bluuebunny/crossref_metadata_2025_split huggingface dataset:
Off-the-shelf, steroid-resistant, IL13Rα2-specific CAR T cells for treatment of glioblastoma
Authors: Brown Christine E , Rodriguez Analiz , Palmer Joycelynne , Ostberg Julie R , Naranjo Araceli , Wagner Jamie R , Aguilar Brenda , Starr Renate , Weng Lihong , Synold Timothy W , Tran Vivi , Wang Shelley , Reik Andreas , D’Apuzzo Massimo , Ressler Julie A , Zhou Yuanyue , Mendel Matthew , Gregory Philip D , Holmes Michael C , Tang Winson W , Forman Stephen J , Jensen Michael C , Badie Behnam 
Published: January 2022

Abstract

Background
Wide-spread application of chimeric antigen receptor (CAR) T cell therapy for cancer is limited by the current use of autologous CAR T cells necessitating the manufacture of individualized therapeutic products for each patient. To address this challenge, we have generated an off-the-shelf, allogeneic CAR T cell product for the treatment of glioblastoma (GBM), and present here the feasibility, safety, and therapeutic potential of this approach.

Methods
We generated for clinical use a healthy-donor derived IL13Rα2-targeted CAR+ (IL13-zetakine+) cytolytic T-lymphocyte (CTL) product genetically engineered using zinc finger nucleases (ZFNs) to permanently disrupt the glucocorticoid receptor (GR) (GRm13Z40-2) and endow resistance to glucocorticoid treatment. In a phase I safety and feasibility trial we evaluated these allogeneic GRm13Z40-2 T cells in combination with intracranial administration of recombinant human IL-2 (rhIL-2; aldesleukin) in six patients with unresectable recurrent GBM that were maintained on systemic dexamethasone (4-12 mg/day).

Results
The GRm13Z40-2 product displayed dexamethasone-resistant effector activity without evidence for in vitro alloreactivity. Intracranial administration of GRm13Z40-2 in four doses of 108 cells over a two-week period with aldesleukin (9 infusions ranging from 2500–5000 IU) was well tolerated, with indications of transient tumor reduction and/or tumor necrosis at the site of T cell infusion in four of the six treated research subjects. Antibody reactivity against GRm13Z40-2 cells was detected in the serum of only one of the four tested subjects.

Conclusions
This first-in-human experience establishes a foundation for future adoptive therapy studies using off-the-shelf, zinc-finger modified, and/or glucocorticoid resistant CAR T cells.
Safety and Tolerability of Carboplatin and Paclitaxel in Cancer Patients with HIV (AMC-078), an AIDS Malignancy Consortium (AMC) Study
Authors: Haigentz Missak , Moore Page , Bimali Milan , Cooley Timothy , Sparano Joseph , Rudek Michelle , Ratner Lee , Henry David , Ramos Juan , Deeken John , Rubinstein Paul , Chiao Elizabeth 
Published: January 2022

Abstract

Background
Persons living with human immunodeficiency virus are an underserved population for evidence-based cancer treatment. Paclitaxel and carboplatin (PCb) is an active regimen against a variety of solid tumors, including several seen in excess in patients with HIV infection. We performed a pilot trial to evaluate the safety of full-dose PCb in people living with human immunodeficiency virus and cancer.

Methods
Eligible patients, stratified by concurrent antiretroviral therapy (ART) that included CYP3A4 inhibitors or not, received paclitaxel (175 mg/m2) in combination with carboplatin (target AUC 6) intravenously every 3 weeks for up to 6 cycles.

Results
Sixteen evaluable patients received 64 cycles of PCb, including 6 patients treated with CYP3A4 inhibiting ART (ritonavir). The adverse event profile was consistent with the known toxicity profile of PCb, with no differences between the 2 strata. There were 4 partial responses (25%, 95% CI: 7%-52%), and overall, CD4+ lymphocyte count was similar after completion of therapy (median: 310/μL) compared with baseline values (median: 389/μL). Pharmacokinetic studies in 6 patients revealed no significant differences in Cmax or AUCinf for paclitaxel between the 2 cohorts.

Conclusion
Full doses of PCb chemotherapy are tolerable when given concurrently with ART in people living with human immunodeficiency virus with cancer, including patients receiving CYP3A4 inhibitors.

