bluuebunny/crossref_metadata_2025 huggingface dataset:
Humanized Mice for Infectious and Neurodegenerative disorders
Authors: Dash Prasanta K. , Gorantla Santhi , Poluektova Larisa , Hasan Mahmudul , Waight Emiko , Zhang Chen , Markovic Milica , Edagwa Benson , Machhi Jatin , Olson Katherine E. , Wang Xinglong , Mosley R. Lee , Kevadiya Bhavesh , Gendelman Howard E.
Published: June 2021

Humanized mice model human disease and as such are used commonly for research studies of infectious, degenerative and cancer disorders. Recent models also reflect hematopoiesis, natural immunity, neurobiology, and molecular pathways that influence disease pathobiology. A spectrum of immunodeficient mouse strains permit long-lived human progenitor cell engraftments. The presence of both innate and adaptive immunity enables high levels of human hematolymphoid reconstitution with cell susceptibility to a broad range of microbial infections. These mice also facilitate investigations of human pathobiology, natural disease processes and therapeutic efficacy in a broad spectrum of human disorders. However, a bridge between humans and mice requires a complete understanding of pathogen dose, co-morbidities, disease progression, environment, and genetics which can be mirrored in these mice. These must be considered for understanding of microbial susceptibility, prevention, and disease progression. With known common limitations for access to human tissues, evaluation of metabolic and physiological changes and limitations in large animal numbers, studies in mice prove important in planning human clinical trials. To these ends, this review serves to outline how humanized mice can be used in viral and pharmacologic research emphasizing both current and future studies of viral and neurodegenerative diseases. In all, humanized mouse provides cost-effective, high throughput studies of infection or degeneration in natural pathogen host cells, and the ability to test transmission and eradication of disease.
Neuroprotection by WldS depends on retinal ganglion cell type and age in glaucoma
Authors: Risner Michael L. , Pasini Silvia , McGrady Nolan R. , D’Alessandro Karis B. , Yao Vincent , Cooper Melissa L. , Calkins David J.
Published: June 2021

Background

Early challenges to axonal physiology, active transport, and ultrastructure are endemic to age-related neurodegenerative disorders, including those affecting the optic nerve. Chief among these, glaucoma causes irreversible vision loss through sensitivity to intraocular pressure (IOP) that challenges retinal ganglion cell (RGC) axons, which comprise the optic nerve. Early RGC axonopathy includes distal to proximal progression that implicates a slow form of Wallerian degeneration. In multiple disease models, including inducible glaucoma, expression of the slow Wallerian degeneration (WldS) allele slows axon degeneration and confers protection to cell bodies.

Methods

Using an inducible model of glaucoma along with whole-cell patch clamp electrophysiology and morphological analysis, we tested if WldS also protects RGC light responses and dendrites and, if so, whether this protection depends upon RGC type. We induced glaucoma in young and aged mice to determine if neuroprotection by WldS on anterograde axonal transport and spatial contrast acuity depends on age.

Results

We found WldS protects dendritic morphology and light-evoked responses of RGCs that signal light onset (αON-Sustained) during IOP elevation. However, IOP elevation significantly reduces dendritic complexity and light responses of RGCs that respond to light offset (αOFF-Sustained) regardless of WldS. As expected, WldS preserves anterograde axon transport and spatial acuity in young adult mice, but its protection is significantly limited in aged mice.

Conclusion

The efficacy of WldS in conferring protection to neurons and their axons varies by cell type and diminishes with age.
“Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies
Authors: Xia Yuxing , Prokop Stefan , Giasson Benoit I.
Published: June 2021

Phosphorylation is one of the most prevalent post-translational modifications found in aggregated tau isolated from Alzheimer’s disease (AD) patient brains. In tauopathies like AD, increased phosphorylation or hyperphosphorylation can contribute to microtubule dysfunction and is associated with tau aggregation. In this review, we provide an overview of the structure and functions of tau protein as well as the physiologic roles of tau phosphorylation. We also extensively survey tau phosphorylation sites identified in brain tissue and cerebrospinal fluid from AD patients compared to age-matched healthy controls, which may serve as disease-specific biomarkers. Recently, new assays have been developed to measure minute amounts of specific forms of phosphorylated tau in both cerebrospinal fluid and plasma, which could potentially be useful for aiding clinical diagnosis and monitoring disease progression. Additionally, multiple therapies targeting phosphorylated tau are in various stages of clinical trials including kinase inhibitors, phosphatase activators, and tau immunotherapy. With promising early results, therapies that target phosphorylated tau  could be useful at slowing tau hyperphosphorylation and aggregation in AD and other tauopathies.
“I try the one that they say is good.” - factors influencing choice of health care provider and pathways to diabetes care for Syrian refugees in Lebanon
Authors: Haderer Flora , Venables Emilie , van Olmen Josefien , Orcutt Miriam , Ghassibe-Sabbagh Michella , van den Boogaard Wilma
Published: June 2021

Background

Navigating health systems in host countries can be a challenge for refugees, particularly in a multi-provider system such as Lebanon. Syrian refugees in Lebanon face a high burden of Non-Communicable Diseases (NCDs) including diabetes mellitus. Evidence on how refugees navigate the health system is essential to improve provision of NCD services. We conducted a qualitative study amongst Syrian diabetes patients visiting Médecins Sans Frontières (MSF) clinics in one urban and one rural setting in Lebanon to explore factors influencing choice of and pathways to diabetes care.

