tbuckley/cabot-search huggingface dataset:
Gemcitabine combined with capecitabine compared to gemcitabine with or without erlotinib as first-line chemotherapy in patients with advanced pancreatic cancer: Comparative effectiveness study.
Authors: Jangho Cho, Jae Yun Lim, Jae Yong Cho
Journal: Journal of Clinical Oncology (2013)

e15132 Background: Gemcitabine is the standard treatment for advanced pancreatic cancer. Though capecitabine and erlotinib are accepted as combination agent with gemcitabine, those two combination regimens have not been compared directly in clinical trial. This study compared the efficacy and tolerability between gemcitabine plus capecitabine (GEM-X), gemcitabine plus erlotinib (GEM-T), and gemcitabine monotherapy (GEM) as first-line chemotherapy in patients with advanced pancreatic cancer. Methods: We collected data ofpatients if they met the following criteria: histologically or cytologically confirmed ductal adenocarcinoma of the pancreas; unresectable/metastatic disease; treated with one of GEM, GEM-X, and GEM-T as first-line treatment; measurable or evaluable lesion; age more than 18 years; Eastern Cooperative Oncology Group performance status 0, 1, or 2; and adequate hematologic, hepatic, and renal function before first-line chemotherapy. Response rate, progression-free survival (PFS), overall survival (OS), and toxicity were evaluated. Results: Between January 2007 and November 2011, a total of 127 patients received one of GEM (n=47), GEM-T (n=44), and GEM-X (n=36). GEM-X significantly improved the objective response rate (21.2% vs. 12.7% and 15.9%), progression-free survival (8.9 vs. 5.2 and 3.9 months; p &lt; 0.001) and OS (12.1 vs. 10.4 and 9.9 months; p = 0.03) compared to GEM and GEM-T, respectively. The incidence of adverse events was not significantly different among groups. Conclusions: GEM-X presented better clinical efficacy and acceptable tolerability than GEM-T and GEM in locally advanced and metastatic pancreatic cancers. It is worthy to further investigate which agent has clinical advantage as combination drug with gemcitabine in pancreatic cancer and to explore predictive markers for each regimen leading to personalize anti-cancer treatment.
Oral health and the frailty syndrome
Authors: Michael I. MacEntee, Leeann R. Donnelly
Journal: Periodontology 2000 (2016)

Abstract The frailty syndrome is an ever‐growing area of study among older adults because of its association with an increased risk of falls, hospitalization, institutionalization, dependency and mortality. Frailty is neither a disease nor a disability but is better understood as a medical syndrome of multisystem dysregulation that results in a diminished ability to overcome everyday stressors. The prevalence of frailty in any given population can vary widely, in part because of the way in which it is defined and measured, but in general it is higher among women and in those with advanced age and declining health. Whilst it is largely understood that older adults will differ biologically, psychologically and socially, and that each of these domains can impact oral health, we are only beginning to investigate how the mouth is affected in frailty. Given that both hard and soft structures contribute to oral health and disease status among older adults with varying degrees of impairment and disability, frailty adds yet another dimension to be considered. This paper will discuss how frailty can influence and be influenced by oral disorders, as well as the potential relationship to oral neglect and the resultant consequences among this vulnerable population.
Should we use gait speed in COPD, FEV<sub>1</sub>in frailty and dyspnoea in both?
Authors: Jean Bousquet, Anh Tuan Dinh-Xuan, Thomas Similowski, João Malva, Joël Ankri, Mario Barbagallo, Leonardo Fabbri, Marc Humbert, Jacques Mercier, Carlos Robalo-Cordeiro, Leocadio Rodriguez-Manas, Bruno Vellas
Journal: European Respiratory Journal (2016)

Frailty is a progressive physiological decline in multiple organ systems marked by loss of function, loss of physiological reserve and increased vulnerability to disease [1]. Biological (inflammation and loss of hormones), clinical ( e.g. sarcopenia and osteoporosis) and social factors are involved in frailty onset, evolution and prognosis [2, 3]. Links between frailty, dyspnoea and chronic respiratory diseases represent a novel and practical approach <http://ow.ly/10zIvj>
Recurrent <i>PPP2R1A</i> Mutations in Uterine Cancer Act through a Dominant-Negative Mechanism to Promote Malignant Cell Growth
Authors: Dorien Haesen, Layka Abbasi Asbagh, Rita Derua, Antoine Hubert, Stefanie Schrauwen, Yana Hoorne, Frédéric Amant, Etienne Waelkens, Anna Sablina, Veerle Janssens
Journal: Cancer Research (2016)

