tbuckley/cabot-search huggingface dataset:
Patient HLA Germline Variation and Transplant Survivorship
Authors: Effie W. Petersdorf, Philip Stevenson, Mari Malkki, Roland K. Strong, Stephen R. Spellman, Michael D. Haagenson, Mary M. Horowitz, Ted Gooley, Tao Wang
Journal: Journal of Clinical Oncology (2018)

Purpose HLA mismatching increases mortality after unrelated donor hematopoietic cell transplantation. The role of the patient's germline variation on survival is not known. Patients and Methods We previously identified 12 single nucleotide polymorphisms within the HLA region as markers of transplantation determinants and tested these in an independent cohort of 1,555 HLA-mismatched unrelated transplants. Linkage disequilibrium mapping across class II identified candidate susceptibility features. The candidate gene was confirmed in an independent cohort of 3,061 patients. Results Patient rs429916AA/AC was associated with increased transplantation-related mortality compared with rs429916CC (hazard ratio [HR], 1.39; 95% CI, 1.12 to 1.73; P = .003); rs429916A positivity was a proxy for DOA*01:01:05. Mortality increased with one (HR, 1.17; 95% CI, 1.0 to 1.36; P = .05) and two (HR, 2.51; 95% CI, 1.41 to 4.45; P = .002) DOA*01:01:05 alleles. HLA-DOA*01:01:05 was a proxy for HLA-DRB1 alleles encoding FEY ( P < 10E-15) and FDH ( P < 10E-15) amino acid substitutions at residues 26/28/30 that influence HLA-DRβ peptide repertoire. FEY- and FDH-positive alleles were positively associated with rs429916A ( P < 10E-15); FDY-positive alleles were negatively associated. Mortality was increased with FEY (HR, 1.66; 95% CI, 1.29 to 2.13; P = .00008) and FDH (HR, 1.40; 95% CI, 1.02 to 1.93; P = .04), whereas FDY was protective (HR, 0.88; 95% CI, 0.78 to 0.98; P = .02). Of the three candidate motifs, FEY was validated as the susceptibility determinant for mortality (HR, 1.29; 95% CI, 1.00 to 1.67; P = .05). Although FEY was found frequently among African and Hispanic Americans, it increased mortality independently of ancestry. Conclusion Patient germline HLA-DRB1 alleles that encode amino acid substitutions that influence the peptide repertoire of HLA-DRβ predispose to increased death after transplantation. Patient germline variation informs transplantation outcomes across US populations and may provide a means to reduce risks for high-risk patients through pretransplantation screening and evaluation.
Slice-level diffusion encoding for motion and distortion correction
Authors: Jana Hutter, Daan J Christiaens, Torben Schneider, Lucilio Cordero-Grande, Paddy J Slator, Maria Deprez, Anthony N Price, J-Donald Tournier, Mary Rutherford, Joseph V Hajnal
Journal: Medical Image Analysis (2018)

Advances in microstructural modelling are leading to growing requirements on diffusion MRI acquisitions, namely sensitivity to smaller structures and better resolution of the geometric orientations. The resulting acquisitions contain highly attenuated images that present particular challenges when there is motion and geometric distortion. This study proposes to address these challenges by breaking with the conventional one-volume-one-encoding paradigm employed in conventional diffusion imaging using single-shot Echo Planar Imaging. By enabling free choice of the diffusion encoding on the slice level, a higher temporal sampling of slices with low b-value can be achieved. These allow more robust motion correction, and in combination with a second reversed phase-encoded echo, also dynamic distortion correction. These proposed advances are validated on phantom and adult experiments and employed in a study of eight foetal subjects. Equivalence in obtained diffusion quantities with the conventional method is demonstrated as well as benefits in distortion and motion correction. The resulting capability can be combined with any acquisition parameters including multiband imaging and allows application to diffusion MRI studies in general.
Actionable fusions in colorectal cancer using a cell-free circulating tumor DNA (ctDNA) assay.
