bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination of thermally ablative focused ultrasound with gemcitabine controls breast cancer via adaptive immunity
Authors: Sheybani Natasha D , Witter Alexandra R , Thim Eric A , Yagita Hideo , Bullock Timothy N J , Price Richard J 
Published: August 2020

BackgroundTriple-negative breast cancer (TNBC) remains recalcitrant to most targeted therapy approaches. However, recent clinical studies suggest that inducing tumor damage can render TNBC responsive to immunotherapy. We therefore tested a strategy for immune sensitization of murine TNBC (4T1 tumors) through combination of focused ultrasound (FUS) thermal ablation and a chemotherapy, gemcitabine (GEM), known to attenuate myeloid-derived suppressor cells (MDSCs).MethodsWe applied a sparse-scan thermally ablative FUS regimen at the tumor site in combination with systemically administered GEM. We used flow cytometry analysis to investigate the roles of monotherapy and combinatorial therapy in mediating local and systemic immunity. We also tested this combination in Rag1−/−mice or T cell-depleted wild-type mice to determine the essentiality of adaptive immunity. Further, we layered Programmed cell death protein 1 (PD-1) blockade onto this combination to evaluate its impact on tumor outgrowth and survival.ResultsThe immune-modulatory effect of FUS monotherapy was insufficient to promote a robust T cell response against 4T1, consistent with the dominant MDSC-driven immunosuppression evident in this model. The combination of FUS+GEM significantly constrained primary TNBC tumor outgrowth and extended overall survival of mice. Tumor control correlated with increased circulating antigen-experienced T cells and was entirely dependent on T cell-mediated immunity. The ability of FUS+GEM to control primary tumor outgrowth was moderately enhanced by either neoadjuvant or adjuvant treatment with anti-PD-1.ConclusionThermally ablative FUS in combination with GEM restricts primary tumor outgrowth, improves survival and enhances immunogenicity in a murine metastatic TNBC model. This treatment strategy promises a novel option for potentiating the role of FUS in immunotherapy of metastatic TNBC and is worthy of future clinical evaluation.Trial registration numbersNCT03237572andNCT04116320.
Chimeric Ad5.F35 vector evades anti-adenovirus serotype 5 neutralization opposing GUCY2C-targeted antitumor immunity
Authors: Flickinger Jr John C , Singh Jagmohan , Carlson Robert , Leong Elinor , Baybutt Trevor R , Barton Joshua , Caparosa Ellen , Pattison Amanda , Rappaport Jeffrey A , Roh Jamin , Zhan Tingting , Bashir Babar , Waldman Scott A , Snook Adam E 
Published: August 2020

BackgroundAdenovirus serotype 5 (Ad5) is a commonly used viral vector for transient delivery of transgenes, primarily for vaccination against pathogen and tumor antigens. However, endemic infections with Ad5 produce virus-specific neutralizing antibodies (NAbs) that limit transgene delivery and constrain target-directed immunity following exposure to Ad5-based vaccines. Indeed, clinical trials have revealed the limitations that virus-specific NAbs impose on the efficacy of Ad5-based vaccines. In that context, the emerging focus on immunological approaches targeting cancer self-antigens or neoepitopes underscores the unmet therapeutic need for more efficacious vaccine vectors.MethodsHere, we evaluated the ability of a chimeric adenoviral vector (Ad5.F35) derived from the capsid of Ad5 and fiber of the rare adenovirus serotype 35 (Ad35) to induce immune responses to the tumor-associated antigen guanylyl cyclase C (GUCY2C).ResultsIn the absence of pre-existing immunity to Ad5, GUCY2C-specific T-cell responses and antitumor efficacy induced by Ad5.F35 were comparable to Ad5 in a mouse model of metastatic colorectal cancer. Furthermore, like Ad5, Ad5.F35 vector expressing GUCY2C was safe and produced no toxicity in tissues with, or without, GUCY2C expression. Importantly, this chimeric vector resisted neutralization in Ad5-immunized mice and by sera collected from patients with colorectal cancer naturally exposed to Ad5.ConclusionsThese data suggest that Ad5.F35-based vaccines targeting GUCY2C, or other tumor or pathogen antigens, may produce clinically relevant immune responses in more (≥90%) patients compared with Ad5-based vaccines (~50%).
High-dose versus low-dose angiotensin converting enzyme inhibitors in heart failure: systematic review and meta-analysis
Authors: Migliavaca Celina Borges , Stein Cinara , Colpani Verônica , Eibel Bruna , Bgeginski Roberta , Simões Marcus Vinicius , Rohde Luiz Eduardo , Falavigna Maicon 
Published: August 2020