Methods

In-depth interviews were conducted with male and female adult participants with DM type 1 or type 2 who were receiving treatment at MSF clinics. Participants were recruited using convenience sampling. Interviews were conducted in Arabic and directly transcribed and translated into English. Data were coded in NVivo and analyzed using an inductive thematic approach.

Results

A total of 29 in-depth interviews were conducted with 13 men and 16 women. Knowledge and understanding of diabetes management differed among participants. Syrian refugees in Lebanon gathered information about health services for diabetes largely from social networks of family and peers rather than through formal means. Pathways to care included different combinations of providers such as clinics, pharmacists and informal providers.

Conclusions

Syrian refugees with diabetes in Lebanon face considerable challenges in navigating the health care system due to their vulnerable status and limited knowledge of the host country systems. To ensure access to care for diabetes, efforts need to be made to support patients’ orientation in the Lebanese health system.
Antibody-drug conjugates for the treatment of lymphoma: clinical advances and latest progress
Authors: Chu Yurou , Zhou Xiangxiang , Wang Xin
Published: June 2021

Antibody-drug conjugates (ADCs) are a promising class of immunotherapies with the potential to specifically target tumor cells and ameliorate the therapeutic index of cytotoxic drugs. ADCs comprise monoclonal antibodies, cytotoxic payloads with inherent antitumor activity, and specialized linkers connecting the two. In recent years, three ADCs, brentuximab vedotin, polatuzumab vedotin, and loncastuximab tesirine, have been approved and are already establishing their place in lymphoma treatment. As the efficacy and safety of ADCs have moved in synchrony with advances in their design, a plethora of novel ADCs have garnered growing interest as treatments. In this review, we provide an overview of the essential elements of ADC strategies in lymphoma and elucidate the up-to-date progress, current challenges, and novel targets of ADCs in this rapidly evolving field.
Standardized post-resuscitation damage assessment of two mechanical chest compression devices: a prospective randomized large animal trial
Authors: Ruemmler Robert , Stein Jakob , Duenges Bastian , Renz Miriam , Hartmann Erik Kristoffer
Published: June 2021

Background

Mechanical chest compression devices are accepted alternatives for cardiopulmonary resuscitation (CPR) under specific circumstances. Current devices lack prospective and comparative data on their specific cardiovascular effects and potential for severe thoracic injuries.

Objectives

To compare CPR effectiveness and thoracic injuries of two mechanical chest compression devices in pigs.

Study design

Prospective randomised trial.

Animals

Eighteen male German landrace pigs.

Methods

Ventricular fibrillation was induced in anaesthetised and instrumented pigs and the animals were randomised into two intervention groups. Mechanical CPR was initiated by means of LUCAS™ 2 (mCCD1) or Corpuls™ cpr (mCCD2) device. Advanced life support was applied for a maximum of 10 cycles and animals achieving ROSC were monitored for 8 h. Ventilation/perfusion measurements were performed and blood gas analyses were taken. Thoracic injuries were assessed via a standardised damage score.

Results

Five animals of the mCCD1 group and one animal of the mCCD2 group achieved ROSC (p = 0.048). Only the mCCD1 animals survived until the end of the monitoring period (p < 0.01). MCCD1 animals showed less pulmonary shunt (p = 0.025) and higher normal V/Q (p = 0.017) during CPR. MCCD2 animals showed significantly more severe thoracic injuries (p = 0.046).

Conclusion

The LUCAS 2 device shows superior resuscitation outcomes and less thoracic injuries compared to Corpuls cpr when used for experimental CPR in juvenile pigs. Researchers should be aware that different mCCDs for experimental studies may significantly influence the respective outcome of resuscitation studies and affect comparability of different trials. Controlled human and animal CPR studies and a standardised post-resuscitation injury evaluation could help to confirm potential hazards.

Trial registration

Trial approval number: G16–1-042-E4.
Prevalence of SARS-CoV-2 infection in Italian pediatric population: a regional seroepidemiological study
Authors: Comar Manola , Benvenuto Simone , Lazzerini Marzia , Fedele Giorgio , Barbi Egidio , Amaddeo Alessandro , Risso Francesco Maria , Strajn Tamara , Di Rocco Paola , Stefanelli Paola , Rezza Giovanni
Published: June 2021

Background

Data on the effective burden of the SARS-CoV-2 pandemic in pediatric population are very limited, mostly because of the higher rate of asymptomatic or paucisymptomatic cases among children. Updated data on COVID-19 prevalence are needed for their relevance in public health and for infection control policies. In this single-centre cross-sectional study we aimed to assess prevalence of SARS-CoV-2 infection through IgG antibodies detection in an Italian pediatric cohort.

Methods

The study was conducted in January 2021 among both inpatients and outpatients referring to Research Institute for Maternal and Child Health “Burlo Garofolo” in Trieste, Friuli Venezia-Giulia, Italy, who needed for blood test for any reason. Collected samples were sent to Italian National Institute of Health for analysis through chemiluminescent immunoassay (CLIA).

Results

One hundred sixty-nine patients were included in the study, with a median age of 10.5 ± 4.1 years, an equal distribution for sex (49.7% female patients), and a 55.6% prevalence of comorbidities. Prevalence of anti-SARS-CoV-2 trimeric Spike protein IgG antibodies was 9.5% (n = 16), with a medium titre of 482.3 ± 387.1 BAU/mL. Having an infected cohabitant strongly correlated with IgG positivity (OR 23.83, 95% CI 7.19–78.98, p < 0.0001), while a cohabitant healthcare worker wasn’t associated with a higher risk (OR 1.53, 95% CI 0.4–5.86, p 0.46). All of the 5 patients who had previously tested positive to a nasopharyngeal swab belonged to the IgG positive group, with a 3-month interval from the infection at most.

