bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Knowledge Networks and Boundary Organizations in Coproduction: A Short History of a Decision-Support Tool and Model for Adapting Multiuse Reservoir and Water-Energy Governance to Climate Change in California
Authors: Ziaja S. 
Published: July 2019

AbstractClimate adaptation relies on theoretical frameworks of coproduced science and knowledge networks to produce acceptable outcomes for politically contentious resources. As adaptation moves from theory to implementation, there is a need for positive case studies to use as benchmarks. Building from literature on actionable science this paper presents one such positive case—the development of a hydropower and reservoir decision-support tool. The focus of this history is on the multiple phases of interaction (and noninteraction) between researchers and a semidefined community of stakeholders. The lessons presented from the Integrated Forecast and Reservoir Management (INFORM) system project stress that collaborations between managers and researchers were crucial to the success of the project by building knowledge networks, which could outlast formal processes, and by incorporating policy preferences of end users into the model. The history also provides examples of how even successful collaborative projects do not always follow the usual expectations for coproduced science and shows that, even when those guidelines are followed, external circumstances can threaten the adoption of research products. Ultimately, this paper argues for the importance of building strong knowledge networks alongside more formal processes—like those in boundary organizations—for effective collaborative engagement.
Emotional breakthrough and psychedelics: Validation of the Emotional Breakthrough Inventory
Authors: Roseman Leor , Haijen Eline , Idialu-Ikato Kelvin , Kaelen Mendel , Watts Rosalind , Carhart-Harris Robin 
Published: July 2019

Background: Psychedelic therapy is gaining recognition and the nature of the psychedelic experience itself has been found to mediate subsequent long-term psychological changes. Much emphasis has been placed on the occurrence of mystical-type experiences in determining long-term responses to psychedelics yet here we demonstrate the importance of another component, namely: emotional breakthrough. Methods: Three hundred and seventy-nine participants completed online surveys before and after a planned psychedelic experience. Items pertaining to emotional breakthrough were completed one day after the psychedelic experience, as were items comprising the already validated Mystical Experience Questionnaire and the Challenging Experience Questionnaire. Emotional breakthrough, Mystical Experience Questionnaire and Challenging Experience Questionnaire scores were used to predict changes in well-being (Warwick-Edinburgh Mental Wellbeing Scale) in a subsample of 75 participants with low well-being baseline scores (⩽45). Results: Factor analyses revealed six emotional breakthrough items with high internal consistency (Cronbach’s alpha=0.932) and supported our prior hypothesis that emotional breakthrough is a distinct component of the psychedelic experience. Emotional breakthrough scores behaved dose-dependently, and were higher if the psychedelic was taken with therapeutic planning and intent. Emotional breakthrough, Mystical Experience Questionnaire and Challenging Experience Questionnaire scores combined, significantly predicted subsequent changes in well-being ( r=0.45, p=0.0005, n=75), with each scale contributing significant predictive value. Emotional breakthrough and Mystical Experience Questionnaire scores predicted increases in well-being and Challenging Experience Questionnaire scores predicted less increases. Conclusions: Here we validate a six-item ‘Emotional Breakthrough Inventory’. Emotional breakthrough is an important and distinct component of the acute psychedelic experience that appears to be a key mediator of subsequent longer-term psychological changes. Implications for psychedelic therapy are discussed.
Integrative genomic analysis identifies key pathogenic mechanisms in primary mediastinal large B-cell lymphoma
Authors: Mottok Anja , Hung Stacy S. , Chavez Elizabeth A. , Woolcock Bruce , Telenius Adèle , Chong Lauren C. , Meissner Barbara , Nakamura Hisae , Rushton Christopher , Viganò Elena , Sarkozy Clementine , Gascoyne Randy D. , Connors Joseph M. , Ben-Neriah Susana , Mungall Andrew , Marra Marco A. , Siebert Reiner , Scott David W. , Savage Kerry J. , Steidl Christian 
Published: July 2019

