tbuckley/cabot-search huggingface dataset:
Identifying priority areas for research into the diagnosis, treatment and prevention of cellulitis (erysipelas): results of a James Lind Alliance Priority Setting Partnership
Authors: K.S. Thomas, R. Brindle, J.R. Chalmers, B. Gamble, N.A. Francis, D. Hardy, J. Hooper, V. Keeley, N.J. Levell, M. McPhee, L. Metcalf, M. Santer, M. Tarpey, P. Smart, A. Wallace, S. Wilkes
Journal: British Journal of Dermatology (2017)

Priority setting partnerships give patients and heath care professionals an equal voice in driving priorities for future research. This ensures that research answers the most important questions that are needed to inform clinical practice1.

Cellulitis (also known as erysipelas) is an acute infection of the skin and underlying tissue that often recurs.
Treatment of refractory metastatic renal cell carcinoma (RCC) with lenvatinib (E7080) and everolimus.
Authors: Ana M. Molina, Robert John Motzer, Thomas E. Hutson, James M. G. Larkin, Anne Gold, Corina Andresen, Karen Wood, M. Dror Michaelson
Journal: Journal of Clinical Oncology (2012)

TPS4682 Background: Lenvatinib (E7080) is an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor 1-4, RET, KIT and platelet-derived growth factor receptor beta. Lenvatinib has demonstrated acceptable toxicity and antitumor activity in Phase I and II studies (Glen H et al. JCO 2008, 26;15S: 3526;Yamada K et. al. Clin Cancer Res 2011, 17:2528-2537; Sherman S I et al. JCO 2011, 29; 15S: 5503). Improved understanding of the molecular basis of renal cell carcinoma (RCC) has led to the development of targeted therapies (inhibitors of mTOR and of the VEGF pathway) that have shown clinical benefit in patients with metastatic RCC. However patients develop resistance and ultimately progress during treatment with available single agents. Combination therapy targeting different pathways have the potential to improve efficacy. Methods: This multicenter, randomized, open-label, phase Ib/II study is investigating everolimus (an oral mTOR inhibitor) in combination with lenvatinib in RCC patients with unresectable or metastatic disease (NCT01136733). The study is being conducted in two phases. The phase Ib dose-escalation component will determine the maximum tolerated dose (MTD) of the combination; starting doses are 12 mg/day lenvatinib and 5 mg/day everolimus. A cohort expansion will follow to confirm the MTD and establish a recommended phase II dose (RP2 dose). Approximately 150 patients will be enrolled in phase II and randomized 1:1:1 to receive: lenvatinib and everolimus at the RP2 dose (Arm A); lenvatinib 24 mg/day (Arm B); or everolimus 10 mg/day (Arm C). Patients with clear cell RCC, ECOG performance score &lt;2 and progression during or after one prior VEGF-targeted treatment are eligible for phase II. The primary endpoint for Phase II is to compare progression-free survival of the investigational arms (A and B) with single agent everolimus (Arm C). Three phase Ib dose escalation cohorts have completed enrollment, and enrollment of the expansion cohort commenced in November 2011. Participating phase II centers will be located in the US, UK, Spain, Poland and Czech Republic and are expected to enroll patients throughout 2012.
Significance of the Glasgow Prognostic Score for patients with colorectal liver metastasis
Authors: Sho Okimoto, Tsuyoshi Kobayashi, Hirotaka Tashiro, Shintaro Kuroda, Kohei Ishiyama, Kentaro Ide, Tomoyuki Abe, Masakazu Hashimoto, Hiroshi Iwako, Michinori Hamaoka, Naruhiko Honmyo, Megumi Yamaguchi, Hideki Ohdan
Journal: International Journal of Surgery (2017)
Holocarboxylase Synthetase: A Moonlighting Transcriptional Coregulator of Gene Expression and a Cytosolic Regulator of Biotin Utilization
Authors: Alfonso León-Del-Río, Viviana Valadez-Graham, Roy A. Gravel
Journal: Annual Review of Nutrition (2017)

