bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma
Authors: Sauter Craig S. , Senechal Brigitte , Rivière Isabelle , Ni Ai , Bernal Yvette , Wang Xiuyan , Purdon Terence , Hall Malloury , Singh Ashvin N. , Szenes Victoria Z. , Yoo Sarah , Dogan Ahmet , Wang Yongzeng , Moskowitz Craig H. , Giralt Sergio , Matasar Matthew J. , Perales Miguel-Angel , Curran Kevin J. , Park Jae , Sadelain Michel , Brentjens Renier J. 
Published: July 2019

AbstractHigh-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) is the standard of care for relapsed or primary refractory (rel/ref) chemorefractory diffuse large B-cell lymphoma. Only 50% of patients are cured with this approach. We investigated safety and efficacy of CD19-specific chimeric antigen receptor (CAR) T cells administered following HDT-ASCT. Eligibility for this study includes poor-risk rel/ref aggressive B-cell non-Hodgkin lymphoma chemosensitive to salvage therapy with: (1) positron emission tomography–positive disease or (2) bone marrow involvement. Patients underwent standard HDT-ASCT followed by 19-28z CAR T cells on days +2 and +3. Of 15 subjects treated on study, dose-limiting toxicity was observed at both dose levels (5 × 106 and 1 × 107 19-28z CAR T per kilogram). Ten of 15 subjects experienced CAR T-cell–induced neurotoxicity and/or cytokine release syndrome (CRS), which were associated with greater CAR T-cell persistence (P = .05) but not peak CAR T-cell expansion. Serum interferon-γ elevation (P &lt; .001) and possibly interleukin-10 (P = .07) were associated with toxicity. The 2-year progression-free survival (PFS) is 30% (95% confidence interval, 20% to 70%). Subjects given decreased naive-like (CD45RA+CCR7+) CD4+ and CD8+ CAR T cells experienced superior PFS (P = .02 and .04, respectively). There was no association between CAR T-cell peak expansion, persistence, or cytokine changes and PFS. 19-28z CAR T cells following HDT-ASCT were associated with a high incidence of reversible neurotoxicity and CRS. Following HDT-ASCT, effector CD4+ and CD8+ immunophenotypes may improve disease control. This trial was registered at www.clinicaltrials.gov as #NCT01840566.
Platelet hyaluronidase-2 regulates the early stages of inflammatory disease in colitis
Authors: Petrey Aaron C. , Obery Dana R. , Kessler Sean P. , Zawerton Ash , Flamion Bruno , de la Motte Carol A. 
Published: July 2019

Abstract
Platelets are specialized cells essential for hemostasis that also function as crucial effectors capable of mediating inflammatory and immune responses. These sentinels continually survey their environment and discriminate between homeostatic and danger signals such as modified components of the extracellular matrix. The glycosaminoglycan hyaluronan (HA) is a major extracellular matrix component that coats the vascular lumen and, under normal conditions, restricts access of inflammatory cells. In response to tissue damage, the endothelial HA matrix enhances leukocyte recruitment and regulates the early stages of the inflammatory response. We have shown that platelets can degrade HA from the surface of activated endothelial cells via the enzyme hyaluronidase-2 (HYAL2) and that HYAL2 is deficient in platelets isolated from patients with inflammatory bowel disease (IBD). Platelets are known to be involved in the pathogenesis of several chronic disease states, including IBD, but they have been largely overlooked in the context of intestinal inflammation. We therefore wanted to define the mechanism by which platelet HYAL2 regulates the inflammatory response during colitis. In this study, we provide evidence that HA catabolism is disrupted in human intestinal microvascular endothelial cells isolated from patients with IBD. Furthermore, mice deficient in HYAL2 are more susceptible to an acute model of colitis, and this increased susceptibility is abrogated by transfusion of HYAL2-competent platelets. Finally, we show that platelets, via HYAL2-dependent degradation of endothelial HA, regulate the early stages of inflammation in colitis by limiting leukocyte extravasation.
Proximity proteomics of endothelial Weibel-Palade bodies identifies novel regulator of von Willebrand factor secretion
Authors: Holthenrich Anna , Drexler Hannes C. A. , Chehab Tarek , Naß Johannes , Gerke Volker 
Published: July 2019

