tbuckley/cabot-search huggingface dataset:
Abstract 165: Single-cell transcriptome analysis guides tailored combinatorial therapeutics in refractory kidney cancer
Authors: Kyu-Tae Kim, Hye Won Lee, Hae-Ock Lee, Hye Jin Song, Da Eun Jeong, Sang Shin, Hyunho Kim, Yoojin Shin, Do-Hyun Nam, Byong Chang Jeong, David G. Kirsch, Kyeung Min Joo, Woong-Yang Park
Journal: Cancer Research (2016)

Abstract Metastatic renal cell carcinoma (mRCC) evolves from primary RCC (pRCC) and harbors multiple subpopulations with distinct molecular and phenotypic features. Such underlying intratumoral heterogeneity (ITH) imposes difficulties in designing marker-based clinical trials because targeted mono-therapy eliminates a specific subpopulation of tumor cells while leaving others unharmed. Accordingly, a rational combination strategy that minimizes the survival of the drug-resistant subpopulation in a given heterogeneous tumor is essential for long-term therapeutic efficacy. Here, we examined the ITH of a paired mRCC and pRCC using single-cell mRNA sequencing (scRNA-seq) to identify specific tumor cell populations with drug target pathway activation. From the single cell expression profiles, we found the highly activated status of the EGFR and Src signaling pathways in the mRCC compared to the pRCC, with supporting in vitro high-throughput drug screening results. Distinct features of intratumoral expression variability across mRCC single cells that were masked in the bulk measurement prompted us to test the co-targeting strategy for the EGFR and Src pathways with increased likelihood for complete response. This combinatorial strategy showed significantly better treatment effects on mRCC-derived xenograft platforms in vitro and in vivo than monotherapies. Taken together, our findings show clinical implications of scRNA-seq in designing effective treatment regimens for overcoming treatment failure to conventional monotherapies, and also provide novel insights to the unmet clinical needs in effective personalized treatments. Citation Format: Kyu-Tae Kim, Hye Won Lee, Hae-Ock Lee, Hye Jin Song, Da Eun Jeong, Sang Shin, Hyunho Kim, Yoojin Shin, Do-Hyun Nam, Byong Chang Jeong, David G. Kirsch, Kyeung Min Joo, Woong-Yang Park. Single-cell transcriptome analysis guides tailored combinatorial therapeutics in refractory kidney cancer. [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 165.
Phase II trial of mifepristone (RU-486) in advanced or recurrent endometrioid adenocarcinoma or low-grade endometrial stromal sarcoma (LGESS)
Authors: T. W. Burke, M. A. Navo, J. A. Smith, M. S. Jung, R. Broaddus, R. B. Iyer, K. H. Lu, C. C. Sun, E. N. Atkinson, L. M. Ramondetta
Journal: Journal of Clinical Oncology (2007)

5595 Background: Endometrial cancer is the most common cancer of the female genital tract. It affected 41,200 women in the year 2006 and caused 7,350 deaths. Therapy options for recurrent/advanced endometrial cancer are limited. Treatment with radiation and chemotherapy has shown only limited success. Methods: In a phase II IRB approved trial, Mifepristone was given to patients with progesterone receptor positive advanced or recurrent endometrioid adenocarcinoma or low-grade endometrial stromal sarcoma at a dose of 200mg/day orally. Patients were evaluated every 4 weeks to assess treatment-related toxicities and response. Imaging was obtained initially at 8 weeks then every 12 weeks for evaluation of response. Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 was used to assess toxicity. Results: Twelve of 13 enrolled patients were evaluable for response in the first phase of accrual. Stable disease was noted in 3/12 (16, 20, and 44+ weeks). Two were endometrioid endometrial cancer and one with LGESS. No complete responses were seen, one patient remains in treatment. The most frequently reported grade 1–2 tumor related toxicities were anorexia, mood alterations, and fatigue (55%). Twenty-seven percent had asymptomatic elevations of ACTH. The most common Grade 3 toxicities were fatigue and dyspnea (27% and 18%). Only one patient experienced a Grade 4 dyspnea. No serious treatment-related adverse events occurred. Conclusions: Single agent mifepristone in patients with recurrent endometrioid adenocarcinoma or low-grade endometrial stromal sarcoma showed no complete responses. Stable disease was reported 25%, one patient remains stable at 44 weeks. Recent reports suggests that mifepristone may also work via non hormonal targets while single agent mifepristone has minimal activity in this setting. Further evaluation in combination therapy in endometrial cancer should be considered. No significant financial relationships to disclose.
Abstract 4734: Inhibitory effects of metformin on epithelial-mesenchymal transition of CD44+/CD117+ ovarian cancer stem cells
Authors: Gary G. Xiao, Rongrong Zhang, Ping Zhang, Hong Wang, Dongming Hou, Wentao Li, Chenwei Li
Journal: Cancer Research (2016)

