 μM after 24-72 h of incubation. These data suggest that TPM-TRP derivatives with optimized hydrophobicity can be used to improve the biological activity of TRP. Citation Format: Ryan Beni, William Boadi, Jawzah Alnakhli. Triphenylmethanol conjugates of triptorelin as anti-cancer prodrugs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4807.
Cardiovascular Magnetic Resonance to Evaluate Aortic Regurgitation After Transcatheter Aortic Valve Replacement
Authors: Henrique B. Ribeiro, Stefan Orwat, Salim S. Hayek, Éric Larose, Vasilis Babaliaros, Abdellaziz Dahou, Florent Le Ven, Sergio Pasian, Rishi Puri, Omar Abdul-Jawad Altisent, Francisco Campelo-Parada, Marie-Annick Clavel, Philippe Pibarot, Stamatios Lerakis, Helmut Baumgartner, Josep Rodés-Cabau
Journal: Journal of the American College of Cardiology (2016)