tbuckley/cabot-search huggingface dataset:
Abstract 684: The difference between gefitinib and serum deprivation in cancer cells
Authors: Mitsuhiro Suenaga, Masatatsu Yamamoto, Tatsuhiko Furukawa, Chuwa Tei
Journal: Cancer Research (2011)

Abstract Gefitinib is a selective inhibitor of epidermal growth factor receptor tyrosine kinase. The serum free condition could resemble to gefitinib exposure since it blocks EGF stimuli. In this study, we examined distinction between gefitinib exposure and serum deprivation in cultured cancer cells. At first, we verified that ERK phosphorylation was downregulated by gefitinib exposure in A431 and A549 cells. We examined the phosphorylation status of ERK under the serum deprivation condition. The phosphorylation of ERK in A431 cells was downregulated after 1hr culture in serum free medium, while after 3-6hr ERK was phosphorylated again. We hypothesized that an auto- or paracrine mechanism would work to phosphorylate ERK. In the cells cultured with the conditioned serum free medium from the dish in which A431 cultured for 24hr, the downregulation of ERK phosphorylation was weaker than with the fresh serum free medium. We confirmed that gefitinib could inhibit the ERK phosphorylation under the serum free condition. Exogenous EGF attenuated the inhibitory effect on ERK phosphorylation with serum free medium. These results suggest EGF may be one of the auto- or paracrine substance that induces ERK phosphorylation. Since the ERK phosphorylation status affects the stability of c-MYC, we also examined whether “gefitinib” and “serum deprivation” affect the expression of c-MYC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 684. doi:10.1158/1538-7445.AM2011-684
203P A phase II trial of trastuzumab combined with irinotecan in patients with advanced HER2-positive chemo-refractory gastric cancer: Osaka Gastrointestinal Cancer Chemotherapy Study Group OGSG1203 (HERBIS-5)
Authors: R. Kawabata, D. Sakai, J. Kawada, K. Nishikawa, T. Kawase, Y. Oka, N. Sugimoto, T. Shimizu, J. Nishijima, H. Hasegawa, S. Endo, Y. Isozaki, Y. Kimura, J. Matsuyama, Y. Kurokawa, T. Shimokawa, K. Fujitani, T. Sato
Journal: Annals of Oncology (2015)
Abstract 5030: Identification of the Her-2 expression-regulating miRNAs by microdissection and RT-PCR in breast cancer tissue
Authors: Yubin Hao, Hangying Xing, Chunnian He
Journal: Cancer Research (2012)

Abstract Her-2/neu oncogene is overexpressed in human breast cancer and is correlated with the tumor cell proliferation, metastasis, and resistance against chemo- and hormonotherapy. The expression levels of both Her-2/neu gene and HER-2 protein are recommended for evaluation of treatment efficacy as well as for selection of treatments. However, clinical studies have shown that the Her-2/neu gene and the HER-2 protein are differently expreesed in 10-15% of human breast cancers and we hypothesized that the expression difference might be related to the post-transcriptional regulation of the Her-2/neu gene by microRNAs (miRNAs). To identify the specific miRNAs, we first analyzed 120 human breast cancer samples for the Her-2/neu gene amplification and protein expression with fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Fourty-four cancer samples (36.7%, 44/120) showed overexpression of HER-2 protein with IHC (IHC+) and 26 samples (26.5%, 26/98) exhibited Her-2/neu gene amplification with FISH (FISH+). Interestingly, five samples exhibited amplification of the Her-2/neu gene, but absence of the HER-2 protein expression (FISH+/IHC-). We then dissected the FISH+/IHC- tumor cells using laser capture microdissection from the five samples. Tumor cells with FISH+/IHC+ from another set of five samples were also dissected and analyzed as the control. Based on TargetScanHuman and literature search, five candidate miRNAs including miR-125b, -1224-3p, -1296, -193a-5, and -331-3p were screened with quantitative real-time RT-PCR and their expression levels in the FISH+/IHC- cells were 3.1-, 2.7-, 1.7-, 1.7-, and 1.3-fold higher than in the FISH+/IHC+ cells, respectively, with a significant difference for miR-1224-3p and miR-1296 (both P &amp;lt; 0.01). These results indicate that miR-1224-3p and miR-1296 may be responsible for the different expressions of Her-2/neu gene and its protein by regulating the Her-2/neu gene posttranscription, thus down-regulating the HER-2 protein expression in FISH+/IHC- breast cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5030. doi:1538-7445.AM2012-5030
A phase Ib study of abemaciclib in combination with multiple single agents in stage IV NSCLC.
Authors: Edward S. Kim, Karen Kelly, Jonathan Wade Goldman, Pilar Garrido Lopez, Shadia Ibrahim Jalal, Daruka Mahadevan, Martin Gutierrez, Mariano Provencio Pulla, Eric Scott Schaefer, Montaser F. Shaheen, Erica L. Johnston, Na Cai, William J. John, Luis Paz-Ares
Journal: Journal of Clinical Oncology (2015)

