tbuckley/cabot-search huggingface dataset:
Abstract 1625: CUB domain-containing protein 1 (CDCP1) promotes metastatic phenotype in pancreatic ductal adenocarcinoma
Authors: Sunnie Kim, Brooke Emerling, Benjamin Hopkins, Ryan Loughran, Salva Naranjos, Lewis Cantley
Journal: Cancer Research (2016)

Abstract CUB domain-containing protein 1 (CDCP1) is a transmembrane glycoprotein that is overexpressed and highly tyrosine phosphorylated in multiple cancer types including pancreatic ductal adenocarcinoma (PDAC), a highly lethal disease. CDCP1 has been implicated in the promotion of metastases, namely cancer cell migration, invasion, and resistance to anoikis. In addition, prior studies in other cancer cell lines have shown that hypoxia inducible factors (HIF-1α and HIF-2α), which are key regulators of metastasis, induce both expression of CDCP1 and phosphorylation at tyrosine 734. The role of CDCP1 and the mechanisms that regulate CDCP1 still need further elucidation in PDAC. In this study, we demonstrated that CDCP1 is highly expressed and tyrosine phosphorylated in PDAC cell lines MiaPaCa2, PaTu89902, and Panc-1 cell lines compared to the non-tumorigenic pancreatic ductal cell line HPNE. shRNA knockdown of CDCP1 showed a reduction in the phosphorylation of Src and PKC-delta. To determine whether HIF regulates CDCP1 in PDAC, we used PDAC cell lines that stably express shRNAs targeting HIF-1α and HIF-2α. Hypoxia induced an increase in CDCP1 expression in a HIF-1α-dependent fashion. Additionally, CDCP1 knockdown in PaTu8902, a highly metastatic PDAC line, impaired cancer cell invasion by transwell invasion assay but did not show resistance to anoikis by soft agar assay. To validate our data in vivo, we performed intra-pancreatic injection of shCDCP1 PaTu8902 cells and scramble control transfected with GFP/luciferase into nude mice. Live imaging demonstrated that 2 weeks after initial injection resulted in decreased tumor establishment in mice injected with the shCDCP1 cell line compared to control. We propose that CDCP1 expression and tyrosine phosphorylation in PDAC is mediated by hypoxia inducible factors and that CDCP1 confers invasive properties in vitro and may play a role in initial tumor establishment in vivo. Based on these results, CDCP1 is a promising novel target for PDAC. Citation Format: Sunnie Kim, Brooke Emerling, Benjamin Hopkins, Ryan Loughran, Salva Naranjos, Lewis Cantley. CUB domain-containing protein 1 (CDCP1) promotes metastatic phenotype in pancreatic ductal adenocarcinoma. [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 1625.
Febrile Neutropenia(Fn)And D-Index
Authors: Michinobu Yoshimura, Yosuke Ikari, Hiroo Katsuya, Atsushi Togawa, Toshitaka Goto, Toshihiro Tanaka, Kenji Ishitsuka, Tohru Takata, Yasushi Takamatsu, Kazuo Tamura
Journal: Annals of Oncology (2014)
Prognostic significance of clinicopathologic features in patients with breast ductal carcinoma in situ who received breast-conserving therapy.
Authors: Sung Hsin Kuo, Yu-Hsuan Chen, Wen-Hung Kuo, Huang-Chun Lien, Ming-Yang Wang, Chao-Ping Wang, Chiun-Sheng Huang
Journal: Journal of Clinical Oncology (2015)

