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Objective: Endometrial cancer (EC) is an oestrogen-dependent tumour, the occurrence of which is closely related to an imbalance of oestrogen homeostasis. Our previous studies explored the effects of Resveratrol(Res) on oestrogen metabolism. However, systematic research on the exact mechanism of action of Res is still lacking. Based on network pharmacology, molecular docking and animal experiments, the effects and molecular mechanisms of Res on endometrial cancer were investigated. Methods: The target of Res was obtained from the high-throughput experiment and reference-guided database of TCM (HERB) and the Encyclopedia of Traditional Chinese Medicine (ETCM) databases, and the target of endometrial cancer was obtained by using the Genecards database. Venny map was used to obtain the intersection target of Res in the treatment of endometrial cancer, and the protein interaction network of the intersection target was constructed by importing the data into the STRING database. Then, the drug–disease–target interaction network was constructed based on Cytoscape 3.9.1 software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for intersection targets using the OmicShare cloud platform. Res and core targets were analysed by molecular docking. EC model mice induced by MNNG were randomly divided into the control group, Res group, MNNG group, MNNG + Res group, and MNNG + Res + MAPK/ERKi group. The protein levels of ERK and p-ERK in the mouse uterus were detected by Western blot. The levels of E1, E2, E3, 16-epiE3, 17-epiE3, 2-MeOE1, 4-MeOE1, 2-MeOE2, 4-MeOE2, 3-MeOE1, 2-OHE1, 4-OHE1, 2-OHE2, 4-OHE2, and 16α-OHE1 in the serum and endometrial tissue of mice were measured by LC‒MS/MS. Results: A total of 174 intersection targets of Res anti-endometrial cancer were obtained. The signalling pathways analysed by KEGG enrichment included the AGE-RAGE signalling pathway in diabetic complications, the PI3K-Akt signalling pathway and the MAPK signalling pathway. The top 10 core targets were MAPK3, JUN, TP53, CASP3, TNF, IL1B, AKT1, FOS, VEGFA and INS. Molecular docking showed that in addition to TNF, other targets had good affinity for Res, and the binding activity with MAPK3 was stable. Western blot results showed that Res increased the phosphorylation level of ERK and that MAPK/ERKi decreased ERK activation. In the LC-MS/MS analysis, the levels of 2-MeOE1, 2-MeOE2 and 4-MeOE1 in serum and uterine tissue showed a significantly decreasing trend in the MNNG group, while that of 4-OHE2 was increased (P < 0.05). The concentrations of 4-MeOE1 in serum and 2-MeOE1 and 2-MeOE2 in the endometrial tissue of mice were significantly increased after Res treatment, and those of 4-OHE2 in the serum and uterus of mice were significantly decreased (P < 0.05). Meanwhile, in the MAPK/ERKi intervention group, the effect of Res on the reversal of oestrogen homeostasis imbalance was obviously weakened. Conclusion: Res has multiple targets and multiple approaches in the treatment of endometrial cancer. In this study, it was found that Res regulates oestrogen metabolism by activating the MAPK/ERK pathway. This finding provides a new perspective for subsequent research on the treatment of endometrial cancer. [ABSTRACT FROM AUTHOR]

Context: Bu-shen-yi-jing-fang (BSYJF) has been reported to reduce amyloid-β (Aβ)1–42 deposition in the brain of APP/PS1 mice and ameliorate cognitive function. However, its neuroprotective mechanism remains unclear. Objective: This study aims to investigate whether BSYJF exerts a protective effect on Aβ1–42-induced oxidative stress injury and explore its possible mechanism. Materials and methods: The platform databases TCMSP, Swiss, TTD, DrugBank, and GeneCards were used to mine the targets of Alzheimer's disease (AD) and BSYJF. The platform databases STRING and Metascape were used to build the interaction network of the target protein, and Cytoscape software was used to analyze this network and screen out the key pathways. Aβ1–42-treated SKNMC cells were established to verify the mechanism of BSYJF and the key proteins. The downstream proteins and antioxidants as well as apoptosis and ferroptosis of the PI3K/AKT/Nrf2 signaling pathway were validated using an in vitro SKNMC cell model experiment. The expression levels of related proteins were detected using Western blotting. Flow cytometry and immunofluorescence staining were used to analyze apoptosis and ferroptosis. Results: Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis considered the key signal pathways, mainly involving the PI3K/AKT signaling pathway. Experimental validation demonstrated that BSYJF treatment markedly increased the activity of the PI3K/AKT pathway, which could exert anti-AD effects. Conclusions: Our data provided compelling evidence that the protective effects of BSYJF might be associated with their regulation of the PI3K/AKT/Nrf2 signaling pathway. These studies offered a potential therapy for natural herbal medicine treatment of AD. [ABSTRACT FROM AUTHOR]

Objective: To provide an overview of the available scientific evidence from in vitro studies regarding the effect induced by the flavonoids contained in grape seed extracts (GSE) and cranberry on the microbiological activity of Streptococcus mutans (S. mutans). Methods: This systematic review was performed following the parameters of the PRISMA statement (Preferred Reporting Items for Systematic Reviews and Meta-Analysis). Electronic and manual searches were conducted using PubMed, ScienceDirect, Web of Science, EBSCO, and Cochrane databases. Reference lists of selected articles were reviewed to identify relevant studies. The search was not limited by year and was conducted solely in English. Eligible studies comprised publications describing in vitro studies that evaluated the effect of flavonoids derived from GSE and cranberry extracts on the microbiological activity of S. mutans. Common variables were identified to consolidate the data. Authors of this review independently screened search results, extracted data, and assessed the risk of bias. Results: Of the 420 studies identified from the different databases, 22 publications were finally selected for review. The risk of bias was low in 13 articles and moderate in 9. The studies analyzed in this review revealed that cranberry extract has an inhibitory effect on the bacterial growth of S. mutans in ranges from 0.5 mg/mL to 25 mg/mL, and GSE exerts a similar effect from 0.5 mg/mL to 250 mg/mL. Additionally, the extracts or their fractions showed reduced biofilm formation capacity, decreased polymicrobial biofilm biomass, deregulation of glycosyltransferases (Gtf) B and C expression, and buffering of pH drop. In addition to adequate antioxidant activity related to polyphenol content. Conclusions: The overall results showed that the extracts of cranberry and grape seed were effective in reducing the virulence factors of the oral pathogen. According to the data, proanthocyanidins are the active components in cranberry and grape seed that effectively resist S. mutans. They can inhibit the formation of insoluble polysaccharides in the extracellular matrix and prevent glycan-mediated adhesion, cohesion, and aggregation of the proteins in S. mutans. This suggests that these natural extracts could play an important role in the prevention of cariogenic bacterial colonization, as well as induce a decrease in their microbiological activity. [ABSTRACT FROM AUTHOR]

Purpose: The present study aimed at evaluating possible synergistic effects between two risk factors for cognitive decline and neurodegenerative disorders, i.e. iron overload and exposure to a hypercaloric/hyperlipidic diet, on cognition, insulin resistance, and hippocampal GLUT1, GLUT3, Insr mRNA expression, and AKT phosporylation. Methods: Male Wistar rats were treated with iron (30 mg/kg carbonyl iron) or vehicle (5% sorbitol in water) from 12 to 14th post-natal days. Iron-treated rats received a standard laboratory diet or a high fat diet from weaning to adulthood (9 months of age). Recognition and emotional memory, peripheral blood glucose and insulin levels were evaluated. Glucose transporters (GLUT 1 and GLUT3) and insulin signaling were analyzed in the hippocampus of rats. Results: Both iron overload and exposure to a high fat diet induced memory deficits. Remarkably, the association of iron with the high fat diet induced more severe cognitive deficits. Iron overload in the neonatal period induced higher insulin levels associated with significantly higher HOMA-IR, an index of insulin resistance. Long-term exposure to a high fat diet resulted in higher fasting glucose levels. Iron treatment induced changes in Insr and GLUT1 expression in the hippocampus. At the level of intracellular signaling, both iron treatment and the high fat diet decreased AKT phosphorylation. Conclusion: The combination of iron overload with exposure to a high fat diet only led to synergistic deleterious effect on emotional memory, while the effects induced by iron and by the high fat diet on AKT phosphorylation were comparable. These findings indicate that there is, at least to some extent, an additive effect of iron combined with the diet. Further studies investigating the mechanisms associated to deleterious effects on cognition and susceptibility for the development of age-associated neurodegenerative disorders are warranted. [ABSTRACT FROM AUTHOR]

