Degree Of Heterogeneity Research Articles

Neuroinflammation in Glioblastoma: The Role of the Microenvironment in Tumour Progression.

Glioblastoma (GBM) stands as the most aggressive and lethal among the main types of primary brain tumors. It exhibits malignant growth, infiltrating the brain tissue, and displaying resistance toward treatment. GBM is a complex disease characterized by high degrees of heterogeneity. During tumour growth, microglia and astrocytes, among other cells, infiltrate the tumour microenvironment and contribute extensively to gliomagenesis. Tumour-associated macrophages (TAMs), either of peripheral origin or representing brain-intrinsic microglia, are the most numerous nonneoplastic populations in the tumour microenvironment in GBM. The complex heterogeneous nature of GBM cells is facilitated by the local inflammatory tumour microenvironment, which mostly induces tumour aggressiveness and drug resistance. The immunosuppressive tumour microenvironment of GBM provides multiple pathways for tumour immune evasion, contributing to tumour progression. Additionally, TAMs and astrocytes can contribute to tumour progression through the release of cytokines and activation of signalling pathways. In this review, we summarize the role of the microenvironment in GBM progression, focusing on neuroinflammation. These recent advancements in research of the microenvironment hold the potential to offer a promising approach to the treatment of GBM in the coming times.

Spatial and Temporal Heterogeneity of Eco-Environmental Quality in Yanhe Watershed (China) Using the Remote-Sensing-Based Ecological Index (RSEI)

The long-term impacts of climate change and human activities have resulted in the Yanhe watershed, a typical watershed in the Loess Plateau region, exhibiting a high degree of vulnerability and significant heterogeneity in ecological environmental quality. This has led to environmental degradation and complex socio-ecological challenges. Consequently, there is an urgent need to carry out research on the spatial and temporal differentiation patterns of ecological environment quality. By utilizing remote sensing data spanning 21 years, this study evaluated the evolutionary trends and consistency of ecological environment quality (EEQ) within the Yanhe watershed based on the remote-sensing-based ecological index (RSEI). Furthermore, it examined global and local spatial autocorrelation of the RSEI by constructing a hexagonal grid, thereby revealing the spatiotemporal characteristics of EEQ at different scales within the Yanhe watershed. The results were as follows: (1) The EEQ has exhibited an overall upward trend in the past two decades, while it has displayed significant fluctuations; (2) the Global Moran’s I values for the years 2000, 2010, and 2020 were 0.18, 0.32, and 0.21, respectively, indicating a presence of spatial autocorrelation within the RSEI; (3) the overall EEQ of the Yanhe watershed will continue to improve, although the ecological quality in certain areas remains unstable due to local natural conditions and human activities. This research not only contributes to the technical framework for analyzing the spatiotemporal heterogeneity of EEQ but also provides actionable insights for ecosystem restoration and sustainability within the Loess Plateau watershed. Our work advances the understanding of ecological dynamics in semi-arid regions and offers a model for assessing ecological quality in similar environmental contexts.

Meta-Analysis on the Therapeutic Effect of Transcatheter Arterial Chemoembolization Combined with Portal Vein Embolization.

The aim of the study was to conduct a systematic review to explore the therapeutic effect of transcatheter arterial chemoembolization (TACE) combined with portal vein embolization (PVE) for patients with hepatocellular carcinoma (HCC). Chinese and English databases (PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wanfang database, and VIP database) were searched from database inception to August 15, 2023. Studies comparing TACE combined with PVE versus TACE alone for patients with HCC were included. The degree of heterogeneity was assessed using I2 statistics and a Q test. The effect size was represented by risk ratio and mean difference (MD), and the effect size range was estimated using a 95% confidence interval (CI). Eight eligible studies were included in the systematic review, involving 689 participants. The results showed that the future liver residual (FLR) of patients treated with TACE combined with PVE was significantly higher than that of those treated with PVE alone (MD = 3.99%; 95% CI: 1.03-6.94). Furthermore, compared with PVE alone, TACE combined with PVE had a positive effect on disease-free survival (odds ratio [OR] = 2.16; 95% CI: 1.20-3.88), recurrence rate (OR = 0.79; 95% CI: 0.07-9.42), and complications (OR = 0.53; 95% CI: 0.30-0.96). There was no statistically significant impact on mortality with TACE combined with PVE treatment. The combination of TACE with PVE can significantly reduce the FLR of patients with HCC, with higher disease-free survival, lower recurrence rate, and fewer complications.

