******* had the highest level of the Human Development Index (HDI) worldwide in 2023 with a value of *****. With a score of ****, ****** followed closely behind *********** and had the second-highest level of human development in that year. The rise of the Asian tigers In the decades after the Cold War, the four so-called Asian tigers, South Korea, Singapore, Taiwan, and Hong Kong (now a Special Administrative Region of China) experienced rapid economic growth and increasing human development. At number eight and number 13 of the HDI, respectively, *********************** are the only Asian locations within the top-15 highest HDI scores. Both locations have experienced tremendous economic growth since the 1980’s and 1990’s. In 1980, the per capita GDP of Hong Kong was ***** U.S. dollars, increasing throughout the decades until reaching ****** in 2023, which is expected to continue to increase in the future. Meanwhile, in 1989, Singapore had a GDP of nearly ** billion U.S. dollars, which has risen to nearly *** billion U.S. dollars today and is also expected to keep increasing. Growth of the UAE The United Arab Emirates (UAE) is the only Middle Eastern country besides Israel within the highest ranking HDI scores globally. Within the Middle East and North Africa (MENA) region, the UAE has the third-largest GDP behind Saudi Arabia and Israel, reaching nearly *** billion U.S. dollars by 2022. Per capita, the UAE GDP was around ****** U.S. dollars in 1989, and has nearly doubled to ****** U.S. dollars by 2021. Moreover, this is expected to reach over ****** U.S. dollars by 2029. On top of being a major oil producer, the UAE has become a hub for finance and business and attracts millions of tourists annually.

In 2021, Massachusetts, Connecticut, and Minnesota had the highest Human Development Index (HDI) score of any other states at ****. Many more states had a score just below this at ****. Mississippi had the lowest HDI score at ****, and the U.S. average was ****.

In 2023 Zurich was both the leading smart city based on the IMD smart city index as well as the city with the highest human development index score, making it one of the premier places on earth to live in. Notable exceptions to the HDI to IMD index score were Beijing, Dubai, and Abu Dhabi. Beijing is a notable outlier because although it ranked 12th on the digital smart cities ranking it was nearly 90 points lower than Zurich on the HDI score. This is compared to Munich, Germany, which was the 20th digital city but had a HDI score of 950.

Smart tech is watching.

CCTV cameras powered by artificial intelligence have become a significant growing market in the modern city. These are predominantly residential, with half the market catering to residential applications of CCTV cameras. However, commercial and business-related CCTV cameras have also seen significant growth, with the market reaching over 800 million U.S. dollars in 2023.

Digital cities need data and data needs infrastructure.

The leading issue with AI infrastructure is data management. AI is a strong influence on how digital cities work and requires a considerable amount of infrastructure to be effective. Storage of AI software is a minor concern, accounting for less than ten percent of challenges globally in 2023.

The average for 2023 based on 27 countries was 0.915 points. The highest value was in Denmark: 0.962 points and the lowest value was in Bulgaria: 0.845 points. The indicator is available from 1980 to 2023. Below is a chart for all countries where data are available.

Compared to other African countries, Seychelles scored the highest in the Human Development Index (HDI) in 2022. The country also ranked 67th globally, as one of the countries with a very high human development. This was followed by Mauritius, Libya, Egypt, and Tunisia, with scores ranging from 0.80 to 0.73 points. On the other hand, Central African Republic, South Sudan, and Somalia were among the countries in the region with the lowest index scores, indicating a low level of human development.

The average for 2023 based on 184 countries was 0.744 points. The highest value was in Iceland: 0.972 points and the lowest value was in South Africa: 0.388 points. The indicator is available from 1980 to 2023. Below is a chart for all countries where data are available.

