tbuckley/cabot-search huggingface dataset:
Induction of cell apoptosis and regulation of inhibitor of apoptosis protein-1 (IAP-1) and cyclin D1 gene expression in head and neck cancer cell lines by PS-341/bortezomib (VELCADE™), a novel proteasome inhibitor
Authors: Jordi Codony, Marian Tapia, Josep Domingo-Domenech, Begoña Mellado, Jeffrey S. Ross, Pere Gascon, Ana Rovira, Joan Albanell
Journal: Cancer Research (2004)

4007  Head and neck squamous cell carcinomas (HNSCC) exhibit constitutive activation of transcription factor nuclear factor-kappa B (NF-κB), which regulates genes important in tumor progression. Bortezomib, a novel proteasome inhibitor, has been previously found to inhibit NF-κB activation and induce apoptosis in vitro, as well as inhibit angiogenesis and growth of murine and human tumors in vivo. In this study, we screened a panel of nine HNSCC cell lines (UMSCC-1, -5, -6, -9, -11A, -11B, -22A, -22B, -38) and observed a logarithmic difference in their sensitivity to bortezomib in vitro by cell proliferation (MTT) assays. UMSCC-9 and -38 were found to be the most resistant to bortezomib, which is consistent with their relatively lower constitutive NF-κB activity. UMSCC-11B, which exhibits higher constitutive NF-κB activity, was the most sensitive cell line to bortezomib. We further investigated bortezomib-induced cell death in UMSCC-11A and -11B, serial isolates from the hypopharyngeal tumor of the same patient which both exhibit relatively high constitutive NF-κB activity. Cell death was observed in UMSCC-11B cells treated with 10-7 M bortezomib at 4 hours, whereas cell death was delayed for 24 hours in UMSCC-11A. DNA cell cycle analysis revealed that UMSCC-11A exhibits cell cycle arrest and delayed cell apoptosis following treatment when compared with UMSCC-11B. To identify potential molecular mechanisms affecting the differential kinetics of cell cycle and death responses to bortezomib, expression of key NF-κB-regulated anti-apoptotic and cell cycle genes IAP-1 and cyclin D1 were measured by real-time RT-PCR. After bortezomib treatment, the expression of IAP-1 exhibited an initial increase at 4 hours followed by a decrease at 8 hours and 12 hours in both cell lines. Bortezomib significantly suppressed cyclin D1 gene expression in the UMSCC-11B cell line 4 hours following treatment, whereas the suppression in UMSCC-11A cells did not occur until 8 hours after treatment. This observation is consistent with DNA cell cycle analysis, in which UMSCC-11A showed cell cycle arrest and delayed cell apoptosis following bortezomib treatment when compared to UMSCC-11B. We conclude that suppression of IAP-1 and cyclin D1 gene expression in HNSCC cells may contribute to the anti-proliferative and apoptotic effects of bortezomib in vitro, and the difference in the inhibition of cyclin gene expression may affect the kinetics of cell apoptosis in HNSCC cells.
Sulforaphane attenuates lung fibrosis in bleomycin-induced pulmonary fibrosis via inhibition of TGF-β/Smad signaling
Authors: Sun Young Kyung, You Jin Kim, Sang Min Lee, Sin Myung Kang, Sang Pyo Lee, Jeong-Woong Park, Sung Hwan Jeong
Journal: European Respiratory Journal (2014)

Sulforaphane(SFN) is a isothiocyanate that has chemoproventive, anti-inflammatory effects via NF-E2-related factor2 (Nrf2)-mediated induction of antioxidant/phase II enzymes. We evaluated the effects of sulforaphane on pulmonary fibrosis and profibrotic TGF-β/Smad signaling.

