bluuebunny/crossref_metadata_2025 huggingface dataset:
Frequencies of glycophorin variants and alloantibodies against Hil and MINY antigens in Japanese
Authors: Kaito Sayaka , Suzuki Yumi , Masuno Atsuko , Isa Kazumi , Toyoda Chizu , Onodera Takayuki , Ogasawara Kenichi , Uchikawa Makoto , Tsuno Nelson‐Hirokazu , Satake Masahiro
Published: July 2021

Background and Objectives

Antigens of the MNS blood group system are expressed on the red blood cell (RBC) membrane on glycophorin A (GPA) and glycophorin B (GPB) or on hybrid molecules of GPA and GPB. This study investigated the distribution of glycophorin variants and alloantibodies against Hil and MINY among Japanese individuals.

Methods

Mi(a+) or Hil+ RBCs were screened using an automated blood grouping machine (PK7300) with monoclonal anti‐Mia or polyclonal anti‐Hil. Glycophorin variants were defined by serology with monoclonal antibodies against Mia, Vw, MUT and Mur, and polyclonal antibodies against Hil, MINY and Hop + Nob (KIPP). The glycophorin variants were further confirmed by immunoblotting and Sanger sequencing. Alloanti‐Hil and alloanti‐MINY in the plasma were screened using GP.Hil RBCs in an antiglobulin test. The specificity of anti‐Hil or anti‐MINY was assessed using GP.Hil (Hil+MINY+) and GP.JL (Hil‒MINY+) RBCs.

Results

The GP.HF, GP.Mur, GP.Hut, GP.Vw, GP.Kip and GP.Bun frequencies in 1 005 594 individuals were 0·0357%, 0·0256%, 0·0181%, 0·0017%, 0·0009% and 0·0007%, respectively. GP.Hil was found in as four of the 13 546 individuals (0·0295%). Of 137 370 donors, 10 had anti‐Hil (0·0073%) and three had anti‐MINY (0·0022%).

Conclusions

Glycophorin variants were relatively rare in Japanese individuals, with the major variants being GP.HF (0·0357%), GP.Hil (0·0295%) and GP.Mur (0·0256%). Only one example of anti‐MINY was previously reported, but we found three more in this study.
Seroepidemiology of Toxoplasma gondii in wild ruminants in Spain
Authors: Castro‐Scholten Sabrina , Cano‐Terriza David , Jiménez‐Ruiz Saúl , Almería Sonia , Risalde María A. , Vicente Joaquín , Acevedo Pelayo , Arnal María C. , Balseiro Ana , Gómez‐Guillamón Félix , Escribano Fernando , Puig‐Ribas María , Dubey Jitender P. , García‐Bocanegra Ignacio
Published: July 2021

Toxoplasmosis is a parasitic zoonosis caused by Toxoplasma gondii which infects warm‐blooded species worldwide. Humans can be infected through ingestion of tissue cysts from raw or undercooked meat, including game meat. A nationwide large‐scale cross‐sectional study was conducted to assess exposure to T. gondii in seven wild ruminant species in Spain. A total of 2,040 serum samples from 77 sampling sites randomly distributed in the five bioregions (BRs) covering mainland Spain were tested for antibodies against T. gondii using the modified agglutination test. The overall seroprevalence was 22.0% (449/2,040). Seroprevalence by species in decreasing order was as follows: 39.6% (141/356) in roe deer (Capreolus capreolus), 37.1% (138/372) in fallow deer (Dama dama), 16.6% (92/553) in red deer (Cervus elaphus), 14.0% (26/186) in Southern chamois (Rupicapra pyrenaica), 11.5% (24/209) in mouflon (Ovis aries musimon), 7.8% (27/346) in Iberian wild goat (Capra pyrenaica) and 5.6% (1/18) in Barbary sheep (Ammotragus lervia). Seropositivity was detected in 74.0% (57/77) of the sampling sites. Results indicate widespread but not homogeneous exposure to T. gondii in wild ruminant populations in Spain during the last two decades and highlight differences related to animal species and spatial distribution of these species in this country; this implies potential consequences of T. gondii for animal health, conservation and public health.
Corticoreticulospinal tract neurophysiology in an arm and hand muscle in healthy and stroke subjects
Authors: Taga Myriam , Charalambous Charalambos C. , Raju Sharmila , Lin Jing , Zhang Yian , Stern Elisa , Schambra Heidi M.
Published: July 2021

Key points

The corticoreticulospinal tract (CReST) is a descending motor pathway that reorganizes after corticospinal tract (CST) injury in animals.

In humans, the pattern of CReST innervation to upper limb muscles has not been carefully examined in healthy individuals or individuals with CST injury.

In the present study, we assessed CReST projections to an arm and hand muscle on the same side of the body in healthy and chronic stoke subjects using transcranial magnetic stimulation.

We show that CReST connection strength to the muscles differs between healthy and stroke subjects, with stronger connections to the hand than arm in healthy subjects, and stronger connections to the arm than hand in stroke subjects.

These results help us better understand CReST innervation patterns in the upper limb, and may point to its role in normal motor function and motor recovery in humans.