Conclusion

We assessed a 9.5% SARS-CoV-2 seroprevalence in a pediatric cohort from Friuli Venezia-Giulia region in January 2021, showing a substantial increase after the second peak of the pandemic occurred starting from October 2020, compared to 1% prevalence observed by National Institute of Statistics (ISTAT) in July 2020.
Efficacy of pediatric integrative manual therapy in positional plagiocephaly: a randomized controlled trial
Authors: Pastor-Pons Iñaki , Lucha-López María Orosia , Barrau-Lalmolda Marta , Rodes-Pastor Iñaki , Rodríguez-Fernández Ángel Luis , Hidalgo-García César , Tricás-Moreno Jose Miguel
Published: June 2021

Background

Positional plagiocephaly frequently affects healthy babies. It is hypothesized that manual therapy tailored to pediatrics is more effective in improving plagiocephalic cranial asymmetry than just repositioning and sensory and motor stimulation.

Methods

Thirty-four neurologically healthy subjects aged less than 28 weeks old with a difference of at least 5 mm between cranial diagonal diameters were randomly distributed into 2 groups. For 10 weeks, the pediatric integrative manual therapy (PIMT) group received manual therapy plus a caregiver education program, while the controls received the same education program exclusively. Cranial shape was evaluated using anthropometry; cranial index (CI) and cranial vault asymmetry index (CVAI) were calculated. Parental perception of change was assessed using a visual analogue scale (− 10 cm to + 10 cm).

Results

CVAI presented a greater decrease in PIMT group: 3.72 ± 1.40% compared with 0.34 ± 1.72% in the control group (p = 0.000). CI did not present significant differences between groups. Manual therapy led to a more positive parental perception of cranial changes (manual therapy: 6.66 ± 2.07 cm; control: 4.25 ± 2.31 cm; p = 0.004).

Conclusion

Manual therapy plus a caregiver education program improved CVAI and led to parental satisfaction more effectively than solely a caregiver education program.

Trial registration

Trial registration number: NCT03659032; registration date: September 1, 2018. Retrospectively registered.
Association between maternal iron supplementation and newborn birth weight: a quantile regression analysis
Authors: Shi Guoshuai , Zhang Zhuo , Ma Lu , Zhang Binyan , Dang Shaonong , Yan Hong
Published: June 2021

Objective

Our study aimed to explore the association between maternal iron supplementation and newborn birth weight (BW) in Shaanxi Province using quantile regression (QR).

Method

The data used in this study were derived from a large cross-sectional survey of a population in Shaanxi Province, Northwest China. A total of 28,209 women and their infants were selected using a stratified multistage random sampling method. The effect of iron supplementation on the newborn BW was assessed by a multiple linear regression model and QR.

Results

A total of 5.15% of the women took iron supplements during pregnancy. Multiple linear regression showed that the iron supplementation during pregnancy had positive effects on the BW, with an average increase of 43.07 g (β = 43.07, t = 3.55, and p < 0.001). The QR showed that the iron supplementation during pregnancy was associated with an increased newborn BW from very low to higher percentiles (quantiles: 0 ~ 0.40), with the β ranging from 136.51 to 43.86. As the percentiles of the BW increased, the neonatal BW gain gradually declined in the iron supplementation group compared with the group that did not receive iron supplementation (quantiles: 0 ~ 0.40, with the β ranging from 136.51 to 43.86). Iron supplementation was more effective among women who suffered from anemia during pregnancy (β = 45.84, t = 2.05, and p = 0.04; quantiles: 0 ~ 0.15, 0.30, 0.80, with β ranging from 150.00 to 39.29) than it was in any other group (β = 38.18, t = 2.62, and p = 0.009; quantiles: 0 ~ 0.15, with β ranging from 133.33 to 28.32).

Conclusions

Iron supplementation during pregnancy is associated with an increased newborn BW, and the effect was more obvious in the newborns with the lower BW and newborns whose mothers suffered from anemia during pregnancy.
Circulating immune cell populations related to primary breast cancer, surgical removal, and radiotherapy revealed by flow cytometry analysis
Authors: Cattin Sarah , Fellay Benoît , Calderoni Antonello , Christinat Alexandre , Negretti Laura , Biggiogero Maira , Badellino Alberto , Schneider Anne-Lise , Tsoutsou Pelagia , Pellanda Alessandra Franzetti , Rüegg Curzio
Published: June 2021

Background

Advanced breast cancer (BC) impact immune cells in the blood but whether such effects may reflect the presence of early BC and its therapeutic management remains elusive.

Methods

To address this question, we used multiparametric flow cytometry to analyze circulating leukocytes in patients with early BC (n = 13) at the time of diagnosis, after surgery, and after adjuvant radiotherapy, compared to healthy individuals. Data were analyzed using a minimally supervised approach based on FlowSOM algorithm and validated manually.

Results

At the time of diagnosis, BC patients have an increased frequency of CD117+CD11b+ granulocytes, which was significantly reduced after tumor removal. Adjuvant radiotherapy increased the frequency of CD45RO+ memory CD4+ T cells and CD4+ regulatory T cells. FlowSOM algorithm analysis revealed several unanticipated populations, including cells negative for all markers tested, CD11b+CD15low, CD3+CD4−CD8−, CD3+CD4+CD8+, and CD3+CD8+CD127+CD45RO+ cells, associated with BC or radiotherapy.

