Editorial on the Research TopicMast cells in allergic diseasesεRI, which upon IgE and antigen cross-linkage, triggers the release of mediators that are directly responsible for allergic symptomatology. As part of the ongoing effort to demystify allergic inflammation, many studies have focused on the mast cell since its discovery in 1879 by Paul Ehrlich, followed by renewed interest after the discovery of IgE in 1967 by Kimishige Ishikaka. This editorial will summarize recent efforts which have been published in the Research Topic Mast Cells in Allergic Diseases in the journal Frontiers in Allergy.Allergic disease poses a major public health concern that affects 10%–30% of the global population. The etiology of allergic diseases is complex and multifaceted. Although enormous strides have been made in the elucidation and treatment of allergic conditions, many questions remain. Mast cells are sentinel innate immune cells that play a key effector function in the allergic diathesis. Mast cells express the high affinity IgE receptor FcMacDonald et al. demonstrated that sodium butyrate suppresses the cell cycle progression of three malignant human mast cell lines. Butyrate is a short chain fatty acid microbial metabolite that functions as a class I histone deacetylase inhibitor (HDACi). The role of butyrate in promoting gastrointestinal health is well accepted, however its role in allergy remains controversial and unclear. Although multiple murine studies demonstrated that butyrate and butyrate-producing microbes attenuate allergic diseases, human association studies remain conflicting and uncertain, most likely due to the complex function of butyrate in multiple immune cell types . Thi. ThiMacDToshiaki Kawakami et al. summarized the role of IgE in the rhinovirus exacerbation of asthma in a prospective review. It is well known that rhinoviruses are associated with asthma exacerbations, and this was recently reviewed by David Jackson and James Gern  plays a negative role in IgE-mediated cytokine production, possibly by altering SYK activation  are single stranded noncoding RNA molecules that have been shown to profoundly regulate various physiological processes through post-transcriptional gene regulation, including the immune system. In particular, the association between miR-155 and allergic diseases have been examined in multiple studies. Previously, miR-155 was shown to play both a negative and positive role in IgE-mediated mast cell functions by two independent groups. One group demonstrated that activity . Anotheractivity .Mohammed et al. demonstrated that IgE and antigen cross-linking induced miR-155 in human and murine mast cells in vitro. Furthermore, using murine bone marrow derived mast cells, the authors showed that miR-155 deficiency resulted in diminished Cyclooxygenase-2 expression as well as cytokine production (Adding to these discoveries, oduction . The conTaken together, this Research Topic on mast cells in allergic diseases has led to a positive step towards understanding the complex regulation of mast cells via butyrates, anti-viral receptors, and miRs, as summarized in


The role of imaging in pretreatment staging and management of prostate cancer (PCa) is constantly evolving. In the last decade, there has been an ever-growing interest in radiomics as an image analysis approach able to extract objective quantitative features that are missed by human eye. However, most of PCa radiomics studies have been focused on cancer detection and characterisation. With this narrative review we aimed to provide a synopsis of the recently proposed potential applications of radiomics for PCa with a management-based approach, focusing on primary treatments with curative intent and active surveillance as well as highlighting on recurrent disease after primary treatment. Current evidence is encouraging, with radiomics and artificial intelligence appearing as feasible tools to aid physicians in planning PCa management. However, the lack of external independent datasets for validation and prospectively designed studies casts a shadow on the reliability and generalisability of radiomics models, delaying their translation into clinical practice.Key points• Artificial intelligence solutions have been proposed to streamline prostate cancer radiotherapy planning.• Radiomics models could improve risk assessment for radical prostatectomy patient selection.• Delta-radiomics appears promising for the management of patients under active surveillance.• Radiomics might outperform current nomograms for prostate cancer recurrence risk assessment.• Reproducibility of results, methodological and ethical issues must still be faced before clinical implementation. Prostate cancer (PCa) is the second most common cancer and the fifth cause of cancer-related death in men worldwide . PCa shoDespite multiparametric magnetic resonance imaging (mpMRI) and prostate-specific membrane antigen (PSMA)-ligand positron emission tomography/computed tomography (PET/CT) have revolutionised the diagnostic pathway of PCa, their role in preoperative staging, treatment planning, and in the PCa recurrence setting is less defined , 6. CurrTo address these issues, radiomics has been proposed as an image analysis approach that allows a high-throughput extraction of objective quantitative features  that are missed by human eye , 13. Rade.g., nerve-sparing, pelvic lymph node dissection). Radiomics and machine learning (ML)-based solutions could assist radiation oncologist in their daily practice, from treatment planning to toxicity prediction. Also, a better characterisation of tumour aggressiveness may help in defining which patients may benefit from adjuvant therapies, to reduce post-treatment recurrence Ga-PSMA-11 PET/MRI in vivo models for predicting low-versus-high lesion risk as well as BCR of 52 patients with PCa underwent RP with a ML approach. Their supervised predictive model for BCR selected seven radiomic features  and clinical data. This model outperformed the standard routine analysis based on PSA, biopsy GS, and TNM staging .Finally, in a recent investigation, part of a single-centre pilot to a randomised prospective trial, Papp et al.  investigRadiomics is still in its infancy, but it is foreseeable that AI and radiomics solutions will become a key component of radiologists’ everyday work in the future. Overall, the majority of research efforts have been focused on PCa detection , 96. Howe.g., more data is needed for studies on treatment response, such as follow-up data). It is also possible that less encouraging results have been found for more complex classification tasks and these are not emerging due to publication bias, a well-known issue in the field of radiomics [It could be speculated that studies on PCa detection are more common because it might be easier to obtain good quality datasets to work on (adiomics .The limitations of current evidence should be taken into account, and overly optimistic claims should be avoided. Indeed, each step in the radiomics pipeline hidden methodological pitfalls to be aware of . Above aFinally, medical-legal guidance to address the liability for clinical practice use of radiomics has not been yet provided by official regulatory offices but could aid physicians in gaining confidence with these tools and encourage their safe use .In conclusion, this review highlighted excellent future prospects for a role of radiomics in powering decision support tools to aid physicians in the management and treatment planning of PCa patients. However, great efforts are advocated to confirm these encouraging premises and eventually produce the high-level evidence required to turn these exciting perspectives into medical practice realities.


Residual cardiovascular risk persists despite statin therapy. In REDUCE-IT, icosapent ethyl (IPE) reduced total events, but the mechanisms of benefit are not fully understood. EVAPORATE evaluated the effects of IPE on plaque characteristics by coronary computed tomography angiography (CCTA). Given the conclusion that the IPE-treated patients demonstrate that plaque burden decreases has already been published in the primary study analysis, we aimed to demonstrate whether the use of an analytic technique defined and validated in histological terms could extend the primary study in terms of whether such changes could be reliably seen in less time on drug, at the individual (rather than only at the cohort) level, or both, as neither of these were established by the primary study result.3 vs. an increase of 41 mm3, p = 0.008), widening at 18 months  were observed. While not statistically significant on a univariable basis, reductions in wall thickness and increases in cap thickness motivated multivariable modeling on an individual patient basis. The per-patient response assessment was possible using a multivariable model of lipid-rich phenotype at the 9-month follow-up, p < 0.01 (sustained at 18 months), generalizing well to a validation cohort.EVAPORATE randomized the patients to IPE 4 g/day or placebo. Plaque morphology, including lipid-rich necrotic core (LRNC), fibrous cap thickness, and intraplaque hemorrhage (IPH), was assessed using the ElucidVivo® (Elucid Bioimaging Inc.) on CCTA. The changes in plaque morphology between the treatment groups were analyzed. A neural network to predict treatment assignment was used to infer patient representation that encodes significant morphological changes. Fifty-five patients completed the 18-month visit in EVAPORATE with interpretable images at each of the three time points. The decrease of LRNC between the patients on IPE vs. placebo at 9 months (reduction of 2 mmPlaques in the IPE-treated patients acquired more characteristics of stability. Reliable assessment using histologically validated analysis of individual response is possible at 9 months, with sustained stabilization at 18 months, providing a quantitative basis to elucidate drug mechanism and assess individual patient response. IPE iGiven that LAP lacks an objective definition, our study aimed to compare this result with what could be done using objectively defined tissue markers such as histologically defined and validated lipid-rich necrotic core (LRNC). Specifically, this study used a software validated using histologic assessment to provide specific