bluuebunny/crossref_metadata_2025_split huggingface dataset:
Attenuating CD3 affinity in a PSMAxCD3 bispecific antibody enables killing of prostate tumor cells with reduced cytokine release
Authors: Dang Kevin , Castello Giulia , Clarke Starlynn C , Li Yuping , Balasubramani Aarti , Boudreau Andrew , Davison Laura , Harris Katherine E , Pham Duy , Sankaran Preethi , Ugamraj Harshad S , Deng Rong , Kwek Serena , Starzinski Alec , Iyer Suhasini , van Schooten Wim , Schellenberger Ute , Sun Wenchao , Trinklein Nathan D , Buelow Roland , Buelow Ben , Fong Lawrence , Dalvi Pranjali 
Published: June 2021

BackgroundTherapeutic options currently available for metastatic castration-resistant prostate cancer (mCRPC) do not extend median overall survival >6 months. Therefore, the development of novel and effective therapies for mCRPC represents an urgent medical need. T cell engagers (TCEs) have emerged as a promising approach for the treatment of mCRPC due to their targeted mechanism of action. However, challenges remain in the clinic due to the limited efficacy of TCEs observed thus far in solid tumors as well as the toxicities associated with cytokine release syndrome (CRS) due to the usage of high-affinity anti-CD3 moieties such as OKT3.MethodsUsing genetically engineered transgenic rats (UniRat and OmniFlic) that express fully human IgG antibodies together with an NGS-based antibody discovery pipeline, we developed TNB-585, an anti-CD3xPSMA TCE for the treatment of mCRPC. TNB-585 pairs a tumor-targeting anti-PSMA arm together with a unique, low-affinity anti-CD3 arm in bispecific format. We tested TNB-585 in T cell-redirected cytotoxicity assays against PSMA+ tumor cells in both two-dimensional (2D) cultures and three-dimensional (3D) spheroids as well as against patient-derived prostate tumor cells. Cytokines were measured in culture supernatants to assess the ability of TNB-585 to induce tumor killing with low cytokine release. TNB-585-mediated T cell activation, proliferation, and cytotoxic granule formation were measured to investigate the mechanism of action. Additionally, TNB-585 efficacy was evaluated in vivo against C4-2 tumor-bearing NCG mice.ResultsIn vitro, TNB-585 induced activation and proliferation of human T cells resulting in the killing of PSMA+ prostate tumor cells in both 2D cultures and 3D spheroids with minimal cytokine release and reduced regulatory T cell activation compared with a positive control antibody that contains the same anti-PSMA arm but a higher affinity anti-CD3 arm (comparable with OKT3). In addition, TNB-585 demonstrated potent efficacy against patient-derived prostate tumors ex vivo and induced immune cell infiltration and dose-dependent tumor regression in vivo.ConclusionsOur data suggest that TNB-585, with its low-affinity anti-CD3, may be efficacious while inducing a lower incidence and severity of CRS in patients with prostate cancer compared with TCEs that incorporate high-affinity anti-CD3 domains.
Baseline and early functional immune response is associated with subsequent clinical outcomes of PD-1 inhibition therapy in metastatic melanoma patients
Authors: Gérard Alexandre , Doyen Jerome , Cremoni Marion , Bailly Laurent , Zorzi Kevin , Ruetsch-Chelli Caroline , Brglez Vesna , Picard-Gauci Alexandra , Troin Laura , Esnault Vincent L.M. , Passeron Thierry , Montaudié Henri , Seitz-Polski Barbara 
Published: June 2021