Unraveling the characteristic spatial scale of habitat selection for forest grouse species in the boreal landscape

The characteristic spatial scale at which species respond strongest to forest structure is unclear and species-specific and depends on the degree of landscape heterogeneity. Research often analyzes a pre-defined spatial scale when constructing species distribution models relating forest variables with occupancy patterns. This is a limitation, as forest characteristics shape the species use of habitat at multiple spatial scales. To explore the drivers of this relationship, we conducted an in-depth investigation into how scaling forest variables at biologically relevant spatial scales affects occupancy of grouse species in boreal forest. We used 4,790 grouse observations (broods and adults) collected over 39,303 stands for 15 years of four forest grouse species (capercaillie, black grouse, hazel grouse, and willow grouse) obtained from comprehensive Finnish wildlife triangle census data and forest variables obtained from Airborne Laser Scanning and satellite data originally sampled at 16 m resolution. We fitted Generalized Additive Mixed Models linking grouse presence/absence in the Finnish boreal forest with forest stand structure and composition. We estimated the effects of predictor variables aggregated at three spatial scales reflecting the species use of the landscape: local level at stand scale, home range level at 1 km radius, and regional level at 5 km radius. Multi-grain models considering forest-species relationships at multiple scales were used to evaluate whether there is a specific scale at which forest characteristics best predict local grouse occupancy. We found that that the spatial scale affected the predictive capacity of the grouse occupancy models and the characteristic scale of habitat selection was the same (i.e., stand scale) among species. Different grouse species exhibited varying optimal spatial scales for occupancy prediction. Forest structure was more important than compositional diversity in predicting grouse occupancy irrespective of the scale. A limited number of forest predictors related to availability of multi-layered vegetation and of suitable thickets explained the occupancy patterns for all the grouse species at different scales. In conclusion, modeling grouse occupancy using forest predictors at different spatial scales can inform forest managers about the scale at which the species perceive the landscape. This evidence calls for an integrated multiscale approach to habitat modelling for forest species.

Augmenting X-ray micro-CT data with MICP data for high resolution pore-scale simulations of flow properties of carbonate rocks

Pore-scale modeling is essential in understanding and predicting flow and transport properties of rocks. Generally, pore-scale modeling is dependent on imaging technologies such as Micro Computed Tomography (micro-CT), which provides visual confirmation into the pore microstructures of rocks at a representative scale. However, this technique is limited in the ability to provide high resolution images showing the pore-throats connecting pore bodies. Pore scale simulations of flow and transport properties of rocks are generally done on a single 3D pore microstructure image. As such, the simulated properties are only representative of the simulated pore-scale rock volume. These are the technological and computational limitations which we address here by using a stochastic pore-scale simulation approach. This approach consists of constructing hundreds of 3D pore microstructures of the same pore size distribution and overall porosity but different pore connectivity. The construction of the 3D pore microstructures incorporates the use of Mercury Injection Capillary Pressure (MICP) data to account for pore throat size distribution, and micro-CT images to account for pore body size distribution. The approach requires a small micro-CT image volume (7–19 mm3) to reveal key pore microstructural features that control flow and transport properties of highly heterogeneous rocks at the core-scale. Four carbonate rock samples were used to test the proposed approach. Permeability calculations from the introduced approach were validated by comparing laboratory measured permeability of rock cores and permeability estimated using five well-known core-scale empirical model equations. The results show that accounting for the stochastic connectivity of pores results in a probabilistic distribution of flow properties which can be used to upscale pore-scale simulated flow properties to the core-scale. The use of the introduced stochastic pore-scale simulation approach is more beneficial when there is a higher degree of heterogeneity in pore size distribution. This is shown to be the case with permeability and hydraulic tortuosity which are key controls of flow and transport processes in rocks.