Conclusions

This study revealed changes in blood leukocytes associated with primary BC, surgical removal, and adjuvant radiotherapy. Specifically, it identified increased levels of CD117+ granulocytes, memory, and regulatory CD4+ T cells as potential biomarkers of BC and radiotherapy, respectively. Importantly, the study demonstrates the value of unsupervised analysis of complex flow cytometry data to unravel new cell populations of potential clinical relevance.
Temperature and food sources influence subadult development and blood-feeding response of Culicoides obsoletus (sensu lato) under laboratory conditions
Authors: Van den Eynde Claudia , Sohier Charlotte , Matthijs Severine , De Regge Nick
Published: June 2021

Background

Culicoides obsoletus (s.l.) is the most abundant Culicoides species in northern Europe and an important vector of bluetongue virus and Schmallenberg virus. Nevertheless, information on its subadult life stages remains scarce and no laboratory-reared colony exists.

Methods

C. obsoletus (s.l.) adults were collected in Belgium and transferred to the laboratory in an attempt to establish a laboratory-reared colony. C. obsoletus (s.l.) were reared from eggs to adults at different temperatures (28 °C, 24 °C, 20/16 °C) and under different food regimes.

Results

The most suitable temperature for rearing seemed to be 24 °C for most developmental parameters, but resulted in a biased 3:1 male/female sex ratio. The latter could be optimized to a 1:1 sex ratio when a 20/16 °C day/night temperature gradient was applied, but rearing at these low temperature conditions resulted in significantly lower egg hatching and pupation rates and a longer subadult development time. Independent of the rearing temperature, adding dung as an additional food source during larval development resulted in a significantly higher adult emergence rate and a decrease in subadult development time. Furthermore, blood-feeding rates of field-collected C. obsoletus (s.l.) were compared for different blood sources and feeding systems. The overall blood-feeding success was low and only successful with cotton pledgets (2.7% blood-fed midges) and through a membrane system with chicken skin (3.5% blood-fed midges). Higher feeding rates were obtained on cattle blood compared to sheep blood.

Conclusions

These results will help us to determine the necessary conditions to rear a viable laboratory colony of this important vector species, although further optimization is still required.

Graphical abstract
Recent aspects on epidemiology, clinical disease, and genetic diversity of Toxoplasma gondii infections in Australasian marsupials
Authors: Dubey Jitender P. , Murata Fernando H. A. , Cerqueira-Cézar Camila K. , Kwok Oliver C. H. , Su Chunlei , Grigg Michael E.
Published: June 2021

Background

Toxoplasma gondiiinfections are common in humans and animals worldwide. Among all intermediate hosts ofT. gondii, captive marsupials from Australia and New Zealand are highly susceptible to clinical toxoplasmosis. However, most free-range marsupials establish chronicT. gondiiinfection. Infected marsupial meat may serve as a source ofT. gondiiinfection for humans. Differences in mortality patterns in different species of kangaroos and other marsupials are not fully understood. Lifestyle, habitat, and the genotype ofT. gondiiare predicted to be risk factors. For example, koalas are rarely exposed toT. gondiibecause they live on treetops whereas wallabies on land are frequently exposed to infection.

Methods

The present review summarizes worldwide information on the prevalence of clinical and subclinical infections, epidemiology, and genetic diversity ofT. gondiiinfecting Australasian marsupials in their native habitat and among exported animals over the past decade. The role of genetic types ofT. gondiiand clinical disease is discussed.

Results

Fatal toxoplasmosis has been diagnosed in captive Australasian marsupials in Argentina, Chile, China, Germany, Hungary, Japan, Spain, Turkey, and the USA. Most deaths occurred because of disseminated toxoplasmosis. Genetic characterization ofT. gondiistrains isolated from fatal marsupial infections identified Type III as well as atypical, nonclonal genotypes. Fatal toxoplasmosis was also diagnosed in free-ranging wombats (Vombatus ursinus) in Australia. Genetic characterization of DNA amplified directly from host tissues of subclinical culled kangaroos at slaughter identified many mixed-strain infections with both atypical and recombinant genotypes ofT. gondii.

Conclusions

Most Australasian marsupials in their native land, Australia and New Zealand, have high prevalence ofT. gondii, and kangaroo meat can be a source of infection for humans if consumed uncooked/undercooked. The genotypes prevalent in kangaroos in Australia and New Zealand were genetically distinct from those isolated or genotyped from most macropods in the USA and other countries. Thus, clinical toxoplasmosis in marsupials imported from Australia is most likely to occur from infections acquired after importation.

Graphical Abstract
Mosquito vector proteins homologous to α1-3 galactosyl transferases of tick vectors in the context of protective immunity against malaria and hypersensitivity to vector bites
Authors: Ramasamy Ranjan
Published: June 2021

Background

An epitope, Galα1-3Galβ1-4GlcNAc-R, termed α-gal, is present in glycoconjugates of New World monkeys (platyrrhines) and other mammals but not in hominoids and Old World monkeys (catarrhines). The difference is due to the inactivation of α1-3 galactosyl transferase (α1-3 GT) genes in catarrhines. Natural antibodies to α-gal are therefore developed in catarrhines but not platyrrhines and other mammals. Hypersensitivity reactions are commonly elicited by mosquito and tick vector bites. IgE antibodies against α-gal cause food allergy to red meat in persons who have been exposed to tick bites. Three enzymes synthesising the terminal α1-3-linked galactose in α-gal, that are homologous to mammalian α and β1-4 GTs but not mammalian α1-3 GTs, were recently identified in the tick vectorIxodes scapularis. IgG and IgM antibodies to α-gal are reported to protect against malaria because mosquito-derived sporozoites of malaria parasites express α-gal on their surface. This article explores the possibility that the α-gal in sporozoites are acquired from glycoconjugates synthesised by mosquitoes rather than through de novo synthesis by sporozoites.