Somatic missense mutations in the Ser/Thr protein phosphatase 2A (PP2A) Aα scaffold subunit gene PPP2R1A are among the few genomic alterations that occur frequently in serous endometrial carcinoma (EC) and carcinosarcoma, two clinically aggressive subtypes of uterine cancer with few therapeutic options. Previous studies reported that cancer-associated Aα mutants exhibit defects in binding to other PP2A subunits and contribute to cancer development by a mechanism of haploinsufficiency. Here we report on the functional significance of the most recurrent PPP2R1A mutations in human EC, which cluster in Aα HEAT repeats 5 and 7. Beyond predicted loss-of-function effects on the formation of a subset of PP2A holoenzymes, we discovered that Aα mutants behave in a dominant-negative manner due to gain-of-function interactions with the PP2A inhibitor TIPRL1. Dominant-negative Aα mutants retain binding to specific subunits of the B56/B' family and form substrate trapping complexes with impaired phosphatase activity via increased recruitment of TIPRL1. Accordingly, overexpression of the Aα mutants in EC cells harboring wild-type PPP2R1A increased anchorage-independent growth and tumor formation, and triggered hyperphosphorylation of oncogenic PP2A-B56/B' substrates in the GSK3β, Akt, and mTOR/p70S6K signaling pathways. TIPRL1 silencing restored GSK3β phosphorylation and rescued the EC cell growth advantage. Our results reveal how PPP2R1A mutations affect PP2A function and oncogenic signaling, illuminating the genetic basis for serous EC development and its potential control by rationally targeted therapies. Cancer Res; 76(19); 5719-31. ©2016 AACR.
Aurora‐A Kinase: A Potent Oncogene and Target for Cancer Therapy
Authors: Min Yan, Chunli Wang, Bin He, Mengying Yang, Mengying Tong, Zijie Long, Bing Liu, Fei Peng, Lingzhi Xu, Yan Zhang, Dapeng Liang, Haixin Lei, Sen Subrata, Keith W. Kelley, Eric W.‐F. Lam, Bilian Jin, Quentin Liu
Journal: Medicinal Research Reviews (2016)

The Aurora kinase family is comprised of three serine/threonine kinases, Aurora-A, Aurora-B, and Aurora-C. Among these, Aurora-A and Aurora-B play central roles in mitosis, whereas Aurora-C executes unique roles in meiosis. Overexpression or gene amplification of Aurora kinases has been reported in a broad range of human malignancies, pointing to their role as potent oncogenes in tumorigenesis. Aurora kinases therefore represent promising targets for anticancer therapeutics. A number of Aurora kinase inhibitors (AKIs) have been generated; some of which are currently undergoing clinical evaluation. Recent studies have unveiled novel unexpected functions of Aurora kinases during cancer development and the mechanisms underlying the anticancer actions of AKIs. In this review, we discuss the most recent advances in Aurora-A kinase research and targeted cancer therapy, focusing on the oncogenic roles and signaling pathways of Aurora-A kinases in promoting tumorigenesis, the recent preclinical and clinical AKI data, and potential alternative routes for Aurora-A kinase inhibition.
Abstract 2602: The nonclinical toxicology profile of pacritinib, a JAK2/FLT3 inhibitor with no dose-limiting clinical myelosuppression
Authors: Rebecca Watson, Suliman Al-Fayoumi
Journal: Cancer Research (2016)