ClinicalTrials.gov Identifier
NCT01249443.
Impact of the COVID-19 Pandemic on Management of Patients with Metastatic Pancreatic Ductal Adenocarcinoma in the United States
Authors: Paluri Ravi , Laursen Ashley , Gaeta Joseph , Wang Shu , Surinach Andy , Cockrum Paul 
Published: January 2022

Abstract

Background
The purpose of this study was to understand how the COVID-19 pandemic has affected health care patterns and outcomes for patients diagnosed with metastatic pancreatic ductal adenocarcinoma (mPDAC) in 2020 compared with those diagnosed with mPDAC in 2019.

Patients and Methods
We used the Flatiron Health database to identify adults diagnosed with mPDAC from March 1 to September 30, 2019 (pre-COVID-19 cohort) and March 1 to September 30, 2020 (post-COVID-19 cohort). Between-cohort comparisons included demographic and clinical characteristics and year-over-year data for diagnosis of mPDAC, newly treated patients, time to and types of first-line therapy, and adverse events (AEs) during first-line therapy. Overall survival (OS) and milestone survival rates were evaluated. Kaplan-Meier methods were used to assess OS.

Results
Pre-COVID-19 (n = 923) and post-COVID-19 (n = 796) cohorts had similar baseline demographic characteristics. A smaller proportion of patients in the pre-COVID-19 cohort were initially diagnosed with stage IV disease versus the post-COVID-19 cohort (62.2% vs 69.7%). Between 2019 and 2020, there was a 13.8% decrease in diagnosis of mPDAC and a 13.0% decrease in newly treated patients. Median (interquartile range) times to first-line treatment were similar (21 [13-40] and 19 [12-32] days). Median OS (months) was significantly longer in the pre-COVID-19 cohort (8·4 [95% CI: 7·5, 9·0]) versus the post-COVID-19 cohort (6·1 [95% CI: 5·4, 6·9]; P &lt; .001). Survival rates were higher in the pre-COVID-19 versus post-COVID-19 cohorts.

Conclusions
During the pandemic, patients were initially diagnosed with PDAC at more advanced stages. While patients in both cohorts appeared to receive similar care, survival outcomes were adversely affected.
Does R&D tax credit impact firm behaviour? Micro evidence for Portugal
Authors: Paredes Alexandre , Mendonça Joana , Bação Fernando , Damásio Bruno 
Published: January 2022

AbstractIn this study, we use panel data to analyse the impact of an R&D tax credit on R&D personnel, particularly the impact on Ph.D. holders allocation, comparing low R&D intensity firms with medium-high and high R&D intensity firms. The results show that, in medium-high and high R&D intensity firms, the R&D tax credit had a significant impact on allocating Ph.D. holders in firms after 3 years of participation in the tax incentive scheme. We use a database covering 7,710 firms that performed R&D at least once in Portugal over the 23-year period 1995 to 2017, provided by the official business R&D survey data and a database of firms that applied for tax credit incentives at least once in the same period. Based on the estimation of impulse-response functions by local projections, we assess the impact of introducing the tax incentive scheme for corporate R&D in firms from different R&D intensity sectors.
Conversion of the MDHAQ to the HAQ score: a simple algorithm developed and validated in a cohort of 13 391 real-world patients
Authors: Ørnbjerg Lykke M , Svensson Elisabeth , Løngaard Katja , Meincke Rikke H , Pedersen Jens Kristian , Dreyer Lene , Krogh Niels Steen , Jensen Dorte V , Hetland Merete L 
Published: January 2022

Abstract

Objectives
To develop and validate in real-world patients a conversion algorithm from the Multidimensionel Health Assessment Questionnaire physical function scale (MDHAQ) to the Stanford Health Assessment Questionnaire disability index physical function scale (HAQ) score.

Methods
From the DANBIO registry, 13 391 patients with RA (n = 8983), PsA (n = 2649) and axial spondyloarthritis (axSpA, n = 1759) with longitudinal data on HAQ and MDHAQ were included, stratified by diagnosis, and randomized 1:1 into development and validation cohorts. Conversion algorithms were developed by linear regression and applied in validation cohorts. From MDHAQ, the HAQ was calculated (cHAQ) and validated against the observed HAQ for criterion, correlational and construct validity.

