tbuckley/cabot-search huggingface dataset:
Mapping H4K20me3 onto the chromatin landscape of senescent cells indicates a function in control of cell senescence and tumor suppression through preservation of genetic and epigenetic stability
Authors: David M. Nelson, Farah Jaber-Hijazi, John J. Cole, Neil A. Robertson, Jeffrey S. Pawlikowski, Kevin T. Norris, Steven W. Criscione, Nikolay A. Pchelintsev, Desiree Piscitello, Nicholas Stong, Taranjit Singh Rai, Tony McBryan, Gabriel L. Otte, Colin Nixon, William Clark, Harold Riethman, Hong Wu, Gunnar Schotta, Benjamin A. Garcia, Nicola Neretti, Duncan M. Baird, Shelley L. Berger, Peter D. Adams
Journal: Genome biology (2016)

Histone modification H4K20me3 and its methyltransferase SUV420H2 have been implicated in suppression of tumorigenesis. The underlying mechanism is unclear, although H4K20me3 abundance increases during cellular senescence, a stable proliferation arrest and tumor suppressor process, triggered by diverse molecular cues, including activated oncogenes. Here, we investigate the function of H4K20me3 in senescence and tumor suppression. Using immunofluorescence and ChIP-seq we determine the distribution of H4K20me3 in proliferating and senescent human cells. Altered H4K20me3 in senescence is coupled to H4K16ac and DNA methylation changes in senescence. In senescent cells, H4K20me3 is especially enriched at DNA sequences contained within specialized domains of senescence-associated heterochromatin foci (SAHF), as well as specific families of non-genic and genic repeats. Altered H4K20me3 does not correlate strongly with changes in gene expression between proliferating and senescent cells; however, in senescent cells, but not proliferating cells, H4K20me3 enrichment at gene bodies correlates inversely with gene expression, reflecting de novo accumulation of H4K20me3 at repressed genes in senescent cells, including at genes also repressed in proliferating cells. Although elevated SUV420H2 upregulates H4K20me3, this does not accelerate senescence of primary human cells. However, elevated SUV420H2/H4K20me3 reinforces oncogene-induced senescence-associated proliferation arrest and slows tumorigenesis in vivo. These results corroborate a role for chromatin in underpinning the senescence phenotype but do not support a major role for H4K20me3 in initiation of senescence. Rather, we speculate that H4K20me3 plays a role in heterochromatinization and stabilization of the epigenome and genome of pre-malignant, oncogene-expressing senescent cells, thereby suppressing epigenetic and genetic instability and contributing to long-term senescence-mediated tumor suppression.
A thrifty variant in CREBRF strongly influences body mass index in Samoans
Authors: Ryan L Minster, Nicola L Hawley, Chi-Ting Su, Guangyun Sun, Erin E Kershaw, Hong Cheng, Olive D Buhule, Jerome Lin, Muagututi'a Sefuiva Reupena, Satupa'itea Viali, John Tuitele, Take Naseri, Zsolt Urban, Ranjan Deka, Daniel E Weeks, Stephen T McGarvey
Journal: Nature Genetics (2016)
Abstract 105: Bioinformatic analysis of RNA-Seq data to search for novel diagnostic/prognostic biomarkers of pancreatic ductal adenocarcinoma
Authors: Omar J. Sosa, Vinícius F. Paixão, João C. Setubal, Eduardo M. Reis
Journal: Cancer Research (2016)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly human malignancies. The only curative treatment available is the surgical removal of the tumor in early stages of the disease. Current methods for early detection and treatment are poor, justifying more studies in this field. We aim to generate a high-resolution catalog of the PDAC transcriptome, to reveal transcriptional alterations associated with the malignant phenotype of PDAC. To that end 28 patient matched samples of PDAC and nontumor adjacent pancreatic tissue were processed for the production of rRNA subtracted cDNAs libraries and subsequently sequenced in the Illumina HiSeq platform producing 17 million 100 nt paired-end reads per sample on average. We are implementing an informatics pipeline to detect and evaluate the differential expression in PDAC of well-annotated genes, including long noncoding RNAs (lncRNAs). In addition, we will search for novel lncRNAs and alternative splicing isoforms of protein-coding genes expressed in pancreatic tissues. Following the initial quality control (FastQC) and trimming of low quality regions (Trimmomatic), reads from each sample were aligned to the human genome (TopHat2) and a count table with the number of reads per gene for each sample was created (HTSeq). For evidence of changes across experimental conditions we use DESeq2, identifying 310 genes up-regulated and 354 down-regulated (p-adjusted&amp;lt;0.001 and lfc&amp;lt;|3.3|), including 156 lncRNAs. The differentially expressed genes detected are involved in pathways related to cancer, regulation of cell cycle process, membrane and secreted proteins. De novo transcript assembly (Trinity) revealed a number of yet unannotated transcripts and isoforms expressed in pancreatic tissues. Altogether, the transcript catalog generated herein provides a valuable resource for the identification of novel putative candidate biomarkers to improve the early detection or evaluation of therapeutic response in PDAC. Work supported by FAPESP, CNPq and CAPES. Citation Format: Omar J. Sosa, Vinícius F. Paixão, João C. Setubal, Eduardo M. Reis. Bioinformatic analysis of RNA-Seq data to search for novel diagnostic/prognostic biomarkers of 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 105.
Abstract 3063: Discovery of a third-generation EGFR inhibitor, which is highly selective and potent against both resistant and activating EGFR mutations for NSCLC therapy
Authors: Rudi Bao, Peng Gao, Fujun Zhang, Zhaolong Tong, Hongping Yu, Yaochang Xu
Journal: Cancer Research (2016)