Authors: Katherine Clifton, Victoria M. Raymond, A. Dasari, Kanwal Pratap Singh Raghav, Christine Megerdichian Parseghian, Allan Andresson Lima Pereira, Jonathan M. Loree, Rona Yaeger, John H. Strickler, Ryan Bruce Corcoran, Richard B. Lanman, Scott Kopetz, Van Karlyle Morris
Journal: Journal of Clinical Oncology (2018)

3507 Background: The presence of gene fusions affects clinical management of patients (pts) with NSCLC, GIST, and CML. Likewise, identification of actionable fusions provides another potential approach to offering effective therapies to pts with advanced colorectal cancer (CRC). Here we detail the frequencies and clinicopathological features of gene fusions in CRC using a comprehensive ctDNA NGS assay. Methods: Pts with advanced, pre-treated CRC underwent molecular profiling using a plasma-based ctDNA NGS assay (Guardant360®), which includes testing for fusions in FGFR2, FGFR3, RET, ALK, NTRK1, and ROS1. Correlations between fusions and clinicopathological features were measured using a Fisher’s exact test. Relative frequencies of genomic alterations (point mutations, indels, and splice variants) were compared according to fusion status using an unpaired t-test. Results: 45 unique fusions were detected in 41 of 4290 pts tested (0.96%, 95% CI 0.70-1.3%): RET (N = 16, 0.37%), FGFR3 (N = 13, 0.30%), ALK (N = 10, 0.23%), NTRK1 (N = 3, 0.07%), ROS1 (N = 2, 0.05%), and FGFR2 (N = 1, 0.02%). Among pts with multiple fusions (N = 4 total), RET fusions accounted for 3, all subclonal. Fusions were detected at a median variant frequency of 0.31% (IQR, 0.11-1.5%). FGFR fusions were associated concomitant RAS mutations (OR 3.5, P = 0.03). All NTRK1 fusions were KRAS/NRAS/BRAF wild-type. Genomic alterations were more common for the fusion-present cases than non-fusion cases (mean 10.2 vs. 5.1, P < 0.0001). Conclusions: This is the first large series in CRC patients to demonstrate that plasma-based detection of a broad array of actionable fusions is practical. Fusion presence was associated with a higher mutation frequency, also characteristic of microsatellite instability in CRC. Since these fusions are actionable in other solid tumors, our data provide rationale to utilize ctDNA to identify fusions for targeted therapy trials in metastatic CRC.
Dual MAPK Inhibition Is an Effective Therapeutic Strategy for a Subset of Class II BRAF Mutant Melanomas
Authors: Matthew Dankner, Mathieu Lajoie, Dan Moldoveanu, Tan-Trieu Nguyen, Paul Savage, Shivshankari Rajkumar, Xiu Huang, Maria Lvova, Alexei Protopopov, Dana Vuzman, David Hogg, Morag Park, Marie-Christine Guiot, Kevin Petrecca, Catalin Mihalcioiu, Ian R. Watson, Peter M. Siegel, April A.N. Rose
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Dual MAPK pathway inhibition (dMAPKi) with BRAF and MEK inhibitors improves survival in BRAF V600E/K mutant melanoma, but the efficacy of dMAPKi in non-V600 BRAF mutant tumors is poorly understood. We sought to characterize the responsiveness of class II (enhanced kinase activity, dimerization dependent) BRAF mutant melanoma to dMAPKi. Experimental Design: Tumors from patients with BRAF wild-type (WT), V600E (class I), and L597S (class II) metastatic melanoma were used to generate patient-derived xenografts (PDX). We assembled a panel of melanoma cell lines with class IIa (activation segment) or IIb (p-loop) mutations and compared these with WT or V600E/K BRAF mutant cells. Cell lines and PDXs were treated with BRAFi (vemurafenib, dabrafenib, encorafenib, and LY3009120), MEKi (cobimetinib, trametinib, and binimetinib), or the combination. We identified 2 patients with BRAF L597S metastatic melanoma who were treated with dMAPKi. Results: BRAFi impaired MAPK signaling and cell growth in class I and II BRAF mutant cells. dMAPKi was more effective than either single MAPKi at inhibiting cell growth in all class II BRAF mutant cells tested. dMAPKi caused tumor regression in two melanoma PDXs with class II BRAF mutations and prolonged survival of mice with class II BRAF mutant melanoma brain metastases. Two patients with BRAF L597S mutant melanoma clinically responded to dMAPKi. Conclusions: Class II BRAF mutant melanoma is growth inhibited by dMAPKi. Responses to dMAPKi have been observed in 2 patients with class II BRAF mutant melanoma. These data provide rationale for clinical investigation of dMAPKi in patients with class II BRAF mutant metastatic melanoma. See related commentary by Johnson and Dahlman, p. 6107.