e11574 Background: Radiotherapy (RT) following breast-conserving therapy (BCT) is commonly used in breast ductal carcinoma in situ (DCIS) to decrease local recurrence. However, adjuvant breast RT has significant short and longer-term side effects. In this study, we investigated whether updated Van Nuys Prognostic Index (VNPI) score and lower-risk criteria of ECOG study 5194 (size ≤ 2.5 cm, low to intermediate risk, and surgical margin ≥ 3 mm) can help us predict local recurrence of breast DCIS patients treated with BCT alone. Methods: The updated VNPI score (tumor size, histologic grade, comedo necrosis, surgical margin, and age) is a clinical tool in treatment decision making for post-BCT breast DCIS patients in our hospital since 2003. We analyzed the clinicopathologic features, including tumor size, histologic grade, comedo necrosis, surgical margin, and age, of breast DCIS patients who received BCT with and without adjuvant RT between Jan. 2004 and June 2009. The relationship between updated VNPI score and ECOG criteria and disease-free survival (DFS) in patients with BCT alone was analyzed. Results: A total of 241 DCIS patients treated with BCT, including 106 with adjuvant RT, and 135 without adjuvant RT were included. There were no significant differences in age, tamoxifen used, and estrogen receptor status between the 2 groups. However, patients with RT had higher score of VNPI, ECOG high-risk, and less recurrence than those without RT. At a median follow-up of 5.1 years, 10 patients developed an ipsilateral recurrence, of whom four were invasive: two were classified in the VNPI score (4-6) and 8 patients in the VNPI score (7-9). Patients with VNPI score (4-6) had a significantly better 5-year DFS than those with VNPI score (7-8) (98.6% vs 82.7%, P = 0.030). In addition, the ECOG criteria (low-risk) was significantly associated with a better 5-year DFS (low-risk vs high-risk; 95.9% vs 77.7%, P= 0.007). Conclusions: These findings suggest that breast DCIS patients with low-risk (updated VNPI score 4-6 or low-risk ECOG criteria) may receive BCT alone and do not need further adjuvant RT. Further prospective study to validate these findings is warranted.
The Inhibitor Antibody Response Is More Complex in Hemophilia A Patients Than in Most Nonhemophiliacs With Factor VIII Autoantibodies
Authors: Richard Prescott, Hiroaki Nakai, Evgueni L. Saenko, Inge Scharrer, Inga Marie Nilsson, John E. Humphries, Deborah Hurst, Gordon Bray, Dorothea Scandella
Journal: Blood (1997)
Efficacy of cobimetinib (C) and vemurafenib (V) in advanced <i>BRAF</i>-mutated melanoma patients (pts) with poor and favorable prognosis in the coBRIM phase III study.
Authors: Grant A. McArthur, James M. G. Larkin, Paolo Antonio Ascierto, Jessie J. Hsu, Yibing Yan, Isabelle Anne Rooney, Daniel O. Koralek, Brigitte Dréno, Antoni Ribas
Journal: Journal of Clinical Oncology (2016)

9530 Background: In coBRIM, C+V significantly improved PFS and OS versus placebo (P)+V in pts with BRAFV600-mutated advanced melanoma, with benefit in all prespecified subgroups evaluated (Larkin J et al. N Engl J Med. 2014;371:1867-1876; McArthur GA et al. Eur J Cancer. 2015;51:S720-S723; Atkinson V et al. Presented at: Society for Melanoma Research Congress; Nov 18-21, 2015; San Francisco, CA.). Prognostic factors in melanoma include LDH level, stage of disease, disease burden, number of organs involved, liver metastasis status, and ECOG status. Here we correlate efficacy outcomes with known prognostic factors in coBRIM pts (ClinicalTrials.gov ID, NCT01689519). Methods: Study methods were previously described (Larkin J et al. N Engl J Med. 2014;371:1867-1876.). Disease burden was sum of longest diameters (SLDs) of target lesions; presence of liver metastases was determined from case report forms. Results: Across all known melanoma poor prognostic factors, pts on C+V had greater PFS and OS benefit compared with P+V. PFS and OS were improved in C+V pts with all LDH levels ( < 0.8×upper limit of normal [ULN] and > 2×ULN), in pts with and without liver metastases at screening, those with disease burden > and ≤ the median disease burden in this population, those with ≥3 target organs, and among pts with the worst prognostic factors (stage M1c, LDH ≥2×ULN, and ECOG PS ≥1, and stage M1c + LDH > ULN) (Table). Conclusions: C+V treatment results in PFS and OS improvement among BRAF-mutated melanoma with favorable and poor prognoses both. This benefit is apparent even among patients with a constellation of favorable and poor prognoses. Clinical trial information: NCT01689519.PFS and OS in pts by prognostic factor. n Median PFS, mo Median OS, mo P+V C+V P+V C+V P+V C+V ITT 248 247 7.2 12.3 17.4 22.3 LDH level < 0.8×ULN 84 76 11.0 16.5 25.0 NE > 2× ULN 38 31 3.7 6.7 6.3 9.2 Stage M1c + LDH ≥2× ULN + ECOG PS ≥1 14 11 3.5 6.6 4.6 10.0 M1C + LDH M1C + LDH ≤ULN 68 58 6.5 12.9 18.0 NE M1C + LDH > ULN 82 86 4.1 7.8 8.3 14.5 Liver metastases Yes 78 83 4.3 10.6 12.7 18.5 No 170 164 7.8 12.7 19.8 NE SLD > median 119 125 5.6 9.2 13.5 18.6 ≤ median 127 121 9.3 14.8 24.9 NE No. of target organs ≥3 91 82 5.5 9.3 15.0 16.3 <3 157 165 7.7 14.9 19.6 NE
Treatments For Relapsed Or Refractory Follicular Lymphoma (RRFL): Results Of a Systematic Literature Review (SLR) and Meta-Analysis
Authors: Rachel Lee Police, Peter C Trask, Ann Colosia, Robert Olivares, Shahnaz Khan, Adeline Abbe, Annete Njue, Jianmin Wang, Sherrill Elizabeth, James A. Kaye, Rodrigo Ruiz-Soto, Mehdi Hamadani
Journal: Blood (2013)
Abstract 932: AR signaling differentially regulates the growth of prostate epithelial cells
Authors: Xiuping Yu, Shu Yang
Journal: Cancer Research (2016)

