tbuckley/cabot-search huggingface dataset:
Abstract 5563: Tripterygium induces apoptosis in NSCLC via mitochondria dysfunction
Authors: Xing-Xing Fan, Na Li, Jin-Lin Wu, Yan-Ling Zhou, Liang Liu, Jian-Xing He, Elaine L. Leung
Journal: Cancer Research (2015)

Abstract Lung cancer remains the leading cause of cancer deaths globally. Patients with non-small cell lung cancer (NSCLC) account for 80% of all lung cancer cases. Active mutation of EGFR was identified as one of the key anti-cancer target for NSCLC patients. Recently, tyrosine kinase inhibitor, like gefitinib which can specifically inhibit the activation of EGFR, emerges as a new potential anticancer drug. However, drug resistance remains an unsolved problem. Most of patient acquired resistance to this inhibitor within 12 months. Therefore, it is necessary and urgent to discover more effective potential agents as candidate drugs for treating gefitinib resistant NSCLC. Tripterygium, a triterpene extracted from the Chinese herb “Thunder of God Vine”, has been shown to have multiple bioactivities. Its anti-cancer effect has been proved in many kinds of cancers. However, the effect of Tripterygium on gefitinib-resistant NSCLC cells is still unknown. In this study, we examined the potency of Tripterygium in induction of apoptosis in a gefitinib-resistant NSCLC cell line and explored its underlying anti-cancer mechanism. Our results demonstrated that Tripterygium induced its apoptotic effect on NSCLC cells in a dose- and time-dependent manner. Moreover, the function of mitochondria was disrupted by the treatment of Tripterygium. The mitochondria membrane potential was gradually loss, and the ratio of Bax/Bcl-2 which is the indicator of mitochondria membrane integrity, was significantly up-regulated after the treatment of Tripterygium. Although the caspases were activated, the treatment of pan-caspase inhibitor could only partially inhibit the level of apoptosis. Moreover, the level of Hsp90 client proteins, EGFR and its downstream target AKT, were measured. Interestingly, both of them were remarkably decreased after Tripterygium treatment. Taken together, our data suggest that Tripterygium, which may be developed as a promising agent for gefitinib-resistant NSCLC patient, induced apoptosis through mitochondria dysfunction and EGFR degradation in gefitinib-resistant NSCLC cells. Citation Format: Xing-Xing Fan, Na Li, Jin-Lin Wu, Yan-Ling Zhou, Liang Liu, Jian-Xing He, Elaine L. Leung. Tripterygium induces apoptosis in NSCLC via mitochondria dysfunction. [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 5563. doi:10.1158/1538-7445.AM2015-5563
97. Large Scale Purification of AAV with Continuous Flow Ultracentrifugation
Authors: Haifeng Chen, Sandra Marino, Ching Yi Ho
Journal: Molecular Therapy (2016)

Since its first approval in Europe as gene therapy drug in human use in 2012, adeno-associated viral (AAV) vectors have gained more and more attentions in the field for gene therapy research. So far AAV vectors have usually been purified through either density gradient ultracentrifugation in small volume centrifuge tubes or column chromatography. Though these purification methods have their unique benefits, there is still a need for technology that can process large volume of lysate with high AAV recovery rate. We reasoned that continuous flow ultracentrifugation could meet these requirements. We tested the Alfa Wasserman's AW Promatix 1000™, a research scale continuous flow ultracentrifuge, as a prove of concept for AAV vector purification. In the initial experiments, we tested cesium chloride (CsCl) solution as density gradient media for AAV vector purification but found out that CsCl solution was not stable enough to form a linear gradient even when sucrose was added to increase its viscosity for AAV purification. We then tested iodixanol solution as density gradient media and got satisfactory purification of AAV vectors. Our results indicate that we can obtain near-purified AAV vectors in a single-step of centrifugation with AAV recovery rate exceeding 50%. Further experiments indicate that minor impurities associated with the purified AAV vectors could be removed by adding salts to the iodixanol solution such as CsCl to increase the ionic strength of the density gradient. The data presented here indicate that continuous flow ultracentrifugation can be used for large scale purification of AAV vectors and it should provide an additional tool to facilitate the translation from research to the clinic.