PTH-069 Validating a classification system using ISCAN optical enhancement for detection of early barrett’s oesophagus neoplasia
Authors: Martin Everson, Raf Bisschops, Sachin Wani, Jacobo Ortiz Fernandez Sordo, Jose Miguel Esteban, Rami Sweis, Matt Banks, David Graham, Laurence Lovat, Krish Ragunath, Rehan Haidry
Journal: Endoscopy (2018)

<h3>Introduction</h3> Magnification endoscopy (ME) offers an additional tool for endoscopists undertaking BE surveillance to guide biopsies or direct endoscopic eradication therapy (EET) for early neoplasia. Mucosal patterns and oesophageal mucosal microvasculature can be interrogated. We propose a simple classification based on mucosal (M) and vascular (V) patterns, to differentiate dysplastic BE (DBE) mucosa from non-dysplastic (NDBE) mucosa. We assessed if magnification endoscopy paired with a new imaging platform, iScan OE (Pentax, Hoya, Japan) improves detection of early BE associated neoplasia. We validate our MV classification with this new platform. <h3>Methods</h3> Patients undergoing BE surveillance from Jan 2016-Nov 2017, were recruited from 3 international centres. ME was used to image the mucosa at up to 136x magnification. Endoscopists targeted normal and abnormal areas suspicious for neoplasia. Where possible, each area was imaged in HD-WLE and OE and matched histology was acquired from recorded areas. 7 experts blinded to histology classified HD images using our MV classification as NDBE or DBE. Mucosal patterns were graded as M1 (regular/gyric pits); M2 (irregular/featureless pits). Vascular patterns were graded as V1 (regular, normal calibre); V2 (dilated, irregular). M1V1 was considered NDBE; M2V1, M1V2 or M2V2 as DBE. Classifications were compared with histology. Accuracy, sensitivity, specificity were calculated. Krippendorf's alpha was used to assess interobserver agreement (IA). <h3>Results</h3> 54 patients were recruited: 63 HD-WLE and 90 OE magnified images were obtained. The proportion of dysplastic areas imaged between WLE and OE was similar (29/63 vs 49/90 p=NS). Using the MV classification, experts classified tissue as DBE or NDBE with 66.3%(±0.05) accuracy using HD-WLE vs 80.1% (±0.02) with OE [65–76% p&lt;0.001]. Sensitivity improved from 81.2% (±13) with HD-WLE to 87.4% (±5.6) with OE [79–92%] Specificity improved with OE; from 54.3% (±17.6) in HD-WLE to 70% (±4.4) in OE [62.–76]. Both modalities showed fair IA between experts (0.28 in HD-WLE and 0.25 in OE). <h3>Conclusion</h3> ME allows interrogation of the oesophageal mucosa and microvessels. We show that using iScan OE with ME in combination with the MV classification, confers a significant improvement in the accuracy, sensitivity and specificity of endoscopists in identifying early neoplasia, compared to HD-WLE alone.