The vitamin biotin is an essential nutrient for the metabolism and survival of all organisms owing to its function as a cofactor of enzymes collectively known as biotin-dependent carboxylases. These enzymes use covalently attached biotin as a vector to transfer a carboxyl group between donor and acceptor molecules during carboxylation reactions. In human cells, biotin-dependent carboxylases catalyze key reactions in gluconeogenesis, fatty acid synthesis, and amino acid catabolism. Biotin is attached to apocarboxylases by a biotin ligase: holocarboxylase synthetase (HCS) in mammalian cells and BirA in microbes. Despite their evolutionary distance, these proteins share structural and sequence similarities, underscoring their importance across all life forms. However, beyond its role in metabolism, HCS participates in the regulation of biotin utilization and acts as a nuclear transcriptional coregulator of gene expression. In this review, we discuss the function of HCS and biotin in metabolism and human disease, a putative role for the enzyme in histone biotinylation, and its participation as a nuclear factor in chromatin dynamics. We suggest that HCS be classified as a moonlighting protein, with two biotin-dependent cytosolic metabolic roles and a distinct biotin-independent nuclear coregulatory function.
Regression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice
Authors: Gui-Wei He, Claudia Günther, Veronika Thonn, Yu-Qiang Yu, Eva Martini, Barbara Buchen, Markus F. Neurath, Michael Stürzl, Christoph Becker
Journal: The Journal of Experimental Medicine (2017)

Cancer cells often acquire capabilities to evade cell death induced by current chemotherapeutic treatment approaches. Caspase-8, a central initiator of death receptor–mediated apoptosis, for example, is frequently inactivated in human cancers via multiple mechanisms such as mutation. Here, we show an approach to overcome cell death resistance in caspase-8–deficient colorectal cancer (CRC) by induction of necroptosis. In both a hereditary and a xenograft mouse model of caspase-8–deficient CRC, second mitochondria-derived activator of caspase (SMAC) mimetic treatment induced massive cell death and led to regression of tumors. We further demonstrate that receptor-interacting protein kinase 3 (RIP3), which is highly expressed in mouse models of CRC and in a subset of human CRC cell lines, is the deciding factor of cancer cell susceptibility to SMAC mimetic–induced necroptosis. Thus, our data implicate that it may be worthwhile to selectively evaluate the efficacy of SMAC mimetic treatment in CRC patients with caspase-8 deficiency in clinical trials for the development of more effective personalized therapy.
Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women's Cancers: A Dose-Escalation, Phase I Study
Authors: Jung-Min Lee, Ashley Cimino-Mathews, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Maria I. Harrell, Elizabeth M. Swisher, Nicole Houston, Dana-Adriana Botesteanu, Janis M. Taube, Elizabeth Thompson, Aleksandra Ogurtsova, Haiying Xu, Jeffers Nguyen, Tony W. Ho, William D. Figg, Elise C. Kohn
Journal: Journal of Clinical Oncology (2017)