Abstract
Primary mediastinal large B-cell lymphoma (PMBL) represents a clinically and pathologically distinct subtype of large B-cell lymphomas. Furthermore, molecular studies, including global gene expression profiling, have provided evidence that PMBL is more closely related to classical Hodgkin lymphoma (cHL). Although targeted sequencing studies have revealed a number of mutations involved in PMBL pathogenesis, a comprehensive description of disease-associated genetic alterations and perturbed pathways is still lacking. Here, we performed whole-exome sequencing of 95 PMBL tumors to inform on oncogenic driver genes and recurrent copy number alterations. The integration of somatic gene mutations with gene expression signatures provides further insights into genotype–phenotype interrelation in PMBL. We identified highly recurrent oncogenic mutations in the Janus kinase-signal transducer and activator of transcription and nuclear factor κB pathways, and provide additional evidence of the importance of immune evasion in PMBL (CIITA, CD58, B2M, CD274, and PDCD1LG2). Our analyses highlight the interferon response factor (IRF) pathway as a putative novel hallmark with frequent alterations in multiple pathway members (IRF2BP2, IRF4, and IRF8). In addition, our integrative analysis illustrates the importance of JAK1, RELB, and EP300 mutations driving oncogenic signaling. The identified driver genes were significantly more frequently mutated in PMBL compared with diffuse large B-cell lymphoma, whereas only a limited number of genes were significantly different between PMBL and cHL, emphasizing the close relation between these entities. Our study, performed on a large cohort of PMBL, highlights the importance of distinctive genetic alterations for disease taxonomy with relevance for diagnostic evaluation and therapeutic decision-making.
In vivo dynamics of T cells and their interactions with dendritic cells in mouse cutaneous graft-versus-host disease
Authors: Morin-Zorman Sarah , Wysocki Christian , Zhu Jieqing , Li Hongmei , Zorman Sylvain , Matte-Martone Catherine , Kisanga Edwina , McNiff Jennifer , Jain Dhanpat , Gonzalez David , Rothstein David M. , Lakkis Fadi G. , Haberman Ann , Shlomchik Warren D. 
Published: July 2019

Abstract
Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (alloSCT). By static microscopy, cutaneous GVHD lesions contain a mix of T cells and myeloid cells. We used 2-photon intravital microscopy to investigate the dynamics of CD4+ and CD8+ T cells and donor dendritic cells (DCs) in cutaneous GVHD lesions in an MHC-matched, multiple minor histocompatibility antigen-mismatched (miHA) model. The majority of CD4 and CD8 cells were stationary, and few cells entered and stopped or were stopped and left the imaged volumes. CD8 cells made TCR:MHCI-dependent interactions with CD11c+ cells, as measured by the durations that CD8 cells contacted MHCI+ vs MHCI− DCs. The acute deletion of Langerin+CD103+ DCs, which were relatively rare, did not affect CD8 cell motility and DC contact times, indicating that Langerin−CD103− DCs provide stop signals to CD8 cells. CD4 cells, in contrast, had similar contact durations with MHCII+ and MHCII− DCs. However, CD4 motility rapidly increased after the infusion of an MHCII-blocking antibody, indicating that TCR signaling actively suppressed CD4 movements. Many CD4 cells still were stationary after anti-MHCII antibody infusion, suggesting CD4 cell heterogeneity within the lesion. These data support a model of local GVHD maintenance within target tissues.
Analysis of loss to follow-up in 4099 multidrug-resistant pulmonary tuberculosis patients
Authors: Walker Ian F. , Shi Oumin , Hicks Joseph P. , Elsey Helen , Wei Xiaolin , Menzies Dick , Lan Zhiyi , Falzon Dennis , Migliori Giovanni Battista , Pérez-Guzmán Carlos , Vargas Mario H. , García-García Lourdes , Sifuentes Osornio José , Ponce-De-León Alfredo , van der Walt Martie , Newell James N. 
Published: July 2019

Loss to follow-up (LFU) of ≥2 consecutive months contributes to the poor levels of treatment success in multidrug-resistant tuberculosis (MDR-TB) reported by TB programmes. We explored the timing of when LFU occurs by month of MDR-TB treatment and identified patient-level risk factors associated with LFU.We analysed a dataset of individual MDR-TB patient data (4099 patients from 22 countries). We used Kaplan–Meier survival curves to plot time to LFU and a Cox proportional hazards model to explore the association of potential risk factors with LFU.Around one-sixth (n=702) of patients were recorded as LFU. Median (interquartile range) time to LFU was 7 (3–11) months. The majority of LFU occurred in the initial phase of treatment (75% in the first 11 months). Major risk factors associated with LFU were: age 36–50 years (HR 1.3, 95% CI 1.0–1.6; p=0.04) compared with age 0–25 years, being HIV positive (HR 1.8, 95% CI 1.2–2.7; p<0.01) compared with HIV negative, on an individualised treatment regimen (HR 0.7, 95% CI 0.6–1.0; p=0.03) compared with a standardised regimen and a recorded serious adverse event (HR 0.5, 95% CI 0.4–0.6; p<0.01) compared with no serious adverse event.Both patient- and regimen-related factors were associated with LFU, which may guide interventions to improve treatment adherence, particularly in the first 11 months.
High therapeutic efficacy of artemether–lumefantrine and dihydroartemisinin–piperaquine for the treatment of uncomplicated falciparum malaria in Somalia
Authors: Warsame Marian , Hassan Abdillahi Mohamed , Hassan Abdikarim Hussein , Jibril Ali Mohamed , Khim Nimol , Arale Abdulkadir Mohamed , Gomey Ahamed Hassan , Nur Zainab Said , Osman Said Mohamed , Mohamed Marian Said , Abdulrahman Ali , Yusuf Fahmi Essa , Amran Jamal Ghilan Hefzullah , Witkowski Benoit , Ringwald Pascal 
Published: July 2019