Sulforaphane inhibited TGF-β-induced expression of fibronectin and collagen I in human pulmonary fibroblast cell lines (MRC-5 cells). Sulforaphane suppressed TGF-β-induced phosphorylation of Smad2/3. C57BL/6 male-gender mice in each group (control, BLM, BLM+SFN) were treated with BLM or SFN for 4 weeks. And then mice lungs were analyzed with histology (H&E, trichrome stain), western blot for TGF-β, fibronectin. The histological changes demonstrated that BLM instillation induced severe destruction of lung structure and accumulation of collagen in mice lungs. SFN treatment attenuated BLM-induced fibrotic lesions and collagen accumulation (hydroxyproline assay) in mice lungs. BLM increased TGF-β and fibronectin protein expression in lung tissues which was downregulated by SFN treatment.

These findings suggest SFN treatment attenuates pulmonary fibrosis via inhibition of TGF-β/Smad signaling.
Abstract 3489: Novel translational pharmacology approaches on dose reduction and alternative scheduling for the combination of JAK inhibitor, ruxolitinib, PIM inhibitor, LGH447, and CDK4/6 inhibitor, LEE011 in a preclinical model of myeloproliferative neoplasia
Authors: Maria Pinzon-Ortiz, Xianhui Rong, Gary Vanasse, Z. Alexander Cao
Journal: Cancer Research (2015)

Abstract The JAK-STAT pathway is an important signaling pathway downstream of multiple cytokine and growth factor receptors. It has been implicated in the pathogenesis of multiple human diseases. The genetic aberration of JAK2V617F and the associated activation of STAT in myeloproliferative neoplasia (MPN) is one example of the involvement of this pathway in human cancer. We have shown the combination benefits of combining ruxolitinib (Jak1, 2 inhibitor), with LGH447 (PIM inhibitor) and LEE011 (CDK4/6 inhibitor) in a Ba/F3-JAK2V617F-driven MPN model. This triple combination resulted in ∼99% reduction of total tumor burden and a ∼96% reduction of spleen weight. Furthermore, the triple combination of ruxolitinib, LGH447 and LEE011 reduced JAK2V617F allele burden by &amp;gt; 80%. To translate this combination from preclinical setting to the clinic, it is critical to evaluate dose to efficacy relationship for each agents and scheduling to efficacy correlation for this combination. Here, the preclinical doses for ruxolitinib, LGH447 and LEE011 were determined, based on their clinically achieved exposure. We then examined “intermittent dosing” of this combination in the same preclinical model. Our data suggest that the combination efficacy of ruxolitinib-LGH447-LEE011 is dependent on continuous administration of the agents. Finally, we examined the effect of dose reduction for each of the three agents on the combination efficacy in the Ba/F3-JAK2V617F-driven MPN model. By modifying the doses for ruxolitinib, LGH447 and LEE011 separately in the combination, our study reveals that the triple combination efficacy is most sensitive to LEE011 dose reduction, and it is least sensitive to LGH447 dose reduction. In summary, our studies aim to design novel preclinical approaches to inform and the design of clinical dose escalation in novel combination therapies. Citation Format: Maria Pinzon-Ortiz, Xianhui Rong, Gary Vanasse, Z. Alexander Cao. Novel translational pharmacology approaches on dose reduction and alternative scheduling for the combination of JAK inhibitor, ruxolitinib, PIM inhibitor, LGH447, and CDK4/6 inhibitor, LEE011 in a preclinical model of myeloproliferative neoplasia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3489. doi:10.1158/1538-7445.AM2015-3489
Outcome Of Patients (pts) With Low and Intermediate-1 Risk Myelodysplastic Syndrome (MDS) After Hypomethylating Agent (HMA) Failure
Authors: Elias Jabbour, Guillermo Garcia-Manero, Lianchun Xiao, Al Ali Najla, Asmita Mishra, Eric Padron, Jeffrey E Lancet, Jeffery Bryan, Hillary Prescott, David P. Steensma, Mikkael A. Sekeres, Gail J. Roboz, Alan List, Hagop M Kantarjian, Rami S Komrokji
Journal: Blood (2013)
Abstract 17614: Multidimensional Post-Ectopic Response Pattern Predicts Mortality of Post-Infarction Patients
Authors: Daniel Sinnecker, Petra Barthel, Alexander Müller, Karl-Ludwig Laugwitz, Georg Schmidt
Journal: Circulation (2014)