Purpose Data suggest that DNA damage by poly (ADP-ribose) polymerase inhibition and/or reduced vascular endothelial growth factor signaling by vascular endothelial growth factor receptor inhibition may complement antitumor activity of immune checkpoint blockade. We hypothesize the programmed death-ligand 1 (PD-L1) inhibitor, durvalumab, olaparib, or cediranib combinations are tolerable and active in recurrent women's cancers. Patients and Methods This phase I study tested durvalumab doublets in parallel 3 + 3 dose escalations. Durvalumab was administered at 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks with either olaparib tablets twice daily or cediranib on two schedules. The primary end point was the recommended phase II dose (RP2D). Response rate and pharmacokinetic analysis were secondary end points. Results Between June 2015 and May 2016, 26 women were enrolled. The RP2D was durvalumab 1,500 mg every 4 weeks with olaparib 300 mg twice a day, or cediranib 20 mg, 5 days on/2 days off. No dose-limiting toxicity was recorded with durvalumab plus olaparib. The cediranib intermittent schedule (n = 6) was examined because of recurrent grade 2 and non-dose-limiting toxicity grade 3 and 4 adverse events (AEs) on the daily schedule (n = 8). Treatment-emergent AEs included hypertension (two of eight), diarrhea (two of eight), pulmonary embolism (two of eight), pulmonary hypertension (one of eight), and lymphopenia (one of eight). Durvalumab plus intermittent cediranib grade 3 and 4 AEs were hypertension (one of six) and fatigue (one of six). Exposure to durvalumab increased cediranib area under the curve and maximum plasma concentration on the daily, but not intermittent, schedules. Two partial responses (≥15 months and ≥ 11 months) and eight stable diseases ≥ 4 months (median, 8 months [4 to 14.5 months]) were seen in patients who received durvalumab plus olaparib, yielding an 83% disease control rate. Six partial responses (≥ 5 to ≥ 8 months) and three stable diseases ≥ 4 months (4 to ≥ 8 months) were seen in 12 evaluable patients who received durvalumab plus cediranib, for a 50% response rate and a 75% disease control rate. Response to therapy was independent of PD-L1 expression. Conclusion To our knowledge, this is the first reported anti-PD-L1 plus olaparib or cediranib combination therapy. The RP2Ds of durvalumab plus olaparib and durvalumab plus intermittent cediranib are tolerable and active. Phase II studies with biomarker evaluation are ongoing.
Prognostic Implications of Multiple Cytogenetic High-Risk Abnormalities in Patients with Newly Diagnosed Multiple Myeloma
Authors: Moritz Binder, S. Vincent Rajkumar, Rhett P. Ketterling, Angela Dispenzieri, Martha Q. Lacy, Morie A. Gertz, Francis K Buadi, Suzanne R. Hayman, Yi L. Hwa, Steven R. Zeldenrust, John A Lust, Stephen J. Russell, Nelson Leung, Prashant Kapoor, Ronald S. Go, Wilson I Gonsalves, Robert A. Kyle, Shaji Kumar
Journal: Blood (2016)
Aortic Valve Bioprostheses
Authors: David R. Holmes, Michael J. Mack
Journal: Circulation (2017)