ObjectiveTo systematically review evidence comparing the effect of low-dose versus high-dose ACE inhibitors (ACEIs) on all-cause and cardiovascular mortality and hospitalisation, functional capacity and side effects in patients with heart failure (HF).MethodsWe searched PubMed, Embase, Cochrane CENTRAL and LILACS up to January 2019. We included randomised controlled trials (RCTs) comparing low-dose versus high-dose ACEIs in adults with HF with reduced left ventricular ejection fraction (HFrEF). Study selection and data extraction were performed by two independent reviewers. Risk of bias was assessed with RoB 2.0, and quality of evidence with Grading of Recommendations Assessment, Development and Evaluation (GRADE). We conducted random effects meta-analysis and trial sequential analysis.ResultsWe included eight RCTs (5829 patients with HF). In comparison with low-dose ACEIs, high-dose ACEIs showed a non-significant effect on all-cause mortality (8 RCTs, n=5828, relative risk (RR) 0.95, 95% CI 0.88 to 1.02; moderate quality of evidence), cardiovascular mortality (6 RCTs, n=4048, RR 0.93, 95% CI 0.85 to 1.01; moderate quality of evidence), all-cause hospitalisation (5 RCTs, n=5394, RR 0.95, 95% CI 0.82 to 1.10; moderate quality of evidence) and cardiovascular hospitalisation (4 RCTs, n=5242, RR 0.98, 95% CI 0.83 to 1.17; low quality of evidence). High-dose ACEI increased functional capacity (4 studies, n=555, standardised mean difference 0.38, 95% CI 0.20 to 0.55; low quality of evidence) and the risk of hypotension (4 RCTs, n=3783, RR 1.64, 95% CI 1.30 to 2.05; moderate quality of evidence). High-dose ACEI had no effect on dizziness (3 RCTs, n=4994, RR 1.37, 95% CI 0.97 to 1.93; low quality of evidence), but decreased the risk of cough (4 RCTs, n=5146, RR 0.85, 95% CI 0.73 to 0.98; moderate quality of evidence).ConclusionsThe magnitude of benefit of using high dose versus low to intermediate doses of ACEIs might be less than traditionally suggested in clinical guidelines. These findings might help clinicians address the complex task of HF management in a more rational and timely fashion, saving efforts to implement strategies with the greatest net clinical benefit.
Severe respiratory viral infection induces procalcitonin in the absence of bacterial pneumonia
Authors: Gautam Samir , Cohen Avi J , Stahl Yannick , Valda Toro Patricia , Young Grant M , Datta Rupak , Yan Xiting , Ristic Nicholas T , Bermejo Santos D , Sharma Lokesh , Restrepo Marcos I , Dela Cruz Charles S 
Published: August 2020

IntroductionProcalcitonin expression is thought to be stimulated by bacteria and suppressed by viruses via interferon signalling. Consequently, during respiratory viral illness, clinicians often interpret elevated procalcitonin as evidence of bacterial coinfection, prompting antibiotic administration. We sought to evaluate the validity of this practice and the underlying assumption that viral infection inhibits procalcitonin synthesis.MethodsWe conducted a retrospective cohort study of patients hospitalised with pure viral infection (n=2075) versus bacterial coinfection (n=179). The ability of procalcitonin to distinguish these groups was assessed. In addition, procalcitonin and interferon gene expression were evaluated in murine and cellular models of influenza infection.ResultsPatients with bacterial coinfection had higher procalcitonin than those with pure viral infection, but also more severe disease and higher mortality (p<0.001). After matching for severity, the specificity of procalcitonin for bacterial coinfection dropped substantially, from 72% to 61%. In fact, receiver operating characteristic curve analysis showed that procalcitonin was a better indicator of multiple indices of severity (eg, organ failures and mortality) than of coinfection. Accordingly, patients with severe viral infection had elevated procalcitonin. In murine and cellular models of influenza infection, procalcitonin was also elevated despite bacteriologic sterility and correlated with markers of severity. Interferon signalling did not abrogate procalcitonin synthesis.DiscussionThese studies reveal that procalcitonin rises during pure viral infection in proportion to disease severity and is not suppressed by interferon signalling, in contrast to prior models of procalcitonin regulation. Applied clinically, our data suggest that procalcitonin represents a better indicator of disease severity than bacterial coinfection during viral respiratory infection.
Isolation and characterisation of Vibrio cholerae from fish examined postmortem at ZSL London Zoo between 2014 and 2018
Authors: Flach Edmund J , LeNette‐Dawson Demi , Greig David R , Ismail Ahmed Amina , Jenkins Claire , John Shinto K , Macgregor Shaheed K , Masters Nic , Stidworthy Mark F , Zimmerman Brian , Chattaway Marie A 
Published: August 2020

