tbuckley/cabot-search huggingface dataset:
Effects of the pan-DAC inhibitor LBH589 in estrogen-sensitive and -insensitive breast cancer cells.
Authors: N. Fortunati, M. Catalano, F. Marano, M. Pugliese, V. Mugoni, F. Mainini, G. Boccuzzi
Journal: Journal of Clinical Oncology (2010)

e13618 Background: The pan-deacetylase inhibitor LBH589 (panobinostat), that is now in phase I-II trials for its antitumor activity in advanced refractory solid tumors and hematologic malignancies, is one of those drugs with both antitumor activity and the ability of modulating the expression of selected molecules involved in different response to therapy. Advanced breast cancer, becoming resistant to conventional treatment, or metastatic disease are potential application of these new approaches. Methods: In the present study, we report the effects of LBH589 in estrogen-sensitive MCF-7 and T47D, and estrogen-insensitive MDA-MB 231 breast cancer cells. Cells were treated with 5-100 nM LBH589 for different periods (untreated cells were used as control). After treatment, we evaluated: 1. cell viability and cytotoxicity with the WST-1 method; 2. apoptosis induction with the Cell Death Detection ELISA PLUS (Roche Applied Science, Germany); 3. cell cycle progression with flow cytometry; 4. estrogen sensitivity gene expression with RT- real time PCR for estrogen receptor (ER), progesterone receptor (PR), and FOXA1. Results: LBH589 caused a significant reduction in cell viability within nanomolar range and the anti-tumour effect was sustained by apoptosis induction and cell cycle arrest in G2/M. The cytotoxic effect was evident in both estrogen-sensitive and insensitive cells. LBH589 at concentrations higher than 50 nM caused also a reduction of ER alpha, PR and FOXA1 expression in MCF7 and T47D cells; no effect was observed in MDA-MB 231 cells where ER alpha, PR and FOXA1 were not detectable before and after treatment. LBH589 is able to smooth down estrogen-sensitivity pathway, almost certainly causing additional modification in cell behavior, that deserves further studies. Conclusions: Our data suggest that LBH589 is a useful compound in the managing of breast cancer due to its potent cytotoxic effect that is detectable in both estrogen-sensitive and insensitive cells (differently by what reported for other DAC-inhibitors). Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis
The prognostic significance of HER2/neu, p27 and sonic hedgehog proteins in urothelial cell carcinoma of the bladder in Saudi Arabia.
Authors: Taoufik Nedjadi, Abdelbaset Buhmeida, Mourad Assidi, Adel Al-Ammari, Ahmed Al-Sayyad, Syed A. Hussain, Jaudah Al-Maghrabi
Journal: Journal of Clinical Oncology (2016)

e16020 Background: Urothelial bladder carcinoma (BC) is characterized by high recurrence ratio and greater risk for progression to invasive form that necessitates regular surveillance to monitor disease recurrence. Therefore, there is an urgent need for a reliable biomarker that could be used in clinical setting to assist with the current staging and grading systems to accurately predict for BC progression. The aim of the current study was to analyze the status of her2/neu, p27 and sonic hedgehog (SHh) expression and their clinical value as a prognostic markers in BC. Methods: Formalin-fixed paraffin-embedded BC samples were collected from patients who underwent surgical resection at King Abdulaziz University Hospital- KSA. One hundred and sixty samples were arranged on a tissue microarray (TMA) and stained with anti-her2, p27 and SHh antibodies using immunohistochemistry (IHC). Her2 gene amplification was evaluated using bright-field dual in situ hybridization (BDISH) method. The results were correlated with clinicopathological parameters and survival. Results: Immunostaining of BC TMA revealed that Her2, p27 and SHh proteins are expressed in 85%, 50% and 76% respectively of the analyzed BC cohort. Overexpression of her2 (3+) was observed in 24% and significantly associated with tumour staging (p= 0.002), lymph node invasion (p= 0.04) and vascular invasion (p= 0.01). BDISH revealed that her2 gene is amplified in 25% of patients and significant correlation with tumour grade (p= 0.03). p27 expression inversely correlates with tumour grade (p= 0.001) and muscle invasion (p= 0.014). Positive correlation between the level of SHh expression and lymph node metastasis (p= 0.02) and poor cancer-specific survival in BC (p < 0.04, log-rank test). Conclusions: The expression of her2, p27 and SHh was correlated with the invasive phenotype of BC and might serve as potential markers for cancer metastasis and poor prognosis. This finding indicates that high proportion (24%) of BC patients could potentially benefit fron anti-her2 targeted therapy. Acknowledgement: The authors thank King Abdulaziz City for Science and Technology for the financial support to the project (ات-33-26).
Enalapril decreases prevalence of ventricular tachycardia in patients with chronic congestive heart failure
Authors: R. D. Fletcher, G. B. Cintron, G. Johnson, J. Orndorff, P. Carson, J. N. Cohn
Journal: Circulation (1993)