BackgroundDespite significant progress with antiprogrammed cell death protein 1 (PD-1) therapy, a substantial fraction of metastatic melanoma patients show upfront therapy resistance. Biomarkers for outcome are missing and the association of baseline immune function and clinical outcome remains to be determined. We assessed the in vitro nonspecific stimulation of immune response at baseline and during anti-PD-1 therapy for metastatic melanoma.MethodsPreviously untreated metastatic melanoma patients received nivolumab and radiotherapy as part of the multicentric phase II trial NIRVANA (NCT02799901). The levels of Th1, Th2 and Th17 cytokines on in vitro non-specific stimulation of innate and adaptive immune cells were measured in patient sera before treatment, and at week 2 and week 6 after the beginning of the treatment, and correlated with tumorous response, progression-free survival (PFS) and occurrence of immune-related adverse events (irAEs). The results in melanoma patients were compared with those of a cohort of 9 sex and age-matched healthy donors.ResultsSeventeen patients were enrolled in this ancillary study. Median follow-up was 16 months (2.2–28.4). The 12-month PFS rate was 67.7%. The incidence of irAEs of any grade was 58.8%. Without in vitro stimulation no differences in cytokines levels were observed between responders and non-responders. On in vitro stimulation, metastatic patients had lower Th1 cytokine levels than healthy donors at baseline for tumor necrosis factor-α and interferon-γ (IFN-γ) (1136 pg/mL vs 5558 pg/mL, p<0.0001; and 3894 pg/mL vs 17 129 pg/mL, p=0.02, respectively). Responders exhibited increasing cytokine levels from baseline to week 6. Non-responders had lower interleukin 17A (IL-17A) levels at baseline than responders (7 pg/mL vs 32 pg/mL, p=0.03), and lower IFN-γ levels at week 6 (3.3 ng/mL vs 14.5 ng/mL, p=0.03). A lower level of IL-17A at week 2 and a lower level of IFN-γ at week 6 correlated with worse PFS (p=0.04 and p=0.04 respectively). At baseline, patients who developed irAEs had higher IL-6 levels (19.3 ng/mL vs 9.2 ng/mL, p=0.03) and higher IL-17A levels (52.5 pg/mL vs 2.5 pg/mL, p=0.009) than those without irAEs.ConclusionsOur findings indicate that cytokine levels after in vitro non-specific stimulation could be a promising biomarker to predict the outcome of PD-1 inhibition therapy.
Translating 6 key insights from research on leadership and management in times of crisis
Authors: Reyes Denise Lucia , Bisbey Tiffany , Day David , Salas Eduardo 
Published: June 2021

BackgroundCertain leadership behaviours are particularly helpful for healthcare teams remain effective through crisis situations, such as the Covid-19 pandemic. This paper summarizes evidence-based insights based on their importance and prevalence in the crisis leadership literature to provide recommendations that apply to medical team leaders broadly construed. We recommend that leaders adopt these behaviours in conditions of intense difficulty, uncertainty, as well as physical and psychological peril.ResultsWe draw from research on workplace resilience, as well as leadership literature (ie, team leadership, transformational leadership, shared leadership, and crisis leadership) to provide six key insights along with evidence and practical guidance for healthcare leaders to help their teams in the midst of a crisis: (1) remain optimistic when communicating a vision, (2) adapt to the changing situation by deferring to team members’ expertise, (3) support organizational resilience by providing relational resources, (4) be present to signal commitment, (5) be empathetic to help prevent burnout, and (6) be transparent in order to remain trustworthy.
Effects of geometric frustration in Kitaev chains
Authors: Maiellaro Alfonso , Romeo Francesco , Citro Roberta 
Published: June 2021

AbstractWe study the topological phase transitions of a Kitaev chain frustrated by the addition of a single long-range hopping. In order to study the topological properties of the resulting legged-ring geometry (Kitaev tie model), we generalize the transfer matrix approach through which the emergence of Majorana edge modes is analyzed. We find that geometric frustration gives rise to a topological phase diagram in which non-trivial phases alternate with trivial ones at varying the range of the hopping and the chemical potential. Robustness to disorder of non-trivial phases is also proven. Moreover, geometric frustration effects persist when translational invariance is restored by considering a multiple-tie system. These findings shed light on an entire class of experimentally realizable topological systems with long-range couplings.
A Systematic Framework to Identify Violations of Scenario-dependent Driving Rules in Autonomous Vehicle Software
Authors: Zhang Qingzhao , Hong David Ke , Zhang Ze , Chen Qi Alfred , Mahlke Scott , Mao Z. Morley 
Published: June 2021