In humans, MAPK8IP3 (also known as JIP3) is a neurodevelopmental disorder-associated gene. In Caenorhabditis elegans , the UNC-16 ortholog of the MAPK8IP3 protein can regulate the termination of axon growth. However, its role in this process is not well understood. Here, we report that UNC-16 promotes axon termination through a process that includes the LRK-1 (LRRK-1/LRRK-2) kinase and the WDFY-3 (WDFY3/Alfy) selective autophagy protein. Genetic analysis suggests that UNC-16 promotes axon termination through an interaction between its RH1 domain and the dynein complex. Loss of unc-16 function causes accumulation of late endosomes specifically in the distal axon. Moreover, we observe synergistic interactions between loss of unc-16 function and disruptors of endolysosomal function, indicating that the endolysosomal system promotes axon termination. We also find that the axon termination defects caused by loss of UNC-16 function require the function of a genetic pathway that includes lrk-1 and wdfy-3 , 2 genes that have been implicated in autophagy. These observations suggest a model where UNC-16 promotes axon termination by interacting with the endolysosomal system to regulate a pathway that includes LRK-1 and WDFY-3. [ABSTRACT FROM AUTHOR]

l -cysteine, a primary building block of mycothiol, plays an essential role in the defense mechanism of Mycobacterium tuberculosis (Mtb). However, it is unclear how Mtb regulates cysteine biosynthesis as no study has reported the cysteine regulatory complex (CRC) in Mtb. Serine acetyltransferase (SAT) and cysteine synthase (CS) interact to form CRC. Although Mt CS has been characterized well, minimal information is available on Mt SAT, which synthesizes, O-acetylserine (OAS), the precursor of cysteine. This study fills the gap and provides experimental evidence for the presence of Mt CRC and a non-canonical multi-oligomeric Mt SAT. We employed multiple analytical methods to characterize the oligomeric and kinetic properties of Mt SAT and Mt CRC. Results show that Mt SAT, lacking >75 N-terminal amino acids exists in three different assembly states; trimer, hexamer, and dodecamer, compared to the single hexameric state of SAT of other bacteria. While hexamers display the highest catalytic turnover, the trimer is the least active. The predominance of trimers at low physiologically relevant concentrations suggests that Mt SAT displays the lowest catalytic potential known. Further, the catalytic potential of Mt SAT is also significantly reduced in CRC state, in contrast to enhanced activity of SAT in CRC of other organisms. Our study provides insights into multi-oligomeric Mt SAT with reduced catalytic potential and demonstrates that both Mt SAT and Mt CS of Mycobacterium interact to form CRC, although with altered catalytic properties. We discuss our results in light of the altered biochemistry of the last step of canonical sulfate-dependent cysteine biosynthesis of Mycobacterium. [Display omitted] • Serine acetyltransferase from Mycobacterium tuberculosis (Mt SAT) lacks four N-terminal helices. • Mt SAT exists in three states, with the trimer demonstrating the least catalytic efficiency. • Only hexamers can form cysteine regulatory complex (CRC) with cysteine synthase, not trimers. • Together, results indicate that compromised catalytic efficiency of Mt SAT may be an evolutionary adaptation. [ABSTRACT FROM AUTHOR]

Objective SIRT1, an NAD+-dependent deacetylase, is upregulated in CD4+ T cells from SLE patients and MRL/lpr lupus-like mice. This study aimed to explore the role of SIRT1 in follicular helper T (Tfh) cell expansion and its potential value as a therapeutic target for SLE. Methods Frequencies of CD4+CXCR5+PD-1+ Tfh cells in peripheral blood from SLE patients and their expression of SIRT1 and B cell lymphoma 6 (BCL-6) were determined with flow cytometry. Naïve CD4+ T cells were transfected with SIRT1 -expressing lentivirus and small interfering RNA (siRNA) targeting SIRT1 , respectively, and then cultured under Tfh-polarizing conditions to study the impact of SIRT1 on Tfh cell differentiation. This impact was also evaluated in both CD4+ T cells and naïve CD4+ T cells by treatment with SIRT1 inhibitors (EX527 and nicotinamide) in vitro. MRL/lpr mice and pristane-induced lupus mice were treated with continuous daily intake of nicotinamide, and their lupus phenotypes (including skin rash, arthritis, proteinuria and serum anti-dsDNA autoantibodies) were compared with those of controls. Results Expression of SIRT1 was elevated in Tfh cells from SLE patients and was positively correlated with Tfh cell frequencies. SIRT1 expression gradually increased during Tfh cell differentiation. Overexpression of SIRT1 by lentiviral vectors significantly promoted Tfh cell differentiation/proliferation. Reciprocally, suppressing expression of SIRT1 by siRNA and inhibiting SIRT1 activity by EX-527 or nicotinamide hindered Tfh cell expansion. Continuous daily intake of nicotinamide alleviated lupus-like phenotypes and decreased serum CXCL13 in the two mouse models. Conclusion SIRT1 overexpression contributed to the expansion of Tfh cells in SLE and may serve as a potential target for treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer of the penis is a relatively uncommon cancer that nevertheless can be life threatening when it is at an advanced stage. We summarized the published laboratory results that might lead to new and better treatment approaches, including those that harness the immune system. We identified several opportunities for drug development and corresponding clinical trials that are or will soon be testing these ideas in patients. In conclusion, we outline how these ongoing efforts will hopefully improve outcomes for patients with advanced penile cancer. Discovery of effective systemic therapies for patients with advanced penile cancer has been slow to occur. Comprehensive genomic profiling from several studies shed light on the molecular oncogenesis of penile squamous cell carcinoma (PSCC) and differences between HPV-related and unrelated tumors. While these two subsets of PSCC appear distinct in their biology, there are not yet specific treatment strategies recommended on that basis. Cell surface proteins have been identified that may potentially serve as drug targets for monoclonal antibodies or small molecule inhibitors. Here, we review some of the new biological insights regarding PSCC that could lead to improved therapies, as well as the related clinical trials recently completed or in progress. We conclude that antibody-drug conjugates are especially promising, as are the combinations of immune checkpoint inhibitors with other types of drugs. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with glioblastoma have very few treatment options; even with best treatment, including surgery, radiotherapy and chemotherapy, overall survival time is poor. Cancer cells need very high levels of energy to maintain their rapid growth, and a key component of this is a chemical called NAD. We can block the production of NAD in cancer cells by using inhibitors of specific substances in cells, limiting the growth of the tumour. This study highlights how cancer cells might exhibit resistance to inhibitors of NAD production, and how we can select a subset of patients that are uniquely responsive to these types of inhibitors. Furthermore, this study demonstrates that these inhibitors improve the effectiveness of the type of chemotherapy most often used to treat patients with aggressive brain tumours, called temozolomide. Patients may therefore benefit from the use of inhibitors of NAD production in combination with temozolomide. Glioblastoma (GBM) cells require high levels of nicotinamide adenine dinucleotide (NAD) to fuel metabolic reactions, regulate their cell cycle and support DNA repair in response to chemotherapy and radiation. Inhibition of a key enzyme in NAD biosynthesis, NAMPT, has demonstrated significant anti-neoplastic activity. Here, we sought to characterise NAD biosynthetic pathways in GBM to determine resistance mechanisms to NAD inhibitors. GBM cells were treated with the NAMPT inhibitor FK866 with and without NAD precursors, and were analysed by qPCR, Western blot and proliferation assays (monolayer and spheroid). We also measured changes in the cell cycle, apoptosis, NAD/NADH levels and energy production. We performed orthoptic xenograft experiments in athymic nude mice to test the efficacy of FK866 in combination with temozolomide (TMZ). We show that the expression of key genes involved in NAD biosynthesis is highly variable across GBM tumours. FK866 inhibits proliferation, reduces NAD levels and limits oxidative metabolism, leading to G2/M cell cycle arrest; however, this can be reversed by supplementation with specific NAD precursors. Furthermore, FK866 potentiates the effects of radiation and TMZ in vitro and in vivo. NAMPT inhibitors should be considered for the treatment of GBM, with patients stratified based on their expression of key enzymes in other NAD biosynthetic pathways. [ABSTRACT FROM AUTHOR]