Background: The integrity of the cardiovascular system is maintained by regulatory mechanisms at multiple levels. Distortions introduced by ventricular premature contractions (VPCs) result in typical response patterns that contain information about the integrity of these regulatory mechanisms and may inform risk stratification of cardiac patients. For example, heart rate turbulence (HRT, the post-ectopic heart rate response), or post-extrasystolic potentiation (PESP, the post-ectopic blood pressure response) are strong mortality predictors. The frequently observed post-extrasystolic T-wave change (PEST) might also have potential for risk stratification. Study Aim: To investigate whether HRT, PESP, and PEST provide independent risk stratification information in post-infarction patients. Methods: 941 patients with acute myocardial infarction and sinus rhythm were prospectively enrolled and followed up for five-year all-cause mortality. Simultaneous 30-minute recordings of ECG and continuous blood pressure were obtained. HRT and PESP were calculated and dichotomized as described previously. Post-ectopic and normal T waves were compared in the three-dimensional vectorcardiogram space. PEST was quantified both as the change in T wave area (PEST area ) and the angle between T wave main vectors (PEST angle ). Dichotomies for PEST area and PEST angle were optimized by log rank statistics. Results: In multivariable Cox analysis, HRT, PESP, and PEST were independent mortality predictors with hazard ratios (HR) of 2.8, 4.7, and 3.0, respectively. A combined parameter termed M-PERP (multidimensional post-ectopic response pattern) was a particularly strong mortality predictor (see Figure). M-PERP was significantly associated with mortality in a multivariable Cox model considering also LVEF, VPC count, and GRACE score (HR 7.8, p&lt;0.0001). Conclusions: M-PERP is a strong and independent mortality predictor in post-infarction patients.
Is there indeed a difference between smokers' and nonsmokers' lung cancer? A single-institute prospective study of 489 patients from India.
Authors: N. V. Raut, K. Prabhash, V. Noronha, C. Pramesh, R. Dikshit, A. Munshi, B. Bagal, N. Purandare, G. Karimundackal, V. R. Pai
Journal: Journal of Clinical Oncology (2010)

e12004 Background: Lung cancer in nonsmokers as a separate category ranks as the seventh most common cause of cancer deaths worldwide. This study aimed to identify clinically meaningful differences in epidemiologic and patient characteristic in never-smokers with non-small cell lung cancer (NSCLC) as compared to smokers in India. Methods: All consecutive patients registered in the thoracic working group from November 2008 to November 2009 were interviewed with the help indigenously designed questionnaire. Detailed patient history, disease staging on the basis of imaging, histopathologic subtype of carcinoma, and treatment plan were entered in SPSS-14. Results: For the 489 patients, see Table for results. Nonsmokers patients had a trend of higher history of tuberculosis, advanced stage at presentation, bilateral disease, and were in peripheral location (p=NS). Anti-Koch's treatment delayed diagnosis by 3.7 months in nonsmokers and 4.2 months in smokers (p=0.45). There was no significant correlation between incidence of nonsmoker's lung cancer and the place of residence, preexisting comorbidities, clinical features, past history of tuberculosis, location of the primary tumor, site of metastasis. All patients were offered the same treatment irrespective of the smoking status. Conclusions: The increasing incidence of lung cancer in nonsmokers is alarming. Definite epidemiologic differences exist between never-smokers and smokers in terms of age, sex, histology, and history of smokeless tobacco. Successful prevention and treatment of lung cancer requires acceptance that this is not a single disease. Future concerted efforts should focus on conducting to further delineate underlying biologic differences, identify potential non–tobacco-related risk factors and further refine treatment strategies for these groups of patients. Variables Smokers Nonsmokers p value (Pearson's test) No. of patients 234 (48%) 255 (52%) Age Median 59 53 0.000 Sex Male 58.2% 41.8% 0.000 Female 11.9% 88.1% Histology Small cell ca 9.8% 5.5% p = 0.001 Squamous cell 29.9% 16.1% Adeno ca 33.3% 42.4% Smokeless tobacco 50 (37.6%) 83 (62.4%) p = 0.004 No significant financial relationships to disclose.
A phase I study of the anti-kappa monoclonal antibody, MDX-1097, in previously treated multiple myeloma patients.
Authors: A. Spencer, P. Walker, P. Asvadi, M. Wong, D. Campbell, K. Reed, M. C. Copeman, G. Nichol, L. J. Cohen, R. Dunn
Journal: Journal of Clinical Oncology (2010)