Abstract Background: Although metformin, a first-line drug for treating diabetes, may play an important role in inhibition of epithelial ovarian cancer cell growth and cancer stem cells (CSCs), metformin at low dose showed less effect on proliferation of ovarian cancer cells. In this study, we evaluated the effect of metformin at low dose on ovarian CSCs in order to understand the molecular mechanisms underlying ovarian tumorigenesis. Methods: The inhibitory effects of metformin at los dose on proliferation and population of ovarian cancer cells including SKOV3 and A2780 were assessed by cell proliferation assay and flow cytometry. Quantitative real-time PCR assays on expression of Bcl-2, Survivin and Bax were performed to determine the effect of the metformin at low dose on epithelial-mesenchymal transition (EMT) of cancer cells and CSCs. Tumor sphere formation assay was also performed to evaluate the effect of metformin on spheres forming ability of CSCs. The therapeutic efficacy and the anti-CSC effects of metformin at low dose were investigated by using both SKOV3 cells and primary tumor xenografts. In addition, the CSC frequency and EMT in tumor xenograft models were also assessed by flow cytometry and quantitative real-time PCR. Results: Metformin at low dose did not affect proliferation of ovarian cancer cells, however, it inhibited the population of the CD44+/CD117+ selectively, neither CD133+ nor ALDH+ cells. It suppressed expression of snail2, twist and vimentin significantly in cancer cells and CD44+/CD117+ CSCs in vitro. Low dose of metformin reduced survivin expression in CSCs leading to arrest of cell cycle. Metformin at low concentration inhibited the secondary and the tertiary tumor sphere formation, decreased the growth of either SKOV3 or primary ovarian tumor xenograft, enhanced the anticancer effect of the cisplatin, and lowered the proportion of the CD44+/CD117+ CSCs in the xenograft tissue. Metformin was also associated with a reduction of snail2, twist, and vimentin in CD44+/CD117+ ovarian CSCs in vivo. Conclusions: Our results implicate that metformin at low dose inhibits selectively CD44+/CD117+ ovarian CSCs through inhibition of EMT and potentiates the effect of the cisplatin. Citation Format: Gary G. Xiao, Rongrong Zhang, Ping Zhang, Hong Wang, Dongming Hou, Wentao Li, Chenwei Li. Inhibitory effects of metformin on epithelial-mesenchymal transition of CD44+/CD117+ ovarian cancer stem cells. [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 4734.
A multicenter open-label phase 1b/2 study of ibrutinib in steroid dependent or refractory chronic graft versus host disease (cGVHD).
Authors: David Bernard Miklos, Mukta Arora, Corey S. Cutler, Ryotaro Nakamura, Manuela Juretic, Yunfeng Li, Lori Appel Styles, Danelle Frances James, Samantha Mary Jaglowski
Journal: Journal of Clinical Oncology (2015)

