Multiple Signaling Research Articles

Bioactive Constituents and the Molecular Mechanism of Melastoma dodecandrum Lour. in the Treatment of Inflammation Based on Network Pharmacology and Molecular Docking

Background: Melastoma dodecandrum Lour. (MD) is a component used in traditional Chinese medicine that is widely distributed in southern China. MD has long been used clinically to treat various diseases, such as inflammation. However, the potential anti-inflammatory mechanism of MD remains to be elucidated. Objective: In this study, network pharmacology and experimental validation have been used to explore the underlying mechanism of MD in inflammation. Methods: The chemical composition of MD was determined using ultra-high performance liquid chromatography-electrospray ionization-high resolution mass spectrometry (UHPLC-ESI-HRMS). The effects of MD on pro-inflammatory cytokines, such as NO, i-NOS, IL-1β, and TNF-α, in RAW264.7 cells stimulated by lipopolysaccharide (LPS) were determined by ELISA and QRT-PCR. Through the analysis of multiple databases, targets for the treatment of inflammation with MD were identified. Other extensive analyses included PPI, GO, and KEGG pathway enrichment, which were completed through the use of the STRING database, Cytoscape software, and the DAVID database. Key targets and key components have been selected for molecular docking. Results: A total of 33 active components were identified in MD, and 134 common targets were obtained and used to construct the networks. Of these, 10 core components and 10 core targets of MD in the treatment of inflammation were identified. The GO and KEGG enrichment analyses revealed that the common targets were involved in multiple signaling pathways, including the PI3K-Akt signaling pathway, NOD-like receptor signaling pathway, chemokine signaling pathway, and IL-17 signaling pathway. The molecular docking methods confirmed the high affinity between bioactive molecules of MD and their targets in inflammation. Two core targets (PIK3CA and AKT) and three core components (asiatic acid, apigenin, and kaempferol) were found to be closely related to MD in the treatment of inflammation. In vitro, MD exerted a significant effect on LPS-stimulated NO, IL- 1β, and TNF-α secretion, and iNOS, IL-1β, and TNF-α expressions in macrophages. Conclusion: This study has demonstrated the bioactive constituents and mechanisms of MD in inhibiting the secretion of inflammatory factors and the multicomponent, multitarget, and multipathway treatment characteristics involved in inflammation, but this still needs further in vivo/in vitro experiments.

Network Pharmacology Prediction and Molecular Docking-based Strategy to Explore the Potential Mechanism of Guiyi Tonglong Prescription in the Treatment of Benign Prostatic Hyperplasia

Background: Benign prostatic hyperplasia (BPH) is a common condition affecting the urinary tract. This study aimed at exploring the potential of Guiyi Tonglong (GYTL) prescription for the treatment of benign prostatic hyperplasia using network pharmacology and molecular docking technology. Methods: The main active ingredients in GYTL prescription were identified from the Traditional Chinese Medicine Systems Pharmacology and the Integrative Pharmacology-based Traditional Chinese Medicine (TCMIP) databases based on drug similarity of ≥ 30% and oral bioavailability of ≥ 0.18. Protein–protein interaction (PPI) networks, gene ontology, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to study the interactions and pathway enrichment and establish ingredient-target-pathway networks. The structure of the active ingredient was docked to that of the potential protein target using the AutoDock molecular docking software. Results: A total of 86 active ingredients and 130 potential targets were screened from GYTL prescription, and a PPI network was constructed to identify the five most important core targets, namely SRC, TP53, STAT3, AKT1, and PIK3CA. Enrichment analysis revealed that GYTL prescription may play a role in the treatment of BPH through multiple signaling pathways, such as PI3K-Akt, EGFR, AGE-RAGE, and HIF-1. Molecular docking indicated a potential interaction between the active ingredients and targets. Conclusion: These results provide further information regarding the active ingredients and molecular mechanisms of GYTL prescription in treating BPH.