Abstract
Background
Artemether–lumefantrine (AL) and dihydroartemisinin–piperaquine (DHA/PPQ) are the recommended first- and second-line treatments, respectively, for uncomplicated falciparum malaria in Somalia. The studies reported here were conducted to assess the efficacy of these artemisinin-based combinations and the mutations in Plasmodium falciparum K13-propeller (Pfk13) domain and amplification in Pfplasmepsin 2 (Pfpm2) gene in Somalia.

Methods
One-arm prospective studies were conducted to assess the clinical and parasitological responses to DHA/PPQ and AL at two sites in 2016 and 2017, respectively, using the standard WHO protocol. The patterns of molecular markers associated with artemisinin and PPQ resistance were investigated for the first time in Somalia.

Results
A total of 339 patients were enrolled with 139 for AL and 200 for DHA/PPQ. With AL, no parasite recurrence was observed among patients treated at either site, corresponding to 100% clinical and parasitological responses. For DHA–PPQ, an adequate clinical and parasitological response rate > 97% was observed. All study patients on both treatments at both sites were parasite-free on day 3. Of the 138 samples with interpretable results for the polymorphism in Pfk13, only one (0.7%), from Bosaso, contained a non-synonymous mutation (R622I), which is not one of the known markers of artemisinin resistance. No Pfpm2 amplification was observed among the 135 samples with interpretable results.

Conclusions
AL and DHA/PPQ were highly effective in the treatment of uncomplicated falciparum malaria, and there was no evidence of resistance to artemisinin or PPQ. These two combinations are thus relevant in the chemotherapeutic strategy for malaria control in Somalia.
Trial registration ACTRN12616001005448 (Jowhar DP study), ACTRN12616000553471 (Bosaso DP study), ACTRN12617001055392 (AL study in Bosaso and Jowhar)
Early shifts in immune cell subsets to predict response to immune checkpoint blockade in non-small cell lung cancer (NSCLC).
Authors: Rosner Samuel , Forde Patrick M. , Naidoo Jarushka , Marrone Kristen , Reuss Joshua E. , Feliciano Josephine Louella , Levy Benjamin Philip , Hann Christine L. , Velculescu Victor E. , Brahmer Julie R. , Anagnostou Valsamo 
Published: July 2019

105 Background: The use of immune targeted agents for NSCLC has improved outcomes for patients (pts) with metastatic disease. Biomarkers such as the neutrophil-to-lymphocyte ratio (NLR) prior to therapy have been shown to predict outcomes however little is known about dynamic changes in immune subset composition during therapy. Methods: A single institution, retrospective review was performed of 88 NSCLC pts who received anti-PD1 therapy. NLR and relative lymphocyte count (RLC) were recorded at baseline, 4 weeks after treatment initiation, and at every subsequent computed tomography scan until time of progression. Endpoints included overall survival (OS) and durable clinical benefit (DCB), defined as stable disease or response at 6 months after therapy. Non parametric tests were used to compare NLR and RLC between responders and non-responders, cox-proportional hazards regression analysis was used for univariate associations with OS and Kaplan-Meier survival curves were compared by the log-rank test. Results: Our cohort comprised of 60 male pts with a median age of 63 years and a median OS of 38.5 months. Baseline NLR and RLC were not associated with response to therapy (Mann Whitney p=0.25 and p=0.23, respectively). We identified a statistically significant higher RLC and lower NLR at week 4 in pts with DCB (Mann Whitney p=0.001). Continuous NLR and RLC values at 4 weeks were statistically significantly correlated with OS (HR=1.008, 95% CI 1.001-1.015, p=0.03 and HR=0.939, 95% CI 0.9-0.98, p=0.004 respectively). Using median RLC at 4 weeks as a threshold, pts with high RLC at 4 weeks had significantly favorable survival (log-rank p<0.0001). Using the previously reported cut-off point of NLR=4, pts with NLR>4 had significantly worse OS (log-rank p<0.0001). For pts with acquired resistance to therapy, RLC increased early during treatment followed by a decrease at the time of progression. Conclusions: Our findings suggest early immune cell subset dynamics are associated with clinical outcomes for NSCLC pts treated with anti-PD1 therapy. Our observations reflect the differential immune repertoire shifts and if prospectively validated may be used to stratify pts receiving immune targeted agents.
Serum NY-ESO-1 and XAGE1 antibodies as predictive biomarkers in anti-PD-1 therapy for non-small-cell lung cancer.
Authors: Oka Mikio , Ohue Yoshihiro , Kurose Koji , Karasaki Takahiro , Masuda Takeshi , Fukuda Masaaki , Kinoshita Akitoshi , Shimizu Katsuhiko , Nakata Masao , Hattori Noboru , Kakimi Kazuhiro , Yamaguchi Hiroyuki , Fukuda Minoru 
Published: July 2019

