bluuebunny/crossref_metadata_2025_split huggingface dataset:
BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression
Authors: Konkle Barbara A. , Walsh Christopher E. , Escobar Miguel A. , Josephson Neil C. , Young Guy , von Drygalski Annette , McPhee Scott W. J. , Samulski R. Jude , Bilic Ivan , de la Rosa Maurus , Reipert Birgit M. , Rottensteiner Hanspeter , Scheiflinger Friedrich , Chapin John C. , Ewenstein Bruce , Monahan Paul E. 
Published: October 2020

Abstract
Gene therapy has the potential to maintain therapeutic blood clotting factor IX (FIX) levels in patients with hemophilia B by delivering a functional human F9 gene into liver cells. This phase 1/2, open-label dose-escalation study investigated BAX 335 (AskBio009, AAV8.sc-TTR-FIXR338Lopt), an adeno-associated virus serotype 8 (AAV8)–based FIX Padua gene therapy, in patients with hemophilia B. This report focuses on 12-month interim analyses of safety, pharmacokinetic variables, effects on FIX activity, and immune responses for dosed participants. Eight adult male participants (aged 20-69 years; range FIX activity, 0.5% to 2.0%) received 1 of 3 BAX 335 IV doses: 2.0 × 1011; 1.0 × 1012; or 3.0 × 1012 vector genomes/kg. Three (37.5%) participants had 4 serious adverse events, all considered unrelated to BAX 335. No serious adverse event led to death. No clinical thrombosis, inhibitors, or other FIX Padua–directed immunity was reported. FIX expression was measurable in 7 of 8 participants; peak FIX activity displayed dose dependence (32.0% to 58.5% in cohort 3). One participant achieved sustained therapeutic FIX activity of ∼20%, without bleeding or replacement therapy, for 4 years; in others, FIX activity was not sustained beyond 5 to 11 weeks. In contrast to some previous studies, corticosteroid treatment did not stabilize FIX activity loss. We hypothesize that the loss of transgene expression could have been caused by stimulation of innate immune responses, including CpG oligodeoxynucleotides introduced into the BAX 335 coding sequence by codon optimization. This trial was registered at www.clinicaltrials.gov as #NCT01687608.
High frequency of clonal hematopoiesis in Erdheim-Chester disease
Authors: Cohen Aubart Fleur , Roos-Weil Damien , Armand Marine , Marceau-Renaut Alice , Emile Jean-François , Duployez Nicolas , Charlotte Frédéric , Poulain Stéphanie , Lhote Raphael , Hélias-Rodzewicz Zofia , Della-Valle Véronique , Bernard Olivier , Maloum Karim , Nguyen-Khac Florence , Donadieu Jean , Amoura Zahir , Abdel-Wahab Omar , Haroche Julien 
Published: October 2020

Abstract
Erdheim-Chester disease (ECD) is a clonal hematopoietic disorder characterized by the accumulation of foamy histiocytes within organs (in particular, frequent retroperitoneal involvement) and a high frequency of BRAFV600E mutations. Although ECD is not commonly recognized to have overt peripheral blood (PB) or bone marrow (BM) disease, we recently identified that ECD patients have a high frequency of a concomitant myeloid malignancy. We thus conducted a systematic clinical and molecular analysis of the BM from 120 ECD patients. Surprisingly, 42.5% of ECD patients (51 of 120) had clonal hematopoiesis whereas 15.8% of patients (19 of 120) developed an overt hematologic malignancy (nearly all of which were a myeloid neoplasm). The most frequently mutated genes in BM were TET2, ASXL1, DNMT3A, and NRAS. ECD patients with clonal hematopoiesis were more likely to be older (P &lt; .0001), have retroperitoneal involvement (P = .02), and harbor a BRAFV600E mutation (P = .049) than those without clonal hematopoiesis. The presence of the TET2 mutation was associated with a BRAFV600E mutation in tissue ECD lesions (P = .0006) and TET2-mutant ECD patients were more likely to have vascular involvement than TET2 wild-type ECD patients. Clonal hematopoiesis mutations in ECD were detected in cells derived from CD34+CD38− BM progenitors and PB monocytes but less frequently present in PB B and T lymphocytes. These data identify a heretofore unrecognized high frequency of clonal hematopoiesis in ECD patients, reaffirm the development of additional high risk of myeloid neoplasms in ECD, and provide evidence of a BM-based precursor cell of origin for many patients with ECD.
Evaluation of Longitudinal Pain Study in Sickle Cell Disease (ELIPSIS) by patient-reported outcomes, actigraphy, and biomarkers
Authors: Pittman Debra D. , Hines Patrick C. , Beidler David , Rybin Denis , Frelinger Andrew L. , Michelson Alan D. , Liu Ke , Gao Xiufeng , White Jennell , Zaidi Ahmar U. , Charnigo Robert J. , Callaghan Michael U. 
Published: October 2020

