bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oncolytic herpesvirus expressing PD-L1 BiTE for cancer therapy: exploiting tumor immune suppression as an opportunity for targeted immunotherapy
Authors: Khalique Hena , Baugh Richard , Dyer Arthur , Scott Eleanor M. , Frost Sally , Larkin Sarah , Lei-Rossmann Janet , Seymour Leonard W. 
Published: April 2021

BackgroundProgrammed death-ligand 1 (PD-L1) is an important immune checkpoint protein that can be regarded as a pan-cancer antigen expressed by multiple different cell types within the tumor. While antagonizing PD-L1 is well known to relieve PD-1/PD-L1-mediated T cell suppression, here we have combined this approach with an immunotherapy strategy to target T cell cytotoxicity directly toward PD-L1-expressing cells. We developed a bi-specific T cell engager (BiTE) crosslinking PD-L1 and CD3ε and demonstrated targeted cytotoxicity using a clinically relevant patient-derived ascites model. This approach represents an immunological ‘volte-face’ whereby a tumor immunological defense mechanism can be instantly transformed into an Achilles’ heel for targeted immunotherapy.MethodsThe PD-L1 targeting BiTE comprises an anti-PD-L1 single-chain variable fragment (scFv) or nanobody (NB) domain and an anti-CD3 scFv domain in a tandem repeat. The ability to activate T cell cytotoxicity toward PD-L1-expressing cells was established using human carcinoma cells and PD-L1-expressing human (‘M2’) macrophages in the presence of autologous T cells. Furthermore, we armed oncolytic herpes simplex virus-1 (oHSV-1) with PD-L1 BiTE and demonstrated successful delivery and targeted cytotoxicity in unpurified cultures of malignant ascites derived from different cancer patients.ResultsPD-L1 BiTE crosslinks PD-L1-positive cells and CD3ε on T cells in a ‘pseudo-synapse’ and triggers T cell activation and release of proinflammatory cytokines such as interferon-gamma (IFN-γ), interferon gamma-induced protein 10 (IP-10) and tumour necrosis factor-α (TNF-α). Activation of endogenous T cells within ascites samples led to significant lysis of tumor cells and M2-like macrophages (CD11b+CD64+ and CD206+/CD163+). The survival of CD3+ T cells (which can also express PD-L1) was unaffected. Intriguingly, ascites fluid that appeared particularly immunosuppressive led to higher expression of PD-L1 on tumor cells, resulting in improved BiTE-mediated T cell activation.ConclusionsThe study reveals that PD-L1 BiTE is an effective immunotherapeutic approach to kill PD-L1-positive tumor cells and macrophages while leaving T cells unharmed. This approach activates endogenous T cells within malignant ascites, generates a proinflammatory response and eliminates cells promoting tumor progression. Using an oncolytic virus for local expression of PD-L1 BiTE also prevents ‘on-target off-tumor’ systemic toxicities and harnesses immunosuppressive protumor conditions to augment immunotherapy in immunologically ‘cold’ clinical cancers.
Quantification of von Willebrand factor and ADAMTS-13 after traumatic injury: a pilot study
Authors: MacArthur Taleen A , Goswami Julie , Moon Tasson Laurie , Tischer Alexander , Bailey Kent R , Spears Grant M , Dong Jing-Fei , Auton Matthew , Kozar Rosemary , Park Myung S 
Published: April 2021