Abstract Pacritinib is an orally active kinase inhibitor being developed for the treatment of myelofibrosis (MF). Pacritinib is a particularly potent inhibitor of wild-type and mutant isoforms of JAK2 and FLT3 (IC50 values &amp;lt; 15 nM), and it does not suppress JAK1 at clinically relevant concentrations. Additional kinases targeted by pacritinib include IRAK1 (IC50 = 13.6 nM) and c-fms (or CSF1R; IC50 = 39.5 nM). Pacritinib is pharmacologically active in nonclinical tumor models driven by JAK2 or FLT3 overexpression, and clinical trials have demonstrated that pacritinib can ameliorate symptoms in MF patients. A key differentiating feature of pacritinib over currently available JAK2 inhibitors is its lack of dose-limiting clinical myelosuppression, allowing for treatment of patients with cytopenias. The comparatively reduced myelosuppressive activity of pacritinib is thought to be due to its lack of pharmacological activity on JAK1, and/or its inhibition of IRAK1 and c-fms, which may contribute to anti-inflammatory activity. Nonclinical pacritinib data from rodent and canine studies were evaluated in comparison to publicly available information for other JAK2 inhibitors to determine if differences in nonclinical endpoints might correlate with the observed clinical differences in myelosuppressive effects. The qualitative nonclinical findings seen in rodents were similar for all JAK2 inhibitors, and included decreases in leukocytes, red cell mass, and reticulocytes; lymphoid depletion in the spleen, thymus, and/or lymph nodes; and hypocellularity of the bone marrow. Interestingly, platelet decreases were not observed in rodent or canine nonclinical models, even with JAK2 inhibitors associated with clinical thrombocytopenia. However, in the dog, pacritinib is unique for its minimal myelosuppressive effects in the pivotal 30-day and 39-week studies, despite being performed at higher exposure levels relative to other similar JAK2 inhibitor studies. With pacritinib, non-adverse lymphoid reduction was seen in the spleen, lymph nodes, Peyer's patches, and/or thymus; but there were no clinical pathology findings indicative of marked myelosuppression, nor were there any treatment-related findings in detailed bone marrow evaluations. Overall, these comparisons suggest that nonclinical bone marrow data and clinical pathology in the dog may be informative endpoints for estimating the myelosuppressive potential of JAK2 inhibitors in the clinic. Citation Format: Rebecca Watson, Suliman Al-Fayoumi. The nonclinical toxicology profile of pacritinib, a JAK2/FLT3 inhibitor with no dose-limiting clinical myelosuppression. [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 2602.
Abstract 879: Single cell analysis resolves combinatory targeted therapy for arresting the BRAFi-induced cellular dedifferentiation of metastatic melanomas
Authors: Yapeng Su, Wei Wei, Min Xue, Lidia Robert, Jennifer Tsoi, Thomas Graeber, Antoni Ribas, James Heath
Journal: Cancer Research (2016)

Abstract Targeted therapy that inhibits the BRAF (V600E) protein has shown impressive initial responses in metastatic melanoma patients. However, acquired drug resistance, derived from tumor heterogeneity, always limits its efficacy and compromises its treatment outcomes. Melanocyte to neural crest transition (MNT) has been observed to play crucial role in early stage adaptive drug tolerance, and the mathematic modeling indicates the transition is contributed from both stochastic phenotypic transition and non-genetic selection. Whole transcriptomic analysis enriched important signaling proteins that are involved in the resistance development process. Single cell proteomic analysis of those proteins was performed on patient-derived melanoma models to further study the early stage drug tolerance. This resolves how protein signaling network coordination rewires in the process, which cannot be resolved from proteomic analysis of bulk tumor tissue. Signaling network coordination analysis indicates that co-inhibiting the hubs of the network (MEK, NFKB-p65) could keep cells in the drug-susceptible stages. The combination therapy that co-inhibits mutant BRAF, MEK and NFKB-p65 together successfully arrested the MNT transition and induced a sustained tumor growth suppression in multiple patient-derived melanoma cell lines. This study provides us a brand-new way of using single cell proteomic analysis to infer effective combinations by resolving protein signaling network coordination that is inaccessible through traditional bulk-level proteomic measurement. Citation Format: Yapeng Su, Wei Wei, Min Xue, Lidia Robert, Jennifer Tsoi, Thomas Graeber, Antoni Ribas, James Heath. Single cell analysis resolves combinatory targeted therapy for arresting the BRAFi-induced cellular dedifferentiation of metastatic melanomas. [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 879.
Abstract 5099: Abrogation of cancer cell extravasation in renal cell carcinoma PDX lines via invadopodia dysregulation mediated by PAK1 inhibitors
Authors: Karla Williams, Clarisse Mazzola, James Brugarolas, Nicholas Power, Ann Chambers, Hon Leong
Journal: Cancer Research (2015)