AbstractClinical trials in sickle cell disease (SCD) often focus on health care utilization for painful vaso-occlusive crises (VOCs). However, no objective, quantifiable pain biomarkers exist, pain is not specific to VOCs, health care utilization varies between patients, unreported at-home VOCs likely contribute to long-term outcomes, and patient-reported outcomes are seldom considered. This noninterventional, longitudinal, 6-month study aimed to develop tools to identify VOCs in SCD patients with or without health care utilization. Participants wore an actigraph device, tracking sleep and activity. Patients with SCD used an electronic patient-reported outcome (ePRO) tool to collect data on pain, medication, fatigue, and daily function. Patients self-reported when they experienced VOC pain (VOC day). Biomarkers were collected every 3 weeks (non-VOC). Self-reported VOCs triggered at-home or in-hospital blood collection. The study enrolled 37 participants with SCD; 35 completed the study. Participants reported 114 VOC events and 346 VOC days, of which 62.3% and 78.3%, respectively, were self-treated at home. The ePRO and actigraphy captured end points of pain, functionality, fatigue, activity, and sleep; each was significantly altered on VOC days compared with non-VOC days. Biomarkers collected at home or in the hospital on VOC days were significantly altered compared with non-VOC baseline values, including leukocyte-platelet aggregates, microfluidic-based blood cell adhesion, interleukin-6, C-reactive protein, interleukin-10, tumor necrosis factor-α, and thrombin–antithrombin. The Evaluation of Longitudinal Pain Study in Sickle Cell Disease (ELIPSIS) trial shows the feasibility of accurately monitoring out-of-hospital pain by using patient-reported VOC days as potential end points for clinical trials in SCD; it describes the changes in biomarkers and activity measured by actigraphy that may enable improved identification and assessment of VOCs.
An epitope-based approach of HLA-matched platelets for transfusion: a noninferiority crossover randomized trial
Authors: Marsh Judith C. , Stanworth Simon J. , Pankhurst Laura A. , Kallon Delordson , Gilbertson Adeline Z. , Pigden Collette , Deary Alison J. , Mora Ana S. , Brown Joanne , Laing Emma S. , Choo Louise L. , Hodge Renate , Llewelyn Charlotte A. , Harding Kay , Sage Deborah , Mijovic Aleksandar , Mufti Ghulam J. , Navarrete Cristina V. , Brown Colin J. 
Published: October 2020