BackgroundVon Willebrand factor (VWF) is an acute phase reactant synthesized in the megakaryocytes and endothelial cells. VWF forms ultra-large multimers (ULVWF) which are cleaved by the metalloprotease ADAMTS-13, preventing spontaneous VWF–platelet interaction. After trauma, ULVWF is released into circulation as part of the acute phase reaction. We hypothesized that trauma patients would have increased levels of VWF and decreased levels of ADAMTS-13 and that these patients would have accelerated thrombin generation.MethodsWe assessed plasma concentrations of VWF antigen and ADAMTS-13 antigen, the Rapid Enzyme Assays for Autoimmune Diseases (REAADS) activity of VWF, which measure exposure of the platelet-binding A1 domain, and thrombin generation kinetics in 50 samples from 30 trauma patients and an additional 21 samples from volunteers. Samples were analyzed at 0 to 2 hours and at 6 hours from the time of injury. Data are presented as median (IQR) and Kruskal-Wallis test was performed between trauma patients and volunteers at both time points.ResultsREAADS activity was greater in trauma patients than volunteers both at 0 to 2 hours (190.0 (132.0–264.0) vs. 92.0 (71.0–114.0), p<0.002) and at 6 hours (167.5 (108.0–312.5.0) vs. 92.0 (71.0–114.0), p<0.001). ADAMTS-13 antigen levels were also decreased in trauma patients both at 0 to 2 hours (0.84 (0.51–0.94) vs. 1.00 (0.89–1.09), p=0.010) and at 6 hours (0.653 (0.531–0.821) vs. 1.00 (0.89–1.09), p<0.001). Trauma patients had accelerated thrombin generation kinetics, with greater peak height and shorter time to peak than healthy volunteers at both time points.DiscussionTrauma patients have increased exposure of the VWF A1 domain and decreased levels of ADAMTS-13 compared with healthy volunteers. This suggests that the VWF burst after trauma may exceed the proteolytic capacity of ADAMTS-13, allowing circulating ULVWF multimers to bind platelets, potentially contributing to trauma-induced coagulopathy.Level of evidenceProspective case cohort study.
The Effect of Simultaneous Interaction of the Entrepreneurial Orientation and the Leader’s Psychological Traits on the Performance of SMEs
Authors: Gaied Chiraz Ben Salem Ben , Zouaoui Mahmoud 
Published: April 2021

This research work investigates the simultaneous interaction of entrepreneurial orientation dimensions of the firm with the leader’s psychological factors for a better explanation of SMEs’ performance. The universal and contingency approach are reductionist and do not allow us to achieve the research objective. So, to study the simultaneous interaction between a great number of variables, we are mobilizing for this purpose the configurational approach and particularly, the perspective of alignment (fit) as “configuration”. Indeed, we are pursuing a quantitative methodological approach and conducting a field survey through a research questionnaire distributed to 100 industrial Tunisian SMEs. The results of this research reveal a taxonomy of four configurations of industrial Tunisian SMEs significantly different from each other and which have different effects on performance. The configurations are named, the “Leader”, the “Creative”, the “Ambitious” and the “Conservative”.
On a Sum Involving the Sum-of-Divisors Function
Authors: Zhao Feng , Wu Jie 
Published: April 2021

Let

σ

n

be the sum of all divisors of

n

and let

t

be the integral part of

t

. In this paper, we shall prove that

∑

n
≤
x

σ

x
/
n

=

π

2

/
6

x

log

x
+
O

x

log

x

2
/
3

log

2

x

4
/
3

for

x
⟶
∞

, and that the error term of this asymptotic formula is

Ω

x

.
Rational Treatment of Metastatic Colorectal Cancer: A Reverse Tale of Men, Mice, and Culture Dishes
Authors: Avolio Marco , Trusolino Livio 
Published: April 2021

Abstract

Stratification of colorectal cancer into subgroups with different response to therapy was initially guided by descriptive associations between specific biomarkers and treatment outcome. Recently, preclinical models based on propagatable patient-derived tumor samples have yielded an improved understanding of disease biology, which has facilitated the functional validation of correlative information and the discovery of novel response determinants, therapeutic targets, and mechanisms of tumor adaptation and drug resistance. We review the contribution of patient-derived models to advancing colorectal cancer characterization, discuss their influence on clinical decision-making, and highlight emerging challenges in the interpretation and clinical transferability of results obtainable with such approaches.

Significance:
Association studies in patients with colorectal cancer have led to the identification of response biomarkers, some of which have been implemented as companion diagnostics for therapeutic decisions. By enabling biological investigation in a clinically relevant experimental context, patient-derived colorectal cancer models have proved useful to examine the causal role of such biomarkers in dictating drug sensitivity and are providing fresh knowledge on new actionable targets, dynamics of tumor evolution and adaptation, and mechanisms of drug resistance.
Mechanisms of Resistance to KRASG12C-Targeted Therapy
Authors: Akhave Neal S. , Biter Amadeo B. , Hong David S. 
Published: April 2021

Abstract

KRAS mutations are among the most common drivers of human carcinogenesis, and are associated with poor prognosis and an aggressive disease course. With the advent of KRASG12C inhibitors, the RAS protein is now targetable, with such inhibitors showing marked clinical responses across multiple tumor types. However, these responses are short-lived due to the development of resistance. Preclinical studies now suggest MAPK reactivation, stimulation of CDK4/6-dependent cell-cycle transition, and immune defects as possible mechanisms of resistance. Devising strategies to overcome such resistance mechanisms, which are a barrier to long-term clinical response, remain an active area of research.