Abstract Cellular remodeling of the extracellular matrix (ECM), facilitating tumour cell invasion, is a key intrinsic quality in metastatic cells. Invadopodia are actin-driven protease-rich subcellular membrane protrusions formed by tumor cells for localized degradation and remodeling of the ECM. Invadopodia mediate tumor cell extravasation, a key step in the metastatic cascade in which tumor cells undergo transendothelial migration when arrested at distant sites. Using several PDX cell lines, we determine that treatment with PAK1 inhibitors leads to significantly decreased rates of cancer cell extravasation in vivo (IPA-3, 1 uM final concentration) with no impacts on cell viability in vitro. Interestingly, in vitro, there was no significant change in the number of cells forming invadopodia; however, there was more gelatin degradation per cell as determined by in vitro gelatin-Alexa594 invadopodia assays. Time lapse imaging of invadopodia formation in PDX cell lines reveal a decrease in invadopodia disassembly in vitro, resulting in alterations to adhesions to maintain tumor cell anchorage to the CAM vessel wall in vivo. These results reveal the feasibility of targeting extravasation through other mechanisms whilst impairing invadopodia disassembly prior to cancer cell transportation to the underlying tissue. Citation Format: Karla Williams, Clarisse Mazzola, James Brugarolas, Nicholas Power, Ann Chambers, Hon Leong. Abrogation of cancer cell extravasation in renal cell carcinoma PDX lines via invadopodia dysregulation mediated by PAK1 inhibitors. [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 5099. doi:10.1158/1538-7445.AM2015-5099
Abstract 3549: The role of programed necrosis in oncolytic adenovirus-induced cell death in ovarian cancer
Authors: Melanie Weigert, Alexander Binks, Stephen Tait, Iain McNeish
Journal: Cancer Research (2016)

Abstract Introduction. Oncolytic viruses preferentially replicate within and kill cancer cells and are a promising novel cancer treatment. However, the mechanisms by which oncolytic adenoviruses induce death in cancer remains unclear. It was long thought that DNA viruses trigger classical apoptosis but there is now evidence that cell death induced by both adenovirus and vaccinia displays features of necrosis-like programmed cell death. Methods and Results. In order to investigate the role of necrosis in cell death following oncolytic adenovirus infection, a panel of ovarian cancer cells with varying sensitivities was infected with the E1A CR2-deleted adenoviral mutant dl922-947. By electron microscopy, dl922-947 infection induces key morphological features of necrotic death, including membrane rupture, nuclear swelling and cytoplasmic vacuolation. Using specific necrosis inhibitors (necrostatin-1, necrosulfonamide, GSK’840B, GSK’872B and GSK’843A) as well as RNAi-mediated knockdown of receptor interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like (MLKL), we show that adenovirus-infected ovarian cancer cells undergo RIPK3-dependent necrosis and that blockage of the downstream effector MLKL significantly attenuates cell death. Co-immunoprecipitation of caspase 8 shows formation of a complex containing RIPK1, FADD and caspase 8 during adenovirus infection. However, unlike Tumour Necrosis Factor-α (TNF-α)-induced programmed necrosis, which relies on the RHIM-dependent interaction of RIPK1 and RIPK3, RIPK1 appears redundant in adenovirus-induced death. Furthermore, the addition of a TNF-α blocking antibody to virus-infected cells has no effect on either cell death or overall cell survival. In a RIPK3 overexpression model, we show a direct correlation between adenovirus-induced cell death and the extent of RIPK3 expression. Moreover, RIPK3 expression has no effect on infectivity, viral protein expression or infectious virus production. Finally, expression of RIPK3 increases necrosis induction in vivo following direct intra-tumoural dl922-947 injection, and significantly improves anti-tumour efficacy. Conclusions. Our data suggest that cell death induced by oncolytic adenoviruses differs from TNF-induced programmed necrosis but still relies on the kinase RIPK3 and its downstream component MLKL, making these two proteins possible targets for future oncolytic virotherapies. Citation Format: Melanie Weigert, Alexander Binks, Stephen Tait, Iain McNeish. The role of programed necrosis in oncolytic adenovirus-induced cell death in ovarian 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 3549.
2PD Crizotinib could overcome acquired resistance to alectinib caused by HGF autocrine in ALK rearranged non-small cell lung cancer
Authors: H. Isozaki, E. Ichihara, N. Takigawa, K. Ohashi, N. Ochi, M. Yasugi, T. Ninomiya, H. Yamane, D. Minami, T. Kubo, A. Sato, K. Hotta, K. Sakai, K. Matsumoto, S. Hosokawa, A. Bessho, T. Sendo, M. Tanimoto, K. Kiura
Journal: Annals of Oncology (2015)
Abstract 4028: Oncogenic <i>KRAS</i> mutations induce PD-L1 overexpression through MAPK pathway activation in non-small cell lung cancer cells
Authors: Yosuke Miura, Noriaki Sunaga, Kyoichi Kaira, Yusuke Tsukagoshi, Takashi Osaki, Reiko Sakurai, Takeshi Hisada, Luc Girard, John D. Minna, Masanobu Yamada
Journal: Cancer Research (2016)

