tbuckley/cabot-search huggingface dataset:
Preventive Management of Nonobstructive CAD After Coronary CT Angiography in the Emergency Department
Authors: Michael C. Honigberg, Bradley S. Lander, Vinit Baliyan, Maeve Jones-O’Connor, Emma W. Healy, Jan-Erik Scholtz, John T. Nagurney, Udo Hoffmann, Brian B. Ghoshhajra, Pradeep Natarajan
Journal: JACC. Cardiovascular imaging (2019)
Loss of Function of DOCK4 in Myelodysplastic Syndromes Stem Cells is Restored by Inhibitors of DOCK4 Signaling Networks
Authors: Sriram Sundaravel, Wen-Liang Kuo, Jong Jin Jeong, Gaurav S. Choudhary, Shanisha Gordon-Mitchell, Hui Liu, Tushar D. Bhagat, Kathy L. McGraw, Sandeep Gurbuxani, Alan F. List, Amit Verma, Amittha Wickrema
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Myelodysplastic syndromes (MDS) with deletion of chromosome 7q/7 [-7/(del)7q MDS] is associated with worse outcomes and needs novel insights into pathogenesis. Reduced expression of signaling protein dedicator of cytokinesis 4 (DOCK4) in patients with -7/(del)7q MDS leads to a block in hematopoietic stem cell (HSC) differentiation. Identification of targetable signaling networks downstream of DOCK4 will provide means to restore hematopoietic differentiation in MDS. Experimental Design: We utilized phosphoproteomics approaches to identify signaling proteins perturbed as a result of reduced expression of DOCK4 in human HSCs and tested their functional significance in primary model systems. Results: We demonstrate that reduced levels of DOCK4 lead to increased global tyrosine phosphorylation of proteins in primary human HSCs. LYN kinase and phosphatases INPP5D (SHIP1) and PTPN6 (SHP1) displayed greatest levels of tyrosine phosphorylation when DOCK4 expression levels were reduced using DOCK4-specific siRNA. Our data also found that increased phosphorylation of SHIP1 and SHP1 phosphatases were due to LYN kinase targeting these phosphatases as substrates. Increased migration and impediment of HSC differentiation were consequences of these signaling alterations. Pharmacologic inhibition of SHP1 reversed these functional aberrations in HSCs expressing low DOCK4 levels. In addition, differentiation block seen in DOCK4 haplo-insufficient [-7/(del)7q] MDS was rescued by inhibition of SHP1 phosphatase. Conclusions: LYN kinase and phosphatases SHP1 and SHIP1 are perturbed when DOCK4 expression levels are low. Inhibition of SHP1 promotes erythroid differentiation in healthy HSCs and in -7/(del)7q MDS samples with low DOCK4 expression. Inhibitors of LYN, SHP1 and SHIP1 also abrogated increased migratory properties in HSCs expressing reduced levels of DOCK4.
Investigating hereditary risk from T790M (inherit): A prospective multicentered study of risk associated with germ-line EGFR T790M.
Authors: Geoffrey R. Oxnard, Jennifer C. Heng, Irene R. Rainville, Suzanne Eleanor Dahlberg, Alicia L. Sable-Hunt, Georgia L. Wiesner, Kelly A. Taylor, David Michael Jackman, Pasi A. Janne, Judy Ellen Garber
Journal: Journal of Clinical Oncology (2013)

