tbuckley/cabot-search huggingface dataset:
Comprehensive Longitudinal Surveillance of the IgG Autoantibody Repertoire in Established Systemic Lupus Erythematosus
Authors: Stefan Vordenbäumen, Ralph Brinks, Annika Hoyer, Rebecca Fischer‐Betz, Georg Pongratz, Torsten Lowin, Hans‐Dieter Zucht, Petra Budde, Ellen Bleck, Peter Schulz‐Knappe, Matthias Schneider
Journal: Arthritis & Rheumatology (2018)

Objective To investigate the role of epitope spreading in established systemic lupus erythematosus ( SLE ). Methods IgG autoantibody reactivity with 398 distinct recombinant proteins was measured over a period of 6 years in 69 SLE patients and compared to that in 45 controls. Changes in mean fluorescence intensity ( MFI ), number of autoantibodies to distinct antigens, and reactivity with distinct clones of established antigenic targets (e.g., U1 RNP , Sm, and ribosomal P) representing epitope fine mapping were assessed. Linear mixed modeling, adjusted with Bonferroni correction for age and sex, was applied. Results The total number of autoantibodies, mean MFI , and number of autoantibodies in epitope fine mapping were higher in SLE patients compared to controls ( P &lt; 0.0001). The total number of antibodies to distinct autoantigens remained stable over time, while the mean MFI decreased over time in SLE ( P &lt; 0.021). SLE patients showed variable recognition of epitopes in fine mapping over time. In particular, in SLE patients, more clones of the U1 RNP complex were recognized at the time of new organ involvement (+0.65) ( P = 0.007). Mean MFI was higher in patients with lupus nephritis ( P = 0.047). The time‐averaged MFI s of 22 individual autoantibodies (including double‐stranded DNA [ds DNA ]) were higher, after Bonferroni correction, in SLE ( P &lt; 0.0001). The MFI s of ds DNA and histone cluster 2 H3c were associated with scores on the Systemic Lupus Activity Measure ( P &lt; 0.0001). Conclusion Longitudinal surveillance of the IgG autoantibody repertoire in established SLE reveals evidence of sustained breadth of autoantibody repertoire without significant expansion. Associations of disease activity with ds DNA and with histone H3 autoantibodies were confirmed.
Prognostic Impact of Circulating Tumor DNA Status Post-Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome
Authors: Sousuke Nakamura, Kazuaki Yokoyama, Eigo Shimizu, Nozomi Yusa, Miho Ogawa, Tomomi Takei, Asako Kobayashi, Mika Ito, Masamichi Isobe, Takaaki Konuma, Seiko Kato, Rika Kasajima, Yuka Wada, Tokiko Nagamura-Inoue, Rui Yamaguchi, Satoshi Takahashi, Seiya Imoto, Satoru Miyano, Arinobu Tojo
Journal: Blood (2018)
“Let the patient decide” – Person-centered postoperative follow-up contacts, initiated via a phone app after day surgery: Secondary analysis of a randomized controlled trial
Authors: Karuna Dahlberg, Maria Jaensson, Ulrica Nilsson
Journal: International Journal of Surgery (2018)

Patients undergoing day surgery are expected to manage their recovery on their own. Follow-up routines differ, but many patients have expressed a need for more professional support during recovery. The aim of this study was to describe how many follow-up contacts were initiated, and when and why, via a digital solution. Also, we wanted to compare postoperative recovery and characteristics between patients requesting, and patients not requesting, contact. This was a secondary analysis of a multicenter, two-group, parallel randomized controlled trial. Participants used a digital solution called "Recovery Assessment by Phone Points (RAPP)" for initiating follow-up contacts after day surgery. The quality of postoperative recovery was measured with the Swedish web-version of Quality of Recovery. Of 494 patients, 84 (17%) initiated contact via RAPP. The most common reasons for initiating contact were related to the surgical wound and pain. Contacts were initiated across the 14-day assessment period, with 62% (62/100) in the first postoperative week. The RAPP contact group had significantly poorer postoperative recovery on days 1–14 compared to those not requesting contact via RAPP (p < 0.001). There was a significantly higher proportion of patients who had undergone general anesthesia in the RAPP contact group (85% [71/84]) compared to the non-RAPP contact group (71% [291/410]), p = 0.003. Letting the patient decide him/herself whether, and when, contact and support is needed during the postoperative period, is possible and does not increase the frequency of contacts. This study investigates a digital solution, RAPP, as one example of a person-centered approach that can be implemented in day surgery follow-up.