8047 Background: Abemaciclib, a cell cycle kinase inhibitor of CDK4/CDK6, demonstrated acceptable safety and early clinical activity in metastatic NSCLC, given orally as monotherapy on a continuous schedule. In preclinical models of KRAS-mutant NSCLC, combinations of abemaciclib with other agents showed greater antitumor activity compared with monotherapy. Primary aim in study NCT02079636 was safety and tolerability of combination therapy with abemaciclib; secondary aims were pharmacokinetics (PK), antitumor activity, and patient (pt) reported outcomes. Methods: In this phase Ib open-label 3 + 3 dose-escalation study with expansion cohorts, pts received abemaciclib in combination with pemetrexed (Part A, nonsquamous), gemcitabine (Part B), ramucirumab (Part C), or LY3023414 (dual PI3K-mTOR inhibitor, Part D). Pts with stage IV NSCLC, ECOG PS ≤ 1, and 1-3 prior therapies were eligible. In escalation, pts were dosed continuously until progression with abemaciclib at 150 mg or 200 mg orally Q12H. Doses for other agents were: pemetrexed (500 mg/m2 IV day 1), gemcitabine (1250 mg/m2 IV days 1 and 8), ramucirumab (8 mg/kg IV days 1 and 8, or 10 mg/kg IV day 1) (Q21). In Part D, pts will receive LY3023414 at 100 mg, 150 mg or 200 mg orally Q12H. Results: Asof 27-OCT-2014, 40 pts received ≥ 1 dose of treatment; 15 pts at 150 mg and 25 pts (including all 10 pts in expansion) at 200 mg Q12H abemaciclib. In escalation, 3 dose-limiting toxicities were observed: 2 in Part A (150 mg: G4 neutropenia, 200 mg: G4 febrile neutropenia), and 1 in Part C (200 mg: G3 diarrhea). Possibly related G3/4 TEAEs in ≥ 2 pts (% Parts A, B, C) were: neutropenia (38, 15, 9), leukopenia (19, 8, 9), diarrhea (0, 8, 18), fatigue (13, 8, 0), anemia (13, 8, 0), and thrombocytopenia (0, 8, 9). Among 25 pts remaining on treatment, 5 pts (3 in Part A; 2 in Part C) received treatment ≥ 4 cycles. In Part C, 2 pts had unconfirmed PRs (RECIST v1.1), 1 pt (150 mg) with nonsquamous histology and KRAS mutation, and 1 pt (200 mg) with squamous histology and unknown KRAS status. Conclusions: Abemaciclib could be combined with other agents in NSCLC. Toxicities of combinations were consistent with those of the single agents. Findings will be reviewed with PK to support the recommended dose for each combination. Clinical trial information: NCT02079636.
Abstract B61: HEF1-dependent Aurora A kinase phosphorylation activates HDAC6
Authors: Varvara K. Kozyreva, Sarah L. McLaughlin, Laura Kelley, Elena N. Pugacheva
Journal: Cancer Research (2011)