8143 Background: Previous in vitro studies have described an anti-kappa light chain chimeric antibody, MDX-1097, that specifically recognizes a cell surface antigen designated kappa myeloma antigen (KMA) expressed on multiple myeloma (MM) cell lines and malignant plasma cells isolated from MM and Waldenstrom's macroglobulinemia patients. MDX-1097 mediated anti-tumour activity in vitro via antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). In addition, MDX-1097 had a favorable pre-clinical toxicological profile in human tissue cross-reactivity and non human primate studies. Based on these promising pre-clinical data a Phase I single ascending dose study was conducted to determine the safety, tolerability and MTD of MDX-1097. Methods: Patients with kappa type MM who had received at least one prior line of standard treatment, achieved at least a minimal response and had stable measurable disease were eligible. Twelve patients completed the study, each receiving a single dose of MDX-1097 on day 1 (n = 3 for dose levels: 0.3, 1.0, 3.0 or 10 mg/kg) and followed until day 45 post-infusion. Results: No serious adverse events and no dose limiting toxicities were reported. Importantly, no soluble antigen related sink was observed over the dose range studied and the terminal elimination half- life of the antibody ranged from 237 hours at 0.3 mg/kg to 124 hours at 10 mg/kg. No patients developed antibody responses to MDX-1097 by day 45. A transient increase in serum kappa light chain levels was seen immediately following the infusion of MDX-1097 in all patients. This was considered to be due to binding of MDX-1097 to serum kappa light chains resulting in transient impairment of renal clearance. No responses based on the established protocol parameters were observed. However, a single patient with bone pain and multi-focal areas of disease as demonstrated on PET scanning had resolution of her bone pain and normalization of her PET scan following treatment. Conclusions: Based on the favorable safety data and pharmacokinetic profile seen in this Phase I study, a Phase II multi-dose efficacy study of MDX-1097 at a dose of 10 mg/kg will commence soon. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, Immune System Therapeutics, Medarex Immune System Therapeutics Immune System Therapeutics
Differential canonical pathways derived from microarrays using RNA from paraffin-embedded non-small cell lung cancer tissue
Authors: M. M. Joshi, R. P. Petersen, D. H. Conlon, K. Tanaka, D. Shimizu, H. Kuramochi, M. Williams, P. V. Danenberg, K. D. Danenberg, D. H. Harpole
Journal: Journal of Clinical Oncology (2006)