106 Background: Programmed death-1 (PD-1) inhibitors effectively treat non-small-cell lung cancer (NSCLC) and prolong survival, but the clinical benefits are limited in a small population. However, robust biomarkers for predicting clinical benefits with anti-PD-1 therapy have yet to be identified, therefore, predictive biomarkers are needed to select patients with benefits. On the other hand, NSCLC expresses NY-ESO-1 and XAGE1 cancer-testis antigens, which elicit spontaneous immune responses in NSCLC patients. Methods: We conducted a prospective multicenter study to investigate whether serum antibody against NY-ESO-1 and/or XAGE1 antigens was a predictive biomarker in anti-PD-1 therapy for NSCLC. Serum antibody was serially detected by ELISA, and antibody titers were monitored during anti-PD-1 therapy. Tumor tissues were analyzed by immunohistochemistry and whole exome sequencing. Objective response rate (ORR) and survival were the primary and secondary endpoint, respectively. Results: In the discovery cohort (n = 13), six antibody-positive NSCLC responded to anti-PD-1 therapy (two complete and four partial responses), whereas seven antibody-negative NSCLC did not. Antibody positivity was associated with good response and survival, regardless of tumor PD-ligand1 expression, mutation burden, and CD8 T-cell infiltration. In the independent validation cohort (n = 40), ten antibody-positive NSCLC obtained the significant clinical benefits with anti-PD-1 therapy as compared with 30 negative NSCLC (ORR 50% vs 6.7%, P = 0.006). In the multivariate analysis, only antibody positivity was a significantly better predictive biomarker of progression free survival (HR 0.04, 95% CI 0.0 to 0.3) and overall survival (HR 0.2, 95% CI 0.0 to 0.9) after anti-PD-1 therapy. Antibody titers in responders transiently increased with spikes and gradually decreased with tumor shrinkage after anti-PD-1 therapy, and strongly correlated with tumor reduction rates and tumor burden. Conclusions: Our results suggest that NY-ESO-1 and/or XAGE1 serum antibodies are useful biomarkers for predicting clinical benefits and monitoring tumor burden in anti-PD-1 therapy for NSCLC.
Phase Ib/II trial of lenvatinib plus pembrolizumab in urothelial cancer.
Authors: Vogelzang Nicholas J. , Encarnacion Carlos A. , Cohn Allen Lee , DiSimone Christopher , Rasco Drew W. , Richards Donald A. , Taylor Matthew H. , Dutcus Corina E. , Stepan Daniel E. , Shumaker Robert Charles , Guo Matthew , Schmidt Emmett V. , Mier James Walter 
Published: July 2019