BackgroundWhen suspect Vibrio cholerae were cultured from fish at ZSL London Zoo, investigations were carried out to determine whether they were possible causes of cholera.MethodsBacterial culture was carried out on fish examined postmortem and colonies were identified using standard techniques including the API 20NE biochemical test kits. Suspect isolates were submitted to the Public Health England laboratory for additional testing. Separately, a number of fish were submitted for routine histopathology.ResultsOn 13 occasions between 2014 and 2018, suspected V cholerae were cultured from individuals of eight different freshwater fish species. Archived cultures for eight of these (from six different fish species) were investigated and seven isolates (from five fish species) were confirmed as V cholerae, but all were non‐O1, non‐O139 strains. Whole‐genome sequencing showed that the five fish species had unique V cholerae multilocus sequence types (three isolates from Aphanius danfordii were identical), all of which were genetically distant from human isolates.ConclusionsThere was no evidence that these isolates could cause cholera. Histopathological changes consistent with vibriosis were seen in several fish, suggesting that V cholerae were causing the disease, but there were also concurrent infections or predisposing stress factors.
Assessing methods to live‐capture wild boars (Sus scrofa) in urban and peri‐urban environments
Authors: Torres‐Blas Irene , Mentaberre Gregorio , Castillo‐Contreras Raquel , Fernández‐Aguilar Xavier , Conejero Carles , Valldeperes Marta , González‐Crespo Carlos , Colom‐Cadena Andreu , Lavín Santiago , López‐Olvera Jorge Ramón 
Published: August 2020

BackgroundWild boar (Sus scrofa) populations are increasing worldwide and invading urban areas. Live‐capture can improve the management of this challenge, maximising efficiency, allowing scientific studies and potentially improving animal welfare. This study assesses teleanaesthesia, drop‐net, corral trap and cage trap to live‐capture wild boar in urban and peri‐urban areas, evaluating efficiency and animal stress through haematology and serum biochemistry.MethodsFrom 2012 to 2018, 655 wild boars were captured in 279 operations (drop‐net=17, teleanaesthesia=186, cage trap=66 and corral trap=10) in the urban and peri‐urban areas of Barcelona (Spain). Haematological and serum biochemical variables were determined in 145 wild boars (42 drop‐netted, 41 teleanaesthetised, 38 cage‐trapped and 24 corral‐trapped).ResultsPerformance (wild boars captured per operation) was highest for drop‐net, followed by corral and cage traps, and finally teleanaesthesia. The three physical capture methods were more stressful than teleanaesthesia, causing a more intense physiological reaction, muscular damage, renal function impairment and homeostasis adaption. Stress response was predominantly adrenergic for drop‐net and cortisol‐induced for cage and corral traps.ConclusionTeleanaesthesia is the choice in reactive urban situations thanks to its adaptability; drop‐net effectively targets wild boars in peri‐urban environments; cage and corral traps are useful as long‐term methods in specific areas.
Use of cefovecin in dogs and cats attending first‐opinion veterinary practices in Australia
Authors: Hardefeldt Laura , Hur Brian , Verspoor Karin , Baldwin Timothy , Bailey Kirsten E , Scarborough Ri , Richards Suzanna , Billman‐Jacobe Helen , Browning Glenn Francis , Gilkerson James 
Published: August 2020

BackgroundCefovecin is a long‐acting third‐generation cephalosporin commonly used in veterinary medicine. Third‐generation cephalosporins are critically important antimicrobials that should only be used after culture and susceptibility testing. The authors describe the common indications for cefovecin use in dogs and cats, and the frequency of culture and susceptibility testing.Materials and methodsA cross‐sectional study was performed using clinical records extracted from VetCompass Australia. A previously described method was used to identify records containing cefovecin. The reason for cefovecin use was annotated in situ in each consultation text.ResultsOver a six‐month period (February and September 2018), 5180 (0.4 per cent) consultations involved cefovecin administration, of which 151 were excluded. Cats were administered cefovecin more frequently than dogs (1.9 per cent of cat consultations and 0.1 per cent of dog consultations). The most common reasons for cefovecin administration to cats were cat fight injuries and abscesses (28 per cent) and dermatitis (13 per cent). For dogs, the most common reasons for cefovecin administration were surgical prophylaxis (24 per cent) and dermatitis (19 per cent). Culture and susceptibility testing were reported in 16 cases (0.3 per cent).ConclusionCefovecin is used in many scenarios in dogs and cats where antimicrobials may be either not indicated or where an antimicrobial of lower importance to human health is recommended.
Flat-band physics in the spin-1/2 sawtooth chain
Authors: Derzhko Oleg , Schnack Jürgen , Dmitriev Dmitry V. , Krivnov Valery Ya. , Richter Johannes 
Published: August 2020

