tbuckley/cabot-search huggingface dataset:
Single Centre Analysis Of Autologous Stem Cell Transplant Outcomes In Multiple Myeloma In 338 Consecutive Patients: Maintenance/Consolidation Is Associated With Superior Survival, But Early Relapse Is The Single Most Important Predictor Of Survival and May Override Genetic Risk
Authors: Paul M Maciocia, Nicholas Counsell, Antonia Bird, Laura Percy, Sally Moore, Neil Rabin, Shirley D'Sa, Manuel Rodriguez-Justo, Kwee L Yong
Journal: Blood (2013)
Variable discharge of older UK patients is “unacceptable,” say MPs
Authors: Gareth Iacobucci
Journal: BMJ (2016)

An influential committee of MPs has urged the UK government to take urgent action to tackle costly and damaging delays in discharging elderly patients from hospital. The House of Commons Committee of Public Accounts said that there was “unacceptable variation” in local performance on discharging patients aged 65 or over, which was bad for patients’ health and the financial sustainability of the NHS and local government.

In its report on the issue the committee advised the government to implement new measures that included improving on the currently poor level of sharing of patient information, which they considered a “significant barrier” to effective discharge.

“Patients and …
A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC).
Authors: Georgina V. Long, Victoria Atkinson, Alexander M. Menzies, Serigne Lo, Alexander David Guminski, Michael Paul Brown, Maria Magdalena Gonzalez, Katrina Diamante, Shahneen Kaur Sandhu, Richard A. Scolyer, Louise Emmett, Grant A. McArthur
Journal: Journal of Clinical Oncology (2017)

9508 Background: Nivolumab (nivo) and the combination of nivo + ipilimumab (ipi) improve response rates (RR) and progression-free survival (PFS) compared with ipi alone in clinical trials of metastatic melanoma pts, but pts with untreated brain mets were excluded. Brain mets are a major cause of morbidity and mortality in melanoma and their management is critical. We sought to determine the antitumour activity and safety of nivo and nivo+ipi in pts with active melanoma brain mets (NCT02374242). Methods: This open-label, ph II trial enrolled 3 cohorts of pts naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014 - Feb 2017. Pts with asymptomatic melanoma brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3W x4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets 1) that failed local therapy (new +/- progressed in previously treated met), 2) were neurologically symptomatic and/or 3) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥ wk12. Secondary endpoints were best extracranial response (ECR), best overall response (OR), IC PFS, EC PFS, overall PFS, OS, and safety. Results: A total of 66 pts (med f/u 14 mo) were included in this analysis of total 76 planned; median age 60y, 77% male. For cohorts A, B and C: elevated LDH 48%, 58% and 19%; V600BRAF 44%, 56% and 81%; prior BRAFi 24%, 24%, 75%. Table shows RR, PFS and OS. ICR in cohort A treatment naïve vs prior BRAFi was 53% vs 16%. Treatment-related gd 3/4 toxicity in cohorts A, B and C were 68%, 40% and 56%, respectively. There were no treatment-related deaths. Conclusions:Nivo monotherapy and ipi+nivo and are active in melanoma brain mets. Ipi+nivo had reduced activity in pts who progressed on BRAFi. Pts with symptomatic brain mets, leptomeningeal mets or previous local therapy responded poorly to nivo alone. Clinical trial information: NCT02374242. [Table: see text]
Enhancing cell infiltration of electrospun fibrous scaffolds in tissue regeneration
Authors: Jinglei Wu, Yi Hong
Journal: Bioactive Materials (2016)

Electrospinning is one of the most effective approaches to fabricate tissue-engineered scaffolds composed of nano-to sub-microscale fibers that simulate a native extracellular matrix. However, one major concern about electrospun scaffolds for tissue repair and regeneration is that their small pores defined by densely compacted fibers markedly hinder cell infiltration and tissue ingrowth. To address this problem, researchers have developed and investigated various methods of manipulating scaffold structures to increase pore size or loosen the scaffold. These methods involve the use of physical treatments, such as salt leaching, gas foaming and custom-made collectors, and combined techniques to obtain electrospun scaffolds with loose fibrous structures and large pores. This article provides a summary of these motivating electrospinning techniques to enhance cell infiltration of electrospun scaffolds, which may inspire new electrospinning techniques and their new biomedical applications.
Abstract 5012: Nuclear expression of lysyl oxidase enzyme is an independent prognostic factor in rectal cancer patients
Authors: Na Liu, Thomas R. Cox, Weiyingqi Cui, Gunnar Adell, Birgitta Holmlund, Janine T. Erler, Xiaofeng Sun
Journal: Cancer Research (2016)