Abstract
Weibel-Palade (WPB) bodies are endothelial cell organelles that store von Willebrand factor (VWF) and other proteins important for vascular hemostasis. Holthenrich and colleagues used an elegant proximity proteomics approach to compile a complete catalog of WPB-associated proteins and identify Munc13-2 as a novel factor mediating VWF secretion via WPB exocytosis.
Hormonal Regulation of Patient-Derived Endometrial Cancer Stem-like Cells Generated by Three-Dimensional Culture
Authors: Shiba Sachiko , Ikeda Kazuhiro , Suzuki Takashi , Shintani Daisuke , Okamoto Koji , Horie-Inoue Kuniko , Hasegawa Kosei , Inoue Satoshi 
Published: July 2019

Abstract
Low-grade and early-stage endometrial cancer usually has a favorable prognosis, whereas recurrent or metastatic disease is often difficult to cure. Thus, the molecular mechanisms underlying advanced pathophysiology remain to be elucidated. From the perspective of the origin of advanced endometrial cancer, the characterization of cancer stem-like cells (CSCs) will be the first step toward the development of clinical management. We established long-term culturable patient-derived cancer cells (PDCs) from patient endometrial tumors by spheroid cell culture, which is favorable for the enrichment of CSCs. PDC-derived xenograft tumors were generated in immunodeficient NOD/Shi-scid, IL-2RγKO Jic mice. Morphologically, PDCs derived from three distinct patient samples and their xenograft tumors recapitulated the corresponding original patient tumors. Of note, CSC-related genes including ALDH1A1 were upregulated in all of these PDCs, and the therapeutic potentiality of aldehyde dehydrogenase inhibitors was demonstrated. In addition, these PDCs and their patient-derived xenograft (PDX) models exhibited distinct characteristics on the basis of their hormone responsiveness and metastatic features. Interestingly, genes associated with inflammation and tumor immunity were upregulated by 17β-estradiol in PDC lines with high estrogen receptor expression and were also overexpressed in secondary PDCs obtained from metastatic tumor models. These results suggest that PDC and PDX models from endometrial cancer specimens would be useful to elucidate CSC traits and to develop alternative diagnostic and therapeutic options for advanced disease.
In Silico Predictions of Endocrine Disruptors Properties
Authors: Schneider Melanie , Pons Jean-Luc , Labesse Gilles , Bourguet William 
Published: July 2019

Abstract
Endocrine-disrupting chemicals (EDCs) are a broad class of molecules present in our environment that are suspected to cause adverse effects in the endocrine system by interfering with the synthesis, transport, degradation, or action of endogenous ligands. The characterization of the harmful interaction between environmental compounds and their potential cellular targets and the development of robust in vivo, in vitro, and in silico screening methods are important for assessment of the toxic potential of large numbers of chemicals. In this context, computer-aided technologies that will allow for activity prediction of endocrine disruptors and environmental risk assessments are being developed. These technologies must be able to cope with diverse data and connect chemistry at the atomic level with the biological activity at the cellular, organ, and organism levels. Quantitative structure–activity relationship methods became popular for toxicity issues. They correlate the chemical structure of compounds with biological activity through a number of molecular descriptors (e.g., molecular weight and parameters to account for hydrophobicity, topology, or electronic properties). Chemical structure analysis is a first step; however, modeling intermolecular interactions and cellular behavior will also be essential. The increasing number of three-dimensional crystal structures of EDCs’ targets has provided a wealth of structural information that can be used to predict their interactions with EDCs using docking and scoring procedures. In the present review, we have described the various computer-assisted approaches that use ligands and targets properties to predict endocrine disruptor activities.
Antidepressants Reduced Risk of Mortality in Patients With Diabetes Mellitus: A Population-Based Cohort Study in Taiwan
Authors: Chen Hong-Ming , Yang Yao-Hsu , Chen Ko-Jung , Lee Yena , McIntyre Roger S , Lu Mong-Liang , Lee Yi-Chen , Hsieh Ming-Chia , Chen Vincent Chin-Hung 
Published: July 2019

Abstract

Context
The effect of antidepressant (ATD) use on mortality in patients with diabetes mellitus (DM) has not yet been sufficiently studied, although comorbid depression is common in this population.

Objective
To explore the impact of ATDs on mortality among DM patients.

Design
A retrospective cohort study in a national database.

Setting
This population-based study used the National Health Insurance Research Database in Taiwan. Since 2000, we identified 53,412 cases of newly diagnosed patients with DM and depression. Patient cases were followed for assessing mortality until 2013.