Results
For RA, we developed the conversion algorithm cHAQ = 0.15+MDHAQ*1.08, and validated it in the RA validation cohort. Criterion validity: HAQ and cHAQ had comparable discriminative power to distinguish between high and low patient global scores (standardized mean difference: HAQ:–1.29, cHAQ:–1.35). Kappa value between HAQ and cHAQ functional states indicated good agreement (0.83). Correlational validity: baseline HAQ and cHAQ, respectively, correlated well with patient global scores (r = 0.65/0.67). Bland–Altman plots showed good agreement across all functional states. Construct validity: HAQ and cHAQ discriminated equally well between patients reporting symptom state as acceptable vs not, and across responses to an external anchor. Aiming for a common algorithm, the RA conversion algorithm was validated for PsA and axSpA with similar results.

Conclusion
This study suggests that in observational datasets with only the MDHAQ available, a simple algorithm allows valid conversion to HAQ on the group level in RA, PsA and axSpA.
Effects of transcranial direct current stimulation over the right dorsolateral prefrontal cortex on fairness-related decision-making
Authors: Hu Xinmu , Zhang Yu , Liu Xiaoqing , Guo Yunfei , Liu Chao , Mai Xiaoqin 
Published: January 2022

AbstractNeuroimaging studies suggest that the right dorsolateral prefrontal cortex (rDLPFC) is an important brain area involved in fairness-related decision-making. In the present study, we used transcranial direct current stimulation (tDCS) over the rDLPFC to investigate the effects of changed cortical excitability on fairness norm enforcement in social decision-making. Participants received anodal, cathodal or sham stimulation before performing a modified ultimatum game task, in which participants were asked to accept or reject the proposer’s offer and self-rate the intensity of their anger at offers on a 7-point scale. The results showed that the rejection rate of unfair offers and anger level were higher in the anodal compared to the sham and cathodal groups and that the level of anger at unfair offers can predict the rejection rate. Furthermore, the fairness effect of RTs was more prominent in the anodal group than in the sham and cathodal groups. Our findings validate the causal role of the rDLPFC in fairness-related decision-making through tDCS, suggesting that strengthening the rDLPFC increases individuals’ reciprocal fairness in social decision-making, both in subjective rating and behaviors.
Mine or ours? Neural basis of the exploitation of common-pool resources
Authors: Martinez-Saito Mario , Andraszewicz Sandra , Klucharev Vasily , Rieskamp Jörg 
Published: January 2022

AbstractWhy do people often exhaust unregulated common (shared) natural resources but manage to preserve similar private resources? To answer this question, in this study we combine a neurobiological, economic and cognitive modeling approach. Using functional magnetic resonance imaging on 50 participants, we show that a sharp decrease of common and private resources is associated with deactivation of the ventral striatum, a brain region involved in the valuation of outcomes. Across individuals, when facing a common resource, ventral striatal activity is anticorrelated with resource preservation (less harvesting), whereas with private resources the opposite pattern is observed. This indicates that neural value signals distinctly modulate behavior in response to the depletion of common vs private resources. Computational modeling suggested that overharvesting of common resources was facilitated by the modulatory effect of social comparison on value signals. These results provide an explanation of people’s tendency to over-exploit unregulated common natural resources.
Cadmium Suppresses Bone Marrow Thrombopoietin Production and Impairs Megakaryocytopoiesis in Mice
Authors: Zhao Yifan , Zhang Yufan , He Jinyi , Zhai Yue , Yang Guangrui , Xue Peng , Yao Ye , He Miao , Qu Weidong , Zhang Yubin 
Published: January 2022

