bluuebunny/crossref_metadata_2025 huggingface dataset:
Incorporating physiology into species distribution models moderates the projected impact of warming on selected Mediterranean marine species
Authors: Gamliel Inbal , Buba Yehezkel , Guy‐Haim Tamar , Garval Tal , Willette Demian , Rilov Gil , Belmaker Jonathan
Published: March 2020

Species distribution models (SDMs) correlate species occurrences with environmental predictors, and can be used to forecast distributions under future climates. SDMs have been criticized for not explicitly including the physiological processes underlying the species response to the environment. Recently, new methods have been suggested to combine SDMs with physiological estimates of performance (physiology‐SDMs). In this study, we compare SDM and physiology‐SDM predictions for select marine species in the Mediterranean Sea, a region subjected to exceptionally rapid climate change. We focused on six species and created physiology‐SDMs that incorporate physiological thermal performance curves from experimental data with species occurrence records. We then contrasted projections of SDMs and physiology‐SDMs under future climate (year 2100) for the entire Mediterranean Sea, and particularly the ‘warm’ trailing edge in the Levant region. Across the Mediterranean, we found cross‐validation model performance to be similar for regular SDMs and physiology‐SDMs. However, we also show that for around half the species the physiology‐SDMs substantially outperform regular SDM in the warm Levant. Moreover, for all species the uncertainty associated with the coefficients estimated from the physiology‐SDMs were much lower than in the regular SDMs. Under future climate, we find that both SDMs and physiology‐SDMs showed similar patterns, with species predicted to shift their distribution north‐west in accordance with warming sea temperatures. However, for the physiology‐SDMs predicted distributional changes are more moderate than those predicted by regular SDMs. We conclude, that while physiology‐SDM predictions generally agree with the regular SDMs, incorporation of the physiological data led to less extreme range shift forecasts. The results suggest that climate‐induced range shifts may be less drastic than previously predicted, and thus most species are unlikely to completely disappear with warming climate. Taken together, the findings emphasize that physiological experimental data can provide valuable supplemental information to predict range shifts of marine species.
Disentangling the effects of plant species invasion and urban development on arthropod community composition
Authors: Jesse Wendy A. M. , Molleman Jasper , Franken Oscar , Lammers Mark , Berg Matty P. , Behm Jocelyn E. , Helmus Matthew R. , Ellers Jacintha
Published: March 2020

Urban development and species invasion are two major global threats to biodiversity. These threats often co‐occur, as developed areas are more prone to species invasion. However, few empirical studies have tested if both factors affect biodiversity in similar ways. Here we study the individual and combined effects of urban development and plant invasion on the composition of arthropod communities. We assessed 36 paired invaded and non‐invaded sample plots, invaded by the plant Antigonon leptopus, with half of these pairs located in natural and the other half in developed land‐use types on the Caribbean island of St. Eustatius. We used several taxonomic and functional variables to describe community composition and diversity. Our results show that both urban development and A. leptopus invasion affected community composition, albeit in different ways. Development significantly increased species richness and exponential Shannon diversity, while invasion had no effect on these variables. However, invasion significantly increased arthropod abundance and caused biotic homogenization. Specifically, uninvaded arthropod communities were distinctly different in species composition between developed and natural sites, while they became undistinguishable after A. leptopus invasion. Moreover, functional variables were significantly affected by species invasion, but not by urban development. Invaded communities had higher community‐weighted mean body size and the feeding guild composition of invaded arthropod communities was characterized by the exceptional numbers of nectarivores, herbivores, and detritivores. With the exception of species richness and exponential Shannon diversity, invasion influenced four out of six response variables to a greater degree than urban development did. Hence, we can conclude that species invasion is not just a passenger of urban development but also a driver of change.
Pharmacokinetics of low‐dose methotrexate in horses
Authors: Rostang Antoine , Desjardins Isabelle , Espana Bernadette , Panzuti Pauline , Berny Philippe , Prouillac Caroline , Pin Didier
Published: March 2020

This study aimed to investigate both the pharmacokinetic behavior and tolerance of methotrexate (MTX) in horses to design a specific dosing regimen as a new immunomodulatory drug for long‐term treatment. To determine the primary plasma pharmacokinetic variables after single intravenous, subcutaneous or oral administration, six horses were administered 0.3 mg/kg MTX in a crossover design study. After a 10‐week washout, MTX was administered subcutaneously to three of the six previously treated horses at a dose of 0.3 mg/kg once per week for 3 months. In both studies, MTX and metabolite concentrations were measured using LC‐MS/MS. The absolute bioavailability of MTX was 73% following subcutaneous administration but less than 1% following oral administration. The plasma clearance was 1.54 ml min−1 kg−1 (extraction ratio = 2%). After 24 hr, plasma concentrations were below the LOQ. No adverse effects were noted except for a moderate reversible elevation in liver enzymes (GLDH). With regards to the main metabolites of MTX, very low concentrations of 7‐hydroxy‐MTX were found, whereas polyglutamated forms (mainly short chains) were found in red blood cells. A subcutaneous dose of 0.2 mg kg−1 week−1 may be safe and relevant in horses, although this has yet to be clinically confirmed.
Parallels in patient‐, student‐ and faculty‐centred education: Identity development in health science educators
Authors: Snook Abigail Grover
Published: March 2020

By juxtaposing student‐, patient‐, faculty‐centered education Snook recommends how common principles can develop educator identity in tenured, sessional faculty members.
Synergistic effects: a common theme in mixed‐species litter decomposition
Authors: Liu Jun , Liu Xiaoyu , Song Qingni , Compson Zacchaeus G. , LeRoy Carri J. , Luan Fenggang , Wang Hui , Hu Yalin , Yang Qingpei
Published: March 2020

Litter decomposition plays a key role in nutrient cycling across ecosystems, yet to date, we lack a comprehensive understanding of the nonadditive decomposition effects in leaf litter mixing experiments.