JAK Activity Regulates Mesoderm Cell Fate by controlling MESP1 expression

Cardiac development requires precise gene expression programs at each developmental stage guided by multiple signaling pathways and transcription factors (TFs). MESP1 is transiently expressed in mesoderm, and is essential for subsequent cardiac development, while the precise mechanism regulating its own transcription and mesoderm cell fate is not fully understood. Therefore, we developed a high content screen assay to identify regulators of MESP1 expression in mesodermal cells differentiated from human pluripotent stem cells (hPSCs). The screen identified CYT387, a JAK1/JAK2 kinase inhibitor, as a potent activator of MESP1 expression, which was also found to promote cardiomyocyte differentiation in vitro. Mechanistic studies found that JAK inhibition promotes MESP1 expression by reducing cytoplasmic calcium concentration and subsequently activating canonical WNT signaling. Our study identified a role of JAK signaling in early mesodermal cells, and sheds light on the connection between the JAK-STAT pathway and transcriptional regulation of MESP1, which expands our understanding of mesoderm and cardiac development.

Comprehensive analysis of the oligopeptide transporter gene family in maize: Genome-wide identification, structural characterization, and stress-responsive expression

Oligopeptide transporter (OPT) proteins are integral proteins in cell membranes that perform a crucial role in cellular metal homeostasis, mineral uptake, transport of small peptides and abiotic stress tolerance. Hence, in-depth evolutionary, structural, molecular and expression analysis could guide in exploring the mechanism of how these transporters contribute to nutrient balance and abiotic stress tolerance in maize. Following a series of bioinformatic analyses, eight OPTs in maize were identified. These transporters showed significant variations in molecular weight, and have one to five introns, 11 to 15 motifs, 11 to 18 transmembrane domains, multiple beta-strands, multiple alpha and transmembrane helices. ZmOPT1, 5, and 6 are plasma membranes and the rest are endoplasmic reticulum localized. All ZmOPTs are distributed in six different chromosomes having significant phytohormone-responsive cis-elements might be due to their great roles in hormonal regulation in maize. The significant transport activity of these transporters plays a great role in biological processes, cellular components and molecular functions in maize during gene ontology analysis. Co-expression of five genes among eight OPTs with 56 genes might be due to their great role in regulating other genes in multiple signaling pathways or vice-versa. Significant tissue-specific and drought, salinity, nitrogen starvation, and heat stress induced in silico expression following real time PCR validation of ZmOPT1, 7, and 8 genes might guide to elucidate the potential roles of these transporters in specific tissues and abiotic stress tolerance. Hence, the findings of the research might guide plant biologists to develop new varieties of maize having higher efficiency of peptide and metal ion transport, balance, and abiotic stress tolerance. Findings of these structural and expression analyzes might guide the plant biologist for single transgenesis, or developing and transforming programming-based synthetic genetic circuits in maize for advancing research in peptide transport, metal hemostasis, and increasing abiotic stress tolerance in maize.

Broad-spectrum inflammasome inhibition by thiomuscimol.

Inflammasome formation, arising from pathogen or internal activating signals, is a key step in canonical pyroptosis, a gasdermin-mediated inflammatory cell death. Inhibition of pyroptosis has great clinical relevance due to its involvement in many different disease states. Current inhibitors of pyroptosis either only inhibit the final lytic step, which still allows inflammatory signal release, or only inhibit a single inflammasome, which does not account for inherent redundancy in activation of other inflammatory pathways. Here, we show that thiomuscimol, a structural analog of the lysis inhibitor muscimol, exhibits unique inhibitory activity upstream of plasma membrane rupture. We find that thiomuscimol inhibits inflammasome formation, as well as downstream caspase-1 activation, initiated by multiple pyroptotic signals, regardless of whether NLR recruitment of caspase-1 to the inflammasome relies on the ASC adapter protein. The ability of thiomuscimol to block multiple different inflammasomes opens the door for development of therapeutics with increased applications to broadly inhibit pyroptosis in multiple pathological settings.