The corticoreticulospinal tract (CReST) is a major descending motor pathway in many animals, but little is known about its innervation patterns in proximal and distal upper extremity muscles in humans. The contralesional CReST furthermore reorganizes after corticospinal tract (CST) injury in animals, but it is less clear whether CReST innervation changes after stroke in humans. We thus examined CReST functional connectivity, connection strength, and modulation in an arm and hand muscle of healthy (n = 15) and chronic stroke (n = 16) subjects. We delivered transcranial magnetic stimulation to the contralesional hemisphere (assigned in healthy subjects) to elicit ipsilateral motor evoked potentials (iMEPs) from the paretic biceps (BIC) and first dorsal interosseous (FDI) muscle. We operationalized CReST functional connectivity as iMEP presence/absence, CReST projection strength as iMEP size and CReST modulation as change in iMEP size by head rotation. We found comparable CReST functional connectivity to the BICs and FDIs in both subject groups. However, the pattern of CReST connection strength to the muscles diverged between groups, with stronger connections to FDIs than BICs in healthy subjects and stronger connections to BICs than FDIs in stroke subjects. Head rotation modulated only FDI iMEPs of healthy subjects. Our findings indicate that the healthy CReST does not have a proximal innervation bias, and its strong FDI connections may have functional relevance to finger individuation. The reversed CReST innervation pattern in stroke subjects confirms its reorganization after CST injury, and its strong BIC connections may indicate upregulation for particular upper extremity muscles or their functional actions.
Finite Element Analysis as an Iterative Design Tool for Students in an Introductory Biomechanics Course
Authors: Higbee Steven , Miller Sharon
Published: July 2021

Insufficient engineering analysis is a common weakness of student capstone design projects. Efforts made earlier in a curriculum to introduce analysis techniques should improve student confidence in applying these important skills toward design. To address student shortcomings in design, we implemented a new design project assignment for second-year undergraduate biomedical engineering students. The project involves the iterative design of a fracture fixation plate and is part of a broader effort to integrate relevant hands-on projects throughout our curriculum. Students are tasked with (1) using computer-aided design (CAD) software to make design changes to a fixation plate, (2) creating and executing finite element models to assess performance after each change, (3) iterating through three design changes, and (4) performing mechanical testing of the final device to verify model results. Quantitative and qualitative methods were used to assess student knowledge, confidence, and achievement in design. Students exhibited design knowledge gains and cognizance of prior coursework knowledge integration into their designs. Further, student's self-reported confidence gains in approaching design, working with hardware and software, and communicating results. Finally, student self-assessments exceeded instructor assessment of student design reports, indicating that students have significant room for growth as they progress through the curriculum. Beyond the gains observed in design knowledge, confidence, and achievement, the fracture fixation project described here builds student experience with CAD, finite element analysis, three-dimensional printing, mechanical testing, and design communication. These skills contribute to the growing toolbox that students ultimately bring to capstone design.
A Direct Comparison of Node and Element-Based Finite Element Modeling Approaches to Study Tissue Growth
Authors: Howe Danielle , Dixit Nikhil N. , Saul Katherine R. , Fisher Matthew B.
Published: July 2021

Finite element analysis is a useful tool to model growth of biological tissues and predict how growth can be impacted by stimuli. Previous work has simulated growth using node-based or element-based approaches, and this implementation choice may influence predicted growth, irrespective of the applied growth model. This study directly compared node-based and element-based approaches to understand the isolated impact of implementation method on growth predictions by simulating growth of a bone rudiment geometry, and determined what conditions produce similar results between the approaches. We used a previously reported node-based approach implemented via thermal expansion and an element-based approach implemented via osmotic swelling, and we derived a mathematical relationship to relate the growth resulting from these approaches. We found that material properties (modulus) affected growth in the element-based approach, with growth completely restricted for high modulus values relative to the growth stimulus, and no restriction for low modulus values. The node-based approach was unaffected by modulus. Node- and element-based approaches matched marginally better when the conversion coefficient to relate the approaches was optimized based on the results of initial simulations, rather than using the theoretically predicted conversion coefficient (median difference in node position 0.042 cm versus 0.052 cm, respectively). In summary, we illustrate here the importance of the choice of implementation approach for modeling growth, provide a framework for converting models between implementation approaches, and highlight important considerations for comparing results in prior work and developing new models of tissue growth.
Assessing Wear Evolutions in Railway Wheelsets Using a Survival Modeling Approach
Authors: Caldeira Guilherme A. C. , Braga Joaquim A. P. , Andrade António R.
Published: July 2021

This paper provides a method to predict maintenance needs for the railway wheelsets by modeling the wear out affecting the wheelsets during its life cycle using survival analysis. Wear variations of wheel profiles are discretized and modeled through a censored survival approach, which is appropriate for modeling wheel profile degradation using real operation data from the condition monitoring systems that currently exist in railway companies. Several parametric distributions for the wear variations are modeled, and the behavior of the selected ones is analyzed and compared with wear trajectories computed by a Monte Carlo simulation procedure. This procedure aims to test the independence of events by adding small fractions of wear to reach larger wear values. The results show that the independence of wear events is not true for all the established events, but it is confirmed for small wear values. Overall, the proposed framework is developed in such a way that the outputs can be used to support predictions in condition-based maintenance models and to optimize the maintenance of wheelsets.
Investigating the Design and Manufacture of PneuNet Actuators as a Prosthetic Tongue for Mimicking Human Deglutition
Authors: Darmont Araya Francis , Radhakrishnan Pradeep
Published: July 2021