To fill that gap, we compiled 69 individual studies with the aim to perform two meta‐analyses on nonadditive effects.

We show that a significant synergistic effect (faster decomposition in mixtures than expected) occurs at a global scale, with an average increase of 3–5% in litter mixtures. In particular, low‐quality litter in mixtures shows a significant synergistic effect, while additive effects are observed for high‐quality species. Additionally, synergistic effects turn into antagonistic effects when soil fauna are absent or litter is in very late stages of decomposition (near‐humus). In contrast to temperate and tropical areas, studies in boreal regions show significant antagonistic effects.

Our two meta‐analyses provide a systematic evaluation of nonadditive effects in mixed litter decomposition studies and show that litter quality alters the effects of litter mixing. Our results indicate that nutrient transfer, soil fauna and inhibitory secondary compounds can influence mixing effects. We also highlight that synergistic and antagonistic effects occur concurrently, and the final litter mixing effect results from the interplay between them.
Moral Explanations of Moral Beliefs: Inappropriate to Demand Them?
Authors: Tilley John J.
Published: March 2020

A familiar claim, meant as a challenge to moral knowledge, is that we can credibly accept putative moral facts just in case they explain natural facts. This article critically addresses Elizabeth Tropman's response to a version of that claim. Her response has interest partly because it falls within, and extends, an influential philosophical tradition – that of trying to expose (some) sceptical challenges as spurious or ill‐conceived. Also, Tropman's target is not just any version of the claim just mentioned. It is Gilbert Harman's classic version, according to which putative moral facts must earn credibility by explaining the formation of moral beliefs. This version has wide influence, and variations of it are possible in many areas. Tropman's response is thus well worth attention.
Feline post‐sterilization hyphema
Authors: Schenk Alex P. , McGrath Ann M. , Beatty Cheryl A. , Ottney Jennifer L. , Gratch Ellen K. , Robertson Sheilah A. , Komáromy András M.
Published: March 2020

Objective

To determine incidence and risk factors of post‐sterilization hyphema in shelter cats.

Animals studied

Retrospective medical record review of 1204 cats and prospective screening of 195 cats.

Procedures

The study consisted of three parts: (a) Survey responses were collected from 20 veterinarians, who perform high‐quality high‐volume spay‐neuter (HQHVSN) in both shelter and public clinic settings; (b) medical records of 1204 cats were analyzed retrospectively over a 14‐month time period; and (c) ophthalmic examinations, including tonometry, were performed prospectively on 195 cats before and after sterilization surgery over 8 weeks.

Results

Nine of 20 surveyed veterinarians reported having witnessed hyphema in cats following sterilization surgery. Retrospective review of 1204 medical record and prospective screening of 195 cats showed that three juvenile (<1 year of age) male cats (<2 kg) developed hyphema within 1 hour following surgery (0.2% incidence). In all three affected cats, anesthesia was induced with tiletamine/zolazepam (3 of 523 cats induced with this drug combination; 0.6% incidence), and hyphema resolved within 20 hours. Mean intraocular pressures as measured by Icare® TonoVet were (mean ± standard deviation) 11.5 ± 3.8 mm Hg and 21.7 ± 4.6 mm Hg for juvenile (<1 year of age) and adult (>1 year of age) cats, respectively.

Conclusions

Survey responses and three observed cases confirm the existence of feline post‐sterilization hyphema with an estimated incidence of 0.2%. The underlying mechanism for this occurrence remains unknown.
Advances in Bayesian Probabilistic Modeling for Industrial Applications
Authors: Ghosh Sayan , Pandita Piyush , Atkinson Steven , Subber Waad , Zhang Yiming , Kumar Natarajan Chennimalai , Chakrabarti Suryarghya , Wang Liping
Published: March 2020

Industrial applications frequently pose a notorious challenge for state-of-the-art methods in the contexts of optimization, designing experiments and modeling unknown physical response. This problem is aggravated by limited availability of clean data, uncertainty in available physics-based models and additional logistic and computational expense associated with experiments. In such a scenario, Bayesian methods have played an impactful role in alleviating the aforementioned obstacles by quantifying uncertainty of different types under limited resources. These methods, usually deployed as a framework, allows decision makers to make informed choices under uncertainty while being able to incorporate information on the fly, usually in the form of data, from multiple sources while being consistent with the physical intuition about the problem. This is a major advantage that Bayesian methods bring to fruition especially in the industrial context. This paper is a compendium of the Bayesian modeling methodology that is being consistently developed at GE Research. The methodology, called GE's Bayesian hybrid modeling (GEBHM), is a probabilistic modeling method, based on the Kennedy and O'Hagan framework, that has been continuously scaled-up and industrialized over several years. In this work, we explain the various advancements in GEBHM's methods and demonstrate their impact on several challenging industrial problems.
Transcription polymerase–catalyzed emergence of novel RNA replicons
Authors: Jain Nimit , Blauch Lucas R. , Szymanski Michal R. , Das Rhiju , Tang Sindy K. Y. , Yin Y. Whitney , Fire Andrew Z.
Published: March 2020