Objectives Our previous study showed that resveratrol (Res) attenuates apoptosis and mitochondrial dysfunction in alveolar epithelial cell injury induced by hyperoxia by activating the SIRT1/PGC-1α signaling pathway. In the present study, we investigated whether Res protects against hyperoxia-induced lung injury in neonatal rats by activating SIRT1/PGC-1α signaling pathway. Methods Naturally delivered neonatal rats were randomly divided into six groups: normoxia + normal saline, normoxia + dimethyl sulfoxide (DMSO), normoxia + Res, hyperoxia + normal saline, hyperoxia + DMSO, and hyperoxia + Res. Lung tissue samples were collected on postnatal days 1, 7, and 14. Hematoxylin and eosin staining was used to evaluate lung development. Dual-immunofluorescence staining, real-time polymerase chain reaction, and western blotting were used to evaluate the levels of silencing information regulator 2-related enzyme 1 (SIRT1), peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), nuclear respiratory factor 1 (Nrf1), Nrf2, transcription factor A (TFAM) and citrate synthase, the number of mitochondrial DNA (mtDNA) and mitochondria, the integrity of mtDNA, and the expression of TFAM in mitochondria. Results We found that hyperoxia insulted lung development, whereas Res attenuated the hyperoxia lung injury. Res significantly upregulated the levels of SIRT1, PGC-1α, Nrf1, Nrf2, TFAM, and citrate synthase; promoted TFAM expression in the mitochondria; and increased the copy number of ND1 and the ratio of ND4/ND1. Conclusion Our data suggest that Res attenuates hyperoxia-induced lung injury in neonatal rats, and this was achieved, in part, by activating the SIRT1/PGC-1α signaling pathway to promote mitochondrial biogenesis. Key Points Hyperoxia insulted lung development in neonatal rats. Resveratrol promoted mitochondrial biogenesis to attenuate hyperoxia lung injury in neonatal rats. Resveratrol, at least in part, promoted mitochondrial biogenesis by activating the SIRT1/PGC-1α signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress indicators affect chronic orofacial pain (COFP), but how to reduce these effects is uncertain. Objectives: 11 oxidative stress biomarkers were collected as exposures, while four forms of COFP were chosen as outcomes for Mendelian randomization (MR) study. Methods: The effect estimates between oxidative stress and COFP were calculated using inverse variance‐weighted MR (IVW‐MR). Then, functional mapping and annotation (FUMA) was utilized in order to carry out SNP‐based functional enrichment analyses. In addition, the IVW‐MR method was applied to combine effect estimates when using genetic variants associated with oxidative stress biomarkers as an instrument for exploring potential druggable targets. Results: The results indicated that oxidative stress biomarkers (causal OR of uric acid (UA), 0.998 for myofascial pain, 95% CI 0.996–1.000, p <.05; and OR of glutathione transferase (GST), 1.002 for dentoalveolar pain, 95% CI 1.000–1.003, p <.05) were significantly linked with the probability of COFP. Functional analysis also demonstrated that UA and myofascial pain genes were prominent in nitrogen and uracil metabolism, while GST and dentoalveolar pain genes were enriched in glutathione metabolism. Also, the study provided evidence that solute carrier family 2 member 9 (SLC2A9) and glutathione S‐transferase alpha 2 (GSTA2) cause discomfort in the myofascial pain (OR = 1.003, 95% CI 1.000–1.006; p <.05) and dentoalveolar region (OR = 1.001, 95% CI 1.000–1.002; p <.05), respectively. Conclusions: In conclusion, this MR study indicates that genetically predicted myofascial pain was significantly associated with decreased UA and dentoalveolar pain was significantly associated with increased GST level. SLC2A9 inhibitor and GSTA2 inhibitor were novel chronic orofacial pain therapies and biomarkers, but clinical trials are called to examine if these oxidative biomarkers have the protective effect against orofacial pain, and further research are needed to explore the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Ebola virus glycoprotein (EBOV GP) is one of the most heavily O-glycosylated viral glycoproteins, yet we still lack a fundamental understanding of the structure of its large O-glycosylated mucin-like domain and to what degree the host O-glycosylation capacity influences EBOV replication. Using tandem mass spectrometry, we identified 47 O-glycosites on EBOV GP and found similar glycosylation signatures on virus-like particle- and cell lysate-derived GP. Furthermore, we performed quantitative differential O-glycoproteomics on proteins produced in wild-type HEK293 cells and cell lines ablated for the three key initiators of O-linked glycosylation, GalNAc-T1, -T2, and -T3. The data show that 12 out of the 47 O-glycosylated sites were regulated, predominantly by GalNAc-T1. Using the glycoengineered cell lines for authentic EBOV propagation, we demonstrate the importance of O-linked glycan initiation and elongation for the production of viral particles and the titers of progeny virus. The mapped O-glycan positions and structures allowed to generate molecular dynamics simulations probing the largely unknown spatial arrangements of the mucin-like domain. The data highlight targeting GALNT1 or C1GALT1C1 as a possible way to modulate O-glycan density on EBOV GP for novel vaccine designs and tailored intervention approaches. IMPORTANCE Ebola virus glycoprotein acquires its extensive glycan shield in the host cell, where it is decorated with N-linked glycans and mucin-type O-linked glycans. The latter is initiated by a family of polypeptide GalNAc-transferases that have different preferences for optimal peptide substrates resulting in a spectrum of both very selective and redundant substrates for each isoform. In this work, we map the exact locations of O-glycans on Ebola virus glycoprotein and identify subsets of sites preferentially initiated by one of the three key isoforms of GalNAc-Ts, demonstrating that each enzyme contributes to the glycan shield integrity. We further show that altering host O-glycosylation capacity has detrimental effects on Ebola virus replication, with both isoform-specific initiation and elongation playing a role. The combined structural and functional data highlight glycoengineered cell lines as useful tools for investigating molecular mechanisms imposed by specific glycans and for steering the immune responses in future vaccine designs. [ABSTRACT FROM AUTHOR]

Breast cancer is a leading cause of death in women worldwide. Cancer therapy based on stem cells is considered as a novel and promising platform. In the present study, we explore the therapeutic effects of human amniotic mesenchymal stromal cells (hAMSCs) through the reduction of focal adhesion kinase (FAK) activity, SHP-2, and cell adhesion proteins such as Paxillin, Vinculin, Fibronectin, Talin, and integrin αvβ3 expression in MDA-MB-231 breast cancer cells. For this purpose, we employed a co-culture system using 6-well plate transwell. After 72 h, hAMSCs-treated MDA-MB-231 breast cancer cells, the activity of focal adhesion kinase (FAK) and the expression of SHP-2 and cell adhesion proteins such as Paxillin, Vinculin, Fibronectin, Talin, and integrin αvβ3 expression were analyzed using western blot. The shape and migration of cells were also analyzed. Based on our results, a significant reduction in tumor cell motility through downregulation of the tyrosine phosphorylation level of FAK (at Y397 and Y576/577 sites) and cell adhesion expression in MDA-MB-231 breast cancer cells was demonstrated. Our findings indicate that hAMSCS secretome has therapeutic effects on cancer cell migration through downregulation of FAK activity and expression of cell adhesion proteins. [ABSTRACT FROM AUTHOR]