Early Detection of Bone Metastasis in Small Cell Neuroendocrine Carcinoma of the Cervix by 68Ga-DOTATATE PET/CT Imaging
Authors: Andres Damian, Graciela Lago, Susana Rossi, Omar Alonso, Henry Engler
Journal: Clinical Nuclear Medicine (2016)

The neuroendocrine small cell carcinoma of the cervix is a rare malignancy that has a poor prognosis due to early lymphatic and hematogenous spread. We herein report a case of a 27- year-old woman who was referred for initial staging of a neuroendocrine small cell carcinoma with previous unremarkable structural imaging. Ga-DOTATATE PET/CT revealed focal uptake at the primary tumor and in a solitary pelvic bone lesion suggestive of metastases that was further confirmed by CT-guided biopsy. Somatostatin receptor PET/CT may be a useful image modality for early detection of metastases to guide treatment in these patients.
742. A Therapeutic miRNA for Brain Disorders
Authors: Kai C. Sonntag, Woori Kim, Yenarae Lee, Donna L. McPhie, Kwang-Soo Kim, Gordana Vitaliano, Bruce M. Cohen
Journal: Molecular Therapy (2016)

One of the main hurdles in developing novel therapeutics for age-related disorders is the still limited understanding of both the biology of normal aging and the pathologic mechanisms of the diseases seen in old age. Brain aging and age-related brain disorders are characterized by slow progressive deterioration or death of neurons, and are influenced by age- and disease-specific neurotoxicity, and compensatory neuroprotective mechanisms that are important in cell survival. If the cellular defense and restorative mechanisms are compromised, the penetrance of neurotoxic factors becomes higher and cell survival less likely. Among the key regulatory factors that govern gene and protein networks and, consequently, influence neuronal health and function are small non-coding RNA molecules such as miRNAs. It is increasingly appreciated that even modest disturbances of these regulatory factors can have profound effects on cell survival in response to stress. We have identified a novel mechanism in neurons, mediated by miR-126, which regulates the effects of numerous neurotrophic and neuroprotective growth factors (GF). Specifically, we found that elevated levels of this miRNA are neurotoxic and increase the vulnerability of neurons to a variety of non-specific and disease-specific toxic factors, including Staurosporine (STS), Alzheimer's disease (AD)-associated amyloid beta 1-42 oligomers (Aβ1-42), and 6-OHDA, which induces oxidative stress in dopamine (DA) neurons, thereby mimicking Parkinson's disease (PD) pathology. Mechanistically, miR-126 targets a series of factors in PI3K/AKT/GSK-3β and MAPK/ERK signaling pathways and small increases of this miRNA cause a downregulation of these signaling cascades, impairing the effects of neurotrophic and neuroprotective GF, such as IGF-1, NGF, BDNF, and soluble amyloid precursor protein α (sAPPα). In turn, inhibiting miR-126 enhances the actions of GF without disturbing normal neuronal cell function. Our data indicate that miR-126 may play a profound role in neuronal cell survival, at least in part by regulating GF/PI3K/AKT and MAPK/ERK signaling. While its elevation is neurotoxic, its inhibition is neuroprotective, suggesting that targeting this miRNA may have therapeutic potential for neurological and age-related disorders. To experimentally address this concept, we have developed a therapeutic strategy using a nanotechnology approach to prevent disease onset in a mouse model of AD.
Prognostic and predictive value of HER2 extracellular domain in patients with early and metastatic breast cancer treated with trastuzumab and lapatinib: Correlation with clinicopathological parameters and response.