Revisiting replicating RNAs

DNA-dependent RNA polymerases are well known for their ability to produce RNA from DNA templates. Much less is known about their noncanonical activity: the generation and replication of RNA from RNA templates. Deeper insights into this process could shed light on questions relating to the origin of life, molecular evolution, and the replication of certain RNA pathogens such as hepatitis delta virus and plant viroids. Jain
et al.
explore in detail how the bacteriophage T7 RNA polymerase generates and amplifies diverse RNA sequences in vitro. Using sequencing, microfluidics, and bioinformatics, they chart the emergence and evolution of replicating RNA motifs and identify mechanisms that explain their selection and structures.

Science
, this issue p.
eaay0688
The evolutionary dynamics and fitness landscape of clonal hematopoiesis
Authors: Watson Caroline J. , Papula A. L. , Poon Gladys Y. P. , Wong Wing H. , Young Andrew L. , Druley Todd E. , Fisher Daniel S. , Blundell Jamie R.
Published: March 2020

Evolutionary dynamics in hematopoiesis

Cells accumulate mutations as we age, and these mutations can be a source of diseases such as cancer. How cells containing mutations evolve, are maintained, and proliferate within the body has not been well characterized. Using a quantitative framework, Watsonet al.applied population genetic theory to estimate mutation accumulation in cells in blood from sequencing data derived from nearly 50,000 healthy individuals (see the Perspective by Curtis). By evaluating how mutations differ between blood cell populations, a phenomenon known as clonal hematopoiesis, the researchers could observe how recurrent mutations can drive certain clonal lineages to high frequencies within an individual. The risk of specific mutations, some of which are associated with leukemias, rising to high frequencies may therefore be a function of cellular selection and the age at which the mutation originated.

Science, this issue p.1449; see also p.1426
Antisense oligonucleotides for neurodegeneration
Authors: Leavitt Blair R. , Tabrizi Sarah J.
Published: March 2020

Promising clinical results for Huntington's disease give hope for other diseases
Trans-Acting Small RNAs and Their Effects on Gene Expression in
Escherichia coli
and
Salmonella enterica
Authors: Hör Jens , Matera Gianluca , Vogel Jörg , Gottesman Susan , Storz Gisela
Published: March 2020

The last few decades have led to an explosion in our understanding of the major roles that small regulatory RNAs (sRNAs) play in regulatory circuits and the responses to stress in many bacterial species. Much of the foundational work was carried out with
Escherichia coli
and
Salmonella enterica
serovar Typhimurium. The studies of these organisms provided an overview of how the sRNAs function and their impact on bacterial physiology, serving as a blueprint for sRNA biology in many other prokaryotes. They also led to the development of new technologies. In this chapter, we first summarize how these sRNAs were identified, defining them in the process. We discuss how they are regulated and how they act and provide selected examples of their roles in regulatory circuits and the consequences of this regulation. Throughout, we summarize the methodologies that were developed to identify and study the regulatory RNAs, most of which are applicable to other bacteria. Newly updated databases of the known sRNAs in
E. coli
K-12 and
S. enterica
Typhimurium SL1344 serve as a reference point for much of the discussion and, hopefully, as a resource for readers and for future experiments to address open questions raised in this review.
Costs and consequences of using average demand to plan baseline nurse staffing levels: a computer simulation study
Authors: Saville Christina , Monks Thomas , Griffiths Peter , Ball Jane Elisabeth
Published: March 2020

Background

Planning numbers of nursing staff allocated to each hospital ward (the ‘staffing establishment’) is challenging because both demand for and supply of staff vary. Having low numbers of registered nurses working on a shift is associated with worse quality of care and adverse patient outcomes, including higher risk of patient safety incidents. Most nurse staffing tools recommend setting staffing levels at the average needed but modelling studies suggest that this may not lead to optimal levels.

Objective

Using computer simulation to estimate the costs and understaffing/overstaffing rates delivered/caused by different approaches to setting staffing establishments.

Methods

We used patient and roster data from 81 inpatient wards in four English hospital Trusts to develop a simulation of nurse staffing. Outcome measures were understaffed/overstaffed patient shifts and the cost per patient-day. We compared staffing establishments based on average demand with higher and lower baseline levels, using an evidence-based tool to assess daily demand and to guide flexible staff redeployments and temporary staffing hires to make up any shortfalls.

Results

When baseline staffing was set to meet the average demand, 32% of patient shifts were understaffed by more than 15% after redeployment and hiring from a limited pool of temporary staff. Higher baseline staffing reduced understaffing rates to 21% of patient shifts. Flexible staffing reduced both overstaffing and understaffing but when used with low staffing establishments, the risk of critical understaffing was high, unless temporary staff were unlimited, which was associated with high costs.