Significance:
Although KRAS-targeted cancer therapy is revolutionary, tumors rapidly develop resistance. Understanding the mechanisms driving this resistance and designing combination strategies to overcome it are integral to achieving long-term disease control.
Robust Antitumor Immunity in a Patient with Metastatic Colorectal Cancer Treated with Cytotoxic Regimens
Authors: Rajamanickam Venkatesh , Ballesteros-Merino Carmen , Samson Kimberly , Ross David , Bernard Brady , Fox Bernard A. , Tran Eric , Newell Pippa , Duhen Thomas 
Published: April 2021

Abstract
Microsatellite-stable (MSS) colorectal cancers are characterized by low mutation burden and limited immune-cell infiltration and thereby respond poorly to immunotherapy. Here, we report a case of metastatic MSS colorectal cancer with a robust anticancer immune response. The primary tumor was resected in 2012, and the patient received several cycles of chemotherapy until 2017. In 2018, the patient underwent a left hepatectomy to remove a new metastasis. Analysis of the metastatic tumor revealed a strong CD8+ T-cell response. A high frequency of CD8+ T cells coexpressed CD39 and CD103, a phenotype characteristic of tumor-reactive cells. Using whole-exome sequencing, we identified somatic mutations that generated peptides recognized by CD39+CD103+CD8+ T cells. The observed reactivity against the tumor was dominated by the response to a single mutation that emerged in the metastasis. Somatic mutations that were not immunogenic in the primary tumor led to robust CD8+ T-cell expansion later during disease progression. Our data suggest that the cytotoxic treatment regimen received by the patient might be responsible for this effect. Hence, the capacity of cytotoxic regimens to prime the immune system in colorectal cancer patients should be investigated further and might provide a rationale for combination with immunotherapy.
Characteristics and Outcomes of COVID-19 in Patients on Left Ventricular Assist Device Support
Authors: Birati Edo Y. , Najjar Samer S. , Tedford Ryan J. , Houston Brian A. , Shore Supriya , Vorovich Esther , Atluri Pavan , Urgo Kimberly , Molina Maria , Chambers Susan , Escobar Nicole , Hsich Eileen , Estep Jerry D. , Alexander Kevin M. , Teuteberg Jeffrey J. , Chaudhry Sunit-Preet , Ravichandran Ashwin , DeVore Adam D. , Margulies Kenneth B. , Hanff Thomas C. , Zimmer Ross , Kilic Arman , Wald Joyce W. , Vidula Himabindu , Martens John , Blumberg Emily A. , Mazurek Jeremy A. , Owens Anjali T. , Goldberg Lee R. , Alvarez-Garcia Jesus , Mancini Donna M. , Moss Noah , Genuardi Michael V. 
Published: April 2021

Background:
The coronavirus disease 2019 (COVID-19) pandemic continues to afflict millions of people worldwide. Patients with end-stage heart failure and left ventricular assist devices (LVADs) may be at risk for severe COVID-19 given a high prevalence of complex comorbidities and functional impaired immunity. The objective of this study is to describe the clinical characteristics and outcomes of COVID-19 in patients with end-stage heart failure and durable LVADs.

Methods:
The Trans-CoV-VAD registry is a multi-center registry of LVAD and cardiac transplant patients in the United States with confirmed COVID-19. Patient characteristics, exposure history, presentation, laboratory data, course, and clinical outcomes were collected by participating institutions and reviewed by a central data repository. This report represents the participation of the first 9 centers to report LVAD data into the registry.

Results:
A total of 40 patients were included in this cohort. The median age was 56 years (interquartile range, 46–68), 14 (35%) were women, and 21 (52%) were Black. Among the most common presenting symptoms were cough (41%), fever, and fatigue (both 38%). A total of 18% were asymptomatic at diagnosis. Only 43% of the patients reported either subjective or measured fever during the entire course of illness. Over half (60%) required hospitalization, and 8 patients (20%) died, often after lengthy hospitalizations.