AbstractPlatelet transfusion refractoriness results in adverse outcomes and increased health care costs. Managing refractoriness resulting from HLA alloimmunization necessitates the use of HLA antigen–matched platelets but requires a large platelet donor pool and does not guarantee full matching. We report the first randomized, double-blind, noninferiority, crossover trial comparing HLA epitope–matched (HEM) platelets with HLA standard antigen–matched (HSM) platelet transfusions. Alloimmunized, platelet-refractory, thrombocytopenic patients with aplastic anemia, myelodysplastic syndrome, or acute myeloid leukemia were eligible. HEM platelets were selected using HLAMatchMaker epitope (specifically eplet) matching. Patients received up to 8 prophylactic HEM and HSM transfusions provided in random order. The primary outcome was 1-hour posttransfusion platelet count increment (PCI). Forty-nine patients were randomized at 14 UK hospitals. For intention to treat, numbers of evaluable transfusions were 107 and 112 for HEM and HSM methods, respectively. Unadjusted mean PCIs for HEM and HSM methods were 23.9 (standard deviation [SD], 15) and 23.5 (SD, 14.1), respectively (adjusted mean difference, −0.1; 95% confidence interval [CI], −2.9 to 2.8). Because the lower limit of the 95% CI was not greater than the predefined noninferiority limit, the HEM approach was declared noninferior to the HSM approach. There were no differences in secondary outcomes of platelet counts, transfusion requirements, and bleeding events. Adequate 1-hour PCI was more frequently observed, with a mean number of 3.2 epitope mismatches, compared with 5.5 epitope mismatches for inadequate 1-hour increments. For every additional epitope mismatch, the likelihood of an adequate PCI decreased by 15%. Epitope-matched platelets should be considered to support HLA alloimmunized patients. This trial was registered at www.isrctn.com as #ISRCTN23996532.
A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study)
Authors: Brivio Erica , Locatelli Franco , Lopez-Yurda Marta , Malone Andrea , Díaz-de-Heredia Cristina , Bielorai Bella , Rossig Claudia , van der Velden Vincent H. J. , Ammerlaan Anneke C. J. , Thano Adriana , van der Sluis Inge M. , den Boer Monique L. , Chen Ying , Sleight Barbara , Brethon Benoit , Nysom Karsten , Sramkova Lucie , Øra Ingrid , Vinti Luciana , Chen-Santel Christiane , Zwaan Christian Michel 
Published: October 2020

Abstract
This phase 1 study investigated the recommended phase 2 dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple relapsed/refractory (R/R) CD22+ acute lymphoblastic leukemia (ALL). Patients (age ≥1 year or &lt;18 years) received 3 doses of InO (days 1, 8, and 15) per course. Dose escalation was based on dose-limiting toxicities (DLTs) during course 1. Dose level 1 (DL1) was 1.4 mg/m2 (0.6, 0.4, 0.4 mg/m2) and DL2 was 1.8 mg/m2 (0.8, 0.5, 0.5 mg/m2). Secondary end points included safety, antileukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLTs) were enrolled. In course 1, the first cohort had 1 of 6 (DL1) and 2 of 5 (DL2) patients who experienced DLTs; subsequent review considered DL2 DLTs to be non–dose-limiting. Dose was de-escalated to DL1 while awaiting protocol amendment to re-evaluate DL2 in a second cohort, in which 0 of 6 (DL1) and 1 of 6 (DL2) patients had a DLT. Twenty-three patients experienced grade 3 to 4 adverse events; hepatic sinusoidal obstruction syndrome was reported in 2 patients after subsequent chemotherapy. Overall response rate after course 1 was 80% (95% confidence interval [CI], 59% to 93%) (20 of 25 patients; DL1: 75% [95% CI, 43% to 95%], DL2: 85% [95% CI, 55% to 98%]). Of the responders, 84% (95% CI, 60% to 97%) achieved minimal residual disease (MRD)-negative complete response, and 12-month overall survival was 40% (95% CI, 25% to 66%). Nine patients received hematopoietic stem cell transplantation or chimeric antigen receptor T cells after InO. InO median maximum concentrations were comparable to simulated adult concentrations. InO was well tolerated, demonstrating antileukemic activity in heavily pretreated children with CD22+ R/R ALL. RP2D was established as 1.8 mg/m2 per course, as in adults. This trial was registered at https://www.clinicaltrialsregister.eu as EUDRA-CT 2016-000227-71.
Incidence, risk factors, and outcomes of venous and arterial thromboembolism in immune checkpoint inhibitor therapy
Authors: Moik Florian , Chan Wei-Shin Evelyn , Wiedemann Sarah , Hoeller Christoph , Tuchmann Felix , Aretin Marie-Bernadette , Fuereder Thorsten , Zöchbauer-Müller Sabine , Preusser Matthias , Pabinger Ingrid , Ay Cihan 
Published: October 2020