Conclusion

While it is common practice to base staffing establishments on average demand, our results suggest that this may lead to more understaffing than setting establishments at higher levels. Flexible staffing, while an important adjunct to the baseline staffing, was most effective at avoiding understaffing when high numbers of permanent staff were employed. Low staffing establishments with flexible staffing saved money because shifts were unfilled rather than due to efficiencies. Thus, employing low numbers of permanent staff (and relying on temporary staff and redeployments) risks quality of care and patient safety.
Integrated care programmes for sport and work participation, performance of physical activities and quality of life among orthopaedic surgery patients: a systematic review with meta-analysis
Authors: Coenen Pieter , Hulsegge Gerben , Daams Joost G , van Geenen Rutger C , Kerkhoffs Gino M , van Tulder Maurits W , Huirne Judith A , Anema Johannes R , Kuijer P Paul
Published: March 2020

Objectives

Orthopaedic surgery is primarily aimed at improving function and pain reduction. Additional integrated care may enhance patient’s participation in sports and work, possibly improving performance of physical activities and quality of life (QoL). We aimed to assess the effectiveness of integrated care among orthopaedic surgery patients.

Design

Systematic review with meta-analysis.

Data source

Medline, EMBASE and CINAHL (until 17 June 2019).

Eligibility for selecting studies

We searched for controlled studies on integrated care interventions consisting of active referral to case managers, rehabilitation with participation-based goals and/or e/mHealth, with outcomes of sports and work participation, performance of physical activities and/or QoL. Outcomes were normalised to 0–100 scales and statistically pooled.

Results

Seventeen articles (n=2494) of moderate quality were included reporting on patients receiving back, upper limb, knee or hip surgery. Only one study reported on return to sports and found no significant benefit. For return to work, one study did (90% vs 82%) and one did not (relative risk=1.18 (0.80 to 1.70)) observe significant benefits. Integrated care showed small effects for improving performance of physical activities (2.69 (–0.20 to 5.58); eight studies, n=1267) and QoL (2.62 (1.16 to 5.05); nine studies, n=1158) compared with usual care.

Summary/Conclusion

We found insufficient and inconsistent evidence for the effectiveness of integrated care for orthopaedic surgery patients regarding sport and work participation. Small effects were found for performance of physical activities and QoL. High quality research on integrated care focusing on sports and work participation is needed before integrated care can be implemented for orthopaedic surgery patients.
Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinoma
Authors: Jühling Frank , Hamdane Nourdine , Crouchet Emilie , Li Shen , El Saghire Houssein , Mukherji Atish , Fujiwara Naoto , Oudot Marine A , Thumann Christine , Saviano Antonio , Roca Suarez Armando Andres , Goto Kaku , Masia Ricard , Sojoodi Mozhdeh , Arora Gunisha , Aikata Hiroshi , Ono Atsushi , Tabrizian Parissa , Schwartz Myron , Polyak Stephen J , Davidson Irwin , Schmidl Christian , Bock Christoph , Schuster Catherine , Chayama Kazuaki , Pessaux Patrick , Tanabe Kenneth K , Hoshida Yujin , Zeisel Mirjam B , Duong François HT , Fuchs Bryan C , Baumert Thomas F
Published: March 2020

Objective

Hepatocellular carcinoma (HCC) is the fastest-growing cause of cancer-related mortality with chronic viral hepatitis and non-alcoholic steatohepatitis (NASH) as major aetiologies. Treatment options for HCC are unsatisfactory and chemopreventive approaches are absent. Chronic hepatitis C (CHC) results in epigenetic alterations driving HCC risk and persisting following cure. Here, we aimed to investigate epigenetic modifications as targets for liver cancer chemoprevention.

Design

Liver tissues from patients with NASH and CHC were analysed by ChIP-Seq (H3K27ac) and RNA-Seq. The liver disease-specific epigenetic and transcriptional reprogramming in patients was modelled in a liver cell culture system. Perturbation studies combined with a targeted small molecule screen followed by in vivoandex vivovalidation were used to identify chromatin modifiers and readers for HCC chemoprevention.

Results

In patients, CHC and NASH share similar epigenetic and transcriptomic modifications driving cancer risk. Using a cell-based system modelling epigenetic modifications in patients, we identified chromatin readers as targets to revert liver gene transcription driving clinical HCC risk. Proof-of-concept studies in a NASH-HCC mouse model showed that the pharmacological inhibition of chromatin reader bromodomain 4 inhibited liver disease progression and hepatocarcinogenesis by restoring transcriptional reprogramming of the genes that were epigenetically altered in patients.

Conclusion

Our results unravel the functional relevance of metabolic and virus-induced epigenetic alterations for pathogenesis of HCC development and identify chromatin readers as targets for chemoprevention in patients with chronic liver diseases.
Population impact of direct-acting antiviral treatment on new presentations of hepatitis C-related decompensated cirrhosis: a national record-linkage study
Authors: Hutchinson Sharon J , Valerio Heather , McDonald Scott A , Yeung Alan , Pollock Kevin , Smith Shanley , Barclay Stephen , Dillon John F , Fox Raymond , Bramley Peter , Fraser Andrew , Kennedy Nicholas , Gunson Rory N , Templeton Kate , Innes Hamish , McLeod Allan , Weir Amanda , Hayes Peter C , Goldberg David
Published: March 2020

Objective

Population-based studies demonstrating the clinical impact of interferon-free direct-acting antiviral (DAA) therapies are lacking. We examined the impact of the introduction of DAAs on HCV-related decompensated cirrhosis (DC) through analysis of population-based data from Scotland.