Leaflet immobility and valve thrombosis have been reported with both transcatheter and surgical aortic valve bioprostheses. The relationships between these abnormalities and their incidence, time course, clinical significance, predisposing factors, optimal imaging modality, and current therapeutic options remain uncertain but are rapidly evolving. Four-dimensional computerized tomographic imaging has been determined to have the highest sensitivity in studies evaluating leaflet immobility and valve thrombosis. Echocardiography is also used during surveillance, but it appears to be less sensitive. The definitive diagnosis of valve thrombosis is based on a combination of diagnostic 4-dimensional computerized tomographic imaging findings, resolution of imaging abnormalities, and elevated transcatheter gradients with anticoagulation or surgical or pathological confirmation. Uncertainty about the incidence and clinical significance of the findings is the basis of 2 US Food and Drug Administration–approved studies comparing transcatheter and surgical aortic valve replacement with a subset undergoing surveillance 4-dimensional computerized tomographic imaging. Given the expansion of transcatheter aortic valve procedures, including potentially lower-risk patients, the resolution of these uncertainties is critical.
Patient-Reported Outcomes and Patient-Performed Testing in Measuring Functional Impairment after Stem Cell Transplant in Patients with Multiple Myeloma
Authors: Nina Shah, Sergio A. Giralt, Qiuling Shi, Loretta A. Williams, Qaiser Bashir, Muzaffar Qazilbash, Richard E. Champlin, Charles S. Cleeland, Xin Shelley Wang
Journal: Blood (2016)
03.19 Mast cells are reprogrammed through repeated triggering
Authors: Tobias Messemaker, Jolien Suurmond, Kim L Habets, Marieke Heijink, Joris J Schonkeren, Annemarie Dorjee, Martin Giera, Tom W Huizinga, Rene E Toes, Fina Kurreeman
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Traditionally, immunological responses have been studied <i>in-vitro</i> whereby immune cells are subject to certain stimuli following which alterations in RNA and/or protein expression are measured. Recently, we have challenged this model by showing that mast cells (cells specialised in allergic reactions) triggered repeatedly through their Ig Fc epsilon receptor undergo a reprogramming of their responses (<i>Suurmond et al. JACI, 2016</i>). The differential expression of genes upon a single trigger were dampened and <i>de-novo</i> transcribed genes were observed. The latter belonged to the antigen presentation and pathogen defence response pathways implying a dramatic change in the cellular response mode. We have now extended this work by challenging mast cells with plate-bound IgG in a repeated mode, a model relevant for arthritic diseases where mast cells and IgG immune complexes are likely to interact. <h3>Materials and methods</h3> Human cord blood-derived mast cells were treated for 2 weeks with plate-bound IgG. The expression profile of naive or treated mast cells was measured through RNA sequencing, quantitative RT-PCR, flow cytometry. Protein secretion was measured with ELISA and Luminex assays. Metabolic changes were measured using HPLC mass-spectrometry. <h3>Results</h3> Similar to our previous work on Fc Epsilon receptor, we observe a dampening of the normal IgG responses with a set of novel genes upregulated. Interestingly, <i>de-novo</i> expressed genes consisted of <i>DHCR7</i> and <i>DHCR24</i>, key enzymes in the cholesterol pathway. Pathway analysis confirms an enrichment of genes in this pathway following repeated IgG triggering. Preliminary data on metabolic profiling reveals a decrease in phospholipid levels in repeatedly activated mast cells. <h3>Conclusions</h3> Our study provides evidence that mast cells are also reprogrammed upon repeated IgG triggering. In contrast to repeated Fc Epsilon Receptor triggering, different pathways are affected, implying stimulus-specific effects. Our work has important implications for revisiting the traditional immunological models in the (<i>in-vitro</i>) modelling of chronic (arthritic) diseases.
Cross-reactivity in fish allergy: A double-blind, placebo-controlled food-challenge trial
Authors: Martin Sørensen, Annette Kuehn, E.N. Clare Mills, Carol Ann Costello, Markus Ollert, Lars Småbrekke, Raul Primicerio, Magnus Wickman, Claus Klingenberg
Journal: Journal of Allergy and Clinical Immunology (2017)
Comprehensive analysis of genetic polymorphisms and irinotecan-induced adverse events in Japanese gastrointestinal cancer patients: A DMET microarray profiling study.
Authors: Hidekazu Kuramochi, Hitoshi Kanno, Tomotaka Uchiyama, Go Nakajima, Kayoko Saito, Kazuhiko Hayashi
Journal: Journal of Clinical Oncology (2012)

e21108 Background: Irinotecan is a key drug in the treatment of colorectal and gastric cancer, that may occasionally cause severe adverse events (AEs), especially neutropenia and diarrhea. Although UDP-glucuronosyltransferase (UGT)1A1 polymorphisms are used as biomarkers for predicting AEs, the effect of UGT1A1 polymorphism in clinical use is limited, suggesting that there is a possibility of the existence of other, unknown biomarkers. Methods: Fourteen gastrointestinal cancer (5 gastric, 9 colorectal) patients who had undergone irinotecan-based chemotherapy were enrolled. DNA extracted from peripheral blood cells was genotyped by the DMET Plus microarray system, and 1,931 gene polymorphisms were investigated. The relationship between AEs and polymorphisms was analyzed statistically. Results: Eleven polymorphisms showed the P value &lt; 0.05 with grade 3,4 neutropenia, but no statistically significant polymorphisms were found after the correction of multiple comparisons. With respect to the association with diarrhea, 12 polymorphisms showed P &lt;0.05, and even after the correction of multiple comparisons, CYP2F1_96G&gt;A(P32P) showed a significant relationship (P&lt;0.00001). With respect to the relationship between UGT1A1*6, *28 polymorphisms and AEs, *6 polymorphism showed significant (P=0.044) association with grade 4 neutropenia. Conclusions: CYP2F1_96G&gt;A showed significant association with diarrhea. The association of UGT1A1*6 polymorphism and neutropenia was confirmed, as in previous reports.
Most recent cancer drugs offer few benefits, India’s top cancer hospital says
Authors: Sumi S Dutta
Journal: BMJ (2017)

India’s top cancer hospital, the Tata Memorial Centre (TMC) in Mumbai, has said that the country should not spend public health resources on most of the 49 oncology drugs released worldwide over the past five years, several of which are currently available in India.