Authors: M. Ciccarese, M. M. Galante, R. Forcignano, V. E. Chiuri, G. Cairo, G. Ronzino, G. Romano, C. Accettura, M. Giampaglia, A. Pellegrino, S. A. Leo, V. Saracino, L. Petrucelli, L. Lupo, G. Leo, M. Pisanò, V. Lorusso
Journal: Journal of Clinical Oncology (2011)

e11123 Background: HER-2 is a 185 kd protein composed of three domains: a cytoplasmatic domain, a transmembrane domain and an extracellular domain (ECD). The ECD of HER-2 can be cleaved from the surface of breast cancer cells by matrix metalloproteases and released into the serum where it is detectable using an enzyme-linked immunosorbent assay (ELISA). The role of high level of ECD as a surrogate of response to trastuzumab treatment in metastatic setting is debated. Its role as predictive factor of response to lapatinib in HER-2 +metastatic breast cancer (MBC) progressing to trastuzumab is unexplored. Moreover it is unknown if high level of ECD in the adjuvant setting of HER-2+ pts with early breast cancer (EBC) could be an early marker of resistance to trastuzumab. Methods: serum was obtained from 40 HER-2 +pts: 19 MBC/21 EBC. Serum ECD was determined using commercial ELISA-kits (Oncogene Science). This ELISA uses a measure of 15 ng/ml as the upper limit of normal. A median of 3 samples was collected (2-5) every three months (+/-1 month). Median age was 55 (34-77), median PS was 1 (0-2) median number of therapy performed for MBC was 2 (2-6), 11 of these pts were treated with lapatinib for metastatic disease. Results: High level of ECD was detectable in 10 of MBC (25%) and in 4 of EBC pts (10%). Median PFS of MBC pts was 51 wks (CI 32-71). No relation was observed with high ECD levels and response to trastuzumab (p= 0.42) or lapatinib (p= 0.11) in MBC. HER-2 ECD level in EBC pts were not significantly associated with high istological grade (G1-G2 vs G3) (p=0.71), lymphonode involvement (N0-N1vsN2) (p= 0.63), degree of endocrine responsiveness respectively estrogen (<50% vs >50%) (p =0.5) and progesterone (<50% vs >50% )(p= 0.3), Ki67 high(≥ 15%) vs low (<15%) (p=0.9). Conclusions: ECD measure in our experience did not predict benefit to trastuzumab or lapatinib. The prognostic value of ECD in EBC needs a larger population to be validated. Our study is ongoing and we have planned to enroll exclusively EBC pts in order to define the role of ECD in this setting, if any.
Phase I study of biweekly liposome irinotecan (PEP02, MM-398) in metastatic colorectal cancer failed on first-line oxaliplatin-based chemotherapy.
Authors: Li-Tzong Chen, Her-Shyong Shiah, Peng-Chan Lin, Jenq-Chang Lee, Wu-Chou Su, Yi-Wen Wang, Grace Yeh, Jang-Yang Chang
Journal: Journal of Clinical Oncology (2012)

613 Background: PEP02 (MM-398) is a nanoliposomal formulation of irinotecan (CPT-11) that has improved pharmacokinetics (PK) and tumor distribution of CPT-11 and its active metabolite, SN-38. PEP02 single agent q3w has shown preliminary efficacy and safety in Phase II pancreatic and gastric cancer studies. Since irinotecan is approved for metastatic colorectal cancer (mCRC) and biweekly regimens are widely used, the aims of this study are to determine the maximum tolerated dose (MTD), characterize the PK and pharmacogenetics (PGx), and explore the efficacy of PEP02 q2w in mCRC. Methods: Patients (pts) with disease progression after 1 st -line oxaliplatin-based chemotherapy, ECOG PS 0-1, and without prior exposure to irinotecan were eligible. PEP02 was given on day 1 and 15 of each 28 day treatment cycle. The starting dose was 80 mg/m 2 and escalated by 10 mg/m 2 to the target dose of 100 mg/m 2 . PK was evaluated during the 1 st cycle and the tumor response was assessed by RECIST. Results: A total of 18 pts (M/F 9/9; median age 57.5) were enrolled, with 6 at each dose level. Dose-limiting toxicity manifested as G3 diarrhea was observed in one pt per dose level. The target dose of 100 mg/m 