IntroductionDiffuse high-grade gliomas are the most common malignant adult neuroepithelial tumors in humans and a leading cause of cancer-related death worldwide. The advancement of high throughput transcriptome sequencing technology enables rapid and comprehensive acquisition of transcriptome data from target cells or tissues. This technology aids researchers in understanding and identifying critical therapeutic targets for the prognosis and treatment of diffuse high-grade glioma.MethodsSpatial transcriptomics was conducted on two cases of isocitrate dehydrogenase (IDH) wild-type diffuse high-grade glioma (Glio-IDH-wt) and two cases of IDH-mutant diffuse high-grade glioma (Glio-IDH-mut). Gene set enrichment analysis and clustering analysis were employed to pinpoint differentially expressed genes (DEGs) involved in the progression of diffuse high-grade gliomas. The spatial distribution of DEGs in the spatially defined regions of human glioma tissues was overlaid in the t-distributed stochastic neighbor embedding (t-SNE) plots.ResultsWe identified a total of 10,693 DEGs, with 5,677 upregulated and 5,016 downregulated, in spatially defined regions of diffuse high-grade gliomas. Specifically, SPP1, IGFBP2, CALD1, and TMSB4X exhibited high expression in carcinoma regions of both Glio-IDH-wt and Glio-IDH-mut, and 3 upregulated DEGs (SMOC1, APOE, and HIPK2) and 4 upregulated DEGs (PPP1CB, UBA52, S100A6, and CTSB) were only identified in tumor regions of Glio-IDH-wt and Glio-IDH-mut, respectively. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analyses revealed that upregulated DEGs were closely related to PI3K/Akt signaling pathway, virus infection, and cytokine-cytokine receptor interaction. Importantly, the expression of these DEGs was validated using GEPIA databases. Furthermore, the study identified spatial expression patterns of key regulatory genes, including those involved in protein post-translational modification and RNA binding protein-encoding genes, with spatially defined regions of diffuse high-grade glioma.DiscussionSpatial transcriptome analysis is one of the breakthroughs in the field of medical biotechnology as this can map the analytes such as RNA information in their physical location in tissue sections. Our findings illuminate previously unexplored spatial expression profiles of key biomarkers in diffuse high-grade glioma, offering novel insight for the development of therapeutic strategies in glioma.

BackgroundOnly a small group of patients with glioblastoma multiforme (GBM) survives more than 36 months, so-called long-term survivors. Recent studies have shown that chromosomal instability (CIN) plays a prognostic and predictive role among different cancer types. Here, we compared histological (chromosome missegregation) and bioinformatic metrics (CIN signatures) of CIN in tumors of GBM typical survivors (≤36 months overall survival), GBM long-term survivors and isocitrate dehydrogenase (IDH)-mutant grade 4 astrocytomas.MethodsTumor sections of all gliomas were examined for anaphases and chromosome missegregation. Further CIN signature activity analysis in the The Cancer Genome Atlas (TCGA)-GBM cohort was performed.ResultsOur data show that chromosome missegregation is pervasive in high grade gliomas and is not different between the 3 groups. We find only limited evidence of altered CIN levels in tumors of GBM long-term survivors relative to the other groups, since a significant depletion in CIN signature 11 relative to GBM typical survivors was the only alteration detected. In contrast, within IDH-mutant grade 4 astrocytomas we detected a significant enrichment of CIN signature 5 and 10 activities and a depletion of CIN signature 1 activity relative to tumors of GBM typical survivors.ConclusionsOur data suggest that CIN is pervasive in high grade gliomas, however this is unlikely to be a major contributor to the phenomenon of long-term survivorship in GBM. Nevertheless, further evaluation of specific types of CIN (signatures) could have prognostic value in patients suffering from grade 4 gliomas.

The Human Development Index (HDI) of Germany has increased from ***** in 1990 to ***** by 2021, indicating that Germany has reached very high levels of human development. The HDI itself is a statistic that combines life-expectancy, education levels and GDP per capita. Countries with scores over ***** are considered to have very high levels of development, compared with countries that score lower. Germany's HDI score has increased from ***** in 1990 to ***** by 2019, implying that Germany has consistently had a very high level of human development.