Main Outcome Measure
The association between mortality and ATD use was explored adjusting for cumulative dosing.

Results
Using the time-dependent Cox regression model, ATD use was associated with significantly reduced mortality among patients with DM [in the highest dose group: hazard ratio (HR), 0.65; 95% CI, 0.59 to 0.71]. Further analysis showed that differences in mortality existed across ATD categories: selective serotonin reuptake inhibitors (HR, 0.63; 95% CI, 0.56 to 0.71), serotonin-norepinephrine reuptake inhibitors (HR, 0.58; 95% CI, 0.44 to 0.78), norepinephrine-dopamine reuptake inhibitors (HR, 0.20; 95% CI, 0.07 to 0.63), mirtazapine (HR, 0.60; 95% CI, 0.45 to 0.82), tricyclic/tetracyclic antidepressants (HR, 0.73; 95% CI, 0.54 to 0.97), and trazodone (HR, 0.52; 95% CI, 0.29 to 0.91). However, reversible inhibitor of monoamine oxidase A (RIMA) was found to be associated with an increase, rather than a decrease, in total mortality (HR, 1.48; 95% CI, 1.09 to 1.99).

Conclusion
Most ATDs, but not RIMA, were associated with significantly reduced mortality among a population with comorbid DM and depression.
New Insights Into Pheochromocytoma Surveillance of Young Patients With VHL Missense Mutations
Authors: Fagundes Gustavo F C , Petenuci Janaina , Lourenco Delmar M , Trarbach Ericka B , Pereira Maria Adelaide A , Correa D’Eur Joya Emilie , Hoff Ana O , Lerario Antonio M , Zerbini Maria Claudia N , Siqueira Sheila , Yamauchi Fernando , Srougi Victor , Tanno Fabio Y , Chambo Jose Luis , Latronico Ana Claudia , Mendonca Berenice B , Fragoso Maria Candida B V , Almeida Madson Q 
Published: July 2019

Abstract

Context
Von Hippel-Lindau (VHL) disease is an autosomal dominant syndrome caused by germline mutations in the VHL gene. Guidelines recommend pheochromocytoma (PHEO) biochemical screening should start at age 5 years.

Objective
Genotype–phenotype correlations in VHL, focusing on PHEO penetrance in children, were studied.

Design
We retrospectively evaluated 31 individuals (median age at diagnosis was 26 years) with diagnosed VHL disease.

Results
PHEO was diagnosed in six children with VHL. A large PHEO (5 cm) was detected in a 4-year-old boy with p.Gly114Ser mutation. PHEO penetrance was 55% starting at age 4 years. VHL missense mutations were identified in 11 of 22 families (50%), frameshift mutations in four (18.2%), stop codon in three (13.6%), splicing site in two (9.1%), and large gene deletion in two (9.1%). The codon 167 (n = 10) was a hotspot for VHL mutations and was significantly associated with PHEO (90% vs. 38%; P = 0.007). PHEOs and pancreatic neuroendocrine tumors (PNETs) were strongly associated with VHL missense mutations compared with other mutations (89.5% vs. 0% and 73.7% vs. 16.7%; P = 0.0001 and 0.002, respectively). In contrast, pancreatic cysts (91.7% vs. 26.3%; P = 0.0001), renal cysts (66.7% vs. 26.3%; P = 0.027), and central nervous system hemangioblastomas (91.7% vs. 47.3%; P = 0.012) were more frequent in VHL with nonmissense mutations.

Conclusion
VHL missense mutations were highly associated with PHEO and PNETs. Our data support that in children with VHL harboring missense mutations, biochemical screening for PHEO should be initiated at diagnosis.
Dosimetric comparison of protons vs photons in re-irradiation of intracranial meningioma
Authors: Poel Robert , Stuessi Lobmaier Anja , Andratschke Nicolaus , Unkelbach Jan , Tanadini-Lang Stephanie , Guckenberger Matthias , Foerster Robert 
Published: July 2019

Objectives:
Re-irradiation of recurrent intracranial meningiomas represents a major challenge due to dose limits of critical structures and the necessity of sufficient dose coverage of the recurrent tumor for local control. The aim of this study was to investigate dosimetric differences between pencil beam scanning protons (PBS) and volumetric modulated arc therapy (VMAT) photons for intracranial re-irradiation of meningiomas.