2 was determined to be the MTD. Nine pts had dose delayed (4, 3, 2 at 80, 90, 100 mg/m 2 ), mostly because of neutropenia. The PK and PGx are being analysed. As of August 2011, there are 3 pts still on study treatment and 17 pts evaluable for tumor response. Four pts (2 at 80 mg/m 2 , 1 each at 90 and 100 mg/m 2 ) showed partial response (3 after 2 cycles and 1 after 8 cycles) and 8 pts (3 each at 80 and 90 mg/m 2 , 2 at 100 mg/m 2 ) maintained stable disease for at least 2 cycles, which resulted in a response rate (RR) of 23.5% and a disease control rate (DCR) of 70.6%. Current median progression-free survival (PFS) is 4 months and 8 pts (47%) had PFS ≥ 6 months. Conclusions: The MTD of biweekly PEP02 is 100 mg/m 2 . As a 2 nd -line monotherapy after oxaliplatin-based chemotherapy, the efficacy results indicate the potential benefit of PEP02 for mCRC (FOLFIRI-1 achieved only 4% RR, 34% DCR, and 2.5 months PFS in FOLFOX pretreated pts). A randomized Phase II study evaluating PEP02 plus 5-FU/LV (FUPEP regimen) vs. FOLFIRI is currently ongoing in France.
Minimal Residual Disease Detected By Multiparameter Flow Cytometry and Complex Karyotype Are the Major Prognostic Factors for Relapse after HCT
Authors: Betul Oran, Jeffrey L. Jorgensen, Sa A. Wang, David Marin, Uday R. Popat, Julianne Chen, Stefan O. Ciurea, Sairah Ahmed, Qaiser Bashir, Katayoun Rezvani, Elizabeth J. Shpall, Partow Kebriaei, Richard E. Champlin
Journal: Blood (2015)
Abstract 4574: Genomic copy number variations characterize prognosis of oropharyngeal squamous cell carcinoma, including p16 positive subset, after surgery-based treatment
Authors: Yuh-S. Jung, Arang Rhie, Jong-Il Kim, Jin Soo Lee, Junsun Ryu, Weon Seo Park
Journal: Cancer Research (2015)

Abstract Background High-risk human papillomavirus (HPV)-related (+) oropharyngeal squamous cell carcinoma (OSCC) exhibits unique clinical and molecular characteristics, compared to HPV-unrelated - OSCCs. As different patterns of genomic instability is expected in HPV-driven carcinogenesis, we questioned if patterns of genomic copy number variations (CNVs) differ depending on HPV association, and predict prognosis, after surgery-based treatment for OSCCs in Korean population. Methods Fifty-eight OSCCs patients, who underwent surgery-based treatment and followed for 42 months on median, were enrolled. HPV status was determined by p16 immunohistochemistry (IHC), and HPV DNA PCR. Genome-wide CNV analysis was performed using array-based comparative genomic hybridization of genomic DNA from paraffin-embedded specimen. Clinical association and survival analyses were followed. Results p16 predicted the overall survival (HR = 0.27, CI: 0.39-0.80, p = 0.0006), better than HPV DNA PCR (HR = 0.83, CI: 0.66-1.29, p = 0.64) or smoking history (HR = 2.18, CI: 0.92-5.18, p = 0.071). In overall, number of CNVs did not significantly differed between p16+/- groups. However, 30 locus showed different CNV pattern between these groups. PRDM2 was amplified only in p16+ group, while EGFR and 11q13.3 was more amplified in p16- patients. Loss of FGF18 lead to worse prognosis, and gain of CDK10 and RAD18 was linked to better prognosis in all patients. Amplification of HRAS and loss of KDR lead to better OS in p16+ group. Conclusions After surgery-based treatment, p16+ OSCCs exhibits different CNV patterns at some loci, compared with p16- counterpart. Specific patterns of CNVs do predict better survival, especially in p16+ OSCCs. In the future, clinical trials should stratify patients based on these patterns to apply escalated treatment to obtain better survival. Citation Format: Yuh-S. Jung, Arang Rhie, Jong-Il Kim, Jin Soo Lee, Junsun Ryu, Weon Seo Park. Genomic copy number variations characterize prognosis of oropharyngeal squamous cell carcinoma, including p16 positive subset, after surgery-based treatment. [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 4574. doi:10.1158/1538-7445.AM2015-4574