Palliative radiotherapy education in hospice and palliative medicine fellowship: A national needs assessment.
Authors: Emily Jean Martin, Joshua Adam Jones
Journal: Journal of Clinical Oncology (2018)

87 Background: Educational deficiencies among hospice and palliative medicine (HPM) physicians are thought to contribute to sub-optimal utilization of palliative radiotherapy (PRT) for patients with advanced cancer. We conducted a national survey of HPM fellowship program directors and fellows to assess the need for increased PRT education in HPM fellowship. Methods: A 17-item, anonymous, electronic survey was distributed via email in May 2018 to the directors of all US Accreditation Council for Graduate Medical Education-accredited HPM fellowship programs with at least one enrolled fellow. A similar 19-item survey was emailed to the coordinators of these programs for distribution to enrolled fellows. Three reminder emails were sent over a one-month period. Results: Eighty-one (68%) of 120 eligible program directors and 114 (34%) of 338 eligible fellows completed the surveys. Nearly all respondents (98% of program directors and 99% of fellows) agreed that HPM physicians should be familiar with the principles of PRT and 95% of both groups agreed that this topic should be taught in HPM fellowship. Thirty percent of programs, however, lacked any PRT curriculum and 57% of programs provided only 1 or 2 hours of didactic PRT education. The minority of fellows felt confident in their ability to identify radiation oncology emergencies (43%) or to manage symptoms associated with radiotherapy toxicities (42%) and only 56% felt confident in their ability to assess which patients should be referred to radiation oncology for possible PRT. Notably, the majority of fellows reported that if they were more knowledgeable about PRT they would be more likely to consider referral to radiation oncology (78%), to collaborate with the radiation oncologists involved in their patients’ care (76%), and to advocate for shorter fractionation schedules or possible omission of radiation therapy altogether based on a patient’s prognosis or goals of care (78%). Conclusions: HPM fellowship program directors and fellows agree that that there is a need for increased education in PRT in HPM fellowship. Curricular interventions that address this need may result in more appropriate utilization of PRT.
Pathologic Assessment After Neoadjuvant Chemotherapy for NSCLC: Importance and Implications of Distinguishing Adenocarcinoma From Squamous Cell Carcinoma
Authors: Yang Qu, Katsura Emoto, Takashi Eguchi, Rania G. Aly, Hua Zheng, Jamie E. Chaft, Kay See Tan, David R. Jones, Mark G. Kris, Prasad S. Adusumilli, William D. Travis
Journal: Journal of Thoracic Oncology (2018)
Serum miRNA–based Prediction of Axillary Lymph Node Metastasis in Breast Cancer
Authors: Sho Shiino, Juntaro Matsuzaki, Akihiko Shimomura, Junpei Kawauchi, Satoko Takizawa, Hiromi Sakamoto, Yoshiaki Aoki, Masayuki Yoshida, Kenji Tamura, Ken Kato, Takayuki Kinoshita, Yuko Kitagawa, Takahiro Ochiya
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Sentinel lymph node biopsy (SLNB) is the gold-standard procedure for evaluating axillary lymph node (ALN) status in patients with breast cancer. However, the morbidity of SLNB is not negligible, and the procedure is invasive for patients without ALN metastasis. Here, we developed a diagnostic model for evaluating ALN status using a combination of serum miRNAs and clinicopathologic factors as a novel less-invasive biomarker. Experimental Design: Preoperative serum samples were collected from patients who underwent surgery for primary breast cancer or breast benign diseases between 2008 and 2014. A total of 958 serum samples (921 cases of primary breast cancer, including 630 cases in the no ALN metastasis group and 291 cases in the ALN metastasis group, and 37 patients with benign breast diseases) were analyzed by miRNA microarray. Samples were randomly divided into training and test sets. Logistic LASSO regression analysis was used to construct diagnostic models in the training set, which were validated in the test set. Results: An optimal diagnostic model was identified using a combination of two miRNAs (miR-629-3p and miR-4710) and three clinicopathologic factors (T stage, lymphovascular invasion, and ultrasound findings), which showed a sensitivity of 0.88 (0.84–0.92), a specificity of 0.69 (0.61–0.76), an accuracy of 0.818, and an area under the receiver operating characteristic curve of 0.86 in the test set. Conclusions: Serum miRNA profiles may be useful for the diagnosis of ALN metastasis before surgery in a less-invasive manner than SLNB.