Abstract Emerging evidence implies that the complex and seemingly paradoxical role of lysyl oxidase (LOX) in cancer may depend on its subcellular localization. LOX expression has been reported extracellularly, as well as intracellularly in both the cytoplasmic and nuclear compartments. In this study we analyze previously unreported LOX expression patterns in the nucleus of rectal cancer patient samples and determine the clinical significance of this expression. LOX expression was examined by immunohistochemistry in 137 primary rectal cancer patients who participated in the randomized Swedish rectal cancer trial of preoperative radiotherapy between 1987 and 1990. Location and expression of LOX protein were detected by confocal microscopy and Western blot in three colon cancer cell lines. LOX nuclear expression was high in normal mucosal and showed a significant decrease in primary rectal cancer (P&amp;lt;0.001). Furthermore, a significant increase was observed from primary cancer to lymph node metastasis (P&amp;lt;0.01). High nuclear LOX expression was correlated with a high rate of distant metastasis and total recurrence (P = 0.046, P = 0.048, respectively). It was also confirmed that LOX (50-kDa and 32-kDa isoforms) are located in the nucleus of in vitro colon cancer cells. High nuclear LOX expression was found in the metastatic cell line SW620 compared to the parental primary cancer cell line SW480. Radiotherapy had no effect on LOX expression and localization in cancer tissues as well as in in vitro culture. Moreover, multivariable analysis showed that high nuclear LOX expression correlated with poor overall survival (P = 0.003) and disease free survival (P = 0.006), independent of age, gender, TNM stage, differentiation and radiotherapy treatment. Nuclear LOX also correlated with other biological factors (such as NF-κB) known to be associated with patient survival suggesting a possible mechanism. Cytoplasmic LOX is high in primary cancer and metastasis compared with normal tissue, but not prognostic. So here we firstly proved the nuclear expression of LOX enzyme both in patient rectal cancer tissues and in in vitro colon cancer cells. The strong correlation of nuclear LOX expression to survival offers a promising prognostic biomarker in rectal cancer. Citation Format: Na Liu, Thomas R. Cox, Weiyingqi Cui, Gunnar Adell, Birgitta Holmlund, Janine T. Erler, Xiaofeng Sun. Nuclear expression of lysyl oxidase enzyme is an independent prognostic factor in rectal cancer patients. [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 5012.
Abstract 3872: Quantification of mutant SPOP proteins in prostate cancer using targeted proteomics
Authors: Hui Wang, Christopher Barbieri, Jintang He, Yuqian Gao, Chaochao Wu, Athena Schepmoes, Thomas Fillmore, Tujin Shi, Sung-Suk Chae, Dennis Huang, Juan Miguel Mosquera, Wei-Jun Qian, Richard Smith, Sudhir Srivastava, Jacob Kagan, David Camp, Karin Rodland, Mark Rubin, Tao Liu
Journal: Cancer Research (2016)