Abstract
The risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE) associated with immune checkpoint inhibitors is currently unclear. Our aim was to quantify the risk of VTE/ATE in patients with cancer treated with immune checkpoint inhibitors, explore clinical impact, and investigate potential clinical risk factors. Patients treated with immune checkpoint inhibitors at the Medical University of Vienna from 2015 to 2018 were identified using in-house pharmacy records (n = 672; most frequent entities: 30.4% melanoma, 24.1% non-small cell lung cancer; 86% stage IV disease). A retrospective chart review was performed to screen for VTE and/or ATE. Cumulative incidences and between-group differences were estimated in competing-risk analysis. The impact of VTE/ATE on mortality was studied by multistate modelling. Over a median follow-up of 8.5 months, 47 VTEs and 9 ATEs were observed. Cumulative incidences of VTE and ATE were 12.9% (95% confidence interval [CI], 8.2-18.5) and 1.8% (95% CI, 0.7-3.6). Occurrence of VTE was associated with increased mortality (transition hazard ratio, 3.09; 95% CI, 2.07-4.60). History of VTE predicted VTE occurrence (subdistribution hazard ratio [SHR], 3.69; 95% CI, 2.00-6.81), and distant metastasis was nonsignificantly associated with VTE risk (SHR, 1.71; 95% CI, 0.62-4.73). No association of VTE with Eastern Cooperative Oncology Group performance status, Charlson comorbidity index, or Khorana score was observed, and rates of VTE were comparable between tumor types and checkpoint-inhibitory agents. In conclusion, patients with cancer under immune checkpoint inhibitor therapy are at high risk of thromboembolism, especially VTE. Furthermore, VTE occurrence was associated with increased mortality.
Nanotechnology approaches to addressing HER2-positive breast cancer
Authors: White Bryan E. , White Molly K. , Adhvaryu Het , Makhoul Issam , Nima Zeid A. , Biris Alexandru S. , Ali Nawab 
Published: October 2020

AbstractBreast cancer is a major cause of cancer-associated deaths in the United States. It was estimated that 12% of women in the U.S. will develop invasive breast cancer in their lifetime. The human epidermal growth factor receptor (HER2/neu) is a growth-promoting protein that is overexpressed in 15–20% of breast cancers (HER2-positive breast cancer). HER2-positive breast cancer generally grows and spreads more quickly than other breast cancers, but it can be targeted therapeutically. Targeting drugs have been developed with a specific design to stop the growth and even the spread of cancer. These drugs include trastuzumab (Herceptin), pertuzumab (Perjeta), ado-trastuzumab emtansine (Kadcyla, or TDM-1), fam-trastuzumab deruxtecan, lapatinib, neratinib and tucatinib. However, the need for better targeted therapy and efficacy still exists. Nanotechnology could have major advantages in terms of detection, targeting, drug delivery, and destruction of cancer cells and tumors. Although a great deal of progress has been accomplished major challenges still need to be addressed. In this review, we examine the major areas of research in the area of nanotechnology and HER2-positive breast cancer.
Genome-wide analysis and prediction of genes involved in the biosynthesis of polysaccharides and bioactive secondary metabolites in high-temperature-tolerant wild Flammulina filiformis
Authors: Chen Juan , Li Jia-Mei , Tang Yan-Jing , Ma Ke , Li Bing , Zeng Xu , Liu Xiao-Bin , Li Yang , Yang Zhu-Liang , Xu Wei-Nan , Xie Bao-Gui , Liu Hong-Wei , Guo Shun-Xing 
Published: October 2020

Abstract
Background
Flammulina filiformis (previously known as Asian F. velutipes) is a popular commercial edible mushroom. Many bioactive compounds with medicinal effects, such as polysaccharides and sesquiterpenoids, have been isolated and identified from F. filiformis, but their biosynthesis and regulation at the molecular level remains unclear. In this study, we sequenced the genome of the wild strain F. filiformis Liu355, predicted its biosynthetic gene clusters (BGCs) and profiled the expression of these genes in wild and cultivar strains and in different developmental stages of the wild F. filiformis strain by a comparative transcriptomic analysis.