tissue characterization meeting requirements to be considered a biomarker, which enables granular mechanistic insight underlying the primary and secondary endpoints  using ob2.The EVAPORATE trial randomized the statin-treated patients with high TG 135–499 mg/dl), well-controlled LDL, and known atherosclerosis to IPE 4 g/day or placebo. The plaque morphological characteristics, including LRNC, fibrous cap thickness (distance from the lumen to LRNC), and intraplaque hemorrhage (IPH), were assessed using ElucidVivo®  on CCTA. The per-patient multivariable predictive models discriminate the relevant mechanistic changes while allowing for individual physiological variation used to evaluate plaque morphology and provide a per-patient assessment tool. Specifically, multivariable modeling of LRNC together with wall and cap thickness was applied. The study endpoints, population, and design are as previously described , IPH, matrix (MATX), perivascular adipose tissue (PVAT), cap thickness , and structural anatomic measurements such as degree of stenosis. LRNC is objectively defined as the accumulation of lipids by intimal/medial cells leading to progressive cell loss, cell death, degeneration, and necrosis. LRNC is a mixture of lipid, cellular debris, blood, water in various concentrations, lipid droplets intermixed extracellular matrix, necrotic amorphous eosinophilic material and is acellular, often surrounded by fibrotic tissue generated by smooth muscle cells/fibroblasts, and without microvasculature. CALC is a biological process that may stabilize plaque in some forms, and has a mechanism akin to bone formation, is observed as intimal/medial spaces with evidence of calcium primarily in the form of hydroxyapatite, osteoblasts or osteoid present, and no appreciable lipid or necrotic tissue. IPH is the accumulation of erythrocytes in the deeper regions of the plaque, with or without communication to the lumen or neovasculature, marked as erythrocytes, often in the deeper regions of the plaque. Fresh IPH is characterized by red blood cells (RBCs), intact and unorganized, whereas recent (5+ days) is observed as an inflammatory response with organized RBCs via hemolysis, fibroblast activity, and macrophage activity. MATX is the organization of macromolecules  that provide structural support, tensile strength, or elasticity to the arterial wall, is observed as an intimal meshwork of dense or loose, homogeneous/organized collagen ECM (appear striated), embedded smooth muscle cells/fibroblasts (note elongated nuclei), and may have microvasculature.Statistical analyses: Demographic and baseline characteristics were compared between the two treatment groups using the Fisher's exact test for categorical variables and the Wilcoxon rank-sum test for continuous variables. The variables were generally well-balanced between the two cohorts with minor exceptions. The changes from baseline to 9- and 18-month measurements were analyzed for each morphological characteristic to evaluate differences between the two groups. Student’s t-test was used to compare group means. Linear regression models were used to assess how baseline morphology changes differ across the two arms while adjusting for the effects of the variable EPA that showed an imbalance in the baseline comparisons of the arms. The models were adjusted by age, sex, diabetes, hypertension, and baseline triglyceride levels , can identify specific responses to the drug agents. The multivariable combination of all the morphological changes from baseline was used to derive the individual patient representation, encoding all the significant information of morphological change, using supervised machine learning classifiers to predict the correct treatment assignment. The data were partitioned to train (70%) and validation test (30%) sets in a stratified manner by making random splits in each treatment arm. All modeling was implemented using the Caret package in R. Unacceptably high correlations (>0.8) were identified in a heatmap where a clustering algorithm determines the order of columns and rows. A range of models  were trained using the 10-fold cross-validation resampling scheme. They were optimized for the area under the receiver operating characteristic curve (AUROC) and Kappa . The differing sets of morphological measurements according to hypothesized physiological rationale confirmed by an unsupervised clustering were used. The predictors were mean-centered, scaled to unit variance, and Yeo–Johnson transformed  to place3.p-values to detect changes at 9 and 18 months from baseline in morphological characteristics between the drug/placebo groups, reported from Student's t-test and linear regression models, respectively. The change in LRNC increased among those on placebo and initially decreased among those on IPE, but then modestly grew from 9 to 18 months, which yielded a large net difference in favor of IPE . r of IPE . The chap < 0.01. The best-performing multivariable model for the individual patient response was an averaged neural network  of a lip4.Cardiovascular disease, including stroke, peripheral artery disease, and coronary artery disease, is the most common cause of death and disability worldwide. Despite treatment with relatively low-cost statins to lower the low-density lipoprotein, high levels of residual risk remain, necessitating additional treatments. Hypertriglyceridemia possibly contributes to this residual risk. The REDUCE-IT established that IPE reduces CV risk in the patients with hypertriglyceridemia. Nonetheless, the CV benefit of IPE probably did not result primarily from triglyceride lowering . To gainThe primary study analysis demonstrated that plaque burden decreases in the IPE-treated patients . The preSpecifically, the maximum wall thickness increased in the placebo arm and decreased in the IPE arm. The majority of the reduction in wall thickness was evident at 9 months but continued through 18 months. The fibrous cap thickness decreased in the placebo arm and increased in the IPE arm, a feature that may reflect plaques being less prone to rupture and provoke thrombosis. We conjecture that this is due to the regression of LRNC but could also be due to luminal surface changes that may warrant additional study. The change in LRNC increased among those on placebo and initially decreased among those on IPE, but then modestly grew from 9 to 18 months, which yielded a large net difference in favor of IPE. The wall thicknesses increased in both arms but less in the IPE arm at both 9 and 18 months. Given the wall thickness changes, IPE appears to improve uniformity, and features associated with more stable lesions. The morphological patient representation inferred from this supervised classification model could benefit other tasks, such as predicting adverse events.IPE improved multiple morphological characteristics associated with more stable lesions, and the patients on placebo developed less stable characteristics. Lesions with high-risk features (large necrotic core and thin cap) portend a greater likelihood of provoking future events –33 than p < 0.01).The primary outcome measure of this new analysis advances prior reported results in two important ways. First, the single-variable significance of LAP, as previously reported, was substantially improved with the more accurate analytic software and achieved significance at 9 months vs. 18 months. Second, the multivariable model made possible with the granularity of measurands for plaque characterization demonstrated statistical significance of the primary outcome measure . The patients on IPE demonstrated large decreases in all three measures of wall remodeling , overall plaque burden, LRNC, and calcification by volume, maximum area, and proportional occupancy of the tissue type relative to the whole wall for the patients on IPE compared with the patients on placebo. The patients showed favorable increases in cap thickness on IPE compared with those on placebo. As plaques in the placebo group continued to expand despite maximum doses of statins, this study provides evidence that the LRNC reduction resulted solely from the IPE treatment.Our study had limitations. First, this study is limited to EVAPORATE trial data, thus its generalization to other drugs and populations would require validation in other trials. This initial finding should encourage this undertaking. Second, the small sample size is a limitation of this study. Whereas the sample size was adequate as a feasibility study, larger cohorts should be studied to assess the generalizability of the results. Specifically, larger scale comparisons between this and other methods, as well as between different multivariable modeling approaches for individual patient response in larger cohorts, are warranted. In addition, while we quantified the link of drug effect on plaque, a confirmation that those plaque changes relate causally to event reduction warrants further study.5.We build on the primary EVAPORATE analysis, which concluded that adding IPE to statin therapy yields quantitatively assessed changes in plaque morphology assessed by CTA that reached statistical significance at 18 months. This study used a software analytic technique that showed such changes in less time on drug (being significant at 9 months) and also demonstrated the feasibility of measuring such changes at the individual level, thereby extending the primary study results. This new analysis further demonstrated that the use of histologically defined terms and approaches allows for a more direct assessment of tissues consistent with reduced likelihood of plaque disruption and thrombosis. Specifically, IPE-induced decreases in LRNC and increases in cap thickness may mechanistically contribute to the reduction in clinical events shown in the REDUCE-IT. Using our technique, such effects can not only be measured at a cohort level, but also determined reliably for individual patients, which may be used as a response marker in clinical practice. These measurements further elucidate the mechanisms of IPE action by providing a quantitative window into LRNC growth, cap thickness modulation, and remodeling. These initial results should encourage larger studies, investigations with other drugs, and further validation of the use of individual patient models.