High-Resolution Estimation of Soil Saturated Hydraulic Conductivity via Upscaling and Karhunen–Loève Expansion within DREAM(ZS)

Quantification of the soil hydraulic conductivity is key to the study of water flow and solute transport in unsaturated soils. Rapid advances in measurement technology have provided a large number of observations at different scales, offering unprecedented opportunities and challenges for the estimation of hydraulic parameters. This paper proposes an inverse estimation method for downscaling of observations on coarse scales to estimate hydraulic parameters on high-resolution scales. Due to the significant spatial heterogeneity, the inversion faces the problems of dynamics-based integration of data at different scales, model uncertainty due to hundreds and thousands of parameters, and computational consumption due to the large number of forward simulations. To overcome these problems, this paper uses an efficient Bayesian optimization DREAM(ZS) as an inverse framework, and incorporates an analytical upscaling method and Karhunen–Loève (KL) expansion to infer finer-scale saturated hydraulic conductivity distribution conditioned on coarse-scale measurements. The efficient upscaling method is used to link measurements and hydraulic parameters at different scales, and Karhunen–Loève (KL) expansion is incorporated to greatly reduce the dimension of the parameter to be estimated. To further improve the efficiency of the inversion, a locally one-dimensional (LOD) algorithm is used to solve the multidimensional water flow model at coarse scales. The proposed inverse model is applied in a series of numerical experiments to demonstrate its applicability and effectiveness under different flow boundary conditions, different levels of ratio between coarse- and fine-scale grids, different densities of observation points, and different degrees of statistic heterogeneity of soil mediums.

Metabolic dysfunction-associated steatotic liver disease heterogeneity: Need of subtyping

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread global disease with significant health burden. Unhealthy lifestyle, obesity, diabetes mellitus (DM), insulin resistance, and genetics have been implicated in the pathogenesis of MASLD. A significant degree of heterogeneity exists among each of above-mentioned risk factors. Heterogeneity of these risk factors translates into the heterogeneity of MASLD. On the other hand, MASLD can itself lead to insulin resistance and DM. Such heterogeneity makes it difficult to assess the natural course of an individual with MASLD in clinical practice. At present MASLD is considered as one disease despite the variability of etiopathogenic processes, and we lack the consensus definitions of unique subtypes of MASLD. In this review, pathogenic processes of MASLD are discussed and a need of subtyping is recommended.

Effect of Strain Rate on Mechanical Deformation Behavior in CuZr Metallic Glass.

Tensile tests were performed on Cu64Zr36 metallic glass at strain rates of 107/s, 108/s, and 109/s via classical molecular dynamics simulations to explore the underlying mechanism by which strain rate affects deformation behavior. It was found that strain rate has a great impact on the deformation behavior of metallic glass. The higher the strain rate is, the larger the yield strength. We also found that the strain rate changes the atomic structure evolution during deformation, but that the difference in the atomic structure evolution induced by different strain rates is not significant. However, the mechanical response under deformation conditions is found to be significantly different with the change in strain rate. The average von Mises strain of a system in the case of 107/s is much larger than that of 109/s. In contrast, more atoms tend to participate in deformation with increasing strain rate, indicating that the strain localization degree is more significant in cases of lower strain rates. Therefore, increasing the strain rate reduces the degree of deformation heterogeneity, leading to an increase in yield strength. Further analysis shows that the structural features of atomic clusters faded out during deformation as the strain rate increased, benefiting more homogeneous deformation behavior. Our findings provide more useful insights into the deformation mechanisms of metallic glass.