TPS1606 Background: The EGFR T790M mutation, commonly associated with acquired resistance to EGFR kinase inhibitors, has also been seen as a germline mutation in association with familial lung cancer. In collaboration with the Addario Lung Cancer Medical Institute (www.ALCMI.net), we initiated a prospective trial to identify patients and families carrying germline EGFR mutations in order to characterize their cancer risk. Preliminary data: In a prior study (Oxnard et al, JTO, 2012), it was found that patients with lung cancers found to harbor EGFRT790M at diagnosis have a 50% chance of carrying an underlying germline T790M mutation. This suggests that study of patients known to carry T790M in their cancer will enrich for a germline event that otherwise is too rare to study prospectively. Subject eligibility: Three cohorts are eligible: (1) Patients with a cancer (lung or other) harboring EGFR T790M on tumor genotyping; lung cancers that acquire EGFR T790M only after treatment are ineligible. (2) First-degree relatives of patients carrying a germline EGFR mutation. (3) Patients already known to carry a germline EGFRmutation on prior testing. Subjects are referred to cohort 1 based upon routine genotyping results from commercial laboratories (e.g. Response Genetics Inc., Los Angeles, CA). Methods: Subjects may present at a participating cancer center or may participate remotely through a study website (www.Dana-Farber.org/T790Mstudy). Eligible patients submit a saliva and/or blood specimen for central testing in a CLIA lab. After counseling, patients carrying germline EGFR mutations have the option of inviting first-degree relatives to participate. Genetic counseling is coordinated at the participating center or offered over the phone. Chest CT scans are collected from germline carriers and analyzed centrally to study nodule characteristics. Patients are clinically followed for 2 years. At time of submission, 6 subjects have enrolled from 3 different families and 4 different US states. (NCT01754025) Funding: Supported by grants from the Conquer Cancer Foundation of ASCO and the Bonnie J. Addario Lung Cancer Foundation. Clinical trial information: NCT01754025.
Ileal Neuroendocrine Tumor With Bilateral Breast and Ovarian Metastases
Authors: Sarthak Tripathy, Niraj Naswa, Pragati Jha, Sreenivasa Reddy, Girish Kumar Parida
Journal: Clinical Nuclear Medicine (2019)

Abstract Metastasis to the breast is a rare occurrence and constitutes less than 2% of all breast tumors. Similarly, ovarian metastases from neuroendocrine tumors are also uncommon, and if the adnexal masses are bilateral, then the chances of it being metastatic rather than being primary range from 88% to 94%. We present a case of 61-year-old woman who in the course of workup for abdominal pain and diarrhea was eventually diagnosed as ileal neuroendocrine tumor with breast, ovarian, and lymph nodal metastases on 68 Ga-DOTANOC PET/CT scan.
Prospective evaluation of host biomarkers other than interferon gamma in QuantiFERON Plus supernatants as candidates for the diagnosis of tuberculosis in symptomatic individuals
Authors: Portia M. Manngo, Andrea Gutschmidt, Candice I. Snyders, Hygon Mutavhatsindi, Charles M. Manyelo, Nonjabulo S. Makhoba, Petri Ahlers, Andriette Hiemstra, Kim Stanley, Shirley McAnda, Martin Kidd, Stephanus T. Malherbe, Gerhard Walzl, Novel N. Chegou
Journal: Journal of Infection (2019)

BackgroundThere is an urgent need for new tools for the diagnosis of TB. We evaluated the usefulness recently described host biomarkers in supernatants from the newest generation of the QuantiFERON test (QuantiFERON Plus) as tools for the diagnosis of active TB.MethodsWe recruited individuals presenting at primary health care clinics in Cape Town, South Africa with symptoms requiring investigation for TB disease, prior to the establishment of a clinical diagnosis. Participants were later classified as TB or other respiratory diseases (ORD) based on the results of clinical and laboratory tests. Using a multiplex platform, we evaluated the concentrations of 37 host biomarkers in QuantiFERON Plus supernatants from study participants as tools for the diagnosis of TB.ResultsOut of 120 study participants, 35(29.2%) were diagnosed with active TB, 69(57.5%) with ORD whereas 16(13.3%) were excluded. 14(11.6%) of the study participants were HIV infected. Although individual host markers showed potential as diagnostic candidates, the main finding of the study was the identification of a six-marker biosignature in unstimulated supernatants (Apo-ACIII, CXCL1, CXCL9, CCL8, CCL-1, CD56) which diagnosed TB with sensitivity and specificity of 73.9%(95% CI; 51.6–87.8) and 87.6%(95% CI; 77.2–94.5), respectively, after leave-one-out cross validation. Combinations between TB-antigen specific biomarkers also showed potential (sensitivity of 77.3% and specificity of 69.2%, respectively), with multiple biomarkers being significantly different between TB patients, Quantiferon Plus Positive and Quantiferon Plus negative individuals with ORD, regardless of HIV status.ConclusionsBiomarkers detected in QuantiFERON Plus supernatants may contribute to adjunctive diagnosis of TB.
Hafnium oxide nanoparticles activated by SBRT: a new interventional radiation therapy approach for the treatment of unresectable liver cancers
Authors: T. De Baere, M. Pracht, Y. Rolland, F. Nguyen, J. Bronowicki, V. Vendrely, A. Sa Cunha, A. Baumann, V. Croisé-Laurent, E. Rio, S. Le Sourd, P. Gustin, C. Perret, D. Peiffert, E. Deutsch, E. Chajon
Journal: Annals of Oncology (2019)
Neurological patients experience long delays to see specialists, finds survey
Authors: Susan Mayor
Journal: BMJ (2019)