Background Melanoma incidence is on the rise in East Asia, yet studies of the molecular landscape are lacking in this population. We examined patients with melanoma who underwent next-generation sequencing (NGS) at a single tertiary center in South Korea, focusing on patients harboring NRAS or RAF alterations who received belvarafenib, a pan-RAF dimer inhibitor, through the Expanded Access Program (EAP). Patients and Methods Data were collected from 192 patients with melanoma who underwent NGS between November 2017 and May 2023. Variant call format data were obtained and annotated. Patients in the EAP received 450 mg twice daily doses of belvarafenib. Results Alterations in the RAS/RTK pathway were the most prevalent, with BRAF and NRAS alteration rates of 22.4% and 17.7%, respectively. NGS enabled additional detection of fusion mutations, including 6 BRAF and 1 RAF1 fusion. Sixteen patients with NRAS or RAF alterations received belvarafenib through the EAP, and disease control was observed in 50%, with 2 patients demonstrating remarkable responses. Conclusions Our study highlights the value of NGS in detecting BRAF , NRAS mutations and RAF fusions, expanding possibilities for targeted therapies in malignant melanoma. Belvarafenib showed clinical benefit in patients harboring these alterations. Ongoing trials will provide further insights into the safety and efficacy of belvarafenib. [ABSTRACT FROM AUTHOR]

Background One of the most common sporadic homozygous deletions in cancers is 9p21 loss, which includes the genes methylthioadenosine phosphorylase (MTAP), CDKN2A , and CDKN2B , and has been correlated with worsened outcomes and immunotherapy resistance. MTAP -loss is a developing drug target through synthetic lethality with MAT2A and PMRT5 inhibitors. The purpose of this study is to investigate the prevalence and genomic landscape of MTAP- loss in advanced gastrointestinal (GI) tumors and investigate its role as a prognostic biomarker. Materials and Methods We performed next-generation sequencing and comparative genomic and clinical analysis on an extensive cohort of 64 860 tumors comprising 5 GI cancers. We compared the clinical outcomes of patients with GI cancer harboring MTAP- loss and MTAP- intact tumors in a retrospective study. Results The prevalence of MTAP -loss in GI cancers is 8.30%. MTAP -loss was most prevalent in pancreatic ductal adenocarcinoma (PDAC) at 21.7% and least in colorectal carcinoma (CRC) at 1.1%. MTAP -loss tumors were more prevalent in East Asian patients with PDAC (4.4% vs 3.2%, P  = .005) or intrahepatic cholangiocarcinoma (IHCC; 6.4% vs 4.3%, P  = .036). Significant differences in the prevalence of potentially targetable genomic alterations (ATM , BRAF , BRCA2 , ERBB2 , IDH1 , PIK3CA , and PTEN) were observed in MTAP -loss tumors and varied according to tumor type. MTAP -loss PDAC, IHCC, and CRC had a lower prevalence of microsatellite instability or elevated tumor mutational burden. Positive PD-L1 tumor cell expression was less frequent among MTAP -loss versus MTAP -intact IHCC tumors (23.2% vs 31.2%, P  = .017). Conclusion In GI cancers, MTAP -loss occurs as part of 9p21 loss and has an overall prevalence of 8%. MTAP -loss occurs in 22% of PDAC, 15% of IHCC, 8.7% of gastroesophageal adenocarcinoma, 2.4% of hepatocellular carcinoma, and 1.1% of CRC and is not mutually exclusive with other targetable mutations. [ABSTRACT FROM AUTHOR]

Methionine adenosyl transferases (MATs) catalyze the synthesis of the biological methyl donor adenosylmethionine (SAM). Dysregulation of MATs has been associated with carcinogenesis in humans. We previously found that downregulation of the MAT1A gene enriches the protein-associated translation process and worsens liver hepatocellular carcinoma (LIHC) prognosis. We also discovered that subcellular localization of the MAT2A protein has independently prognostic relevance in breast cancer patients. The present study aimed to examined the clinical relevance of MAT2A translocation in human LIHC. Essential methionine cycle gene expressions in TCGA LIHC datasets were analyzed using Gene Expression Profiling Interactive Analysis 2 (GEPIA2). The protein expression pattern of MAT2A was determined in the tissue array of our own LIHC cohort (n = 261) using immuno-histochemistry, and the prognostic relevance of MAT2A protein's subcellular localization expression was examined using Kaplan-Meier survival curves. LIHC patients with higher MAT2A mRNA expression had a worse survival rate (p = 0.0083). MAT2A protein immunoreactivity was observed in both cytoplasm and nucleus fractions in the tissue array. Tumor tissues had elevated MAT2A protein expression in both cytoplasm and nucleus compared to their adjacent normal tissues. A higher cytoplasmic to nuclear MAT2A protein expression ratio (C/N) was found in female LIHC patients compared to that of male patients (p = 0.047). Kaplan-Meier survival curves showed that a lower MAT2A C/N correlated with poor overall survival in female LIHC patients (10-year survival rate: 29.2% vs. 68.8%, C/N ≤ 1.0 vs. C/N > 1.0, log-rank p = 0.004). Moreover, we found that specificity protein 1 (SP1) may have a potential interaction with nuclear MAT2A protein, using protein-protein interaction; this we found using the GeneMANIA algorithm. We explored the possible protective effects of the estrogen axis in LIHC using the Human Protein Atlas (HPA), and found evidence supporting a possible protective effect of estrogen-related protein ESSRG in LIHC. The localization of SP1 and MAT2 appeared to be inversely associated with ESRRG expression in LIHC. The present study demonstrated the translocation of MAT2A and its prognostic relevance in female LIHC patients. Our findings suggest the potential of estrogen in SP1 regulation and localization of MAT2A, as therapeutic modalities against in female LIHC patients.

Background: This review article aims to investigate the prevalence and spectrum of rat sarcoma (RAS) and V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) mutations, and their connection with geographical location, clinicopathological features, and other relevant factors in colorectal cancer (CRC) patients in the Middle East. Methods: A systematic literature review, employing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework, was conducted to investigate the association between the frequency of relevant mutations and the descriptive clinicopathological characteristics of CRC patients. Multiple electronic databases, including PubMed, Science Direct, Web of Science, Scopus, and Google Scholar, were searched to analyze the relevant literature. Results: A total of 19 eligible studies comprising 2960 patients with CRC were included in this review. A comprehensive analysis of the collected literature data as well as descriptive and methodological insights is provided. Men were predominant in reviewed studies for the region, accounting for 58.6%. Overall, RAS mutation prevalence was 38.1%. Kirsten RAS Viral Oncogene Homolog (KRAS) mutations were the most common, accounting for 37.1% of cases and distributed among different exons, with the G12D mutation being the most frequent in exon 2 (23.2%) followed by G12V (13.7%), G13D (10.1%), G12C (5.1%), G12A (5.04%), and G12S (3.6%). Neuroblastoma RAS Viral Oncogene Homolog (NRAS) mutations were identified in 3.3% of tumor samples, with the most common mutation site located in exons 2, 3, and 4, and codon 61 being the most common location for the region. The total mutation frequency in the BRAF gene was 2.6%, with the V600E mutation being the most common. Conclusion: The distribution patterns of RAS and BRAF mutations among CRC patients exhibit notable variations across diverse ethnic groups. Our study sheds light on this phenomenon by demonstrating a higher prevalence of KRAS mutations in CRC patients from the Middle East, as compared with those from other regions. The identification of these mutations and geographical differences is important for personalized treatment planning and could potentially aid in the development of novel targeted therapies. The distinct distribution patterns of RAS and BRAF mutations among CRC patients across different ethnic groups, as well as the regional variability in mutation prevalence, highlight the need for further research in this area. [ABSTRACT FROM AUTHOR]