Direction of Arrival Estimation of Meteors Echoes using Array Radio Antennas

Array antennas have an interesting role in the radio astronomy field. The array antennas allow astronomers to obtain high-resolution signals with high sensitivity to weak signals. This paper estimates the meteors' positions entering the Earth's atmosphere and develops a simulation for array antenna radar to analyze the meteor's echoes. The GNU radio software was used to process the echoes, which is a free open-source software development toolkit that provides signal processing blocks to implement in radio projects. Then, the simulation determines the azimuth and elevation of the meteors. An improved Multiple Signal Classification (MUSIC) algorithm has been suggested to analyze these echoes. The detected power of each meteor echo has a Doppler frequency shift due to the high speed of the meteors, which impacts the accuracy of the Direction of Arrival (DOA) estimation. The Doppler shift was considered in this simulation, and the results showed that the suggested method has low complexity and high resolution and can estimate the meteors' position with the minimum error.

Closely spaced modes identification of skyscraper buildings via variational mode decomposition with multiple signal classification algorithm and recursive Hilbert transform

Closely spaced modes identification of skyscraper buildings via variational mode decomposition with multiple signal classification algorithm and recursive Hilbert transform

Open-ended molecular recording of sequential cellular events into DNA.

Genetically encoded DNA recorders noninvasively convert transient biological events into durable mutations in a cell's genome, allowing for the later reconstruction of cellular experiences by DNA sequencing. We present a DNA recorder, peCHYRON, that achieves high-information, durable, and temporally resolved multiplexed recording of multiple cellular signals in mammalian cells. In each step of recording, prime editor, a Cas9-reverse transcriptase fusion protein, inserts a variable triplet DNA sequence alongside a constant propagator sequence that deactivates the previous and activates the next step of insertion. Insertions accumulate sequentially in a unidirectional order, editing can continue indefinitely, and high information is achieved by coexpressing a variety of prime editing guide RNAs (pegRNAs), each harboring unique triplet DNA sequences. We demonstrate that the constitutive expression of pegRNA collections generates insertion patterns for the straightforward reconstruction of cell lineage relationships and that the inducible expression of specific pegRNAs results in the accurate recording of exposures to biological stimuli.

Immuno-PET/CT Imaging of Trop2 with [18F]AlF-RESCA-T4 Differentiates Lung Cancer from Inflammation.

Immuno-PET/CT imaging, a branch of molecular imaging, can noninvasively and specifically visualize biomarker expression across the body. Trophoblast cell surface antigen 2 (Trop2) is a pan-cancer biomarker and plays a crucial role in tumorigenesis through multiple signaling pathways. The study aims to develop and translate novel Trop2 single-domain antibody (sdAb) tracers for clinical use. Methods: Two sdAbs (i.e., His-tagged T4 and His-tag-free RT4) are recombinantly expressed in Chinese hamster ovary cells. The purities and binding kinetics are determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis, high-performance liquid chromatography, and surface plasmon resonance assays. The AlF restrained complexing agent (RESCA) method is applied to develop 18F-labeled sdAb tracers ([18F]AlF-RESCA-T4 and [18F]AlF-RESCA-RT4), followed by thorough preclinical imaging and blocking studies on tumor-bearing mice and a pilot clinical trial evaluating the clinical imaging safety and feasibility of [18F]AlF-RESCA-T4 immuno-PET/CT. Results: [18F]AlF-RESCA-T4 and [18F]AlF-RESCA-RT4 possess high radiochemical purities. Preclinical imaging in the T3M-4 tumor model revealed prominent uptake (percentage injected dose/g) of [18F]AlF-RESCA-T4 (11.13 ± 1.53, n = 4) and [18F]AlF-RESCA-RT4 (8.83 ± 1.22, n = 4), which were significantly reduced by coinjection of unlabeled T4 and RT4 in blocking studies. The His-tag removal strategy further optimized the probe's invivo pharmacokinetics and reduced renal radioactivity accumulation without significantly decreasing tumor uptake. In a pilot clinical trial, [18F]AlF-RESCA-T4 immuno-PET/CT showed promising potency in annotating Trop2 expression and differentiating tumors from inflammatory diseases such as tuberculosis. Conclusion: [18F]AlF-RESCA-T4 and [18F]AlF-RESCA-RT4 can specifically annotate Trop2 expression. Clinical [18F]AlF-RESCA-T4 immuno-PET/CT imaging can screen patients for Trop2-targeted therapies and differentiate lung inflammation from cancer.

