bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of rottlerin on astrocyte phenotype polarization after trimethyltin insult in the dentate gyrus of mice
Authors: Hwang Yeonggwang , Kim Hyoung-Chun , Shin Eun-Joo
Published: June 2022

Background

It has been demonstrated that reactive astrocytes can be polarized into pro-inflammatory A1 phenotype or anti-inflammatory A2 phenotype under neurotoxic and neurodegenerative conditions. Microglia have been suggested to play a critical role in astrocyte phenotype polarization by releasing pro- and anti-inflammatory mediators. In this study, we examined whether trimethyltin (TMT) insult can induce astrocyte polarization in the dentate gyrus of mice, and whether protein kinase Cδ (PKCδ) plays a role in TMT-induced astrocyte phenotype polarization.

Methods

Male C57BL/6 N mice received TMT (2.6 mg/kg, i.p.), and temporal changes in the mRNA expression of A1 and A2 phenotype markers were evaluated in the hippocampus. In addition, temporal and spatial changes in the protein expression of C3, S100A10, Iba-1, and p-PKCδ were examined in the dentate gyrus. Rottlerin (5 mg/kg, i.p. × 5 at 12-h intervals) was administered 3–5 days after TMT treatment, and the expression of A1 and A2 transcripts, p-PKCδ, Iba-1, C3, S100A10, and C1q was evaluated 6 days after TMT treatment.

Results

TMT treatment significantly increased the mRNA expression of A1 and A2 phenotype markers, and the increased expression of A1 markers remained longer than that of A2 markers. The immunoreactivity of the representative A1 phenotype marker, C3 and A2 phenotype marker, S100A10 peaked 6 days after TMT insult in the dentate gyrus. While C3 was expressed evenly throughout the dentate gyrus, S100A10 was highly expressed in the hilus and inner molecular layer. In addition, TMT insult induced microglial p-PKCδ expression. Treatment with rottlerin, a PKCδ inhibitor, decreased Iba-1 and C3 expression, but did not affect S100A10 expression, suggesting that PKCδ inhibition attenuates microglial activation and A1 astrocyte phenotype polarization. Consistently, rottlerin significantly reduced the expression of C1q and tumor necrosis factor-α (TNFα), which has been suggested to be released by activated microglia and induce A1 astrocyte polarization.

Conclusion

We demonstrated the temporal and spatial profiles of astrocyte polarization after TMT insult in the dentate gyrus of mice. Taken together, our results suggest that PKCδ plays a role in inducing A1 astrocyte polarization by promoting microglial activation and consequently increasing the expression of pro-inflammatory mediators after TMT insult.
Neuroprotective effects of ex vivo-expanded regulatory T cells on trimethyltin-induced neurodegeneration in mice
Authors: Park Seon-Young , Yang HyeJin , Ye Minsook , Liu Xiao , Shim Insop , Chang Young-Tae , Bae Hyunsu
Published: June 2022

Background

Trimethyltin (TMT) is a potent neurotoxicant that leads to hippocampal neurodegeneration. Regulatory T cells (Tregs) play an important role in maintaining the immune balance in the central nervous system (CNS), but their activities are impaired in neurodegenerative diseases. In this study, we aimed to determine whether adoptive transfer of Tregs, as a living drug, ameliorates hippocampal neurodegeneration in TMT-intoxicated mice.

Methods

CD4+CD25+Tregs were expanded in vitro and adoptively transferred to TMT-treated mice. First, we explored the effects of Tregs on behavioral deficits using the Morris water maze and elevated plus maze tests. Biomarkers related to memory formation, such as cAMP response element-binding protein (CREB), protein kinase C (PKC), neuronal nuclear protein (NeuN), nerve growth factor (NGF), and ionized calcium binding adaptor molecule 1 (Iba1) in the hippocampus were examined by immunohistochemistry after killing the mouse. To investigate the neuroinflammatory responses, the polarization status of microglia was examined in vivo and in vitro using real-time reverse transcription polymerase chain reaction (rtPCR) and Enzyme-linked immunosorbent assay (ELISA). Additionally, the inhibitory effects of Tregs on TMT-induced microglial activation were examined using time-lapse live imaging in vitro with an activation-specific fluorescence probe, CDr20.

Results

Adoptive transfer of Tregs improved spatial learning and memory functions and reduced anxiety in TMT-intoxicated mice. Additionally, adoptive transfer of Tregs reduced neuronal loss and recovered the expression of neurogenesis enhancing molecules in the hippocampi of TMT-intoxicated mice. In particular, Tregs inhibited microglial activation and pro-inflammatory cytokine release in the hippocampi of TMT-intoxicated mice. The inhibitory effects of TMT were also confirmed via in vitro live time-lapse imaging in a Treg/microglia co-culture system.