Methods:
Nine patients who received an initial dose &gt;50 Gy for intracranial meningioma and who were re-irradiated for recurrence were selected for plan comparison. A volumetric modulated arc therapy photon and a pencil beam scanning proton plan were generated (prescription dose: 15 × 3 Gy) based on the targets used in the re-irradiation treatment.

Results:
In all cases, where the cumulative dose exceeded 100 or 90 Gy, these high dose volumes were larger for the proton plans. The integral doses were significantly higher in all photon plans (reduction with protons: 48.6%, p &lt; 0.01). In two cases (22.2%), organ at risk (OAR) sparing was superior with the proton plan. In one case (11.1%), the photon plan showed a dosimetric advantage. In the remaining six cases (66.7%), we found no clinically relevant differences in dose to the OARs.

Conclusions:
The dosimetric results of the accumulated dose for a re-irradiation with protons and with photons were very similar. The photon plans had a steeper dose falloff directly outside the target and were superior in minimizing the high dose volumes. The proton plans achieved a lower integral dose. Clinically relevant OAR sparing was extremely case specific. The optimal treatment modality should be assessed individually.

Advances in knowledge:
Dose sparing in re-irradiation of intracranial meningiomas with protons or photons is highly case specific and the optimal treatment modality needs to be assessed on an individual basis.
Effectiveness of a small breast screening programme: 25 year evaluation (25 year breast screening evaluation)
Authors: Nisbet Andrew Patric , Borthwick-Clarke Andrew , Scott Nic , Goulding Helen , Jane Harwood 
Published: July 2019

Objective: To evaluate mammography screening quality on the Island of Jersey over a 25-year period from Jan 1990 to end March 2015 from females invited between ages 50 to 75 using a 2 yearly screening interval. Jersey had a population of only around 67,000 at onset, rising to around 100,000 at the end of the 25 years. Methods: An analysis was performed of key routinely collected measures that are important to determining if a screening programme is on course to reduce breast cancer mortality such as uptake, recall rates, screen detected cancer and interval cancer rates. Further supporting indicators including grade, stage and comparative deaths from breast cancer in screen detected and not screen detected females were also assessed. Results: Over the 25-year period 19,768 females were invited to screening and 16,866 attended, giving an uptake of 85.2%. There were 501 screen detected cancers of which 400 were invasive, and 101 DCIS. 125 interval cancers presented outside screening over the 25 years. The annual recall rate over the last 20 years was <6% for prevalent round and 4% for incident round screening. Based on the standardized detection ratio (SDR) and uptake, the estimated reduction in mortality from breast cancer was calculated as 40.2%. Conclusions: Recommended population sizes for breast units range from a quarter to half a million people. For very small units like Jersey serving smaller populations, rigorous quality control is essential to maintain credibility. Despite the small size of the programme evidence shows a similar detection rate to the UK NHS Breast screening programme was achieved. In small programmes careful monitoring of rates of uptake, recall, cancer detection and interval rates are required over adequate time periods together with supporting information to show that small units can achieve national standards and detection rates necessary to reduce breast cancer mortality. Advances in knowledge: Running a small breast cancer screening programme is challenging for quality control. The impact on mortality can be predicted for small screening programmes despite their size. 10-year group survival in screen detected invasive breast cancer >90%. Interval cancers are more advanced than screen detected invasive cancers, so high suspicion is still required in breast symptoms after "normal" screen result. Mortality in lapsed/ceased attenders suggest that extending age range could be beneficial.
Balancing accuracy and interpretability of machine learning approaches for radiation treatment outcomes modeling
Authors: Luo Yi , Tseng Huan-Hsin , Cui Sunan , Wei Lise , Ten Haken Randall K , El Naqa Issam 
Published: July 2019