Key roles of two-component systems in intestinal signal sensing and virulence regulation in enterohemorrhagic Escherichia coli.

Enterohemorrhagic Escherichia coli (EHEC) is a foodborne pathogen that infects humans by colonizing the large intestine. Upon reaching the large intestine, EHEC mediates local signal recognition and the transcriptional regulation of virulence genes to promote adherence and colonization in a highly site-specific manner. Two-component systems (TCSs) represent an important strategy used by EHEC to couple external stimuli with the regulation of gene expression, thereby allowing EHEC to rapidly adapt to changing environmental conditions. An increasing number of studies published in recent years have shown that EHEC senses a variety of host- and microbiota-derived signals present in the human intestinal tract and coordinates the expression of virulence genes via multiple TCS-mediated signal transduction pathways to initiate the disease-causing process. Here, we summarize how EHEC detects a wide range of intestinal signals and precisely regulates virulence gene expression through multiple signal transduction pathways during the initial stages of infection, with a particular emphasis on the key roles of TCSs. This review provides valuable insights into the importance of TCSs in EHEC pathogenesis, which have relevant implications for the development of antibacterial therapies against EHEC infection.

Accurate felt-tip pen brands classification based on a convolutional neural network using data augmentation.

Ink analysis played an important role in document examination, but the limited dataset made it difficult for many algorithms to distinguish inks accurately. This article aimed to evaluate the feasibility of two data augmentation (DA) methods, Gaussian noise data augmentation (GNDA) and extended multiplicative signal augmentation (EMSA), for the classification of felt-tip pen ink brands. Four brands of felt-tip pens were analyzed using FT-IR spectroscopy. Five classification models were used, convolutional neural network (CNN), K-nearest neighbor (KNN), support vector machine (SVM), random forest (RF), and partial least squares discriminant analysis (PLS-DA). The results showed that the datasets generated by GNDA and EMSA are similar to the original datasets and have some diversity. The EMSA method had optimal classification results when combined with CNN, with classification accuracy (ACC), precision (PRE), recall (REC) and F1 score reaching 99.86%, 99.87%, 99.86%, 99.86%, and 99.86%, compared with GNDA-CNN method (ACC = 80.90%, PRE = 87.34%, REC = 81.62%, F1 score = 79.23%). This study shows that when raw spectral data is small, DA methods can be combined with neural network models to identify ink brands effectively.

Extracellular vesicles: multiple signaling capabilities and translation into promising therapeutic targets to promote neuronal plasticity

Extracellular vesicles: multiple signaling capabilities and translation into promising therapeutic targets to promote neuronal plasticity

Identification of Goat Supernumerary Teat Phenotype Using Wide-Genomic Copy Number Variants

Supernumerary teats (SNTs) or nipples often emerge around the mammary line. This study performed a genome-wide selective sweep analysis (GWS) at the copy number variant (CNV) level using two selected signal calculation methods (VST and FST) to identify candidate genes associated with SNTs in goats. A total of 12,310 CNVs were identified from 37 animals and 123 CNVs, with the top 1% VST values including 84 candidate genes (CDGs). Of these CDGs, minichromosome maintenance complex component 3, ectodysplasin A receptor associated via death domain, and cullin 5 demonstrated functions closely related to mammary gland development. In addition, 123 CNVs with the top 1% FST values were annotated to 97 CDGs. 5-Hydroxytryptamine receptor 2A, CCAAT/enhancer-binding protein alpha, and the polymeric immunoglobulin receptor affect colostrum secretion through multiple signaling pathways. Two genes, namely, RNA-binding motif protein 46 and β-1,3-galactosyltransferase 5, showed a close relation to mammary gland development. Six CNVs were identified and annotated to five genes by intersecting the top 1% of candidate CNVs with both parameters. These genes include LOC102185621, LOC102190481, and UDP-glucose pyrophosphorylase 2, which potentially affect the occurrence of BC through multiple biological processes, such as cell detoxification, glycogen synthesis, and phospholipid metabolism. In conclusion, we discovered numerous genes related to mammary development and breast cancer (BC) through a GWS, which suggests the mechanism of SNTs in goats and a certain association between mammary cancer and SNTs.