Abstract The prostate is an androgen-dependent organ. Androgen stimulates the growth of normal prostatic cells, as well as prostate cancer (PCa). However, AR signaling does not always promote cell proliferation, in some cases, it may even inhibit the growth of prostatic cells. In this study, we used NHPrE, a cell line derived from normal human prostate epithelia, to study how AR signaling modulates the growth of prostatic cells and to explore the mechanisms involved in AR's differential function in vitro and in vivo. Our results showed that inducing AR signaling in NHPrE cells suppressed their growth in vitro, concomitant with a reduction of Myc. In contrast, ectopic expression of AR in NHPrE cells induced the expression of Myc and pSTAT3 and drove the development of invasive PCa in vivo, suggesting a distinct in vivo function of AR signaling in prostatic cells. Furthermore, our data showed that the presence of prostate stromal cells over-rode androgen-mediated growth inhibition on NHPrE/AR cells in vitro; and IL-6/pSTAT3 was implicated in this stromal/epithelial communication. In conclusion, our study showed that AR signaling differentially regulated the growth of prostatic cells in vitro and in vivo through a mechanism that involved stromal/epithelial interactions. Citation Format: Xiuping Yu, Shu Yang. AR signaling differentially regulates the growth of prostate epithelial 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 932.
Higher Incidence of Treatment-Related Toxicities in Non-Hispanic Patients Undergoing Therapy for Newly Diagnosed Pediatric Acute Lymphoblastic Leukemia on Dana-Farber Cancer Institute ALL Consortium Protocol 05-001
Authors: Justine Kahn, Sergio Barrera, Randy Davila, Emily Roberts, ZheZhen Jin, Kristen Stevenson, Traci M. Blonquist, Donna S Neuberg, Uma H. Athale, Luis A. Clavell, Peter Cole, Caroline Laverdiere, Bruno Michon, Marshall A. Schorin, Jennifer J.G. Welch, Stephen E. Sallan, Lewis B. Silverman, Kara M. Kelly
Journal: Blood (2015)
Endothelial Nox2 overexpression potentiates vascular oxidative stress and hemodynamic response to angiotensin II: Studies in endothelial-targeted Nox2 transgenic mice
Authors: J K Bendall, D Adlam, C A Bursill, J de Bono, A L Tatham, R Rinze, K M Channon
Journal: Circulation (2006)
Impact of TCFA on Unanticipated Ischemic Events in Medically Treated Diabetes Mellitus
Authors: Elvin Kedhi, Mark W. Kennedy, Akiko Maehara, Alexandra J. Lansky, Thomas C. McAndrew, Steven P. Marso, Bernard De Bruyne, Patrick W. Serruys, Gregg W. Stone
Journal: JACC. Cardiovascular imaging (2016)
<i>HHITT</i>for concussion evaluation and management
Authors: Nash Anderson, Reidar P Lystad
Journal: British Journal of Sports Medicine (2016)

HHITT (Handheld Head Injury Treatment Tool).

Sports medicine, Health and Fitness.

Requires iOS 6.0 or later or Android 4.1 and later. Compatible with iPhone, iPad and iPod touch.

Free.

Concussion stories are now endemic in mainstream media. Multimillion dollar class action lawsuits have been filed against sport governing bodies such as the National Football League and the National Hockey League, to name but two. Young athletes are retiring from sport because of persistent postconcussion symptoms, while some retired athletes are dying prematurely from neurodegenerative diseases or suicide.1 ,2 It is no surprise, therefore, that concussion evaluation and management standards have been raised in recent years. Although concussion protocols have been implemented in some sports, in particular at the elite levels, there is good reason to believe that there is considerable variation in the standard of care of many concussed athletes. Younger athletes and amateur athletes are at risk of receiving suboptimal or inadequate care.