Design

Through analysis of national surveillance data (involving linkage of HCV diagnosis and clinical databases to hospital and deaths registers), we determined i) the scale-up in the number of patients treated and achieving a sustained viral response (SVR), and ii) the change in the trend of new presentations with HCV-related DC, with the introduction of DAAs.

Results

Approximately 11 000 patients had been treated in Scotland over the 8-year period 2010/11 to 2017/18. The scale-up in the number of patients achieving SVR between the pre-DAA and DAA eras was 2.3-fold overall and 5.9-fold among those with compensated cirrhosis (the group at immediate risk of developing DC). In the pre-DAA era, the annual number of HCV-related DC presentations increased 4.6-fold between 2000 (30) and 2014 (142). In the DAA era, presentations decreased by 51% to 69 in 2018 (and by 67% among those with chronic infection at presentation), representing a significant change in trend (rate ratio 0.88, 95% CI 0.85 to 0.90). With the introduction of DAAs, an estimated 330 DC cases had been averted during 2015–18.

Conclusions

National scale-up in interferon-free DAA treatment is associated with the rapid downturn in presentations of HCV-related DC at the population-level. Major progress in averting HCV-related DC in the short-term is feasible, and thus other countries should strive to achieve the same.
Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotype
Authors: Dong Hongliang , Yang Yueyao , Gao Chenhui , Sun Hehe , Wang Hongmin , Hong Chao , Wang Jun , Gong Fangyuan , Gao Xiaoming
Published: March 2020

Background

Tumor-associated macrophages (TAMs) resemble M2-polarized cells with potent immunosuppressive activity and play a pivotal role in tumor growth and progression. Converting TAMs to proinflammatory M1-like phenotype is thus an attractive strategy for antitumor immunotherapy.

Methods

A mouse IgG1(kappa) monoclonal Ab, M-860, specific to human lactoferrin (LTF) was generated by using the traditional hybridoma cell fusion technology. TAMs were generated by culturing human and mouse CD14+monocytes in tumor-conditioned media containing a cytokine cocktail containing recombinant interleukin-4 (IL-4), interleukin-10 (IL-10) and macrophage colony stimulating factor (M-CSF). TAMs after treatment with immunocomplex (IC) between human LTF and M860 (LTF-IC) were phenotypically and functionally characterized by flow cytometry (FACS), ELISA, Q-PCR and killing assays. The antitumor effects of LTF-IC were further analyzed using in vivo experiments employing tumor-bearing human FcγRIIa-transgenic mouse models.

Results

Through coligation of membrane-bound CD14 and FcγRIIa, LTF-IC rendered TAMs not only M2 to M1 conversion, evidenced by increased tumor necrosis factor α production, down-regulated M2-specific markers (CD206, arginase-1 and vascular endothelial growth factor) and upregulated M1-specific markers (CD86 and HLA-DR) expression, but also potent tumoricidal activity in vitro. LTF-IC administration conferred antitumor protective efficacy and prolonged animal survival in FcγRIIa-transgenic mice, accompanied by accumulation of M1-like macrophages as well as significantly reduced infiltration of immunosuppressive myeloid-derived suppressor cells and regulatory T cells in solid tumor tissues.

Conclusions

LTF-IC is a promising cancer therapeutic agent capable of converting TAMs into tumoricidal M1-like cells.
A new oncolyticVacciniavirusaugments antitumor immune responses to prevent tumor recurrence and metastasis after surgery
Authors: Ahmed Jahangir , Chard Louisa S , Yuan Ming , Wang Jiwei , Howells Anwen , Li Yuenan , Li Haoze , Zhang Zhongxian , Lu Shuangshuang , Gao Dongling , Wang Pengju , Chu Yongchao , Al Yaghchi Chadwan , Schwartz Joel , Alusi Ghassan , Lemoine Nicholas , Wang Yaohe
Published: March 2020

Background

Local recurrence and remote metastasis are major challenges to overcome in order to improve the survival of patients with cancer after surgery. Oncolytic viruses are a particularly attractive option for prevention of postsurgical disease as they offer a non-toxic treatment option that can directly target residual tumor deposits and beneficially modulate the systemic immune environment that is suppressed post surgery and allows residual disease escape from control. Here, we report that a novelVaccinia virus(VV), VVΔTKΔN1L (with deletion of both thymidine kinase (TK) and N1L genes) armed with interleukin 12 (IL-12), can prolong postoperative survival when used as a neoadjuvant treatment in different murine and hamster surgical models of cancer.

Methods

A tumor-targeted replicating VV with deletion of TK gene and N1L gene (VVΔTKΔN1L) was created. This virus was armed rationally with IL-12. The effect of VVΔTKΔN1L and VVΔTKΔN1L-IL12 on modulation of the tumor microenvironment and induction of tumor-specific immunity as well the feasibility and safety as a neoadjuvant agent for preventing recurrence and metastasis after surgery were assessed in several clinically relevant models.

Results

VVΔTKΔN1L can significantly prolong postoperative survival when used as a neoadjuvant treatment in three different surgery-induced metastatic models of cancer. Efficacy was critically dependent on elevation of circulating natural killer cells that was achieved by virus-induced cytokine production from cells infected with N1L-deleted, but not N1L-intact VV. This effect was further enhanced by arming VVΔTKΔN1L with IL-12, a potent antitumor cytokine. Five daily treatments with VVΔTKΔN1L-IL12 before surgery dramatically improved postsurgical survival. VVΔTKΔN1L armed with human IL-12 completely prevented tumor recurrence in surgical models of head and neck cancer in Syrian hamsters.