Abstract Speckle-type POZ protein (SPOP) is an E3 ubiquitin ligase adaptor protein that functions as a potential tumor suppressor, and SPOP mutations have been identified in ∼10% of human prostate cancers. However, it remains unclear if mutant SPOP proteins can be utilized as biomarkers for diagnosis, prognosis or targeted therapy of prostate cancer. To address this issue, selected reaction monitoring (SRM) and PRISM (high-pressure, high-resolution separations coupled with intelligent selection and multiplexing) -SRM mass spectrometry assays have been developed for quantifying mutant SPOP proteins. SRM assays for wild-type SPOP protein and 11 prostate cancer-derived mutations were developed. The presence of multiple lysine residues in the mutation regions precludes the use of conventional tryptic digestion. Arg-C was selected instead due to its superior performance in generating mutation site(s) containing SPOP peptides that are more suitable for SRM analysis comparing to other proteases (e.g., Asp-N). Although the resulting Arg-C peptides are longer and more hydrophobic than typical tryptic peptides, all the SRM assays showed a linear dynamic range of more than two orders of magnitude. The limits of quantification for the mutation site(s) containing peptides range from 10 to 100 fmol/μg of total protein in the cell lysate. Applying these SRM assays to analyze 293T cells with and without expression of the three most frequent SPOP mutations in prostate cancer (Y87N, F102C or F133V) led to confident detection of all three SPOP mutations in corresponding positive cell lines but not in the negative cell lines. Expression of the F133V mutation and wild-type SPOP was at much lower levels compared to that of F102C and Y87N mutations, which agrees with RT-PCR results. It is unknown if this is related to activity of the SPOP protein. PRISM-SRM assays have shown further improvement in sensitivity. SRM enables multiplexed, isoform-specific detection of mutant SPOP proteins in cell lysates, which holds great potential in biomarker development for prostate cancer. Citation Format: Hui Wang, Christopher Barbieri, Jintang He, Yuqian Gao, Chaochao Wu, Athena Schepmoes, Thomas Fillmore, Tujin Shi, Sung-Suk Chae, Dennis Huang, Juan Miguel Mosquera, Wei-Jun Qian, Richard Smith, Sudhir Srivastava, Jacob Kagan, David Camp, Karin Rodland, Mark Rubin, Tao Liu. Quantification of mutant SPOP proteins in prostate cancer using targeted proteomics. [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 3872.
Abstract 3237: Assessment and targeting of M2-tumor associated macrophages (M2-TAMs) in prostate cancer
Authors: Jelani C. Zarif, James R. Henandez, Kenneth J. Pienta
Journal: Cancer Research (2016)

Abstract Prostate cancer is a leading cause of cancer-related deaths of men in the U.S., and in the past year, over 30,000 men died from this disease. While localized prostate cancer is highly treatable by surgical resection and radiation, cancer that has metastasized remains incurable. Alternatively activated macrophages, also known as M2-macrophages, primarily scavenge debris and in the process, promote angiogenesis and wound repair. M2-macrophages are phenotypically similar to M2 tumor-associated macrophages (M2-TAMs) have been reported to associate with solid tumors such as prostate cancer to facilitate epithelial to mesenchymal transition (EMT), tumor invasiveness, metastasis, and resistance to therapy. As an invasive species within the tumor microenvironment, this makes M2-TAMs an ideal therapeutic target in prostate cancer. The purpose of this project is to develop novel therapeutics that will directly target M2-TAMs for destruction and subsequently attenuate prostate tumor growth, progression and metastasis. The central hypothesis of this study is to determine if targeting of M2-TAMs using specific surface antigens will be an effective therapy for lethal prostate cancer and potentially, other cancers. Our study elucidated M2-Macrophage biology including creating homogenous populations of both M1 and M2 macrophages using a new strategy as to allow for identification of novel surface antigen markers. While using our new method for polarization of human monocyte polarization into macrophages, we found that M2 macrophages polarization was stymied in vitro after glutamine deprivation. We then assessed novel markers of macrophage populations, cytokine and chemokine production, T-Cell inactivation and we also assessed whether these surface antigens that are expressed on M2-macrophages are were found in metastatic human prostate cancers indicative of myeloid infiltration. Validation studies using metastatic prostate cancer tissues from rapid autopsies and surgical specimens supplied by the Department of Urology at Johns Hopkins University School of Medicine were also be performed. Complementary studies will be executed to target these markers for anti-tumor cell efficacy using these relevant model systems. By identifying and targeting specific markers on M2-TAMs, we predict that this targeting will provide a better prognosis for patients who have been diagnosed with lethal prostate cancer. Citation Format: Jelani C. Zarif, James R. Henandez, Kenneth J. Pienta. Assessment and targeting of M2-tumor associated macrophages (M2-TAMs) in prostate 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 3237.
Abstract 1518: Lung adenocarcinoma differential expression analysis using the Maverix RNA-Seq pipeline
Authors: Michael S. Fitzsimons, Mei-Chong Wendy Lee, Byung-In Lee, Lenin Subramanian
Journal: Cancer Research (2016)

