tbuckley/cabot-search huggingface dataset:
Phylogenomic Data Yield New and Robust Insights into the Phylogeny and Evolution of Weevils
Authors: Seunggwan Shin, Dave J Clarke, Alan R Lemmon, Emily Moriarty Lemmon, Alexander L Aitken, Stephanie Haddad, Brian D Farrell, Adriana E Marvaldi, Rolf G Oberprieler, Duane D McKenna
Journal: Molecular Biology and Evolution (2017)

The phylogeny and evolution of weevils (the beetle superfamily Curculionoidea) has been extensively studied, but many relationships, especially in the large family Curculionidae (true weevils; > 50,000 species), remain uncertain. We used phylogenomic methods to obtain DNA sequences from 522 protein-coding genes for representatives of all families of weevils and all subfamilies of Curculionidae. Most of our phylogenomic results had strong statistical support, and the inferred relationships were generally congruent with those reported in previous studies, but with some interesting exceptions. Notably, the backbone relationships of the weevil phylogeny were consistently strongly supported, and the former Nemonychidae (pine flower snout beetles) were polyphyletic, with the subfamily Cimberidinae (here elevated to Cimberididae) placed as sister group of all other weevils. The clade comprising the sister families Brentidae (straight-snouted weevils) and Curculionidae was maximally supported and the composition of both families was firmly established. The contributions of substitution modeling, codon usage and/or mutational bias to differences between trees reconstructed from amino acid and nucleotide sequences were explored. A reconstructed timetree for weevils is consistent with a Mesozoic radiation of gymnosperm-associated taxa to form most extant families and diversification of Curculionidae alongside flowering plants—first monocots, then other groups—beginning in the Cretaceous.
Abstract 18727: Incidence and Clinical Predictors of Late Atrioventricular Conduction Recovery Among Patients Requiring Pacemaker for Complete Heart Block After Cardiac Surgery
Authors: Erich L Kiehl, Tarek Makki, Ralph M Matar, Douglas R Johnston, John W Rickard, Mohamed Kanj, Oussama M Wazni, Walid I Saliba, Niraj Varma, Bruce L Wilkoff, Daniel J Cantillon
Journal: Circulation (2016)

Background:  The incidence and clinical predictors of atrioventricular (AV) conduction recovery among patients requiring pacemaker (PM) for complete heart block (CHB) after cardiac surgery are unknown.   Methods:  Consecutive patients receiving PM for new CHB following cardiac surgery at a high-volume US center from 2000-2014 were evaluated, excluding biventricular PM and PM implanted after the index surgical hospitalization. The primary outcome was AV nodal conduction recovery, defined as a reduction in ventricular pacing to  1 month post-implant. Multi-variable analysis was performed via logistic regression.   Results:  326 patients (66 ± 14 years, 57% male) were retained over 4.2 ± 4.1 years follow-up. Late AV conduction recovery occurred in 11.4% of patients (n = 37). The median ventricular pacing requirement for patients with recovery decreased from 96% at implant to 6% at 1 month and 0% at 6 months. Recovery was less common for patients with prolonged pre-operative conduction, including PR (181 ± 34 msec recovery vs. 198 ± 57 msec none, ρ=0.03) and QRS (103 ± 22 msec recovery vs. 118 ± 28 msec none, ρ 200 msec and QRS>120 msec demonstrated recovery (n = 45, 14%). In multi-variable analysis, only female gender (HR 0.38, ρ=0.01), tricuspid valve surgery (HR 0.30, ρ=0.03), and transient intact post-operative AV conduction (HR 0.33, ρ=0.03) were independently associated with recovery. There were otherwise no differences by surgery subtype nor timing from surgery to PM implant (Table 1).   Conclusions:  Late AV conduction recovery is uncommon among patients requiring PM for CHB following cardiac surgery, particularly with prolonged pre-operative AV conduction. Only female gender, tricuspid valve surgery, and transient intact post-operative AV conduction were independently associated with recovery.
MicroRNA regulation of type 2 innate lymphoid cell homeostasis and function in allergic inflammation
Authors: Priti B. Singh, Heather H. Pua, Hannah C. Happ, Christoph Schneider, Jakob von Moltke, Richard M. Locksley, Dirk Baumjohann, K. Mark Ansel
Journal: The Journal of Experimental Medicine (2017)