7226 Background: Several molecular targets have been approved for use in patients with non-small cell lung cancer (NSCLC) and several hundred are in various phases of investigation. However, the efficacy of these targets range from 5–15% of the overall population of NSCLC patients. Therefore, the challenge remains to appropriately match the most active target with the individual patient. Our goal was to investigate a novel strategy for identifying active pathways from formalin-fixed, paraffin-embedded (FFPE) NSCLC samples. Methods: Ten 5 um sections of FFPE tumor were collected from 66 NSCLC patients consisting of equal numbers of long- (+5-year) and short-term (&lt;2 year cancer death) survivors. Sixty samples were microdissected (6 samples contained no tumor tissue) and RNA was extracted using a proprietary procedure of Response Genetics, Inc. Amplification and labeling of RNA were done using the Affymetrix two cycle amplification kit. Resulting cRNA was hybridized to the U133 plus 2.0 GeneChip. A differentially expressed gene list between long and short survivors was determined. These data were also analyzed for differential canonical pathways using Ingenuity Pathway Analysis. Results: We identified the differential pathways indicated by the unique gene signatures between early stage patients surviving &lt;2 yrs and &gt;2 yrs for both adenocarcinomas and squamous cell carcinomas. Adenocarcinoma pathways that differed between short- and long-term survivors were: G2M DNA damage checkpoint, EGF, estrogen receptor, hypoxia, VEGF, PDGF, IL-6 JAK/Stat and neurotrophin/Trk signaling. In contrast, for squamous cell carcinomas the main differing pathways were: Wnt/b-catenin signaling and retinol metabolism. Conclusions: We have demonstrated the feasibility of generating differential canonical pathways from FFPE NSCLC specimens which may serve as a tool to guide selection of molecular targets for the individual patient. In addition, these pathways may be a rational method for selecting the correct subset of patients most likely to respond to agents being investigated in early phase clinical trials. These data require validation in a larger prospective study. [Table: see text]
Clinical features and outcomes of patients with diffuse alveolar hemorrhage during antithrombotic therapy
Authors: Takehiro Otoshi, Ryoji Kato, Ryoko Shimizu, Daichi Hujimoto, Takahisa Kawamura, Koji Tamai, Takeshi Matsumoto, Kazuma Nagata, Kyoko Otsuka, Atsushi Nakagawa, Kojiro Otsuka, Keisuke Tomii
Journal: European Respiratory Journal (2014)

Introduction: Antithrombotic therapy has been increasingly recognized as a cause of diffuse alveolar hemorrhage(DAH). However, there have been few reports on clinical features and outcomes of patients with DAH during antithrombotic therapy.

Aims: To clarify features and mortality of DAH during antithrombotic therapy.

Methods: We retrospectively reviewed 54 patients who were diagnosed with DAH from January 2009 to July 2013. DAH was confirmed when bronchoalveolar lavage aliquots were progressively more hemorrhagic.

Results: Twenty-eight patients were associated with antithrombotic thrapy, but 7 of them had another cause of DAH (1 patient had drug-induced pneumonia, 2 patients had acute exacerbation of interstitial pneumonia, 3 patients had anti-neutrophil cytoplasmic antibody(ANCA)-associated vasculitis, and 1 patient had thrombocytopenia due to myelodysplastic syndromes). Among the remaining 21 patients, 15 (71%) had heart failure and 11 (52%) had renal failure. Five (24%) of the 21 patients died, and 3 (14%) of them needed dialysis. The number of patients who needed dialysis during treatment of DAH was statistically higher among non-survivors than among survivors (60% vs. 13%, P=0.03)

Conclusions: DAH due to antithrombotic therapy occurred frequently among patients with heart failure or renal failure. Patients who needed dialysis during treatment of DAH had poorer outcomes.
Abstract 12541: Features and Causes of Death of Patients With Atrial Fibrillation Seen in French Hospitals in 2012
Authors: Laurent Fauchier, Adeline Samson, Gwendoline Chaize, Anne-Françoise Gaudin, Alexandre Vainchtock, Cécile Bailly, François-Emery Cotté
Journal: Circulation (2014)

