bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of brolucizumab versus aflibercept in eyes with polypoidal choroidal vasculopathy in Japanese participants of HAWK
Authors: Ogura Yuichiro , Jaffe Glenn J , Cheung Chui Ming Gemmy , Kokame Gregg T , Iida Tomohiro , Takahashi Kanji , Lee Won Ki , Chang Andrew A , Monés Jordi , D’Souza Divya , Weissgerber Georges , Gedif Kinfemichael , Koh Adrian 
Published: July 2021

PurposeTo compare the efficacy and safety of brolucizumab versus aflibercept in eyes with polypoidal choroidal vasculopathy (PCV) over 96 weeks in the HAWK study.DesignHAWK was a global, 2-year, randomised, double-masked, multicentre phase III trial in participants with neovascular age-related macular degeneration.MethodsOf the Japanese participants with PCV, 39 received brolucizumab 6 mg and 30 received aflibercept 2 mg. After 3 monthly loading doses, brolucizumab-treated eyes received an injection every 12 weeks (q12w) but were adjusted to q8w if disease activity was detected. Aflibercept-treated eyes received fixed q8w dosing. Mean change in best-corrected visual acuity (BCVA), the proportion of participants on q12w, retinal thickness, retinal fluid changes and safety were assessed to Week 96.ResultsMean change in BCVA (early treatment diabetic retinopathy study (ETDRS) letters) from baseline to week 48/week 96 was+10.4/+11.4 for brolucizumab and +11.6/+11.1 for aflibercept. For brolucizumab-treated eyes, the probability of only q12w dosing after loading through week 48 was 76%, and 68% through week 96. Fluid resolution was greater with brolucizumab than aflibercept: respective proportions of eyes with intraretinal fluid and/or subretinal fluid were 7.7% and 30% at week 48% and 12.8% and 16.7% at week 96. Brolucizumab exhibited an overall well-tolerated safety profile despite a higher rate of intraocular inflammation compared with aflibercept.ConclusionIn Japanese eyes with PCV, brolucizumab q12w/q8w monotherapy resulted in robust and consistent BCVA gains that were comparable to q8w aflibercept dosing. Anatomical outcomes favoured brolucizumab over aflibercept, with 76% of brolucizumab participants maintained on q12w dosing after loading to week 48.
Clinical and magnetic resonance study of a case of subacute sclerosing panencephalitis treated with ketogenic diet
Authors: Valente Mariarosaria , Del Negro Ilaria , Bagatto Daniele , Garbo Riccardo , Lettieri Christian , Bernardini Andrea , Nilo Annacarmen , Peri Maria Rosaria , Pecori Davide , Gigli Gian Luigi 
Published: July 2021

BackgroundSubacute sclerosing panencephalitis is a progressive neurodegenerative disorder caused by a latent and mutant measles virus which is extremely rare in developed countries. The lack of effective treatments leads to the research of other anti-inflammatory and neuroprotective treatments.CaseHere we present a case of a 17-year-old patient affected by subacute sclerosing panencephalitis who manifest a dramatic improvement in neurological and general clinical conditions, as well as an arrest in the progression of demyelinating process in the central nervous system, after the beginning of a high ratio ketogenic diet.ConclusionsGiven its anti-inflammatory, antioxidant and metabolic effects, we believe that ketogenic diet utilisation could be a rational approach, can be considered a safe add-on therapy, carrying on with only a minimal risk of adverse effects or interactions.
Prognostic value of proliferation, PD-L1 and nuclear size in patients with superior sulcus tumours treated with chemoradiotherapy and surgery
Authors: Blaauwgeers Hans , Lissenberg-Witte Birgit I , Dickhoff Chris , Duin Sylvia , Thunnissen Erik 
Published: July 2021