The Isocitrate Dehydrogenase (IDH) inhibitors market is experiencing robust growth, projected to reach a market size of $1142 million by 2025, exhibiting a Compound Annual Growth Rate (CAGR) of 11.4% from 2019 to 2033. This significant expansion is driven by several factors, including the increasing prevalence of IDH-mutated cancers, such as acute myeloid leukemia (AML) and glioblastoma, coupled with the rising awareness and adoption of targeted therapies among healthcare professionals. Furthermore, ongoing research and development efforts are focused on enhancing the efficacy and safety profiles of IDH inhibitors, leading to the development of novel treatment strategies and expanding the treatment landscape for these challenging cancers. The success of currently available therapies and the potential for new drug approvals continue to fuel market growth. Key players, including Agios Pharmaceuticals, Bristol-Myers Squibb, Idenix Pharmaceuticals, Novartis, and Bayer AG, are actively involved in developing and commercializing these innovative therapies. This competitive landscape is further driving innovation and improvements within the market. The market's sustained growth is expected to continue throughout the forecast period (2025-2033), driven by factors such as increased investment in research and development, a greater understanding of IDH mutations, and improved diagnostic capabilities enabling earlier and more accurate diagnosis of IDH-mutated cancers. The emergence of combination therapies incorporating IDH inhibitors with other targeted agents or chemotherapeutic drugs is also poised to significantly impact the market. However, potential challenges such as the high cost of treatment and the potential for treatment resistance could influence the market's trajectory in the coming years. Nevertheless, the overall outlook for the IDH inhibitors market remains positive, with continued growth anticipated due to the unmet medical need and the ongoing advancements in the field.

Intra-Dialytic Hypotension (IDH) Market Outlook

The global market size for Intra-Dialytic Hypotension (IDH) was valued at approximately USD 1.2 billion in 2023 and is expected to reach USD 1.8 billion by 2032, growing at a compound annual growth rate (CAGR) of 4.8%. This anticipated growth is driven by an increasing prevalence of chronic kidney diseases worldwide, which has heightened demand for effective dialysis treatments and enhanced patient safety measures during dialysis sessions. The growing aging population, advancements in healthcare technology, and increased awareness about kidney health are other significant factors contributing to the expanding market size and expected growth trajectory.

The rise in chronic kidney disease incidence is a major growth factor for the IDH market. With the global increase in lifestyle-related diseases such as diabetes and hypertension, the number of patients experiencing kidney-related complications has risen sharply. This has directly influenced the demand for dialysis treatments, thereby increasing the occurrence of intra-dialytic hypotension, a common complication during dialysis. As healthcare providers work to mitigate these side effects, the demand for both pharmacological and non-pharmacological interventions continues to grow. Furthermore, the increasing availability of resources to better monitor and manage these patients during dialysis sessions ensures constant market demand for these interventions.

Technological advancements in dialysis machines and patient monitoring have also contributed significantly to market growth. Innovations in dialysis equipment now offer advanced features that allow for more precise control of fluid removal rates and patient monitoring, thus reducing the incidence of IDH. These advancements not only improve patient outcomes but also enhance the efficiency of dialysis centers. Additionally, the integration of AI and machine learning into healthcare systems offers predictive insights into potential hypotensive events during dialysis, allowing for preemptive interventions which are leading to a demand surge for technologically advanced solutions in the IDH market.

Another growth factor is the increasing emphasis on personalized medicine and patient-specific treatment protocols. As understanding of IDH and its risk factors expands, healthcare providers are better equipped to tailor interventions to individual patient needs, improving outcomes and patient satisfaction. This trend towards personalized care is supported by a rising number of clinical trials focused on developing targeted therapies and novel pharmacological treatments for IDH. The shift from a one-size-fits-all approach to more individualized care protocols is expected to drive market growth, as it necessitates the development and adoption of diverse treatment strategies tailored to unique patient profiles.

Regionally, North America continues to dominate the IDH market, attributed to advanced healthcare infrastructure, high awareness levels, and a substantial patient pool suffering from chronic kidney diseases. However, significant growth is projected in the Asia Pacific region, with a CAGR of approximately 6.2%, fueled by a growing population, increasing healthcare expenditures, and improving medical infrastructure. Countries like India and China are witnessing rapid urbanization and lifestyle changes, leading to a higher prevalence of kidney diseases and subsequently increasing the demand for effective dialysis treatments and IDH management solutions.