Targeting DNA Repair in Cancer: Beyond PARP Inhibitors
Authors: Jessica S. Brown, Brent O'Carrigan, Stephen P. Jackson, Timothy A. Yap
Journal: Cancer Discovery (2016)

Abstract Germline aberrations in critical DNA-repair and DNA damage–response (DDR) genes cause cancer predisposition, whereas various tumors harbor somatic mutations causing defective DDR/DNA repair. The concept of synthetic lethality can be exploited in such malignancies, as exemplified by approval of poly(ADP-ribose) polymerase inhibitors for treating BRCA1/2-mutated ovarian cancers. Herein, we detail how cellular DDR processes engage various proteins that sense DNA damage, initiate signaling pathways to promote cell-cycle checkpoint activation, trigger apoptosis, and coordinate DNA repair. We focus on novel therapeutic strategies targeting promising DDR targets and discuss challenges of patient selection and the development of rational drug combinations. Significance: Various inhibitors of DDR components are in preclinical and clinical development. A thorough understanding of DDR pathway complexities must now be combined with strategies and lessons learned from the successful registration of PARP inhibitors in order to fully exploit the potential of DDR inhibitors and to ensure their long-term clinical success. Cancer Discov; 7(1); 20–37. ©2016 AACR.
Health-related quality of life (HRQoL) of bosutinib (SKI-606) in imatinib-resistant (IM-R) or imatinib-intolerant (IM-I) chronic phase chronic myeloid leukemia (CP CML).
Authors: P. C. Trask, D. Cella, N. Besson, V. Kelly, T. Masszi, D. Kim
Journal: Journal of Clinical Oncology (2011)

6620 Background: Bosutinib, a dual Src/Abl tyrosine kinase inhibitor (TKI), has demonstrated efficacy in a phase 1/2 single-arm study of patients (pts) with IM-R or IM-I CP CML. Given the potential for CP CML pts receiving 2nd-generation TKIs to be treated for significant durations, evaluation of concomitant HRQoL is important. The effect of bosutinib on HRQoL was assessed as an exploratory endpoint. Methods: In the phase 2 part of the trial, 253 pts with IM-R (n = 170) or IM-I (n = 83) CP CML were treated with bosutinib 500 mg/d. HRQoL was measured using the 44-item Functional Assessment of Cancer Therapy–Leukemia (FACT-Leu), which consists of 5 domains: Physical Well-being (PWB), Social/Family Well-being (SFWB), Emotional Well-being (EWB), Functional Well-being (FWB), and Leukemia Subscale (LeuS); and 3 summary scales: Treatment Outcome Index (TOI), FACT-General, and FACT-Leu Total. FACT-Leu items are rated on a scale of 0-4. Scores are obtained for each scale by summing item responses; higher scores reflect better HRQoL. The FACT-Leu was completed at baseline, wks 4, 8, and 12, every 12 wks thereafter, and at treatment completion. Within-cohort comparisons were assessed using paired t-tests. Results: In this interim analysis, median follow-up was 97 wks (range, 2-215 wks); 51% of pts were still receiving treatment. At 12 wks, IM-R pts reported significant improvements (P <0.05 to P <0.01) in the PWB, EWB, LeuS, Total, and TOI; IM-I pts reported improvement in the LeuS (P <0.05). At 24 wks, IM-R pts reported improvements from baseline in the EWB, LeuS, Total, and TOI; IM-I pts noted significant improvements (P <0.001 to P <0.05) in the PWB, EWB, LeuS, Total, and TOI. At 48 and 96 wks, the LeuS (P <0.01) and TOI (P <0.05) remained improved for IM-R pts, with additional improvements in PWB, Total (P <0.05), and EWB (P <0.01) observed at 96 wks. EWB, LeuS, Total, and TOI were improved for IM-I pts (P <0.001 to P <0.05) at 48 wks, although not at 96 wks. Conclusions: When examined in the context of previously reported efficacy, these early HRQoL data suggest that bosutinib is associated with improved HRQoL among pts with IM-R or IM-I CP CML who remained on therapy.