It is hoped that new technologies such as smartphone apps will help to improve the standard of …
Abstract 3062: Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy
Authors: Junjian Wang, Haibin Wang, Lingyu Wang, Demin Cai, Zhijian Duan, Peng Chen, June X Zou, Jianzhen Xu, Xinbin Chen, Hsing-Jien Kung, Hong-wu Chen
Journal: Cancer Research (2016)

Abstract Recombinant TRAIL and agonistic antibodies to death receptors (DRs) have been in clinical trial but displayed limited anti-cancer efficacy. Lack of functional DR expression in tumors is a major limiting factor. We report here that chromatin regulator KDM4A/JMJD2A, not KDM4B, plays a pivotal role in silencing tumor cell expression of both TRAIL and its receptor DR5. In TRAIL-sensitive and -resistant cancer cells of lung, breast and prostate, KDM4A small-molecule inhibitor compound 4 (C-4) or genetic silencing strongly induces TRAIL and DR5 expression, and causes TRAIL-dependent apoptotic cell death. KDM4A inhibition also strongly sensitizes cells to TRAIL. C-4 alone potently inhibits tumor growth with marked induction of TRAIL and DR5 expression in the treated tumors and effectively sensitizes them to the newly developed TRAIL-inducer therapeutics ONC201. Mechanistically, C-4 does not appear to act through the Akt-ERK-FOXO3a pathway. Instead, it switches histone modifying enzyme complexes at TRAIL and DR5 transcriptional activator CHOP gene promoters by dissociating KDM4A and NCoR-HDAC corepressor complex, and inducing the recruitment of histone acetylase CBP. Thus, our results reveal KDM4A as a key epigenetic silencer of TRAIL and DR5 in tumors and establish inhibitors of KDM4A as a novel strategy for effectively sensitizing tumors to TRAIL pathway-based therapeutics. Citation Format: Junjian Wang, Haibin Wang, Lingyu Wang, Demin Cai, Zhijian Duan, Peng Chen, June X Zou, Jianzhen Xu, Xinbin Chen, Hsing-Jien Kung, Hong-wu Chen. Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy. [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 3062.
Somatic Therapy of a Mouse SMA Model with a U7 snRNA Gene Correcting SMN2 Splicing
Authors: Philipp Odermatt, Judith Trüb, Lavinia Furrer, Roger Fricker, Andreas Marti, Daniel Schümperli
Journal: Molecular Therapy (2016)

Spinal Muscular Atrophy is due to the loss of SMN1 gene function. The duplicate gene SMN2 produces some, but not enough, SMN protein because most transcripts lack exon 7. Thus, promoting the inclusion of this exon is a therapeutic option. We show that a somatic gene therapy using the gene for a modified U7 RNA which stimulates this splicing has a profound and persistent therapeutic effect on the phenotype of a severe Spinal Muscular Atrophy mouse model. To this end, the U7 gene and vector and the production of pure, highly concentrated self-complementary (sc) adenovirus-associated virus 9 vector particles were optimized. Introduction of the functional vector into motoneurons of newborn Spinal Muscular Atrophy mice by intracerebroventricular injection led to a highly significant, dose-dependent increase in life span and improvement of muscle functions. Besides the central nervous system, the therapeutic U7 RNA was expressed in the heart and liver which may additionally have contributed to the observed therapeutic efficacy. This approach provides an additional therapeutic option for Spinal Muscular Atrophy and could also be adapted to treat other diseases of the central nervous system with regulatory small RNA genes. Spinal Muscular Atrophy is due to the loss of SMN1 gene function. The duplicate gene SMN2 produces some, but not enough, SMN protein because most transcripts lack exon 7. Thus, promoting the inclusion of this exon is a therapeutic option. We show that a somatic gene therapy using the gene for a modified U7 RNA which stimulates this splicing has a profound and persistent therapeutic effect on the phenotype of a severe Spinal Muscular Atrophy mouse model. To this end, the U7 gene and vector and the production of pure, highly concentrated self-complementary (sc) adenovirus-associated virus 9 vector particles were optimized. Introduction of the functional vector into motoneurons of newborn Spinal Muscular Atrophy mice by intracerebroventricular injection led to a highly significant, dose-dependent increase in life span and improvement of muscle functions. Besides the central nervous system, the therapeutic U7 RNA was expressed in the heart and liver which may additionally have contributed to the observed therapeutic efficacy. This approach provides an additional therapeutic option for Spinal Muscular Atrophy and could also be adapted to treat other diseases of the central nervous system with regulatory small RNA genes.
Higher Stem Cell Dose Infusion As Rescue After Intensive Chemotherapy Does Not Improve Symptom Burden In Older Patients With Multiple Myeloma and Amyloidosis
Authors: Nina Shah, Loretta A Williams, Audrey Worthing, Qiuling Shi, Xin Shelley Wang, Valen Johnson, Tito R Mendoza, Muzaffar H. Qazilbash, Richard E Champlin, Sergio A Giralt, Charles S. Cleeland
Journal: Blood (2013)
Abstract 2672: Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures
Authors: Nicholas A. Graham, Aspram Minasyan, Heather R. Christofk, Ingo K. Mellinghoff, Thomas G. Graeber
Journal: Cancer Research (2016)