Results
We found that the genome of the F. filiformis was 35.01 Mb in length and harbored 10,396 gene models. Thirteen putative terpenoid gene clusters were predicted and 12 sesquiterpene synthase genes belonging to four different groups and two type I polyketide synthase gene clusters were identified in the F. filiformis genome. The number of genes related to terpenoid biosynthesis was higher in the wild strain (119 genes) than in the cultivar strain (81 genes). Most terpenoid biosynthesis genes were upregulated in the primordium and fruiting body of the wild strain, while the polyketide synthase genes were generally upregulated in the mycelium of the wild strain. Moreover, genes encoding UDP-glucose pyrophosphorylase and UDP-glucose dehydrogenase, which are involved in polysaccharide biosynthesis, had relatively high transcript levels both in the mycelium and fruiting body of the wild F. filiformis strain.

Conclusions
F. filiformis is enriched in a number of gene clusters involved in the biosynthesis of polysaccharides and terpenoid bioactive compounds and these genes usually display differential expression between wild and cultivar strains, even in different developmental stages. This study expands our knowledge of the biology of F. filiformis and provides valuable data for elucidating the regulation of secondary metabolites in this unique F. filiformis strain.
Combination of modified carbapenem inactivation method (mCIM) and EDTA-CIM (eCIM) for phenotypic detection of carbapenemase-producing Enterobacteriaceae
Authors: Tsai Ya-Min , Wang Shining , Chiu Hui-Chuan , Kao Cheng-Yen , Wen Li-Li 
Published: October 2020

Abstract
Background
Carbapenemase-resistant Enterobacteriaceae (CRE) cause many serious infections resulting in increasing treatment cost, prolonged hospitalization, and mortality rate. Reduced expression and/or mutations of porins and the presence of carbapenemase promote Enterobacteriaceae survival under carbapenem treatments. Development of accurate methods for the detection of antimicrobial resistance is required not only for therapy but also to monitor the spread of resistant bacteria or resistance genes throughout the hospital and community. In this study, we aimed to evaluate the phenotypic methods, Modified Hodge test (MHT), modified carbapenem inactivation method (mCIM), and EDTA-CIM (eCIM) for the detection of carbapenemase-producing Enterobacteriaceae (CPE).

Results
The results showed that mCIM had a sensitivity of 100% and a specificity of 100%, whereas the MHT had a sensitivity of 84.8% and a specificity of 97.8% for the 195 CRE isolates tested (105 CPE and 90 non-CPE isolates). The sensitivity of the mCIM/eCIM to detect metallo-carbapenemases in this study was 89.3% and the specificity was 98.7% as compared to the genotypic PCR detection.

Conclusions
These findings indicate that the mCIM combined with eCIM is useful for detecting and distinguishing different types of carbapenemase in Enterobacteriaceae.
Changes in hepatic fibrosis and vitamin D levels after viral hepatitis C eradication using direct-acting antiviral therapy
Authors: Sriphoosanaphan Supachaya , Thanapirom Kessarin , Suksawatamnuay Sirinporn , Thaimai Panarat , Sittisomwong Sukanya , Sonsiri Kanokwan , Srisoonthorn Nunthiya , Teeratorn Nicha , Tanpowpong Nattaporn , Chaopathomkul Bundit , Treeprasertsuk Sombat , Poovorawan Yong , Komolmit Piyawat 
Published: October 2020

Abstract
Background
Vitamin D (VD) is important in hepatic fibrogenesis in animal models and human studies. VD deficiency is associated with liver fibrosis progression. Metabolic dysfunction of the liver, as an intermediate organ for VD metabolism, contributes partly to this deficiency. We hypothesized that improving hepatic fibrosis and inflammation in chronic hepatitis C (CHC) patients after eradication with direct-acting antivirals (DAA) would increase 25-hydroxyVD [25(OH)VD] levels.