AimsThe aim of this study was to determine the relationship between proliferative activity, PD-L1 status and nuclear size changes after preoperative chemoradiotherapy (CRT) and the clinical outcome in patients with superior sulcus tumours.MethodsProliferative activity (MIB-1) and PD-L1 status were estimated by immunohistochemistry in the tumour cells of resection specimen in a series of 33 patients with residual tumour after trimodality therapy for a sulcus superior tumour between 2005 and 2014. A morphometric analysis of both pretreatment and post-treatment tumour materials was also performed. Results were related to disease-free survival and overall survival.ResultsLow proliferative activity (<20% MIB-1) was associated with better overall survival: 2-year overall survival of 73% compared with 43% and 25%, respectively, for moderate (MIB-1 20%–50%) and high (MIB-1 >50%) proliferative activity (p=0.016). A negative PD-L1 status (<1% positive tumour cells) was also associated with better overall survival (p=0.021). The mean nuclear size of normal lung tissue pneumocytes was significantly smaller compared with the mean nuclear size of tumour cells of the resection specimens (median difference −38.1; range −115.2 to 16.0; p<0.001). The mean nuclear size of tumour cells did not differ between pretreatment biopsies and resection specimens (median difference −4.6; range −75.2 to 86.7; p=0.14). Nuclear size was not associated with survival (p=0.82).ConclusionsLow proliferative activity determined by MIB-1 as well as a negative PD-L1 expression are significantly associated with better overall survival in patients with residual tumour after CRT for superior sulcus tumour.
CX-072 (pacmilimab), a Probody PD-L1 inhibitor, in combination with ipilimumab in patients with advanced solid tumors (PROCLAIM-CX-072): a first-in-human, dose-finding study
Authors: Sanborn Rachel E , Hamid Omid , de Vries Elisabeth GE , Ott Patrick A , Garcia-Corbacho Javier , Boni Valentina , Bendell Johanna , Autio Karen A , Cho Daniel C , Plummer Ruth , Stroh Mark , Lu Lawrence , Thistlethwaite Fiona 
Published: July 2021

BackgroundProbody® therapeutics are antibody prodrugs designed to be activated by tumor-associated proteases. This conditional activation restricts antibody binding to the tumor microenvironment, thereby minimizing ‘off-tumor’ toxicity. Here, we report the phase 1 data from the first-in-human study of CX-072 (pacmilimab), a Probody immune checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1), in combination with the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab.MethodsAdults (n=27) with advanced solid tumors (naive to PD-L1/programmed cell death protein 1 or CTLA-4 inhibitors) were enrolled in the phase 1 combination therapy dose-escalation portion of this multicenter, open-label, phase 1/2 study (NCT03013491). Dose-escalation pacmilimab/ipilimumab followed a standard 3+3 design and continued until the maximum tolerated dose (MTD) was determined. Pacmilimab+ipilimumab was administered intravenously every 3 weeks for four cycles, followed by pacmilimab administered every 2 weeks as monotherapy. The primary objective was identification of dose-limiting toxicities and determination of the MTD. Other endpoints included the rate of objective response (Response Evaluation Criteria In Solid Tumors v.1.1).ResultsTwenty-seven patients were enrolled in pacmilimab (mg/kg)+ipilimumab (mg/kg) dose-escalation cohorts: 0.3+3 (n=6); 1+3 (n=3); 3+3 (n=3); 10+3 (n=8); 10+6 (n=6); and 10+10 (n=1). Dose-limiting toxicities occurred in three patients, one at the 0.3+3 dose level (grade 3 dyspnea/pneumonitis) and two at the 10+6 dose level (grade 3 colitis, grade 3 increased aspartate aminotransferase). The MTD and recommended phase 2 dose was pacmilimab 10 mg/kg+ipilimumab 3 mg/kg administered every 3 weeks. Pacmilimab-related grade 3–4 adverse events (AEs) and grade 3–4 immune-related AEs were reported in nine (33%) and six (22%) patients, respectively. Three patients (11%) discontinued treatment because of AEs. The overall response rate was 19% (95% CI 6.3 to 38.1), with one complete (anal squamous cell carcinoma) and four partial responses (cancer of unknown primary, leiomyosarcoma, mesothelioma, testicular cancer). Responses lasted for >12 months in four patients.ConclusionsThe MTD and recommended phase 2 dose of pacmilimab (10 mg/kg)+ipilimumab (3 mg/kg) every 3 weeks is active and has a favorable tolerability profile.
Factors associated with receipt of intracranial pressure monitoring in older adults with traumatic brain injury
Authors: Ghneim Mira , Albrecht Jennifer , Brasel Karen , Knight Ariel , Liveris Anna , Watras Jill , Michetti Christopher P , Haan James , Lightwine Kelly , Winfield Robert D , Adams Sasha D , Podbielski Jeanette , Armen Scott , Zacko J Christopher , Nasrallah Fady S , Schaffer Kathryn B , Dunn Julie A , Smoot Brittany , Schroeppel Thomas J , Stillman Zachery , Cooper Zara , Stein Deborah M 
Published: July 2021