7024 Background: Chronic GVHD (cGVHD) is a common and serious complication after allogeneic stem cell transplantation (SCT). Both B and T cell-mediated mechanisms have been implicated in the pathophysiology of cGVHD. There are no approved therapies for cGVHD. In murine models, ibrutinib (ibr) reduces the severity of cGVHD (Dubovksy JCI 2014). In humans, ibr was tolerable in post-SCT patients (pts) and may improve donor chimerism and/or graft-vs-leukemia effects while reducing cGVHD (Miklos ASH 2014, Coutre ASH 2014). Methods: This ongoing phase 1b/2 study was designed to evaluate the safety and efficacy of ibr in pts with steroid-dependent/refractory cGVHD. Eligible pts had to have ≤ 3 prior regimens for cGVHD and either > 25% BSA erythema or an NIH mouth score > 4. Phase 1b was designed to determine the recommended phase 2 dose (RP2D) with the initial being 420 mg. Response was assessed every 3 months using the NIH consensus cGVHD Activity Assessment. Results: 6 pts (median age, 56 yrs, mean Karnofsky score, 85) were enrolled in phase 1b. Median time from transplant was 23 mo. Median time on ibr was 19.3 wks. Ibr dose was reduced to 280 mg in 1 pt due to recurrent stomatitis. Most common treatment-emergent AEs included fatigue (n = 5), diarrhea (n = 4), ecchymosis/bruising (n = 3) and stomatitis (n = 2), all grade 1/2. SAEs (all grade 3) occurred in 2 pts including one pt with pneumonia and another with pyrexia and fungal brain abscess. The latter was the only event leading to discontinuation of ibr (at 10.9 weeks). Preliminary analysis of efficacy for pts receiving at least 3 months of treatment indicated that all 5 evaluable pts achieved PR. The 2 pts evaluable at 6 months remain in PR. Improvements in clinician assessed GVHD-score, skin erythema and mouth score were observed in pts at these early time points. RP2D was determined to be 420 mg. Conclusions: Ibrutinib given for steroid-dependent/refractory cGVHD was well tolerated; AEs were consistent with the known safety profile for ibrutinib. The efficacy data observed at this early time point is preliminary and needs confirmation in a larger number of pts for longer duration. Phase 2 enrollment is ongoing. Clinical trial information: NCT02195869.
Happle-Tinschert syndrome can be caused by a mosaic<i>SMO</i>mutation and is suggested to be a variant of Curry-Jones syndrome
Authors: R. Happle, S. Tinschert
Journal: British Journal of Dermatology (2016)

Recently, Khamaysi et al. described a postzygotic activating SMO mutation in a patient with “segmental basal cell naevus syndrome”, which the authors took as a mosaic form of Gorlin syndrome (MIM #109400).1 Here we want to argue that their patient did not suffer from a mosaic manifestation of Gorlin syndrome but from Happle-Tinschert syndrome (HTS).2 In 2008 we delineated this distinct disorder characterized by segmentally arranged basaloid follicular hamartomas (BFHs) associated with osseous, dental and cerebral abnormalities.3 Meanwhile, several similar cases were published by dermatologists under the designation “Happle-Tinschert syndrome”.2 As discussed in detail in 2008, this complex mosaic phenotype often has been erroneously described under the ambiguous term “basal cell naevus syndrome”.3

This article is protected by copyright. All rights reserved.
Role of p53 Gene Mutation Type in B-CLL Prognosis.
Authors: Sarka Pospisilova, Jitka Malcikova, Jiri Damborsky, Jana Smardova, Martin Trbusek, Boris Tichy, Yvona Brychtova, Michael Doubek, Jiri Vorlicek, Jiri Mayer
Journal: Blood (2006)
Direct Intra-Bone Marrow Transplant of Cord Blood Cells: A Way To Overcome Delayed Engraftment.
Authors: Adalberto Ibatici, Anna Maria Raiola, Marina Podesta, Sarah Pozzi, Silvia Lucchetti, Lucia Casarino, Domenico Occhini, Maria Teresa van Lint, Francesca Gualandi, Francesco Gamaleri, Andrea Bacigalupo, Francesco Frassoni
Journal: Blood (2006)
Comparative Outcome of Myeloablative and Reduced Intensity Allogeneic Stem Cell Transplantation for Chronic Lymphocytic Leukemia.
Authors: Jennifer R Brown, Kristen Stevenson, Haesook T. Kim, Philippe Armand, Corey Cutler, David C. Fisher, Vincent Ho, John Koreth, Jerome Ritz, Joseph H. Antin, Robert J. Soiffer, John G. Gribben, Edwin Alyea
Journal: Blood (2008)
Abstract 1701: CCR6 associates with colon cancer metastasis
Authors: Neeraj Kapur, Hina Mir, Clarence E. Clark, Uma Krishnamurti, Derrick J. Beech, James W. Lillard, Shailesh Singh
Journal: Cancer Research (2016)