Abstract

We consider the strongly anisotropic spin-1/2 XXZ model on the sawtooth-chain lattice with ferromagnetic longitudinal interaction Jzz = ΔJ and aniferromagnetic transversal interaction Jxx = Jyy = J > 0. At Δ = −1∕2 the lowest one-magnon excitation band is dispersionless (flat) leading to a massively degenerate set of ground states. Interestingly, this model admits a three-coloring representation of the ground-state manifold [H.J. Changlani et al., Phys. Rev. Lett. 120, 117202 (2018)]. We characterize this ground-state manifold and elaborate the low-temperature thermodynamics of the system. We illustrate the manifestation of the flat-band physics of the anisotropic model by comparison with two isotropic flat-band Heisenberg sawtooth chains. Our analytical consideration is complemented by exact diagonalization and finite-temperature Lanczos method calculations.

Graphical abstract
A transportable quantum gravimeter employing delta-kick collimated Bose–Einstein condensates
Authors: Heine Nina , Matthias Jonas , Sahelgozin Maral , Herr Waldemar , Abend Sven , Timmen Ludger , Müller Jürgen , Rasel Ernst Maria 
Published: August 2020

Abstract
Gravimetry with low uncertainty and long-term stability opens up new fields of research in geodesy, especially in hydrology and volcanology. The main limitations in the accuracy of current generation cold atom gravimeters stem from the expansion rate and the residual centre-of-mass motion of their atomic test masses. Our transportable quantum gravimeter QG-1 aims at overcoming these limitations by performing atom interferometry with delta-kick collimated Bose–Einstein condensates generated by an atom chip. With our approach we anticipate to measure the local gravitational acceleration at geodetic campaigns with an uncertainty less than 1 nm/s2 surpassing the state-of-the-art classic and quantum based systems. In this paper, we discuss the design and performance assessment of QG-1.

Graphical abstract
The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies
Authors: Su Angela , Ling Frank , Vaganay Camille , Sodaro Gaetano , Benaksas Chaïma , Dal Bello Reinaldo , Forget Antoine , Pardieu Bryann , Lin Kevin H. , Rutter Justine C. , Bassil Christopher F. , Fortin Gael , Pasanisi Justine , Antony-Debré Iléana , Alexe Gabriela , Benoist Jean-François , Pruvost Alain , Pikman Yana , Qi Jun , Schlageter Marie-Hélène , Micol Jean-Baptiste , Roti Giovanni , Cluzeau Thomas , Dombret Hervé , Preudhomme Claude , Fenouille Nina , Benajiba Lina , Golan Hava M. , Stegmaier Kimberly , Lobry Camille , Wood Kris C. , Itzykson Raphael , Puissant Alexandre 
Published: August 2020

Abstract

Deciphering the impact of metabolic intervention on response to anticancer therapy may elucidate a path toward improved clinical responses. Here, we identify amino acid–related pathways connected to the folate cycle whose activation predicts sensitivity to MYC-targeting therapies in acute myeloid leukemia (AML). We establish that folate restriction and deficiency of the rate-limiting folate cycle enzyme MTHFR, which exhibits reduced-function polymorphisms in about 10% of Caucasians, induce resistance to MYC targeting by BET and CDK7 inhibitors in cell lines, primary patient samples, and syngeneic mouse models of AML. Furthermore, this effect is abrogated by supplementation with the MTHFR enzymatic product CH3-THF. Mechanistically, folate cycle disturbance reduces H3K27/K9 histone methylation and activates a SPI1 transcriptional program counteracting the effect of BET inhibition. Our data provide a rationale for screening MTHFR polymorphisms and folate cycle status to nominate patients most likely to benefit from MYC-targeting therapies.