Novel Flt-3/KDR inhibitor is effective against activated Flt-3 and is cytotoxic against Flt-3-driven leukemias in vitro and in vivo
Authors: Stephen Beck, Lenora Davis, Jennifer Shipman, Laura Schina, Bin Shi, Kathleen Coll, Keith Rickert, Anne Johnson, Qinwen Zeng, Bo-Sheng Pan, Kenneth Thomas, Aimee Dallob, Mary Flynn, Wesley Tanaka, Maricel Torrent, Yih Lee, Kathryn Mazina, Sarah Liou, Dale Schaar, Malgorzata Wojtowicz, Paul Deutsch, Marian Iwamoto, Jackson Gibbs, Nancy Kohl, Laura Sepp-Lorenzino
Journal: Cancer Research (2004)

5629  Flt-3 is a hematopoietic progenitor cell receptor that promotes stem cell proliferation, development and survival. Flt-3 also plays a role in leukemogenesis, being both highly expressed and frequently mutated in adult and pediatric acute leukemia. Mutations in Flt-3 result in a constitutive activation of the receptor tyrosine kinase, conferring ligand independence for growth and for activation of Flt-3 signaling pathways. The most frequently identified mutation in Flt-3 is an internal tandem duplication (ITD), an in-frame insertion of 2-60 amino acids which duplicates a sequence within the juxtamembrane domain of Flt-3. Additionally, point mutations or a single-residue deletion in the activation loop of the tyrosine kinase domain have been identified. The presence of these mutations correlates with an increased risk for relapse and is an indicator of poor prognosis for response to currently available therapy. The transforming potential of Flt-3 was shown to be dependent on its kinase activity, a finding that has led several companies to develop small molecule kinase inhibitors for treating Flt-3-driven leukemias. To provide proof-of-concept support for a leukemic indication for Flt-3 inhibitors, we cloned the most prevalent Flt-3 mutations and established cell-based assays to evaluate their sensitivity to inhibitors. Compounds in the indolyl quinolinone series were identified as potent inhibitors of wild-type as well as of mutant Flt-3 proteins in biochemical (IC50 range = 9-24 nM) and cellular phosphorylation assays (IC50 = 1-76 nM). Inhibition of receptor phosphorylation resulted in dose-dependent anti-proliferative effects, including G1 arrest and apoptosis in cells dependent on Flt-3 for growth. In vivo studies in nude mice bearing MV4;11 (ITD-Flt-3) human xenografts demonstrated that chronic treatment with the inhibitor led to inhibition of tumor Flt-3 activity and caused tumor regressions. These observations provided support for a clinical trial of a novel orally bioavailable Flt-3 kinase inhibitor in AML patients. Pharmacodynamic responses were observed in bone marrow and peripheral blood from leukemic patients with an estimated potency of 61 nM against constitutively activated Flt-3.