The loss of RAB25 expression—RAS superfamily of GTPase characteristic of numerous breast cancers—corresponds with H-RAS point mutations, particularly in triple-negative breast cancers (TNBC), a subtype associated with a poor prognosis. To address the poorly understood factors dictating the progression of TNBC tumors, we examine the cooperative effects that loss of RAB25 expression in human mammary epithelial cell (HMEC) lines with H-RAS mutations confers in tumorigenesis. HMECs were immortalized by transduction with LXSN CDK4 R24C, a mutant form of cyclin-dependent kinase, followed by transduction with hTERT, a catalytic subunit of the telomerase enzyme. We found that with the loss of RAB25 and overexpression of mutant H-RAS61L, immortal HMECs transformed toward anchorage-independent growth and acquired an increased ability to migrate. Furthermore, cells express low CD24, high CD44, and low claudin levels, indicating stem-like properties upon transformation. Besides, loss of RAB25 and overexpression of H-RAS61L resulted in increased expression of transcription factors Snail and Slug that drive these cells to lose E-cadherin and undergo epithelial-mesenchymal transition (EMT). This study confirms that loss of RAB25 and overexpression of mutant H-RAS can drive HMECs toward a mesenchymal stem-like state. Our findings reveal that RAB25 functions as a tumor suppressor gene, and loss of RAB25 could serve as a novel biomarker of the claudin-low type of TNBC. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma continues to be one of the deadliest cancers worldwide. Preclinical studies involving animals rarely include sex as a major biological variable in testing the efficacy of new drugs. In an animal model of pancreatic cancer, we analyzed the impact of sex on the pathological features of the disease and on an experimental small molecule-based therapy tested in vivo for the first time. While the therapy shows potential, the obtained results are confounded by sex-specific effects. This study, therefore, highlights the importance of sex-inclusive research while simultaneously providing a basis for further studies of the therapy tested. Preclinical studies rarely test the efficacy of therapies in both sexes. The field of oncology is no exception in this regard. In a model of syngeneic, orthotopic, metastasized pancreatic ductal adenocarcinoma we evaluated the impact of sex on pathological features of this disease as well as on the efficacy and possible adverse side effects of a novel, small molecule-based therapy inhibiting KRAS:SOS1, MEK1/2 and PI3K signaling in male and female C57BL/6J mice. Male mice had less tumor infiltration of CD8-positive cells, developed bigger tumors, had more lung metastasis and a lower probability of survival compared to female mice. These more severe pathological features in male animals were accompanied by higher distress at the end of the experiment. The evaluated inhibitors BI-3406, trametinib and BKM120 showed synergistic effects in vitro. This combinatorial therapy reduced tumor weight more efficiently in male animals, although the drug concentrations were similar in the tumors of both sexes. These results underline the importance of sex-specific preclinical research and at the same time provide a solid basis for future studies with the tested compounds. [ABSTRACT FROM AUTHOR]

Simple Summary: The research explores the potential of the Wnt receptor ROR1 as a target for cancer treatment, an area gaining significant attention. Despite ongoing therapeutic investigations, the understanding of ROR1's presence in different tissues remains limited. To address this, the study conducted immunohistochemistry analyses on a large variety of tumor types, including sarcomas and carcinomas, revealing a diverse ROR1 expression pattern. Notably, high ROR1 prevalence was observed in mesothelioma, liposarcoma, gastrointestinal stromal tumors, and uterine endometrioid carcinoma. Conversely, other cancers showed lower expression. These findings highlight the potential for ROR1-targeted therapies, particularly in mesothelioma, which exhibits frequent and high ROR1 expression, suggesting a novel therapeutic avenue. This research may inform the development of more effective cancer treatments targeting ROR1. The Wnt receptor ROR1 has generated increased interest as a cancer therapeutic target. Research on several therapeutic approaches involving this receptor is ongoing; however, ROR1 tissue expression remains understudied. We performed an immunohistochemistry analysis of ROR1 protein expression in a large cohort of multiple tumor and histologic types. We analyzed 12 anonymized multi-tumor tissue microarrays (TMAs), including mesothelioma, esophageal and upper gastrointestinal carcinomas, and uterine endometrioid carcinoma, among other tumor types. Additionally, we studied 5 different sarcoma types of TMAs and 6 patient-derived xenografts (PDX) TMAs developed from 19 different anatomic sites and tumor histologic types. A total of 1142 patient cases from different histologic types and 140 PDXs placed in TMAs were evaluated. Pathologists assessed the percentage of tumor cells in each case that were positive for ROR1 and the intensity of staining. For determining the prevalence of staining for each tumor type, a case was considered positive if >1% of its tumor cells showed ROR1 staining. Our immunohistochemistry assays revealed a heterogeneous ROR1 expression profile. A high prevalence of ROR1 expression was found in mesothelioma (84.6%), liposarcoma (36.1%), gastrointestinal stromal tumors (33.3%), and uterine endometrioid carcinoma (28.9%). Other histologic types such as breast, lung, renal cell, hepatocellular, urothelial carcinoma, and colon carcinomas; glioblastoma; cholangiocarcinoma; and leiomyosarcoma showed less ROR1 overall expression, ranging between 0.9 and 13%. No ROR1 expression was seen in mesenchymal chondrosarcoma, rhabdomyosarcoma, or gastric adenocarcinoma cases. Overall, ROR1 expression was relatively infrequent and low in most tumor types investigated; however, ROR1 expression was infrequent but high in selected tumor types, such as gastroesophageal GIST, suggesting that ROR1 prescreening may be preferable for those indications. Further, mesothelioma exhibited frequent and high levels of ROR1 expression, which represents a previously unrecognized therapeutic opportunity. These findings can contribute to the development of ROR1-targeted therapies. [ABSTRACT FROM AUTHOR]

Background. Selumetinib, a mitogen-activated protein kinase kinase 1/2 inhibitor, has been approved in several countries and regions, including Japan, for the treatment of pediatric patients with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas at a body surface area (BSA)-based dose of 25 mg/m2 twice daily. The objective of this population pharmacokinetic analysis was to evaluate ethnic sensitivity in the pharmacokinetics of selumetinib and N-desmethyl selumetinib between Japanese and non-Japanese pediatric patients. Methods. This population pharmacokinetic analysis was based on data from 80 pediatric patients enrolled in two clinical trials, one conducted in Japan and one conducted in the United States, comprising 12 Japanese participants and 68 non-Japanese participants. Both clinical trials used BSA-based dosing schemes. A two-compartment model with first-order elimination and sequential zero-order and first-order delayed absorption for selumetinib, combined with a one-compartment model with first-order elimination for N-desmethyl selumetinib, was used for this analysis. Ethnic sensitivity in pharmacokinetics was evaluated by covariate modeling and comparison of model-predicted exposures. Results. Covariate modeling showed that BSA had a clinically relevant impact on the pharmacokinetics of selumetinib. None of the other investigated covariates, such as race, had a significant impact. The predicted exposure in Japanese and non-Japanese patients showed a considerably overlapping distribution, and no clinically relevant difference in exposure was apparent. Conclusions. These findings support the use of the same BSA-based dosing regimen for Japanese and non-Japanese pediatric patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas. Subsequent to this analysis, selumetinib was approved at the BSA-based dose of 25 mg/m2 in Japan, which is consistent with the recommended dosage and administration in other regions and countries. This analysis used data from trial registered with NCT04495127, and NCT01362803. [ABSTRACT FROM AUTHOR]

Background: Cuscutae Semen (CS) has been prescribed in traditional Chinese medicine (TCM) for millennia as an aging inhibitor, an anti-inflammatory agent, a pain reliever, and an aphrodisiac. Its three main forms include crude Cuscutae Semen (CCS), wine-processed CS (WCS), and stir-frying-processed CS (SFCS). Premature ovarian insufficiency (POI) is a globally occurring medical condition. The present work sought a highly efficacious multi-target therapeutic approach against POI with minimal side effects. Finally, it analyzed the relative differences among CCS, WCS and SFCS in terms of their therapeutic efficacy and modes of action against H2O2-challenged KGN human granulosa cell line. Methods: In this study, ultrahigh-performance liquid chromatography (UPLC)-Q-ExactiveTM Orbitrap-mass spectrometry (MS), oxidative stress indices, reactive oxygen species (ROS), Mitochondrial membrane potential (MMP), real-time PCR, Western blotting, and molecular docking were used to investigate the protective effect of CCS, WCS and SFCS on KGN cells oxidative stress and apoptosis mechanisms. Results: The results confirmed that pretreatment with CCS, WCS and SFCS reduced H2O2-induced oxidative damage, accompanied by declining ROS levels and malondialdehyde (MDA) accumulation in the KGN cells. CCS, WCS and SFCS upregulated the expression of antioxidative levels (GSH, GSH/GSSG ratio, SOD, T-AOC),mitochondrial membrane potential (MMP) and the relative mRNA(Nrf2, Keap1, NQO-1, HO-1, SOD-1, CAT). They inhibited apoptosis by upregulating Bcl-2, downregulating Bax, cleaved caspase-9, and cleaved caspase-3, and lowering the Bax/Bcl-2 ratio. They also exerted antioxidant efficacy by partially activating the PI3K/Akt and Keap1-Nrf2/HO-1 signaling pathways. Conclusions: The results of the present work demonstrated the inhibitory efficacy of CCS, WCS and SFCS against H2O2-induced oxidative stress and apoptosis in KGN cells and showed that the associated mechanisms included Keap1-Nrf2/HO-1 activation, P-PI3K upregulation, and P-Akt-mediated PI3K-Akt pathway induction. [ABSTRACT FROM AUTHOR]