Conclusions:
We present the largest case series of LVAD patients with COVID-19 to date. Understanding these characteristics is essential in an effort to improve the outcome of this complex patient population.
Occipital Cortical Calcifications in Cerebral Amyloid Angiopathy
Authors: Rasing Ingeborg , Voigt Sabine , Koemans Emma A. , van Zwet Erik , de Kruijff Paul C. , van Harten Thijs W. , van Etten Ellis S. , van Rooden Sanneke , van der Weerd Louise , van Buchem Mark A. , van Osch Matthias J.P. , Greenberg Steven M. , van Walderveen Marianne A.A. , Terwindt Gisela M. , Wermer Marieke J.H. 
Published: April 2021

Background and Purpose:
Cortical calcifications have been reported in patients with cerebral amyloid angiopathy (CAA), although their prevalence and pathophysiology are unknown. We investigated the frequency of calcifications on computed tomography, their association with intracerebral hemorrhage (ICH) and their coexistence with a striped pattern of the occipital cortex reflecting microcalcifications on ultra-high-field 7T-magnetic resonance imaging in Dutch-type hereditary CAA (D-CAA) and sporadic CAA.

Methods:
We included D-CAA mutation carriers with a proven APP (amyloid precursor protein) mutation or ≥1 lobar ICH and ≥1 first-degree relative with D-CAA and sporadic CAA patients with probable CAA according to the modified Boston criteria. D-CAA carriers were regarded symptomatic when they had a history of symptomatic ICH. We assessed the presence, location, and progression of calcifications and their association with ICH and the striped occipital cortex.

Results:

We found cortical calcifications in 15/81 (19% [95% CI, 11–29]) D-CAA mutation carriers (15/69 symptomatic and 0/12 presymptomatic) and in 1/59 (2% [95% CI, 0–9]) sporadic CAA patients. Calcifications were all bilateral located in the occipital lobes. In 3/15 (20%) of the symptomatic D-CAA patients the calcifications progressed over a period up to 10 years. There was evidence of an association between cortical calcifications and new ICH development (hazard ratio, 7.1 [95% CI, 0.9–54.9], log-rank
P
=0.03). In 7/25 D-CAA symptomatic carriers in whom a 7T-magnetic resonance imaging was performed, a striped pattern of the occipital cortex was present; in 3/3 (100%) of those with calcifications on computed tomography and 4/22 (18%) of those without calcifications.

Conclusions:
Occipital cortical calcifications are frequent in D-CAA but seem to be rare in sporadic CAA. Their absence in presymptomatic carriers and their association with ICH might suggest that they are a marker for advanced CAA. Cortical calcifications on computed tomography seem to be associated with the striped occipital cortex on 7T-magnetic resonance imaging which may possibly represent an early stage of calcification.
The Variable Nature of Ownership of Emission Units in the Intersection of Climate Law, Property Law, and the Regulation of Financial Markets
Authors: Yliheljo Emilie 
Published: April 2021

Abstract
The article analyses the impact of the origins of emission units in transnational climate policy on market participants in the EU ets and the extension of financial-market regulation to the European carbon market. To assess the consequences of the public-private nature of emission units, a broad view of ownership is taken. Ownership is understood as the legal position of the holder of emission units, being an aggregate of elements of private law but also climate law and financial-market regulation. As a consequence, a picture emerges of a legal position variable in the personal, temporal, and spatial dimensions, following policy-design choices and the evolution of regulation of carbon markets. The ownership of emission units reflects the ongoing balancing of the different public-policy goals of the EU ets and differs from economic theories laying the foundations of emission trading. Due to the necessity for a proactive management of the scheme, regulatory intervention and risk have become inherent features of the ownership of the units, and the impact of changes will vary across different market participants.
Changing Climate, Unchanged Mandate: bric Countries in the UN Security Council
Authors: Bruner Tomáš 
Published: April 2021