Abstract The proto-oncogene KRAS is a frequently mutated oncogenic drivers in non-small cell lung cancer (NSCLC) and druggable molecular targets for KRAS-mutated NSCLC have been under investigation. Recent studies have reported promising results of nivolumab, a programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, for previously treated NSCLC patients and suggested that the programmed-death ligand 1 (PD-L1) is a candidate surrogate marker for the anti-PD-1 therapy. By microarray analysis, we found that short hairpin RNA (shRNA)-mediated stable knockdown of mutant KRAS downregulated the expression of the CD274 gene (encoding PD-L1) in the NSCLC cell lines, H358 (-2.68 fold-change) and H441 (-1.98 fold-change). Additionally, we confirmed that small interfering RNAs (siRNAs) targeting mutant KRAS, but not wild-type KRAS, reduced CD274 mRNA expression in these cell lines. As expected, the CD274 expression levels were higher in these cell lines when examining the expression in a panel of NSCLC cell lines by quantitative RT-PCR analysis. Furthermore, CD274 mRNA expression was downregulated by MEK and ERK inhibitors (U0126, FR180204, selumetinib) in H358 and H441 cells. On the other hand, the expression analysis also revealed that CD274 mRNA levels vary among KRAS-mutated cell lines. These results suggest that oncogenic KRAS mutations induce PD-L1 overexpression through activation of the MAPK pathway in NSCLC cells, whereas other unknown mechanisms that modulate PD-L1 expression underlie in different KRAS-mutated NSCLCs. Citation Format: Yosuke Miura, Noriaki Sunaga, Kyoichi Kaira, Yusuke Tsukagoshi, Takashi Osaki, Reiko Sakurai, Takeshi Hisada, Luc Girard, John D. Minna, Masanobu Yamada. Oncogenic KRAS mutations induce PD-L1 overexpression through MAPK pathway activation in non-small cell lung cancer 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 4028.
Abstract P1-08-02: Mutant GATA3 actively promotes the growth of normal and malignant mammary cells
Authors: PA Kenny, N Chandiramani, KA Lofgren
Journal: Cancer Research (2017)

Abstract GATA3 is a transcription factor expressed in luminal breast epithelial cells and is required for mammary gland development. Analysis of TCGA data reveals that somatic heterozygous mutations in GATA3 occur in up to 15% of estrogen receptor positive breast tumors, and that these tumors are diagnosed a median of eight years earlier than other estrogen receptor positive tumors, suggesting a more aggressive phenotype. These mutants have been proposed to be null alleles resulting in haploinsufficiency, however the mutation spectrum of GATA3 in breast cancer is in sharp contrast to that found in HDR syndrome, a true GATA3 haploinsufficiency disease. Based on this disparity, we propose that there is a selective pressure to mutate and retain a portion of the GATA3 in breast cancer. Here we focus on the GATA3 mutants which lack the second zinc finger which is responsible for GATA motif binding. Expression of these mutants accelerated xenograft tumor growth by ZR751 cells, and transgenic expression in mouse mammary glands promoted precocious lobuloalveolar development. We have used integrated gene expression and ChIP-Seq profiling to demonstrate that these zinc-finger deleted proteins retain the ability to associate with the genome by tethering to complexes associated with FOXA1 and AP-2gamma recognition motifs, where they modulate the expression of adjacent genes. These data support a model in which the GATA3 mutations recently observed in breast cancer encode for active transcription factors which elicit proliferative phenotypes in normal mammary epithelium and promote the growth of estrogen receptor positive breast cancer cell lines. Citation Format: Kenny PA, Chandiramani N, Lofgren KA. Mutant GATA3 actively promotes the growth of normal and malignant mammary cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-08-02.