The number of total glossectomy cases in the United States is seeing an increasing trend as per the nationwide inpatient sample database. Patients, who have undergone such aggressive surgical procedures, have extensive limitations in performing basic oral functions such as swallowing (deglutition), eating, and speaking. Current rehabilitation prostheses do little in restoring the functionality of the original tongue. This is true especially in deglutition, which is necessary to transfer a bolus to the esophagus. Such patients need advanced prosthetic devices and through this research, investigations into potential solutions for prosthetic tongues to aid in deglutition were carried out. Different designs were considered and based on a decision matrix, pneumatic networks (PneuNets) were adopted as the foundational basis for generating prosthetic tongue designs. Several prototypes were fabricated that used the Fused Filament Deposition process for producing the mold and silicone Eco-flex 00-30 for producing the mechanism. The resulting mechanism with dimensions 2.4 in. × 1.8 in. × 0.24 in. was powered using pneumatic input and kinematic data was collected. The experiments carried out showed potential in the concept but at the same time, there were challenges related to validating the kinematics and in the transfer of the bolus due to uncontrolled silicone expansions. Details from the literature review, design iterations, simulations, validation processes, manufacturing challenges, and conclusions will be discussed in-depth in this paper.
Plume Stability During Direct Contact Condensation of Steam in a Crossflow of Subcooled Water, at High Mass Flux and With a Small Nozzle Diameter
Authors: Alden Zach R. , Maples Gunnar D. , Dressler Kristofer M. , Nellis Gregory F. , Berson Arganthaël
Published: July 2021

The stability of a steam plume during direct-contact condensation into a crossflow of subcooled water is investigated for mass fluxes that are higher (>600 kg/m2s) and a nozzle diameter (2.4 mm) that is smaller than typically seen in the literature. The transition from a stable steam plume to an unstable plume associated with the formation and collapse of steam bubbles is characterized by high-speed imaging and high-frequency pressure measurements. Four regimes are observed: stable, condensation oscillation, transition, and unstable. A regime map and spectral signatures of the different flow regimes are provided. Results are compared with correlations from the literature, which are typically derived for lower mass fluxes, larger nozzles, and injection into stagnant pools of water.
Prediction of Squeal Instabilities of a Finite Element Model Automotive Brake With Uncertain Structural and Environmental Parameters With a Hybrid Surrogate Model
Authors: Denimal Enora , Sinou Jean-Jacques , Nacivet Samuel
Published: July 2021

This study focuses on the prediction of the stability behavior of an industrial automotive brake system under structural and environmental uncertainties. Uncertainties are modeled with a random distribution or an interval and are propagated with a hybrid surrogate model associating polynomial chaos and kriging. The objective is to create a surrogate model of each eigenvalue computed with the complex eigenvalue analysis (CEA). As the modes can be tracked only when unstable, the effective size of the training sets can become extremely small. Despite this limitation, it is shown the hybrid meta-model is still able to predict the stability of the brake system. Moreover, the hybrid meta-model gives a direct access to the mean and variance of the eigenvalues with respect to the design parameters without any additional Monte Carlo simulations (MCS). By considering different probability density function for the friction coefficient, it is shown it has a high influence on the stability and the latter should be accurately estimated.
Tigecycline-Induced Tooth Discoloration in Children Younger than Eight Years
Authors: Zhu Zhengyi , Yu Qi , Qi Ganggang , Yang Jufei , Ni Yinghua , Ruan Wenhua , Fang Luo
Published: July 2021

Tetracycline may cause tooth discoloration when used in young children during tooth development. Whether tigecycline, a tetracycline derivative, has either a similar adverse event or not remains unclear.
Antimalarial Activities of (
Z
)-2-(Nitroheteroarylmethylene)-3(2
H
)-Benzofuranone Derivatives:
In Vitro
and
In Vivo
Assessment and β-Hematin Formation Inhibition Activity
Authors: Navidpour Latifeh , Chibale Kelly , Esmaeili Somayeh , Ghiaee Azadeh , Hadj-esfandiari Narges , Irani Mahboubeh , Ahmadi Koulaei Sheyda , Yassa Narguess
Published: July 2021

A series of (
Z
)-2-(nitroheteroarylmethylene)-3(2
H
)-benzofuranones possessing nitroheteroaryl groups of nitroimidazole, nitrofuran, and nitrothiophene moieties was screened for antiplasmodium activity against a drug-sensitive strain (3D7 strain) and a multidrug-resistant (chloroquine [CQ] and pyrimethamine) strain (K1 strain) of
Plasmodium falciparum
. 5-Nitroimidazole and 4-nitroimidazole analogs were highly selective and active against resistant parasites, while 5-nitrofuran and 5-nitrothiophene derivatives were more potent against the 3D7 strain than against the K1 strain. Among the synthetic analogues, (
Z
)-6-chloro-2-(1-methyl-5-nitroimidazol-2-ylmethylene)-3(2
H
)-benzofuranone (compound
5h
) exhibited the highest activity (50% inhibitory concentration [IC
50
], 0.654 nM) against the K1 strain and (
Z
)-7-methoxy-2-(5-nitrothiophen-2-ylmethylene)-3(2
H
)-benzofuranone (
10g
) showed the highest activity (IC
50
, 0.28 μM) against the 3D7 strain in comparison with the activities of CQ (IC
50
s of 3.13 and 206.3 nM against 3D7 and K1 strains, respectively).
Identifying the Basis for VirS/VirR Two-Component Regulatory System Control of Clostridium perfringens Beta-Toxin Production
Authors: Mehdizadeh Gohari Iman , Li Jihong , McClane Bruce A.
Published: July 2021

Clostridium perfringens
beta toxin (CPB) is only produced by type B and C strains. Production of CPB is essential for the pathogenesis of type C-associated infections, which include hemorrhagic necrotizing enteritis and enterotoxemia in both humans and animals.
Stable Positions of Epigenetically Inherited Centromeres in the Emerging Fungal Pathogen
Candida auris
and Its Relatives
Authors: Rusche Laura N.
Published: July 2021