Treatment Type Analysis

The treatment types for IDH can be broadly categorized into pharmacological and non-pharmacological interventions. Pharmacological interventions involve the use of medications to manage blood pressure levels during dialysis sessions. This segment is expected to witness steady growth due to ongoing research and development activities aimed at discovering new drugs and improving existing ones. The market is driven by the need to control the severe drops in blood pressure that can lead to complications such as dizziness, cramping, and even loss of consciousness during dialysis. Continuous innovation in drug formulations and delivery methods plays a crucial role in expanding this segment.

Non-pharmacological interventions encompass several strategies, including the adjustment of dialysis parameters, use of biofeedback systems, and dietary modifications. These interventions are gaining popularity due to their ability to reduce the reliance on medications and their associated side effects. By optimizing dialysis settings, such as blood flow rates and ultrafilt

The global Intra-Dialytic Hypotension (IDH) market is experiencing robust growth, driven by the increasing prevalence of chronic kidney disease (CKD) and the rising geriatric population. The market, estimated at $500 million in 2025, is projected to witness a Compound Annual Growth Rate (CAGR) of 7% from 2025 to 2033, reaching approximately $900 million by 2033. This expansion is fueled by several key factors. Technological advancements in IDH monitoring and management systems, such as improved sensors and data analytics capabilities, are leading to more effective and timely interventions. Furthermore, increasing awareness among healthcare professionals and patients regarding the risks associated with IDH is driving demand for advanced diagnostic tools and treatment strategies. The hospital and research institute segment is currently the largest application area, followed by pharmaceutical companies, reflecting the significant role of research and development in improving IDH management. The Instruments segment holds a larger market share compared to Systems, driven by the wider availability and lower cost of entry for individual monitoring devices. Geographic distribution shows North America and Europe currently dominating the market due to advanced healthcare infrastructure and higher awareness levels, while the Asia-Pacific region is anticipated to exhibit substantial growth in the coming years due to rising CKD prevalence and increasing healthcare spending. However, market growth is not without its challenges. High costs associated with advanced IDH monitoring and treatment systems can pose a barrier to wider adoption, particularly in developing economies. Additionally, variations in healthcare reimbursement policies across different regions can impact market penetration. Regulatory hurdles and the need for robust clinical evidence supporting the efficacy of new technologies also present limitations. To mitigate these restraints, market players are focusing on developing cost-effective solutions and engaging in strategic partnerships to enhance market access and expand their global reach. This includes collaborations with government agencies and healthcare providers to ensure wider adoption and better patient outcomes. The future of the IDH market hinges on continued innovation, improving accessibility, and addressing the cost-effectiveness of current treatment modalities.

Mutations in isocitrate dehydrogenase (IDH) 1 are high-frequency events in low-grade glioma and secondary glioblastoma, and IDH1 mutant gliomas are vulnerable to interventions. Metabolic reprogramming is a hallmark of cancer. In this study, comprehensive metabolism investigation of clinical IDH1 mutant glioma specimens was performed to explore its specific metabolic reprogramming in real microenvironment. Massive metabolic alterations from glycolysis to lipid metabolism were identified in the IDH1 mutant glioma tissue when compared to IDH1 wild-type glioma. Of note, tricarboxylic acid (TCA) cycle intermediates were in similar levels in both groups, with more pyruvate found entering the TCA cycle in IDH1 mutant glioma. The pool of fatty acyl chains was also reduced, displayed as decreased triglycerides and sphingolipids, although membrane phosphatidyl lipids were not changed. The lower fatty acyl pool may be mediated by the lower protein expression levels of long-chain acyl-CoA synthetase 1 (ACSL1), ACSL4, and very long-chain acyl-CoA synthetase 3 (ACSVL3) in IDH1 mutant glioma. Lower ACSL1 was further found to contribute to the better survival of IDH1 mutant glioma patients based on the The Cancer Genome Atlas (TCGA) RNA sequencing data. Our research provides valuable insights into the tissue metabolism of human IDH1 mutant glioma and unravels new lipid-related targets.

The Human development index (HDI) for European countries in 2022 shows that although all of the countries in this statistic have scores which imply high levels of development, ************* score of ***** was the highest in this year. The HDI is a statistic that combines life-expectancy, education levels and GDP per capita. Countries with scores over ***** are considered to have very high levels of development, compared with countries that score lower.