Methods

The presence of proteins homologous to the three identified tick α1-3 GTs and mammalian α1-3 GTs in two important mosquito vectors,Aedes aegyptiandAnopheles gambiae, as well asPlasmodiummalaria parasites, was investigated by BLASTp analysis to help clarify the source of the α-gal on sporozoite surfaces.

Results

Anopheles gambiaeandAe. aegyptipossessed several different proteins homologous to the threeI. scapularisproteins with α1-3 GT activity, but not mammalian α1-3 GTs. The putative mosquito α1-3 GTs possessed conserved protein domains characteristic of glycosyl transferases. However, the genusPlasmodiumlacked proteins homologous to the threeI. scapularisproteins with α1-3 GT activity and mammalian α1-3 GTs.

Conclusions

The putative α1-3 GTs identified in the two mosquito vectors may synthesise glycoconjugates containing α-gal that can be transferred to sporozoite surfaces before they are inoculated into skin during blood feeding. The findings merit further investigation because of their implications for immunity against malaria, hypersensitivity to mosquito bites, primate evolution, and proposals for immunisation against α-gal.

Graphical Abstract
Lack of detectable short-term effects of a single dose of ivermectin on the human immune system
Authors: Wilson Natalie E. , Reaves Barbara J. , Wolstenholme Adrian J.
Published: June 2021

Background

Ivermectin is widely used in human and animal medicine to treat and prevent parasite nematode infections. It has been suggested that its mode of action requires the host immune system, as it is difficult to reproduce its clinical efficacy in vitro. We therefore studied the effects of a single dose of ivermectin (Stromectol®—0.15 mg/kg) on cytokine levels and immune cell gene expression in human volunteers. This dose reduces bloodstream microfilariae rapidly and for several months when given in mass drug administration programmes.

Methods

Healthy volunteers with no travel history to endemic regions were given 3–4 tablets, depending on their weight, of either ivermectin or a placebo. Blood samples were drawn immediately prior to administration, 4 h and 24 h afterwards, and complete blood counts performed. Serum levels of 41 cytokines and chemokines were measured using Luminex® and expression levels of 770 myeloid-cell-related genes determined using the NanoString nCounter®. Cytokine levels at 4 h and 24 h post-treatment were compared to the levels pre-treatment using simple t tests to determine if any individual results required further investigation, taking p =  < 0.05 as the level of significance. NanoString data were analysed on the proprietary software, nSolver™.

Results

No significant differences were observed in complete blood counts or cytokine levels at either time point between people given ivermectin versus placebo. Only three genes showed a significant change in expression in peripheral blood mononuclear cells 4 h after ivermectin was given; there were no significant changes 24 h after drug administration or in polymorphonuclear cells at either time point. Leukocytes isolated from those participants given ivermectin showed no difference in their ability to kill Brugia malayi microfilariae in vitro.

Conclusions

Overall, our data do not support a direct effect of ivermectin, when given at the dose used in current filarial elimination programmes, on the human immune system.

Trial registration ClinicalTrials.gov NCT03459794 Registered 9th March 2018, Retrospectively registered https://clinicaltrials.gov/ct2/show/NCT03459794?term=NCT03459794&draw=2&rank=1.

Graphical Abstract
Pain-Track: a time-series approach for the description and analysis of the burden of pain
Authors: Alonso Wladimir J. , Schuck-Paim Cynthia
Published: June 2021

Objective

To present the Pain-Track, a novel framework for the description and analysis of the pain experience based on its temporal evolution, around which intensity and other attributes of pain (texture, anatomy), interventions and clinical symptoms can be registered. This time-series approach can provide valuable insight on the expected evolution of the pain typically associated with different medical conditions and on time-varying (risk) factors associated with the temporal dynamics of pain.

Results

We illustrate the use of the framework to explore hypotheses on the temporal profile of the pain associated with an acute injury (bone fracture), and the magnitude of the pain burden it represents. We also show that, by focusing on the critical dimensions of the pain experience (intensity and time), the approach can help map different conditions to a common scale directly relating to the experiences of those who endure them (time in pain), providing the basis for the quantification of the burden of pain inflicted upon individuals or populations. An electronic version for data entry and interpretation is also presented.
Chromatin accessibility changes at intergenic regions are associated with ovarian cancer drug resistance
Authors: Gallon John , Loomis Erick , Curry Edward , Martin Nicholas , Brody Leigh , Garner Ian , Brown Robert , Flanagan James M.
Published: June 2021

Background

Resistance to DNA damaging chemotherapies leads to cancer treatment failure and poor patient prognosis. We investigated how genomic distribution of accessible chromatin sites is altered during acquisition of cisplatin resistance using matched ovarian cell lines from high grade serous ovarian cancer (HGSOC) patients before and after becoming clinically resistant to platinum-based chemotherapy.

Results

Resistant lines show altered chromatin accessibility at intergenic regions, but less so at gene promoters. Clusters of cis-regulatory elements at these intergenic regions show chromatin changes that are associated with altered expression of linked genes, with enrichment for genes involved in the Fanconi anemia/BRCA DNA damage response pathway. Further, genome-wide distribution of platinum adducts associates with the chromatin changes observed and distinguish sensitive from resistant lines. In the resistant line, we observe fewer adducts around gene promoters and more adducts at intergenic regions.