Background: Bawei Chenxiang Wan (BCW) is among the most effective and widely used therapies for coronary heart disease and angina pectoris in Tibet. However, whether it confers protection through a right-ventricle (RV) myocardial metabolic mechanism is unknown. Methods: Male Sprague–Dawley rats were orally administrated with BCW, which was injected concurrently with a bolus of Sugen5416, and subjected to hypoxia exposure (SuHx; 5000 m altitude) for 4 weeks. Right ventricular hypertrophy (RVH) in high-altitude heart disease (HAHD) was assessed using Fulton's index (FI; ratio of RV to left ventricle + septum weights) and heart-weight-to-body-weight ratio (HW/BW). The effect of therapeutic administration of BCW on the RVH hemodynamics was assessed through catheterization (mean right ventricular pressure and mean pulmonary artery pressure (mRVP and mPAP, respectively)). Tissue samples were used to perform histological staining, and confirmatory analyses of mRNA and protein levels were conducted to detect alterations in the mechanisms of RVH in HAHD. The protective mechanism of BCW was further verified via cell culture. Results: BCW considerably reduced SuHx-associated RVH, as indicated by macro morphology, HW/BW ratio, FI, mPAP, mRVP, hypertrophy markers, heart function, pathological structure, and myocardial enzymes. Moreover, BCW can alleviate the disorder of glucose and fatty acid metabolism through upregulation of carnitine palmitoyltransferase1ɑ, citrate synthase, and acetyl-CoA and downregulation of glucose transport-4, phosphofructokinase, and pyruvate, which resulted in the reduced levels of free fatty acid and lactic acid and increased aerobic oxidation. This process may be mediated via the regulation of sirtuin 3 (SIRT3)-hypoxia-inducible factor 1α (HIF1α)-pyruvate dehydrogenase kinase (PDK)/pyruvate dehydrogenase (PDH) signaling pathway. Subsequently, the inhibition of SIRT3 expression by 3-TYP (a selective inhibitor of SIRT3) can reverse substantially the anti-RVH effect of BCW in HAHD, as indicated by hypertrophy marker and serum myocardial enzyme levels. Conclusions: BCW prevented SuHx-induced RVH in HAHD via the SIRT3-HIF1ɑ-PDK/PDH signaling pathway to alleviate the disturbance in fatty acid and glucose metabolism. Therefore, BCW can be used as an alternative drug for the treatment of RVH in HAHD. [ABSTRACT FROM AUTHOR]

Background: Sirtuins have an important role in the regulation of metabolic and biological processess. Thus, we hypothesized that foods that could activate sirtuins, known as "sirtfood", may improve health status. So, this study was aimed at investigating the association between the amount of sirtfood intake and the risk of major adverse cardiovascular events (MACE). Methods: In this cohort study, 2918 adults who had no history of MACE at the start of the study (2006–2008) participated and were followed up on until 2018. The amount of sirtfoods intake (servings per week) was computed using a validated food frequency questionnaire. Each patient's medical records were evaluated to detect MACE. The Cox proportional hazards model was applied to assess the association between the amount of sirtfood intake and the risk of MACE. Results: The median duration of the study was 10.6 years. The hazard ratio (HR) for the risk of MACE was 0.70 for the second (95% CI: 0.50, 0.98) and 0.60 (95% CI: 0.42, 0.86) for the third tertile of sirtfoods intake compared with the first tertile. This association was nonlinear, and sirtfoods consumption of more than five servings per week did not result in a lower risk of MACE. In addition, there was a significant interaction between age (P-interaction < 0.001) and sirtfoods intake in relation to MACE occurrence. When assessing sirtfood components, compared with the lowest intake, the highest amount of soy (HR: 0.74, 95% CI: 0.56, 0.99) and parsley (HR: 0.62, 95% CI: 0.47, 0.83) intake was related to a lower risk of MACE. Conclusion: Our results indicated an inverse association between a higher amount of sirtfood intake and a lower risk of MACE incidents. This association was nonlinear, and having more than five servings of sirtfood per week did not reduce the risk of MACE any further. [ABSTRACT FROM AUTHOR]

The primary inflammatory process in atherosclerosis, a major contributor to cardiovascular disease, begins with monocyte adhering to vascular endothelial cells. Actinidia arguta (kiwiberry) is an edible fruit that contains various bioactive components. While A. arguta extract (AAE) has been recognized for its anti-inflammatory characteristics, its specific inhibitory effect on early atherogenic events has not been clarified. We used tumor necrosis factor-α (TNF-α)–stimulated human umbilical vein endothelial cells (HUVECs) for an in vitro model. AAE effectively hindered the attachment of THP-1 monocytes and reduced the expression of vascular cell adhesion molecule-1 (VCAM-1) in HUVECs. Transcriptome analysis revealed that AAE treatment upregulated phosphatase and tensin homolog (PTEN), subsequently inhibiting phosphorylation of AKT and glycogen synthase kinase 3β (GSK3β) in HUVECs. AAE further hindered phosphorylation of AKT downstream of the nuclear factor kappa B (NF-κB) signaling pathway, leading to suppression of target gene expression. Oral administration of AAE suppressed TNF-α–stimulated VCAM-1 expression, monocyte-derived macrophage infiltration, and proinflammatory cytokine expression in C57BL/6 mouse aortas. Myo-inositol, identified as the major compound in AAE, played a key role in suppressing THP-1 monocyte adhesion in HUVECs. These findings suggest that AAE could serve as a nutraceutical for preventing atherosclerosis by inhibiting its initial pathogenesis. [ABSTRACT FROM AUTHOR]

Although hair loss contributes to various social and economic, research methods for material development are currently limited. In this study, we established a research model for developing materials for hair growth through the regulation of β-catenin. We confirmed that 100 nM tegatrabetan (TG), a β-catenin inhibitor, decreased the proliferation of human hair follicle dermal papilla cells (HFDPCs) at 72 h. In addition, TG-induced apoptosis suppressed the phosphorylation of GSK-3β and Akt, translocation of β-catenin from the cytosol to the nucleus, and the expression of cyclin D1. Interestingly, TG significantly increased the G2/M arrest in HFDPCs. Subcutaneous injection of TG suppressed hair growth and the number of hair follicles in C57BL/6 mice. Moreover, TG inhibited the expression of cyclin D1, β-catenin, keratin 14, and Ki67. These results suggest that TG-induced inhibition of hair growth can be a promising model for developing new materials for enhancing β-catenin-mediated hair growth. [ABSTRACT FROM AUTHOR]

Background: The RNA-dependent RNA polymerase (RdRp) inhibitors, molnupiravir and VV116, have the potential to maximize clinical benefits in the oral treatment of COVID-19. Subjects who consume these drugs may experience an increased incidence of adverse events. This study aimed to evaluate the safety profile of molnupiravir and VV116. Methods: A comprehensive search of scientific and medical databases, such as PubMed Central/Medline, Embase, Web of Science, and Cochrane Library, was conducted to find relevant articles in English from January 2020 to June 2023. Any kind of adverse events reported in the study were pooled and analyzed in the drug group versus the control group. Estimates of risk effects were summarized through the random effects model using Review Manager version 5.2, and sensitivity analysis was performed by Stata 17.0 software. Results: Fifteen studies involving 32,796 subjects were included. Eleven studies were placebo-controlled, and four were Paxlovid-controlled. Twelve studies reported adverse events for molnupiravir, and three studies described adverse events for VV116. The total odds ratio (OR) for adverse events in the RdRp inhibitor versus the placebo-controlled group was 1.01 (95% CI=0.84-1.22; I〉=26%), P=0.88. The total OR for adverse events in the RdRp inhibitor versus the Paxlovid-controlled group was 0.32 (95% CI=0.16-0.65; I〉=87%), P=0.002. Individual drug subgroup analysis in the placebo-controlled study showed that compared with the placebo group, a total OR for adverse events was 0.97 (95% CI, 0.85-1.10; I〉=0%) in the molnupiravir group and 3.77 (95% CI=0.08-175.77; I〉=85%) in the VV116 group. Conclusion: The RdRp inhibitors molnupiravir and VV116 are safe for oral treatment of COVID-19. Further evidence is necessary that RdRp inhibitors have a higher safety profile than Paxlovid. [ABSTRACT FROM AUTHOR]