BackgroundThe Brain Trauma Foundation (BTF) Guidelines for the Management of Severe Traumatic Brain Injury (TBI) include intracranial pressure monitoring (ICPM), yet very little is known about ICPM in older adults. Our objectives were to characterize the utilization of ICPM in older adults and identify factors associated with ICPM in those who met the BTF guidelines.MethodsWe analyzed data from the American Association for the Surgery of Trauma Geriatric TBI Study, a registry study conducted among individuals with isolated, CT-confirmed TBI across 45 trauma centers. The analysis was restricted to those aged ≥60. Independent factors associated with ICPM for those who did and did not meet the BTF guidelines were identified using logistic regression.ResultsOur sample was composed of 2303 patients, of whom 66 (2.9%) underwent ICPM. Relative to Glasgow Coma Scale (GCS) score of 13 to 15, GCS score of 9 to 12 (OR 10.2; 95% CI 4.3 to 24.4) and GCS score of <9 (OR 15.0; 95% CI 7.2 to 31.1), intraventricular hemorrhage (OR 2.4; 95% CI 1.2 to 4.83), skull fractures (OR 3.6; 95% CI 2.0 to 6.6), CT worsening (OR 3.3; 95% CI 1.8 to 5.9), and neurosurgical interventions (OR 3.8; 95% CI 2.1 to 7.0) were significantly associated with ICPM. Restricting to those who met the BTF guidelines, only 43 of 240 (18%) underwent ICPM. Factors independently associated with ICPM included intraparenchymal hemorrhage (OR 2.2; 95% CI 1.0 to 4.7), skull fractures (OR 3.9; 95% CI 1.9 to 8.2), and neurosurgical interventions (OR 3.5; 95% CI 1.7 to 7.2).DiscussionWorsening GCS, intraparenchymal/intraventricular hemorrhage, and skull fractures were associated with ICPM among older adults with TBI, yet utilization of ICPM remains low, especially among those meeting the BTF guidelines, and potential benefits remain unclear. This study highlights the need for better understanding of factors that influence compliance with BTF guidelines and the risks versus benefits of ICPM in this population.Level of evidencePrognostic and epidemiological, level III.
Effect of environmental factors on polyketide synthase gene expression, usnic acid biosynthesis, and ground cover of a lichen-fungus, Cladonia uncialis
Authors: Gunawardana W.G. Duleeka I. , Sveshnikova Natalia , Arsenault André , Piercey-Normore Michele D. 
Published: July 2021

Lichens are composed of symbiotic slow-growing organisms and are often exposed to extreme microenvironmental conditions, resulting in the production of unique secondary metabolites. One of the most commonly produced secondary metabolites is usnic acid, which is thought to be produced by two genes. The objectives of the present study were to compare polyketide synthase (PKS) gene expression and usnic acid concentration in Cladonia uncialis (L.) Weber ex F.H. Wigg., with two environmental factors. Seventy-five lichen samples were collected from three locations in Newfoundland, Canada, using a strip transect method (×5 transects, ×5 quadrats). Usnic acid concentration was measured using the liquid chromatography tandem mass-spectrometric method and gene expression of two PKS genes (methylphloracetophenone oxidase (MPAO) and methylphloracetophenone synthase (MPAS)) was examined using quantitative real-time PCR. The results showed that percent ground cover of C. uncialis was affected by soil pH level but not soil moisture, and usnic acid concentration was not affected by either soil pH or soil moisture. MPAO gene expression level was significantly affected by soil pH level but not soil moisture, and MPAS gene expression level was not affected by either soil pH level or soil moisture. There was no significant relationship between MPAS and MPAO gene expression levels and usnic acid concentration. These findings suggest that soil pH may be important for the production of usnic acid by C. uncialis but the genes involved require further study.
High-resolution remote sensing and multistate occupancy estimation identify drivers of spawning site selection in fall chum salmon (Oncorhynchus keta) across a sub-Arctic riverscape
Authors: Clawson Chelsea M. , Falke Jeffrey A. , Bailey Larissa L. , Rose Joshua , Prakash Anupma , Martin Aaron E. 
Published: July 2021