Abstract Histone deacetylase 6 (HDAC6) is known to be important participant of many tumorgenesis processes including cytoskeleton rearrangement, cell migration and invasion. Activation of HDAC6 promotes cell motility and proteolytic degradation of the extracellular matrix which thereby facilitates invasion and metastasis of cancer cells. But precise mechanisms of HDAC6 regulation are still unknown. Human enhancer of filamentation 1 (HEF1/Cas-L/Nedd9) is scaffolding protein implicated in essential normal cell functions like cell division as well as pathologic conditions such as in cancer progression. It has been shown that HEF1 is over-expressed in multiple tumor types and is well known marker of malignancy. HEF1 possesses a key role in cancer development by acting as a signaling hub to coordinate tumor associated signaling. Among numerous targets which are regulated by HEF1 one of the most important is Aurora A kinase (AurA). It is known that up-regulation of AurA launches a cascade of reactions promoting oncogenic cell transformation. In our experiments, we demonstrated that HEF1 knockdown leads to impairment of cell capability to invade into extracellular matrix. We hypothesize that invasion deficiency in HEF1 depleted cells is directly linked to inability of AurA to phosphorylate/activate HDAC6. We have shown previously that depletion of HEF1 decreases AurA activity and demonstrated that HDAC6 is a substrate of AurA kinase. In this work we have determined AurA phosphorylation sites in HDAC6 using site-directed mutagenesis and in vitro kinase assay with wild-type HDAC6 and HDAC6 phospho-mutants. We revealed that AurA phosphorylates HDAC6 at Ser479/Thr481. We will test the effect of this AurA phosphorylation event on HDAC6 activation. Biological effect of such regulation will be explored in breast cancer cell lines. Our observation allows us to establish a mechanistic pathway that describes the convergent roles of HDAC6, AurA and HEF1 in tumor progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B61.
Three Synchronous Primary Malignancies Detected by F-18 FDG PET/CT
Authors: William Makis, Anthony Ciarallo, Robert Lisbona
Journal: Clinical Nuclear Medicine (2011)

A 66-year-old woman with long-standing multiple sclerosis presented with a several month history of diarrhea and weight loss. F-18 FDG PET/CT imaging revealed breast, rectal, and urinary bladder masses which were biopsied to reveal 3 different synchronous primary malignancies. PET/CT is able to detect a variety of synchronous malignancies; however, the situation of detecting 3 different synchronous primaries is extremely rare, and this case highlights the importance of paying close attention to anatomic areas that are difficult to evaluate on PET/CT, even after successfully identifying one or several FDG-avid primary malignancies.
Pulse Wave as an Alternate Signal for Data Synchronization During Gated Myocardial Perfusion SPECT Imaging
Authors: Otto Lang, Helena Trojanova, Helena R. Balon, Ivana Kunikova, Milos Bilwachs, Martin Penicka, Milan Kaminek, Miroslav Myslivecek
Journal: Clinical Nuclear Medicine (2011)

Proper identification of the cardiac cycle is essential for gated SPECT myocardial perfusion imaging. We have developed an alternate method of ECG for gating, that is, using the peripheral pulse wave (PW) as the triggering signal for gated SPECT acquisition. The aim of this study is to compare the use of this method of gating with the standard ECG trigger.We tested the PW triggering by comparing it with the ECG trigger. We evaluated 33 patients (25 males, 8 females), average age of 61 years (39-80) referred for stress myocardial perfusion imaging. Data from all patients were acquired twice and were processed by CEqual and QGS software. We compared the left ventricular ejection fraction (LVEF), end-diastolic and end-systolic volumes (EDV, ESV). Paired t test and Pearson correlation coefficient were used for comparison.The mean LVEF, EDV, and ESV calculated with the ECG trigger were 0.52, 120, and 64, respectively, those with the pulse-wave trigger were 0.48, 126, and 71, respectively. Mean paired difference for LVEF was -0.034 (P<0.001), for EDV 5.9 (P=0.012), and for ESV 7.9 (P<0.001). Pearson correlation coefficient for LVEF was 0.955, for EDV 0.987, and for ESV 0.991 (P<0.001 for all correlations).Triggering of gated-data acquisition by the PW is feasible. Quantitative parameters of cardiac function correlate highly with those obtained from the ECG trigger and the absolute differences are not clinically significant across a wide range of values.
Abstract 363: Therapeutic targeting of insulin receptor-A with a dual IGF-1R/IR inhibitor: Overcoming a potential escape mechanism from IGF-1R-specific signaling inhibition in insulin receptor-A transfected cancer cells
Authors: Stephen M. Hillerman, Ann F. Greer, Warren Hurlburt, Fei Huang, Karen Reeves, Rolf Ryseck, Friedrich Graf Finckenstein, Arindam Dhar, Robert A. Kramer, Marco M. Gottardis, Joan M. Carboni
Journal: Cancer Research (2010)