Abstract Background RNA-Seq is a powerful means of identifying changes in gene expression in cancerous tissue. Widespread adoption of RNA-Seq is hampered by lack of familiarity with the appropriate analysis tools and excessive turn around time. Maverix Biomics, Inc offers a scalable, reliable, validated, and easily accessible differential expression pipeline for translational and clinical researchers to analyze and explore RNA-Seq data. Here we describe the pipeline, demonstrate the available tools and visualizations, and provide benchmarks for completion time from lung adenocarcinoma. Results Lung adenocarcinoma samples appear very different compared to their normal counterparts in terms of overall gene expression and exhibit many differentially expressed genes. For analysis completion time, parallelization is far superior than the theoretical curve without parallelization. It took 7.9 hours to analyze two samples, but took only 13.1 hours to analyze 25 samples. We found 2246 significant genes common to three different differential expression tools: DESeq, edgeR, and cuffdiff. Conclusions The Maverix RNA-Seq pipeline is demonstrated here to be highly scalable, easy to use, and includes a range of tools and visualizations for understanding differential expressions results. This pipeline is a great analytic option to accelerate translational and clinical research in the field of oncology. Citation Format: Michael S. Fitzsimons, Mei-Chong Wendy Lee, Byung-In Lee, Lenin Subramanian. Lung adenocarcinoma differential expression analysis using the Maverix RNA-Seq pipeline. [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 1518.
Relationship between arterial impedance and concentric remodeling in patients with normal systolic function: Impact on prevalence and survival
Authors: Carl J. Lavie, Elise L. Milani, Hector O. Ventura
Journal: Circulation (2011)

Background: Cardiac remodeling, including concentric remodeling (CR), develops in response to abnormal hemodynamics. Although CR is associated with increased morbidity and mortality, little is know...
Abstract 13702: Serum Albumin Predicts Mortality in Patients With Pulmonary Arterial Hypertension
Authors: Jacob C Jentzer, Jacqueline Morris, Chelcie Costabile, Zeina Dardari, Omar Batal, Michael Mathier
Journal: Circulation (2015)

Introduction: Low serum albumin predicts adverse outcomes in heart failure, reflecting poor nutritional status, liver dysfunction and systemic inflammation. The predictive value of albumin for mortality is not well-described in pulmonary arterial hypertension (PAH). Hypothesis: Low serum albumin will significantly predict increased mortality in patients with PAH. Methods: We constructed a database of 273 WHO group 1 PAH patients followed at our center from 03/2001 through 08/2008, including echocardiography, invasive hemodynamics, laboratory data and mortality outcomes. Serum albumin levels were available in 163 patients. The association between albumin and mortality was assessed using Cox regression and Kaplan-Meier analysis. Results: Patients were followed for a mean of 3.6 ± 2.6 years. On univariate analysis, serum albumin significantly predicted mortality with HR = 0.746 (p = 0.01, 95% CI 0.598-0.932) per 1 g/dl increase. On multivariate analysis, serum albumin significantly predicted mortality with HR = 0.491 (p = 0.009, 95% CI 0.288-0.835) per 1 g/dl increase when adjusted for age, gender, NYHA functional class, mean right atrial pressure, Fick cardiac output, connective tissue disease, right ventricular function, right atrial systolic area and serum creatinine. Patients with serum albumin below the 25th percentile (&lt;=3.3 g/dl) had significantly higher mortality by Kaplan-Meier curve analysis (p = 0.01 by log-rank test) despite similar clinical characteristics, when compared with patients with higher serum albumin. Conclusion: Higher serum albumin is an independent predictor of decreased mortality in PAH patients when adjusted for clinical, echocardiographic and hemodynamic variables. Patients with low serum albumin values had significantly higher mortality despite similar characteristics.
Association of somatic <i>ERCC2</i> mutations with cisplatin sensitivity in muscle-invasive urothelial carcinoma.
Authors: Jonathan E. Rosenberg, Eliezer Mendel Van Allen, Kent William Mouw, Philip H. Kim, Nikhil Wagle, Hikmat Al-Ahmadie, Cong Zhu, Irina Ostrovnaya, Gopa Iyer, Sabina Signoretti, Victor E. Reuter, Gad Getz, Philip W. Kantoff, Bernard H. Bochner, Toni K. Choueiri, Dean F. Bajorin, David B. Solit, Stacey B. Gabriel, Alan D. D'Andrea, Levi A. Garraway
Journal: Journal of Clinical Oncology (2014)