Safety compliance is paramount to the safe deployment of autonomous vehicle (AV) technologies in real-world transportation systems. As AVs will share road infrastructures with human drivers and pedestrians, it is an important requirement for AVs to obey standard driving rules. Existing AV software testing methods, including simulation and road testing, only check fundamental safety rules such as collision avoidance and safety distance. Scenario-dependent driving rules, including crosswalk and intersection rules, are more complicated because the expected driving behavior heavily depends on the surrounding circumstances. However, a testing framework is missing for checking scenario-dependent driving rules on various AV software.
In this paper, we design and implement a systematic framework AVChecker for identifying violations of scenario-dependent driving rules in AV software using formal methods. AVChecker represents both the code logic of AV software and driving rules in proposed formal specifications and leverages satisfiability modulo theory (SMT) solvers to identify driving rule violations. To improve the automation of systematic rule-based checking, AVChecker provides a powerful user interface for writing driving rule specifications and applies static code analysis to extract rule-related code logic from the AV software codebase. Evaluations on two open-source AV software platforms, Baidu Apollo and Autoware, uncover 19 true violations out of 28 real-world driving rules covering crosswalks, traffic lights, stop signs, and intersections. Seven of the violations can lead to severe risks of a collision with pedestrians or blocking traffic.
Nudge: Stochastically Improving upon FCFS
Authors: Grosof Isaac , Yang Kunhe , Scully Ziv , Harchol-Balter Mor 
Published: June 2021

The First-Come First-Served (FCFS) scheduling policy is the most popular scheduling algorithm used in practice. Furthermore, its usage is theoretically validated: for light-tailed job size distributions, FCFS has weakly optimal asymptotic tail of response time. But what if we don't just care about the asymptotic tail? What if we also care about the 99th percentile of response time, or the fraction of jobs that complete in under one second? Is FCFS still best? Outside of the asymptotic regime, only loose bounds on the tail of FCFS are known, and optimality is completely open.
In this paper, we introduce a new policy, Nudge, which is the first policy to provably stochastically improve upon FCFS. We prove that Nudge simultaneously improves upon FCFS at every point along the tail, for light-tailed job size distributions. As a result, Nudge outperforms FCFS for every moment and every percentile of response time. Moreover, Nudge provides a multiplicative improvement over FCFS in the asymptotic tail. This resolves a long-standing open problem by showing that, counter to previous conjecture, FCFS is not strongly asymptotically optimal.
Compliance With Preferred Reporting Items for Systematic Review and Meta-Analysis Individual Participant Data Statement for Meta-Analyses Published for Stroke Studies
Authors: Jumah Fareed , Chotai Silky , Ashraf Omar , Rallo Michael S. , Raju Bharath , Gadhiya Arjun , Sun Hai , Narayan Vinayak , Gupta Gaurav , Nanda Anil 
Published: June 2021

Background and Purpose:
Individual-participant data meta-analyses (IPD-MA) are powerful evidence synthesis studies which are considered the gold-standard of MA. The quality of reporting in these studies is guided by the 2015 Preferred Reporting Items for Systematic Review and Meta-Analysis of Individual Participant Data (PRISMA-IPD) guidelines. The growing number of IPD-MA published for stroke studies calls for an assessment of the compliance of these studies with the PRISMA-IPD statement.

Methods:
PubMed and EMBASE were searched for MA in stroke published between January 1, 2016, and March 30, 2020, in journals with impact factor >2. Literature reviews, scoping reviews, and aggregate MA were excluded. The final articles were scored using the 31-item PRISMA-IPD checklist. Results were depicted using descriptive statistics. Compliance with each item in PRISM-IPD guideline was recorded. The study was defined as compliant to IPD analyses if it satisfied all IPD specific items.