Intra Dialytic Hypotension (IDH) Market Outlook

The global Intra Dialytic Hypotension (IDH) market size was valued at approximately $1.23 billion in 2023 and is projected to grow to $2.11 billion by 2032, demonstrating a Compound Annual Growth Rate (CAGR) of 6.2% over the forecast period. A significant growth factor driving this market is the increasing prevalence of chronic kidney disease (CKD) and the rising number of patients undergoing dialysis worldwide.

The rising prevalence of chronic kidney diseases, particularly among the aging population, is one of the primary growth factors fueling the IDH market. As the global population ages, the incidence of CKD has surged, leading to a higher number of patients requiring dialysis treatments. Intra Dialytic Hypotension, a common complication during hemodialysis, necessitates effective management and treatment solutions, thereby driving the demand for products and therapies in this market. Furthermore, technological advancements in dialysis machines and monitoring devices are enhancing the safety and efficacy of dialysis procedures, contributing to market growth.

Another key growth factor is the increasing awareness and diagnosis of kidney-related disorders. Governments and healthcare organizations are emphasizing the early detection and management of CKD, leading to a heightened demand for dialysis services. This proactive approach not only improves patient outcomes but also increases the need for advanced dialysis machines, blood pressure monitors, and other related medical devices, further boosting the IDH market. Moreover, the growing adoption of home dialysis is expanding the market's scope, as patients require reliable equipment and medications to manage hypotension episodes during home treatments.

Additionally, the development of innovative pharmacological and non-pharmacological treatments for IDH is playing a crucial role in market expansion. Pharmaceutical companies are investing significantly in research and development to introduce new drugs and therapies that mitigate the effects of hypotension during dialysis. Non-pharmacological approaches, such as fluid management techniques and advanced dialysis protocols, are also gaining traction, offering comprehensive solutions for managing IDH. This multifaceted approach to treatment is enhancing patient care and propelling market growth.

On the regional front, North America is expected to dominate the IDH market, driven by the high prevalence of CKD and the well-established healthcare infrastructure. The region's advanced healthcare systems, coupled with significant investments in research and development, are fostering the adoption of innovative dialysis solutions. Europe is also anticipated to witness substantial growth, supported by increasing awareness about kidney health and a robust healthcare framework. Meanwhile, the Asia Pacific region is poised for rapid expansion, owing to the rising incidence of kidney diseases and improving healthcare access in emerging economies. The growing focus on healthcare modernization and the increasing availability of dialysis services are key factors driving market growth in this region.

Product Type Analysis

The product type segment in the Intra Dialytic Hypotension market encompasses a variety of crucial components such as dialysis machines, blood pressure monitors, intravenous fluids, medications, and others. Dialysis machines, being the cornerstone of hemodialysis treatment, play a pivotal role in managing IDH. The continuous advancements in dialysis technology, including the development of more efficient and patient-friendly machines, are driving the demand in this segment. These machines are increasingly being equipped with advanced sensors and software to monitor and adjust treatment parameters in real-time, reducing the risk of hypotension during dialysis sessions.

Blood pressure monitors are another critical product type in this market. These devices are essential for continuously monitoring a patient’s blood pressure during dialysis, allowing for timely interventions when hypotension episodes occur. The integration of advanced data analytics and connectivity features in modern blood pressure monitors is enhancing their accuracy and usability, which in turn is propelling market growth. As the demand for better patient monitoring and personalized treatment increases, the blood pressure monitors segment is expected to witness significant growth.

Intravenous fluids are indispensable in the management of IDH, as they help maintain the fluid balance in patients unde

High resolution melting (HRM) is a simple and rapid method for screening mutations. It offers various advantages for clinical diagnostic applications. Conventional HRM analysis often yields equivocal results, especially for surgically obtained tissues. We attempted to improve HRM analyses for more effective applications to clinical diagnostics. HRM analyses were performed for IDH1R132 and IDH2R172 mutations in 192 clinical glioma samples in duplicate and these results were compared with sequencing results. BRAFV600E mutations were analyzed in 52 additional brain tumor samples. The melting profiles were used for differential calculus analyses. Negative second derivative plots revealed additional peaks derived from heteroduplexes in PCR products that contained mutations; this enabled unequivocal visual discrimination of the mutations. We further developed a numerical expression, the HRM-mutation index (MI), to quantify the heteroduplex-derived peak of the mutational curves. Using this expression, all IDH1 mutation statuses matched those ascertained by sequencing, with the exception of three samples. These discordant results were all derived from the misinterpretation of sequencing data. The effectiveness of our approach was further validated by analyses of IDH2R172 and BRAFV600E mutations. The present analytical method enabled an unequivocal and objective HRM analysis and is suitable for reliable mutation scanning in surgically obtained glioma tissues. This approach could facilitate molecular diagnostics in clinical environments.