Background. Patients with heart failure have a high prevalence of serious arrhythmias and sudden cardiac death. Methods and Results. Male patients aged 18-75 years with chronic heart failure were randomized to enalapril or hydralazine-isosorhide dinitrate. Short-term (4-hour to 8-hour) Holter tape recordings were performed before randomization, at 3 months, at 1 year, and yearly thereafter. Of 804 patients randomized to therapy, 715 had Holters at baseline. Couplets were noted in 56% versus 60% and ventricular tachycardia (VT) (three or more consecutive ventricular premature beats) in 27% versus 29% of patients randomized to enalapril versus hydralazine-isosorbide dinitrate, respectively
Induction of Endogenous Repair Mechanisms by Single-Stranded DNA Oligonucleotide Therapy for Correction of the DNA-PK Mutation in Murine Severe Combined Immune Deficiency.
Authors: Jakub Tolar, Angela Panoskaltsis-Mortari, Anton K. Yerich, Ron T. McElmurry, Georg A. Hollander, Betsy T. Kren, Clifford J. Steer, Bruce R. Blazar
Journal: Blood (2006)
Abstract 870: Derivation and characterization of antibodies from immune checkpoint blockade treated cancer patients
Authors: Mark Branum, Laura Smith, Heather Brett, Paul Algate, Brad Greenfield, William Brown, Kristine M. Swiderek
Journal: Cancer Research (2016)

Abstract The IgG+ memory B cell repertoire of cancer patients demonstrating durable responses to immune checkpoint blockade therapy has been interrogated to identify tumor specific antibodies. Matched serum and PBMC samples have been collected from 10 melanoma patients with durable responses to treatment with ipilimumab. A panel of 7 well characterized melanoma cell lines with a diverse set of oncogenic driver mutations has been employed to assess durable responder patient serum reactivity to cell surface determinants in a live-cell flow cytometry assay. IgG+ memory B cells obtained from several prioritized durable responder melanoma patients have been plated out on 384 well plates at monoclonal density. The memory B cells have been activated in a short term culture system optimized to expand the clonal B cells and induce secretion of IgG. Antibodies secreted from clonally expanded B cells have been screened using live cell high throughput multiplex flow cytometry assays against a panel of melanoma cell lines. A prioritized subset of antibodies, selected on the basis of tumor cell line binding profiles and antibody v-region sequences, has been cloned and expressed as recombinant IgG1. A cell surface target for a prioritized antibody has been identified and the in vitro analysis and characterization of the antibody including functional activity and immunohistochemistry staining on tumor and normal tissues has been carried out in preparation for in vivo testing of efficacy. Citation Format: Mark Branum, Laura Smith, Heather Brett, Paul Algate, Brad Greenfield, William Brown, Kristine M. Swiderek. Derivation and characterization of antibodies from immune checkpoint blockade treated cancer patients. [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 870.
Impact of systemic alitretinoin treatment on skin barrier gene and protein expression in patients with chronic hand eczema
Authors: V. Kumari, K. Timm, A.A. Kühl, G. Heine, M. Worm
Journal: British Journal of Dermatology (2016)

Chronic hand eczema (CHE) is a common inflammatory skin disease that affects approximately 10% of the population. Systemic alitretinoin has been shown to be effective in patients with CHE who are refractory to topical corticosteroids. To analyse the impact of alitretinoin on the skin barrier genes and protein expression in the skin lesions of patients with CHE. Fifteen patients with CHE were treated with 30 mg daily of alitretinoin for up to 27 weeks. Disease severity was assessed using a clinical score. Skin biopsies from all the patients were evaluated before and after therapy for the expression of Ki‐67, various skin barrier genes and thymic stromal lymphopoietin (TSLP) by real‐time quantitative polymerase chain reaction and immunohistochemistry. After alitretinoin application, an improvement in the clinical severity of CHE was observed in the majority of patients. Analysis of skin biopsies before treatment showed a significant increase in Ki‐67‐positive cells in the suprabasal layer and a dysregulated expression of various skin barrier genes, such as claudin 1, loricrin, filaggrin and cytokeratin 10, which were normalized after treatment. TSLP was significantly upregulated in patients with CHE and also normalized after alitretinoin treatment and negatively correlated with filaggrin. Our data indicate that the expression of barrier genes and proteins was normalized following treatment with alitretinoin in patients with CHE. The change in expression levels of these genes correlated with the clinical efficacy, suggesting that alitretinoin exhibits a disease‐modifying activity. TSLP is upregulated in CHE and seems to counteract filaggrin expression in the skin.
Abstract 2503: NQO1's role in maintaining the cancer stem cell phenotype in NSCLC
Authors: Brian Madajewski, Erik A. Bey
Journal: Cancer Research (2016)