Acute Effects of Smoked and Vaporized Cannabis in Healthy Adults Who Infrequently Use Cannabis
Authors: Tory R. Spindle, Edward J. Cone, Nicolas J. Schlienz, John M. Mitchell, George E. Bigelow, Ronald Flegel, Eugene Hayes, Ryan Vandrey
Journal: JAMA Network Open (2018)

<h3>Importance</h3> Vaporization is an increasingly popular method for cannabis administration, and policy changes have increased adult access to cannabis drastically. Controlled examinations of cannabis vaporization among adults with infrequent current cannabis use patterns (&gt;30 days since last use) are needed. <h3>Objective</h3> To evaluate the acute dose effects of smoked and vaporized cannabis using controlled administration methods. <h3>Design, Setting, and Participants</h3> This within-participant, double-blind, crossover study was conducted from June 2016 to January 2017 at the Behavioral Pharmacology Research Unit, Johns Hopkins University School of Medicine, and included 17 healthy adults. Six smoked and vaporized outpatient experimental sessions (1-week washout between sessions) were completed in clusters (order counterbalanced across participants); dose order was randomized within each cluster. <h3>Interventions</h3> Cannabis containing Δ9-tetrahydrocannabinol (THC) doses of 0 mg, 10 mg, and 25 mg was vaporized and smoked by each participant. <h3>Main Outcomes and Measures</h3> Change from baseline scores for subjective drug effects, cognitive and psychomotor performance, vital signs, and blood THC concentration. <h3>Results</h3> The sample included 17 healthy adults (mean [SD] age, 27.3 [5.7] years; 9 men and 8 women) with no cannabis use in the prior month (mean [SD] days since last cannabis use, 398 [437] days). Inhalation of cannabis containing 10 mg of THC produced discriminative drug effects (mean [SD] ratings on a 100-point visual analog scale, smoked: 46 [26]; vaporized: 69 [26]) and modest impairment of cognitive functioning. The 25-mg dose produced significant drug effects (mean [SD] ratings, smoked: 66 [29]; vaporized: 78 [24]), increased incidence of adverse effects, and pronounced impairment of cognitive and psychomotor ability (eg, significant decreased task performance compared with placebo in vaporized conditions). Vaporized cannabis resulted in qualitatively stronger drug effects for most pharmacodynamic outcomes and higher peak concentrations of THC in blood, compared with equal doses of smoked cannabis (25-mg dose: smoked, 10.2 ng/mL; vaporized, 14.4 ng/mL). Blood THC concentrations and heart rate peaked within 30 minutes after cannabis administration and returned to baseline within 3 to 4 hours. Several subjective drug effects and observed cognitive and psychomotor impairments persisted for up to 6 hours on average. <h3>Conclusions and Relevance</h3> Vaporized and smoked cannabis produced dose-orderly drug effects, which were stronger when vaporized. These data can inform regulatory and clinical decisions surrounding the use of cannabis among adults with little or no prior cannabis exposure. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier: NCT03676166.
Predictive Analysis on Prognostic Impact of Monosomy 7 in AML and Identified Therapy Options for This Cohort
Authors: Shireen Vali, Christopher R. Cogle, Neeraj Arora, Krishnan Shekhar, Mammen Chandy, Manju Sengar, Hasmukh Jain, Girish Chinnaswamy, Neeraj Kumar Singh, Shahabuddin Usmani, Anusha Pampana, Vijayashree P Shyamasundar, Huzaifa Sikora, Ansu Kumar, Taher Abbasi, Vivek S Radhakrishnan
Journal: Blood (2018)
Using implementation science to initiate survivorship care plan practice change.
Authors: Betty Goracke Olguin, Lindsay L. Benes
Journal: Journal of Clinical Oncology (2018)

175 Background: Failure to address coordination of cancer survivorship care can result in physical disability, emotional distress, and increased health care costs. The Institute of Medicine (IOM) recommended Survivorship Care Plans (SCPs) to improve care coordination among cancer survivors. Despite evidence supporting SCPs there remains limited implementation of SCPs. The use of implementation science, frameworks, and strategies that address contextual and process factors, could improve use of SCPs in oncology clinics (Selove et al., 2016). Methods: This innovation used the Quality Implementation Framework (QIF) (Meyers, Durlak, &amp; Wandersman, 2012) to guide implementation. The QIF outlines steps and strategies for four phases of implementation; initial considerations regarding the host setting, creating a structure for implementation, ongoing structure once implementation begins, and improving future application. Results: During the project period (January 29, 2018 through April 23, 2018), 17 SCP visits were conducted; all 17 patients completed study surveys. In response to, “My health care providers work together as a team to ensure that my needs are met,” 65% reported strongly agree, 29% reported agree, 5% reported disagree, and 0% reported strongly disagree. When asked “My health care providers have informed me of what my follow-up care should be” 65% reported strongly agree and 35% reported agree. Of the 17 PCP surveys mailed, four were returned. In response to “For this patient the SCP helps me coordinate follow-up care,” three PCPs responded “agree.” When asked “For this patient, the SCP helps me provide better care,” three responded “strongly agree.” One PCP reported neutral feelings toward both statements. All PCPs reported SCP helped them better understand cancer treatment given and side effects. Conclusions: Successful SCP implementation, replicating outcomes of trials supporting SCPs, is attributable to the use of implementation science. Results from this project demonstrated SCPs achieved care coordination and patient satisfaction. SCPs enhanced PCPs’ understanding of cancer treatment and side effects which could increase likelihood PCPs discuss survivorship issues, as demonstrated in literature.