Conclusions

Chromatin changes at intergenic regulators of gene expression are associated with in vivo derived drug resistance and Pt-adduct distribution in patient-derived HGSOC drug resistance models.
Optimising NK cell metabolism to increase the efficacy of cancer immunotherapy
Authors: Choi Chloe , Finlay David K.
Published: June 2021

Immunotherapy has ushered in an exciting new era for cancer treatment. The recent discovery and success of immune checkpoint blockade and chimeric antigen receptor (CAR) T cell adoptive cell transfer has raised interest in using other immune cells, including Natural Killer (NK) cells, which might overcome some limitations with CAR T cell therapy. In this review article, we discuss the evidence that cellular metabolism is crucial for NK cell effector function. Additionally, potential strategies to optimise the metabolism of therapeutic NK cells for improved function within the metabolically adverse tumour microenvironment will be explored.
Bone marrow mesenchymal stem cells and their derived exosomes resolve doxorubicin-induced chemobrain: critical role of their miRNA cargo
Authors: El-Derany Marwa O. , Noureldein Mohamed H.
Published: June 2021

Background

Doxorubicin (DOX), a widely used chemotherapeutic agent, can cause neurodegeneration in the brain, which leads to a condition known as chemobrain. In fact, chemobrain is a deteriorating condition which adversely affects the lives of cancer survivors. This study aimed to examine the potential therapeutic effects of bone marrow mesenchymal stem cells (BMSCs) and their derived exosomes (BMSCs-Exo) in DOX-induced chemobrain in rat models.

Methods

Chemobrain was induced by exposing rats to DOX (2 mg/kg, i.p) once weekly for 4 consecutive weeks. After 48 h of the last DOX dose, a subset of rats was supplied with either an intravenous injection of BMSCs (1 × 106) or a single dose of 150 μg of BMSCs-Exo. Behavioral tests were conducted 7 days post injection. Rats were sacrificed after 14 days from BMSCs or BMSCs-Exo injection.

Results

BMSCs and BMSCs-Exo successfully restored DOX-induced cognitive and behavioral distortion. These actions were mediated via decreasing hippocampal neurodegeneration and neural demyelination through upregulating neural myelination factors (myelin%, Olig2, Opalin expression), neurotropic growth factors (BDNF, FGF-2), synaptic factors (synaptophysin), and fractalkine receptor expression (Cx3cr1). Halting neurodegeneration in DOX-induced chemobrain was achieved through epigenetic induction of key factors in Wnt/β-catenin and hedgehog signaling pathways mediated primarily by the most abundant secreted exosomal miRNAs (miR-21-5p, miR-125b-5p, miR-199a-3p, miR-24-3p, let-7a-5p). Moreover, BMSCs and BMSCs-Exo significantly abrogate the inflammatory state (IL-6, TNF-α), apoptotic state (BAX/Bcl2), astrocyte, and microglia activation (GFAP, IBA-1) in DOX-induced chemobrain with a significant increase in the antioxidant mediators (GSH, GPx, SOD activity).

Conclusions

BMSCs and their derived exosomes offer neuroprotection against DOX-induced chemobrain via genetic and epigenetic abrogation of hippocampal neurodegeneration through modulating Wnt/β-catenin and hedgehog signaling pathways and through reducing inflammatory, apoptotic, and oxidative stress state.

Graphical abstract

Proposed mechanisms of the protective effects of bone marrow stem cells (BMSCs) and their exosomes (BMSCs-Exo) in doxorubicin (DOX)-induced chemobrain. Blue arrows: induce. Red arrows: inhibit.
IL-1β pre-stimulation enhances the therapeutic effects of endometrial regenerative cells on experimental colitis
Authors: Yu Dingding , Zhao Yiming , Wang Hongda , Kong Dejun , Jin Wang , Hu Yonghao , Qin Yafei , Zhang Baoren , Li Xiang , Hao Jingpeng , Li Guangming , Wang Hao
Published: June 2021

Background

Ulcerative colitis (UC) is a chronic, relapsing, and non-specific inflammatory bowel disease, and the current treatment strategies were mainly used to relieve symptoms or for maintenance. Endometrial regenerative cells (ERCs) are mesenchymal-like stromal cells and have been demonstrated to alleviate multiple immune-dysregulation diseases. Pro-inflammatory stimuli were reported to enhance the immunosuppressive functions of ERCs, but the mechanism underlined is not fully understood. Here, we have designed this study to investigate the therapeutic effects of IL-1β-primed ERCs in the attenuation of experimental colitis.

Methods

BALB/c mice were given 3% dextran sodium sulfate (DSS) for 7 consecutive days and free tap water for 3 days sequentially to induce experimental colitis. PBS (200 μL), ERCs, and IL-1β-primed ERCs (10ng/mL, 48 h) were injected (1 million/mouse/day, i.v.) on day 2, 5, and 8, respectively. Colonic and splenic samples were harvested on day 10 after DSS induction.

Results

It was found that IL-1β-primed ERC treatment markedly attenuated colonic damage, body weight loss, and colon length shortening in colitis mice. Compared with other treatments, cell populations of CD4+IL-4+Th2 cells, CD4+CD25+FOXP3+ regulatory T cells (Tregs), and CD68+CD206+ macrophages in spleens were also significantly upregulated in the IL-1β-primed ERC-treated group (p < 0.05). In addition, lower expression of pro-inflammatory (IFN-γ, IL-17, TNF-α, and IL-6), but higher levels of anti-inflammatory cytokines (IL-4 and IL-10) were detected in colons in the IL-1β-primed ERC-treated group (p < 0.05 vs. other groups). Importantly, we also found that different generations of ERCs had an overall lower secretion of Dickkopf-1 (DKK1) by IL-1β pre-stimulation (p < 0.05) and a higher expression of β-catenin in colonic and splenic tissues after the administration of IL-1β-primed ERCs.