Abstract Despite established benefits of screening, colon cancer remains a leading cause of cancer death in the U.S. Majority of colon cancer deaths result from metastasis. Effective treatments are not available for advanced disease because molecular mechanisms of initiation and progression of this disease are yet to be defined. Chemokine-chemokine receptor interaction plays an important role in cancer progression. In this study, using colon cancer tissue microarray, we have shown that expression of CCR6 was significantly higher in advanced colon cancer (p&amp;lt;0.0001) with distant and regional lymph node metastasis as compared to non-metastatic and adjacent normal tissues. Expression of CCR6 was further confirmed in cell lines derived from Dukes's type C and type D colon cancer patients using flow cytometric analysis. Like tissues, CCR6 expression was significantly (p&amp;lt;0.0001) higher in colon cancer cell lines compared to normal colon epithelial cells. Furthermore, colon cancer cells showed higher migratory potential toward chemotactic gradient of its only known natural ligand, CCL20. Cell proliferation was also inhibited in presence of CCL20. Significant decrease in E-cadherin, increased expression of vimentin, β-catenin, N-cadherin, α-SMA, SNAIL and ZEB1 was observed following CCL20 treatment. These results suggest the importance of CCR6-CCL20 axis in the etiopathogenesis of colon cancer and highlight its potential as therapeutic target. Citation Format: Neeraj Kapur, Hina Mir, Clarence E. Clark, Uma Krishnamurti, Derrick J. Beech, James W. Lillard, Shailesh Singh. CCR6 associates with colon cancer metastasis. [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 1701.
Information technology (IT) and chemotherapy (CT) prescribing errors.
Authors: M. Aita, O. Belvedere, F. De Pauli, L. Deroma, L. Gurrieri, J. Menis, V. Merlo, F. Puglisi, L. Zanier, G. Fasola
Journal: Journal of Clinical Oncology (2010)

6080 Background: The role of IT in preventing CT prescribing errors is unclear. Comparing their frequency across different studies is unworthy, due to inconsistencies in error classification, strategies of detection and functions of the IT system in use. Still, an intraorganizational study of error incidence, type and clinical relevance may reveal existing drawbacks and help to implement system applications. Methods: The study was part of a Health Department safety project. The study setting was the Cancer Unit at the University Hospital in Udine, Italy, where a computerized order entry system is fully operative since the end of 2006. Eligible prescriptions were made between January 2007-July 2008, by staff physicians with at least 2-year experience. Records of pts enrolled in clinical trials were excluded. A maximum of 3 random orders per eligible record were analyzed by trained residents and 2 oncology specialists. Errors were classified as inappropriate, incomplete or incorrect prescriptions and their severity was rated on a 4-point scale. Results: Among 237 eligible records (19% of screened charts), 125 have been analyzed so far, for a total of 305 prescriptions. The error rate was 18% and increased to 22% when considering that each order could contain > 1 error. Excluding a priori errors in the default CT protocol entry, the error rate fell to 7%. Most (62%) wrong prescriptions were incomplete - 95% because the route of administration was missing; 23% were incorrect – all because of under/overdosage; 15% were inappropriate. Inappropriateness was mainly due to errors in drug dose (50%) or treatment (30%) selection with respect to pts' age, organ function or tumor type; one patient was re-exposed to a drug causing a previous adverse reaction; and no CSF prophylaxis was given to a pt at high risk of febrile neutropenia. Among errors having caused injury (3%) or with potential for harm (9%), 25% were classified as minor, 37% as serious, 37% as potentially life-threatening. There was no fatal error. All errors were judged preventable or strongly preventable. Conclusions: CT prescribing errors may arise even in a fully computerized order entry system. Errors detection may help to identify system flaws and to fine-tune and improve its performance and utilization. No significant financial relationships to disclose.
Abstract 4523: Decreased H2B monoubiquitination is associated with enhanced proliferation and resistance to apoptosis in human lung cancer
Authors: Keqiang Zhang, Jinhui Wang, Xiwei Wu, Theresa A. Reno, Tommy R. Tong, Jae Kim, Dan Raz
Journal: Cancer Research (2016)