Abstract EGFR T790M mutation which renders resistance to the first-generation EGFR inhibitors,accounts for about 50% of all originally responsive non-small cell lung cancer patients. In order to overcome this type of resistance, we have developed a small molecular drug candidate with unique structural features that offer differentiated pharmacological and safety profiles pre-clinically when compared with other leading third-generation EGFR inhibitors. The compound selectively inhibits T790M as well as activating EGFR mutations, with much less inhibition to the wild type EGFR. Enzymatic inhibition IC50 against EGFR T790M,T790M/Del19 and T790M/L858R is less than 1nM. In addition, enzymatic inhibition IC50 against EGFR activating mutations Del19 and L858R is around 1nM, with much less inhibition to the wild type EGFR, a 10-time selection ratio. In cell based assays, the compound potently inhibits proliferation of EGFR T790M mutated NSCLC cell lines H1975(T790M/L858R)and PC9-GR(T790M/Del19)with an IC50 around 3nM. Similarly, it potently inhibits EGFR activating mutant NSCLC cell lines HCC827(Del19)and PC9(Del19). However, the compound displays about 200-fold less sensitivity to the EGFR wild type cancer cell line A431, with an IC50 around 600nM. When dosed to tumor-bearing animals, the compound dose-dependently induces profound regression of xenografts derived from both H1975 and primary human lung cancer LU1868, both of which carry an EGFR T790M mutation. It also induces regression of HCC827 xenografts potently, similarly to the first- and second-generation EGFR inhibitors; whereas it displays much less inhibition to the EGFR wild type A431 xenografts, demonstrating a higher specificity to the mutated EGFR forms when compared with the EGFR inhibitors on market. The drug candidate displays favorable PK and safety profiles. These properties warrant further development of this compound as first- as well as second-line therapy for NSCLC. Citation Format: Rudi Bao, Peng Gao, Fujun Zhang, Zhaolong Tong, Hongping Yu, Yaochang Xu. Discovery of a third-generation EGFR inhibitor, which is highly selective and potent against both resistant and activating EGFR mutations for NSCLC 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 3063.
Somatically Hypermutated Plasmodium-Specific IgM+ Memory B Cells Are Rapid, Plastic, Early Responders upon Malaria Rechallenge
Authors: Akshay T. Krishnamurty, Christopher D. Thouvenel, Silvia Portugal, Gladys J. Keitany, Karen S. Kim, Anthony Holder, Peter D. Crompton, David J. Rawlings, Marion Pepper
Journal: Immunity (2016)