Conclusions

These data suggest that adoptive transfer of Tregs ameliorates disease progression in TMT-induced neurodegeneration by promoting neurogenesis and modulating microglial activation and polarization.
The impact of genetic manipulation of laminin and integrins at the blood–brain barrier
Authors: Halder Sebok K. , Sapkota Arjun , Milner Richard
Published: June 2022

Blood vessels in the central nervous system (CNS) are unique in having high electrical resistance and low permeability, which creates a selective barrier protecting sensitive neural cells within the CNS from potentially harmful components in the blood. The molecular basis of this blood–brain barrier (BBB) is found at the level of endothelial adherens and tight junction protein complexes, extracellular matrix (ECM) components of the vascular basement membrane (BM), and the influence of adjacent pericytes and astrocyte endfeet. Current evidence supports the concept that instructive cues from the BBB ECM are not only important for the development and maturation of CNS blood vessels, but they are also essential for the maintenance of vascular stability and BBB integrity. In this review, we examine the contributions of one of the most abundant ECM proteins, laminin to BBB integrity, and summarize how genetic deletions of different laminin isoforms or their integrin receptors impact BBB development, maturation, and stability.
Self-efficacy in breastfeeding predicts how mothers perceive their preterm infant’s state-regulation
Authors: Rosenblad Andreas Karlsson , Funkquist Eva-Lotta
Published: June 2022

Background

Mothers of preterm infants often perceive the infant as having problems with crying, sleeping and feeding, sometimes summarised as ‘state-regulation’. Breastfeeding rates are lower among preterm infants, and the mother’s self-efficacy in breastfeeding is central to understanding which mothers are going to breastfeed their infants. We have previously shown that mothers with higher self-efficacy have an easier time adapting to the infant and in this study we hypothesised that the degree of self-efficacy also is associated with how difficult the mother believes it is to take care of the infant. The aim of this study was to investigate whether the late preterm infant’s mother’s self-efficacy in breastfeeding was associated with how the mother experienced her infant’s state-regulation at three months of corrected age.

Methods

The study had a prospective and longitudinal design with a consecutive data collection through questionnaires. Inclusion criteria were mothers (n = 105) with a singleton infant born between 34 + 0 and 36 + 6 weeks of gestation. At term age, the mothers completed the Breastfeeding Self-efficacy Scale-Short Form and at the three months corrected age follow-up, mothers completed the Infant state-regulation index: questions related to whether the infant had difficulties with colic, persistent crying, comforting, falling asleep, sleep problems, breastfeeding, eating or poor weight gain.

Results

The analyses showed that being an older mother, perceiving breastfeeding support, and having a higher breastfeeding self-efficacy were all significantly associated with identifying the infant as having better state-regulation.

Conclusions

There was an association between mothers’ self-efficacy in breastfeeding and her perceptions of how good state-regulation the infant had. This is an important finding, as self-efficacy is a manageable factor that could positively affect how the mother perceives taking care of her infant. Clinical implication: Improved self-efficacy is known to be an important factor in increased breastfeeding prevalence and healthcare professionals should also target mother’s self-efficacy in breastfeeding to improve mother-infant relationship.
Laser-based molecular delivery and its applications in plant science
Authors: Heinemann Dag , Zabic Miroslav , Terakawa Mitsuhiro , Boch Jens
Published: June 2022

Lasers enable modification of living and non-living matter with submicron precision in a contact-free manner which has raised the interest of researchers for decades. Accordingly, laser technologies have drawn interest across disciplines. They have been established as a valuable tool to permeabilize cellular membranes for molecular delivery in a process termed photoinjection. Laser-based molecular delivery was first reported in 1984, when normal kidney cells were successfully transfected with a frequency-multiplied Nd:YAG laser. Due to the rapid development of optical technologies, far more sophisticated laser platforms have become available. In particular, near infrared femtosecond (NIR fs) laser sources enable an increasing progress of laser-based molecular delivery procedures and opened up multiple variations and applications of this technique.

This review is intended to provide a plant science audience with the physical principles as well as the application potentials of laser-based molecular delivery. The historical origins and technical development of laser-based molecular delivery are summarized and the principle physical processes involved in these approaches and their implications for practical use are introduced. Successful cases of laser-based molecular delivery in plant science will be reviewed in detail, and the specific hurdles that plant materials pose will be discussed. Finally, we will give an outlook on current limitations and possible future applications of laser-based molecular delivery in the field of plant science.
Computational fluid dynamics simulation experimental verification and analysis of droplets deposition behaviour on vibrating pear leaves
Authors: Cao Yubin , Xi Te , Xu Lujiang , Qiu Wei , Guo Hongbin , Lv Xiaolan , Li Chao
Published: June 2022

Background

The interaction between canopy and droplets is very important in the process of crop spraying. During the actual air-assisted application process, air-mist flow inevitably disturbs the leaves before droplets reaching them, which will also affect the final deposition state of the droplets on the leaf. Currently, researches on the interaction between droplets and the target leaf surface mainly focuses on the deposition behaviour on the surface of stationary target leaves rather than the dynamic leaves. Therefore, the deposition characteristics after the collision between the droplets and dynamic leaves are important for practical application and worth further study.

Results

Computational fluid dynamics simulations were performed to characterise the surface roughness, contact angle, and mechanical vibration. The interaction platform between the droplet and the vibrating pear leaf was built for experimental verification under laboratory conditions. The simulation results are in good agreement with the experimental results, which revealed the main reason for the droplet spreading and sliding was the inertial force generated by the relative velocity. It also indicated that the pear leaf vibration can improve the deposition of low-velocity and small droplets, which is different from that of static pear leaves.

Conclusion

The deposition effect of droplets in vibrating pear leaves was investigated. This study also provides a simulation method for the collision between a vibrating leaf and moving droplets, and provides reference for the study of droplet deposition characteristics under the vibration of fruit trees.
Identification of safe channels for screws in the anterior pelvic ring fixation system
Authors: Liu Lin , Fan Shicai , Zeng Donggui , Song Hui , Zeng Letian , Wen Xiangyuan , Jin Dadi
Published: June 2022

Background

Minimally invasive surgery for pelvic fracture using anterior ring internal fixator system is increasing gradually, and the way to insert the fixation screws in the fixation system is the key technical points of the method. However, there have been few studies on insertion of fixation screws for the anterior pelvic ring internal fixator system.