Significance:
Although MYC-targeting therapies represent a promising strategy for cancer treatment, evidence of predictors of sensitivity to these agents is limited. We pinpoint that folate cycle disturbance and frequent polymorphisms associated with reduced MTHFR activity promote resistance to BET inhibitors. CH3-THF supplementation thus represents a low-risk intervention to enhance their effects.
See related commentary by Marando and Huntly, p. 1791.
This article is highlighted in the In This Issue feature, p. 1775
Multidimensional Analyses of Donor Memory-Like NK Cells Reveal New Associations with Response after Adoptive Immunotherapy for Leukemia
Authors: Berrien-Elliott Melissa M. , Cashen Amanda F. , Cubitt Celia C. , Neal Carly C. , Wong Pamela , Wagner Julia A. , Foster Mark , Schappe Timothy , Desai Sweta , McClain Ethan , Becker-Hapak Michelle , Foltz Jennifer A. , Cooper Matthew L. , Jaeger Natalia , Srivatsan Sridhar Nonavinkere , Gao Feng , Romee Rizwan , Abboud Camille N. , Uy Geoffrey L. , Westervelt Peter , Jacoby Meagan A. , Pusic Iskra , Stockerl-Goldstein Keith E. , Schroeder Mark A. , DiPersio John , Fehniger Todd A. 
Published: August 2020

Abstract

Natural killer (NK) cells are an emerging cancer cellular therapy and potent mediators of antitumor immunity. Cytokine-induced memory-like (ML) NK cellular therapy is safe and induces remissions in patients with acute myeloid leukemia (AML). However, the dynamic changes in phenotype that occur after NK-cell transfer that affect patient outcomes remain unclear. Here, we report comprehensive multidimensional correlates from ML NK cell–treated patients with AML using mass cytometry. These data identify a unique in vivo differentiated ML NK–cell phenotype distinct from conventional NK cells. Moreover, the inhibitory receptor NKG2A is a dominant, transcriptionally induced checkpoint important for ML, but not conventional NK-cell responses to cancer. The frequency of CD8α+ donor NK cells is negatively associated with AML patient outcomes after ML NK therapy. Thus, elucidating the multidimensional dynamics of donor ML NK cells in vivo revealed critical factors important for clinical response, and new avenues to enhance NK-cell therapeutics.

Significance:
Mass cytometry reveals an in vivo memory-like NK-cell phenotype, where NKG2A is a dominant checkpoint, and CD8α is associated with treatment failure after ML NK–cell therapy. These findings identify multiple avenues for optimizing ML NK–cell immunotherapy for cancer and define mechanisms important for ML NK–cell function.
This article is highlighted in the In This Issue feature, p. 1775
Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation
Authors: Weng Lu-Chen , Hall Amelia Weber , Choi Seung Hoan , Jurgens Sean J. , Haessler Jeffrey , Bihlmeyer Nathan A. , Grarup Niels , Lin Honghuang , Teumer Alexander , Li-Gao Ruifang , Yao Jie , Guo Xiuqing , Brody Jennifer A. , Müller-Nurasyid Martina , Schramm Katharina , Verweij Niek , van den Berg Marten E. , van Setten Jessica , Isaacs Aaron , Ramírez Julia , Warren Helen R. , Padmanabhan Sandosh , Kors Jan A. , de Boer Rudolf A. , van der Meer Peter , Sinner Moritz F. , Waldenberger Melanie , Psaty Bruce M. , Taylor Kent D. , Völker Uwe , Kanters Jørgen K. , Li Man , Alonso Alvaro , Perez Marco V. , Vaartjes Ilonca , Bots Michiel L. , Huang Paul L. , Heckbert Susan R. , Lin Henry J. , Kornej Jelena , Munroe Patricia B. , van Duijn Cornelia M. , Asselbergs Folkert W. , Stricker Bruno H. , van der Harst Pim , Kääb Stefan , Peters Annette , Sotoodehnia Nona , Rotter Jerome I. , Mook-Kanamori Dennis O. , Dörr Marcus , Felix Stephan B. , Linneberg Allan , Hansen Torben , Arking Dan E. , Kooperberg Charles , Benjamin Emelia J. , Lunetta Kathryn L. , Ellinor Patrick T. , Lubitz Steven A. 
Published: August 2020

Background:
The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD.

Methods:
Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies.

Results:

We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (
TTN
,
CAND2
,
SCN10A
,
PITX2
,
CAV1
,
SYNPO2L
,
SOX5
,
TBX5, MYH6, RPL3L
). The top variants at known sarcomere genes (
TTN, MYH6
) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg,
PITX2
and
SCN10A
) were associated with longer PWD but lower AF risk.

Conclusions:
Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.