EWS/ETS-Driven Ewing Sarcoma Requires BET Bromodomain Proteins
Authors: Paradesi Naidu Gollavilli, Aishwarya Pawar, Kari Wilder-Romans, Ramakrishnan Natesan, Carl G. Engelke, Vijaya L. Dommeti, Pranathi M. Krishnamurthy, Archana Nallasivam, Ingrid J. Apel, Tianlei Xu, Zhaohui S. Qin, Felix Y. Feng, Irfan A. Asangani
Journal: Cancer Research (2018)

Abstract The EWS/ETS fusion transcription factors drive Ewing sarcoma (EWS) by orchestrating an oncogenic transcription program. Therapeutic targeting of EWS/ETS has been unsuccessful; however, identifying mediators of the EWS/ETS function could offer new therapeutic options. Here, we describe the dependency of EWS/ETS-driven transcription upon chromatin reader BET bromdomain proteins and investigate the potential of BET inhibitors in treating EWS. EWS/FLI1 and EWS/ERG were found in a transcriptional complex with BRD4, and knockdown of BRD2/3/4 significantly impaired the oncogenic phenotype of EWS cells. RNA-seq analysis following BRD4 knockdown or inhibition with JQ1 revealed an attenuated EWS/ETS transcriptional signature. In contrast to previous reports, JQ1 reduced proliferation and induced apoptosis through MYC-independent mechanisms without affecting EWS/ETS protein levels; this was confirmed by depleting BET proteins using PROTAC-BET degrader (BETd). Polycomb repressive complex 2 (PRC2)-associated factor PHF19 was downregulated by JQ1/BETd or BRD4 knockdown in multiple EWS lines. EWS/FLI1 bound a distal regulatory element of PHF19, and EWS/FLI1 knockdown resulted in downregulation of PHF19 expression. Deletion of PHF19 via CRISPR-Cas9 resulted in a decreased tumorigenic phenotype, a transcriptional signature that overlapped with JQ1 treatment, and increased sensitivity to JQ1. PHF19 expression was also associated with worse prognosis in patients with EWS. In vivo, JQ1 demonstrated antitumor efficacy in multiple mouse xenograft models of EWS. Together these results indicate that EWS/ETS requires BET epigenetic reader proteins for its transcriptional program and can be mitigated by BET inhibitors. This study provides a clear rationale for the clinical utility of BET inhibitors in treating EWS. Significance: These findings reveal the dependency of EWS/ETS transcription factors on BET epigenetic reader proteins and demonstrate the potential of BET inhibitors for the treatment of EWS. Cancer Res; 78(16); 4760–73. ©2018 AACR.
A realistic appraisal of boron neutron capture therapy as a cancer treatment modality
Authors: Rolf F. Barth, Zizhu Zhang, Tong Liu
Journal: Cancer Communications (2018)

Boron neutron capture therapy (BNCT) is a binary therapeutic modality based on the nuclear capture and fission reactions that occur when the stable isotope boron-10 is irradiated with neutrons to produce high-energy alpha particles and recoiling lithium-7 nuclei. In this Commentary we will focus on a number of papers that were presented at a Symposium entitled "Current Clinical Status of Boron Neutron Capture Therapy and Paths to the Future", which was held in September 2017 at the China National Convention Center in Beijing. Results were presented by clinicians from Japan, Finland, the United States, the China mainland and Taiwan, China who have been working in the multiple disciplines that are required for carrying out clinical BNCT. The main focus was on the treatment of patients with malignant brain tumors, recurrent tumors of the head and neck region, and cutaneous melanomas. The results obtained in treating these patients were reported in detail and, although most of the patients with brain tumors and head and neck cancer were not cured, there was evidence of some clinical efficacy. Although there are a number of problems that must be addressed, further clinical studies to evaluate the efficacy of BNCT are warranted. First, despite considerable effort by numerous investigators over the past 40 years, there still are only two boron-containing drugs in clinical use, L-boronophenylalanine (BPA) and sodium borocaptate (BSH). Therefore, until new and more effective boron delivery agents are developed, efforts should be directed to improving the dosing and delivery of BPA and BSH. Second, due to a variety of reasons, nuclear reactor-based BNCT has ended except for its use in the China mainland and Taiwan. Therefore, the future of BNCT depends upon the results of the ongoing Phase II clinical trials that are being carried out in Japan and the soon to be initiated trials that will be carried out in Finland. If the results obtained from these clinical trials are sufficiently promising, then BNCT will have a clear path to the future, especially for patients with the therapeutically challenging malignancies that in the past have been treated with reactor-based BNCT.