Objective

To identify safe channels for fixation screws in the anterior pelvic fixator system and provide the anatomical basis for insertion of fixation screws in clinical operation.

Methods

Screw insertion was simulated into a total of 40 pelvic finite element models as well as 16 fresh pelvic specimens, and the channel parameters were measured.

Results

Finite elements (male, female) include: screws in ilium: length 114.4 ± 4.1 and 107.6 ± 8.3 mm, respectively; diameter 11.7 ± 0.5 and 10.0 ± 0.6 mm, distance between screw and anterior inferior iliac spine: 5.5 ± 1.0 and 5.6 ± 1.0 mm, angle of coronal plane 55.8° ± 2.4° and 50.6° ± 3.1°, angle of sagittal plane 26.6° ± 1.0° and 24.5° ± 1.9° and angle of horizontal plane 64.9 ± 3.7 and 58.1 ± 3.1; screws in pubis: length 47.0 ± 2.0 and 39.8 ± 3.9 mm, diameter 7.1 ± 0.4 and 6.1 ± 0.4 mm. Specimens (male, female) include: distance between screw and anterior inferior iliac spine: 5.5 ± 0.5 and 5.6 ± 0.7 mm, angle of coronal plane 55.9° ± 1.3° and 50.7° ± 1.5°, angle of sagittal plane 26.7° ± 0.5° and 24.1° ± 0.9° and angle of horizontal plane 64.8° ± 0.6° and 58.8° ± 0.8°. In the comparison between female and male in each group, differences in distances between screws and anterior inferior iliac spine and median line of symphysis pubis (P > 0.05) were not statistically significant; differences in the remaining parameters were statistically significant (P < 0.05).

Conclusions

If surgeons paid attention to sex differences, select screws of appropriate diameter and length and hold the insertion position and direction, screws in the anterior pelvic ring fixation system could be safely inserted.
Fibrin glue does not assist migration and proliferation of chondrocytes in collagenic membranes: an in vitro study
Authors: Migliorini Filippo , Prinz Julia , Maffulli Nicola , Eschweiler Jörg , Weber Christian , Lecoutrier Sophie , Hildebrand Frank , Greven Johannes , Schenker Hanno
Published: June 2022

Background

Some authors secured the membrane during matrix-induced autologous chondrocyte implantation (mACI) with fibrin glue or did not use a formal fixation. The real impact of fibrin glue addition on chondrocytes migration and proliferation has not yet been clarified. This study evaluated the impact of fibrin glue on a chondrocyte loaded collagenic membrane.

Methods

A resorbable collagen I/III porcine derived membrane commonly employed in AMIC was used for all experiments. Chondrocytes from three difference donors were used. At 1-, 2-, 3-, 4-, 6-, and at 8-week the membranes were embedded in Mounting Medium with Dapi (ABCAM, Cambridge, UK). The Dapi contained in the mounting medium ties the DNA of the cell nucleus and emits a blue fluorescence. In this way, the spreading of the cells in the membrane can be easily monitored. The outcomes of interest were to evaluate (1) cell migration and (2) cell proliferation within the porous membrane layer. DAPI/nuclei signals were analysed with fluorescence microscope under a magnification of 100-fold.

Results

The no-fibrin group demonstrated greater migration of the cells within the membrane. Although migration resulted higher in the no-fibrin group at every follow-up, this difference was significant only at week 1 (P < 0.001), 2 (P = 0.004), and 3 (P = 0.03). No difference was found at week 3, 6, and 8. The no-fibrin group demonstrated greater proliferation of the chondrocytes within the membrane. These differences were significant at week 4 (P < 0.0001), 6 (P < 0.0001), 8 (P < 0.0001).

Conclusion

The use of fibrin glue over a resorbable membrane leads to lower in vitro proliferation and migration of chondrocytes.
Cell therapies for chondral defects of the talus: a systematic review
Authors: Migliorini Filippo , Eschweiler Jörg , Goetze Christian , Pastor Torsten , Giorgino Riccardo , Hildebrand Frank , Maffulli Nicola
Published: June 2022

Background

This systematic review investigated the efficacy and safety of surgical procedures augmented with cell therapies for chondral defects of the talus.

Methods

The present systematic review was conducted according to the 2020 PRISMA guidelines. PubMed, Google scholar, Embase, and Scopus databases were accessed in March 2022. All the clinical trials investigating surgical procedures for talar chondral defects augmented with cell therapies were accessed. The outcomes of interest were to investigate whether surgical procedures augmented with cell therapies promoted improvement in patients reported outcomes measures (PROMs) with a tolerable rate of complications.

Results

Data from 477 procedures were retrieved. At a mean follow-up of 34.8 ± 9.7 months, the Visual Analogic Scale (VAS) improved of 4.4/10 (P = 0.002) and the American Orthopaedic Foot and Ankle Score (AOFAS) of 31.1/100 (P = 0.0001) points. No improvement was found in Tegner score (P = 0.4). Few articles reported data on complications. At last follow-up, the rate of reoperation and failure were 0.06% and 0.03%, respectively. No graft delamination or hypertrophy was observed.