People with neurological conditions, including epilepsy and Parkinson’s disease, experience long delays before seeing specialists with nearly one in three waiting more than 12 months following a GP referral, a survey of more than 10 000 patients in England1 has shown.

The Neurological Alliance’s National Neurology Patient Experience Survey asked 10 339 patients about their experience of diagnosis, treatment, and care. Participants were recruited through 44 neurological units throughout England or through organisations representing patients with neurological conditions.

Results showed that 28% of respondents waited more than 12 months …
The haplotype of three polymorphisms in the SATB1 promoter-region and impact on survival in breast cancer patients.
Authors: Martin Leonhard Heubner, Rainer Kimmig, Winfried Siffert, Frey Ulrich
Journal: Journal of Clinical Oncology (2013)

584 Background: Special AT-rich sequence binding protein 1 (SATB1) has regulatory effects on gene expression and appears to play an important role in tumor progression. We screened the promoter region of the SATB1 gene for polymorphisms, evaluated the corresponding haplotypes regarding alterations in promoter activity in vitro and analyzed the impact of these haplotypes on the clinical course of breast cancer patients. Methods: 241 caucasian breast cancer patients who had been treated were enrolled in this retrospective analysis. The median follow up time was 93 months (4-155 months). PCR products from DNA of 10 healthy unrelated volunteers were analyzed to identify new polymorphisms within the promoter region. Genotyping was conducted using restriction length polymorphism and pyrosequencing. PCR constructs with the respective alleles from the four most frequent haplotypes were cloned into the vector pGEM-Teasy (Promega Corporation, Madison, WI, USA) and then transferred into the luc2-containing reporter vector pGl 4.10 Vector (Promega) for transfection of HEK293 cells. The pGl 4.73 Vector (Promega), containing hRluc, was used for norming the transfection rates. Results: Sequencing the region -3807bp to -2828 upstream from ATG of ten healthy blood donors, we found three single nucleotide polymorphisms SNPs consisting of base exchanges, -3600T&gt;C, -3363A&gt;G and -2984C&gt;T.The SATB1 -3600T/-3363A/-2984C haplotype had a lower promoter activity than all other constructs in vitro and showed a significant association with the nodal status (p=0.049). Kaplan-Meier survival analysis revealed a significantly better survival for homozygous SATB1 -3600T/-3363A/-2984C haplotype carriers compared with heterozygous or the other haplotypes (p=0.033). Conclusions: The SATB1 -3600T/-3363A/-2984C haplotype is associated with lower promoter activity and appears to impact upon survival in breast cancer patients.
Increasing reproducibility and interpretability of microbiota-gut-brain studies on human neurocognition and intermediary microbial metabolites
Authors: Esther Aarts, Sahar El Aidy
Journal: Behavioral and Brain Sciences (2019)