Multi-targeted effects of D-carvone against Non-Small Cell Lung Cancer (NSCLC): A network pharmacology-based study

Non-small cell lung cancer (NSCLC) is a complex malignancy with a high degree of heterogeneity, representing approximately 85% of all lung cancer cases. The treatment landscape for NSCLC has been revolutionised by incorporating targeted and immunotherapies; however, novel therapeutic modalities are consistently needed to enhance the treatment outcomes. Indeed, alternative anti-cancer therapies involving natural products have drawn the attention of clinicians and scientists owing to their remarkable chemopreventive potential, often displaying minimal toxicity. D-carvone (CN) is one such natural product that has exhibited numerous promising therapeutic benefits, yet its efficacy against NSCLC remains enigmatic. In the present study, network pharmacological studies and molecular docking in conjunction with in-vitro validation were used to elucidate the underlying mechanism of action of CN comprehensively. Different databases revealed a total of 77 putative anti-NSCLC targets of CN. The identified core targets were utilised to construct a “Compound- Target- Disease” network by Cytoscape (v3.9.0). Further analysis identified 5 core/ hub targets of CN including JAK2, ERK1, ESR1, GSK3B and HSP90AA1. Molecular docking indicated a strong binding interaction of the compound with these core targets. Also, Gene Ontology and KEGG analysis validated the involvement of multiple biological processes. Additionally, CN significantly inhibited cell proliferation, clonogenicity, and wound healing potential while promoting apoptosis in a dose-dependent manner in H1299 and A549 cell lines as examined by flow cytometry, morphological assessment, and western blotting. In conclusion, this study delineates the therapeutic effects of CN on NSCLC, thus highlighting CN as a putative drug candidate for further analysis.

Influence of physicochemical characteristics of calcium phosphate-based biomaterials in cranio-maxillofacial bone regeneration. A systematic literature review and meta-analysis of preclinical models

ObjectivesCalcium phosphate-based biomaterials (CaP) are the most widely used biomaterials to enhance bone regeneration in the treatment of alveolar bone deficiencies, cranio-maxillofacial and periodontal infrabony defects, with positive preclinical and clinical results reported. This systematic review aimed to assess the influence of the physicochemical properties of CaP biomaterials on the performance of bone regeneration in preclinical animal models. MethodsThe PubMed, EMBASE and Web of Science databases were searched to retrieve the preclinical studies investigating physicochemical characteristics of CaP biomaterials. The studies were screened for inclusion based on intervention (physicochemical characterization and in vivo evaluation) and reported measurable outcomes. ResultsA total of 1532 articles were retrieved and 58 studies were ultimately included in the systematic review. A wide range of physicochemical characteristics of CaP biomaterials was found to be assessed in the included studies. Despite a high degree of heterogeneity, the meta-analysis was performed on 39 studies and evidenced significant effects of biomaterial characteristics on their bone regeneration outcomes. The study specifically showed that macropore size, Ca/P ratio, and compressive strength exerted significant influence on the formation of newly regenerated bone. Moreover, factors such as particle size, Ca/P ratio, and surface area were found to impact bone-to-material contact during the regeneration process. In terms of biodegradability, the amount of residual graft was determined by macropore size, particle size, and compressive strength. ConclusionThe systematic review showed that the physicochemical characteristics of CaP biomaterials are highly determining for scaffold's performance, emphasizing its usefulness in designing the next generation of bone scaffolds to target higher rates of regeneration.

Breastfeeding and risk of food allergy and allergic rhinitis in offspring: a systematic review and meta-analysis of cohort studies