MicroRNAs (miRNAs) exert powerful effects on immunity through coordinate regulation of multiple target genes in a wide variety of cells. Type 2 innate lymphoid cells (ILC2s) are tissue sentinel mediators of allergic inflammation. We established the physiological requirements for miRNAs in ILC2 homeostasis and immune function and compared the global miRNA repertoire of resting and activated ILC2s and T helper type 2 (TH2) cells. After exposure to the natural allergen papain, mice selectively lacking the miR-17∼92 cluster in ILC2s displayed reduced lung inflammation. Moreover, miR-17∼92–deficient ILC2s exhibited defective growth and cytokine expression in response to IL-33 and thymic stromal lymphopoietin in vitro. The miR-17∼92 cluster member miR-19a promoted IL-13 and IL-5 production and inhibited expression of several targets, including SOCS1 and A20, signaling inhibitors that limit IL-13 and IL-5 production. These findings establish miRNAs as important regulators of ILC2 biology, reveal overlapping but nonidentical miRNA-regulated gene expression networks in ILC2s and TH2 cells, and reinforce the therapeutic potential of targeting miR-19 to alleviate pathogenic allergic responses.
Impact of homologous recombination deficiency biomarkers on outcomes in patients with triple-negative breast cancer treated with adjuvant doxorubicin and cyclophosphamide (SWOG S9313)
Authors: P. Sharma, W.E. Barlow, A.K. Godwin, H. Pathak, K. Isakova, D. Williams, K.M. Timms, A.R. Hartman, R.J. Wenstrup, H.M. Linden, D. Tripathy, G.N. Hortobagyi, D.F. Hayes
Journal: Annals of Oncology (2017)
Incidental Detection of Metastatic Malignant Melanoma on 68Ga–Prostate-Specific Membrane Antigen PET/CT Imaging
Authors: Reut Anconina, Nir Hod, Daniel Levin, Dina Ezroh Kazap, Sophie Lantsberg
Journal: Clinical Nuclear Medicine (2017)

An 80-year-old man with suspected recurrent prostate carcinoma underwent Ga-PSMA PET/CT, which showed enlarged axillary lymph nodes with intensely increased Ga-PSMA uptake, an atypical site for prostate cancer metastasis. Fine-needle aspiration biopsy revealed metastatic malignant melanoma. FDG PET/CT revealed congruent intense FDG uptake. Therefore, malignant melanoma should be included in the list of malignancies that can be seen positive on Ga-PSMA PET/CT. In unclear Ga-PSMA PET-positive lesions, further clarification with other imaging techniques or biopsy is mandatory to avoid scan misinterpretation. Review of the literature revealed other non-prostate cancer causes of elevated PSMA uptake classified into neoplastic and nonneoplastic conditions.
Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis
Authors: Young Ho Lee, Gwan Gyu Song
Journal: Annals of the Rheumatic Diseases (2017)

Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritisWe have read with interest the article by Nakaoka and colleagues 1 on the efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis.The authors have presented a randomised controlled trial in which they suggest a preference for tocilizumab over placebo for time to relapse of Takayasu arteritis, without any new safety concerns.We would like to draw attention to a few points in this regard.First, Takayasu arteritis and giant cell arteritis share some similarities in terms of their clinical, radiological and histological presentations, representing a spectrum of the same disease. 2Tocilizumab, which is used to treat giant cell arteritis, demonstrates an impressive glucocorticoid-sparing effect, 3 which is important because relapses are common during steroid tapering, and it often necessitates the administration of high cumulative doses of glucocorticoids, which could cause significant toxicity. 4 Treatment for Takayasu arteritis is still challenging because glucocorticoids are associated with significant adverse effects.Thus, the use of tocilizumab as a glucocorticoid-sparing agent is appealing.In the context that Takayasu arteritis and giant cell arteritis may be different phenotypes of a single disease, the steroid-tapering effect of tocilizumab is expected in the treatment for Takayasu arteritis.However, this study did not examine the effect of tocilizumab on the tapering of glucocorticoid agents in patients with Takayasu arteritis, because the study was designed with mandatory glucocorticoid tapering. 1 Second, biologic agents are generally used as second-line treatment.Tocilizumab is usually used in patients with large-vessel vasculitis refractory to immunosuppressants, because of its high cost and potential toxicity.Methotrexate (MTX) and mycophenolate mofetil (MMF) are effective means of inducing remission and minimising glucocorticoid therapy and toxicity in Takayasu arteritis. 5 MTX and MMF lower the risk of relapse and reduce exposure to glucocorticoids; thus, MTX and MMF are therapeutic options in addition to the standard-of-care treatment with glucocorticoids for Takayasu arteritis.MTX and MMF might be particularly useful in treating patients at high risk of developing glucocorticoid-related adverse effects.However, the efficacy and safety of tocilizumab compared with these immunosuppressive drugs in patients with Takayasu arteritis were not investigated.Currently, there are no data to show the superiority of tocilizumab over immunosuppressants.Further studies are warranted to determine the benefits of tocilizumab in terms of its glucocorticoid-sparing effect, remission and reduction in relapse, compared with MTX or MMF therapy.
Wild type Kirsten rat sarcoma is a novel microRNA-622-regulated therapeutic target for hepatocellular carcinoma and contributes to sorafenib resistance
Authors: Peter Dietrich, Andreas Koch, Valerie Fritz, Arndt Hartmann, Anja Katrin Bosserhoff, Claus Hellerbrand
Journal: Gut (2017)

Objective Sorafenib is the only effective therapy for advanced hepatocellular carcinoma (HCC). Combinatory approaches targeting mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)- and phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)/protein-kinase B(AKT) signalling yield major therapeutic improvements. RAS proteins regulate both RAF/MAPK and PI3K/AKT signalling. However, the most important RAS isoform in carcinogenesis, Kirsten rat sarcoma (KRAS), remains unexplored in HCC. Design Human HCC tissues and cell lines were used for expression and functional analysis. Sorafenib-resistant HCC cells were newly generated. RNA interference and the novel small molecule deltarasin were used for KRAS inhibition both in vitro and in a murine syngeneic orthotopic HCC model. Results Expression of wild type KRAS messenger RNA and protein was increased in HCC and correlated with extracellular-signal regulated kinase (ERK) activation, proliferation rate, advanced tumour size and poor patient survival. Bioinformatic analysis and reporter assays revealed that KRAS is a direct target of microRNA-622. This microRNA was downregulated in HCC, and functional analysis demonstrated that KRAS-suppression is the major mediator of its inhibitory effect on HCC proliferation. KRAS inhibition markedly suppressed RAF/ERK and PI3K/AKT signalling and proliferation and enhanced apoptosis of HCC cells in vitro and in vivo. Combinatory KRAS inhibition and sorafenib treatment revealed synergistic antitumorigenic effects in HCC. Sorafenib-resistant HCC cells showed elevated KRAS expression, and KRAS inhibition resensitised sorafenib-resistant cells to suppression of proliferation and induction of apoptosis. Conclusions KRAS is dysregulated in HCC by loss of tumour-suppressive microRNA-622, contributing to tumour progression, sorafenib sensitivity and resistance. KRAS inhibition alone or in combination with sorafenib appears as novel promising therapeutic strategy for HCC.
Management decision based on lymphovascular involvement leads to favorable outcomes after endoscopic treatment of esophageal squamous cell carcinoma
Authors: Kazuya Takahashi, Satoru Hashimoto, Ken-ichi Mizuno, Takamasa Kobayashi, Kentaro Tominaga, Hiroki Sato, Junji Kohisa, Satoshi Ikarashi, Kazunao Hayashi, Manabu Takeuchi, Junji Yokoyama, Hirokazu Kawai, Yuichi Sato, Masaaki Kobayashi, Shuji Terai
Journal: Endoscopy (2017)