Candida auris
is an emerging fungal pathogen that is thermotolerant and often resistant to standard antifungal treatments. To trace its evolutionary history, the Sanyal lab conducted a comparative genomic study focusing on the positions of centromeres in
C. auris
and eight other species from the
Clavispora
/
Candida
clade of yeasts (A.
Gene Erosion Can Lead to Gain-of-Function Alleles That Contribute to Bacterial Fitness
Authors: Mortier Julien , Gayán Elisa , Van Eyken Ronald , Torres Montaguth Oscar Enrique , Khodaparast Ladan , Khodaparast Laleh , Houben Bert , Carpentier Sebastien , Rousseau Frederic , Schymkowitz Joost , Aertsen Abram
Published: July 2021

Despite our extensive knowledge of the genetic regulation of heat shock proteins (HSPs), the evolutionary routes that allow bacteria to adaptively tune their HSP levels and corresponding proteostatic robustness have been explored less. In this report, directed evolution experiments using the
Escherichia coli
model system unexpectedly revealed that seemingly random single mutations in its
tnaA
gene can confer significant heat resistance.
Spontaneous bleeding from orbital haemangioma in drug-induced thrombocytopaenia
Authors: Yen Chu Yu , Chen Chun-Chen
Published: July 2021

An 81-year-old woman, a drug-induced thrombocytopaenia (DITP) patient, presented with a case of spontaneous bleeding from an orbital haemangioma manifesting as a sudden onset of ocular pain, proptosis and limited eye movement. Image studies revealed an extraconal, cystic lesion with haemorrhage. The ophthalmopathy was caused by the bleeding of the orbital haemangioma and it was resolved after embolisation of the feeding vessels. Spontaneous bleeding of orbital haemangioma is rare. This case emphasises that DITP may be the cause of spontaneous bleeding of orbital haemangioma by precipitating the inflammatory reactions within the tumour, which further cause the haemodynamic disturbances and ultimate spontaneous bleeding.
Brafmutation induces rapid neoplastic transformation in the aged and aberrantly methylated intestinal epithelium
Authors: Fennell Lochlan , Kane Alexandra , Liu Cheng , McKeone Diane , Hartel Gunter , Su Chang , Bond Catherine , Bettington Mark , Leggett Barbara , Whitehall Vicki
Published: July 2021

Objective

Sessile serrated lesions (SSLs) are common across the age spectrum, but theBRAFmutant cancers arising occur predominantly in the elderly. Aberrant DNA methylation is uncommon in SSL from young patients. Here, we interrogate the role of ageing and DNA methylation in SSL initiation and progression.

Design

We used an inducible model ofBrafmutation to direct recombination of the oncogenicBraf V637Eallele to the murine intestine.BRAFmutation was activated after periods of ageing, and tissue was assessed for histological, DNA methylation and gene expression changes thereafter. We also investigated DNA methylation alterations in human SSLs.

Results

InducingBrafmutation in aged mice was associated with a 10-fold relative risk of serrated lesions compared with young mice. There were extensive differences in age-associated DNA methylation between animals induced at 9 months versus wean, with relatively little differentialBraf-specific methylation. DNA methylation at WNT pathway genes scales with age andBrafmutation accelerated age-associated DNA methylation. In human SSLs, increased epigenetic age was associated with high-risk serrated colorectal neoplasia.

Conclusions

SSLs arising in the aged intestine are at a significantly higher risk of spontaneous neoplastic progression. These findings provide support for a new conceptual model for serrated colorectal carcinogenesis, whereby risk ofBraf-induced neoplastic transformation is dependent on age and may be related to age-associated molecular alterations that accumulate in the ageing intestine, including DNA methylation. This may have implications for surveillance and chemopreventive strategies targeting the epigenome.
Chemoradiation triggers antitumor Th1 and tissue resident memory-polarized immune responses to improve immune checkpoint inhibitors therapy
Authors: Lauret Marie Joseph Elodie , Kirilovsky Amos , Lecoester Benoît , El Sissy Carine , Boullerot Laura , Rangan Laurie , Marguier Amélie , Tochet Florent , Dosset Magalie , Boustani Jihane , Ravel Patrice , Boidot Romain , Spehner Laurie , Haicheur-Adjouri Nacilla , Marliot Florence , Pallandre Jean-René , Bonnefoy Francis , Scripcariu Viorel , Van den Eynde Marc , Cornillot Emmanuel , Mirjolet Céline , Pages Franck , Adotevi Olivier
Published: July 2021

Background

Multiple synergistic combination approaches with cancer drugs are developed to overcome primary resistance to immunotherapy; however, the mechanistic rationale to combine chemoradiotherapy (CRT) with immune checkpoint inhibitors remains elusive.

Methods

This study described the immunological landscape of tumor microenvironment (TME) exposed to CRT. Tumor samples from patients with rectal cancer (n=43) treated with neoadjuvant CRT or radiotherapy were analyzed by nanostring and immunohistochemistry. Studies in mice were performed using three syngeneic tumors (TC1, CT26 and MC38). Tumor-bearing mice were treated either with platinum-based CRT, radiotherapy or chemotherapy. Anti-CTLA-4 and/or anti-Programmed Cell Death Receptor-1 (PD-1) therapy was used in combination with CRT. The therapy-exposed TME was screened by RNA sequencing and flow cytometry and tumor-infiltrating T lymphocyte functionality was evaluated by interferon (IFN)-γ ELIspot and intracellular cytokine staining.