Conclusion

The current evidence suggests that cell therapies may be effective and safe to enhance surgical procedures for chondral defects of the talus. These results should be considered within the limitations of the present study. The current literature should be enriched with randomized controlled clinical trials with larger population size and longer follow-up.
An empirical model for estimating daily atmospheric column-averaged CO2 concentration above São Paulo state, Brazil
Authors: da Costa Luis Miguel , de Araújo Santos Gustavo André , Panosso Alan Rodrigo , de Souza Rolim Glauco , La Scala Newton
Published: June 2022

Background

The recent studies of the variations in the atmospheric column-averaged CO2 concentration ($${\text{X}}_{{{\text{CO}}_{{2}} }}$$

X

CO
2

) above croplands and forests show a negative correlation between $${\text{X}}_{{{\text{CO}}_{{2}} }}$$

X

CO
2

and Sun Induced Chlorophyll Fluorescence (SIF) and confirmed that photosynthesis is the main regulator of the terrestrial uptake for atmospheric CO2. The remote sensing techniques in this context are very important to observe this relation, however, there is still a time gap in orbital data, since the observation is not daily. Here we analyzed the effects of several variables related to the photosynthetic capacity of vegetation on $${\text{X}}_{{{\text{CO}}_{{2}} }}$$

X

CO
2

above São Paulo state during the period from 2015 to 2019 and propose a daily model to estimate the natural changes in atmospheric CO2.

Results

The data retrieved from the Orbiting Carbon Observatory-2 (OCO-2), NASA-POWER and Application for Extracting and Exploring Analysis Ready Samples (AppEEARS) show that Global Radiation (Qg), Sun Induced Chlorophyll Fluorescence (SIF) and, Relative Humidity (RH) are the most significant factors for predicting the annual $${\text{X}}_{{{\text{CO}}_{{2}} }}$$

X

CO
2

cycle. The daily model of $${\text{X}}_{{{\text{CO}}_{{2}} }}$$

X

CO
2

estimated from Qg and RH predicts daily $${\text{X}}_{{{\text{CO}}_{{2}} }}$$

X

CO
2

with root mean squared error of 0.47 ppm (the coefficient of determination is equal to 0.44, p < 0.01).

Conclusion

The obtained results imply that a significant part of daily $${\text{X}}_{{{\text{CO}}_{{2}} }}$$

X

CO
2

variations could be explained by meteorological factors and that further research should be done to quantify the effects of the atmospheric transport and anthropogenic emissions.
Factors impacting antenatal care utilization: a systematic review of 37 fragile and conflict-affected situations
Authors: Alibhai Kameela Miriam , Ziegler Bianca R. , Meddings Louise , Batung Evans , Luginaah Isaac
Published: June 2022

Background

It is estimated that over 930 million people live in fragile and conflict-affected situations (FCAS) worldwide. These regions, characterized by violence, civil unrest, and war, are often governed by corrupt administrations who are unwilling to provide their citizens with basic human rights. Individuals living in FCAS face health inequities; however, women are disproportionally affected and face additional barriers to accessing sexual and reproductive services, including antenatal care (ANC). This systematic review aims to identify the factors that impact ANC usage in the 37 countries or regions classified as FCAS in 2020 by The World Bank.

Methods

Using the PRISMA guidelines, a systematic search of five databases (SCOPUS, Web of Science, PubMed, EMBASE, and CINAHL) was conducted. Results were limited to human studies, written in English, and published between January 2002 and January 2022. Studies that identified factors affecting utilization of ANC or maternal health services were included for review and critically appraised using the National Institute of Health’s Quality Assessment Tools. Findings were summarized using a narrative synthesis approach.

Results

The database search yielded 26,527 studies. After title, abstract and full-text review, and exclusion of duplicate articles, 121 studies remained. Twenty-eight of the 37 FCAS were represented in the included studies. The studies highlighted that women in FCAS’ are still not meeting the World Health Organization’s 2002 recommendation of four ANC visits during pregnancy, a recommendation which has since been increased to eight visits. The most cited factors impacting ANC were socioeconomic status, education, and poor quality of ANC. Despite all studies being conducted in conflict-affected regions, only nine studies explicitly identified conflict as a direct barrier to accessing ANC.

Conclusion

This review demonstrated that there is a paucity in the literature examining the direct and indirect impacts of conflict on ANC utilization. Specifically, research should be conducted in the nine FCAS that are not currently represented in the literature. To mitigate the barriers that prevent utilization of maternal health services identified in this review, policy makers, women utilizing ANC, and global organizations should attempt to collaborate to enact policy change at the local level.
Missing in action: the right to the highest attainable standard of mental health care
Authors: Song Yun Ju C. , Rosenberg Sebastian , Smith Belinda , Occhipinti Jo-An , Mendoza John , Freebairn Louise , Skinner Adam , Hickie Ian B.
Published: June 2022

Background

The right to the highest attainable standard of mental health remains a distant goal worldwide. The Report of the UN Special Rapporteur on the right of all people to enjoyment of the highest attainable standard of physical and mental health pleaded the urgent need for governments to act through appropriate laws and policies. We argue that Australia is in breach of international obligations, with inadequate access to mental health services, inconsistent mental health legislation across jurisdictions and ongoing structural (systematic) and individual discrimination.