Aviva Samach, Fabrizio Mafessoni, Or Gross, and colleagues  present an assay that detects loss of heterozygosity (LOH) and can be used to study the genomic consequences of DSBs. They induce and can visually identify targeted crossover induction  rely on the creation of double-stranded breaks (DSBs) in DNA. However, DSBs pose a threat to the replication process and therefore need to be repaired. The repair of CRISPR-induced DSBs can have varying effects on the genome, with nonhomologous end joining causing small insertions or deletions at the site of the break and homologous recombination potentially leading to crossovers between homologous chromosomes or gene conversion. Targeted crossovers and gene conversion are highly sought-after outcomes in plant breeding for segregating undesirable alleles. These events can enable targeted gene replacement or the elimination of undesirable transgenes, making this process invaluable to the improvement of crops . Aviva Stion see . and alstion see . These mBet) and mapped the hemizygous insertion of that construct in the genome. They designed guides for targeted DSB break induction by CRISPR between the Bet marker and the centromere. If a DSB occurs at that location and results in a crossover, then the resulting LOH can be observed as a twin sector, namely a segment of intensively pigmented Bet/Bet tissue adjacent to a segment of −/− pigment-free tissue (see Betalain marker through somatic crossover enables the selection of transgene-free plants that contain the desired recombination.The authors used tomato plants with a visible reporter that synthesizes the purple pigment betalain (ssue see . The losBet/Bet paired with a yellow −/− sector (see Screening hemizygous light-purple Bet/− plants resulted in the identification of a flower on one plant with a twin sector of dark-purple ctor see . BecauseBet/− seedlings to screen for green plantlets resulting from LOH. After excluding green plants with transgene silencing, they isolated plants with LOH resulting from CRISPR-induced DSBs. They identified a broad range of CRISPR-induced DSB consequences, from the loss of chromosomal fragments to whole chromosome loss. Additionally, they demonstrate that, like in mammals, CRISPR-induced DNA breaks can cause chromothripsis in plants, seen as micronuclei, translocations, dicentric chromosomes, and McClintock's breakage–fusion–bridge cycle. These results and the visual/phenotype-based LOH assay improve our understanding of the genetic and epigenetic context that determines the fate of CRISPR-induced DSBs. This will contribute to more effective use of genome editing in plant breeding applications.Due to the rarity of identifying crossovers by sectors, the authors additionally tissue-cultured


Septo-optic dysplasia (SOD) is a rare condition diagnosed in children with two or more of the following: hypopituitarism, midline brain abnormalities, and optic nerve hypoplasia. Children with SOD experience varied visual impairment and endocrine dysfunction. Autistic-like behaviours have been reported; however, their nature and prevalence remain to be fully understood. The present systematic review aimed to explore the type and prevalence of neurodevelopmental impairments in children with SOD spectrum conditions.The search was conducted in PubMed, EMBASE, and PsycInfo. Hand-searching reference lists of included studies was conducted. All peer-reviewed, observational studies assessing behavioural and cognitive impairments or autism spectrum disorder (ASD) symptoms in children (< 18 years) with SOD, optic nerve hypoplasia, and SOD-plus were included. Studies were excluded if they did not report standardised measures of neurodevelopmental impairments or ASD outcomes.From 2132 screened articles, 20 articles reporting data from a total of 479 children were included in prevalence estimates. Of 14 studies assessing cognitive-developmental outcomes, 175 of 336 (52%) children presented with intellectual disability or developmental delay. A diagnosis of ASD or clinical level of symptoms was observed in 65 of 187 (35%) children across five studies. Only five studies assessed for dysfunction across behavioural, emotional, or social domains and reported impairments in 88 of 184 (48%) of children assessed.Importantly, high heterogeneity among the samples in relation to their neuroanatomical, endocrine, and optic nerve involvement meant that it was not possible to statistically assess the relative contribution of these confounding factors to the specific neurodevelopmental phenotype. This was further limited by the variation in study designs and behavioural assessments used across the included studies, which may have increased the risk of information bias.This systematic review suggests that the prevalence of neurodevelopmental impairments in children within the SOD spectrum may be high. Clinicians should therefore consider including formal assessments of ASD symptoms and neurodevelopmental impairments alongside routine care. There is, additionally, a need for further research to define and validate a standardised battery of tools that accurately identify neurodevelopmental impairments in SOD spectrum conditions, and for research to identify the likely causal mechanisms.The online version contains supplementary material available at 10.1186/s13229-023-00559-0. Septo-optic dysplasia (SOD) is a rare congenital condition diagnosed in children with two or more of: pituitary hormone abnormalities, optic nerve hypoplasia , and midline brain abnormalities  . Males aCurrent understanding of the neurobehavioural phenotype of SOD is largely limited by the heterogeneity of its clinical phenotype. Recent discussions have argued re-defining SOD as a spectrum-based condition to encapsulate all variations of its clinical presentation . For exaReports of neurodevelopmental impairments in SOD spectrum conditions are primarily centred around developmental delay, ranging from observations of isolated deficits (i.e. motor impairment) to global delays . NeuropsThere are additional complexities regarding the assessment of ASD-like features in children with SOD spectrum conditions related to the common presence of visual impairment. First, tools that have been validated for the assessment of neurodevelopmental impairments and neuropsychiatric symptoms in sighted populations may not be suitable for populations with visual impairment. For example, their use may result in the overestimation of social cognitive deficits . An addiThe present systematic review aims to assess the type and prevalence of neurodevelopmental impairments and ASD symptoms in children with SOD spectrum conditions. At present, neurodevelopmental impairments are not routinely assessed and therefore remain untreated. It is only when caregivers raise concerns about experiencing difficulty with managing their child’s behaviour at home and during school that these aspects of the condition are addressed by clinicians. It is anticipated that by improving understanding of the neurodevelopmental impairments and their aetiology in children with SOD spectrum conditions, early intervention and treatment plans may be developed to aid symptom management and improve patient and caregiver quality of life. It should be noted that for the purpose of this review, the term neurodevelopmental impairments will be used to encapsulate all behavioural, social, emotional, and cognitive-developmental impairments.Case exampleA 13-year-old female patient diagnosed with septo-optic dysplasia was seen in paediatric endocrine clinics for multiple pituitary hormone deficiencies. She is treated with hydrocortisone, levothyroxine, and desmopressin acetate, and also received treatment for precocious puberty. She additionally has severe visual impairment. Alongside the somatic features of the condition, she presents with behaviourally induced insufficient sleep syndrome and autistic-like behaviours. Specifically, she experiences heightened auditory sensitivities that severely impact her everyday life including her education, self-care, play, and social interactions. These behavioural difficulties were only addressed when raised by her caregivers. Adjustments have now been put in place so that she attends clinic wearing ear defenders and the clinicians speak in soft tones to help her cope with her auditory sensitivities and minimise distress during clinic visits.https://doi.org/10.17605/OSF.IO/45R9A). The search was performed in PubMed and OVID databases, EMBASE and PsycInfo of peer-reviewed journal articles published in English, from inception through July 16, 2022. These databases were used due to their relevance to the target field. The following search terms were used: (septo-optic dysplasia OR septo-optic dysplasia OR septo-optic dysplasia OR ONH OR optic nerve hypoplasia) AND . Search terms were truncated as appropriate to maximise retrieval. No filters or limits were applied to the search. Additional sources of literature included hand-searching reference lists of included studies and relevant review papers.This systematic review followed the PRISMA guidelines to identify relevant literature assessing neurodevelopmental impairments in children with septo-optic dysplasia (SOD) spectrum conditions. A protocol was developed a priori and registered with the Open Science Framework  to maintain reliability throughout the study selection process. Given the nature of this systematic review, our inclusion criteria were intentionally broad to minimise search bias and comprised of original peer-reviewed articles with: (1) a sample of children up to 18 years old with SOD, SOD-plus, or ONH; and (2) a formal assessment of neurodevelopmental  impairments or autism spectrum disorder symptoms using validated measures, such as the Social Communication Questionnaire (SCQ) , the ChiA data extraction spreadsheet was drafted in Excel during protocol development. Data extraction was trialled in the first five references and adjustments were made to ensure all relevant study information was obtained. Categories in the data extraction spreadsheet included: 1) first author, (2) year of publication, (3) study design and sample size, (4) age and sex of participants, (5) SOD condition type, (6) severity of visual impairment, (7) comparator group demographics  reported samples of only patients with ONH. However, the diagnoses of all but one [N = 8), or due to the lack of such reports  patients with available data  of children presented deficits within behavioural, emotional, or social domains Table . Only thTwo studies discussed how these neurobehavioural outcomes may have been moderated by visual impairment. Children with profound visual impairment were significantly more likely to present one of social communication, repetitive, or restrictive behavioural difficulties as well as presenting all three dysfunctions together, than children with severe visual impairment . Jutley-Controlling for visual loss, Webb et al.  recruiteAutism spectrum disorder was measured using screening tools, validated questionnaires, and formal clinician diagnosis. Across five studies, 65 of 187 (35%) children presented a diagnosis of ASD or clinical level of symptoms Table . EvidencThree studies assessed whether the prevalence of ASD symptoms depended on severity of visual impairment or optic nerve involvement. Parr et al.  found thAmbiguity on the contribution of visual impairment to ASD may be partly limited by available measures. Williams et al.  comparedNeurodevelopmental impairments are known to be associated with SOD spectrum  and otheCognitive-developmental impairment has been the primary focus in research assessing children with SOD spectrum conditions, with the majority of studies assessing intellectual disability and developmental delay, rather than behavioural, social, or emotional outcomes. Notably, heterogeneity among the measures used to evaluate intellectual disability and developmental delay was observed. Additionally, we noted lack of consistency in the use of given measures with respect to the type of impairments they were reported to assess. For example, the Griffiths Mental Developmental Scale has been reported as a measure of developmental delay in one study , but alsA number of studies did not meet the inclusion criteria of this review due to unclear definitions of outcomes, such as developmental delay, or for not reporting formal neurobehavioural assessments  . To mainSelection bias may also have arisen within the included studies, with parents supportive of an ASD diagnosis for their child potentially being more likely to engage with research assessing these outcomes. However, given that it has been argued that parents identify ASD-like traits in their children notably earlier than a diagnosis is reached , this maOverall, this review suggests that the prevalence of neurodevelopmental impairments in children within the SOD spectrum may be as high as 48 to 52%. Similarly, there is preliminary evidence that up to 35% of children with this condition may experience clinically relevant symptoms of ASD. The presence of hypothalamic dysfunction may pose a key shared mechanism underlying neurodevelopmental impairments in SOD spectrum conditions and other disorders with hypothalamic damage, such as Prader-Willi syndrome. However, drawing robust conclusions from the current literature remains challenging. Future research developing valid assessments of neurodevelopmental impairments may aid the delineation of blind-specific abnormalities in children with visual impairment compared to those with ASD and no visual impairment. Once valid measures for visually impaired children have been established, large multi-centre studies characterising the neurobehavioural phenotype of these children may inform future screening protocols for the ASD-like impairments in children with SOD spectrum. Nevertheless, at present, it is evident that children with SOD spectrum conditions experience neurodevelopmental impairments in need of intervention by appropriately trained clinicians, such as psychiatrists or clinical psychologists. Once established, clinicians should use screening tools modified for children with visual impairment alongside their specialist judgement in order to formulate a more valid assessment of neurodevelopmental impairments and ASD. Incorporating these assessments into routine care means diagnosis, which is required for therapeutic intervention by clinicians and educational support in schools, can be made for affected children. Moreover, since SOD spectrum conditions are diagnosed during the neonatal period, awareness that neurodevelopmental impairments are associated with the condition will support early diagnosis and therefore allow for intervention at an earlier developmental stage. In turn, this may improve the prognosis in children with SOD spectrum conditions, and subsequently minimise educational and behavioural challenges for patients and caregivers, and lead to improvements in their quality of life.Additional file 1: Table S1. Comparator group demographics and neurodevelopmental impairments for applicable studies.Additional file 2: Table S2. Studies excluded due to not reporting validated measures of neurodevelopmental impairments.