A mechanistic integration of hypoxia signaling with energy, redox and hormonal cues.

Oxygen deficiency (hypoxia) occurs naturally in many developing plant tissues but can become a major threat during acute flooding stress. Consequently, plants as aerobic organisms must rapidly acclimate to hypoxia and the associated energy crisis to ensure cellular and ultimately organismal survival. In plants, oxygen sensing is tightly linked with oxygen-controlled protein stability of group VII ETHYLENE-RESPONSE FACTORs (ERFVII) which, when stabilized under hypoxia, act as key transcriptional regulators of hypoxia-responsive genes (HRGs). Multiple signaling pathways feed into hypoxia signaling to fine-tune cellular decision making under stress. First, ATP shortage upon hypoxia directly affects the energy status and adjusts anaerobic metabolism. Secondly, altered redox homeostasis leads to reactive oxygen and nitrogen species (ROS and RNS) accumulation, evoking signaling and oxidative stress acclimation. Finally, the phytohormone ethylene promotes hypoxia signaling to improve acute stress acclimation, while hypoxia signaling in turn can alter ethylene, auxin, abscisic acid, salicylic acid and jasmonate signaling to guide development and stress responses. In this Update, we summarize the current knowledge on how energy, redox and hormone signaling pathways are induced under hypoxia and subsequently integrated at the molecular level to ensure stress-tailored cellular responses. We show that some HRGs are responsive to changes in redox, energy and ethylene independently of the oxygen status, and propose an updated HRG list that is more representative for hypoxia marker gene expression. We discuss the synergistic effects of hypoxia, energy, redox and hormone signaling and their phenotypic consequences in the context of both environmental and developmental hypoxia.

CTIM-14. EARLY SAFETY DATA FROM A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PHASE 2B STUDY OF IGV-001, AN AUTOLOGOUS CELL IMMUNOTHERAPY, VERSUS PLACEBO, IN NEWLY DIAGNOSED GLIOBLASTOMA (NDGBM)

Abstract Standard of care (SOC) for ndGBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. IGV-001 is an autologous biologic-device combination immunotherapy for the treatment of ndGBM that consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA, irradiated and administered via biodiffusion chambers implanted in the abdomen. In a phase 1b study, IGV-001 was well tolerated without unexpected adverse events in subjects with ndGBM. Multiple efficacy signals were observed, including significant improvements in progression-free survival (PFS), overall survival (OS), radiographic evidence of tumor response, and changes in immune response biomarkers. Here, we present early safety data from the phase 2b randomized, multicenter, double-blind, placebo-controlled study (NCT04485949) designed to assess efficacy and safety of IGV-001 in subjects with ndGBM across 20 sites in the United States. After surgical resection, subjects were randomized 2:1 and treated with IGV-001 or placebo followed by SOC. The primary outcome is PFS, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include OS, defined as the time from randomization to death due to any cause, and safety. As of May 22, 2024, 99 subjects were randomized and 95 implanted with IGV-001 or placebo plus SOC. A total of 39/45 (86.7%) subjects had sufficient follow-up time after initiated treatment with concurrent radiation and temozolomide. Nine of 72 randomized (12.5%) discontinued treatment, including 7 who stopped during the SOC treatment period. None ceased treatment for adverse events, protocol deviations, or death. A total of 11/72 (15.3%) randomized subjects discontinued the study after randomization. A review of blinded safety data did not show any emerging risk and supports no change to the benefit-risk profile of IGV-001 versus placebo. Updated data will be presented.