Discussion

Inadequate access to mental health services is a worldwide phenomenon. Australia has committed to international law obligations under the Convention on the Rights of Persons with Disabilities (CRPD) to ‘promote, protect and ensure the full and equal enjoyment of all human rights and fundamental freedoms by all persons with disability, with respect to their inherent dignity’. This includes people with mental health impairment and this convention includes the right to ‘the highest attainable standard of mental health’. Under the Australian Constitution, ratification of this convention enables the national government to pass laws to implement the convention obligations, and such national laws would prevail over any inconsistent state (or territory) laws governing mental health service provision.

The authors argue that enabling positive rights through legislation and legally binding mental health service standards may facilitate enhanced accountability and enforcement of such rights. These steps may support critical key stakeholders to improve the standards of mental health service provision supported by the implementation of international obligations, thereby accelerating mental health system reform. Improved legislation would encourage better governance and the evolution of better services, making mental health care more accessible, without structural or individual discrimination, enabling all people to enjoy the highest attainable standard of health.
Foretinib can overcome common on-target resistance mutations after capmatinib/tepotinib treatment in NSCLCs with MET exon 14 skipping mutation
Authors: Fujino Toshio , Suda Kenichi , Koga Takamasa , Hamada Akira , Ohara Shuta , Chiba Masato , Shimoji Masaki , Takemoto Toshiki , Soh Junichi , Mitsudomi Tetsuya
Published: June 2022

Background

Capmatinib and tepotinib are guideline-recommended front-line treatments for non-small-cell lung cancer (NSCLC) patients with MET exon 14 skipping mutations (METex14). However, the emergence of acquired resistance to capmatinib/tepotinib is almost inevitable partially due to D1228X or Y1230X secondary mutations of the MET. In this study, we explored agents that are active against both D1228X and Y1230X MET to propose an ideal sequential treatment after capmatinib/tepotinib treatment failure in NSCLC patients with METex14.

Methods

The inhibitory effects of 300 drugs, including 33 MET-TKIs, were screened in Ba/F3 cells carrying METex14 plus MET D1228A/Y secondary mutations. The screen revealed four-candidate type II MET-TKIs (altiratinib, CEP-40783, foretinib and sitravatinib). Therefore, we performed further growth inhibitory assays using these four MET-TKIs plus cabozantinib and merestinib in Ba/F3 cells carrying MET D1228A/E/G/H/N/V/Y or Y1230C/D/H/N/S secondary mutations. We also performed analyses using Hs746t cell models carrying METex14 (with mutant allele amplification) with/without D1228X or Y1230X in vitro and in vivo to confirm the findings. Furthermore, molecular dynamics (MD) simulations were carried out to examine differences in binding between type II MET-TKIs.

Results

All 6 type II MET-TKIs were active against Y1230X secondary mutations. However, among these 6 agents, only foretinib showed potent activity against D1228X secondary mutations of the MET in the Ba/F3 cell and Hs746t in vitro model and Hs746t in vivo model, and CEP-40783 and altiratinib demonstrated some activity. MD analysis suggested that the long tail of foretinib plays an important role in binding D1228X MET through interaction with a residue at the solvent front (G1163). Tertiary G1163X mutations, together with L1195F/I and F1200I/L, occurred as acquired resistance mechanisms to the second-line treatment foretinib in Ba/F3 cell models.

Conclusions

The type II MET-TKI foretinib may be an appropriate second-line treatment for NSCLCs carrying METex14 after campatinib/tepotinib treatment failure by secondary mutations at residue D1228 or Y1230.
Essential role for STAT3/FOXM1/ATG7 signaling-dependent autophagy in resistance to Icotinib
Authors: Lyu Xin , Zeng Lizhong , Shi Jie , Ming Zongjuan , Li Wei , Liu Boxuan , Chen Yang , Yuan Bo , Sun Ruiying , Yuan Jingyan , Zhao Nannan , Yang Xia , Chen Guoan , Yang Shuanying
Published: June 2022

Background

The contribution of autophagy to cancer therapy resistance remains complex, mainly owing to the discrepancy of autophagy mechanisms in different therapy. However, the potential mechanisms of autophagy-mediated resistance to icotinib have yet to be elucidated.

Methods

The effect of autophagy in icotinib resistance was examined using a series of in vitro and in vivo assays. The results above were further verified in biopsy specimens of lung cancer patients before and after icotinib or gefitinib treatment.

Results

Icotinib increased ATG3, ATG5, and ATG7 expression, but without affecting Beclin-1, VPS34 and ATBG14 levels in icotinib-resistant lung cancer cells. Autophagy blockade by 3-MA or silencing Beclin-1 had no effects on resistance to icotinib. CQ effectively restored lung cancer cell sensitivity to icotinib in vitro and in vivo. Notably, aberrantly activated STAT3 and highly expressed FOXM1 were required for autophagy induced by icotinib, without the involvement of AMPK/mTOR pathway in this process. Alterations of STAT3 activity using genetic and/or pharmacological methods effectively affected FOXM1 and ATG7 levels increased by icotinib, with altering autophagy and icotinib-mediated apoptosis in resistant cells. Furthermore, silencing FOXM1 impaired up-regulated ATG7 induced by STAT3-CA and icotinib. STAT3/FOXM1 signalling blockade also reversed resistance to icotinib in vivo. Finally, we found a negative correlation between STAT3/FOXM1/ATG7 signalling activity and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) treatment efficacy in patients undergoing EGFR-TKIs treatment.

Conclusions

Our findings support that STAT3/FOXM1/ATG7 signalling-induced autophagy is a novel mechanism of resistance to icotinib, and provide insights into potential clinical values of ATG7-dependent autophagy in icotinib treatment.