FRI0368 Comparison of clinical and laboratory profiles in 3575 systemic lupus erythematosus patients with and without sjÖgren’s syndrome: data from a nationwide patient registry (RELESSER)
Authors: J.G. Ovalles-Bonilla, F.J. López-Longo, I. Rúa-Figueroa, M. Galindo, J. Calvo-Alen, R.D. González, B. Serrano, I. Janta, C. González, I. Monteagudo, J.C. Nieto, J. Martínez, C.N. Saenz, J.M. Pego-Reigosa
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The clinical coexistence of Systemic Lupus Erythematosus (SLE) and Sjögren’s Syndrome (SS) was recognised in 1959. The prevalence of SS among patients with SLE varies considerably among the published studies (10%–30%). There is still controversy as to whether or not SLE patients with overlapping SS have a distinct and significantly milder lupus. <h3>Objectives</h3> To address the clinical and serologic features of SLE and differences from SLE that occurs in overlap with SS. <h3>Methods</h3> A retrospective cohort of 3575 unselected SLE patients from 45 Rheumatology Units across Spain was evaluated for the presence of overlapping SS using the American-European consensus criteria. Cumulative clinical data were collected at the moment of the last assessment. Clinical and laboratory parameters in SLE patients with SS (SLEwSS) were compared with those in SLE patients without SS (SLEwoSS). <h3>Results</h3> SS was identified in 516 SLE patients (14.4%). Compared with the SLEwoSS group, patients with SLEwSS were significantly older, had a higher frequency of mucocutaneous manifestations, Raynaud’s phenomenon, peripheral neuropathy, anti-Ro/SSA, anti-La/SSB, neoplasia, and older age at death, but had a significantly lower frequency of renal involvement, thrombocytopenia, anti-DNA, anti-β2-GPI IgM and complement consumption. Both groups displayed a clinically similar presentation of lymphadenopathy, systemic vasculitis, serositis, damage accrual, mortality, musculoskeletal and CNS manifestations. <h3>Conclusions</h3> SLEwSS appears to constitute a subgroup of SLE patients with distinct clinical and serologic features, in whom SS is expressed as an overlapping entity. A particular cluster of clinical variables, namely, mucocutaneous manifestations, Raynaud’s phenomenon, peripheral neuropathy, renal involvement and thrombocytopenia, was found to be important overall for discriminating SLE patients with or without SS. SLEwSS patients constitute a subgroup of patients with SLE characterised by milder lupus: older age at death, similar rates of mortality and SLICC-ACR damage index, less renal and immunological manifestations. <h3>Disclosure of Interest</h3> None declared
Over-expression of IL-6 and altered DNA methylation can regulate miRNA-370 expression in human cholangiocarcinoma
Authors: Fanyin Meng, Hania Wehbe-Janek, Roger Henson, Tushar Patel
Journal: Cancer Research (2007)

1045  Background: The inflammatory cytokine Interleukin-6 (IL-6) is over-expressed in human cholangiocarcinoma and contributes to tumor cell growth. We have recently shown that over-expression of IL-6 can modulate expression of methylation-dependent genes and moreover, can alter the expression of specific microRNAs (miRNAs) involved in tumor growth. Thus, we postulated that IL-6 could regulate miRNA expression via effects on DNA methylation.   Methods: MzChA-1 malignant cholangiocytes were stably transfected to over-express IL-6. Stable transfectants or their respective controls were treated with 5-aza-CdR, an inhibitor of DNA methylation, and miRNA profiling was performed by microarray analysis. The expression of specific miRNAs was confirmed by real-time PCR analysis. Western blot analysis for putative miRNA targets was performed on tumor cells in vitro, or in tumor cell xenografts in vivo.  Results: The expression of the methyltransferases Dnmt-1 and HASJ4442 was increased in IL-6 over-expressing cells compared to MzChA-1 controls (p= 0.002 and 0.0002, respectively). Incubation with 5-aza-CdR decreased the expression of both Dnmt-1 (p=0.003) and HASJ4442 (p  2-fold up-regulated by 5-aza-CdR treatment plus further significantly down-regulated   Summary and conclusions: We have identified selected miRNAs such as miR-370 that may be regulated by a methylation-dependent pathway. Enhanced IL-6 expression may contribute to tumor growth in cholangiocarcinoma by altering methylation and down-regulating the expression of tumor-suppressing miRNA.