Abstract In this commentary, we point to guidelines for performing human neuroimaging studies and their reporting in microbiota-gut-brain (MGB) articles. Moreover, we provide a view on interpretational issues in MGB studies, with a specific focus on gut microbiota–derived metabolites. Thus, extending the target article, we provide recommendations to the field to increase reproducibility and relevance of this type of MGB study.
Final analysis of nelipepimut-S plus GM-CSF with trastuzumab versus trastuzumab alone to prevent recurrences in high-risk, HER2 low-expressing breast cancer: A prospective, randomized, blinded, multicenter phase IIb trial.
Authors: Annelies Hickerson, G. Travis Clifton, Diane F. Hale, Kaitlin M. Peace, Jarrod P. Holmes, Timothy J. Vreeland, Jennifer Keating Litton, Rashmi Krishna Murthy, Jason Jerome Lukas, Elizabeth A. Mittendorf, George Earl Peoples
Journal: Journal of Clinical Oncology (2019)

1 Background: Preclinical data shows synergism between trastuzumab (Tz) and HER2-targeted vaccines. We evaluated adjvuant nelipepimut-S (NPS) + GM-CSF with Tz compared to Tz with GM-CSF alone in HER2 low-expressing (LE) breast cancer (BC) patients (pts) to prevent recurrences. After a planned interim analysis showed benefit in triple negative BC (TNBC) pts, the decision was made to close the trial with guidance from the independent DSMB. Here, we report the final analysis of the trial with 7 months (mo) of added follow-up (f/u). Methods: The phase 2b trial enrolled clinically disease-free BC pts after standard therapy. Pts were HLA-A2, A3, A24, and/or A26+, had HER2-LE (IHC 1-2+, FISH non-amplified) BC and were node positive and/or TNBC. Pts were randomized to placebo with GM-CSF(control group, CG) or NPS with GM-CSF (vaccine group, VG), while all received Tz Q3wk for 1 year. GM-CSF or NPS + GM-CSF were given q3wks x 6 starting with the 3rd Tz dose, and boosters every 6 months x 4. Safety was assessed and pts were followed clinically for recurrences. The primary outcome was DFS at 24 mo. Results: 589 pts were screened at 26 sites. 275 pts were enrolled and randomized (VG:136, CG:139). There were no clinicopathologic differences between groups. Concurrent Tz and NPS was safe with no added overall or cardiac toxicity compared to CG and no grade 4/5 toxicities. In the ITT analysis (median f/u 25.7 mo), the estimated DFS was favorable but did not reach significance in the VG compared with the CG (HR 0.62, 95% CI: 0.31-1.25, p = 0.18). In the TNBC pts, the VG had statistically improved DFS compared to the CG (HR 0.26, 95% CI: 0.08-0.81, p = 0.013). Conclusions: The combination of NPS with Tz is safe with no added toxicity compared to Tz alone, even after prolonged exposure (25.7 mo). In this final analysis, there was a trend towards benefit in the ITT population that improved since the interim analysis with added f/u. The significant benefit seen at interim in the TNBC pts continued to strengthen in the VG group. These findings could position the NPS + Tz combination as an adjuvant therapy for early-stage TNBC and warrant further study. Clinical trial information: NCT01570036.
Circulating Tumor DNA Profiling in Small-Cell Lung Cancer Identifies Potentially Targetable Alterations