Conclusions

These data provide a proof of concept for translation of the regime into clinical trials. VVΔTKΔN1L-IL12 is a promising agent for use as an adjuvant to surgical treatment of solid tumors.
Identification and validation of dichotomous immune subtypes based on intratumoral immune cells infiltration in clear cell renal cell carcinoma patients
Authors: Xiong Ying , Wang Zewei , Zhou Quan , Zeng Han , Zhang Hongyu , Liu Zhaopei , Huang Qiuren , Wang Jiajun , Chang Yuan , Xia Yu , Wang Yiwei , Liu Li , Zhu Yu , Xu Le , Dai Bo , Bai Qi , Guo Jianming , Xu Jiejie
Published: March 2020

Background

Increasing evidence has elucidated the clinical significance of tumor infiltrating immune cells in predicting outcomes and therapeutic efficacy. In this study, we comprehensively analyze the tumor microenvironment (TME) immune cell infiltrations in clear cell renal cell carcinoma (ccRCC) and correlated the infiltration patterns with anti-tumor immunity and clinical outcomes.

Methods

We analyzed immune cell infiltrations in four independent cohorts, including the KIRC cohort of 533 patients, the Zhongshan ccRCC cohorts of 259 patients, the Zhongshan fresh tumor sample cohorts of 20 patients and the Zhongshan metastatic ccRCC cohorts of 87 patients. Intrinsic patterns of immune cell infiltrations were evaluated for associations with clinicopathological characteristics, underlying biological pathways, genetic changes, oncological outcomes and treatment responses.

Results

Unsupervised clustering of tumor infiltrating immune cells identified two microenvironment subtypes, TMEcluster-A and TMEcluster-B. Gene markers and biological pathways referring to immune evasion were upregulated in TMEcluster-B. TMEcluster-B associated with poor overall survival (p<0.001; HR 2.629) and recurrence free survival (p=0.012; HR 1.870) in ccRCC validation cohort. TMEcluster-B cases had worse treatment response (p=0.009), overall survival (p<0.001; HR 2.223) and progression free survival (p=0.015; HR 2.7762) in metastatic ccRCC cohort. The predictive accuracy of International Metastatic Database Consortium risk score was improved after incorporation of TME clusters.

Conclusions

TMEcluster-A featured increased mast cells infiltration, prolonged survival and better treatment response. TMEcluster-B was a heavily infiltrated but immunosuppressed phenotype enriched for macrophages, CD4+T cells, Tregs, CD8+T cells and B cells. TMEcluster-B predicted dismal survival and worse treatment response in clear cell renal cell carcinoma patients.
Preclinical PET imaging of bispecific antibody ERY974 targeting CD3 and glypican 3 reveals that tumor uptake correlates to T cell infiltrate
Authors: Waaijer Stijn JH , Giesen Danique , Ishiguro Takahiro , Sano Yuji , Sugaya Naofumi , Schröder Carolina P , de Vries Elisabeth GE , Lub-de Hooge Marjolijn N
Published: March 2020

Background

Bispecific antibodies redirecting T cells to the tumor obtain increasing interest as potential cancer immunotherapy. ERY974, a full-length bispecific antibody targeting CD3ε on T cells and glypican 3 (GPC3) on tumors, has been in clinical development However, information on the influence of T cells on biodistribution of bispecific antibodies, like ERY974, is scarce. Here, we report the biodistribution and tumor targeting of zirconium-89 (89Zr) labeled ERY974 in mouse models using immuno-positron emission tomography (PET) imaging.

Methods

To study both the role of GPC3 and CD3 on the biodistribution of [89Zr]Zr-N-suc-Df-ERY974,89Zr-labeled control antibodies targeting CD3 and non-mammalian protein keyhole limpet hemocyanin (KLH) or KLH only were used. GPC3 dependent tumor targeting of [89Zr]Zr-N-suc-Df-ERY974 was tested in xenograft models with different levels of GPC3 expression. In addition, CD3 influence on biodistribution of [89Zr]Zr-N-suc-Df-ERY974 was evaluated by comparing biodistribution between tumor-bearing immunodeficient mice and mice reconstituted with human immune cells using microPET imaging and ex vivo biodistribution. Ex vivo autoradiography was used to study deep tissue distribution.

Results

In tumor-bearing immunodeficient mice, [89Zr]Zr-N-suc-Df-ERY974 tumor uptake was GPC3 dependent and specific over [89Zr]Zr-N-suc-Df-KLH/CD3 and [89Zr]Zr-N-suc-Df-KLH/KLH. In mice engrafted with human immune cells, [89Zr]Zr-N-suc-Df-ERY974 specific tumor uptake was higher than in immunodeficient mice. Ex vivo autoradiography demonstrated a preferential distribution of [89Zr]Zr-N-suc-Df-ERY974 to T cell rich tumor tissue. Next to tumor, highest specific [89Zr]Zr-N-suc-Df-ERY974 uptake was observed in spleen and lymph nodes.