Humoral immunity consists of pre-existing antibodies expressed by long-lived plasma cells and rapidly reactive memory B cells (MBC). Recent studies of MBC development and function after protein immunization have uncovered significant MBC heterogeneity. To clarify functional roles for distinct MBC subsets during malaria infection, we generated tetramers that identify Plasmodium-specific MBCs in both humans and mice. Long-lived murine Plasmodium-specific MBCs consisted of three populations: somatically hypermutated immunoglobulin M+ (IgM+) and IgG+ MBC subsets and an unmutated IgD+ MBC population. Rechallenge experiments revealed that high affinity, somatically hypermutated Plasmodium-specific IgM+ MBCs proliferated and gave rise to antibody-secreting cells that dominated the early secondary response to parasite rechallenge. IgM+ MBCs also gave rise to T cell-dependent IgM+ and IgG+B220+CD138+ plasmablasts or T cell-independent B220−CD138+ IgM+ plasma cells. Thus, even in competition with IgG+ MBCs, IgM+ MBCs are rapid, plastic, early responders to a secondary Plasmodium rechallenge and should be targeted by vaccine strategies.
Quality of life as a predicting factor for survival in 235 patients with inoperable hepatocellar carcinoma (HCC)
Authors: W. Yeo, F. K. F. Mo, J. Koh, A. T. Chan, P. Lai, M. Lai, T. Leung, A. Tang, P. Johnson, B. Zee
Journal: Journal of Clinical Oncology (2005)

4125 Background: Patients with inoperable HCC have a dismal prognosis. The objective of this study is to evaluate whether patient-reported baseline quality of life (QOL) measured by the EORTC QLQ-C30 instrument is predictive of survival for these patients. Methods: Two hundred thirty-five patients with inoperable HCC who were recruited into two separate randomized phase III clinical studies, based on palliative chemotherapy and palliative hormonal therapy respectively, were consented and had pre-treatment QOL assessment. EORTC QLQ-C30 scores and clinical variables at the time of study entry (age, sex, ECOG performance score, AFP, total bilirubin, alanine transaminase and albumin levels, prothrombin time, HBsAg positivity, presence of ascites, Child-Pugh's grading of cirrhosis, vascular involvement, Okuda staging of HCC and entries into the two respective studies) were analyzed to identify factors that influenced survival by applying multivariate analysis. Independent prognosticators for survival were studied by Cox regression analysis. Results: Median survival of the 235 patient was 5.5 months (95% C.I. 4.2 - 6.5 months). Significant independent predictors of shorter survival were advanced Okuda staging (p= 0.0060; HR= 1.935), high baseline AFP (p= 0.0382; HR= 1.045) and total bilirubin (p= 0.0004; HR= 1.013), and worse QOL score in the appetite domain (p= 0.0136; HR= 1.006). Patients who were entered into the chemotherapy trial (p= 0.0006; HR= 0.544), those who scored better in the physical functioning domain (p= 0.0102; HR= 0.993) and the global QOL domain (p= 0.0171; HR= 0.991), were associated with longer survival. Conclusion: Baseline QOL is a predictor of survival for patients with inoperable HCC. When used along with traditional clinical factors, patient-reported baseline QOL assessment using the EORTC QLQ-C30 provides additional prognostic information. Acknowledgements: We thank Asia Pacific Hepatocellular Carcinoma Trials Group for providing QOL data for 77 patients from our centre who were consented into the Randomized Trial of High Dose Tamoxifen versus Placebo for the Treatment of Inoperable Hepatocellular Carcinoma. No significant financial relationships to disclose.
Abstract 1574: Neuropilin 2 regulates lung disseminated tumor cell escape from dormancy and progression into metastasis
Authors: Paloma Bragado Domingo, Raul Alonso, Gemma Fuster, Mario Mancino, Patricia Fernandez-Nogueira, Julio Aguirre-Ghiso, Pere Gascon
Journal: Cancer Research (2016)