Results:

From an initial set of 321 articles, 31 met the final eligibility for data extraction. Only 4 (13%) described the use of PRISMA-IPD guidelines in their methodology, while 8/31 (26%) used the old PRISMA guidelines and 19/31 (61%) followed none. Regardless of mention of using IPD specific guidelines, 42% (n=13) of studies were compliant with all 4 IPD specific domains. The poorest areas of compliance were bias assessment within (32%) and across (39%) studies, reporting protocol and registration (42%), and reporting of IPD integrity (48%). The median journal impact factor was similar between the compliant (median, 8.1 [interquartile range, 5.4–39.9]) and noncompliant (median, 6 [interquartile range, 4.5–16.2]) groups (
P
=0.24). Similarly, the journal, country of correspondence, number of authors, number of studies included in MA, study sample size, and funding source were statistically similar between the groups.

Conclusions:
For the published IPD-MA stroke studies, the compliance with PRISMA-IPD statement and compliance with 4 IPD specific items was suboptimal. The journal, author, and study-related factors were not associated with compliance. Additional scrutiny measures to ensure adherence to mandated guidelines might increase the compliance. Several avenues to improve compliance and ensure optimal adherence are discussed.
The Politics of Carnap’s Non-Cognitivism and the Scientific World-Conception of Left-Wing Logical Empiricism
Authors: Damböck Christian 
Published: June 2021

Abstract
Based on a reconstruction of the development of Rudolf Carnap’s views from the Aufbau until the 1960s, this paper provides an account of the philosopher’s understanding of non-cognitivism, which is here seen as in line with the so-called scientific world-conception of left-wing logical empiricism. The starting point of Carnap’s conception is the claim that every human decision depends on certain attitudes that cannot be justified at a cognitive level, that are neither based on empirical facts nor logical reasoning. The key features of Carnap’s non-cognitivism, however, go beyond this general basis and involve several fundamentally moral commitments, such as a commitment toward science, and the embracing of moral attitudes as the result of a long-term process of rational discourse. I argue that these commitments contained in Carnap’s non-cognitivism/scientific world-conception establish a genuinely political worldview that is characteristic of left-wing logical empiricism and converges with socialism and democracy.
Institutional Determinants for Representation of Indigent Defendants: Evidence from Russia
Authors: Kazun Anton 
Published: June 2021

Abstract
Little is known about the motives of lawyers who provide free legal assistance in countries that lack both a developed professional community and developed institutions related to the rule of law. Based on a survey of 3,317 criminal defense lawyers (advokaty) in 35 regions of Russia, we analyze the provision of two types of free legal services: participation in legal proceedings “on appointment” (po naznacheniyu) and the provision of pro bono legal assistance. We show that work on appointment usually involves lawyers with low social capital and a lack of regular clients. In contrast, pro bono legal assistance is encouraged by lawyers’ organizations. It is typically provided by professionals with a high level of social capital and with values aimed at maintaining an excellent professional reputation. We conclude that the provision of free legal services might best be stimulated within the professional community rather than by the government.
Recent trends in summer atmospheric circulation in the North Atlantic/European region: is there a role for anthropogenic aerosols?
Authors: Dong Buwen , Sutton Rowan T. 
Published: June 2021

AbstractThe variability of the westerly jet stream and storm track is crucial for summer weather and climate in the North Atlantic/European region. Observations for recent decades show notable trends in the summer jet from 1970s to 2010s, characterized by an equatorward migration over the North Atlantic accompanied by a poleward migration and weakening of the Mediterranean jet over Europe. These changes in atmospheric circulation were associated with more cyclonic storms traveling across the UK into northern Europe, and fewer over the Mediterranean, leading to wet summers in northern Europe and dry summers in southern Europe.In this study we investigate the potential drivers and processes that may have been responsible for the observed changes in summer atmospheric circulation, with a particular focus on the role of anthropogenic aerosols (AA). We conduct attribution experiments with an atmospheric general circulation model (AGCM) forced with observed changes in sea surface temperatures/sea ice extent (SST/SIE), greenhouse gas concentrations and AA precursor emissions. Comparison between the model results and observations strongly suggests that fast responses to AA changes were likely the primary driver of the observed poleward migration and weakening of the Mediterranean jet, with changes in SST/SIE playing a secondary role. The simulated response shows good agreement with the observed changes in both magnitude and vertical structure, which suggests that common mechanisms - involving aerosol-radiation and aerosol-cloud interactions - are responsible. By contrast, changes in the North Atlantic jet are influenced in the model experiments by changes in both Atlantic SST/SIE (which may themselves have been influenced by changes in AA) and fast responses to AA. In this case, however, there are significant differences between the model response and the observed changes; we argue these differences may be explained by biases in the model climatology.
Disfiguring Firearm Injuries in Children in the United States
Authors: Zeineddin Suhail , Zeineddin Ahmad , Jain Anish , Olufajo Olubode A. , Koolaee Sima , Cornwell Edward E. , Williams Mallory 
Published: June 2021