Abstract Monoubiquitination of histone H2B (H2Bub1) is an important chromatin modification that plays multiple roles in transcription, mRNA processing, DNA repair, cell differentiation, and maintenance of stemness. Recent studies have indicated that dysregulation of H2Bub1 and the resulting alterations of global gene expression are key contributors in cellular transformation and metastasis. However, the importance of H2B ubiquitination in lung cancer is unknown. Here, by using immunohistochemical analysis (IHC), we have demonstrated that the protein level of H2Bub1 is frequently decreased in a cohort of human lung cancer tissues in comparison to paired adjacent normal tissues. We also found that decrease in H2Bub1 is associated with increased cellular proliferation, as measured by Ki67, and is associated with decreased overall survival. Furthermore, using RNA-seq and transcriptional profiling analysis, we identified that reduction of H2Bub1 via attenuating the expression of histone H2B E3 ubiquitin ligase ring finger protein 20 (RNF20) leads to significant changes of global gene expression, modulating multiple malignancy-promoting genes, including c-Met, E2F2, and BMF. Signaling pathways including p53, DNA replication, DNA repair, and cellular proliferation, and regulation of apoptosis in lung cancer cells are also altered. Additionally, we have further shown that decrease of H2Bub1 by RNF20 knockdown significantly promotes growth, migration/invasion, and strongly enhances resistance to cytotoxic chemotherapy-induced apoptosis in lung cancer cells. Our findings suggest that dysregulation of H2Bub1 signaling may play an important role in growth and drug resistance of lung cancers, and may potentially serve as a prognostic biomarker and therapeutic target for lung cancer patients. Citation Format: Keqiang Zhang, Jinhui Wang, Xiwei Wu, Theresa A. Reno, Tommy R. Tong, Jae Kim, Dan Raz. Decreased H2B monoubiquitination is associated with enhanced proliferation and resistance to apoptosis in human lung cancer. [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 4523.
Factors associated with breast cancer genetic knowledge in a local public health district.
Authors: Olayinka David Ajayi, Wendy LeVan, Olugbenga Obasanjo
Journal: Journal of Clinical Oncology (2016)

e13053 Background: Public health (PH) clinics are in the process of optimizing genetic referrals from primary care settings. Adherence to breast cancer genetic screening guidelines depend on patient- and provider-related factors, including knowledge about breast cancer genetics. The objective of this study was to assess factors associated with knowledge about Breast Cancer (BC) genetics among female patients & PH employees across a rural health district. Methods: Cross-sectional study with mixed sampling (convenience & intra stratum systematic randomization) of adult female patients and female PH employees across 12 health clinics in Georgia. Respondents completed a modified, validated BC Genetic Questionnaire (developed from NIH Cancer Genetic Studies Consortium) that assessed socio-demographics, knowledge about BC, interest in genetic screening and Health Belief Model constructs. Factorial analysis of variance and multivariate regression were used compare means & elucidate associations with knowledge scores. Knowledge about BC genetics was the primary outcome of interest. Results: Respondents included 520 patients (83%), 62 non-clinical (10%) and 41 clinical employees (7%). Overall, mean BC genetics knowledge was 6.5 ± 1.3 (score scale 1-11). Clinical employees had higher BC genetics knowledge scores compared to non-clinical employees & patients (7.5 ± 1.2 vs. 6.6 ± 1.1, 6.4 ± 1.2, F = 15.5, p < 0.05). Overall, whites were more knowledgeable compared to ethnic minority respondents (mean difference = 0.8, F = 20.4, p < 0.001). Awareness about genetic screening was directly associated with knowledge about BC genetics among patients (F = 5.1, p < 0.05). This was not observed among clinical or non-clinical employees. Age was directly associated with knowledge about BC genetics among patients and clinical employees (F = 4.1, F = 4.5, all p < 0.05). In all groups, family history of breast/ovarian cancer, education, perceptions (risk, benefit & barrier) and interest in BC genetic screening were not associated with knowledge about BC genetics. Conclusions: Raising awareness about genetic screening option & age-, race-specific educational materials are necessary to reducing BC genetic knowledge gaps among rural dwellers.
Abstract PL02-01: Isogenic tumors can utilize heterogeneous mechanisms of nutrient uptake
Authors: Craig B. Thompson, Wilhelm Palm, Jiangbin Ye, Natalya N. Pavlova, Bryan King
Journal: Cancer Research (2016)

Abstract An emerging feature of cancer cell metabolism is the ability to acquire the anabolic precursors necessary to support cell viability and growth from a nutrient-poor environment. Cell proliferation studies undertaken under nutrient-limiting conditions have led us to define two distinct pathways by which tumor cells gain a competitive advantage over their nontransformed counterparts. One pathway is defined by enhanced capture of existing glucose and amino acids through nutrient-selective transporters. The key mediators of this pathway are AKT and its downstream effector, mTORC1. The other pathway depends on the uptake and degradation of extracellular proteins and lipids. Oncogenic forms of RAS are potent activators of this pathway. Many tumors appear capable of using both nutrient uptake pathways and can switch between them depending on extracellular nutrient conditions. Implications of these findings for tumor heterogeneity and therapeutic responsiveness will be discussed. Citation Format: Craig B. Thompson, Wilhelm Palm, Jiangbin Ye, Natalya N. Pavlova, Bryan King. Isogenic tumors can utilize heterogeneous mechanisms of nutrient uptake. [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 PL02-01.