Açaí seed extract (ASE) is obtained from Euterpe oleracea Mart. (açaí) plant (Amazon region) has high nutritional and functional value. ASE is rich in polyphenolic compounds, mainly proanthocyanidins. Proanthocyanidins can modulate the immune system and oxidative stress by inhibiting the toll-like receptor-4 (TLR-4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor-κB (NF-κB) pathway. A great deal of evidence suggests that inflammatory cytokines and oxidative stress contribute to the pathogenesis of intestinal mucositis, and these events can lead to intestinal dysmotility. We hypothesized that ASE acts as an anti-inflammatory and antioxidant compound in intestinal mucositis induced by 5-fluorouracil (5-FU) through modulation of the TLR-4/MyD88/phosphatidylinositol-3-kinase α/mechanistic target of rapamycin/NF-κBp65 pathway. The animals were divided into linear 5-FU (450 mg/kg) and 5-FU + ASE (10, 30, and 100 mg/kg) groups. The weight loss of the animals was evaluated daily. Samples from duodenum, jejunum, and ileum were obtained for histopathological, biochemical, and functional analyses. ASE reduced weight loss, inflammatory parameters (interleukin-1β; tumor necrosis factor-α; myeloperoxidase activity) and the gene expression of mediators involved in the TLR-2/MyD88/NF-κB pathway. ASE prevented histopathological changes with beneficial effects on gastrointestinal transit delay, gastric emptying, and intestinal absorption/permeability. In conclusion, ASE protects the integrity of the intestinal epithelial barrier by inhibiting the TLR/MyD88/PI3K/mechanistic target of rapamycin/NF-κBp65 pathway. Açaí is a plant from the Amazon region that has a high nutritional and functional value. A polyphenol-rich açaí seed extract showed protective effects against inflammation and oxidative stress, improved histological lesion, and delayed gastric emptying induced by 5-fluorouracil in mice. These effects were observed through TLR-4/MyD88/PI3K/mTOR/NF-κBp65 signaling pathway. Abbreviations: 5-FU, 5-fluorouracil; ASE, açaí seed extract; mTOR, mechanistic target of rapamycin; MyD88, myeloid differentiation primary response 88; NF-κBp65, nuclear factor-κBp65; PI3K, phosphatidylinositol-3-kinase α; TLR-4, toll-like receptor 4. [Display omitted] [ABSTRACT FROM AUTHOR]

Comparative approaches have revealed both divergent and convergent paths to achieving shared developmental outcomes. Thus, only through assembling multiple case studies can we understand biological principles. Yet, despite appreciating the conservation—or lack thereof—of developmental networks, the conservation of epigenetic mechanisms regulating these networks is poorly understood. The nematode Pristionchus pacificus has emerged as a model system of plasticity and epigenetic regulation as it exhibits a bacterivorous or omnivorous morph depending on its environment. Here, we determined the "epigenetic toolkit" available to P. pacificus as a resource for future functional work on plasticity, and as a comparison with Caenorhabditis elegans to investigate the conservation of epigenetic mechanisms. Broadly, we observed a similar cast of genes with putative epigenetic function between C. elegans and P. pacificus. However, we also found striking differences. Most notably, the histone methyltransferase complex PRC2 appears to be missing in P. pacificus. We described the deletion/pseudogenization of the PRC2 genes mes-2 and mes-6 and concluded that both were lost in the last common ancestor of P. pacificus and a related species P. arcanus. Interestingly, we observed the enzymatic product of PRC2 (H3K27me3) by mass spectrometry and immunofluorescence, suggesting that a currently unknown methyltransferase has been co-opted for heterochromatin silencing. Altogether, we have provided an inventory of epigenetic genes in P. pacificus to compare with C. elegans. This inventory will enable reverse-genetic experiments related to plasticity and has revealed the first loss of PRC2 in a multicellular organism. [ABSTRACT FROM AUTHOR]

The sirtuin family is a heterogeneous group of proteins that play a critical role in many cellular activities. Several degenerative diseases have recently been linked to aberrant sirtuin expression and activity because of the involvement of sirtuins in maintaining cell longevity and their putative antiaging function. Idiopathic pulmonary fibrosis and progressive pulmonary fibrosis associated with systemic autoimmune disorders are severe diseases characterized by premature and accelerated exhaustion and failure of alveolar type II cells combined with aberrant activation of fibroblast proliferative pathways leading to dramatic destruction of lung architecture. The mechanisms underlying alveolar type II cell exhaustion in these disorders are not fully understood. In this review, we have focused on the role of sirtuins in the pathogenesis of idiopathic and secondary pulmonary fibrosis and their potential as biomarkers in the diagnosis and management of fibrotic interstitial lung diseases. [ABSTRACT FROM AUTHOR]

Objectives: There is little knowledge about oxidative stress‐induced senescence involvement in apical periodontitis. Here, we explored its molecular mechanism in periapical lesions. Methods: Ten cases of radicular cysts and five cases of periapical granulomas were randomly selected. Immunohistochemical analysis was performed to detect the expression and correlation between Senescence‐associated factor polymerase I and transcript release factor (PTRF) and Akt/FoxO1 signaling. Human periodontal ligament cells (hPDLCs) pretreated with LY294002 were exposed to H2O2‐induced oxidative stress conditions and then cell proliferation, senescence, apoptosis, and associated signaling were evaluated by EdU labeling, β‐galactosidase assay, RT‐qPCR, and western blot analysis, respectively. Results: Polymerase I and transcript release factor and Akt/FoxO1 signaling were more frequently expressed in the radicular cyst than in periapical granulomas. Notably, cells in radicular cysts showed Akt activation, FoxO1 phosphorylation, and cytoplasmic translocation. In vitro, prominent H2O2‐induced senescence was observed in hPDLCs. LY294002, a PI3K inhibitor, attenuated the expression levels of senescence (Klotho, P16INK4), apoptosis (Bad, Fas), phosphorylated Akt, and phosphorylated FoxO1; however, did not affect cell proliferation. Conclusions: Our data indicated that senescence is present in clinical periapical lesions, and Akt/FoxO1 signaling is involved in the H2O2‐induced cellular senescence, which could serve as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Objectives: Circular RNAs (circRNAs), with their multilevel and versatile regulation, have emerged as promising targets for treating complex and heterogeneous malignancies such as oral squamous cell carcinoma (OSCC). It is crucial to explore the function of key circRNAs and elucidate the underlying mechanisms to establish an effective in vivo delivery system to better utilize circRNAs as cancer treatment strategies. Materials and Methods: circRNA (circ‐OCAC) was identified as significantly downregulated in tumor samples compared to paracancerous tissues by RNA‐seq analysis of eight pairs of OSCC tissues. Functional experiments of circ‐OCAC were performed both in vitro and in vivo. The interactions between circ‐OCAC and miR‐411‐5p were clarified by RNA pull down and RNA immunoprecipitation (RIP) assays. Results: We observed that circ‐OCAC inhibits OSCC growth and metastasis by blocking the PI3K/Akt signaling pathway. To translate this observation in vivo, a pH‐responsive nanoparticle (pNP) was developed to target circ‐OCAC. Our results confirmed the advantages of the pNP‐circ‐OCAC system: high tumor enrichment capacity and good biosafety, which resulted in a significantly enhanced antitumor effect. Conclusions: This study demonstrated that targeting circ‐OCAC serves as a promising potential therapeutic strategy for OSCC. [ABSTRACT FROM AUTHOR]