In a statement released on 16 April, the TMC said that most of the drugs were “extremely expensive” and gave only “minor or questionable” benefits. India should instead invest in improving surgery, basic chemotherapy, radiotherapy, diagnostic pathology, and palliative care, it said.

TMC director Rajendra Badwe, deputy director Sudeep Gupta, and senior surgical oncologist C S Pramesh signed the statement that pointed out that the UK’s …
Lenalidomide Inhibits Thioredoxin Reductase (TrxR) in Multiple Myeloma (MM) Cells but Direct Inhibition of Trxr and Thioredoxin (Trx) Can Bypass Requirement of Cereblon (CRBN)
Authors: Sinto Sebastian Chirackal, Esteban Braggio, Yuan Xiao Zhu, Chang-Xin Shi, Scott Van Wier, Gregory Ahmann, Veronica Gonzalez-Calle, Marta Chesi, Leif Bergsagel, Keith Stewart, Rafael Fonseca
Journal: Blood (2016)
Role of p38γ - NFATc4 - IL17A Pathway As a Potential Therapeutic Target in Cutaneous T Cell Lymphoma
Authors: Xu Hannah Zhang, Vu N. Ngo, Natalie Sandoval, Qi Cui, Yanhong Shi, Jasmine M. Zain, Christiane Querfeld, Chao Guo, Xiwei Wu, Steven T. Rosen
Journal: Blood (2016)
CCL2 polymorphism as a predictive marker for bevacizumab (Bev) in combination with FOLFIRI as first-line treatment in metastatic colorectal cancer (mCRC) patients (pts).
Authors: Saadat Siamak, Yu Sunakawa, Fotios Loupakis, Dongyun Yang, Wu Zhang, Yan Ning, Sebastian Stintzing, Stefan Stremitzer, Ana Sebio, Shinichi Yamauchi, Satoshi Matsusaka, Rita Elie El-Khoueiry, Carlotta Antoniotti, Daniele Rossini, Chiara Cremolini, Alfredo Falcone, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2014)

e14556 Background: CCL2 is a chemokine which plays a central role in immunosurveillance in the tumor microenvironment. The CCL2 also controls the recruitment of leukocytes to tissues during inflammation and has a number of tumor-promoting activities. Importantly, the CCL2 promotes the polarization into M2 macrophages which play immunosuppressive roles and secrete angiogenic factors such as vascular endothelial growth factor (VEGF). We hypothesized that single nucleotide polymorphism (SNP) in CCL2 may predict clinical outcome in metastatic colorectal cancer (mCRC) patients (pts) treated with anti-VEGF drug in combination with chemotherapy. Methods: Genomic DNA was extracted from blood of 424 mCRC pts treated with FOLFIRI plus bevacizumab (Bev) as first-line treatment and prospectively enrolled in a prospective pharmacogenomics translational study in Italy. Median follow-up time was 2.8 (range: 0.7-6.0) years, median progression-free survival (PFS) and overall survival (OS) were 10.4 (range: 9.8-10.9) and 27.3 (range: 24.3-30.9) months, respectively. A functionally significant SNP, CCL2 rs4586, was analyzed by polymerase chain reaction (PCR)-based direct sequencing. The SNP was analyzed for association with response rate (RR), PFS, and OS by uni- and multivariate analyses. Results: The median age was 62 (range: 25-81) years, 59% of pts were males. After analyzing all patients, CCL2 rs4586 was not significantly associated with RR, PFS, and OS. However, when stratified by gender, our univariate analysis showed that males, but not females, with any C (T/C or C/C) allele had significant longer PFS than those with T/T genotype (10.7 vs 9.8 months; HR:0.71; 95% CI:0.53-0.94; p=0.01, log-rank test); this remained significant upon multivariate analysis (HR:0.73; 95% CI:0.54-0.99; p=0.04, log-rank test). On the other hand, females with C/C genotype had shorter PFS but not significantly compared to those with T/T genotype (HR:1.78; 95% CI:0.99-3.21). Conclusions: Our results showed that the CCL2 polymorphism, rs4586, may serve as a predictive marker in mCRC pts treated with Bev in combination with FOLFIRI. Interestingly, there may be a gender-related difference in the impact on clinical outcome by CCL2 polymorphism. Prospective validation of this study is warranted.
Abstract 124: Function of the Cytoskeletal Proteins Alpha-catenins in Myocardial Growth Control
Authors: Jifen Li, Sarah Carrante, Roslyn Yi, Frans van Roy, Glenn L. Radice
Journal: Circulation Research (2013)