RBIO-06. STEREOTACTIC RADIOSURGERY ENHANCES T-CELL RECEPTOR REPERTOIRES AND INDUCES IMMUNOGENICITY IN BRAIN METASTASIS

Abstract BACKGROUND Brain metastasis is a frequent and deadly complication of systemic malignancy. The incidence rate is increasing and the prognosis remains poor, in contrast to recent advances in the management of systemic malignancy. Our previous work revealed an immunosuppressive microenvironment in brain metastasis and correlation between T-cell status and patient outcomes, shared across the primary tumor histologies. Therefore, we hypothesize that induction of immunogenicity has potential to improve brain metastasis patient outcome. METHODS Pre-operative stereotactic radiosurgery (SRS) (n = 44) and post-operative SRS (n = 47) brain metastasis specimens were collected from an ongoing clinical trial (MDACC protocol 2018-0552) designed to determine optimal timing of SRS for the treatment of brain metastasis. The patient materials were extracted DNA and RNA, and subjected to T-cell receptor (TCR) repertoire sequencing and mRNA-seq to interrogate radiation-induced immunogenicity. RESULTS In a preliminary analysis of the first 21 specimens, Gene Set Enrichment Analysis revealed that SRS significantly enhanced multiple immune-related signaling pathways including interferon response, along with apoptotic pathways, in brain metastasis. We also found that TCR signaling and PD-1 signaling was upregulated by radiotherapy. TCR repertoire analysis further identified increased density and diversity of TCRs induced by SRS treatment. Profiling of the remaining sample set is currently ongoing. CONCLUSIONS In light of our previous finding regarding the correlation between immune status and outcomes of patients with brain metastases, reversing immunosuppression in brain metastasis could be a key factor on patient prognosis and treatment. Our TCR repertoire and mRNA sequencing analyses with pre-operative and post-operative SRS brain metastasis cohorts support a role for radiation-induced immunogenicity, pointing to a prospective therapeutic approach for brain metastasis management.

DDDR-41. A GENOME-WIDE CRISPR/CAS9 SCREEN IN GLIOBLASTOMA STEM CELLS UNVEILS SYNTHETIC LETHAL INTERACTIONS AND RESISTANCE MECHANISMS OF JIN001, A BLOOD-BRAIN BARRIER-PENETRANT HSP90 INHIBITOR

Abstract Glioblastomas (GBMs) are aggressive brain tumors characterized by extensive genetic heterogeneity and therapeutic resistance. Heat shock protein 90 (Hsp90) is a molecular chaperone that stabilizes and facilitates the proper folding of numerous proteins, including oncogenic drivers and is overexpressed in cancers. Hsp90 inhibitors can disrupt multiple oncogenic signaling pathways by degrading various client proteins essential for tumor growth and survival, making them attractive therapeutic candidates for GBMs. We have previously reported on the efficacy of Hsp90 inhibitors against gliomas. However, cancer cells develop resistance to Hsp90 inhibitors by upregulating compensatory chaperones (e.g., Hsp70), mutating client proteins, or activating alternative survival pathways, reducing the long-term efficacy of these agents. Combination approaches overcoming such resistance mechanisms are needed. JIN001, a novel Hsp90 inhibitor, demonstrates superior blood-brain barrier (BBB) penetration, and high potential for clinical translation. we performed a genome-wide CRISPR/Cas9 knockout screen using the Toronto Knockout Library v3 (TKOv3) with screen selection pressure from JIN001 in GBM stem cells (GSC272) to identify synthetic lethal interactions and resistance mechanisms associated with JIN001 treatment. Experiments were performed in triplicate with two time points, T22 and T37. Quality control analysis of the NGS data indicated excellent quality and consistency between different replicates. DrugZ analysis revealed a set of sensitive and resistant genes, informing potential combination therapies and further elucidating JIN001’s mechanism of action. Validation studies for the top synthetic lethal targets are underway to confirm the identified interactions and will be presented. This CRISPR-Cas9 screen offers valuable insights into JIN001’s therapeutic potential, reveals new combination strategies to overcome resistance to Hsp90 inhibitors and for use of these agents in other cancers, and paves the way for the development of more effective GBM combination treatment strategies.