Chronic inflammation, in general, refers to systemic immune abnormalities most often caused by the environment or lifestyle, which is the basis for various skin diseases, autoimmune diseases, cardiovascular diseases, liver diseases, digestive diseases, cancer, and so on. Therapeutic strategies have focused on immunosuppression and anti-inflammation, but conventional approaches have been poor in enhancing the substantive therapeutic effect of drugs. Nanomaterials continue to attract attention for their high flexibility, durability and simplicity of preparation, as well as high profitability. Nanotechnology is used in various areas of clinical medicine, such as medical diagnosis, monitoring and treatment. However, some related problems cannot be ignored, including various cytotoxic and worsening inflammation caused by the nanomaterials themselves. This paper provides an overview of functional nanomaterial formulations for the prevention, diagnosis and treatment of chronic inflammation-related diseases, with the intention of providing some reference for the enhancement and optimization of existing therapeutic approaches. Inflammation is a response involving immune and non-immune cell activation that promotes tissue repair and protects the host from a variety of infections, toxins and so on. The main categories are acute inflammation and chronic inflammation. Acute inflammation is defined as inflammation that occurs in the short term through interactions between innate immune cells and pathogens or in response to harmful stimuli during cellular stress or injury, while chronic inflammation usually persists through the latter and eventually damages tissues and organs to cause chronic inflammatory disease . The infNanotechnology aims to manipulate the unique properties of matter at the nanoscale, which can be observed instrumentally to exhibit unique characteristics and develop new capabilities with potential applications, which is one of the main reasons why they have various applications across all fields of medicine . Recent The inflammatory response involves many cells and chemical modulators for protection from infection . In mostWhen the inflammatory response is inadequate or excessive, it can disrupt the body’s immune system balance and lead to the development of chronic inflammatory diseases if it is not addressed on time . ChronicMost inflammatory skin diseases have a chronic recurrent course, such as chronic plaque psoriasis (psoriasis vulgaris) and atopic dermatitis, which have an inflammatory component in the pathological model . HoweverNanocarriers can penetrate the stratum corneum without restriction as well as the skin through various routes. Nanotechnology-based carriers improve durability, which protects the drug from degradation and improves the effectiveness of psoriasis treatment . Elmowafin vitro immunoassay has been proposed based on the specific memory T-cell properties for circulating allergens, encapsulating hydrophobic allergens into nanoparticle (NP) carriers that skip the serum analysis, opening up a new avenue for in vitro immunobiological diagnosis of allergic contact dermatitis  is one of the most common chronic joint diseases, causing chronic synovitis and bony joint destruction, as well as other diseases in the body that ultimately lead to increased mortality . SLE is + and CD8+ Tregs, but currently remains in animal models before reaching the clinical stage  17 bc2-specific antigenic responses and enhancement of Th2-type T cell responses . MeanwhiChitosan-based nanomaterials are increasingly being applied and there appears to be great promise for appropriate clinical studies to develop their potential applications in therapy. Notably, nanovaccines are also emerging as another hot topic of research and have achieved some positive results in anti-RA, making them ideal candidates for anti-RA drugs .in vitro by dsDNA and increased in plasma of SLE patients  scavenging material (TPCD) and processed it into NPs (TPCD NP) with an average diameter of 101 nm to construct a multistage targeted nanotherapeutic triphenylphosphine-decorated TPCD NP to evaluates its efficacy in mice with Doxorubicin-induced cardiomyopathy  failure .Prevention of cardiovascular disease is vital, but early diagnosis and treatment are even more crucial. A recent study has designed an all-nano-fiber optic force-acoustic sensor by using a durable, ultra-thin (2.5 µm) nanofiber electrode layer, which shows extremely high sensitivity in the low-frequency region (<500 Hz), high mechanical robustness and bending stability for long-term cardiac monitoring . The delNPs can specifically deliver diagnostic and therapeutic drugs to modulate atherosclerotic pathology . Macroph−/− mice and inhibited atherosclerosis by enhancing plaque stability and significantly reducing lesion size  . In addiDespite the widespread use of NPs in medicine, they are a potentially dangerous chemical that can penetrate animals’ organs and cause functional impairment. Related studies suggest that treatment with melanin, quercetin, and alpha-lipoic acid prevents most of the kidney-damaging effects of Au NPs . Abdelha2+ ions to the C═N functional group of creatinine. Used for preventative diagnosis and clinical evaluation of CKD, it proves the feasibility of detecting salivary creatinine through a catalytic mechanism to assess the extent of kidney disease , mainly transmitted through the oral cavity, is a pathogen associated with cancer, multiple sclerosis and RA, causing hundreds of thousands of deaths each year. The development of an EBV vaccine to prevent this infection is an urgent priority. Malhi H et al. demonstrated that several EBV glycoprotein (gH/gL) NP vaccines were able to elicit an effective neutralizing antibody response and pointed out that a 60-mer NP could protect humanized mice against the lethal challenge of EBV, which have higher immunogenicity compared with gH/gL alone, emphasizing that gH/gL vaccine-induced antibodies have great potential in the development of EBV virus vaccines . In anotBreast cancer continues to afflict women around the world. Determining the regional lymph node status of breast cancer is critical to understanding the course of breast cancer, and the appropriate tracer of sentinel lymph node biopsy plays a key role in diagnosis and axillary staging. Dual tracer-guided techniques are the current standard for detecting sentinel lymph nodes. Zhang L et al. developed an ultrasound-assisted nanocarbon suspension localization technique for early breast cancer patients using dual tracer-guided sentinel lymph node biopsy and proved that the diagnostic performance of ultrasound-assisted carbon NP suspension mapping in early breast cancer patients was not inferior to the dual tracer-guided technique sentinel lymph nodes mapping combined with carbon NP suspension and indocyanine green, which has potential clinical value in patients receiving neoadjuvant chemotherapy . However2O3-ART. The particle size of synthetic hollow mesoporous manganese trioxide NPs was reduced from 6 nm to 1 nm and 4 nm with time in the simulated TME. Co-delivery of Mn2+ and artemisinin, as well as modification of homologous erythrocyte membranes and TKD peptides, resulted in prolonged circulation and tumor targeting in the body. It shows an excellent imaging ability in tumors, generates large amounts of ROS, and induces DNA damage, enabling accurate breast cancer diagnosis and low toxicity treatment  and site specificity. For various drug delivery routes, NPs are highly flexible and can be incorporated into various dosage forms such as capsules, tablets, and hydrogels .Immune-related macrophages play an important role in inflammation and body defense. Moreover, chronic inflammation is inextricably linked to macrophage activation . Macroph2 NPs, NiO NPs, ZnO NPs, and CuO NPs induced a unique inflammatory “footprint” both acutely and chronically with different patterns of neutrophil and eosinophil infiltration elicited by different NPs (However, despite the advantages of functional materials-based nano-formulations for drug delivery and inflammation treatment, materials may also cause worsening inflammation, mostly associated with increased ROS production . Thus, nrent NPs  The studrent NPs . Anotherrent NPs . Howeverrent NPs  Currentlrent NPs . In addirent NPs . A recenrent NPs .In summary, nanomedicine introduces new preventive, diagnostic and therapeutic drugs that can more efficiently integrate effective molecules and utilize their high flexibility and durability combined with a variety of materials to protect the drug from degradation, provide precise targeting, effective control and specific release, as well as reduce toxicity and improve drug therapeutic efficacy. However, the current therapeutic efficacy is still mainly limited to animal models, and further studies are needed to elucidate the protective effects on humans.