Abstract Despite considerable advances in the treatment of cancer, about 50% of patients will still eventually develop metastatic disease which remains the main cause of cancer-related death. Disseminated tumor cells (DTCs) are the precursors of metastasis and understanding their biology is one of the most important challenges for the future of cancer research. Our previous studies have shown that TGFβ2 through binding to TGFβR3 regulates DTCs quiescence through the activation of p38αMAPK and induction of the dormant genes DEC2 and p27. However, these DTCs dormancy may be reversed when micro-environmental conditions shift to support DTCs expansion. Nerve fibers and neural mediators are present in organs that serve as key targets for breast and head and neck cancer metastasis, including lungs and bone. In addition, neuropeptides and neurotransmitters receptors are expressed by both, nerve and cancer cells, which suggests that neurotrophic factors can act as messengers between the nervous system and DTCs and influence metastasis progression. Therefore, we hypothesized that in situations of chronic stress or inflammation, neural mediators might influence DTCs fate at secondary organs. Using bioinformatics tools we have found that the semaphorins receptor Neuropilin 2 (NRP2), a co-receptor for TGFβ ligands, is overexpressed in basal and HER2+ breast cancer patient samples and its expression in primary tumors correlate with worst prognosis. In basal breast cancer cell lines, NRP2 expression correlates with lower levels of DEC2 and p27 dormancy genes. Furthermore, we have found that NRP2 is downregulated in dormant cells and overexpressed in proliferative lung DTCs derived cell lines that express low levels of P-p38, DEC2 and p27 dormancy markers. Our results show that in lung DTCs derived cell lines, NRP2 inhibits TGFβR3 expression favoring TGFβ1 signaling and promoting DTCs growth. In agreement with this, breast cancer lung metastasis express higher levels of NRP2 than quiescence lung DTCs in vivo, suggesting that NRP2 might play a role in lung DTCs proliferation. Therefore, we conclude that NRP2 can regulate breast cancer lung DTCs progression from a dormant state to a proliferative state and promote metastasis formation. Citation Format: Paloma Bragado Domingo, Raul Alonso, Gemma Fuster, Mario Mancino, Patricia Fernandez-Nogueira, Julio Aguirre-Ghiso, Pere Gascon. Neuropilin 2 regulates lung disseminated tumor cell escape from dormancy and progression into 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 1574.
Phase II trial of carboplatin/paclitaxel and cetuximab, followed by carboplatin/paclitaxel/cetuximab and erlotinib, in metastatic or recurrent squamous cell carcinoma of the head and neck.
Authors: Aarti K. Bhatia, Ranee Mehra, Saad A. Khan, Brian L. Egleston, R. Katherine Alpaugh, Miriam Lango, John A. Ridge, Barbara Burtness
Journal: Journal of Clinical Oncology (2016)

6027 Background: Cetuximab (C) improves outcomes when added to chemotherapy in patients with squamous cell carcinoma of the head and neck (SCCHN). C resistance is associated with nuclear localization of the epidermal growth factor receptor (EGFR). We hypothesized that an EGFR tyrosine kinase inhibitor (TKI) would improve response to C through inhibition of nuclear translocation of EGFR and undertook a Phase II study of total EGFR blockade, adding Erlotinib (E) to chemotherapy and C in patients with recurrent/metastatic SCCHN. Methods: 24 patients were enrolled. Following baseline tumor assessment and biopsy, they were treated with carboplatin (AUC 2 weekly)/paclitaxel (80mg/m2 weekly) and C (400mg/m2 loading, then 250mg/m2weekly thereafter). After the first 21-day cycle, biopsy was repeated, then therapy resumed with the addition of E (150mg daily x 2 days followed by 100mg daily) then a repeat biopsy after cycle 2. Treatment continued until disease progression or unacceptable toxicity. Restaging was done prior to cycles 2 and 4 and every 9 weeks thereafter. Primary end point was objective response rate (ORR) by RECIST v 1.1 – complete (CR) and partial (PR) responses. Secondary end points: toxicity, overall survival (OS) and laboratory correlates. Results: Median age for the group was 65.5 years. Patients received a median of 6 (range 1-17) cycles. 12/24 (50%) had objective responses (12 PR, 0 CR). 1 patient had a pathological complete response and 2 were consolidated with definitive radiation with no recurrence at 9 and 41 months. 7/24 (29%) had stable disease. For intent to treat population, median progression-free survival (PFS) and OS were 5.8 and 8.1 months, while for per protocol population, median OS was 10.6 months. 5 patients are alive at the time of analysis. Dose modification for toxicity was required in 50% of patients. Main toxicities were cytopenia, diarrhea, neuropathy, hypomagnesemia and rash. Conclusions: Total EGFR blockade demonstrated excellent efficacy and tolerability in this small sample. ORR, PFS, OS are comparable to historical controls treated with the EXTREME regimen. Correlative analyses are ongoing. Clinical trial information: NCT01316757.
The Witches of<i>Macbeth</i>
Authors: Valencia Long, Leonard J. Hoenig
Journal: JAMA Dermatology (2016)