Abstract Background Esophageal squamous cell carcinoma (ESCC) invading the muscularis mucosae (MM) and submucosa up to 200 µm (SM1) has a risk of metastasis. The aims of this study were to investigate the long-term outcome of endoscopic submucosal dissection (ESD) for MM/SM1 ESCC and to assess the management after ESD in our hospital. Methods This was a retrospective cohort study conducted at a single institution. Patients with MM or SM1 ESCC who were treated with ESD were included. Additional prophylactic therapy was added if lymphovascular involvement (LVI) was noted in the ESD specimens. Results A total of 102 patients were analyzed. The median length of follow-up was 71.5 months (range 9 – 144 months) and the median number of CTs was 6 (range 0 – 24). LVI was found in 21 patients (20.6 %), and 12 patients underwent additional prophylactic therapy. The 5-year overall survival, disease-specific survival, and tumor-free survival rates were 84.1 %, 97.5 %, and 82.1 %, respectively. A total of 26 patients died, but only 2 of them died from ESCC. The cumulative metastasis rate was 11.8 %, and LVI was a significant predictor of metastasis (hazard ratio 5.42, 95 % confidence interval 1.39 – 21.18; P = 0.02). There were no differences between patients with MM ESCC and those with SM1 ESCC. Conclusions The long-term outcome after ESD for MM/SM1 ESCC was favorable with additional prophylactic therapy and strict adherence to follow-up. These results indicate that our management decision based on LVI is a valid approach and that ESD can be offered as a therapeutic option to MM/SM1 ESCCs.
Metastatic Solitary Fibrous Tumor With Doege-Potter Syndrome
Authors: Clement Bailly, Myriam Bichali Alroumani, Frederic Douane, Catherine Ansquer, Delphine Drui
Journal: Clinical Nuclear Medicine (2017)

Solitary fibrous tumor is a rare type of mesenchymal neoplasm that can be associated to a paraneoplastic severe hypoglycemia due to the overproduction of insulinlike growth factor type 2: Doege-Potter syndrome. When surgical resection is impossible or unsuccessful, alternative therapies were described with heterogeneous efficiency. We report the use of radioembolization with Y-labeled glass microspheres in this application. Regarding the excellent results obtained and the potential interest of peptide receptor radionuclide therapy suggested by overexpression of somatostatin receptors in our patient, the place of targeted radionuclide therapies deserves to be explored in this group of tumors.
Abstract 18078: Anemia is a Marker of Volume Status and is Not Associated With Intrinsic Diastolic Dysfunction or Adverse Cardiac Mechanics in Heart Failure With Preserved Ejection Fraction
Authors: Jacob A Burns, Lauren Beussink, Vistasp Daruwalla, Cynthia Sanchez, Sanjiv J Shah
Journal: Circulation (2016)