Cancer research has witnessed remarkable advancements in recent years, with molecularly targeted treatments and immunotherapy revolutionizing patient care. However, some cancer types, such as pancreatic ductal adenocarcinoma, continue to defy treatment, and the emergence of drug resistance remains a significant challenge, hampering efforts to achieve lasting remission, especially in metastatic disease. In the past, cancer development was solely attributed to the appearance of genomic alterations in cancer cells. In the last decades, a broad consensus arose about the necessity for cancer cells to cooperate with host cells, such as fibroblasts, vascular cells, lymphatic cells, and immune cells during carcinogenesis and cancer progression. Therefore, the focus shifted toward understanding the tumor microenvironment (TME) heterogeneity and its impact on cancer evolution and drug resistance. In this dynamic landscape, innovative preclinical models and cutting-edge technologies have emerged as indispensable tools in TME characterization and, in general, in the efforts against cancer Figure 1Understanding the heterogeneous nature of tumors has presented significant challenges, but recent insights into the TME role have lightened up new paths for therapeutic exploration. This Research Topic examine various facets of the TME influence on cancer heterogeneity and drug resistance, encompassing diverse cancer types, including breast, colorectal, pancreatic, liver, and head and neck cancers. While each article offers a unique perspective, they collectively emphasize the role of the TME in shaping tumor behavior and response to treatment.Genta et al., Huang and Tu, and Proietto et al. highlight the advances of preclinical models in deciphering the complexities of the TME. Genetically engineered mouse models, patient-derived organoids and xenografts, and three-dimensional (3D) cell cultures have all emerged as essential tools to study cancer progression, acquired heterogeneity, and predict drug efficacy with an enhanced clinical relevance. Genta et al. encompass both in vitro and in vivo platforms for drug testing, stressing the relevance of patient-derived models to maintain the molecular affinity with the parental tumors and predict patient response. However, the authors also draw attention to the challenge that, despite their use in co-clinical trials and their value in understanding drug resistance, the data generated often arrive too late to modify the therapeutic plans effectively. Huang and Tu dive into the specific challenges posed by tumor heterogeneity and the microenvironment in vascularized tumor models, widely discussing the advantages and limitations of organ-on-a-chip models in replicating the vascularized tumor microenvironment. The addition of different types of supporting cells, namely pericytes, astrocytes, or lymphatic cells, makes those organ-on-a-chip models closely mimic the heterotypic cellular interactions within tumors. Further, the inclusion of organ-specific normal cells allows for assessing general drug toxicity. However, the authors also comment on some limitations, such as the accessibility to quantify cellular forces and cell stiffness. Proietto et al. extensively review the TME preclinical models and broaden the discussion to include the role of emerging single-cell, spatial genomic, and metabolomic technologies in understanding tumor complexity and evolution to design better targeted therapies. The authors highlight the need for multidisciplinary approaches to combat the challenges posed by tumor heterogeneity. Lee et al. remarkably contribute to further highlight the growing significance of cutting-edge spatial omics technologies in dissecting TME heterogeneity, also introducing the value added by artificial intelligence in unraveling the complex interactions within the TME.Yau et al. look at the importance of incorporating diverse cell populations within colorectal cancer spheroid models to mimic the intricate signaling pathways and heterogeneity found in vivo. Salemme et al. extensively discuss the characteristics of breast cancer, a highly heterogeneous disease, that leads to drug resistance and encompass the advances in developing in vivo and in vitro models to recapitulate breast cancer complexity. Another work about breast cancer by Lamouline et al. focuses on in vitro models for breast cancer metastasis in bone, elegantly discussing the cellular heterogeneity of this specific microenvironment, shedding light on the critical need to account for the different microenvironments in in vitro models dedicated to the study of metastasis to accurately mimic tissue-specific cell-cell and cell-extracellular matrix (ECM) interactions when assessing drug sensitivity. Indeed, van Tienderen et al. present a novel in vitro model of cholangiocarcinoma metastasis by ingeniously combining patient-derived organoids with decellularized human tissues, confirming the intricate interplay between cancer cells and the ECM in driving dissemination to distant organs such as lung and lymph nodes. Dedicated to studying drug pharmacological effects and tissue physiology is the model proposed by Greier et al. in their paper, in which they demonstrate the promising potential of 3D primary slice cultures to provide preclinical models for studying head and neck cancer and obtain data in a week frame to guide clinicians in the choice of treatments. Giustarini et al. establish human 3D heterocellular tumor spheroids as models mirroring the complexity of the pancreatic ductal adenocarcinoma environment. Notably, these tissue-specific spheroids reveal immunosuppressive tendencies and mimic spatial and cytokine signatures observed in patients, confirming their value for better therapy testing. The more we advance our ability to reproduce complex high-throughput systems in vitro, particularly through the consistent and standardized utilization of patient-derived samples for drug library testing, the sooner we will have a time-saving and cost-effective alternative to in vivo mouse models. While very powerful and extensively used, these animal models present ethical and variance concerns in rigorously reflecting human tumor evolution and heterogeneity, delaying drug development processes.The other articles in the Research Topic offer innovative insights on specific cancers, discussing advances in their modeling for preclinical studies and their organotypic TME role in drug resistance. This Research Topic presents a comprehensive picture of the recent advancements in understanding the TME influence on cancer heterogeneity and drug resistance. As these studies collectively suggest, it is clear that an accurate understanding of the TME role is pivotal for designing effective cancer therapies. This Research Topic highlights how the essential collaboration between clinicians, researchers, and technologists in developing advanced preclinical models and cutting-edge technologies is uncovering the subtle interactions between cancer cells, immune cells, and the surrounding microenvironment to develop effective therapeutics that will tackle drug resistance and improve patient outcomes worldwide.GA: Writing – original draft. PC: Writing – review & editing. SL: Writing – review & editing.


Mesenchymal stromal/stem cells (MSCs) derived from perinatal tissues have become indispensable sources for clinical applications due to their superior properties, ease of accessibility and minimal ethical concerns. MSCs isolated from different placenta (PL) and umbilical cord (UC) compartments exhibit great potential for stem cell-based therapies. However, their biological activities could vary due to tissue origins and differences in differentiation potentials. This review provides an overview of MSCs derived from various compartments of perinatal tissues, their characteristics and current isolation methods. Factors affecting the yield and purity of MSCs are also discussed as they are important to ensure consistent and unlimited supply for regenerative medicine and tissue engineering. Stem cells hold a great promise for regenerative medicine and tissue engineering due to their capabilities of self-renewal and differentiation into diverse cell types. They can be generally classified into three types: i) embryonic, ii) adult and iii) foetal. Embryonic stem cells (ESCs) are pluripotent cells derived from the inner cell mass of an embryo. However, controversial ethical issues and teratoma formation after transplantation have hampered the use of ESCs in clinical applications. Later, multipotent stem cells or mesenchymal stromal/stem cells (MSCs) with less ethical constrain from adult tissues such as bone marrow (BM), adipose and dental pulp have become alternative sources despite their limited lineage differentiation potentials compared to ESCs . NonetheAs a result, MSCs derived from foetal tissues are of growing interests. Both placenta (PL) and umbilical cord (UC) are considered medical wastes, and they do not encompass ethical issues as these tissues are discarded at birth, and the procedures to obtain these tissues are less invasive . Foetal α/CD19 and human leukocyte antigen-DR (HLA-DR). MSCs are also found to express CD44, CD106 and HLA class I but not HLA class II. At present, no specific surface marker can be used to isolate MSCs like CD34 for haematopoietic stem cells , the minimal criteria for defining MSCs: i) adhere to laboratory plastic culture; ii) able to differentiate to adipocytes, osteocytes and chondrocytes and iii) express surface markers of CD73, CD105 and CD90 but do not express CD45, CD34, CD14/CD11b, CD79Tremendous studies have demonstrated that MSCs from different origins show similarities in the aspects of morphology and immunophenotyping, but differences are also found in their biological properties such as proliferation, surface markers’ expression and differentiation potentials , 8. ThesFactors contributed to the differences of MSCs are the microenvironment, the localised function of each source and the ontogenetic age. However, it can also be caused by the process during isolation and culture condition , 15. IsoThe human PL is rich with stem or progenitor cells and growth factors crucial for tissue repair and regeneration. The developing foetus is protected from external surroundings by a complex structure made of several membranes . PL is aThe foetal membrane consists of two distinct layers surrounding the foetus: amniotic membrane (AM) is the innermost layer of the PL. In contrast, chorionic membrane is at the outer surface of AM. Amnion is avascular tissue, primarily made of monolayer of amniotic epithelial cells (AECs) and amniotic mesoderm cells (AMCs) . AM has As both AECs and AMCs are originated from epiblast during gastrulation, they are believed to acquire stem cell-like properties. AECs can be isolated by trypsinization that removes these cuboid cells from the basal and mesenchymal layers after stripping the AM from the chorion. They have a cobblestone epithelial feature, which is different from the fibroblastic appearance of AM-MSCs . Both huAmong the PL-MSCs, amnion membrane mesenchymal stem cells (AM-MSC) are the most well-studied source. AM-MSCs expressed high levels of typical MSCs markers but did not express hematopoietic markers . They caChorionic villi (CV) consist of four subtrophoblast layers that formed during the first trimester. Chorionic MSCs (Ch-MSCs) can be isolated from the CV and chorionic plate (CP). However, isolating these foetal MSCs is difficult due to maternal cell contamination or heterogeneous nature of the cell population harbouring this tissue as high incidence of maternal-origin MSC populations in Ch-MSC cultures has been reported –26. ThusThe contamination of maternal cells can be differentiated through their distinct features such as morphology, proliferation, adhesion and migration during in vitro expansion. Foetal CV-MSCs migrated faster and less adhesive than maternal cells . They weTorre and Flores  reviewedAmniotic fluid (AF) is a protective layer that keeps the foetus safe by providing mechanical support and supplying nutrients during embryogenesis. The major component of AF is water, although its cellular composition always changes during pregnancy . AF reprAs depicted in As obtaining AF-MSCs from the first and second trimester poses certain risks to the mother and foetus, the compatibility of cells from full-term pregnancy has been investigated as well by some researchers , 31. MorUmbilical cord blood (UCB) is considered one of the most suitable alternatives to obtaining MSCs for clinical applications . The isoIn general, there are two ways to collect cord blood samples: in utero (PL still in uterus) or ex utero (after PL delivery). The in utero approach is preferable because more cells can be collected through this sampling type and less contamination issue. However, relative low total nucleated cell (TNC) is obtained from these conventional