Conclusions

This study has demonstrated that IL-1β pre-stimulation effectively downregulated DKK1 expression in ERCs, which in turn promoted the wnt/β-catenin pathway activation in colonic and splenic tissues. Consequently, IL-1β-primed ERCs exhibited an enhanced therapeutic effect in the attenuation of DSS-induced colitis.
Methylsulfonylmethane enhances MSC chondrogenic commitment and promotes pre-osteoblasts formation
Authors: Dalle Carbonare Luca , Bertacco Jessica , Marchetto Giulia , Cheri Samuele , Deiana Michela , Minoia Arianna , Tiso Natascia , Mottes Monica , Valenti Maria Teresa
Published: June 2021

Background

Methylsulfonylmethane (MSM) is a nutraceutical compound which has been indicated to counteract osteoarthritis, a cartilage degenerative disorder. In addition, MSM has also been shown to increase osteoblast differentiation. So far, few studies have investigated MSM role in the differentiation of mesenchymal stem cells (MSCs), and no study has been performed to evaluate its overall effects on both osteogenic and chondrogenic differentiation. These two mutually regulated processes share the same progenitor cells.

Methods

Therefore, with the aim to evaluate the effects of MSM on chondrogenesis and osteogenesis, we analyzed the expression of SOX9, RUNX2, and SP7 transcription factors in vitro (mesenchymal stem cells and chondrocytes cell lines) and in vivo (zebrafish model). Real-time PCR as well Western blotting, immunofluorescence, and specific in vitro and in vivo staining have been performed. Student’s paired t test was used to compare the variation between the groups.

Results

Our data demonstrated that MSM modulates the expression of differentiation-related genes both in vitro and in vivo. The increased SOX9 expression suggests that MSM promotes chondrogenesis in treated samples. In addition, RUNX2 expression was not particularly affected by MSM while SP7 expression increased in all MSM samples/model analyzed. As SP7 is required for the final commitment of progenitors to preosteoblasts, our data suggest a role of MSM in promoting preosteoblast formation. In addition, we observed a reduced expression of the osteoclast-surface receptor RANK in larvae and in scales as well as a reduced pERK/ERK ratio in fin and scale of MSM treated zebrafish.

Conclusions

In conclusion, our study provides new insights into MSM mode of action and suggests that MSM is a useful tool to counteract skeletal degenerative diseases by targeting MSC commitment and differentiation.
BMSC-derived extracellular vesicles intervened the pathogenic changes of scleroderma in mice through miRNAs
Authors: Jin Jiahui , Ou Qingjian , Wang Zhe , Tian Haibin , Xu Jing-Ying , Gao Furong , Hu Shuqin , Chen Jie , Wang Juan , Zhang Jieping , Lu Lixia , Jin Caixia , Xu Guo-Tong , Zhao Jingjun
Published: June 2021

Background

Systemic sclerosis (SSc) is a disease that features severe fibrosis of the skin and lacks effective therapy. Bone marrow mesenchymal stem cell (BMSC)-derived extracellular vesicles (EVs) are potential stem cell-based tools for the treatment of SSc.

Methods

BMSCs were isolated from the bone marrow of mice and identified with surface markers according to multilineage differentiation. EVs were isolated from the BMSC culture medium by ultracentrifugation and identified with a Nanosight NS300 particle size analyzer, transmission electron microscopy (TEM), and western blot. The microRNAs (miRNAs) of BMSC-derived EVs (BMSC-EVs) were studied via miRNA sequencing (miRNA-seq) and bioinformatic analysis. An SSc mouse model was established via subcutaneous bleomycin (BLM) injection, and the mice were treated with BMSCs or BMSC-derived EVs. Skin tissues were dissociated and analyzed with H&E staining, RNA sequencing (RNA-seq), western blot, and immunohistochemical staining.

Results

Evident pathological changes, like fibrosis and inflammation, were induced in the skin of BLM-treated mice. BMSCs and BMSC-EVs effectively intervened such pathological manifestations and disease processes in a very similar way. The effects of the BMSC-EVs were found to be caused by the miRNAs they carried, which were proven to be involved in regulating the proliferation and differentiation of multiple cell types and in multiple EV-related biological processes. Furthermore, TGF-β1-positive cells and α-SMA-positive myofibroblasts were significantly increased in the scleroderma skin of BLM-treated mice but evidently reduced in the scleroderma skin of the EV-treated SSc group. In addition, the numbers of mast cells and infiltrating macrophages and lymphocytes were evidently increased in the skin of BLM-treated mice but significantly reduced by EV treatment. In line with these observations, there were significantly higher mRNA levels of the inflammatory cytokines Il6, Il10, and Tnf-α in SSc mice than in control mice, but the levels decreased following EV treatment. Through bioinformatics analysis, the TGFβ and WNT signaling pathways were revealed to be closely involved in the pathogenic changes seen in mouse SSc, and these pathways could be therapeutic targets for treating the disease.