Abstract Type I Insulin-like Growth Factor Receptor (IGF-1R) is a tyrosine kinase receptor that is activated by binding to IGF-1 and IGF-II ligands; IGF-1R has been shown to play a role in cancer development and progression and therapies targeting IGF-1R have resulted in clinical benefit in cancer patients. Insulin Receptor (IR) which is closely related to IGF-1R, is expressed in normal tissues and tumors, and is expressed as two isoforms, IR-A and IR-B. IR-A exhibits mitogenic activity and is preferentially found in fetal tissue and cancer cells, whereas IR-B regulates glucose metabolism in response to insulin. Both IR isoforms bind insulin, and IR-A also binds IGF-II. Several cancer cell types that express IR-A also overexpress IGF-II, suggesting a possible autocrine loop that enhances tumor survival. Since IGF-1R antibodies bind specifically to IGF-1R and not to IR, IR signaling could represent a potential escape mechanism to antibody treatment through the IR-A pathway. BMS-754807, a small molecule inhibitor with dual activity against IGF-1R and IR, recently entered clinical development. It is anticipated that BMS-754807 can prevent or overcome therapeutic resistance resulting from increased IR-activated signaling. The goal of the presented studies was to demonstrate whether dual IGF-1R/IR inhibition by BMS-754807 may prevent IR-mediated resistance to IGF-1R inhibition. To test this hypothesis, a human rhabdomyosarcoma cell line, Rh41 expressing IGF-1R, but little IR, was engineered to express either IR-A (Rh41-IR-A) or IR-B (Rh41-IR-B). IR expression was confirmed by PCR analysis of specific IR isoforms. Rh41-IR-A cells showed phosphorylation of IR after stimulation with IGF-II and/or insulin. MAB391, a neutralizing monoclonal antibody to IGF-1R, inhibited the proliferation of parental Rh41 and Rh41-IR-B cells in vitro, but Rh41-IR-A cells exhibited no sensitivity to the IGF-1R mAb. Combination treatment with both IGF-1R and IR antibodies in Rh41-IR-A cells were strongly synergistic, suggesting dual receptor blocking is required for enhanced anti-tumor efficacy. Inhibition of IGF-1R and IR with BMS-754807 showed the same inhibitory activity in Rh41-IR-A cells as was observed in the parental Rh41 cells. Therefore, dual IGF-1R/IR inhibition by BMS-754807 treatment may overcome the ability of cancer cells to utilize the IR-A pathway and provide an advantage over IGF-1R specific antibodies in the treatment of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 363.
Abstract P3-06-23: Predicting response to neoadjuvant letrozole
Authors: A Larionov, A Turnbull, A Sims, L Renshaw, C Kay, D Harrison, JM Dixon
Journal: Cancer Research (2012)

Abstract Background: Approximately 75% of older postmenopausal patients with large operable or locally advanced oestrogen receptor positive breast cancer respond to treatment with neoadjuvant letrozole. Prediction of response is required as approximately 25% fail to respond. The aim of this study was to design a response predicting classifier with two data sets, one published previously [1] and secondly a new dataset. Methods: Patients were treated with Letrozole (Femara, 2.5 mg daily) and tissues were collected before treatment, 2 or 3 weeks on treatment, and between 3 and 5 months on treatment. Response was based on a 3D ultrasound, with response being classified as a 50% reduction in tumour volume at 3 months. To ensure biological relevance of the response groups we also separated patients into Quick Stable Responders (QSR) and Long-Term Non-responders (LNR), as summarised in Table 1. Illumina HT-12 BeadArrays were used for gene expression profiling, allowing platform-independent cross-validation with our previous study using Affymetrix HGU-133 chips [1]. The probe IDs were re-annotated to Ensemble gene IDs and XPN batch correction has been applied to make the datasets directly comparable. A combination of Rank-Product, SAM and Random Forrest analyses have been used to design several alternative signatures separating extreme response groups, the patients who responded rapidly vs those who did not respond for a long time. One of the best performing signatures included 48 informative features: 24 at baseline, 12 at 2-weeks and 12 changes between 0 and 2 weeks. This signature was validated on the independent previously published test set by classifying extreme responses (quick stable responders vs long term non responders) using Support vector machines (SVM) with different kernel functions. Results Are summarised in Table 2. Conclusions – A new sample series has been collected to study neo-adjuvant endocrine response. It can be used for independent validation of previous results [1] and for design of new platform-independent response predictors.– Multi-gene predictors based upon change in gene expression outperform those from baseline or 14 day measurements alone. The best classifiers include all 3 time points.– A classifier has been derived with a 91% accuracy rate of predicting extreme response group in 21 of 23 patients. References [1] Miller 2009 J Clin Oncol 27:1382. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-23.
Abstract 1089: Spontaneous formation of sarcomas in Usp18 knockout mice.
Authors: Fadzai Chinyengetere, Andrew Giustini, David Sekula, Sarah Freemantle, Vincent A. Memoli, Paul Jack Hoopes, Ethan Dmitrovsky
Journal: Cancer Research (2013)