Firearms are a leading cause of injury and death among children in the United States. Most gun violence studies highlight mortality, but few have examined the morbidity in disfiguring injuries suffered by children. Using National Trauma Data Bank 2007-2015, children who suffered gunshot injuries and underwent procedures with lasting physical disfigurement formed the cohort of this study. We identified 28 593 children as victims of firearm injuries. Most were aged 13-18 (84%). There was a preponderance of male gender (86%) and black race/ethnicity (57%). Total mortality was 3774 (13%), and 1500 (5.4%) were identified with one or more disfigurements: 220 amputations, 191 craniectomy, 100 enucleation, 533 ileostomy/colostomy, and 557 tracheostomies. This report highlights the large toll firearm injuries take on American children, specifically in non-concealable disfigurements. These injuries are very impactful to their education and overall socialization and therefore must be a part of the discussion of gun violence in the United States.
White Elephants and Other Non-basic Commodities: Piero Sraffa and Krishna Bharadwaj on the Role and Significance of the Distinction between Basics and Non-basics
Authors: Kurz Heinz D. , Salvadori Neri 
Published: June 2021

After the publication of Production of Commodities by Means of Commodities ( Sraffa, 1960 ), a lot of attention was devoted to ‘reswitching’, that is to the fact that a technique is cost-minimising at two disconnected ranges of the rate of profits and not so in between these ranges. We owe Krishna Bharadwaj (1970, Schweizerische Zeitschrift für Volkswirtschaft und Statistik, 106, 409–429) an important contribution to the debate by stating and proving a general result concerning the maximum number of switches between two techniques that have at least one switch point on the wage-frontier. She proved that the maximum number of switches coincides with the number of distinct commodities, without double counting, that enter directly or indirectly into at least one of the alternative methods of production. This means that if the alternative methods produce a commodity that is basic in both techniques, then non-basics in both techniques play no role in this, whereas if the alternative methods produce a non-basic commodity in at least one technique, then a role is played also by those non-basics that enter directly or indirectly into the production of at least one of the alternative methods of production. JEL Code: B12, B21, B31, B51, D24, D51
The Reception of Structured Proportionality in Australian Constitutional Law
Authors: Wesson Murray 
Published: June 2021

AbstractA majority of the High Court has incorporated a test of structured proportionality into its implied freedom of political communication case law. Structured proportionality developed in the context of constitutional rights adjudication and requires courts to engage in substantive, values-based reasoning. The Australian Constitution does not contain a Bill of Rights and the High Court is known for its commitment to legalism and textualism. Against this background, one might think that the High Court would interpret the elements of structured proportionality so that they assume a highly distinctive form in Australian constitutional law. However, a close reading of recent implied freedom of political communication case law demonstrates that generally this is not the case. Admittedly, the High Court’s approach to the necessity and balancing stages departs from the case law of the Federal German Constitutional Court. However, once a broader comparative perspective is adopted, it becomes apparent that the High Court’s approach is not unusual, especially for courts that are new to applying structured proportionality. By adopting structured proportionality, the High Court may have aligned the implied freedom of political communication with a global model of constitutional rights enforcement. The Australian constitutional context may also be less distinctive than is sometimes supposed.