Graphical abstract
The immune landscape of solid pediatric tumors
Authors: Sherif Shimaa , Roelands Jessica , Mifsud William , Ahmed Eiman I. , Raynaud Christophe M. , Rinchai Darawan , Sathappan Abbirami , Maaz Ata , Saleh Ayman , Ozer Erdener , Fakhro Khalid A. , Mifsud Borbala , Thorsson Vésteinn , Bedognetti Davide , Hendrickx Wouter R. L.
Published: June 2022

Background

Large immunogenomic analyses have demonstrated the prognostic role of the functional orientation of the tumor microenvironment in adult solid tumors, this variable has been poorly explored in the pediatric counterpart.

Methods

We performed a systematic analysis of public RNAseq data (TARGET) for five pediatric tumor types (408 patients): Wilms tumor (WLM), neuroblastoma (NBL), osteosarcoma (OS), clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RT). We assessed the performance of the Immunologic Constant of Rejection (ICR), which captures an active Th1/cytotoxic response. We also performed gene set enrichment analysis (ssGSEA) and clustered more than 100 well characterized immune traits to define immune subtypes and compared their outcome.

Results

A higher ICR score was associated with better survival in OS and high risk NBL without MYCN amplification but with poorer survival in WLM. Clustering of immune traits revealed the same five principal modules previously described in adult tumors (TCGA). These modules divided pediatric patients into six immune subtypes (S1-S6) with distinct survival outcomes. The S2 cluster showed the best overall survival, characterized by low enrichment of the wound healing signature, high Th1, and low Th2 infiltration, while the reverse was observed in S4. Upregulation of the WNT/Beta-catenin pathway was associated with unfavorable outcomes and decreased T-cell infiltration in OS.

Conclusions

We demonstrated that extracranial pediatric tumors could be classified according to their immune disposition, unveiling similarities with adults’ tumors. Immunological parameters might be explored to refine diagnostic and prognostic biomarkers and to identify potential immune-responsive tumors.
NCAPD3 enhances Warburg effect through c-myc and E2F1 and promotes the occurrence and progression of colorectal cancer
Authors: Jing Zuolei , Liu Qianmei , He Xinyuan , Jia Zhirong , Xu Zhizhong , Yang Bolin , Liu Ping
Published: June 2022

Background

NCAPD3 is one of the three non-SMC subunits of condensin II complex, which plays an important role in the chromosome condensation and segregation during mitosis. Notably, elevated levels of NCAPD3 are found in many somatic cancers. However, the clinical role, biological functions of NCAPD3 in cancers especially in colorectal cancer (CRC) and the underlying molecular mechanisms remain poorly elucidated.

Methods

Clinical CRC and adjacent normal tissues were used to confirm the expression of NCAPD3. The association of NCAPD3 expression with clinicopathological characteristics and patient outcomes were analyzed by using online database. In vivo subcutaneous tumor xenograft model, NCAPD3 gene knockout following azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced tumor mouse model, Co-IP, western blot, qRT-PCR, IHC, ChIP assays and cell functional assays were used to investigate the biological functions of NCAPD3 in CRC and the underlying molecular mechanisms.

Results

NCAPD3 was overexpressed in CRC tissues and positively correlated with poor prognosis of CRC patients. NCAPD3 knockout suppressed CRC development in AOM/DSS induced and xenograft mice models. Moreover, we found that NCAPD3 promoted aerobic glycolysis in CRC. Mechanistically, NCAPD3 up-regulated the level of c-Myc and interacted with c-Myc to recruit more c-Myc to the gene promoter of its downstream glycolytic regulators GLUT1, HK2, ENO1, PKM2 and LDHA, and finally enhanced cellular aerobic glycolysis. Also, NCAPD3 increased the level of E2F1 and interacted with E2F1 to recruit more E2F1 to the promoter regions of PDK1 and PDK3 genes, which resulted in the inhibition of PDH activity and TCA cycle.

Conclusions

Our data demonstrated that NCAPD3 promoted glucose metabolism reprogramming and enhanced Warburg effect in colorectal tumorigenesis and CRC progression. These findings reveal a novel mechanism underlying NCAPD3 mediated CRC cell growth and provide new targets for CRC treatment.
Culicoides species community composition and feeding preferences in two aquatic ecosystems in northern Spain
Authors: González Mikel A. , Goiri Fátima , Prosser Sean W. J. , Cevidanes Aitor , Hernández-Triana Luis M. , Barandika Jesús F. , Hebert Paul D. N. , García-Pérez Ana L.
Published: June 2022

Background

Aquatic ecosystems provide breeding sites for blood-sucking insects such asCulicoidesbiting midges (Diptera: Ceratopogonidae), but factors affecting their distribution and host choice are poorly understood. A study was undertaken at two nature reserves in northern Spain to examine the abundance, species composition, population dynamics and feeding patterns of biting midges between 2018 and 2019.

Methods

Culicoideswere captured by light suction traps baited with CO2and by sweep netting vegetation. Blood meals and species identification of blood-fed specimens were determined using cytochromecoxidase I subunit (COI) DNA barcoding. Multivariate generalized linear models were used to evaluate the associations between the abundance ofCulicoides, the species richness and other parameters.