The association between breastfeeding and the occurrence of allergic rhinitis (AR) and food allergy (FA) in offspring remains inconclusive. This review aims to comprehensively explore the potential relationships between various patterns and durations of breastfeeding and allergic diseases in offspring. We systematically searched PubMed, EMBASE, Cochrane, WOS databases, and Google Scholar for observational studies published up to March 30, 2023, that investigated the link between breastfeeding and allergies in offspring. The quality of the studies was assessed using the Newcastle-Ottawa Scale (NOS) and Joanna Briggs Institute (JBI). Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated employing an appropriate model based on the degree of heterogeneity. A total of 68 studies, encompassing 772,142 children, were ultimately included. The findings indicated that breastfeeding for more than 6 months was associated with a reduced risk of AR (OR = 0.88, 95% CI: 0.79 to 0.98) but posed a risk for FA (OR = 1.69, 95% CI: 1.27 to 2.25). Exclusive breastfeeding exhibited a protective effect against AR (OR = 0.94, 95% CI: 0.90 to 0.97), whereas non-breastfeeding was identified as a risk factor for AR (OR = 1.48; 95% CI: 1.03 to 2.12). No significant association was observed between breastfeeding patterns and FA. Conclusion: Breastfeeding for more than 6 months proves to be an effective preventive measure against AR. However, large prospective high-quality studies are needed to investigate the potential risk of FA in children with prolonged breastfeeding.What is Known:• The impact of breastfeeding on allergic rhinitis and food allergy in offspring is controversial.• Previous meta-analyses fail to prove the effect of breastfeeding on food allergy in offspring of all ages.What is New:• Breastfeeding for more than 6 months proves to be an effective preventive measure against AR. However, it potentially elevates the risk of FA in children. Non-breastfeeding is linked to an increased risk of AR in children, but there is no evidence of an association between breastfeeding patterns and FA in children.• The impact of breastfeeding on allergic rhinitis and food allergy in offspring may vary with the time and pattern of breastfeeding.

Non-proportional hazards model with a PVF frailty term: application with a melanoma dataset

Survival data analysis often uses the Cox proportional hazards (PH) model. This model is widely applied due to its straightforward interpretation of the hazard ratio under the assumption that the hazard rates for two subjects remain constant over time. However, in several randomized clinical trials with long-term survival data comparing two new treatments, it is frequently observed that Kaplan-Meier plots exhibit crossing survival curves. This violation of the PH assumption of the Cox PH model can not be applied to evaluate the treatment's effect on survival. This paper introduces a novel long-term survival model with non-PH that incorporates a frailty term into the hazard function. This model allows us to examine the effect of prognostic factors on survival and quantify the degree of unobservable heterogeneity. The model parameters are estimated using the maximum likelihood estimation procedure, and we evaluate the performance of the proposed models through simulation studies. Additionally, we demonstrate the applicability of our approach by fitting the models to a real skin cancer dataset.

Computed tomographic heterogeneous enhancement of spleen in healthy cats: comparing with diffuse infiltrative splenic lesions.

Contrast-enhanced computed tomography (CT) of the spleen in dogs and cats often displays a heterogeneous enhancement pattern. This study aimed to describe the CT appearances and duration of heterogeneous splenic enhancement in clinically healthy cats and to compare those enhancements with diffuse infiltrative splenic lesions (DISL). Spleens of 14 healthy cats were imaged using contrast-enhanced CT protocols which were obtained at 10, 25, and 45 s, and then every 40 s thereafter until 245 s had past from the initiation of contrast medium injection. The presence of transient splenic heterogeneity was evaluated. In addition, the relationships of certain variables including age, weight, systolic blood pressure, and splenic volume to the duration and the degree of splenic enhancement were determined. Also, medical records and CT images of five cats with DISL were retrospectively evaluated. Transient heterogeneous enhancement of the spleen was observed in all 14 healthy cats, and the maximum heterogeneity was observed 25 s after the injection. Splenic heterogeneity lasted more than 5 min in nine of 14 cats (64.3%). No statistically significant relationships were seen between the duration and degree of splenic heterogeneity in the images taken 25 s after the injection and variables including weight, age, systolic blood pressure, and splenic volume. Compared to the healthy group, early homogeneous splenic enhancement along with generalized splenomegaly was observed in all cats with DISL. Transient splenic heterogeneity is highly common in cats undergoing contrast-enhanced CT even in the generally scanned delayed phases, which can help with the interpretation of CT images of feline spleens. In addition, our results suggest that homogeneous splenic enhancement in post-contrast CT scans along with splenomegaly on CT images could be useful as a diagnostic indicator of DISL in cats.