Methods
Eighty CHC patients (17 chronic hepatitis, and 63 cirrhosis) were enrolled. Baseline characteristics, hepatitis C viral load (VL), genotypes, liver enzymes and liver stiffness measurements (LSM) were assessed at baseline. Blood samples for 25(OH)VD and the procollagen type III N-terminal peptide (P3NP) were collected at baseline, 24 and 48 weeks. LSMs were re-evaluated at 48 weeks. Serum 25(OH)VD levels < 30 ng/mL were defined as VD insufficiency/deficiency. Paired t-tests were used for statistical analyses.

Results
Among 80 patients, the mean age was 57.7 ± 10.5 years, and 52.5% were men. The mean VL was 6.1 ± 0.7 logIU/mL with genotype 1 predominance (55%). All patients achieved sustained virological response. The alanine aminotransferase levels decreased from 79.9 ± 53.3 U/L at baseline to 25.7 ± 17.2 and 22.3 ± 11.0 U/L at 24 and 48 weeks, respectively (p < 0.001). The mean LSM decreased from 19.2 ± 15.3 to 11.7 ± 8.0 kPa at 48 weeks (p < 0.001). The P3NP levels decreased from 43.6 ± 22.0 ng/mL before treatment to 35.7 ± 21.1 and 29.4 ± 15.0 ng/mL at 24 and 48 weeks, respectively (p < 0.001). The proportions of VD insufficiency/deficiency were 72.5%, 91.3%, and 86.5% at baseline, 24 and 48 weeks, respectively. The 25(OH)VD levels decreased from 26.3 ± 10.7 ng/mL at baseline to 20.8 ± 8.1 and 20.8 ± 8.5 ng/mL at 24 and 48 weeks, respectively (p < 0.001).

Conclusions
Curative treatment with DAA attenuated the liver stiffness and inflammation but did not improve VD levels. Over 80% of patients remained VD insufficient/deficient. Whether VD replacement during and after DAA therapy can improve hepatic fibrosis remains unclear.

Trial registration The Thai Clinical Trial Registry as TCTR20161025001 (31 October 2016). http://www.clinicaltrials.in.th/index.php?tp=regtrials&menu=trialsearch&smenu=fulltext&task=search&task2=view1&id=2136.
Completeness of tuberculosis case notifications in Germany in 2013–2017: first results of an inventory study
Authors: Domaszewska Teresa , Karo Basel , Preuss Ute , Kollan Christian , Reuss Annicka , Blank Hans-Peter , Brodhun Bonita , Hauer Barbara , Altmann Doris , Fiebig Lena , Haas Walter , Perumal Nita 
Published: October 2020

Abstract
Background
Evaluating the completeness of tuberculosis (TB) notification data is important for monitoring of TB surveillance systems. We conducted an inventory study to calculate TB underreporting in Germany in 2013–2017.

Methods
Acquisition of two pseudonymized case-based data sources (national TB notification data and antibiotic resistance surveillance data) was followed by two-source Capture-recapture (CRC) analysis, as case-based data from a third source was unavailable. Aggregated data on consumption of a key anti-TB drug (pyrazinamide [PZA]) was compared to an estimated need for PZA based on TB notification data to obtain an independent underreporting estimation. Additionally, notified TB incidence was compared to TB rate in an aggregated health insurance fund dataset.

Results
CRC and PZA-based approaches indicated that between 93 and 97% (CRC) and between 91 and 95% (PZA) of estimated cases were captured in the national TB notification data in the years 2013–2017. Insurance fund dataset did not indicate TB underreporting on the national level in 2017.

Conclusions
Our results suggest that more than 90% of estimated TB cases are captured within the German TB surveillance system, and accordingly the TB notification rate is likely a good proxy of the diagnosed TB incidence rate. An increase in underreporting and discrepancies however should be further investigated.