approaches. Vanegas et al.  reportedOne of the major setbacks contributing to the wide-ranging success rate between 10% and 90% in culturing UCB-MSCs is inconsistency in the isolation process , 42. ManThe human UC is an increasingly popular cell source being developed for allogeneic cell-based therapy due to its superior immunopriviledged and immunomodulatory effects to other MSCs . UC is eAccording to Semenova et al. , WJ-MSCsThe primitive stem cells, such as haematopoietic cells and MSCs, are embedded in WJ. Some researchers used the whole piece of WJ for isolation. In contrast, others extracted cells from the cushioning matrix between the umbilical veins and two arteries located in the UC, but not the UCB . StudiesBesides that, it is worth mentioning that the lack of terminological standardisation has led to the difficulty in classifying MSCs based on the anatomical regions of UC. We noticed that sometimes MSCs derived from WJ were generally termed UC-MSCs especially when there is no description of where they are isolated. This misconception can mislead and jeopardise the interpretation of scientific data, especially when comparing the efficacy of MSCs for clinical use.2 incubator (In general, the isolation methods for perinatal tissues are quite similar, except for UCB. Enzymatic treatment and explant culture are commonly used for the isolation of MSCs, although perfusion and flow cytometry can also be used , 58. In ncubator , 67. CelSome studies reported that the enzymatic method affects cell proliferation and viability because of the long incubation period and relies on the type of enzyme and parameters that influence the efficiency of catalytic activity such as time, enzyme-substrates ratio and temperature , 62. By Recently, Yi et al.  demonstrHowever, the drawbacks of selection based on cell adhesive ability on plastic followed by passaging using serum supplemented media are the cellular heterogeneity at early passage and loss of MSC markers after in vitro expansion. The variable composition of not well-defined serum can also cause differences in MSC growth and quality. Moreover, this animal derived component may pose contamination risk and provoke immune response during clinical use. To ameliorate these adverse consequences, serum-free or xeno-free media and the use of biomimetic surface have been adopted in MSC isolation and expansion , 58, 72.Despite the outstanding therapeutic outcomes from preclinical investigations, most of the clinical trials could not be reached at a later stage. The low success rate is due to heterogeneity of MSCs attributed partly by the isolation and expansion methods which are unable to avoid mixed cell population , 76. BesBoth PL and UC are promising sources of MSCs, consensus on understanding their complex tissue structure is important as diverse cell populations can be derived from the same or different regions. It is suggested that isolation techniques based on anatomical structure described by Silini et al.  should bThus, concerted efforts towards standardisation on the isolation and processing of MSC should be emphasised internationally. This will ease the comparison of MSC research across different laboratories and a stepping-stone for ensuring the high quality of MSC production that meets the regulatory standards for clinical use , 78.The considerable interest and applications of MSCs derived from perinatal tissues will undeniably continue growing in various aspects not limited to regenerative medicine and tissue engineering. They have also proven promising for infectious diseases such as COVID-19 recently due to their excellent immunomodulatory potential, although more research is required to further understand the mode of action. However, some challenges still need to be resolved especially safety concerns and consistency supply to guarantee their clinical efficacies. Standardising isolation techniques and in vitro expansion for each cell type from different sources is crucial also because this is one of the key factors influencing self-renewal and differentiation properties.MSCs derived from different compartments of perinatal tissues are also found to have distinct biological properties which impact their differentiation potentials in clinical settings. Besides a comprehensive understanding of their intrinsic properties through multi-omics approaches, integrated interdisciplinary research such as biomaterials and nanotechnology will help in modulating and directing cell fate towards desired specifications for therapeutic purposes. This ultimately bridges the gap between the fundamental knowledge and translational application of these MSCs.


Lymphocytic infundibulo-neurohypophysitis (LINH) is a rare autoimmune inflammatory process that selectively affects the neurohypophysis and the pituitary stalk, typically presenting with central diabetes insipidus (CDI). LINH is considered underdiagnosed because the definitive diagnosis requires invasive pituitary surgery with a high risk of complications. We present a case of CDI resulting from LINH, which was treated with conservative management, eschewing both glucocorticoid treatment and pituitary surgery. At presentation, the hormonal assessment indicated the presence of CDI without anterior pituitary dysfunction. Magnetic resonance imaging revealed stalk thickening without a posterior pituitary bright spot, and anti-rabphilin-3A antibodies were positive in serum. Collectively, we made a diagnosis of LINH. Considering that the patient did not exhibit any symptoms of mass effect, we chose conservative treatment with desmopressin acetate. One year later, the stalk thickening regressed spontaneously without surgical or glucocorticoid treatment, although the posterior pituitary bright spot remained absent, and CDI did not improve. The inflammatory process of LINH is mostly self-limited and recovers spontaneously, whereas life-long desmopressin treatment may be required because of pituitary stalk fibrosis and atrophy. Our case highlights the importance of noninvasive diagnosis and careful follow-up in preventing unnecessary interventions for patients with LINH. Lymphocytic infundibulo-neurohypophysitis (LINH) is a rare autoimmune inflammatory disorder that selectively affects the posterior pituitary and the pituitary stalk, resulting in swelling of the posterior pituitary and stalk on neuroimaging . This diHere, we describe a case of CDI that occurred in a young Japanese woman, apparently without predisposing factors. We noninvasively diagnosed LINH as the etiology of her CDI by performing neuroimaging and detecting serum anti-rabphilin-3A antibodies, a specific biomarker of LINH . FollowiA 31-year-old woman was referred to our hospital with symptoms of polyuria and polydipsia. She noted a marked increase in urine output and water consumption (both more than 10 L daily) in the past year. She had no remarkable medical history, including brain diseases and psychiatric disorders, and no history of pregnancy. She was not taking any medication, including immunomodulating agents. On physical examination, she showed moderately diminished skin turgor and dry mouth. She did not have symptoms of mass effects such as visual disturbance or headache. Laboratory investigations revealed low urinary osmolality (53 mOsm/kg) and low specific gravity (1.001), whereas other laboratory studies were within normal limits. These findings made us consider the possibility of diabetes insipidus, and we performed hypertonic-saline (5%) infusion test and vasopressin challenge test. The hypertonic-saline infusion test revealed a severely blunted arginine vasopressin response . In contNoncontrast magnetic resonance imaging (MRI) of hypothalamic-pituitary regions demonstrated stalk thickening , arrows Although we proposed transsphenoidal pituitary biopsy to the patient for the definitive diagnosis, the patient refused the procedure because of its invasiveness. We therefore decided to undertake conservative management and careful follow-up with serial hormonal and MRI evaluations.Treatment began with oral desmopressin acetate (60 μg twice daily). Subsequently, the patient’s daily urine output decreased to less than 3 L daily, and her polydipsia also drastically improved. We did not perform either GC treatment or surgical decompression, considering her lack of severe or progressive mass effect symptoms and the anterior pituitary dysfunction because conservative management is recommended in patients with mild symptoms or signs [During the 1-year follow-up after the initial diagnosis, the patient did not develop any symptoms associated with mass effects, such as headache or visual field defects. Moreover, she did not develop symptoms or signs of anterior pituitary dysfunction, and routine hormonal assessment of the anterior pituitary function remained normal. Although her CDI did not improve and desmopressin treatment was continuously required, she remained free from pituitary surgery and GC treatment. Notably, 1 year after presentation, she underwent a follow-up MRI that demonstrated the spontaneous regression of the pituitary stalk enlargement, indicating the self-limited inflammatory process of LINH , arrows.Primary lymphocytic hypophysitis (PLH) is a rare autoimmune disorder characterized by inflammation of the pituitary or neuroinfundibulum. However, because of the nonspecific symptoms and the difficulty in making a definitive diagnosis, it is considered to be underdiagnosed . AccordiIn LINH, lymphocytes selectively infiltrate the neurohypophysis, leading to CDI and swelling of the posterior pituitary and the pituitary stalk . As withAlthough MRI scan is useful for distinguishing LINH from other pituitary diseases that cause CDI, it is challenging to completely rule out the possibility of other etiologies, such as tumors because of similar clinical presentation and radiological findings. Hence, we considered performing a pituitary biopsy to make the definitive diagnosis based on the histopathological diagnosis; however, the patient declined the procedure because of its invasiveness. In this regard, the detection of anti-rabphilin-3A antibodies in the patient's serum was a valuable tool in validating the clinical diagnosis of LINH and determining a treatment and follow-up plan. Previous research by Iwama et al demonstrated that rabphilin-3A was a predominant autoantigen in LINH and that testing for anti-rabphilin-3A antibodies can differentiate LINH from other sellar/suprasellar masses with a specificity of 96.2% . Anti-raThe benefits of GC treatment for PLH, including LINH, remain a topic of debate. Because of the rarity of this condition, there have yet to be large-scale randomized controlled trials investigating the efficacy of GC in patients with LINH. Although some cases of LINH have demonstrated radiographic regression and clinical improvement with GC treatment , it is gPituitary surgery is not typically indicated for patients with LINH because pituitary stalk enlargement tends to regress over time, as observed in the present case. Although patients with compromised vision or cranial nerve involvement might require surgical decompression, pituitary surgery is associated with a high risk of postoperative pituitary dysfunction . AdditioWe describe the case of a patient with LINH who presented with CDI without mass effect symptoms and anterior pituitary dysfunction. As is commonly observed in cases of LINH, the autoimmune inflammatory process regressed spontaneously, whereas the stalk dysfunction persisted. In light of these observations, observation is an appropriate initial management strategy in the majority of LINH cases. Our case serves as a demonstration of the importance of using noninvasive investigations at the initial presentation to avoid unnecessary burdens in suspected cases of LINH. MRI scans of hypothalamic-pituitary regions and testing for anti-rabphilin-3A antibodies can effectively aid clinicians in diagnosing LINH without requiring invasive pituitary biopsy. However, given the inability to rule out the possibility of other diseases without biopsy , and thaPatients with CDI of unknown etiology have a good indication for the radiological evaluation of hypothalamic-pituitary regions for the diagnosis of LINH.The lack of a posterior pituitary bright spot presented with the stalk thickening on MRI is highly relevant to LINH.Because the autoimmune inflammatory process regresses spontaneously and conservative management is pertinent in most cases of LINH, appropriate clinical, hormonal, and radiological evaluation at the initial presentation is pivotal to avoid unnecessary interventions such as GC treatment or pituitary surgery.In combination with radiological workup, testing for anti-rabphilin-3A antibodies provides a more specific diagnosis of LINH without invasive pituitary biopsy.Careful follow-up with hormonal and radiological assessment after diagnosis of LINH is mandatory to affirm regression of inflammation.