Abstract Undifferentiated pleomorphic sarcoma (UPS) and leimyosarcoma are two of the most common adult soft tissue sarcomas. Their etiology is unknown hence the need for new models to elucidate the biology of these diseases. We report here a spontaneously occurring mouse model of sarcoma in Usp18 knockout mice. Usp18 is the deconjugase for isgylation. Isgylation is the ubiquitin-like protein modification in which ISG15 is conjugated to proteins. Usp18 removes ISG15 from the target proteins, thus reversing the functional consequences of ISG15 conjugation. Usp18 knockout mice on a C57Bl6 background developed neurological abnormalities and exhibited 100% mortality within 5 months. These mice were also hypersensitive to Type I IFN stimulation, which was attributed to an increased JAK-STAT signaling. We now report that Usp18 knockout mice in a FVB background developed subcutaneous tumors in the neck and trunk regions from ages ranging from 6 months to 16 months. Tumor formation to date shows a penetrance of 77%. Immunohistochemical analysis characterized the tumors as either UPSs or leimyosarcomas. About 30% of these tumors displayed stabilization of p53, a common event also seen in human sarcomas. We derived two cell lines (KHC-1, KHC-2) from the sarcomas of separate mice, and analyzed the levels of STAT family proteins in these cell lines. Stat3 was noted to be constitutively activated in these sarcoma cell lines. Persistent activation of Stat3 is seen in diverse human malignancies such as breast and head and neck cancers. To determine if restoring Usp18 activity reverses tumorigenicity in these cells, human USP18 was introduced retrovirally. Cells re-expressing USP18 versus empty vector showed a substantial decrease in anchorage independent growth in soft agar and also had reduced levels of activated Stat3 (pStat3). Furthermore, treatment of the parental cell lines with a Stat3 inhibitor, JSI-124, led to decreased cell growth, apoptosis and reduced levels of pStat3. In summary, Usp18 knockout mice spontaneously develop sarcomas, whose tumorigenicity can be partially reversed by reintroduction of Usp18. Thus, this new and tractable model should prove useful to elucidate the activity of Stat3 targeting and other agents to treat sarcomas. Citation Format: Fadzai Chinyengetere, Andrew Giustini, David Sekula, Sarah Freemantle, Vincent A. Memoli, Paul Jack Hoopes, Ethan Dmitrovsky. Spontaneous formation of sarcomas in Usp18 knockout mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1089. doi:10.1158/1538-7445.AM2013-1089
Chronic Spinal Cord Injury
Authors: John F. Ditunno, Christopher S. Formal
Journal: New England Journal of Medicine (1994)

In 1927 Harvey Cushing described the outcome for soldiers with spinal cord injuries sustained during World War I: "Fully 80 percent died in the first few weeks in consequence of infection from bedsores and catheterization. . . . Only those cases survived in which the spinal cord lesion was a partial one"1. Today, this picture has been completely reversed, and in well-organized systems of care for trauma and spinal cord injuries 94 percent of patients survive the initial hospitalization2,3. National data on people with spinal cord injuries suggest a population of over 200,000, which will increase each . . .