Results

Front-to-front comparison analysis revealed the synergistic effect of CRT to establish a highly inflamed and Th1-polarized immune signature in the TME of patients and mice. In both settings, CRT-exposed TMEs were highly enriched in newly-infiltrated tumor-specific CD8+ T cells as well as tissue resident memory CD103+CD8+ T cells. In mice, CD8 T cells were involved in the antitumor response mediated by CRT and were primed by CRT-activated CD103+ dendritic cells. In the three tumor models, we showed that concurrent combination of CRT with a dual CTLA-4 and PD-1 blockade was required to achieve an optimal antitumor effect and to establish a broad and long-lasting protective antitumor T cell immunity.

Conclusions

Our results highlight the ability of CRT to stimulate strong antitumor T-cell-mediated immunity and tissue resident memory T activation in TME, to foster immune checkpoint inhibitors action. These findings have implications in clinic for the design clinical trials combining chemoradiation with immunotherapy.
Novel anti-4-1BB×PD-L1 bispecific antibody augments anti-tumor immunity through tumor-directed T-cell activation and checkpoint blockade
Authors: Jeong Seongju , Park Eunyoung , Kim Hyung-Don , Sung Eunsil , Kim Hyunjoo , Jeon Jaehyoung , Kim Youngkwang , Jung Ui-jung , Son Yong-Gyu , Hong Youngeun , Lee Hanbyul , Lee Shinai , Lim Yangmi , Won Jonghwa , Jeon Minwoo , Hwang Shin , Fang Lei , Jiang Wenqing , Wang Zhengyi , Shin Eui-Cheol , Park Su-Hyung , Jung Jaeho
Published: July 2021

Background

Stimulation of 4-1BB with agonistic antibodies is a promising strategy for improving the therapeutic efficacy of immune checkpoint inhibitors (ICIs) or for overcoming resistance to ICIs. However, dose-dependent hepatotoxicity was observed in clinical trials with monoclonal anti-4-1BB agonistic antibodies due to the activation of 4-1BB signaling in liver resident Kupffer cells.

Methods

To avoid this on-target liver toxicity, we developed a novel bispecific antibody (4-1BB×PD-L1 bispecific antibody, termed “ABL503”) uniquely designed to activate 4-1BB signaling only in the context of PD-L1, while also blocking PD-1/PD-L1 signaling.

Results

Functional evaluation using effector cells expressing both 4-1BB and PD-1 revealed superior biological activity of ABL503 compared with the combination of each monoclonal antibody. ABL503 also augmented T-cell activation in in vitro assays and further enhanced the anti-PD-L1-mediated reinvigoration of tumor-infiltrating CD8+ T cells from patients with cancer. Furthermore, in humanized PD-L1/4-1BB transgenic mice challenged with huPD-L1-expressing tumor cells, ABL503 induced superior anti-tumor activity and maintained an anti-tumor response against tumor rechallenge. ABL503 was well tolerated, with normal liver function in monkeys.

Conclusion

The novel anti-4-1BB×PD-L1 bispecific antibody may exert a strong anti-tumor therapeutic efficacy with a low risk of liver toxicity through the restriction of 4-1BB stimulation in tumors.
Evaluating T-cell cross-reactivity between tumors and immune-related adverse events with TCR sequencing: pitfalls in interpretations of functional relevance
Authors: Cottrell Tricia , Zhang Jiajia , Zhang Boyang , Kaunitz Genevieve J , Burman Poromendro , Chan Hok-Yee , Verde Franco , Hooper Jody E , Hammers Hans , Allaf Mohamad E , Ji Hongkai , Taube Janis , Smith Kellie N
Published: July 2021

T-cell receptor sequencing (TCRseq) enables tracking of T-cell clonotypes recognizing the same antigen over time and across biological compartments. TCRseq has been used to test if cross-reactive antitumor T cells are responsible for development of immune-related adverse events (irAEs) following immune checkpoint blockade. Prior studies have interpreted T-cell clones shared among the tumor and irAE as evidence supporting this, but interpretations of these findings are challenging, given the constraints of TCRseq. Here we capitalize on a rare opportunity to understand the impact of potential confounders, such as sample size, tissue compartment, and collection batch/timepoint, on the relative proportion of shared T-cell clones between an irAE and tumor specimens. TCRseq was performed on tumor-involved and -uninvolved tissues, including an irAE, that were obtained throughout disease progression and at the time of rapid autopsy from a patient with renal cell carcinoma treated with programmed death-1 (PD-1) blockade. Our analyses show significant effects of these confounders on our ability to understand T-cell receptor overlap, and we present mitigation strategies and study design recommendations to reduce these errors. Implementation of these strategies will enable more rigorous TCRseq-based studies of immune responses in human tissues, particularly as they relate to antitumor T-cell cross-reactivity in irAEs following checkpoint blockade.
Escherichia coliadhesin protein-conjugated thermal responsive hybrid nanoparticles for photothermal and immunotherapy against cancer and its metastasis
Authors: Hwang Juyoung , Zhang Wei , Park Hae-Bin , Yadav Dhananjay , Jeon Yong Hyun , Jin Jun-O
Published: July 2021

Background

Advanced cancer therapy is targeted at primary tumors and also recurrent or metastatic cancers. Combinational cancer treatment has recently shown high efficiency against recurrent and metastatic cancers. In this study, we synthesized a thermal responsive hybrid nanoparticle (TRH) containing FimH, an immune stimulatory recombinant protein, for the induction of a combination of photothermal therapy (PTT) and immunotherapy against cancer and its metastasis.

Methods

The hybrid nanoparticle was incorporated with a near-infrared (NIR) absorbent, indocyanine green, and decorated with FimH on its surface to form F-TRH. F-TRH was evaluated for its anticancer and antimetastatic effects against CT-26 carcinoma in mice by combining PTT and immunotherapy.