Authors: Siddhartha Devarakonda, Sumithra Sankararaman, Brett H. Herzog, Kathryn A. Gold, Saiama N. Waqar, Jeffrey P. Ward, Victoria M. Raymond, Richard B. Lanman, Aadel A. Chaudhuri, Taofeek K. Owonikoko, Bob T. Li, John T. Poirier, Charles M. Rudin, Ramaswamy Govindan, Daniel Morgensztern
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Patients with SCLC rarely undergo biopsies at relapse. When pursued, tissue obtained can be inadequate for molecular testing, posing a challenge in identifying potentially targetable alterations in a clinically meaningful time frame. We examined the feasibility of circulating tumor DNA (ctDNA) testing in identifying potentially targetable alterations in SCLC. Experimental Design: ctDNA test results were prospectively collected from patients with SCLC between 2014 and 2017 and analyzed. ctDNA profiles of SCLC at diagnosis and relapse were also compared. Results: A total of 609 samples collected from 564 patients between 2014 and 2017 were analyzed. The median turnaround time for test results was 14 days. Among patients with data on treatment status, there were 61 samples from 59 patients and 219 samples from 206 patients collected at diagnosis and relapse, respectively. The number of mutations or amplifications detected per sample did not differ by treatment status. Potentially targetable alterations in DNA repair, MAPK and PI3K pathways, and genes such as MYC and ARID1A were identifiable through ctDNA testing. Furthermore, our results support that it may be possible to reconstruct the clonal relationship between detected variants through ctDNA testing. Conclusions: Patients with relapsed SCLC rarely undergo biopsies for molecular testing and often require prompt treatment initiation. ctDNA testing is less invasive and capable of identifying alterations in relapsed disease in a clinically meaningful timeframe. ctDNA testing on an expanded gene panel has the potential to advance our knowledge of the mechanisms underlying treatment resistance in SCLC and aid in the development of novel treatment strategies.
Expression of chromosome 21-localized genes in acute myeloid leukemia: differences between Down syndrome and non-Down syndrome blast cells and relationship to in vitro sensitivity to cytosine arabinoside and daunorubicin.
Authors: Jeffrey W. Taub, Xi Huang, Larry H. Matherly, Mark L. Stout, Steven A. Buck, Gita V. Massey, David L. Becton, Myron N. Chang, Howard J. Weinstein, Yaddanapudi Ravindranath
Journal: Blood (1999)
Randomized phase 2 trial of chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: CAO/ARO/AIO-12
Authors: R. Hofheinz, E. Fokas, M. Allgäuer, B. Polat, G. Klautke, G. Grabenbauer, R. Fietkau, T. Kuhnt, L. Staib, T. Brunner, A. Grosu, W. Schmiegel, L. Jacobasch, J. Weitz, G. Folprecht, C. Germer, R. Grützmann, M. Schwarzbach, W. Bechstein, T. Friede, M. Ghadimi, C. Rödel
Journal: Annals of Oncology (2019)
Atrial fibrillation groups lobby patients to overturn screening committee decision
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Two patients’ associations that have received funding from drug companies with vested interests are calling on patients to put pressure on the government’s National Screening Committee to overturn its decision not to recommend an atrial fibrillation screening programme.1