Abstract
Cadmium (Cd) is a highly toxic heavy metal in our environment. The influence of Cd on the development of platelets, or megakaryocytopoiesis, remains to be defined. The aim of this study was to investigate the impact of Cd on megakaryocytopoiesis. C57BL/6 (B6) mice aged 6–8 weeks were treated with 10 ppm Cd via drinking water or control for 3 months, and megakaryocytopoiesis was evaluated thereafter. Mice treated with Cd had a decreased number of platelets in the blood, which was associated with the reduced number of megakaryocyte progenitors (MkP) and megakaryocytes (MK) in the bone marrow (BM). Functional analyses indicate that Cd treatment impaired the proliferation and differentiation of MkP as well as the maturation of MK in the BM, suggesting that Cd treatment impeded megakaryocytopoiesis. Intriguingly, the impaired megakaryocytopoiesis in the BM of mice treated with Cd was not caused by increased apoptosis of MkP. Moreover, in vitro treatment of MkP with Cd did not impact their proliferation or differentiation, indicating that the impeded megakaryocytopoiesis in the BM of mice was likely not caused by direct action of Cd on MkP. On the other hand, Cd treatment selectively suppressed thrombopoietin (TPO) production in the BM and decreased the cellular myelocytomatosis oncogene signaling in MkP, thus likely leading to the impeded megakaryocytopoiesis in the BM and thrombocytopenia in the blood of mice. This study revealed a previously unrecognized hematopoietic toxicity of Cd, which may extend our current understanding of Cd toxicity.
Late-day measurement of excised branches results in uncertainty in the estimation of two stomatal parameters derived from response curves inPopulus deltoidesBartr. × Populus nigraL.
Authors: Davidson Kenneth J , Lamour Julien , Rogers Alistair , Serbin Shawn P 
Published: January 2022

AbstractMany terrestrial biosphere models depend on an understanding of the relationship between stomatal conductance and photosynthesis. However, unlike the measurement of photosynthetic parameters, such as the maximum carboxylation capacity, where standard methods (e.g., CO2 response or ACi curves) are widely accepted, a consensus method for empirically measuring parameters representing stomatal response has not yet emerged. Most models of stomatal response to environment represent stomatal conductance as being bounded by a lower intercept parameter (g0), and linearly scaled based on a multivariate term described by the stomatal slope parameter (g1). Here we employ the widely used Unified Stomatal Optimization model, to test whether g1 and g0 parameters are impacted by the choice of measurement method, either on an intact branch or a cut branch segment stored in water. We measured paired stomatal response curves on intact and excised branches of a hybrid poplar clone (Populus deltoides Bartr. × Populus nigra L. OP367), measured twice over a diurnal period. We found that predawn branch excision did not significantly affect measured g0 and g1 when measured within 4 h of excision. Measurement in the afternoon resulted in significantly higher values of g1 and lower values of g0, with values changing by 55% and 56%, respectively. Excision combined with afternoon measurement resulted in a marked effect on parameter estimates, with g1 increasing 89% from morning to afternoon and a 25% lower g1 for cut branches than those measured in situ. We also show that in hybrid poplar the differences in parameter estimates obtained from plants measured under different conditions can directly impact models of canopy function, reducing modeled transpiration by 18% over a simulated 12.5-h period. Although these results are only for a single isohydric woody species, our findings suggest that stomatal optimality parameters may not remain constant throughout the day.
Decisions under the law of European Union: ‘You May Be Six People, But I Love You’
Authors: Cherubini Francesco 
Published: January 2022

Abstract
This article analyses one of the most recurrent and flexible acts in the system of sources of EU law: decisions. After a brief introduction, the second part is devoted to a reconstruction of the general categories of classification of legal acts of the Union. The third part proposes a general classification scheme. The fourth part analyses typical decisions: those of individual application and those of general application. Part Five examines and classifies decisions of atypical nature. The article concludes with a few final considerations.
A Novel Patient-specific Titanium Mesh Implant Design for Reconstruction of Complex Orbital Fracture
Authors: Kittichokechai Pakaporn , Sirichatchai Kanin , Puncreobutr Chedtha , Lohwongwatana Boonrat , Saonanon Preamjit 
Published: January 2022

Background:
Complex orbital fractures, including orbital rims and walls, require precise reconstruction. A titanium-based patient-specific implant (PSI) benefits over other implants when challenged with narrow surgical space and designable implant fixation point.

Methods:
This is a prospective noncomparative case series to evaluate the effect of complex orbital reconstruction using the newly designed lateral fixation patient-specific implant. The PSI was individually fabricated by 3D reconstruction using the mirrored nonaffected orbit as a template. The fixation point was at maxillary or zygomatic bone, depending on the bony remnant. Outcomes were obtained from computed tomography scan to compare orbital tissue volume and exophthalmometry value by posterior clinoid method before and after the surgery and also between both orbits in each patient.