Results

NIR laser irradiation elicited an elevation of temperature in F-TRH, which induced apoptosis in CT-26 carcinoma cells in vitro. In addition, F-TRH and NIR laser irradiation promoted photothermal-mediated therapeutic effects against CT-26 and 4T1 tumors in mice. The release of FimH from F-TRH in response to elevated temperature and apoptotic bodies of cancer cells via PTT elicited dendritic cell-mediated cancer antigen-specific T-cell responses, which subsequently inhibited the second challenge of CT-26 and 4T1 cell growth in the lung.

Conclusions

These data demonstrate the potential use of F-TRH for immuno-photothermal therapy against cancer and its recurrence and metastasis.
Metformin generates profound alterations in systemic and tumor immunity with associated antitumor effects
Authors: Veeramachaneni Ratna , Yu Wangjie , Newton Jared M , Kemnade Jan O , Skinner Heath D , Sikora Andrew G , Sandulache Vlad C
Published: July 2021

Background

Metformin is a commonly used antidiabetic medication which has demonstrated promise as an anticancer agent alone and in combination with conventional treatment regimens. There is increasing evidence that metformin can also generate immunomodulatory effects in solid tumors and is currently being investigated as an adjunct to immune checkpoint inhibitors (ICIs). We hypothesized that metformin would generate a shift in immunity unfavorable to tumor growth and tested this hypothesis in a preclinical model of head and neck cancer.

Methods

Using a syngeneic mouse model of human papillomavirus-associated head and neck cancer (mEER/MTEC), we tested the impact of metformin on systemic and local immunity and tumor growth velocity. We compared the effects of acute and chronic treatment regimens on immunocyte presence and activation using a combination of flow cytometry and targeted transcriptomic analysis.

Results

Acute metformin exposure generated measurable shifts in systemic myeloid and T-cell populations in non-tumor-bearing mice and decreased myeloid derived suppressor cell (MDSC) levels in tumor draining lymph nodes of tumor-bearing mice. Although metformin decreased regulatory T-cell (T-reg) and MDSC levels and increased CD8+ levels in murine tumors when combined with ICIs, acute metformin exposure was insufficient to generate substantial antitumor activity. Conversely, long-term metformin treatment significantly reduced tumor growth velocity, increased the CD8+/T-reg ratio, increased tumor infiltrating lymphocyte levels and upregulated component genes of the previously validated T-cell inflamed expression profile.

Conclusions

Metformin generates complex systemic and local immune effects which vary as a function of treatment duration. Combinatorial strategies with ICIs must take into account both the complexity and variability of these effects in order to generate maximal antitumor activity in future clinical trials.
Phase 1 study of safety, tolerability and immunogenicity of the human telomerase (hTERT)-encoded DNA plasmids INO-1400 and INO-1401 with or without IL-12 DNA plasmid INO-9012 in adult patients with solid tumors
Authors: Vonderheide Robert H , Kraynyak Kimberly A , Shields Anthony F , McRee Autumn J , Johnson Jennifer M , Sun Weijing , Chintakuntlawar Ashish V , Pawlicki Jan , Sylvester Albert J , McMullan Trevor , Samuels Robert , Kim Joseph J , Weiner David , Boyer Jean D , Morrow Matthew P , Humeau Laurent , Skolnik Jeffrey M
Published: July 2021

Background

Human telomerase reverse transcriptase (hTERT) is frequently classified as a ‘universal’ tumor associated antigen due to its expression in a vast number of cancers. We evaluated plasmid DNA-encoded hTERT as an immunotherapy across nine cancer types.

Methods

A phase 1 clinical trial was conducted in adult patients with no evidence of disease following definitive surgery and standard therapy, who were at high risk of relapse. Plasmid DNA encoding one of two hTERT variants (INO-1400 or INO-1401) with or without plasmid DNA encoding interleukin 12 (IL-12) (INO-9012) was delivered intramuscularly concurrent with the application of the CELLECTRA constant-current electroporation device 4 times across 12 weeks. Safety assessments and immune monitoring against native (germline, non-mutated, non-plasmid matched) hTERT antigen were performed. The largest cohort of patients enrolled had pancreatic cancer, allowing for additional targeted assessments for this tumor type.

Results

Of the 93 enrolled patients who received at least one dose, 88 had at least one adverse event; the majority were grade 1 or 2, related to injection site. At 18 months, 54.8% (51/93) patients were disease-free, with median disease-free survival (DFS) not reached by end of study. For patients with pancreatic cancer, the median DFS was 9 months, with 41.4% of these patients remaining disease-free at 18 months. hTERT immunotherapy induced a de novo cellular immune response or enhanced pre-existing cellular responses to native hTERT in 96% (88/92) of patients with various cancer types. Treatment with INO-1400/INO-1401±INO-9012 drove hTERT-specific IFN-γ production, generated hTERT-specific CD4+ and CD8+ T cells expressing the activation marker CD38, and induced hTERT-specific activated CD8 +CTLs as defined by cells expressing perforin and granzymes. The addition of plasmid IL-12 adjuvant elicited higher magnitudes of cellular responses including IFN-γ production, activated CD4+ and CD8+ T cells, and activated CD8+CTLs. In a subset analysis of pancreatic cancer patients, the presence of immunotherapy-induced activated CD8+ T cells expressing PD-1, granzymes and perforin correlated with survival.