Introduction:  Anemia is a poor prognostic marker in heart failure with preserved ejection fraction (HFpEF). Prior studies have reported worse diastolic function in anemic HFpEF patients. These studies used only volume-dependent indices of diastolic dysfunction. This is problematic in anemia, a pathologic state characterized by hypervolemia. We hypothesized that anemia is not associated with worse diastolic function when assessed with intrinsic myocardial markers.   Methods:  We prospectively studied 419 outpatients in a systematic HFpEF program, all of whom underwent comprehensive echocardiography. Myocardial strain was measured in 311 patients using TomTec speckle tracking software. Follow-up evaluations occurred once every 6 months. The association of anemia with clinical, echocardiographic, and strain variables was studied using linear regression models. Outcomes analysis for cardiovascular hospitalization and death was conducted using Cox proportional hazard models.   Results:  222 (53%) patients were anemic, defined as hemoglobin   Conclusions:  In HFpEF, anemia is associated with markers of volume status and not intrinsic markers of myocardial dysfunction. The association of anemia and adverse outcomes in HFpEF is likely due to extracardiac factors, and not intrinsic myocardial dysfunction. Our findings suggest volume status as an important determinant of the apparent worse diastolic function seen in anemia and HFpEF.
Abstract 1349: Functional and mechanistic characterization of PRMT6 regulated autophagy in hepatocellular carcinoma
Authors: Noélia Che, Man Tong, Kai Yu Ng, Phillis WF Kau, Xin Yuan Guan, Michael SY Huen, Stephanie Ma
Journal: Cancer Research (2018)

Abstract Hepatocellular carcinoma (HCC) is a major health burden worldwide. Tumor recurrence and therapy resistance represent major obstacles in the treatment of the disease, with their mechanism of action largely uncharacterized. Autophagy is a critical survival factor for cancer cells, whereby it maintains cellular homeostasis including degradation of damaged organelles and unwanted proteins as well as the support of cellular biosynthesis in response to environmental stress, preventing cells from undergoing apoptosis. Our group has recently reported on the regulatory role of protein arginine methyltransferase 6 (PRMT6) down-regulation in maintenance of HCC, particularly potentiating resistance to sorafenib and chemotherapy. By tandem affinity purification/mass spectrometry analysis of cells with PRMT6 stably overexpressed, we identified a number of autophagy related proteins as potential interacting partners of PRMT6, suggesting a possible role of PRMT6 in modulating autophagy in HCC. Treatment of HCC cells with stress induced conditions, including sorafenib, nutrient deprivation and hypoxic condition, resulted in a marked reduction of PRMT6 expression, concomitant with elevated levels of LC3BII. Further, under these various stimuli, knockdown of PRMT6 in HCC cells would also result in enhanced expression of LC3BII, accumulation of GFP-LC3B positive puncta staining as well as an increase in autophagosome formation. Consistently, treatment of HCC cells with PRMT6 overexpressed would leading to an opposing effect. Further studies by immunoprecipitation analysis validated PRMT6 to physically interact with AMBRA1 (activating molecule in BECN1-regulated autophagy protein 1), a well-known autophagy initiative component, which takes part in autophagy vesicle nucleation, a critical step for autophagic initiation. Our findings suggest PRMT6 down-regulation in HCC tumors to promote tumorigenicity through autophagic flux de-regulation. Targeting the mechanisms of stress response may provide novel therapeutic insights for the disease. Citation Format: Noélia Che, Man Tong, Kai Yu Ng, Phillis WF Kau, Xin Yuan Guan, Michael SY Huen, Stephanie Ma. Functional and mechanistic characterization of PRMT6 regulated autophagy in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1349.
Excellent Outcomes with Radiosurgery for Multiple Brain Metastases in ALK and EGFR Driven Non–Small Cell Lung Cancer
Authors: Tyler P. Robin, D. Ross Camidge, Kelly Stuhr, Sameer K. Nath, Robert E. Breeze, Jose M. Pacheco, Arthur K. Liu, Laurie E. Gaspar, W. Thomas Purcell, Robert C. Doebele, Brian D. Kavanagh, Chad G. Rusthoven
Journal: Journal of Thoracic Oncology (2017)
Structural Alterations of MET Trigger Response to MET Kinase Inhibition in Lung Adenocarcinoma Patients
Authors: Dennis Plenker, Miriam Bertrand, Adrianus J. de Langen, Richard Riedel, Carina Lorenz, Andreas H. Scheel, Judith Müller, Johannes Brägelmann, Juliane Daßler-Plenker, Carsten Kobe, Thorsten Persigehl, Alexander Kluge, Thomas Wurdinger, Pepijn Schellen, Gunther Hartmann, Tobias Zacherle, Roopika Menon, Erik Thunnissen, Reinhard Büttner, Frank Griesinger, Jürgen Wolf, Lukas Heukamp, Martin L. Sos, Johannes M. Heuckmann
Journal: Clinical Cancer Research (2017)