CTIM-11. LONG-TERM SURVIVORS FROM A PHASE 1B STUDY OF IGV-001 IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

Abstract Imvax has developed the Goldspire™ platform to create IGV-001, an autologous biologic-device combination product for the treatment of newly diagnosed glioblastoma (ndGBM). IGV-001 consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA (IMV-001), irradiated and administered via biodiffusion chambers (BDCs) implanted in the abdomen. Together, these components stimulate immunogenic cell death and antigen release. IGV-001 was well tolerated and multiple efficacy signals were observed in a Phase 1b study in patients with ndGBM (Andrews et al., 2021), including significant improvements in progression-free survival (PFS), radiographic evidence of tumor response, and changes in immune response biomarkers. The Phase 1b study enrolled 33 patients in four different cohorts implanted with 10 or 20 BDCs for 24 or 48 hours. Here we report on 6 subjects with survival beyond 4 years, including 5 subjects who survived 5 years or more (15.2%). There were 4 male and 2 female subjects, with a median age of 52 years (range 32-75). At diagnosis the MGMT promoter was methylated in 4 of 5 subjects that survived 5 years or more. We also report on T cell receptor Vβ CDR3 region sequencing of peripheral blood mononuclear cells and tissue infiltrated lymphocytes that was performed in a subset of 9 patients, including 3 subjects who survived beyond 4 years. Immune correlates of IGV-001 suggest an association between peripheral T cell clonal expansion and PFS/OS outcomes. A Phase 2b randomized, multicenter, double-blind, placebo-controlled study to assess the safety and efficacy of IGV-001 in patients with ndGBM (NCT04485949) has completed enrollment and results are expected to be available in 2025.

Insight into the mechanisms regulating liver cancer stem cells by hepatitis B virus X protein.

Hepatocellular carcinoma (HCC) is a heterogeneous disease with high recurrence and mortality. It is well known that a large proportion of HCCs are caused by hepatitis B virus (HBV) infection. In particular, the HBV X protein (HBX), a multifunctional molecule produced by the virus, plays a leading role in hepatocarcinogenesis. However, the molecular mechanisms underlying HBX-mediated HCC remain not fully elucidated. Recently, liver cancer stem cells (LCSCs), a unique heterogeneous subpopulation of the malignancy, have received particular attention owing to their close association with tumorigenesis. Especially, the modulation of LCSCs by HBX by upregulating CD133, CD44, EpCAM, and CD90 plays a significant role in HBV-related HCC development. More importantly, not only multiple signaling pathways, including Wnt/β-catenin signaling, transforming growth factor-β (TGF-β) signaling, phosphatidylinositol-3-kinase (PI-3K)/AKT signaling, and STAT3 signaling pathways, but also epigenetic regulation, such as DNA and histone methylation, and noncoding RNAs, including lncRNA and microRNA, are discovered to participate in regulating LCSCs mediated by HBX. Here, we summarized the mechanisms underlying different signaling pathways and epigenetic alterations that contribute to the modulation of HBX-induced LCSCs to facilitate hepatocarcinogenesis. Because LCSCs are important in hepatic carcinogenesis, understanding the regulatory factors controlled by HBX might open new avenues for HBV-associated liver cancer treatment.

Implementasi dan Pengaruh Time Division Multiplexing (TDM) terhadap Kualitas Transmisi Sinyal

Time Division Multiplexing (TDM) is a multiplexing technique that enables the transmission of multiple signals over a single communication channel by allocating separate time slots for each signal stream. This study aims to analyze the working principles of TDM, examples of its implementation, as well as the benefits and drawbacks of TDM in communication networks. The findings show that TDM can enhance data transmission efficiency through flexible bandwidth allocation, minimizing signal interference and thereby improving signal quality. Due to these advantages, TDM is widely used in fiber optic communication systems, such as telephone and internet networks. Additionally, all data processing is conducted within integrated circuits utilizing Plastic Optical Fiber (POF), allowing TDM to be implemented at a low cost.