4510 Background: Cisplatin-based combination chemotherapy is the standard of care for patients with muscle invasive urothelial carcinoma. Pathologic downstaging to pT0/pTis after neoadjuvant cisplatin-based chemotherapy is associated with improved survival, although the molecular determinants of cisplatin sensitivity are incompletely understood. Recent reports have identified somatic mutations in ERCC2, a nucleotide excision repair gene, in 7-12% of bladder cancers. Preclinical evidence suggests that defects in the nucleotide excision repair (NER) pathway mediate cisplatin sensitivity. Methods: We performed whole exome sequencing of pre-treatment tumor and germline DNA from 51 patients with muscle invasive urothelial carcinoma who received neoadjuvant cisplatin-based chemotherapy followed by cystectomy (26 pT0/pTis “responders”, 25 pT2+ “non-responders”). Computational methods were employed to identify somatic mutations that occurred preferentially in cisplatin responders. Functional validation of significantly enriched mutations was performed using cellular cisplatin and UV sensitivity assays. Results: Somatic ERCC2 mutations were observed in 38.5% of responders and 0% of non-responders (q < 0.01). ERCC2 was the only gene enriched in the cisplatin responders compared with non-responders. ERCC2 mutations clustered within or near conserved helicase domains required for ERCC2 function. Expression of the identified ERCC2 mutants in an ERCC2-deficient cell line failed to rescue cisplatin and UV sensitivity compared to wild-type ERCC2. Conclusions: Somatic ERCC2 mutation is associated with cisplatin sensitivity in muscle invasive urothelial carcinoma. These results may inform the use of cisplatin-containing regimens in muscle invasive urothelial carcinoma, and potentially other ERCC2-mutated tumors.
Abstract 1938: The identification of p53 target genes and noncoding RNAs through the combined analysis of RNA-seq and ChIP-seq data
Authors: Masashi Idogawa, Tomoko Ohashi, Yasushi Sasaki, Takashi Tokino
Journal: Cancer Research (2016)

Abstract p53 is inactivated in approximately half of human cancers. p53 execute various functions by modulating transcriptional regulation. To identify direct p53 transcriptional targets including non-coding RNAs, we performed gene expression analysis with next-generation sequencing (RNA-seq) in osteosarcoma U2OS cells treated with Nutlin-3a which activates endogenous p53. We identified 261 genes increased more than 4-fold and 373 long non-coding RNAs (lncRNAs) increased more than 2-fold. Next, we analyzed the data of chromatin immunoprecipitation with next-generation sequencing (ChIP-seq) and then searched for p53 binding sites in the whole human genome. p53 binding sites were located in the neighborhood of 126/261 (48.3%) genes including 28 known target genes and 122/373 (32.7%) lncRNAs including 7 lncRNAs we already identified in previous study. Recent reports have revealed that lncRNAs play an important role in various biological and pathological processes such as development, differentiation, stemness and carcinogenesis. Although all functions of lncRNAs have not been elucidated, many lncRNAs are involved in transcriptional regulation like transcriptional factors. Therefore, we performed a gene network analysis of cancer transcriptome including lncRNAs using public RNA-seq data of cancer tissues. As a result, we identified several hub lncRNAs which regulate the transcription of many downstream genes. Our results suggest that p53 and lncRNAs comprise a complex transcriptional network for various biological functions and tumor suppression. Citation Format: Masashi Idogawa, Tomoko Ohashi, Yasushi Sasaki, Takashi Tokino. The identification of p53 target genes and noncoding RNAs through the combined analysis of RNA-seq and ChIP-seq data. [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 1938.