Conclusions

Plasmid DNA-encoded hTERT/IL-12 DNA immunotherapy was well-tolerated, immune responses were noted across all tumor types, and a specific CD8+ phenotype increased by the immunotherapy was significantly correlated with survival in patients with pancreatic cancer.
Adaptive servo ventilation for sleep apnoea in heart failure: the FACE study 3-month data
Authors: Tamisier Renaud , Damy Thibaud , Bailly Sebastien , Davy Jean-Marc , Verbraecken Johan , Lavergne Florent , Palot Alain , Goutorbe Frederic , d'Ortho Marie-Pia , Pépin Jean Louis
Published: July 2021

Rationale

Adaptive servo ventilation (ASV) is contraindicated in patients with systolic heart failure (HF) who have a left ventricular ejection fraction (LVEF) below 45% and predominant central sleep apnoea (CSA). However, the effects of ASV in other HF subgroups have not been clearly defined.

Objective

The European, multicentre, prospective, observational cohort trial, FACE, evaluated the effects of ASV therapy on morbidity and mortality in patients with HF with sleep-disordered breathing (SDB); 3-month outcomes in patient subgroups defined using latent class analysis (LCA) are presented.

Methods

Consecutive patients with HF with predominant CSA (±obstructive sleep apnoea) indicated for ASV were included from 2009 to 2018; the non-ASV group included patients who refused/were noncompliant with ASV. The primary endpoint was time to composite first event (all-cause death, lifesaving cardiovascular intervention or unplanned hospitalisation for worsening of chronic HF).

Measurements and main results

Baseline assessments were performed in 503 patients, and 482 underwent 3-month follow-up. LCA identified six discrete patient clusters characterised by variations in LVEF, SDB type, age, comorbidities and ASV acceptance. The 3- month rate of primary outcome events was significantly higher in cluster 1 patients (predominantly men, low LVEF, severe HF, CSA; 13.9% vs 1.5%–5% in other clusters, p<0.01).

Conclusion

For the first time, our data identified homogeneous patient clusters representing clinically relevant subgroups relating to SDB management in patients with HF with different ASV usage, each with a different prognosis. This may improve patient phenotyping in clinical practice and allow individualisation of therapy.
Effects of menthol use and transitions in use on short-term and long-term cessation from cigarettes among US smokers
Authors: Leas Eric C , Benmarhnia Tarik , Strong David R , Pierce John P
Published: July 2021

Objectives

To estimate the effect of menthol use and transitions in use (switching to or from menthol) on short-term and long-term cessation from cigarette smoking and whether this differed across demographic groups (age, sex, race).

Methods

We compared the probability of 30+ day and 12-month abstinence from cigarette smoking by menthol use status using two cohorts of US adult cigarette smokers who attempted to quit smoking in the Population Assessment of Tobacco and Health (wave 1 to wave 3 and wave 2 to wave 4; n=5759), inverse probability of treatment weighting and adjusted risk ratios (aRRs).

Results

Using menthol (vs non-menthol) prior to a quit attempt decreased the probability of 30+ day abstinence by 28% (aRR=0.78; 95% CI 0.67 to 0.91) and the probability of 12-month abstinence by 53% (aRR=0.65; 95% CI 0.47 to 0.88). Additionally, switching from menthol (vs maintaining menthol use) increased the probability of 30+ day abstinence by 58% (aRR=1.58; 95% CI 1.00 to 2.50) and the probability of 12-month abstinence by 97% (aRR=1.86; 95% CI 0.92 to 3.74). Switching to menthol (vs maintaining non-menthol use) was associated with a lower probability of 30+ day (aRR=0.70; 95% CI 0.42 to 1.16) and 12-month abstinence (aRR=0.64; 95% CI 0.30 to 1.36), but these associations were imprecise. The effects of menthol use on impaired quitting were slightly larger for non-Hispanic Black smokers, but not different for other demographic groups.

Conclusion

These results demonstrate that menthol impaired menthol smokers’ attempts to quit smoking but switching from menthol improved success. This suggests that removing menthol may improve menthol smokers’ success during quit attempts.
A comprehensive investigation of the intermolecular interactions between CH2N2and X12Y12(X = B, Al, Ga; Y = N, P, As) nanocages
Authors: Mohammadi Mohsen Doust , Abdullah Hewa Y. , Bhowmick Somnath , Biskos George
Published: July 2021

In this paper, we have theoretically determined the possibility of adsorption of the gaseous CH2N2molecule on the surface of X12Y12nanocages, where X = B, Al, Ga and Y = N, P, As. The electronic structure calculations have been performed by density functional theory (DFT) using four functionals (i.e., B3LYP-D3, M06-2X, ωB97XD, and CAM-B3LYP), together with the 6-311G(d) basis function. We find that the adsorption of CH2N2on top of the X–Y bond of the nanocage is the most preferred site for adsorption. The adsorption process is accompanied by a charge-transfer phenomenon, which results in a strong bond between the terminal N atom of diazomethane and the X atom of the nanocage. This gives rise to significant changes in the highest and lowest occupied molecular orbital (HOMO and LUMO, respectively) energies and thus attribute properties to the nanocages that enable them to act as building blocks of CH2N2sensing materials.
Climate change experiment suggests divergent responses of tree seedlings in eastern North America’s Acadian Forest Region over the 21st century
Authors: Vaughn William R. , Taylor Anthony R. , MacLean David A. , D’Orangeville Loïc , Lavigne Michael B.
Published: July 2021