Mcl-1 Phosphorylation without Degradation Mediates Sensitivity to HDAC Inhibitors by Liberating BH3-Only Proteins
Authors: Jingshan Tong, Xingnan Zheng, Xiao Tan, Rochelle Fletcher, Zaneta Nikolovska-Coleska, Jian Yu, Lin Zhang
Journal: Cancer Research (2018)

Abstract Mcl-1, a prosurvival Bcl-2 family protein, is frequently overexpressed in cancer cells and plays a critical role in therapeutic resistance. It is well known that anticancer agents induce phosphorylation of Mcl-1, which promotes its binding to E3 ubiquitin ligases and subsequent proteasomal degradation and apoptosis. However, other functions of Mcl-1 phosphorylation in cancer cell death have not been well characterized. In this study, we show in colon cancer cells that histone deacetylase inhibitors (HDACi) induce GSK3β-dependent Mcl-1 phosphorylation, but not degradation or downregulation. The in vitro and in vivo anticancer effects of HDACi were dependent on Mcl-1 phosphorylation and were blocked by genetic knock-in of a Mcl-1 phosphorylation site mutant. Phosphorylation-dead Mcl-1 maintained cell survival by binding and sequestering BH3-only Bcl-2 family proteins PUMA, Bim, and Noxa, which were upregulated and necessary for apoptosis induction by HDACi. Resistance to HDACi mediated by phosphorylation-dead Mcl-1 was reversed by small-molecule Mcl-1 inhibitors that liberated BH3-only proteins. These results demonstrate a critical role of Mcl-1 phosphorylation in mediating HDACi sensitivity through a novel and degradation-independent mechanism. These results provide new mechanistic insights on how Mcl-1 maintains cancer cell survival and suggest that Mcl-1–targeting agents are broadly useful for overcoming therapeutic resistance in cancer cells. Significance: These findings present a novel degradation–independent function of Mcl-1 phosphorylation in anticancer therapy that could be useful for developing new Mcl-1–targeting agents to overcome therapeutic resistance. Cancer Res; 78(16); 4704–15. ©2018 AACR.
Differential drug susceptibility patterns of Mycobacterium chimaera and other members of the Mycobacterium avium-intracellulare complex
Authors: F.P. Maurer, P. Pohle, M. Kernbach, D. Sievert, D. Hillemann, J. Rupp, M. Hombach, K. Kranzer
Journal: Clinical Microbiology and Infection (2018)
Fluid Composition, Infusion Rate, and Brain Injury in Diabetic Ketoacidosis
Authors: Mark A. Sperling
Journal: New England Journal of Medicine (2018)

Diabetic ketoacidosis constitutes a profound metabolic disturbance of energy homeostasis with a distinct biochemical profile that is characterized by hyperglycemia, ketonemia, metabolic acidosis, and electrolyte abnormalities. It is caused by deficiency of insulin, the hallmark of type 1 diabetes mellitus. The typical symptoms and signs — polyuria, ketotic breath, and Kussmaul respirations — reflect biochemical and molecular processes caused by insulin deficiency and counterregulatory hormones, as described in recent reviews.1-3 Despite such knowledge, 30 to 50% of all children with new-onset type 1 diabetes have diabetic ketoacidosis at the time of diagnosis, even in highly developed countries.3 Programs that heighten . . .