Abstract NAD(P)H:quinone oxidoreductase 1 (NQO1) is a phase II detoxifying enzyme responsible for quinone reduction, where it scavenges quinone induced reactive oxygen species. In recent studies, NQO1 has been investigated as a possible drug target due to its overexpression in a number of solid tumors. To this end, treatment with the quinone-analog drug, β-lapachone (ARQ-761), has progressed to Phase II clinical trials. In an effort to better understand the necessity of NQO1 in the overall lifecycle of cancer, our earlier work demonstrated that NQO1 played a vital role in a number of tumorigenic processes including anoikis resistance, and most interestingly alteration of aldehyde dehydrogenase (ALDH) activity. Given that ALDH is a widely reported cancer stem cell marker, and loss of NQO1 leads to a decrease in ALDH activity, we have begun to investigate the effect of NQO1 expression on the non-small cell lung cancer (NSCLC) stem cell population. Here, we present data that demonstrates NQO1 is vital to tumorsphere formation as demonstrated by decreased spheroid formation following NQO1 knocked down with shRNA. We also show that NQO1 appears to be necessary for cancer stem cell renewal as illustrated by decreased serial tumorsphere formation. In addition to these aforementioned data, in extreme limited dilution assays we demonstrate a reduced cancer stem cell frequency in NQO1 knockdown cells as compared to controls. Interestingly, in NQO1 knockdown populations, those cells that do form spheres show a remarkable re-expression of NQO1 as well as a rescue of ALDH activity, further supporting NQO1's role in tumorsphere formation and stem cell maintenance. Future work on this project will involve use of the CRISPR-Cas9 system to generate NQO1 knockout cell lines, drug resistance studies, cancer stem cell marker validation, and in vivo limited dilution assays to definitively demonstrate NQO1's necessity in maintaining the NSCLC stem cell population. Citation Format: Brian Madajewski, Erik A. Bey. NQO1's role in maintaining the cancer stem cell phenotype in NSCLC. [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 2503.
Association of long-term exposure to circulating platinum with adverse late effects in testicular cancer survivors.
Authors: Hink Boer, Johannes H Proost, Janine Nuver, Sophie Bunskoek, Joyce Q. Gietema, Barbara M. Geubels, Renske Altena, Nynke Zwart, Sjoukje Oosting, Donald R.A. Uges, Coby Meijer, Elisabeth De Vries, Jourik A. Gietema
Journal: Journal of Clinical Oncology (2012)

4528 Background: Successful platinum(Pt)-based chemotherapy for testicular cancer (TC) comes at the price of late cardiovascular morbidity and neurotoxicity. Damage induced by circulating Pt could be an etiological mechanism. We investigated the relation between circulating Pt and late effects. Methods: In 96 consecutive TC patients (med age 29 [17-53] at chemotherapy), 3 serum samples and a 24h-urine sample were collected on several time-points med 5 yrs (1-13) after treatment. Pt concentrations ([Pt]) were measured with a sensitive voltammetric method (Lancet 2000, 355:1075). Measured [Pt] combined with cisplatin dose, age, weight and height were analyzed simultaneously to construct a population pharmacokinetic (PK) model using NONMEM. Based on the PK parameters of each patient, individual [Pt] at 1, 3, 5, 10 yrs after start and AUC were calculated. Cardiovascular status, paresthesia and markers of vascular damage were assessed after a med follow-up (FU) of 9 yrs (3-15). Results: Decay of [Pt] was best described by a two compartment model. Mean terminal T 1/2 was 3.7 (±0.3) yrs. At all time-points [Pt] correlated with cisplatin dose and renal function during treatment. [Pt] at 3 yrs correlated with systolic blood pressure (BP) (r=.32, p&lt;0.01) and creatinine clearance (CRCL) (r=-.25, p=0.02) at FU. Patients with increased BP had higher Pt AUCs than patients with normal BP (table). Pt AUCs were higher in patients with paresthesia (table). Conclusions: Known late effects of cisplatin-based chemotherapy such as hypertension and paresthesia are related to higher circulating [Pt]. Long-term exposure to Pt is involved in healthy tissue damage in TC survivors. [Table: see text]
Abstract 3575: Ferroptosis: A novel nonapoptotic cell death overcomes head and neck cancer resistance to cisplatin
Authors: Hye Jin Jang, Jin Young Park, Eun Hye Kim, Ji Won Kim, Minsu Kwon, Jong-Lyel Roh
Journal: Cancer Research (2016)