Abstract
Radiation outcomes prediction (ROP) plays an important role in personalized prescription and adaptive radiotherapy. A clinical decision may not only depend on an accurate radiation outcomes’ prediction, but also needs to be made based on an informed understanding of the relationship among patients’ characteristics, radiation response and treatment plans. As more patients’ biophysical information become available, machine learning (ML) techniques will have a great potential for improving ROP. Creating explainable ML methods is an ultimate task for clinical practice but remains a challenging one. Towards complete explainability, the interpretability of ML approaches needs to be first explored. Hence, this review focuses on the application of ML techniques for clinical adoption in radiation oncology by balancing accuracy with interpretability of the predictive model of interest. An ML algorithm can be generally classified into an interpretable (IP) or non-interpretable (NIP) (“black box”) technique. While the former may provide a clearer explanation to aid clinical decision-making, its prediction performance is generally outperformed by the latter. Therefore, great efforts and resources have been dedicated towards balancing the accuracy and the interpretability of ML approaches in ROP, but more still needs to be done. In this review, current progress to increase the accuracy for IP ML approaches is introduced, and major trends to improve the interpretability and alleviate the “black box” stigma of ML in radiation outcomes modeling are summarized. Efforts to integrate IP and NIP ML approaches to produce predictive models with higher accuracy and interpretability for ROP are also discussed.
Current status of stereotactic ablative body radiotherapy in the UK: six years of progress
Authors: Distefano Gail , Garikipati Satya , Grimes Helen , Hatton Matthew 
Published: July 2019

Objective: To update the 2012 UK stereotacticablative radiotherapy (SABR) Consortium survey and assess the development of SABR services across the UK over the past 6 years. Use the results to share practice and continue to drive forward technique development, aid standardization and by highlighting issues, improve access to SABR services and trials across the UK. Methods: In January 2018, an online questionnaire was sent by the UK SABR Consortium to 65 UK radiotherapy institutions covering current service provision and collecting data on immobilization, motion management, scanning protocols, target/OAR delineation, planning, image-guidance, quality assurance and future plans. Results: 50 (77%) institutions responded, 38 ( vs 15 in 2012) indicated they had an active SABR programme with the remaining 12 centres intending to develop a SABR programme Documented changes include the development of Linac delivered SABR to non-lung sites, an increase in centres using abdominal compression (14 vs 2) and the introduction of four-dimensional cone beam CBCT. Current practice is broadly in line with UK SABR Consortium and European guidelines. Conclusion: This 2018 survey shows a welcome increase in SABR provision, surpassing 2012 projections. However, it is clear that the UK SABR program needs to continue to expand to ensure that patients with oligometastatic disease have access and SABR for early stage lung cancer is available in all centres. Updated guidance that addresses variability in target delineation, image guidance and reduces patient specific quality assurance is warranted. Advances in knowledge: Documented progress of UK SABR across all treatment sites over the last six years, barriers to implementation and future plans.
Communicating with Warmth in Distributive Negotiations Is Surprisingly Counterproductive
Authors: Jeong Martha , Minson Julia , Yeomans Michael , Gino Francesca 
Published: July 2019

When entering into a negotiation, individuals have the choice to enact a variety of communication styles. We test the differential impact of being “warm and friendly” versus “tough and firm” in a distributive negotiation when first offers are held constant and concession patterns are tracked. We train a natural language processing algorithm to precisely quantify the difference between how people enact warm and friendly versus tough and firm communication styles. We find that the two styles differ primarily in length and their expressions of politeness (Study 1). Negotiators with a tough and firm communication style achieved better economic outcomes than negotiators with a warm and friendly communication style in both a field experiment (Study 2) and a laboratory experiment (Study 3). This was driven by the fact that offers delivered in tough and firm language elicited more favorable counteroffers. We further find that the counterparts of warm and friendly versus tough and firm negotiators did not report different levels of satisfaction or enjoyment of their interactions (Study 3). Finally, we document that individuals’ lay beliefs are in direct opposition to our findings: participants believe that authors of warmly worded negotiation offers will be better liked and will achieve better economic outcomes (Study 4). This paper was accepted by Yuval Rottenstreich, judgment and decision making.
A Flexible Design for Funding Public Goods
Authors: Buterin Vitalik , Hitzig Zoë , Weyl E. Glen 
Published: July 2019

We propose a design for philanthropic or publicly funded seeding to allow (near) optimal provision of a decentralized, self-organizing ecosystem of public goods. The concept extends ideas from quadratic voting to a funding mechanism for endogenous community formation. Citizens make contributions to public goods of value to them. The amount received by the public good is (proportional to) the square of the sum of the square roots of contributions received. Under the “standard model,” this mechanism yields first best public goods provision. Variations can limit the cost, help protect against collusion, and aid coordination. We discuss applications to campaign finance and highlight directions for future analysis and experimentation.This paper was accepted by Joshua Gans, business strategy.