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Prevention of symptomatic skeletal events with denosumab administered every 4 weeks versus every 12 weeks: A noninferiority phase III trial (SAKK 96/12, REDUSE).
Authors: Arnoud J. Templeton, Lukas Stalder, Juerg Bernhard, Peter Brauchli, Silke Gillessen, Stefanie Hayoz, Dirk Klingbiel, Klazieu Matter-Walstra, Beat J. K. Thurlimann, Roger Von Moos
Journal: Journal of Clinical Oncology (2014)

TPS5095 Background: Denosumab, a monoclonal antibody against RANK-Ligand has been shown to be superior to zoledronic acid in delaying time to a first on-study skeletal-related event (SRE) in patients with solid tumors, with no effects on disease progression or survival (Stopeck et al. JCO 2010, Fizazi et al. Lancet 2011). Many SREs were silent compression fractures found only because of scheduled imaging. The approved dose of denosumab is 120mg sc every 4 weeks (q4w). Although generally well tolerated, there is a dose-dependent increase in osteonecrosis of the jaw in up to 8% of patients (Fizazi et al, ESMO 2012, 937P). Cases of fatal hypocalcaemia were observed during post marketing surveillance. In a study of 255 women with breast cancer and bone metastases randomized to 1 of 5 blinded denosumab cohorts (30mg q4w, 120 mg q4w, 180 mg q4w, 60mg q12w, 180mg q12w) or an open-label iv bisphosphonate, a similar degree of creatinine-corrected urinary N-telopeptide (uNTx/Cr) suppression at weeks 13 and 25 was observed in all cohorts (Lipton et al. CCR 2008). The optimal dose and schedule of denosumab is unknown. Denosumab is associated with considerable costs and adds toxicity; thus a study of de-escalation is warranted. Methods: The aim of the present trial is to test the hypothesis that the benefit of denosumab is maintained if administered 120mg q12w as compared to 120mg q4w. The primary endpoint of this open-label randomized phase III non-inferiority trial is time to first on-trial symptomatic skeletal events (SSE; clinically significant pathological fracture, radiation therapy to bone, surgery to bone or spinal cord compression). With a non-inferiority margin of 1.2 for the hazard ratio, power 80% and type I error 5%, the total sample size is 1380. Secondary endpoints include safety, time to subsequent on-trial SSE, quality of life, health economic outcomes, and change in bone turnover markers. Patients with breast or prostate cancer with bone metastases and adequate organ function are eligible. This trial is open for international collaboration. Clinical trial information: NCT02051218.
Abstract 4467: PRSS8 methylation and its significance in esophageal squamous cell carcinoma
Authors: Yonghua Bao, Qian Wang, Wancai Yang
Journal: Cancer Research (2016)

Abstract Esophageal cancer is one of the most common cancers worldwide, and the incidence and mortality is increasing rapidly in recent years in China, but the underlying mechanisms are largely unclear. Herein we used immunohistochemical staining on an esophageal squamous cell carcinoma (ESCC) tissue microarray (TMA) containing 362 cases of ESCC and found that the expression of PRSS8, serine protease prostasin, was significantly decreased in ESCC. Interestingly, the reduction of PRSS8 was well correlated with poor differentiation, less stromal lymphocyte infiltration, and shorter survival time. PRSS8 mRNA levels were also significantly reduced in ESCC compared to the adjacent normal esophagus assayed by quantitative real-time PCR. Methylation specific PCR showed that PRSS8 promoter region was hypermethylated in ESCC tissues and cell lines, which was associated with downregulation of PRSS8 expression and decreased activities of PRSS8 promoter. Promoter deletion and truncation approaches showed that the CpG island in PRSS8 promoter region played an important role on the determination of promoter activities. De-methylation agent decitabine was able to restrore PRSS8 expression in esophageal cancer cell lines, leading to the inhibition of cancer cell proliferation, motility, migration and cell cycle arrest. However, the restoration of PRSS8 and its tumor inhibition could be reversed by small interfering RNA targeting PRSS8. Immunoblotting results showed that tumor inhibition of PRSS8 may be associated with proliferation- and epithelial-mesenchymal transition - related proteins (e.g. upregulation of E-cadherin and downregulation of Twist and Snail) in ESCC cells. The findings from current study strongly suggested that PRSS8 acted as a tumor suppressor and PRSS8 promoter region hypermethylation has clinical significance of in ESCC. Citation Format: Yonghua Bao, Qian Wang, Wancai Yang. PRSS8 methylation and its significance in esophageal squamous cell carcinoma. [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 4467.