Dietary Lipids Differentially Shape Nonalcoholic Steatohepatitis Progression and the Transcriptome of Kupffer Cells and Infiltrating Macrophages
Authors: Brett McGettigan, Rachel McMahan, David Orlicky, Matthew Burchill, Thomas Danhorn, Prashanth Francis, Lin Ling Cheng, Lucy Golden‐Mason, Claudia V. Jakubzick, Hugo R. Rosen
Journal: Hepatology (2018)

A crucial component of nonalcoholic fatty liver disease (NAFLD) pathogenesis is lipid stress, which may contribute to hepatic inflammation and activation of innate immunity in the liver. However, little is known regarding how dietary lipids, including fat and cholesterol, may facilitate innate immune activation in vivo . We hypothesized that dietary fat and cholesterol drive NAFLD progression to steatohepatitis and hepatic fibrosis by altering the transcription and phenotype of hepatic macrophages. This hypothesis was tested by using RNA‐sequencing methods to characterize and analyze sort‐purified hepatic macrophage populations that were isolated from mice fed diets with varying amounts of fat and cholesterol. The addition of cholesterol to a high‐fat diet triggered hepatic pathology reminiscent of advanced nonalcoholic steatohepatitis (NASH) in humans characterized by signs of cholesterol dysregulation, generation of oxidized low‐density lipoprotein, increased recruitment of hepatic macrophages, and significant fibrosis. RNA‐sequencing analyses of hepatic macrophages in this model revealed that dietary cholesterol induced a tissue repair and regeneration phenotype in Kupffer cells (KCs) and recruited infiltrating macrophages to a greater degree than fat. Furthermore, comparison of diseased KCs and infiltrating macrophages revealed that these two macrophage subsets are transcriptionally diverse. Finally, direct stimulation of murine and human macrophages with oxidized low‐density lipoprotein recapitulated some of the transcriptional changes observed in the RNA‐sequencing study. These findings indicate that fat and cholesterol synergize to alter macrophage phenotype, and they also challenge the dogma that KCs are purely proinflammatory in NASH. Conclusion : This comprehensive view of macrophage populations in NASH indicates mechanisms by which cholesterol contributes to NASH progression and identifies potential therapeutic targets for this common disease.
Efficacy of Ibrutinib-Rituximab versus Real-World (RW) Treatments for Patients with Waldenström's Macroglobulinemia (WM): Adjusted Comparison of iNNOVATE and the Lyon-Sud RW Database
Authors: Lionel Karlin, Hervé Besson, Christoph Tapprich, Jamie Garside, Gilles Salles
Journal: Blood (2018)
Cardiac contractility modulation: mechanisms of action in heart failure with reduced ejection fraction and beyond
Authors: Carsten Tschöpe, Behrouz Kherad, Oliver Klein, Axel Lipp, Florian Blaschke, David Gutterman, Daniel Burkhoff, Nazha Hamdani, Frank Spillmann, Sophie Van Linthout
Journal: European Journal of Heart Failure (2018)

Heart failure (HF) is responsible for substantial morbidity and mortality and is increasing in prevalence. Although there has been remarkable progress in the treatment of HF with reduced ejection fraction (HFrEF), morbidity and mortality are still substantial. Cardiac contractility modulation (CCM) signals, consisting of biphasic high‐voltage bipolar signals delivered to the right ventricular septum during the absolute refractory period, have been shown to improve symptoms, exercise tolerance and quality of life and reduce the rate of HF hospitalizations in patients with ejection fractions (EF) between 25% and 45%. CCM therapy is currently approved in the European Union, China, India, Australia and Brazil for use in symptomatic HFrEF patients with normal or slightly prolonged QRS duration. CCM is particularly beneficial in patients with baseline EF between 35% and 45%, which includes half the range of HF patients with mid‐range EFs (HFmrEF). At the cellular level, CCM has been shown in HFrEF patients to improve calcium handling, to reverse the foetal myocyte gene programme associated with HF, and to facilitate reverse remodelling. This review highlights the preclinical and clinical literature related to CCM in HFrEF and HFmrEF and outlines the potential of CCM for HF with preserved EF, concluding that CCM may fill an important unmet need in the therapeutic approach to HF across the range of EFs.