Conclusions

BMSC-derived EVs could be developed as a potential therapy for treating skin dysfunction in SSc, especially considering that they show similar efficacy to BMSCs but have fewer developmental regulatory requirements than cell therapy. The effects of EVs are generated by the miRNAs they carry, which alleviate SSc pathogenic changes by regulating the WNT and TGFβ signaling pathways.
Optimizing similarity factor of in vitro drug release profile for development of early stage formulation of drug using linear regression model
Authors: Sheth Tulsi Sagar , Acharya Falguni
Published: June 2021

The objective of this article is to optimize the similarity factor within immediate release (IR) and modified release (MR) of in vitro drug release profiles. The least square method is used to minimize the difference between empirical and regression curve fitting data of in vitro IR/MR drug release profiles. An estimation of percentage drug release at intermediate timepoints has been done to improve the similarity factor $f_{2}$

f
2

using linear curve fit method. In this study linear regression model is used to analyze the similarity factor $f_{2}$

f
2

for Nitrofurantoin MR Capsules, Venlafaxine HCl MR Tablets and Lurasidone IR Tablets in order to exhibit the significance as well as similarity owing to the consideration of extra intervening timepoints. This linear regression model may help pharmaceutical industries to examine the inside comparison of IR/MR in vitro drug release profile with few modifications in timepoint selection to improve similarity factor $f_{2}$

f
2

.
Synapse-specific Lrp4 mRNA enrichment requires Lrp4/MuSK signaling, muscle activity and Wnt non-canonical pathway
Authors: Jing Hongyang , Chen Peng , Hui Tiankun , Yu Zheng , Zhou Jin , Fei Erkang , Wang Shunqi , Ren Dongyan , Lai Xinsheng , Li Baoming
Published: June 2021

Background

The neuromuscular junction (NMJ) is a peripheral synapse critical to muscle contraction. Like acetylcholine receptors (AChRs), many essential proteins of NMJ are extremely concentrated at the postjunctional membrane. However, the mechanisms of synapse-specific concentration are not well understood; furthermore, it is unclear whether signaling molecules critical to NMJ formation and maintenance are also locally transcribed.

Results

We studied the β-gal activity encoded by a lacZ cassette driven by the promoter of the Lrp4 gene. As reported for Lrp4 mRNA, β-gal was in the central region in embryonic muscles and at the NMJ after its formation. However, β-gal was no longer in the central areas of muscle fibers in Lrp4 or MuSK mutant mice, indicating a requirement of Lrp4/MuSK signaling. This phenotype could be rescued by transgenic expression of LRP4 with a transmembrane domain but not soluble ECD in Lrp4 mutant mice. β-gal and AChR clusters were distributed in a broader region in lacZ/ECD than that of heterozygous lacZ/+ mice, indicating an important role of the transmembrane domain in Lrp4 signaling. Synaptic β-gal activity became diffused after denervation or treatment with µ-conotoxin, despite its mRNA was increased, indicating synaptic Lrp4 mRNA enrichment requires muscle activity. β-gal was also diffused in aged mice but became re-concentrated after muscle stimulation. Finally, Lrp4 mRNA was increased in C2C12 myotubes by Wnt ligands in a manner that could be inhibited by RKI-1447, an inhibitor of ROCK in Wnt non-canonical signaling. Injecting RKI-1447 into muscles of adult mice diminished Lrp4 synaptic expression.

Conclusions

This study demonstrates that synapse-specific enrichment of Lrp4 mRNA requires a coordinated interaction between Lrp4/MuSK signaling, muscle activity, and Wnt non-canonical signaling. Thus, the study provides a new mechanism for Lrp4 mRNA enrichment. It also provides a potential target for the treatment of NMJ aging and other NMJ-related diseases.
Relating environmental variables with aquatic community structure in an agricultural/urban coldwater stream
Authors: Myers Daniel T. L. , Rediske Richard R. , McNair James N. , Parker Aaron D. , Ogilvie E. Wendy
Published: June 2021

Background

Urban areas are often built along large rivers and surrounded by agricultural land. This may lead to small tributary streams that have agricultural headwaters and urbanized lower reaches. Our study objectives assessed are as follows: (1) landscape, geomorphic, and water quality variables that best explained variation in aquatic communities and their integrity in a stream system following this agricultural-to-urban land use gradient; (2) ways this land use gradient caused aquatic communities to differ from what would be expected for an idealized natural stream or other longitudinal gradients; and (3) whether the impacts of this land use gradient on aquatic communities would grow larger in a downstream direction through the agricultural and urban developments. Our study area was an impaired coldwater stream in Michigan, USA.

Results

Many factors structured the biological communities along the agricultural-to-urban land use gradient. Instream woody debris had the strongest relationship with EPT (Ephemeroptera, Plecoptera, and Trichoptera) abundance and richness and were most common in the lower, urbanized watershed. Fine streambed substrate had the strongest relationship with Diptera taxa and surface air breather macroinvertebrates and was dominant in agricultural headwaters. Fish community assemblage was influenced largely by stream flow and temperature regimes, while poor fish community integrity in lower urban reaches could be impacted by geomorphology and episodic urban pollution events. Scraping macroinvertebrates were most abundant in deforested, first-order agricultural headwaters, while EPT macroinvertebrate richness was the highest downstream of agricultural areas within the urban zone that had extensive forest buffers.

Conclusion

Environmental variables and aquatic communities would often not conform with what we would expect from an idealized natural stream. EPT richness improved downstream of agricultural areas. This shows promise for the recovery of aquatic systems using well-planned management in watersheds with this agricultural-to-urban land use pattern. Small patches of forest can be the key to conserving aquatic biodiversity in urbanized landscapes. These findings are valuable to an international audience of researchers and water resource managers who study stream systems following this common agricultural-to-urban land use gradient, the ecological communities of which may not conform with what is generally known about land use impacts to streams.