Groundwater upwellings provide warmer, stable overwinter temperatures for developing salmon embryos, which may be particularly important in cold, braided, gravel-bed sub-Arctic rivers. We used a three-year time series of aerial counts and remote sensing to estimate the distribution of low and high aggregations of spawning fall chum salmon (Oncorhynchus keta), classify approximately 0.5 km long river segments by geomorphic channel type, and map thermal variability along a 25.4 km stretch of the Teedriinjik River, Alaska. We used a dynamic multistate occupancy model to estimate detectability, occupancy, and the dynamics of spawning aggregations among river segments. Detectability was higher for large (>150) relative to smaller aggregations. Unoccupied segments were likely to remain so from year to year; low abundance spawning segments were dynamic and rarely remained in that state for multiple years, while ∼20%–35% of high abundance segments remained stable, indicating the presence of high-quality spawning habitat. Spawning habitat use was associated with warmer water temperatures likely caused by groundwater upwellings. We identified spawning habitat characteristics and trends in usage by fall chum salmon, which will inform land management decisions and assist in evaluating impacts of shifting climate conditions and resource management on Arctic salmon populations.
Qualifying ringdown and shadow of black holes under general parametrized metrics with photon orbits
Authors: Li Song , Abdujabbarov Ahmadjon A. , Han Wen-Biao 
Published: July 2021

AbstractThe motion of photons around black holes determines the shape of shadow and match the ringdown properties of a perturbed black hole. Observations of shadows and ringdown waveforms will reveal the nature of black holes. In this paper, we study the motion of photons in a general parametrized metric beyond the Kerr hypothesis. We investigated the radius and frequency of the photon circular orbits on the equatorial plane and obtained fitted formula with varied parameters. The Lyapunov exponent which connects to the decay rate of the ringdown amplitude is also calculated. We also analyzed the shape of shadow with full parameters of the generally axisymmetric metric. Our results imply the potential constraint on black hole parameters by combining the Event Horizon Telescope and gravitational wave observations in the future.
Irradiation-driven molecular dynamics: a review
Authors: Verkhovtsev Alexey V. , Solov’yov Ilia A. , Solov’yov Andrey V. 
Published: July 2021

Abstract
This paper reviews Irradiation-Driven Molecular Dynamics (IDMD)—a novel computational methodology for atomistic simulations of the irradiation-driven transformations of complex molecular systems implemented in the MBN Explorer software package. Within the IDMD framework, various quantum processes occurring in irradiated systems are treated as random, fast and local transformations incorporated into the classical MD framework in a stochastic manner with the probabilities elaborated on the basis of quantum mechanics. Major transformations of irradiated molecular systems (such as topological changes, redistribution of atomic partial charges, alteration of interatomic interactions) and possible paths of their further reactive transformations can be simulated by means of MD with reactive force fields, in particular with the reactive CHARMM (rCHARMM) force field implemented in MBN Explorer. This paper reviews the general concept of the IDMD methodology and the rCHARMM force field and provides several exemplary case studies illustrating the utilization of these methods.

Graphic abstract
P4Pi
Authors: Laki Sándor , Stoyanov Radostin , Kis Dávid , Soulé Robert , Vörös Péter , Zilberman Noa 
Published: July 2021

High level, network programming languages, like P4, enable students to gain hands-on experience in the structure of a switch or router. Students can implement the packet processing pipeline themselves, without prior knowledge of circuit design. However, when choosing a P4 programmable target for use in the classroom, instructors face a lack of options. On the one hand, software solutions, such as the behavioral model (BMv2) switch, are overly simplified and offer low performance. On the other hand, existing hardware solutions are closed source and expensive.
In this paper, we present P4Pi, a new, low-cost, open-source hardware platform intended for networking education. P4Pi allows students to design and deploy P4-based network devices using the Raspberry Pi board, which has a price tag of less than many academic textbooks. We describe the high-level design of the P4Pi platform, offer some suggestions for how P4Pi could be used in the classroom, and present some additional use-cases for applications and functionality that could be developed using P4Pi.
Endothelial Reprogramming Stimulated by Oncostatin M Promotes Inflammation and Tumorigenesis inVHL-Deficient Kidney Tissue
Authors: Nguyen-Tran Hieu-Huy , Nguyen Thi-Ngoc , Chen Chen-Yun , Hsu Tien 
Published: July 2021