Introduction: Mammalian heart possesses regenerative potential immediately after birth and lost by one week of age. The mechanisms that govern neonatal cardiomyocyte proliferation and regenerative capacity are poorly understood. Recent reports indicate that Yap-Tead transcriptional complex is necessary and sufficient for cardiomyocyte proliferation. During postnatal development, N-cadherin/catenin adhesion complex becomes concentrated at termini of cardiomyocytes facilitating maturation of a specialized intercellular junction structure, the intercalated disc (ICD). This process coincides with the time cardiomyocytes exit cell cycle soon after birth. Hypothesis: We hypothesize that coincident with maturation of ICD α-catenins sequester transcriptional coactivator Yap in cytosol thus preventing activation of genes critical for cardiomyocyte proliferation. Methods: We deleted αE-catenin / αT-catenin genes (α-cat DKO) in perinatal mouse heart and knockdown (KD) α-catenins in neonatal rat cardiomyocytes to study functional impact of α-catenins ablation on ICD maturation. Results: We previously demonstrated that adult α-cat DKO mice exhibited decrease in scar size and improved function post myocardial infarction. In present study, we investigated function of α-catenins during postnatal heart development. We found increase in the number of Yap-positive nuclei (58.7% in DKO vs. 35.8 % in WT, n=13, p&lt;0.001) and PCNA (53.9% in DKO vs. 47.8%, n=8, p&lt;0.05) at postnatal day 1 and day 7 of α-cat DKO heart, respectively. Loss of α-catenins resulted in reduction in N-cadherin at ICD at day 14. We observed an increase number of mononucleated myocytes and decrease number of binucleated myocytes in α-cat DKO compared to controls. Using siRNA KD, we were able to replicate α-cat DKO proliferative phenotype in vitro. The number of BrdU-positive cells was decreased in α-cat KD after interfering with Yap expression (2.91% in α-cat KD vs. 2.02% in α-cat/Yap KD, n&gt;2500 cells, p&lt;0.05), suggesting α-catenins regulate cell proliferation through Yap in neonatal cardiomyocytes. Conclusion: Our results suggest that maturation of ICD regulates α-catenin-Yap interactions in cytosol, thus preventing Yap nuclear accumulation and cardiomyocyte proliferation.
Ethical dilemma: Retrieving semen from a dead patient Utilitarianism in the absence of definitive guidelines The patient was assaulted Some ethical concerns were ignored An ethic of ambivalence
Authors: M. Swinn, M. Emberton, D. Ralph, M. Smith, P. Serhal, S. Bewley, B. Lichterman, D. L. Steinberg
Journal: BMJ (1998)

Retrieving semen from a dead patientAlthough guidelines for retrieving semen from dead patients exist, they may not cover every case.Here, a team of doctors describes the case of a man who underwent orchidectomy after being certified brain dead, and an obstetrician, neurosurgeon, and sociologist debate the ethical issues.