Conclusion

[89Zr]Zr-N-suc-Df-ERY974 can potentially be used to study ERY974 biodistribution in patients to support drug development.
Comparison of commonly used solid tumor targeted gene sequencing panels for estimating tumor mutation burden shows analytical and prognostic concordance within the cancer genome atlas cohort
Authors: Bevins Nicholas , Sun Shulei , Gaieb Zied , Thorson John A , Murray Sarah S
Published: March 2020

Background

Tumor mutation burden (TMB) is a biomarker frequently reported by clinical laboratories, which is derived by quantifying of the number of single nucleotide or indel variants (mutations) identified by next-generation sequencing of tumors. TMB values can inform prognosis or predict the response of a patient’s tumor to immune checkpoint inhibitor therapy. Methods for the calculation of TMB are not standardized between laboratories, with significant variables being the gene content of the panels sequenced and the inclusion or exclusion of synonymous variants in the calculations. The impact of these methodological differences has not been investigated and the concordance of reported TMB values between laboratories is unknown.

Methods

Sequence variant lists from more than 9000 tumors of various types were downloaded from The Cancer Genome Atlas. Variant lists were filtered to include only appropriate variant types (ie, non-synonymous only or synonymous and non-synonymous variants) within the genes found in five commonly used targeted solid tumor gene panels as well as an in-house gene panel. Calculated TMB was paired with corresponding overall survival (OS) data of each patient.

Results

Regression analysis indicates high concordance of TMB as derived from the examined panels. TMB derived from panels was consistently and significantly lower than that derived from a whole exome. TMB, as derived from whole exome or the examined panels, showed a significant correlation with OS in the examined data.

Conclusions

TMB derived from the examined gene panels was analytically equivalent between panels, but not between panels and whole-exome sequencing. Correlation between TMB and OS is significant if TMB method-specific cut-offs are used. These results suggest that TMB values, as derived from the gene panels examined, are analytically and prognostically equivalent.
Are workplace health promotion programmes effective for all socioeconomic groups? A systematic review
Authors: van de Ven David , Robroek Suzan J W , Burdorf Alex
Published: March 2020

Decreasing socioeconomic health inequalities is considered an important policy priority in many countries. Workplace health promotion programmes (WHPPs) have shown modest improvements in health behaviour. This systematic review aims to determine the presence and magnitude of socioeconomic differences in effectiveness and the influence of programme characteristics on differential effectiveness of WHPPs. Three electronic databases were searched for systematic reviews published from 2013 onwards and for original studies published from 2015 onwards. We synthesised the reported socioeconomic differences in effectiveness of WHPPs on health behaviours, and calculated effectiveness ratios by dividing the programme effects in the lowest socioeconomic group by the programme effects in the highest socioeconomic group. Thirteen studies with 75 comparisons provided information on the effectiveness of WHPPs across socioeconomic groups. Ten studies with 54 comparisons reported equal effectiveness and one study with 3 comparisons reported higher effectiveness for lower socioeconomic groups. Quantitative information on programme effects was available for six studies with 18 comparisons, of which 13 comparisons showed equal effectiveness and 5 comparisons showed significantly higher effect sizes among workers in low socioeconomic position. The differential effectiveness of WHPPs did not vary across programme characteristics. In this study no indications are found that WHPPs increase socioeconomic inequalities in health behaviour. The limited quantitative information available suggests that WHPPs may contribute to reducing socioeconomic inequalities. Better insight is needed on socioeconomic differences in effectiveness of WHPPs to develop strategies to decrease socioeconomic inequalities in health in the workforce.
Social media use by leading US e-cigarette, cigarette, smokeless tobacco, cigar and hookah brands
Authors: O'Brien Erin Keely , Hoffman Leah , Navarro Mario Antonio , Ganz Ollie
Published: March 2020

Background

Youth and young adults frequently use social media and are susceptible to tobacco use. This study is the first to provide a systematic overview of how leading tobacco product brands use popular social media platforms.

Methods

We identified 112 leading brands of e-cigarettes, hookah, cigars, cigarettes and smokeless tobacco based on sales and self-report user data. We searched for each brand on six platforms: Instagram, Facebook, Twitter, YouTube, Pinterest and Tumblr. In early 2019, we conducted a content analysis of each page, coding: age restrictions, warning display, page characteristics and post characteristics.

Results

Cigarette brands were generally not present. Most e-cigarettes, hookah and cigar brands had pages on at least two platforms. One-third of smokeless brands had pages on at least one platform. Few brands had pages on Pinterest and Tumblr. Most pages had existed for 3–5 years. Overall, brand pages rarely used age gating, did not display health warnings, generally posted images of a product alone and often used hashtags unrelated to tobacco. Brands commonly used special features like ephemeral posts on Instagram and pop-up chat windows on Facebook. Many pages displayed images of young people and mentioned flavour. Median followers per brand ranged from about 1 000–10 000, and total followers summed across brands reached over 5 million on Facebook and Instagram alone.