11 Background: Pembrolizumab (PEM), an anti-PD-1 antibody, is approved for advanced urothelial cancer in the second-line setting (objective response rate [ORR] 21%) and in the first-line setting for patients (pts) ineligible for cisplatin with combined positive score ≥10 or ineligible for platinum-based chemotherapy (ORR 29%). Tyrosine kinase inhibitors such as lenvatinib (LEN; a multikinase inhibitor of VEGFR 1-3, FGFR 1-3, PDGFRα, RET and KIT) have demonstrated activity in urothelial cancer and may reverse the immunosuppressive environment that leads to immuno-oncology (IO) failure. We present a phase 1b/2 trial of LEN + PEM in advanced urothelial cancer. Methods: In this multicenter, open-label study, pts with confirmed metastatic urothelial cancer and ECOG PS of 0 or 1 received oral LEN 20 mg/day + PEM (200 mg Q3W, IV). Pts were not preselected for PD-L1 status. The phase 2 primary end point was investigator-assessed ORR at week 24 (ORRwk24) per immune-related RECIST (irRECIST). Secondary end points included ORR, duration of response (DOR), and progression-free survival (PFS). Results: At data cutoff (March 1, 2018), 20 pts were enrolled: 9 (45%) PD-L1(+), 5 (25%) PD-L1(-); 6 (30%) not tested. 4 Pts (20%) were treatment-naïve; 11 (55%) and 5 (25%) pts had had 1 and 2 lines of prior anticancer therapies, respectively. No pt had received prior IO. ORRwk24 was 25% (95% CI: 8.7–49.1). 18 (90%) pts had ≥1 treatment-related adverse event (TRAE). Grade 3 and 4 TRAEs occurred in 5 (25%) and 5 (25%) pts, respectively. There was 1 fatal TRAE (gastrointestinal hemorrhage). The most common any-grade TRAEs were proteinuria (45%), diarrhea (40%), fatigue (30%), hypertension (30%), and hypothyroidism (30%). Conclusions: LEN + PEM demonstrated activity in this study of pts with advanced urothelial cancer, which included pts receiving later-line treatment, and deserves further investigation. Clinical trial information: NCT02501096. [Table: see text]
Responses to immune checkpoint therapy in pulmonary sarcomatoid carcinoma: A retrospective review.
Authors: Sukrithan Vineeth , Sandler Jason , Gucalp Rasim A. , Gralla Richard J. , Halmos Balazs 
Published: July 2019

115 Background: Advanced Pulmonary Sarcomatoid Carcinoma (PSC) is associated with poor response to chemotherapy and a median survival of 4-6 months. PSC have a high frequency of PD-L1 positivity and high tumor mutational burden, which are markers of benefit with immune checkpoint inhibitors (ICPI). The parameters of response and survival for PSC treated in the era of immune checkpoint inhibition are unknown. Methods: A review of all cases of advanced PSC diagnosed at two institutions in Bronx, NY between 6/2015-6/2018 was performed. Responses were assessed by serial imaging obtained during routine care and graded by RECIST criteria v 1.1. Results: Five cases of advanced Stage IV PSC are reported. The median age was 57 years and all had received ICPI. All cases were smokers with a median of 30 pack-years and TPS > 75%. Three patients received Pembrolizumab as front-line therapy. Responses were seen in four out of five patients, including one complete response. The fifth patient had prolonged disease stability. After a median follow-up of 13 months, none of the patients had progressed. One patient died of infectious complications after 23 months with no evidence of progression. Four patients continue to be alive with ongoing OS ranging between 14-33 months. Conclusions: ICPI therapy has robust activity in advanced PSC and offers an effective line of therapy in this treatment-refractory aggressive malignancy. [Table: see text]
Development and correlative analysis of a TML assay in specimens with reference MSI and somatic variant results.
Authors: Mellert Hestia S. , Jackson Leisa , Pestano Gary Anthony 
Published: July 2019

124 Background: Treatment of late-stage non-small cell lung cancer has been greatly impacted by the advances in immunotherapy. Molecular biomarkers such as tumor mutation load (TML or TMB) and micro-satellite instability (MSI) may identify patients with NSCLC that are more likely to respond to immune checkpoint inhibitors. In this report, we describe the development of and NGS-based assay for the robust detection of TML and somatic variants simultaneously using a targeted assay that covers 1.7 Mb of the genome. Methods: Initial feasibility included reference control cell-lines, HCC1143 and NIST8398, as well as FFPE (formalin-fixed, paraffin-embedded) samples from lung and colorectal tumors. In development, eight FFPE specimens from patients with late stage cancer and a reference MSI status were evaluated. FFPE slides were extracted using the MagMax FFPE DNA/RNA Ultra kit, and nucleic acid quality was assessed using qPCR. Extracted DNA was processed through the Oncomine TML Assay with a minimum input of 30 ng of DNA per specimen. Automated library and template preparation were performed followed by sequencing on the Ion GeneStudio S5 Plus system using replicate 540 chips. Eight samples with barcoded adapters were multiplexed per chip. Tumor mutation analysis and variant calling was performed using the Oncomine TML v2.0 workflow. Results: The time from FFPE extraction to result was 96 hours, and all samples passed QC metrics. TML scores ranged from 14.4-36.04 mutations/Mb for all samples with MSI-high reference results. A very high level of inter-chip concordance was also observed (R2=0.990). Additionally, the variant caller function within the TML workflow was used to detect BRAF V600E mutations with 100% concordance to reference testing results. Conclusions: The accurate quantification of somatic mutations paired with fast turn-around time and robust automated workflow is ideal for assessing the tumor mutation load as well as hotspot mutations from limited (FFPE) samples.