Smartphone ODM & IDH Market Outlook

The global Smartphone ODM & IDH market size was valued at approximately $57.3 billion in 2023 and is expected to reach around $86.7 billion by 2032, growing at a Compound Annual Growth Rate (CAGR) of 4.8% during the forecast period. This growth is primarily driven by the increasing demand for customized smartphone solutions and the ongoing advancements in mobile technology.

One of the main factors contributing to the growth of the Smartphone ODM (Original Design Manufacturer) & IDH (Independent Design House) market is the rising demand for innovative and differentiated mobile devices. Consumers are increasingly looking for smartphones that offer unique features, personalized designs, and enhanced functionalities, which ODMs and IDHs are well-positioned to provide. These entities offer customized solutions that cater to the specific needs of OEMs (Original Equipment Manufacturers) and telecom operators, allowing them to differentiate their products in a highly competitive market.

Another significant growth driver for this market is the rapid technological advancements in the smartphone industry. With the advent of technologies such as 5G, artificial intelligence, and the Internet of Things (IoT), there is a growing need for smartphones that can support these advanced features. ODMs and IDHs play a crucial role in designing and manufacturing smartphones that are equipped with the latest technologies, thereby meeting the evolving demands of consumers and businesses alike. Additionally, the increasing focus on energy efficiency and sustainability is also driving the demand for innovative smartphone designs and components.

The expansion of the smartphone market in emerging economies is also fueling the growth of the ODM & IDH market. Countries in regions such as Asia Pacific, Latin America, and Africa are witnessing a surge in smartphone adoption, driven by factors such as rising disposable incomes, improving internet connectivity, and the growing penetration of mobile services. This presents significant opportunities for ODMs and IDHs to expand their operations and cater to the increasing demand for smartphones in these markets. Furthermore, the trend of local manufacturing and assembly in these regions is also boosting the growth of the ODM & IDH market.

The evolution of mobile technology has not only transformed communication but also the way we interact with the world around us. Mobile Smart Device DDIC (Display Driver Integrated Circuit) plays a pivotal role in enhancing the display quality of smartphones, providing sharper images and more vibrant colors. As consumers demand higher resolution screens and more immersive visual experiences, the integration of advanced DDICs becomes increasingly critical. These components are essential in managing the power consumption of displays, thereby extending battery life and improving overall device efficiency. With the rise of OLED and AMOLED displays, the importance of Mobile Smart Device DDICs is set to grow, driving innovation in smartphone design and functionality.

From a regional perspective, Asia Pacific holds the largest share of the Smartphone ODM & IDH market, followed by North America and Europe. The dominance of Asia Pacific can be attributed to the presence of major smartphone manufacturers and a well-established supply chain network in countries such as China, South Korea, and Taiwan. Moreover, the region is witnessing rapid technological advancements and a growing focus on innovation, which is driving the demand for ODM and IDH services. North America and Europe are also significant markets due to the high adoption of advanced technologies and the presence of leading OEMs and telecom operators.

Service Type Analysis

The Smartphone ODM & IDH market is segmented by service type into Design, Manufacturing, Assembly, and Others. The design segment holds a substantial share of the market as it includes critical services such as product conceptualization, industrial design, and detailed engineering. The increasing need for differentiated and innovative products drives the demand for specialized design services. ODMs and IDHs offer tailored design solutions to OEMs, allowing them to create unique smartphones that stand out in the market. This trend is expected to continue as consumer preferences evolve and the emphasis on product design grows.