Results

The 4973 identified specimens comprised 28 species ofCulicoides. These included two species reported for the first time in northern Spain, thus raising to 54 the number ofCulicoidesspecies described in the region. Specimens of all 28 species and 99.6% of the total specimens collected were caught in suction traps, while sweep netting vegetation revealed just 11 species and 0.4% of the total specimens. Midge abundance peaked in June/early July, with five species comprising > 80% of the captures:Culicoides alazanicus(24.9%),Culicoides griseidorsum(20.3%),Culicoides poperinghensis(16.2%),Culicoides kibunensis(10.7%) andCulicoides clastrieri(9.6%). DNA barcode analysis of blood meals from eightCulicoidesspecies revealed that they fed on 17 vertebrate species (3 mammals and 14 birds). Species in the subgenusAvaritiawere primarily ornithophilic, except forC. griseidorsumandC. poperinghensis.Host DNA from blood meals was successfully amplified from 75% of blood-fed females. A pictorial blood meal digestion scale is provided to accurately assess the blood-fed status of femaleCulicoides.

Conclusions

The large number of different blood meal sources identified in the midges captured in this study signals the likely importance of wild birds and mammals (e.g. red deer and wild boar) as reservoir/amplifying hosts for pathogens. Available hosts are more exposed to being bitten by biting midge populations in aquatic ecosystems in late spring and early summer.
The 2021–2022 position of Brazilian Diabetes Society on diabetic kidney disease (DKD) management: an evidence-based guideline to clinical practice. Screening and treatment of hyperglycemia, arterial hypertension, and dyslipidemia in the patient with DKD
Authors: de Sá João Roberto , Rangel Erika Bevilaqua , Canani Luis Henrique , Bauer Andrea Carla , Escott Gustavo Monteiro , Zelmanovitz Themis , Bertoluci Marcello Casaccia , Silveiro Sandra Pinho
Published: June 2022

Background

Diabetic kidney disease is the leading cause of end-stage renal disease and is associated with increased morbidity and mortality. This review is an authorized literal translation of part of the Brazilian Diabetes Society (SBD) Guidelines 2021–2022. This evidence-based guideline provides guidance on the correct management of Diabetic Kidney Disease (DKD) in clinical practice.

Methods

The methodology was published elsewhere in previous SBD guidelines and was approved by the internal institutional Steering Committee for publication. Briefly, the Brazilian Diabetes Society indicated 14 experts to constitute the Central Committee, designed to regulate methodology, review the manuscripts, and make judgments on degrees of recommendations and levels of evidence. SBD Renal Disease Department drafted the manuscript selecting key clinical questions to make a narrative review using MEDLINE via PubMed, with the best evidence available including high-quality clinical trials, metanalysis, and large observational studies related to DKD diagnosis and treatment, by using the MeSH terms [diabetes], [type 2 diabetes], [type 1 diabetes] and [chronic kidney disease].

Results

The extensive review of the literature made by the 14 members of the Central Committee defined 24 recommendations. Three levels of evidence were considered: A. Data from more than 1 randomized clinical trial or 1 metanalysis of randomized clinical trials with low heterogeneity (I2 < 40%). B. Data from metanalysis, including large observational studies, a single randomized clinical trial, or a pre-specified subgroup analysis. C: Data from small or non-randomized studies, exploratory analyses, or consensus of expert opinion. The degree of recommendation was obtained based on a poll sent to the panelists, using the following criteria: Grade I: when more than 90% of agreement; Grade IIa 75–89% of agreement; IIb 50–74% of agreement, and III, when most of the panelist recommends against a defined treatment.

Conclusions

To prevent or at least postpone the advanced stages of DKD with the associated cardiovascular complications, intensive glycemic and blood pressure control are required, as well as the use of renin–angiotensin–aldosterone system blocker agents such as ARB, ACEI, and MRA. Recently, SGLT2 inhibitors and GLP1 receptor agonists have been added to the therapeutic arsenal, with well-proven benefits regarding kidney protection and patients’ survival.
Ion content, antioxidant enzyme activity and transcriptional response under salt stress and recovery condition in the halophyte grass Aeluropus littoralis
Authors: Hashemipetroudi Seyyed Hamidreza , Ahmadian Gholamreza , Fatemi Farzaneh , Nematzadeh Ghorbanali , Yamchi Ahad , Kuhlmann Markus
Published: June 2022

Objective

In contrast to glycophytes, halophyte plants have evolved unique morphological and physiological mechanisms to deal with abiotic stress. This study presents the physiological responses of Aeluropus littoralis, a halophyte grass, to salt stress and recovery conditions on the molecular level.

Results

Elemental analysis showed that Na+ concentration increased in the analyzed tissue during salt stress application, and declined at recovery condition. With the exception of root tissue, comparable trends of K+, Ca2+, and Mg2+ concentrations were observed (decreased during salt stress, increased during recovery). Salinity led to an increase in total chlorophyll (Chl), Chl a, and carotenoids content, while Chl b content decreased. The level of the proline amino acid associated with drought and salt stress was increased. Here APX, POD, and SOD activity were strongly detectable in roots and reduced later under recovery conditions. RT-qPCR revealed up-regulation of antioxidant genes at S1 and S3 in the root but down-regulation in recovery conditions. This study found a significant halophyte index for understanding the processes of salinity tolerance in A. littoralis. These findings may provide insight into the role of antioxidant enzymes during salt stress and the mechanism underlying the plant's response to stress.
Clarifying SABA overuse: Translating Canadian Thoracic Society guidelines into clinical practice
Authors: Ellis Anne K. , Foran Vanessa , Kaplan Alan , Mitchell Patrick D.
Published: June 2022