In this study, we conducted a controlled experiment to assess the growth and survival of balsam fir (Abies balsamea (L.) Mill.), red spruce (Picea rubens Sarg.), and red maple (Acer rubrum L.) seedlings in response to warming, drought, and elevated CO2, as projected under RCP 8.5 for North America’s Acadian Forest Region. In response to warming, only red spruce increased in height; however, this effect varied by CO2and soil moisture treatments. Under the drought treatment, red spruce biomass was not affected, but mortality increased by 2%. With warming, increases in balsam fir height growth were only detected under certain soil moisture and CO2conditions. Balsam fir biomass decreased by 24% under drought, while mortality increased by 5%. Warming did not improve red maple height growth, but it remained 7–50 times greater than that of the conifers and no mortality was observed. Overall, CO2enrichment increased height growth of droughted seedlings relative to the ambient treatment, demonstrating an amelioration of the negative drought effect. Balsam fir was the least adapted to warming and drought, while red spruce displayed some positive responses. Although growth of red maple seedlings did not increase with warming, they exhibited greater absolute growth and survival, which suggests red maple may outperform both conifers under a warming climate.
Quantum theory of $$k(\phi )$$-FLRW-metrics its connection to Chern-Simons-models and the theta vacuum structure of quantum gravity
Authors: Hristov J.
Published: July 2021

We show how a foliated 4-dimensional FLRW-metric becomes a gravitational instanton, if the spatial metric minimizes a three-dimensional Einstein–Hilbert action with positive cosmological constant, which is equal to the demand, that the scale factor satisfies the Bogomolny-equation, where the curvature parameter varies over the one-parameter family of hyperslices and takes the role of a potential depending on the scale factor. Additionally, we draw the connection to SO(4)-Chern–Simons theory and show how the established interpolating solutions describe the gradient flow between the minima of the vacuums of the Einstein–Hilbert action, as well as how they can be used to calculate tunnelling-amplitudes of gravitons and trivialize the calculations of path integrals in quantum gravity. All the calculations are carried out particularly forkadmitting a$${\mathbb {Z}}_{2}$$Z2-symmetry.
Potential linear and angular momentum in the scalar diquark model
Authors: Amor-Quiroz David Arturo , Burkardt Matthias , Focillon William , Lorcé Cédric
Published: July 2021

We present an analytic two-loop calculation within the scalar diquark model of the potential linear and angular momenta, defined as the difference between the Jaffe-Manohar and Ji notions of linear and angular momenta. As expected by parity and time-reversal symmetries, a direct calculation confirms that the potential transverse momentum coincides with the Jaffe-Manohar (or canonical) definition of average quark transverse momentum, also known as the quark Sivers shift. We examine whether initial/final-state interactions at the origin of the Sivers asymmetry can also generate a potential angular momentum in the scalar diquark model.
Multi-component generalized mode-coupling theory: predicting dynamics from structure in glassy mixtures
Authors: Ciarella Simone , Luo Chengjie , Debets Vincent E. , Janssen Liesbeth M. C.
Published: July 2021

The emergence of glassy dynamics and the glass transition in dense disordered systems is still not fully understood theoretically. Mode-coupling theory (MCT) has shown to be effective in describing some of the non-trivial features of glass formation, but it cannot explain the full glassy phenomenology due to the strong approximations on which it is based. Generalized mode-coupling theory (GMCT) is a hierarchical extension of the theory, which is able to outclass MCT by carefully describing the dynamics of higher-order correlations in its generalized framework. Unfortunately, the theory has so far only been developed for single-component systems and as a result works poorly for highly polydisperse materials. In this paper, we solve this problem by developing GMCT for multi-component systems. We use it to predict the glassy dynamics of the binary Kob–Andersen Lennard-Jones mixture, as well as its purely repulsive Weeks–Chandler–Andersen analogue. Our results show that each additional level of the GMCT hierarchy gradually improves the predictive power of GMCT beyond its previous limit. This implies that our theory is able to harvest more information from the static correlations, thus being able to better understand the role of attraction in supercooled liquids from a first-principles perspective.

Graphic abstract
Recent theoretical developments on QCD matter at finite temperature and density
Authors: Sharma Sayantan
Published: July 2021

Quantum Chromodynamics (QCD) matter at finite temperature and density is a subject that has witnessed very impressive theoretical developments in the recent years. In this review, I will discuss some new insights on the microscopic degrees of freedom of the QCD medium near the chiral crossover transition coming from lattice QCD. Latest high precision lattice data on the fluctuations and correlations between conserved charges like the baryon number, strangeness can help us to understand and distinguish between different models of interacting hadrons. Furthermore, the latest constraints on the location of the critical end-point and the curvature of the critical line will be discussed. In the later part of this review, I will discuss about the insights on the thermal nature of the medium created in heavy-ion collision experiments that have come from the theoretical analysis of the particle yields, and to what extent the lattice data on correlations and fluctuations of conserved charges can give us any information about the fireball at freeze out.
Dynamic Behavior Analysis of an Axially Loaded Beam Supported by a Nonlinear Spring-Mass System
Authors: Zhao Yuhao , Du Jingtao
Published: July 2021

Dynamic analysis of an Euler–Bernoulli beam with nonlinear supports is receiving greater research interest in recent years. Current studies usually consider the boundary and internal nonlinear supports separately, and the system rotational restraint is usually ignored. However, there is little study considering the simultaneous existence of axial load, lumped mass and internal supports for such nonlinear problem. Motivated by this limitation, the dynamic behavior of an axially loaded beam supported by a nonlinear spring-mass system is solved and investigated in this paper. Modal functions of an axially loaded Euler–Bernoulli beam with linear elastic supports are taken as trail functions in Galerkin discretization of the nonlinear governing differential equation. Stable steady-state response of such axially loaded beam supported by a nonlinear spring-mass system is solved via Galerkin truncation method, which is also validated by finite difference method. Results show that parameters of nonlinear spring-mass system and boundary condition have a significant influence on system dynamic behavior. Moreover, appropriate nonlinear parameters can switch the system behavior between the single-periodic state and quasi-periodic state effectively.