The sister organisations the Arrhythmia Alliance and AF Association emailed patients asking whether they could “help save lives and those impacted by AF-related strokes” and suggested that they write to the NSC to recommend a national screening programme for people aged 65 or over.

But doctors are concerned that the campaign goes against the evidence. They said that although patients’ groups should express their views they should do so while being transparent about financial conflicts of interests.

The NSC first reviewed the idea of atrial fibrillation screening in 2014 but decided not to recommend it because it was “uncertain” that screening would do “more good than harm to people identified during screening.”2 The committee reviewed more recent evidence last year and concluded that it …
Incidence and patterns of immune related adverse events (irAEs) during chemoimmunotherapy (ChemoIO) in patients with advanced nonsquamous NSCLC.
Authors: Pradnya Dinkar Patil, Alexia Zagouras, Wei (Auston) Wei, Nathan A. Pennell
Journal: Journal of Clinical Oncology (2019)

e20705 Background: Based on superior outcomes noted in KEYNOTE-189 with the addition of pembrolizumab to platinum doublet chemotherapy, a majority of pts with nonsquamous NSCLC are now treated with chemoIO. irAEs can cause significant morbidity and occasionally mortality in pts treated with immunotherapy. Since chemotherapy is immunosuppressive, it is plausible that incidence of irAEs would be lower in pts receiving chemoIO compared to immunotherapy. The incidence of irAEs in KEYNOTE-189 was 22.7% vs 29.2% in KEYNOTE-024 with pembrolizumab monotherapy. We sought to evaluate the incidence and patterns of irAEs in pts with advanced nonsquamous NSCLC treated with chemoIO at our institution and to determine if the rate varied with the intensity of chemotherapy [carboplatin/ pemetrexed/ pembrolizumab (CPP) vs pemetrexed/ pembrolizumab (PP)]. Methods: We retrospectively reviewed the charts of 73 pts with advanced nonsquamous NSCLC who received CPP followed by maintenance PP. In addition to clinicopathologic variables, we noted the date, incidence, type and grade of irAEs. Descriptive statistics were used to report the incidence and patterns of irAEs. McNemar’s test was used to determine if there was a significant difference in rate of irAEs during CPP vs PP. Results: Of the 73 pts, 52% were females, 67% former smokers, 49% had previously received radiation and 11% had a history of autoimmune disease. 35 pts received 4 cycles of CPP. 21 patients (28%) developed irAEs, of which 6 had irAEs during CPP and 15 developed irAEs on PP. The rate of irAEs was significantly higher after stopping carboplatin (p = 0.049). 10 pts (13%) stopped pembrolizumab due to irAEs. Organ systems involved and grade of irAEs are listed below. Conclusions: The immunosuppressive effects of intensive chemotherapy may be protective against irAEs in pts receiving chemoIO. [Table: see text]
Quality of Life in Patients with Advanced NSCLC Treated in Second-or Third-Line with Nab-Paclitaxel plus Durvalumab: ABOUND. 2L+
Authors: D Talbot, R Govindan, M Cobo, S Ponce Aix, P E Postmus, C Lewanski, J Bennouna, J Fischer, O Juan-Vidal, D Stewart, A Ardizzoni, R Bhore, M Wolfsteiner, M Reck, D Morgensztern, T J Ong
Journal: Journal of Thoracic Oncology (2018)
Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study
Authors: Edward Gane, Daniel J. Verdon, Anna E. Brooks, Anuj Gaggar, Anh Hoa Nguyen, G. Mani Subramanian, Christian Schwabe, P. Rod Dunbar
Journal: Journal of Hepatology (2019)
Government Regulation of Sepsis Care
Authors: Demetrios N. Kyriacou
Journal: JAMA (2019)

Jeremy M. Kahn, MD, MS; Billie S. Davis, PhD; Jonathan G. Yabes, PhD; Chung-Chou H. Chang, PhD; David H. Chong, MD; Tina Batra Hershey, JD, MPH; Grant R. Martsolf, PhD, MPH, RN; Derek C. Angus, MD, MPH
Abstract 18922: Radiofrequency Catheter Ablation Reduces Diffuse Myocardial Fibrosis in Atrial Fibrillation
Authors: Promporn Suksaranjit, Brent D Wilson, Christopher J McGann, Eugene G Kholmovski, Imran Haider, Nassir F Marrouche
Journal: Circulation (2015)

Introduction: Atrial fibrillation (AF) is associated with diffuse myocardial fibrosis as quantified by cardiac magnetic resonance (CMR) using T1 mapping methods. Radiofrequency catheter ablation (RFCA) is evolving, and the role in rhythm control may be ideal for reversing left ventricular (LV) remodeling. Hypothesis: We aimed to study the impact of RFCA on diffuse myocardial fibrosis in AF patients. Methods: We retrospectively collected data from consecutive AF patients who underwent RFCA with modified Look-Locker Inversion recovery T1 mapping sequences on pre/post procedural CMR at 3.0-Tesla. Precontrast T1 relaxation time of the mid-LV short-axis view was used as an index of diffuse LV fibrosis. Primary outcome was the change in diffuse LV fibrosis after RFCA. Results: A total of 11 patients (mean age 67 years, 72% male, 67% paroxysmal AF) were enrolled. Median AF duration was 24.6 months [Interquartile range (IQR): 13.3-45.3)] and median CHA2DS2-VASc was 2 [IQR: 1-3]. Post RFCA CMR was obtained 99.5±18.1 days after the RFCA procedure. Mean precontrast T1 time was significantly lower after RFCA (1182ms vs 1158ms; p=0.0157). Conclusions: Based on our preliminary results, RFCA in AF reduces diffuse myocardial fibrosis and may play a role in reverse LV remodeling.