Abstract
The UN Security Council has turned its attention to the link between climate change and security several times. Its members and other UN member states participating in discussions have remained divided over the Council’s engagement. Among vocal opponents are the bric countries: Brazil, Russia, India, and China. This article examines the argumentation of these countries during seven UN Security Council meetings between 2007 and 2020. The bric countries often concede that climate change is a threat, but they strongly resist the idea that such a threat could be addressed by the Council. I use a Critical Legal Studies approach to analyse how the bric countries bolstered their key argumentation before the Council. I find that the bric countries exploited a ‘background rule’ concerning the unsc mandate and used it to reaffirm the limits on the Council’s action. They were thus able to avoid self-contradiction and strengthen their political position through a legal argument. This complemented other objections they raised against the Council’s involvement: its insufficient expertise, inefficient tools, and the inapplicability of the principle of common but differentiated responsibilities to its decision-making.
How interactions between tropical depressions and western disturbances affect heavy precipitation in South Asia
Authors: Hunt Kieran M. R. , Turner Andrew G. , Schiemann Reinhard K. H. 
Published: April 2021

AbstractInteractions over South Asia between tropical depressions (TDs) and extratropical storms known as western disturbances (WDs) are known to cause extreme precipitation events, including those responsible for the 2013 floods over northern India. In this study, existing databases of WD and TD tracks are used to identify potential WD–TD interactions from 1979–2015; these are filtered according to proximity and intensity, leaving 59 cases which form the basis of this paper. Synoptic charts, vorticity budgets, and moisture trajectory analyses are employed to identify and elucidate common interaction types among these cases. Two broad families of interaction emerge. Firstly, a dynamical coupling of the WD and TD, whereby either the upper- and lower-level vortices superpose (a vortex merger), or the TD is intensified as it passes into the entrance region of a jet streak associated with the WD (a jet-streak excitation). Secondly, a moisture exchange between the WD and TD, whereby either anomalous moisture is advected from the TD to the WD, resulting in anomalous precipitation near the WD (a TD-to-WD moisture exchange), or anomalous moisture is advected from the WD to the TD (a WD-to-TD moisture exchange). Interactions are most common in the post-monsoon period as the subtropical jet, which brings WDs to the subcontinent, returns south; there is a smaller peak in May and June, driven by monsoon onset vortices. Precipitation is heaviest in dynamically-coupled interactions, particularly jet-streak excitations. Criteria for automated identification of interaction types are proposed, and schematics for each type are presented to highlight key mechanisms.
Effectiveness of perioperative pain science education on pain, psychological factors and physical functioning: A systematic review
Authors: Van der Gucht Elien , Dams Lore , Haenen Vincent , Godderis Lode , Morlion Bart , Bernar Koen , Evenepoel Margaux , De Vrieze Tessa , Vandendriessche Thomas , Asnong Anne , Geraerts Inge , Devoogdt Nele , De Groef An , Meeus Mira 
Published: April 2021

Objective: To synthesize the evidence on the effectiveness of pain science education on pain, psychological factors and physical functioning in adults who underwent surgery. Data sources: A systematic literature search of English articles using PubMed/Medline, Embase, Web of Science Core Collection, and Cochrane Library. Review methods: The search strategy was constructed as follows: (((pain) AND (education)) OR (pain education)) AND (surgery). Only controlled quantitative studies in adults reporting outcome(s) on pain, psychological factors and/or physical functioning were included. Risk of bias was assessed using the Cochrane risk of bias tools. P-values and corresponding effect sizes for interaction-effect (time × group) portrayed the difference in change over time between groups were of interest. The last search was conducted on February 28, 2021. Results: Nine papers ( n = 1078) were deemed eligible for this review. Two randomized controlled trials showed significant interaction effects. Breast cancer patients who had received one preoperative pain science education session showed a significant increase in postoperative pain compared to controls ( P-value = 0.0394). Furthermore, p sychological factors (pain catastrophizing and kinesiophobia) decreased in participants who had received pain science education before total knee arthroplasty, while this was not the case in the control group ( P-value < 0.001, ƞ2p:0.11). Conclusions: Overall, pain science education did not result in any significant postoperative effects on pain, psychological factors and/or physical functioning compared to controls. There is currently no strong evidence for the implementation of pain science education in the perioperative period. Registration number: PROSPERO: ID 161267, registration number CRD42020161267