While most ancient DNA studies have focused on the last 50,000 years, paleogenomic approaches can now reach into the early Pleistocene, an epoch of repeated environmental changes that shaped present-day biodiversity. Emerging deep-time genomic transects, including from DNA preserved in sediments, will enable inference of adaptive evolution, discovery of unrecognized species, and exploration of how glaciations, volcanism, and paleomagnetic reversals shaped demography and community composition. In this review, we explore the state-of-the-art in paleogenomics and discuss key bottlenecks, including technical limitations, evolutionary divergence and associated biases, and the need for more precise dating of remains and sediments. We conclude that with improvements in laboratory and computational methods the emerging field of deep-time paleogenomics will expand the range of questions addressable using ancient DNA. The Pleistocene epoch  was a time of considerable environmental upheaval that shaped the present worldwide distribution of biodiversity. Environmental changes during the Pleistocene included cyclical fluctuations in global temperatures and precipitation patterns, advances and recessions of high-latitude ice sheets, and dramatic changes in sea-level, together with large-scale volcanism, paleomagnetic reversals, and the global spread of humans , thanks to fine-scale inferences enabled by ancient DNA preserved in fossils dating to this period. Such inferences have allowed insights into population turnover 6-11.7 ka and inteTechnical advances in DNA recovery have extended the ability to make these inferences deeper into the Pleistocene. DNA from bones and teeth that are several hundreds of thousands of years old –9 and beDNA does not survive indefinitely, but it does survive for significantly longer than the earliest models predicted. In 1993, Lindahl estimated that hydrolytic depurination would lead to complete degradation of DNA molecules within several tens of thousands of years . This liDNA begins to degrade immediately following organismal death, initially through microbial and endogenous nuclease activity . In nuclRecovery of increasingly old and damaged DNA is possible in part due to technical advances in the laboratory. Ancient DNA isolation methods are optimized to recover both short DNA molecules and molecules containing nicks and gaps. Extracted molecules are prepared for sequencing by ligating platform-specific adapters to either double-stranded or single-stranded DNA. Single-stranded approaches to genomic library preparation , 25 convThe short nature of deep-time DNA molecules makes them prone to spurious alignment and reference bias , complicXenocyon canids, could shed light on whether these taxa contributed to the genetic make-up of living carnivores. Deep-time paleogenomes could also identify unknown “ghost” lineages that contributed to species’ ancestries, as exemplified in the paleogenomic characterization of the Krestovka mammoth Fig. 1). Since the change in glacial periodicity, the dominant pattern has been cycles of long glaciations separated by short warm interglacials. This pattern is believed to have driven the demography and range dynamics of many species . Long inAbove, we describe insights potentially derived from DNA extracted from remains of individuals that lived during the Middle Pleistocene and earlier. However, the advances that enable deep-time paleogenomics also make it possible to reconstruct entire deep-time ecological communities. To date, only five studies have attempted to use sedimentary ancient DNA to reconstruct plant and/or animal communities dating to the Middle Pleistocene or older: Kjær et al  reconstrDeep-time sedimentary DNA research will allow better understanding of the effect of glacial-interglacial transitions on community composition. Reconstructions of communities spanning the transition into the present Holocene, for example, have revealed rapid biological turnover that closely tracked abiotic changes , 45. ComReconstructions of communities that thrived in past warm interglacials may provide insight into the potential composition of communities in a future, warmer world , and impIt has been shown that DNA can survive in ideal preservation conditions into at least the Early Pleistocene. The next phase of deep-time DNA research is to expand the taxonomic, geographic, and temporal range of recovered and authenticated deep-time DNA. This challenge presents new research opportunities in the field, at the bench, and bioinformatically.Deep-time genomics is today mostly conducted on substrates with optimal DNA preservation such as those derived from permafrost or caves. However, more efficient approaches to recover ancient DNA molecules will continue to expand the range of samples and substrates suitable for analysis. Today, methods for DNA extraction and library conversion do not recover all potentially preserved DNA molecules. For example, Kjaer et al  found thLibrary conversion protocols could also be made more efficient. Optimized library conversion protocols use enzymatic ligation and polymerization, but ancient DNA extracts contain inhibitors as well as molecules with uncharacterized DNA damage. Although we can convert as little as 100 picograms of DNA into libraries using the Santa Cruz method , libraryXenocyon canids and basal members of the elephant and horse families, have no evolutionarily close living relative for which an ideal reference genome can be produced. This presents challenges to ancient DNA authentication and identification as well as to reference-guided genome assembly. Although the average fragment length of deep-time DNA sequences is short, it may be possible to generate de novo assemblies from ancient extracts by capitalizing on methods that use chromosome conformation capture to retain proximity information useful to link short reads within a chromosome  for tooth enamel or luminescence approaches for minerals such as quartz and feldspar, can provide age estimates for samples dating throughout the Pleistocene, but require that sediments have remained undisturbed since burial (for a review see 54). When proteins are preserved, the extent of amino acid racemization, hydrolysis, and decay can also estimate time since death, although amino acid “clocks” vary among species and localities (in situ at sites where the tephra is present. As volcanic eruptions were common throughout the Pleistocene, improved tephrochronology for the Early and Middle Pleistocene will help place deep-time DNA into a chronological context.In some cases, paleoenvironmental, geological, and geophysical markers can provide clues about a sample's age. A fossil might be found in the Arctic with other paleoecological proxies that suggest a warm and wet environment, for example, indicating that the animal lived during a previous interglacial, or in sediments with reversed polarity, suggesting that it lived prior to the last paleomagnetic reversal some 780 ka. In some environments, tephra beds–layers of fine, settled, volcanic ash–can be dated by methods including glass fission-track and argon-argon dating. Tephra beds, which can be detected even when present in only microscopic amounts , have beOther approaches to dating deep-time genomes might rely on the predictable nature of evolutionary change in organisms. Molecular clock methods infer the age of paleogenomes by estimating the amount of “missing” evolution along a phylogenetic branch leading to the paleogenome, often called “branch shortening” . BecauseThe next decade will bring continued technical advances that will increase the taxonomic and geographic range of deep-time paleogenomes and deep-time ancient sedimentary DNA data sets. Most crucially, new insights into what substrates are likely to preserve deep-time ancient DNA as well as refined approaches to release DNA bound to biological or mineralogical matrices will increase the number and taxonomic range of recoverable deep-time paleogenomes. These will need to be placed into chronological context, which will be addressed with developments in geochronology and paleoecology together with increasingly powerful computational tools to estimate the age of samples using a molecular clock. The resulting deep-time DNA will enable increasingly detailed reconstruction of evolutionary history across repeated environmental perturbations, refining understanding of adaptive evolution, community organization, and ecosystem resilience. Moreover, as the past by its nature is different from anything that exists today, access to deep-time DNA provides ample yet unpredictable opportunities for scientific discovery.


Symbiotic fungi are widely distributed and form associations with over 90% of terrestrial plant species, playing an essential role in global agro- and forest ecosystems , fungal endophytes and the plant-associated fungal community.Yu et al. pointed out that AMF are sensitive to N addition over short timescales (1 year). Beneficial AMF associations are promoted under N-deficient conditions  is the available form of P that plants can acquire and utilize. However, Pi is often insufficient in the field due to its low solubility and relative immobilization  Lam.]), a versatile crop with high K requirements for enhanced yield. Their study showed that K application and the presence of AMF Claroideoglomus etunicatum exhibited a synergistic effect on the root development and K acquisition of the “Xu28” variety of sweet potato, which has high K use efficiency, resulting in significant yield promotion. These results, combined with previous studies, expand our knowledge of the influences of soil nutrients on plant-AMF symbiosis.Apart from N and Pi, the AMF-plant interaction is also sensitive to changes in soil K nutrient . They discovered that the fungal community structure in the rhizosphere can vary across vegetation types and is primarily governed by deterministic processes. Additionally, plant metabolism has a significant impact on the plant-associated microbiome (Trivedi et al., Zhu et al. demonstrated that by applying exogenous salicylic acid, beneficial rhizosphere microorganisms were selectively enriched to enhance watermelon resistance to Fusarium wilt. These community analyses provide insights into the potential of plant-associated fungi in sustainable agriculture.The response of the plant-associated fungal community to global changes plays a crucial role in understanding carbon and N cycling processes in agro- and forest ecosystems (Falkowski et al., In this Research Topic, the majority of the studies aimed to elucidate the influences of changing environmental conditions, particularly soil nutrients, on plant-fungal symbiosis. However, more efforts are needed to clarify the molecular mechanisms underlying how nutrient factors drive the maintenance and breakdown of plant-fungi symbionts. Additionally, limited studies have been conducted under field conditions, which could provide better guidance for agricultural production. We anticipate further novel discoveries in the future.KS wrote the manuscript. All authors reviewed and revised the manuscript.