The gut microbiome, resistome, and mycobiome in preterm newborn infants and mouse pups: lack of lasting effects by antimicrobial therapy or probiotic prophylaxis

BackgroundEnhancing our understanding of the underlying influences of medical interventions on the microbiome, resistome and mycobiome of preterm born infants holds significant potential for advancing infection prevention and treatment strategies. We conducted a prospective quasi-intervention study to better understand how antibiotics, and probiotics, and other medical factors influence the gut development of preterm infants. A controlled neonatal mice model was conducted in parallel, designed to closely reflect and predict exposures. Preterm infants and neonatal mice were stratified into four groups: antibiotics only, probiotics only, antibiotics followed by probiotics, and none of these interventions. Stool samples from both preterm infants and neonatal mice were collected at varying time points and analyzed by 16 S rRNA amplicon sequencing, ITS amplicon sequencing and whole genome shotgun sequencing.ResultsThe human infant microbiomes showed an unexpectedly high degree of heterogeneity. Little impact from medical exposure (antibiotics/probiotics) was observed on the strain patterns, however, Bifidobacterium bifidum was found more abundant after exposure to probiotics, regardless of prior antibiotic administration. Twenty-seven antibiotic resistant genes were identified in the resistome. High intra-variability was evident within the different treatment groups. Lastly, we found significant effects of antibiotics and probiotics on the mycobiome but not on the microbiome and resistome of preterm infants.ConclusionsAlthough our analyses showed transient effects, these results provide positive motivation to continue the research on the effects of medical interventions on the microbiome, resistome and mycobiome of preterm infants.

Study on the multifractal characterization and seepage of the shale matrix: A case study of the Longmaxi Formation in southwestern Sichuan Basin, China

The pore structure and heterogeneity of shale significantly impact the occurrence and permeability of shale gas. Studying these aspects is beneficial for exploring and developing shale gas. In this study, organic-rich shale from the Longmaxi Formation in the Luzhou-Changning area was selected as the research subject. Experiments, including spontaneous imbibition, pressure saturation, and nuclear magnetic resonance, were conducted to characterize the pore structure and heterogeneity of the shale in this area. Using multifractal theory, we analyzed and discussed the multifractal characteristics of pores with different connectivities in relation to permeability. The results indicate that the T2 cutoff value (T2f) of the shale is greater than the T2c value, suggesting that the pore size of connected pores exceeds that of pores retaining bound water. The sizes of connected pores primarily range from 1 to 30 nm, predominantly between 1 and 10 nm. Significant differences were observed in the multifractal spectrum functions under dry, spontaneous imbibition, and water-saturated conditions, reflecting varying degrees of heterogeneity. The multifractal parameters differ, with higher ΔD values under water-saturated conditions, indicating that pores with weaker connectivity enhance the overall heterogeneity of the shale when saturated. Conversely, lower ΔD values under dry conditions suggest less heterogeneity in pores containing bound water. Total organic carbon (TOC) and clay content were identified as the main factors influencing the development of connected pores. Based on these findings, a discriminant 3D diagram correlating permeability with porosity, tortuosity, and multifractal parameters (D0-Dmax) of strongly connected pores was established for the Luzhou-Changning area. This diagram serves as an effective tool for evaluating the flow capacity of shale reservoirs and offers guidance for identifying sweet spots within the reservoir.

Graph theory based estimation of probable CO2 plume spreading in siliciclastic reservoirs with lithological heterogeneity