Abstract Ferroptosis was recently identified as a novel form of iron-dependent cell death different from apoptosis or necrosis. Inhibition of key molecules related to ferroptosis, cystine-glutamate antiporter (xCT) and glutathione peroxidase (GPX4), may induce the eradication of cancer cells resistant to conventional chemotherapy or radiotherapy. The present study investigated whether ferroptosis overcome head and neck cancer (HNC) resistant to cisplatin treatment. Three cisplatin-resistant HNC cell lines (AMC-HN3R, -HN4R and -HN9R), their parental lines, and other human HNC lines were used. The effects of cysteine and glutamate alteration and pharmacological and genetic inhibition of xCT were assess by measuring viability, death, total and cytoplasmic lipid reactive oxygen species (ROS) production, mitochondrial membrane potential (ΔΨm), protein expression, and preclinical mouse tumor xenograft models. Conditioned media with no cysteine or high glutamate supplement induced ferroptosis of both cisplatin-sensitive and -resistant HNC cells without apparent change of necrosis and apoptosis markers, RIP1 and RIP3 and casplase-3 expression, and ΔΨm. This was blocked by antioxidants trolox or N-acetyl cysteine pretreatment. Sulfasalazine, artensunate, and erastin inhibited the growth of HNC cells and accumulated cytoplasmic lipid ROS via induction of ferroptosis and inhibition of xCT protein expression. Genetic silencing of xCT with siRNA or shRNA treatment also induced the effective cell death (ferroptosis) of resistant HNC cells. These effects were blocked with trolox or ferrostatin-1 pretreatment. Pharmacological and genetic inhibition of xCT significantly sensitized resistant HNC cells to cisplatin in vitro and in vivo. Cystine deficiency or glutamate excess induces ferroptosis in HNC cells. Further, pharmacological and genetic inhibition of xCT overcomes the cisplatin resistance of HNC cells by inducing ferroptosis. Citation Format: Hye Jin Jang, Jin Young Park, Eun Hye Kim, Ji Won Kim, Minsu Kwon, Jong-Lyel Roh. Ferroptosis: A novel nonapoptotic cell death overcomes head and neck cancer resistance to cisplatin. [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 3575.
Cetuximab, paclitaxel, cisplatin and concurrent radiation in Chinese patients with locally advanced esophageal squamous cell carcinoma: An open-label, multicenter, phase II study.
Authors: Jinming Yu, Xue Meng, Jian hua Wang, Xindong Sun, Lv hua Wang, Ming Ye, Ping bo Feng, Guang ying Zhu, You Lu, Chun Han, Shu chai Zhu, Zhongxing X. Liao
Journal: Journal of Clinical Oncology (2012)

4073 Background: In China more than 90% of esophageal malignancies are of squamous cell carcinoma (SCC). We conducted this Chinese multicenter trial to determine the efficacy and safety of the addition of cetuximab with paclitaxel, cisplatin, and concurrent radiation for patients with esophageal SCC and to determine whether KRAS status predicts response. Methods: Patients with unresectable locally advanced cervical, upper or mid-esophageal SCC without distant metastasis were eligible for this open-label phase II trial. All patients received cetuximab (400 mg/m 2 day 1 before chemoradiotherapy and 250 mg/m 2 q1w × 7 weeks), paclitaxel (45 mg/m 2 q1w × 7 weeks) and cisplatin (20 mg/m 2 q1w × 7 weeks) with 59.4 Gy of radiation. The primary end point was response rate. Second end points included toxicity, overall survival (OS), progression-free survival (PFS), and KRAS mutation status. Results: Fifty-five patients were enrolled and evaluable to safety. Non-hematological adverse events were generally grade 1 or 2, and were most often rash (94.5%), mucositis (58.2%), fatigue (45.5%), nausea (41.8%) and hepatic dyfunction (40%). Hematologic adverse events included grade 3 neutropenia (32.7%) and grade 3 anemia (1.82%). Ten patients did not complete the protocol therapy (6 for chemotherapy dose delays, 1 for paciltaxel hypersensitivity, 1 by the treating physicians for unstated reasons, 1 for concurrent unrelated infection, and 1 for tracheo-esophageal fistula). The response rate was 97.7%. The 1-year OS and median OS was 87.3% and 16.8 months, the 1-year PFS and median PFS was 30.4% and 13.9 months, respectively. No mutations were detected at KRAS codons 12 or 13 in the 52 available specimens. Conclusions: Cetuximab can be safely administered with chemoradiation for Chinese patients with esophageal cancer and may improve the clinical response rate. KRAS mutations were too rare to be analyzed as a predictor of response.
Experimental procedures involving animals rise slightly, show British figures
Authors: Matthew Limb
Journal: BMJ (2016)