Conclusions

Leading brands of most tobacco product types use social media extensively. Several findings identify issues related to youth exposure to and appeal of tobacco social media marketing. Findings can inform tobacco education efforts and regulation.
Criterion-referenced mCAFT cut-points to identify metabolically healthy cardiorespiratory fitness among adults aged 18–69 years: an analysis of the Canadian Health Measures Survey
Authors: Wolfe Phillips Emily , Rao Deepa P. , Kaminsky Leonard A. , Tomkinson Grant R. , Ross Robert , Lang Justin J.
Published: March 2020

This study aimed to develop and validate health-related criterion-referenced cut-points for the modified Canadian Aerobic Fitness Test (mCAFT), a field-based measure to predict cardiorespiratory fitness among adults (18–69 years). Criterion-referenced mCAFT cut-points were developed using nationally representative data from cycles 1 (2007–2009) and 2 (2009–2011) of the Canadian Health Measures Survey (CHMS). Receiver operating characteristic curves were used to identify age- and sex-specific cut-points for measured waist circumference, blood pressure, and high-density lipoprotein. Cut-points were validated against metabolic syndrome using a fasted subsample (n = 1093) from cycle 5 (2016–2017). For the main analyses, 4967 participants (50% women) were retained. The mCAFT cut-points ranged from 28 to 43 mL·kg–1·min–1 (area under the curve (AUC): 0.60–0.87) among men, and 23 to 37 mL·kg–1·min–1 (AUC: 0.61–0.86) among women. The likelihood of meeting the new mCAFT cut-points decreased with an increase in the presence of metabolic risk factors. In total, 54% (95% confidence interval: 42% to 67%) of Canadian adults met the new mCAFT cut-points in 2016–2017. This study developed and validated the first health-related criterion-referenced mCAFT cut-points for metabolic health among Canadian adults aged 18–69 years. These mCAFT cut-points may be useful in health surveillance, clinical, and public health settings.

Novelty We developed and validated new criterion-referenced cut-points for the mCAFT to help identify adults at potential risk of poor metabolic health. These new cut-points could help support national health surveillance efforts.
Heat kernel coefficients on the sphere in any dimension
Authors: Kluth Yannick , Litim Daniel F.
Published: March 2020

We derive all heat kernel coefficients for Laplacians acting on scalars, vectors, and tensors on fully symmetric spaces, in any dimension. Final expressions are easy to evaluate and implement, and confirmed independently using spectral sums and the Euler–Maclaurin formula. We also obtain the Green’s function for Laplacians acting on transverse traceless tensors in any dimension, and new integral representations for heat kernels using known eigenvalue spectra of Laplacians. Applications to quantum gravity and the functional renormalisation group, and other, are indicated.
On the resonances near the continua boundaries of the Dirac equation with a short-range interaction
Authors: Krylov K. S. , Mur V. D. , Fedotov A. M.
Published: March 2020

Using the model of a deep spherically symmetric rectangular well as an example, it is shown that resonant scattering near the boundaries of the lower or upper Dirac continua cannot serve as evidence in favor of spontaneous electron-positron pair production in a supercritical domain.
Understanding the Networking Performance of Wear OS
Authors: Zhu Xiao , Guo Yihua Ethan , Nikravesh Ashkan , Qian Feng , Mao Z. Morley
Published: March 2020

Networking on wearable devices such as smartwatches is becoming increasingly important as fueled by new hardware, OS support, and applications. In this paper, we conduct a first in-depth investigation of the networking performance of Wear OS, one of the most popular OSes for wearables. Through carefully designed controlled experiments conducted in a cross-device, cross-protocol, and cross-layer manner, we identify serious performance issues of Wear OS regarding key aspects that distinguish wearable networking from smartphone networking: Bluetooth (BT) performance, smartphone proxying, network interface selection, and BT-WiFi handover. We pinpoint their root causes and quantify their impacts on network performance and application QoE. We further propose practical suggestions to improve wearable networking performance.
Hyper-Scalable JSQ with Sparse Feedback
Authors: van der Boor Mark , Borst Sem , van Leeuwaarden Johan
Published: March 2020

Load balancing algorithms play a vital role in enhancing performance in data centers and cloud networks. Due to the massive size of these systems, scalability challenges, and especially the communication overhead associated with load balancing mechanisms, have emerged as major concerns. Motivated by these issues, we introduce and analyze a novel class of load balancing schemes where the various servers provide occasional queue updates to guide the load assignment.

We show that the proposed schemes strongly outperform JSQ( d ) strategies with comparable communication overhead per job, and can achieve a vanishing waiting time in the many-server limit with just one message per job, just like the popular JIQ scheme. The proposed schemes are particularly geared however towards the sparse feedback regime with less than one message per job, where they outperform corresponding sparsified JIQ versions.

We investigate fluid limits for synchronous updates as well as asynchronous exponential update intervals. The fixed point of the fluid limit is identified in the latter case, and used to derive the queue length distribution. We also demonstrate that in the ultra-low feedback regime the mean stationary waiting time tends to a constant in the synchronous case, but grows without bound in the asynchronous case.
Computationally Efficient Estimation of the Spectral Gap of a Markov Chain
Authors: Combes Richard , Touati Mikael
Published: March 2020

We consider the problem of estimating from sample paths the absolute spectral gap 1 - λ of a reversible, irreducible and aperiodic Markov chain (X_t)_t∈N over a finite state space Ω. We propose the UCPI (Upper Confidence Power Iteration) algorithm for this problem, a low-complexity algorithm which estimates the spectral gap in time O(n) and memory space O ((łn n)^2) given n samples. This is in stark contrast with most known methods which require at least memory space O(|Ω|), so that they cannot be applied to large state spaces. We also analyze how n should scale to reach a target estimation error. Furthermore, UCPI is amenable to parallel implementation.