Introduction/Hypothesis: Atrial fibrillation (AF) has been associated with worse clinical outcomes in many cardiovascular (CV) disease states. There is a lack of data on real world specific causes of deaths in AF patients. The objective of this study was to provide features and causes of deaths of patients with AF seen in French hospitals. Methods: This French cohort study was based on the national hospitalization database (PMSI) covering hospital care for the entire population. All discharged dead patients in 2012 with a previous diagnosis of AF were identified. Cause of death was defined as the principal diagnosis of the last hospitalization stay. Thromboembolic risk scores (HAS-BLED, HEMORR2HAGES and ATRIA) and bleeding risk scores (CHADS2 and CHA2DS2-VASc) calculations were based on a 5-year look-back period of medical history. Results: In 2012, 533,044 AF patients were identified through the PMSI; among them 50,165 (9.4%) died in French hospitals. Deceased patients were older than patients discharged alive (82.3±9.3 vs. 78.0±11.4; p&lt;0.001). They more often suffered from hypertension (73% vs. 70%), diabetes (27% vs. 24%), renal failure (39% vs. 23%), cancer (30% vs. 19%) and, liver failure (9% vs. 5%) (p&lt;0.001 in all cases). Mean stroke and bleeding risk scores were significantly higher for dead patients: CHADS2 was 2.7±1.3 vs. 2.3±1.3 (p&lt;0.001), CHA2DS2-VASc was 4.6±1.6 vs. 4.0±1.8 (p&lt;0.001), HAS-BLED was 2.6±1.1 vs. 2.2±1.1 (p&lt;0.001), HEMORR2HAGES was 3.0±1.4 vs. 2.3±1.5 (p&lt;0.001) and ATRIA was 4.4±2.4 vs. 3.3±2.4 (p&lt;0.001). Cardiovascular (CV)-related deaths represented 34% of all deaths, including heart failures (15.0%), strokes (8.5%), hemorrhages (1.4%) and, TIA/Systemic embolism (1.3%) (cf. Table1). Conclusions: In this systematic analysis of a real-life contemporary AF population, about 10% of deaths were related to stroke/TIA/SE. Despite CV events were a major cause of deaths; a greater part of deaths was related to non-CV causes.
CSF 5-hydroxyindoleacetic acid levels in suicidal schizophrenic patients
Authors: P T Ninan, D P van Kammen, M Scheinin, M Linnoila, W E Bunney, F K Goodwin
Journal: American Journal of Psychiatry (1984)

Concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in the lumbar CSF were measured in a group of suicidal schizophrenic patients and in a matched group of nonsuicidal schizophrenic patients. The suicidal group had a significantly lower level. This finding is consistent with reports of low levels of CSF 5-HIAA in suicidal patients with other psychiatric diagnoses and suggests that low CSF 5-HIAA may be a generalized marker of aggressive behavior against the self and others.
Short-term effects of repetitive transcranial magnetic stimulation on sleep bruxism – a pilot study
Authors: Wei-Na Zhou, Hai-Yang Fu, Yi-Fei Du, Jian-Hua Sun, Jing-Lu Zhang, Chen Wang, Peter Svensson, Ke-Lun Wang
Journal: International Journal of Oral Science (2015)

The purpose of this study was to investigate the effects of repetitive transcranial magnetic stimulation (rTMS) on patients with sleep bruxism (SB). Twelve patients with SB were included in an open, single-intervention pilot study. rTMS at 1 Hz and an intensity of 80% of the active motor threshold was applied to the 'hot spot' of the masseter muscle representation at the primary motor cortex bilaterally for 20 min per side each day for 5 consecutive days. The jaw-closing muscle electromyographic (EMG) activity during sleep was recorded with a portable EMG recorder at baseline, during rTMS treatment and at follow-up for 5 days. In addition, patients scored their jaw-closing muscle soreness on a 0-10 numerical rating scale (NRS). Data were analysed with analysis of variance. The intensity of the EMG activity was suppressed during and after rTMS compared to the baseline (P = 0.04; P = 0.02, respectively). The NRS score of soreness decreased significantly during and after rTMS compared with baseline (P < 0.01). These findings indicated a significant inhibition of jaw-closing muscle activity during sleep along with a decrease of muscle soreness. This pilot study raises the possibility of therapeutic benefits from rTMS in patients with bruxism and calls for further and more controlled studies.