Abstract Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types. These patterns are suggestive of conserved selection pressures during tumor evolution but cannot be fully explained by known oncogenes and tumor suppressor genes. Using a pan-cancer analysis of CNA data from patient tumors and experimental systems, here we show that principal component analysis-defined CNA signatures are predictive of glycolytic phenotypes, including FDG-avidity of patient tumors, and increased proliferation. The primary CNA signature is enriched for p53 mutations and is associated with glycolysis through coordinate amplification of glycolytic genes and other cancer-linked metabolic enzymes. A cross-species comparison of CNA identified 21 conserved altered DNA regions containing 13 enzymes in the glycolysis and pentose phosphate pathways in addition to known cancer driving genes. Furthermore, exogenous expression of hexokinase and enolase enzymes in an experimental immortalization system altered the copy number status of the corresponding endogenous loci, supporting the hypothesis that these metabolic genes act as drivers within the conserved CNA amplification regions. Taken together, these results demonstrate that metabolic stress acts as a selective pressure underlying the recurrent CNAs observed in human tumors, and further cast genomic instability as an enabling event in tumorigenesis and metabolic evolution. Citation Format: Nicholas A. Graham, Aspram Minasyan, Heather R. Christofk, Ingo K. Mellinghoff, Thomas G. Graeber. Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures. [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 2672.
Characterization of the cryosurgery-induced immune response in kidney cancer patients.
Authors: Taigo Kato, Tomoyuki Iwasaki, Motohide Uemura, Akira Nagahara, Keigo Osuga, Yuji Ikeda, Kazuma Kiyotani, Jae-Hyun Park, Norio Nonomura, Yusuke Nakamura
Journal: Journal of Clinical Oncology (2016)

e16124 Background:Cryosurgery to freeze and destroy cancer cells is now applied widely as one of treatment modalities for kidney cancer. The treatment is expected to induce strong local immune response, and also systemic T cell-mediated anti-cancer immune reaction that sometimes causes spontaneous regression of distant tumor legions. Thus, characterization of T cell repertoires and immune environment in tumors before and after the treatment will improve our understanding of the cryosurgery-induced anti-cancer immunity. Methods: Tumor and peripheral blood samples were collected with written informed consent from 13 kidney cancer patients, pre- and post-cryosurgery at serial time points. We applied our own next generation sequencing approach to characterize T cell receptor (TCR) repertoires using mRNA isolated from PBMC and tumors. The diversity index of TCR was calculated on the basis of CDR3 sequences to assess clonality of T cells. We also measured mRNA expression levels of immune-related genes, CD8, CD4, FOXP3 and Granzyme A in pre- and post- treatment tumor samples. Results: TCR repertoire analysis revealed expansion of certain T cell clones in tumor tissues induced by the treatment. In addition, we found that proportions of most abundant 20 TCR clonotypes in total TCR sequence reads was significantly increased in the post-cryosurgery tumor (p = 0.03) than those of pre-cryosurgery tissues. Some of these TCR clonotypes were also detected in peripheral blood, indicating increase of systemically circulating anti-cancer T cells by cryosurgery. Expression analysis showed significant elevation of expression levels of CD8 (p < 0.0001), CD4 (p < 0.001), Granzyme A (p = 0.04), and the CD8/FOXP3ratio (p = 0.0006) in the post-cryosurgery tumor, suggesting enrichment of anti-tumoral T cells. Conclusions: Our findings revealed that cryosurgery could induce strong immune reactions and result in expansion of oligoclonal anti-tumoral T cells in tumors, and these T cells may also circulate systemically and then attack tumor cells in distant regions. Our approach may accelerate identification of anti-tumoral T cells against kidney cancer-driven potent oncoantigen/neoantigen and lead to application to TCR-engineered T cell therapy.