AbstractClear-cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma (RCC), and its progression has been linked to chronic inflammation. About 70% of the ccRCC cases are associated with inactivation of the von Hippel–Lindau (VHL) tumor-suppressor gene. However, it is still not clear how mutations in VHL, encoding the substrate-recognition subunit of an E3 ubiquitin ligase that targets the alpha subunit of hypoxia-inducible factor-α (HIFα), can coordinate tissue inflammation and tumorigenesis. We previously generated mice with conditional Vhlh knockout in kidney tubules, which resulted in severe inflammation and fibrosis in addition to hyperplasia and the appearance of transformed clear cells. Interestingly, the endothelial cells (EC), although not subject to genetic manipulation, nonetheless showed profound changes in gene expression that suggest a role in promoting inflammation and tumorigenesis. Oncostatin M (OSM) mediated the interaction between VHL-deficient renal tubule cells and the ECs, and the activated ECs in turn induced macrophage recruitment and polarization. The OSM-dependent microenvironment also promoted metastasis of exogenous tumors. Thus, OSM signaling initiates reconstitution of an inflammatory and tumorigenic microenvironment by VHL-deficient renal tubule cells, which plays a critical role in ccRCC initiation and progression.Significance:A novel mechanism of cross-talk between ECs and VHL-deficient kidney tubules that stimulates inflammation and tumorigenesis is discovered, suggesting OSM could be a potential target for ccRCC intervention.
SARS-CoV-2 Initiates Programmed Cell Death in Platelets
Authors: Koupenova Milka , Corkrey Heather A. , Vitseva Olga , Tanriverdi Kahraman , Somasundaran Mohan , Liu Ping , Soofi Shaukat , Bhandari Rohan , Godwin Matthew , Parsi Krishna Mohan , Cousineau Alyssa , Maehr René , Wang Jennifer P. , Cameron Scott J. , Rade Jeffrey , Finberg Robert W. , Freedman Jane E. 
Published: July 2021

Rationale:
Coronavirus disease 2019 (COVID-19) is characterized by increased incidence of microthrombosis with hyperactive platelets sporadically containing viral RNA. It is unclear if SARS-CoV-2 (severe acute respiratory syndrome, corona virus-2) directly alters platelet activation or if these changes are a reaction to infection-mediated global inflammatory alterations. Importantly, the direct effect of SARS-CoV-2 on platelets has yet to be studied.

Objective:
To characterize the direct SARS-CoV-2–platelet interactions using in vitro studies with purified infectious virions and samples from infected patients.

Methods and Results:
Platelet RNA analyzed by ARTIC v3 sequencing for SARS-CoV-2 showed presence of fragmented viral genome in all patients with COVID-19. Immunofluorescent imaging of platelets from patients with COVID-19 confirmed presence of SARS-CoV-2 proteins, whereas there was no detection of viral RNA by real-time quantitative polymerase chain reaction. Transmission electron microscopy of platelets incubated with purified SARS-CoV-2 virions demonstrated rapid internalization and digestion leading to distinct morphological changes and resulted in a release of extracellular vesicles. Interactions between SARS-CoV-2 and platelets occurred with or without ACE (angiotensin-converting enzyme) 2 presence as measured by immunofluorescence. Transmission electron microscopy showed that SARS-CoV-2 virions became internalized when they were attached to microparticles, bypassing the need for ACE2. Enrichment analysis of platelet transcriptome from patients with acute COVID-19, compared with those with clinical thrombosis, suggested upregulation of pathways related to virally mediated cell death, specifically necroptosis and apoptosis. Platelets incubated with infectious virus appeared to undergo cell death in 30 minutes postincubation as assessed by transmission electron microscopy and platelets from patients with COVID-19 showed evidence of increased markers of apoptosis and necroptosis by Western blot. Immunofluorescence confirmed colocalization of SARS-CoV-2 with phospho-MLKL (mixed lineage kinase domain-like pseudokinase) and caspase 3 on nonpermeabilized platelets in vitro and in COVID-19 platelets.

Conclusions:
Platelets internalize SARS-CoV-2 virions, directly or attached to microparticles, and viral internalization leads to rapid digestion, programmed cell death, and extracellular vesicle release. During COVID-19, platelets mediate a rapid response to SARS-CoV-2 and this response can contribute to dysregulated immunity and thrombosis.