Estimating plume spreading in geological CO2 storage reservoirs is critical for several reasons including the assessment of pore space utilization efficiency, preferential CO2 migration pathways and trapping. However, plume spreading critically depends on lithological heterogeneity of the reservoir and CO2 injection rate. It might require numerous high fidelity full physics numerical simulations to constrain the uncertainty in plume spreading for a given reservoir. This might not always be practical due to computational limitations. Hence, reduced physics approaches, such as invasion-percolation method and machine learning, could be useful to answer certain questions on plume spreading in the subsurface. This study presents a new reduced physics approach based on graph theory for estimating probable CO2 plume migration under very low and very high injection rates. The two end-member scenarios are assessed by performing random walk in the 3D reservoir space to constrain 20,000 possible paths of CO2 flow away from the injection well. The resistance to CO2 flow associated with each path is computed for viscous, capillary and gravity forces. The resistances are then transformed into the likelihood of CO2 migration along the path. The algorithm was applied to 45 reservoir models with varying degrees of lithological heterogeneity and the results were compared to those from full physics and invasion percolation simulations. The graph theory results showed a close match with the results from full physics approach for both flow regimes and with results from invasion-percolation approach for capillary-gravity dominated flow regime. The algorithm was further applied to answer key questions on reservoir screening such as pore space utilization potential. The graph theory approach was also integrated with machine learning to predict CO2 saturation. Testing suggested that the graph theory approach can be as much as 50 and 20 times faster than the full physics numerical simulations and invasion-percolation simulations, respectively.

Treatment Outcomes of Pulpotomy in Primary Teeth with Irreversible Pulpitis: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis aimed to evaluate the success rates of pulpotomy treatment for irreversible pulpitis in primary teeth. This study was registered and conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols. Relevant studies published between January 1980 and April 2023 were identified across eight online databases and two paediatric dentistry textbooks. Study selection, data extraction, and quality assessment were conducted by multiple investigators independently. Data analysis involved single-arm and two-arm meta-analyses, leave-one-out sensitivity analysis, meta-regression, and assessment of publication bias. The risks of bias were evaluated using the Cochrane Collaboration's assessment tools. The levels of evidence were determined using the Oxford Centre for Evidence-Based Medicine (OCEBM) tool. Five primary studies were included. The weighted mean overall success rates at 6-month and 12-month follow-ups were 97.2% and 94.4%, respectively. Two-arm meta-analysis revealed no significant difference (p > 0.05) between the use of mineral trioxide aggregate (MTA) and non-MTA bioceramic-based materials as pulpotomy medicaments. The sample size of each study did not affect the degree of data heterogeneity. Egger's test revealed no significant publication bias. Pulpotomy may be regarded as an alternative modality for treating primary teeth with irreversible pulpitis. Nevertheless, future well-designed trials and extended follow-up periods are warranted.

[18F]FMISO-PET imaging reveals the role of hypoxia severity in checkpoint blockade response

ContextHypoxia within the tumor microenvironment is a critical factor influencing the efficacy of immunotherapy, including immune checkpoint inhibition. Insufficient oxygen supply, characteristic of hypoxia, has been recognized as a central determinant in the progression of various cancers. The reemergence of evofosfamide, a hypoxia-activated prodrug, as a potential treatment strategy has sparked interest in addressing the role of hypoxia in immunotherapy response. This investigation sought to understand the kinetics and heterogeneity of tumor hypoxia and their implications in affecting responses to immunotherapeutic interventions with and without evofosfamide. PurposeThis study aimed to investigate the influence of hypoxia on immune checkpoint inhibition, evofosfamide monotherapy, and their combination on colorectal cancer (CRC). Employing positron emission tomography (PET) imaging, we developed novel analytical methods to quantify and characterize tumor hypoxia severity and distribution. ProceduresMurine CRC models were longitudinally imaged with [18F]-fluoromisonidazole (FMISO)-PET to quantify tumor hypoxia during checkpoint blockade (anti-CTLA-4 + and anti-PD1 +/− evofosfamide). Metrics including maximum tumor [18F]FMISO uptake (FMISOmax) and mean tumor [18F]FMISO uptake (FMISOmean) were quantified and compared with normal muscle tissue (average muscle FMISO uptake (mAvg) and muscle standard deviation (mSD)). Histogram distributions were used to evaluate heterogeneity of tumor hypoxia. FindingsSevere hypoxia significantly impeded immunotherapy effectiveness consistent with an immunosuppressive microenvironment. Hypoxia-specific PET imaging revealed a striking degree of spatial heterogeneity in tumor hypoxia, with some regions exhibiting significantly more severe hypoxia than others. The study identified FMISOmax as a robust predictor of immunotherapy response, emphasizing the impact of localized severe hypoxia on tumor volume control during therapy. Interestingly, evofosfamide did not directly reduce hypoxia but markedly improved the response to immunotherapy, uncovering an alternative mechanism for its efficacy. ConclusionsThese results enhance our comprehension of the interplay between hypoxia and immune checkpoint inhibition within the tumor microenvironment, offering crucial insights for the development of personalized cancer treatment strategies. Non-invasive hypoxia quantification through molecular imaging evaluating hypoxia severity may be an effective tool in guiding treatment planning, predicting therapy response, and ultimately improving patient outcomes across diverse cancer types and tumor microenvironments. It sets the stage for the translation of these findings into clinical practice, facilitating the optimization of immunotherapy regimens by addressing tumor hypoxia and thereby enhancing the efficacy of cancer treatments.