Patients with asthma frequently over rely on short-acting beta-agonists (SABA) to treat acute symptoms. This can adversely impact quality of life and increase the risk of exacerbations. SABA overuse is also associated with an increased risk of mortality. In their 2021 update on the diagnosis and management of mild asthma, the Canadian Thoracic Society (CTS) newly recommended that a combination inhaled corticosteroid (ICS) and long-acting beta-agonist, specifically budesonide/formoterol, may be used as-needed (PRN) as an alternative reliever to SABA. The CTS developed an algorithm as a guide for deciding for whom PRN budesonide/formoterol versus PRN SABA is appropriate as a reliever. While the CTS algorithm provides necessary and precise guidance, the somewhat complicated requirements for determining control and exacerbation risk may still end up leaving some patients at-risk of SABA overreliance. This communication simplifies the reliever decision algorithm developed by the CTS for application in daily practice. A 30-s evaluation of 2 simple questions related to reliever use can usually accurately assess if a patient’s asthma is controlled: How many SABA canisters do you use a year AND how many times do you use SABA a week? If the patient indicates use of > 2 SABA canisters per year or > 2 administrations of SABA per week for any reason, the patient does not have controlled asthma and PRN SABA is not an appropriate treatment regimen. Similarly, for patients using PRN ICS/formoterol, more than 2 administrations per week indicates a clinical review and reevaluation of their management, including augmentation. An education process is essential to inform patients, caregivers, and healthcare providers that overuse of any reliever is not acceptable and is potentially harmful.
Large multicenter randomized trials in autism: key insights gained from the balovaptan clinical development program
Authors: Jacob Suma , Anagnostou Evdokia , Hollander Eric , Jou Roger , McNamara Nora , Sikich Linmarie , Tobe Russell , Murphy Declan , McCracken James , Ashford Elizabeth , Chatham Christopher , Clinch Susanne , Smith Janice , Sanders Kevin , Murtagh Lorraine , Noeldeke Jana , Veenstra-VanderWeele Jeremy
Published: June 2022

Background

Autism spectrum disorder (ASD) is a common and heterogeneous neurodevelopmental condition that is characterized by the core symptoms of social communication difficulties and restricted and repetitive behaviors. At present, there is an unmet medical need for therapies to ameliorate these core symptoms in order to improve quality of life of autistic individuals. However, several challenges are currently faced by the ASD community relating to the development of pharmacotherapies, namely in the conduct of clinical trials. Balovaptan is a V1a receptor antagonist that has been investigated to improve social communication difficulties in individuals with ASD. In this viewpoint, we draw upon our recent first-hand experiences of the balovaptan clinical development program to describe current challenges of ASD trials.

Discussion points

The balovaptan trials were conducted in a wide age range of individuals with ASD with the added complexities associated with international trials. When summarizing all three randomized trials of balovaptan, a placebo response was observed across several outcome measures. Placebo response was predicted by greater baseline symptom severity, online recruitment of participants, and less experienced or non-academic trial sites. We also highlight challenges relating to selection of outcome measures in ASD, the impact of baseline characteristics, and the role of expectation bias in influencing trial results.

Conclusion

Taken together, the balovaptan clinical development program has advanced our understanding of the key challenges facing ASD treatment research. The insights gained can be used to inform and improve the design of future clinical trials with the collective aim of developing efficacious therapies to support individuals with ASD.
Predictors of cord blood unit cell content in a volume unrestricted large series collections: a chance for a fast and cheap multiparameter selection model
Authors: Fumarola Stefania , Lucarini Alessandra , Lucchetti Giovanna , Piroli Luana , Pierelli Luca
Published: June 2022

Background

Cord blood plays a very important role in stem cell transplantation and therapy with an emerging implication also in regenerative medicine. The number of cells available in a single cord blood unit (CBU), in particular, the CD34+ and total nucleated cell (TNC) content influences the transplantation clinical outcome. We analysed a very large series of CBUs, collected for private banking without any specific volume restriction, to deeply investigate the best predictors of cord blood stem cells content.

Methods

Maternal and neonatal clinic laboratory data of a total 2583 UCBs were obtained from the InScientiaFides cord blood bank based in Republic of San Marino. Univariate and multivariate analysis were conducted to better interpret the data and to build a predictive model to select, the CBU with high CD34+ content.

Results

Our univariate analysis shows that seasonality and the geographical area affects the quality of umbilical cord blood. Gestational age, babie’s gender and birth weight have a positive correlation with CB TNC content. The babie’s birth weight affects positively also CD34+ content and CBU volume while the cesarean delivery affect the CB volume only. Our predictive model, based on multivariate analysis, shows that male babie’s, gestational age lower to 39 weeks, cesarean delivery and CBUs with a content of TNC higher than 3.44 × 108 (group A) have a significant higher CD34+ content than group B (female babie’s, gestational age higher than 39 weeks and vaginal delivery). The group A have a 37.5% of CBUs with a concentration of CD34+  > 2 × 106, while no CBUs with high concentration of CD34+ were detect in group B.

Conclusion

This study, conducted on a very large series of CBUs without any specific volume constraint, highlighted the prenatal and maternal factors that significantly influence the quality of the CBU collected. Specifically, it highlights that volume is not the best predictor of CD34+ CBU content; for this reason it cannot be taken into consideration alone for the analysis of the collected samples. Our final aim is to identify relevant factors, immediately available, that help to choice UCB with high CD34+ cell content, especially in simultaneous deliveries.