Blood vessels are well-known to play roles in organ development and repair, primarily owing to their fundamental function in delivering oxygen and nutrients to tissues to promote their growth and homeostasis. Endothelial cells however are not merely passive conduits for carrying blood. There is now evidence that endothelial cells of the vasculature actively regulate tissue-specific development, morphogenesis and organ function, as well as playing roles in disease and cancer. Angiocrine factors are growth factors, cytokines, signaling molecules or other regulators produced directly from endothelial cells to instruct a diverse range of signaling outcomes in the cellular microenvironment, and are critical mediators of the vascular control of organ function. The roles of angiocrine signaling are only beginning to be uncovered in diverse fields such as homeostasis, regeneration, organogenesis, stem-cell maintenance, cell differentiation and tumour growth. While in some cases the specific angiocrine factor involved in these processes has been identified, in many cases the molecular identity of the angiocrine factor(s) remain to be discovered, even though the importance of angiocrine signaling has been implicated. In this review, we will specifically focus on roles for endothelial-derived angiocrine signaling in instructing tissue morphogenesis and organogenesis during embryonic and perinatal development. The cardiovascular network forms during early embryogenesis, and is essential for the delivery of oxygen and nutrients, as well as removal of waste products from cells and tissues, which is essential for correct growth of the developing embryo. The vasculature forms primarily through angiogenesis, whereby endothelial cells, which make up the inner lining of vessels, respond to angiogenic signals which stimulate their proliferation, sprouting and remodeling into an organized network of arteries, veins and capillaries . In addiin vivo in animal models.Over recent years, with the advent of new technologies such as single-cell analysis, it has now become possible to interrogate the molecular interactions between endothelial cells and their microenvironment, and in turn how endothelial cells influence organogenesis in a tissue-specific manner. While in some cases tissue-specific vasculature has long been known to direct development and differentiation of surrounding cells, the molecular identity of the specific endothelial-derived angiocrine factors directing these processes have often remained elusive. Given the recent emergence of new technologies in transcriptomics, proteomics, and genetic engineering, many of these previously uncharacterised angiocrine factors are now beginning to be identified and validated in vivo evidence for roles in instructing normal embryo development are presented in Other recent reviews  have docin vivo. Angiopoietin signaling has also been implicated in vessel wall assembly. The tyrosine kinase receptor Tie2 is expressed on endothelial cells, and is stimulated by its ligand angiopoietin-1, which is secreted by the mesenchyme surrounding vessels (One of the first identified angiocrine factors was platelet-derived growth factor B (PDGF-B), known for its role in mediating pericytes recruitment and blood vessel wall assembly. Early work showed PDGF-B is secreted from the basal surface of endothelial cells and is chemotactic for smooth muscle cells , which e vessels . Angiopo vessels , however vessels . Mouse e vessels , suggest vessels  and hepa vessels , both ofin vitro 3D pericytes/endothelial co-culturing system has also revealed the complexity of endothelial-derived factors in pericytes recruitment and capillary network formation. Factors such as TGF-β1 were shown to prime pericytes to respond to PDGFs and ET-1 which drive pericytes invasion, with HB-EGF rather stimulating pericytes proliferation  valves. Valve formation is preceded by endothelial-to-mesenchymal transition (EndoMT) of a subpopulation of endocardial cells to form valve interstitial cells which expand the cardiac jelly located between the endocardium and myocardium . These eocardium . This suocardium . In thisocardium . In agreocardium . Recentlocardium , and thuogenesis . Endocarogenesis . Wnt9b wogenesis . Endocarogenesis . Furtherogenesis .in vivo, with lymphatic endothelial cell conditioned medium shown to promote cardiomyocyte proliferation in vitro  and human bone marrow osteoprogenitor stromal cells (HBMSC) mediated by gap junctions involving connexin-43, with this interaction essential to drive osteoprogenitor differentiation, and upregulation of osteoblast markers  specifically in liver endothelial cells , which attracts angioblasts expressing chemokine receptor type 4 (CXCR4) . EndoderIn vitro co-culture studies have attempted to address the interactions between endothelial cells and pancreatic progenitors. Embryoid bodies derived from human pluripotent stem cells were co-cultured with endothelial cells, to assess effects on differentiation of insulin-producing pancreatic β-cells, which exhibited enhanced insulin secretion in vitro, as well as in vivo upon transplantation into mice  mice lack formation of the dorsal pancreas, owing to failure of dorsal pancreatic mesenchymal cell survival  (S1P1−/−) additional roles were uncovered for vasculature in later stages of pancreas branching and morphogenesis. S1P1 is specifically expressed in endothelium  . Howeverte (S1P)  these reothelium , and the/− mice . Unexpecelopment . Indeed,elopment . Furtherelopment . Converselopment . The finelopment  and adulelopment ]. While Blood vessels constitute an integral component of the lung alveoli, facilitating delivery of oxygen to tissues while also removing carbon dioxide via gas-exchange between alveolar epithelial cells and capillary endothelial cells through the thin alveolar membrane . Blood vSuggestions of cross-talk between endothelial and epithelial cells in the developing lung arose through studies in endothelial NO synthase (eNOS) knockout mice, which exhibit defective pulmonary development, in part attributed to defective vascular development, thickening of the saccular septal and defective surfactant production . HoweverIn agreeance with a critical role for VEGF in lung development, conditional removal of VEGF specifically in lung epithelial cells resulted in almost complete absence of pulmonary capillary development, and associated defects in saccular septation . Interesex vivo cell culture assays using pulmonary endothelial cells and lung fibroblasts, VEGF was shown to stimulate expression of retinoic acid synthesising enzymes (RALDHs) and RA in endothelial cells, and in turn RA was shown to stimulate expression of FGF-18, which regulates elastin production, in lung fibroblasts  has also been implicated as an angiocrine factor in lung development. In roblasts . Furtherroblasts . Anotherroblasts . Additioelopment . These sEndothelial-derived MMP14 has also been shown to drive release of matrix-associated EGFR ligands that are essential to promote regenerative alveolarization after lung injury , as wellcloche mutant, podocytes are able to form a basement membrane, but their structure and maintenance are affected , podocytes  and a basement membrane . In addiaffected . Blood faffected  and for affected . Blood faffected . This fiaffected . As in oaffected . More reaffected . These nCoordinated development of the neuronal and vascular systems has been appreciated since the first anatomical description of the mammalian body plan which described precise alignment of major axonal tracts alongside the major blood vessels . One of Within the central nervous system, neural stem cells play a key role in promoting vessel growth through the expression of growth factors such as VEGF and WNT family members . In turnIn other regions of the central nervous system, blood vessels have instead been proposed to positively regulate cell divisions that promote differentiation. The first study to detail this phenomenon forced excessive vessel growth in the mouse cortex by ectopic expression of VEGF which led to advanced neural precursor maturation . Using gOutside of their roles on neurons, vessels also affect the development of additional cell types within the nervous system. Soluble factors from endothelial cells were found to promote growth dynamics of astrocytes from neonatal rat brains  and lateHaematopoiesis is the process by which blood cells are produced. It is first observed during embryogenesis and continues indefinitely throughout life to maintain blood cell populations . Most reEarly reports of angiocrine signalling involvement in haematopoiesis originated from studies investigating liver organogenesis, where sinusoidal endothelial cell-specific knockout of GATA4 resulted in significant disruption to the vascular architecture during liver development . In addiThe advent of single-cell RNA sequencing provided a significant breakthrough in elucidating the mechanisms involved in fetal haematopoiesis. Single-cell sequencing of fetal bone marrow cells indicates that Wnt2 expression is upregulated in arterial endothelial cells of mice at E18.5, and that Wnt2 receptors Frizzled-5 and Frizzled-9 are upregulated in HSCs . Geneticex vivo organ culture models, depletion of endothelial cells or inhibition of VEGFR2 signalling, disrupted epithelial patterning of the gland  under investigation are derived from the endothelium, and that their removal specifically from the endothelium regulates the biological process in target cell-types. Conditional mouse models taking advantage of endothelial-specific Cre expression, such as Cdh5-CreERT2 and Tie2-Cre mouse lines, have been used in many studies to uncover and explore the roles of angiocrine factors. However, a potential caveat of this approach, which is not always controlled for, are the cell-autonomous changes to gene expression and function resulting from gene deletion, Cre expression and treatment with activators such as Tamoxifen (A bottleneck in the field is the provision of amoxifen . ExpandiWhile this review has focused on the discussion of angiocrine factors in embryonic development, it should also be noted that angiocrine and lymphangiocrine signaling has important roles in regeneration, homeostasis and disease, which have been explored in other recent reviews . As the