The manufacturing segment is another key c

C) Quantification of several high mass metabolites differentially present in IDHm PDXs (IDHwt glioblastomas (GBM) in blue, IDHm GBM in orange, IDHm lower grade gliomas (LGG) in red, contralateral control brain (CB) in grey). Box plots represent log values of metabolite intensities measured within a large ROI (>500 pixels). Many metabolites in this mass range (m/z 700-900) have been putatively assigned to phospholipids (Tables EV2-3). m/z represents the mass over charge ratio of ionized metabolites, as measured by the mass spectrometer. Except where otherwise indicated, statistical significance was calculated for IDHm (n=3) versus IDHwt (n=3) PDXs using T test. pv: p-values.. List of tagged entities: high mass metabolites, phospholipid (CHEBI:16247), Idh1 (ncbigene:15926), mass spectrometry (bao:BAO_0000055),xenograft (obi:OBI_0100058)

BackgroundProteins containing the caspase recruitment domain (CARD) play critical roles in cell apoptosis and immunity. However, the impact of CARD genes in tumor immune cell infiltration, responsiveness to checkpoint immunotherapy, and clinical outcomes of gliomas remains unclear. Here, we explore using CARD genes to depict the immune microenvironment and predict the responsiveness of gliomas to anti-PD-1 therapy.MethodsThe genome and transcriptome data of 231 patients with isocitrate dehydrogenase wild-type (IDH-wt) gliomas were retrieved from The Cancer Genome Atlas (TCGA) database to screen CARD genes associated with T lymphocyte infiltration in gliomas. Weighted co-expression network and LASSO penalized regression were employed to generate a CARD-associated risk score (CARS). Two independent and publicly available datasets were used to validate the effectiveness of CARS.ResultsThe CARS divided the 231 glioma patients into high- and low-risk subgroups with distinct immune microenvironment and molecular features. The high-risk group had high CARS and was characterized by enrichment of dysfunctional T lymphocytes in a profound immunosuppressive microenvironment, whereas the low-risk group had low CARS and exhibited an immune exclusion genotype. Moreover, signaling aberrations including upregulation of PI3K/Akt/mTOR, NF-κB, and TGF-β were found in the high-risk group. In contrast, the activated WNT pathway was more evident in the low-risk group. Furthermore, we found that an elevated CARS indicated a decreased overall survival for IDH-wt gliomas under standard care but a clinical benefit from checkpoint immunotherapy.ConclusionThis study developed an immune- and prognosis-relevant risk score, which could be used to enhance our understanding of the heterogeneity of immune microenvironment of gliomas and facilitate to identify patients who will benefit from checkpoint immunotherapy.

B7H3 (also known as CD276) is a co-stimulator checkpoint protein of the cell surface B7 superfamily. Recently, the function beyond immune regulation of B7H3 has been widely studied. However, the expression preference and the regulation mechanism underlying B7H3 in different subtypes of gliomas is rarely understood. We show here that B7H3 expression is significantly decreased in IDH-mutated gliomas and in cultured IDH1-R132H glioma cells. Accumulation of 2-HG leads to a remarkable downregulation of B7H3 protein and the activity of IDH1-R132H mutant is responsible for B7H3 reduction in glioma cells. Inhibition of autophagy by inhibitors like leupeptin, chloroquine (CQ), and Bafilomycin A1 (Baf-A1) blocks the degradation of B7H3 in glioma cells. In the meantime, the autophagy flux is more active with higher LC3B-II and lower p62 in IDH1-R132H glioma cells than in IDH1-WT cells. Furthermore, sequence alignment analysis reveals potential LC3-interacting region (LIR) motifs “F-V-S/N-I/V” in B7H3. Moreover, B7H3 interacts with p62 and CQ treatment significantly enhances this interaction. Additionally, we find that B7H3 is positively correlated with VEGFA and MMP2 by bioinformatics analysis in gliomas. B7H3 and VEGFA are decreased in IDH-mutated gliomas and further reduced in 2-HGhigh gliomas compared to 2-HGlow glioma sections by IHC staining. Our study demonstrates that B7H3 is preferentially overexpressed in IDH wild-type gliomas and could serve as a potential theranostic target for the precise treatment of glioma patients with wild-type IDH.