The number of experimental scientific procedures involving animals has increased slightly, but those causing a major change in the animals’ health or wellbeing have decreased, the latest figures for Great Britain have shown.

The figures for 2015 reported that the proportion of “severe” experimental procedures had reduced since 2014, when the government started to assess what animals actually experienced in laboratories (previous data did not cover severity of procedures). Procedures were classified as severe if they caused a “major departure in animals’ usual state of health and wellbeing.” The proportion of severe procedures fell to 6% (123 000) in 2015, from 8% the previous year, Home Office statistics reported. …
Abstract 5006: Docetaxel-platinum-fluorouracil (TPF) induction chemotherapy increases PD-L1 positivity and CD8+ / FOXP3+ immune infiltrates in advanced head and neck squamous cell carcinoma (HNSCC)
Authors: Charlotte Leduc, Julien Adam, Emilie Louvet, Marine Bernard, Elodie Maingot, Caroline Even, Ken A. Olaussen, Stéphane Temam, Jean-Charles Soria, Sophie Postel-Vinay
Journal: Cancer Research (2016)

Abstract Introduction: Checkpoint inhibitors targeting programmed cell death-1/-ligand1 (PD-1/-L1) have demonstrated promising clinical activity in locally advanced head and neck squamous cell carcinoma (LA-HNSCC), with overall response rates (ORR) of ≈20% in unselected patients (pts). Moreover, significant improvements have been observed when selecting pts on PD-L1 positivity, with ORR reaching 50-78%. It is therefore crucial to optimize therapeutic sequence between induction chemotherapy (Docetaxel, Platinum, Fluorouracile,TPF) and anti-PD-1/-L1 in order to maximize the number of pts that benefit from these drugs. Methods: All patients with LA-HNSCC treated at Gustave Roussy between 2006 and 2013 by induction TPF followed by surgery were considered. Only patients for who paired samples (pre and post-TPF) were available were kept for further analysis. PD-L1 expression was quantified by immunochemistry (IHC) (clone E1L3N, Cell Signaling) on a Ventana Discovery Ultra autostainer by a senior pathologist according to a validated protocol. PD-L1 IHC staining on tumor cells (TC) and tumor-infiltrating immune cells (IC) was quantified with a positivity threshold of ≥5%. The density of CD8+ and FOXP3+ lymphocytes was also assessed. Results: Out of 313 pts receiving induction TPF, 86 underwent surgery; paired samples were available for 21. Baseline PD-L1 expression was positive in only 2 and 5 samples for TC and IC respectively. An increased PD-L1 expression was observed post-TPF in 3 (14%) and 15 (71%; p = 0.0003, T-test) samples for TC and IC respectively. Tumor-infiltrating CD8+ and FOXP3+ populations also significantly increased post-TPF. Conclusion: TPF induction in LA-HNSCC increases PD-L1 positivity on tumor-infiltrating immune cells as well as CD8+ and FOXP3+ populations. This suggests that anti-PD-1/-L1 therapy might be more effective as a second-line than first-line strategy, but warrants clinical evaluation. IHC staining resultspre-TPFpost-TPFpaired samplesmedianCImedianCIT-testPD-L1 positive IC (%)2110-10100-300.0003***PD-L1 positive IC (%)2100-2010-200.08 NSCD8+ cell density (n/mm3)171194-77942653-11900.016*FoxP3 cell density (n/mm3)179126-1801774-4670.018* Citation Format: Charlotte Leduc, Julien Adam, Emilie Louvet, Marine Bernard, Elodie Maingot, Caroline Even, Ken A. Olaussen, Stéphane Temam, Jean-Charles Soria, Sophie Postel-Vinay. Docetaxel-platinum-fluorouracil (TPF) induction chemotherapy increases PD-L1 positivity and CD8+ / FOXP3+ immune infiltrates in advanced head and neck squamous cell carcinoma (HNSCC). [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 5006.