Results:
Sixteen patients with complex orbital fracture with inferior orbital rim defect were enrolled. Seven were previously repaired with other implants. Compared with the preoperative measurement, the postoperative mean difference of orbital volume and exophthalmometry value between both eyes was significantly decreased (reduction of the mean difference of 2904.40 mm3; P < 0.001 and 2.89 mm; P < 0.001, respectively). The mean orbital volume and exophthalmometry value between affected and unaffected eyes were not different after surgical correction (P = 0.57 and P = 0.28, respectively). There was one infected wound from retained foreign body and one unresolved vertical diplopia after the reconstruction.

Conclusions:
Reconstruction of complex orbital fractures using the novel designed-PSI had excellent outcomes. Appropriate implant design with caution of orbital anatomy and placement techniques are keys for successful results.
Ambulatory blood pressure and hypertension control in children with autosomal recessive polycystic kidney disease: clinical experience from two central European tertiary centres
Authors: Seeman Tomáš , Blažík Radek , Fencl Fencl , Bláhová Květa , Obeidová Lena , Štekrová Jitka , Weigel Friederike , John-Kroegel Ulrike 
Published: January 2022

Objective
: Arterial hypertension is a common complication in patients with autosomal recessive polycystic kidney disease (ARPKD), occurring in 33–75% of children when measured by office blood pressure (OBP). Ambulatory blood pressure monitoring (ABPM) is a superior tool for investigating blood pressure relative to OBP. The aim of our study was to investigate the prevalence and control of hypertension in children with ARPKD based on ABPM.

Methods:
This retrospective study evaluated 36 children with ARPKD and at least one ABPM performed in two our tertiary paediatric nephrology centres and 29 children with at least two ABPM. Ambulatory hypertension was defined as mean daytime or night-time BP at least 95th percentile or use of antihypertensives and controlled hypertension as normal ambulatory BP in children on antihypertensive drugs.

Results:
The first ABPM study revealed ambulatory hypertension in 94% of children. Untreated or uncontrolled ambulatory hypertension was diagnosed in 67% and controlled hypertension in only 28%. Masked hypertension was found in 5.5% and white-coat hypertension in 14%. The last ABPM study revealed ambulatory hypertension in 86% (all 86% hypertensive children on drugs, i.e. no untreated hypertension), the prevalence of controlled hypertension increased to 59%. Masked hypertension was detected in 8.3% and white-coat hypertension in 10%. Ambulatory blood pressure correlated neither with kidney length nor with glomerular filtration rate. Echocardiography demonstrated left ventricular hypertrophy (LVH) in 27% of children at the time of their first ABPM.

Conclusion:
The prevalence of ambulatory hypertension is very high in children with ARPKD, while the control of hypertension improves over time.
Effects of hypnosis vs mindfulness meditation vs education on chronic pain intensity and secondary outcomes in veterans: a randomized clinical trial
Authors: Williams Rhonda M. , Day Melissa A. , Ehde Dawn M. , Turner Aaron P. , Ciol Marcia A. , Gertz Kevin J. , Patterson David , Hakimian Shahin , Suri Pradeep , Jensen Mark P. 
Published: January 2022

Abstract
Effective, rigorously evaluated nonpharmacological treatments for chronic pain are needed. This study compared the effectiveness of training in hypnosis (HYP) and mindfulness meditation (MM) with an active education control (ED). Veterans (N = 328) were randomly assigned to 8 manualized, group-based, in-person sessions of HYP (n = 110), MM (n = 108), or ED (n = 110). Primary (average pain intensity [API]) and secondary outcomes were assessed at pretreatment, posttreatment, and 3 and 6 months posttreatment. Treatment effects were evaluated using linear regression, a generalized estimating equation approach, or a Fisher exact test, depending on the variable. There were no significant omnibus between-group differences in pretreatment to posttreatment change in API; however, pretreatment to posttreatment improvements in API and several secondary variables were seen for participants in all 3 conditions. Participation in MM resulted in greater decreases in API and pain interference at 6 months posttreatment relative to ED. Participation in HYP resulted in greater decreases in API, pain interference, and depressive symptoms at 3 and 6 months posttreatment compared with ED. No significant differences on outcomes between HYP and MM were detected at any time point. This study suggests that all 3 interventions provide posttreatment benefits on a range of outcomes, but the benefits of HYP and MM continue beyond the end of treatment, while the improvements associated with ED dissipate over time. Future research is needed to determine whether the between-group differences that emerged posttreatment are reliable, whether there are benefits of combining treatments, and to explore moderating and mediating factors.