Purpose: We sought to investigate the clinical response to MET inhibition in patients diagnosed with structural MET alterations and to characterize their functional relevance in cellular models.Experimental Design: Patients were selected for treatment with crizotinib upon results of hybrid capture-based next-generation sequencing. To confirm the clinical observations, we analyzed cellular models that express these MET kinase alterations.Results: Three individual patients were identified to harbor alterations within the MET receptor. Two patients showed genomic rearrangements, leading to a gene fusion of KIF5B or STARD3NL and MET One patient diagnosed with an EML4-ALK rearrangement developed a MET kinase domain duplication as a resistance mechanism to ceritinib. All 3 patients showed a partial response to crizotinib that effectively inhibits MET and ALK among other kinases. The results were further confirmed using orthogonal cellular models.Conclusions: Crizotinib leads to a clinical response in patients with MET rearrangements. Our functional analyses together with the clinical data suggest that these structural alterations may represent actionable targets in lung cancer patients. Clin Cancer Res; 24(6); 1337-43. ©2017 AACR.
Risk Factors of Sudden Cardiac Death in the Young
Authors: Reshmy Jayaraman, Kyndaron Reinier, Sandeep Nair, Aapo L. Aro, Audrey Uy-Evanado, Carmen Rusinaru, Eric C. Stecker, Karen Gunson, Jonathan Jui, Sumeet S. Chugh
Journal: Circulation (2017)

Prevention of sudden cardiac arrest (SCA) in the young remains a largely unsolved public health problem, and sports activity is an established trigger. Although the presence of standard cardiovascular risk factors in the young can link to future morbidity and mortality in adulthood, the potential contribution of these risk factors to SCA in the young has not been evaluated.We prospectively ascertained subjects who experienced SCA between the ages of 5 and 34 years in the Portland, Oregon, metropolitan area (2002-2015, catchment population ≈1 million). We assessed the circumstances, resuscitation outcomes, and clinical profile of subjects who had SCA by a detailed evaluation of emergency response records, lifetime clinical records, and autopsy examinations. We specifically evaluated the association of standard cardiovascular risk factors and SCA, and sports as a trigger for SCA in the young.Of 3775 SCAs in all age groups, 186 (5%) occurred in the young (mean age 25.9±6.8, 67% male). In SCA in the young, overall prevalence of warning signs before SCA was low (29%), and 26 (14%) were associated with sports as a trigger. The remainder (n=160) occurred in other settings categorized as nonsports. Sports-related SCAs accounted for 39% of SCAs in patients aged ≤18, 13% of SCAs in patients aged 19 to 25, and 7% of SCAs in patients aged 25 to 34. Sports-related SCA cases were more likely to present with shockable rhythms, and survival from cardiac arrest was 2.5-fold higher in sports-related versus nonsports SCA (28% versus 11%; P=0.05). Overall, the most common SCA-related conditions were sudden arrhythmic death syndrome (31%), coronary artery disease (22%), and hypertrophic cardiomyopathy (14%). There was an unexpectedly high overall prevalence of established cardiovascular risk factors (obesity, diabetes mellitus, hypertension, hyperlipidemia, smoking) with ≥1 risk factors in 58% of SCA cases.Sports was a trigger of SCA in a minority of cases, and, in most patients, SCA occurred without warning symptoms. Standard cardiovascular risk factors were found in over half of patients, suggesting the potential role of public health approaches that screen for cardiovascular risk factors at earlier ages.