Prevalence of human papillomavirus in oral cancer in Asia: A systematic review and meta-analysis.

To determine the prevalence of human papillomavirus (HPV) in oral squamous cell carcinoma (OSCC) across Asian countries, focusing on South and Southeast Asia. A systematic search of four databases-MEDLINE/PubMed, EMBASE, Scopus, and ProQuest-was conducted to identify observational studies published between January 2013 and December 2023. The pooled prevalence of HPV was estimated using random-effects models, and subgroup analysis was performed to investigate the source of heterogeneity. A total of 77 studies were included, comprising 7289 OSCC cases from 11 countries. The pooled HPV prevalence in OSCC was 23.1% (95% CI 17.9-28.7, I2 = 96.7%). South Asia had the highest prevalence (27.1%), followed by East Asia (19.4%), and Southeast Asia (16.7%). Two subtypes were commonly reported: HPV-16 (9.1%) and HPV-18 (5.1%). Anatomical subsites, buccal mucosa (34.0%), and floor of the mouth (33.2%) had similar ranges of HPV prevalence. All studies exhibited a high degree of heterogeneity, with the OSCC location and risk of bias identified as potential sources of heterogeneity. Due to the high HPV prevalence in OSCC in Asia, HPV detection in routine pathology practice is recommended. Future studies should be conducted in multicentre settings using similar HPV detection methods and reporting detailed demographic and clinical information on oral sub-sites.

Cellular diversity through space and time: adding new dimensions to GBM therapeutic development.

The current median survival for glioblastoma (GBM) patients is only about 16 months, with many patients succumbing to the disease in just a matter of months, making it the most common and aggressive primary brain cancer in adults. This poor outcome is, in part, due to the lack of new treatment options with only one FDA-approved treatment in the last decade. Advances in sequencing techniques and transcriptomic analyses have revealed a vast degree of heterogeneity in GBM, from inter-patient diversity to intra-tumoral cellular variability. These cutting-edge approaches are providing new molecular insights highlighting a critical role for the tumor microenvironment (TME) as a driver of cellular plasticity and phenotypic heterogeneity. With this expanded molecular toolbox, the influence of TME factors, including endogenous (e.g., oxygen and nutrient availability and interactions with non-malignant cells) and iatrogenically induced (e.g., post-therapeutic intervention) stimuli, on tumor cell states can be explored to a greater depth. There exists a critical need for interrogating the temporal and spatial aspects of patient tumors at a high, cell-level resolution to identify therapeutically targetable states, interactions and mechanisms. In this review, we discuss advancements in our understanding of spatiotemporal diversity in GBM with an emphasis on the influence of hypoxia and immune cell interactions on tumor cell heterogeneity. Additionally, we describe specific high-resolution spatially resolved methodologies and their potential to expand the impact of pre-clinical GBM studies. Finally, we highlight clinical attempts at targeting hypoxia- and immune-related mechanisms of malignancy and the potential therapeutic opportunities afforded by single-cell and spatial exploration of GBM patient specimens.