Dynamin 2 (DNM2) and PACSIN2 Regulate Megakaryocyte Demarcation Membrane System Formation and Platelet Production in Concert
Authors: Silvia Giannini, Markus Bender, Fred G. Pluthero, Hilary Christensen, Richard Leung, Richard W. Lo, Jan Kormann, Markus Plomann, Walter H.A. Kahr, Hervé Falet
Journal: Blood (2015)
A Multidisciplinary Quality Initiative for Stem Cell Transplantation in Multiple Myeloma: Outpatient Transplant with Low Therapy Related Mortality
Authors: Morie Abraham Gertz, Stephen M Ansell, David Dingli, Angela Dispenzieri, Francis K. Buadi, Michelle A Elliott, Dennis A Gastineau, Suzanne R Hayman, William J Hogan, David J Inwards, Patrick B Johnston, Shaji Kumar, Martha Q Lacy, Nelson Leung, Ivana NM Micallef, Luis F Porrata, Barbara A Schafer, Robert C Wolf, Mark R Litzow
Journal: Blood (2008)
OC-080 A systematic approach identifying the causes of duodenal intraepithelial lymphocytosis: Abstract OC-080
Authors: I Aziz, K E Evans, A D Hopper, D S Sanders
Journal: Gut (2010)

<h3>Introduction</h3> Increased intraepithelial lymphocytes (IELs) with normal small bowel villous architecture (also known as Marsh 1) is found in ∼2% of duodenal biopsies. Some of the identifiable causes of raised IELs include coeliac disease (CD), non-steroidal anti-inflammatory drugs (NSAIDs), <i>H pylori</i>, autoimmune disorders, immunodeficiency, gastrointestinal infections and inflammatory bowel disease (IBD). Most studies have focused on evaluating/investigating individual disease entities causing raised IELs and in particular those patients belonging to the spectrum of CD. Very few studies have taken a prospective and systematic approach in identifying the underlying causes for raised IELs. <h3>Methods</h3> To determine the causes of raised duodenal IELs in a large series of patients using a 2-step approach. Step 1: Revisit patient history (ie, autoimmune disorders, dermatitis herpetiformis, family history, NSAID usage), coeliac serology, immunoglobulins, stool cultures, glucose hydrogen breath test, colonoscopy and <i>H pylori</i> testing. Step 2: In those where no cause was apparent/unclear or where coeliac disease was a possibility, patients then went on to also have HLA status performed and/or a 6-week gluten challenge with repeat coeliac serology and duodenal biopsies (n=81 patients with raised IELs on first biopsy, female=60 (74%), age range 19–83, median age=47). <h3>Results</h3> Of the 31 cases where no cause was found, 29 did have a second biopsy on gluten challenge (see Abstract 080). The IEL count had normalised in 22 (76%), with persistent marsh 1 changes in the others. In addition, more than half with no cause found had clinical symptoms consistent with a diagnosis of irritable bowel syndrome (IBS). <h3>Conclusion</h3> The three most common identifiable causes of raised IELs are NSAIDs, <i>H pylori</i> and coeliac disease. Despite being extensively investigated, more than a third of cases with raised IELs have no identifiable cause. The significance and association of duodenal IELs in IBS is not yet clear. Studies have shown conflicting data, with reported IEL levels ranging from normal to slightly elevated. Nevertheless, we have reported the largest systematic experience to date and would suggest that in the group of patients with "no cause found" they can be reassured as their IEL count is likely to normalise.