Objectives: Exosomes derived from stem cells are a potential cell‐free tool for tissue regeneration with therapeutic potential. However, its application in cementum repair is unclear. This study aimed to investigate the effect of human periodontal ligament stem cell‐derived exosomes on the biological activity of cementoblasts, the main effector cells in cementum synthesis. Materials and Methods: OCCM‐30 cementoblasts were cultured with various human periodontal ligament stem cell‐derived exosome concentrations. OCCM‐30 cells proliferation, migration, and cementogenic mineralization were examined, along with the gene and protein expression of factors associated with cementoblastic mineralization. Results: Exosomal promoted the migration, proliferation, and mineralization of OCCM‐30 cells. The exosome‐treated group significantly increased the expression of cementogenic‐related genes and proteins. Furthermore, the expression of p‐PI3K and p‐AKT was enhanced by exosome administration. Treatment with a PI3K/AKT inhibitor markedly attenuated the gene and protein expression of cementoblastic factors, and this effect was partially reversed by exosome administration. Conclusions: Human periodontal ligament stem cell‐derived exosomes can promote the activity of cementoblasts via the PI3K/AKT signaling pathway, providing a scientific basis for promoting the repair process in orthodontically induced inflammatory root resorption. [ABSTRACT FROM AUTHOR]

Simple Summary: FAM46C is a tumour suppressor protein originally characterized in multiple myeloma. Recent findings, however, suggest a much broader involvement of FAM46C in cancer, underlining the clinical importance of fully dissecting the intracellular pathways it modulates. To date, FAM46C mechanistic role is still disputed and studies regarding its mode of action are sometimes contradictory, urging the need to summarize and clarify the results obtained so far. Here, by focusing primarily on the intracellular pathways modulated by FAM46C, the currently accepted models regarding its mode of action, the regulators of its expression and how it associates with increased/decreased cell sensitivity to anticancer agents, we provide the first comprehensive review on FAM46C. FAM46C is a well-established tumour suppressor with a role that is not completely defined or universally accepted. Although FAM46C expression is down-modulated in several tumours, significant mutations in the FAM46C gene are only found in multiple myeloma (MM). Consequently, its tumour suppressor activity has primarily been studied in the MM context. However, emerging evidence suggests that FAM46C is involved also in other cancer types, namely colorectal, prostate and gastric cancer and squamous cell and hepatocellular carcinoma, where FAM46C expression was found to be significantly reduced in tumoural versus non-tumoural tissues and where FAM46C was shown to possess anti-proliferative properties. Accordingly, FAM46C was recently proposed to function as a pan-cancer prognostic marker, bringing FAM46C under the spotlight and attracting growing interest from the scientific community in the pathways modulated by FAM46C and in its mechanistic activity. Here, we will provide the first comprehensive review regarding FAM46C by covering (1) the intracellular pathways regulated by FAM46C, namely the MAPK/ERK, PI3K/AKT, β-catenin and TGF-β/SMAD pathways; (2) the models regarding its mode of action, specifically the poly(A) polymerase, intracellular trafficking modulator and inhibitor of centriole duplication models, focusing on connections and interdependencies; (3) the regulation of FAM46C expression in different environments by interferons, IL-4, TLR engagement or transcriptional modulators; and, lastly, (4) how FAM46C expression levels associate with increased/decreased tumour cell sensitivity to anticancer agents, such as bortezomib, dexamethasone, lenalidomide, pomalidomide, doxorubicin, melphalan, SK1-I, docetaxel and norcantharidin. [ABSTRACT FROM AUTHOR]

The bacterial genus Rhodococcus comprises organisms performing oleaginous behaviors under certain growth conditions and ratios of carbon and nitrogen availability. Rhodococci are outstanding producers of biofuel precursors, where lipid and glycogen metabolisms are closely related. Thus, a better understanding of rhodococcal carbon partitioning requires identifying catalytic steps redirecting sugar moieties to storage molecules. Here, we analyzed two GT4 glycosyl-transferases from Rhodococcus jostii (RjoGlgAb and RjoGlgAc) annotated as α-glucan-α-1,4-glucosyl transferases, putatively involved in glycogen synthesis. Both enzymes were produced in Escherichia coli cells, purified to homogeneity, and kinetically characterized. RjoGlgAb and RjoGlgAc presented the "canonical" glycogen synthase activity and were actives as maltose-1P synthases, although to a different extent. Then, RjoGlgAc is a homologous enzyme to the mycobacterial GlgM, with similar kinetic behavior and glucosyl-donor preference. RjoGlgAc was two orders of magnitude more efficient to glucosylate glucose-1P than glycogen, also using glucosamine-1P as a catalytically efficient aglycon. Instead, RjoGlgAb exhibited both activities with similar kinetic efficiency and preference for short-branched α-1,4-glucans. Curiously, RjoGlgAb presented a super-oligomeric conformation (higher than 15 subunits), representing a novel enzyme with a unique structure-to-function relationship. Kinetic results presented herein constitute a hint to infer on polysaccharides biosynthesis in rhodococci from an enzymological point of view. [ABSTRACT FROM AUTHOR]

Idebenone, a mitochondrial regulator, has exhibited anti-cancer activity in neurogenic and prostate tumor cells; however, its efficacy and specific targets in the treatment of triple-negative breast cancer (TNBC) remain unclear. This study aims to evaluate the potential of Idebenone as a therapeutic agent for TNBC. TNBC cell lines and Xenograft mouse models were used to assess the effect of Idebenone on TNBC both in vitro and in vivo. To investigate the underlying mechanism of Idebenone's effect on TNBC, cell viability assay, transwell invasion assay, cell cycle analysis, apoptosis assay, mitochondrial membrane potential assay, immunofluorescence staining, and transcriptome sequencing were utilized. The results showed that Idebenone impeded the proliferation, colony formation, migration, and invasion of TNBC cells, suppressed apoptosis, and halted the cell cycle in the G2/M phase. The inhibitory effect of Idebenone on TNBC was associated with the GADD45/CyclinB/CDK1 signaling pathway. By disrupting the mitochondrial membrane potential (MMP) and promoting mitophagy, Idebenone promoted cell autophagy through the AMPK/mTOR pathway, thus further suppressing the proliferation of TNBC cells. Furthermore, we found that Idebenone inhibited the development of TNBC in vivo. In conclusion, Idebenone may be a promising therapeutic option for TNBC as it is capable of inducing autophagy and apoptosis. [ABSTRACT FROM AUTHOR]

Alzheimer's causes cognitive dysfunction. This study investigated the neuro-promoting effects of cordycepin on amyloid-beta precursor protein (APP) synthesis in human neuroblastoma SH-SY5Y cells. Cordycepin was found to boost SH-SY5Y cell proliferation and decreased AD pathology. APP, PS1, and PS2 were downregulated whereas ADAM10 and SIRT1 were upregulated by cordycepin. Cordycepin also reduced APP secretion in a dose-dependent manner. Cordycepin alleviated oxidative stress by the upregulation of GPX and SOD, as well as autophagy genes (LC3, ATG5, and ATG12). Cordycepin activity was also found to be SIRT1-dependent. Therefore, cordycepin may relieve the neuronal degeneration caused by APP overproduction, and oxidative stress. [ABSTRACT FROM AUTHOR]

Nicotinamide phosphoribosyltransferase (Nampt) is an adipocytokine that is elevated in obesity, type 2 diabetes and increased levels are associated with inflammatory processes. Nampt serum concentrations have been suggested to follow a diurnal rhythm peaking in the afternoon in lean males. However, no data exists regarding the effects of gender and body weight. We measured Nampt serum levels over 24 h in a cohort of healthy individuals living with either normal weight or obesity. Furthermore, effects of meals, oral glucose tolerance test and physical exercise on Nampt concentrations were evaluated. Correlation analyses to other hormonal- and lab parameters and anthropometric measurements were performed. Nampt showed a diurnal rhythm with increased levels at daytime and a peak in the early afternoon. This diurnal rhythm was significant for all groups but obese males. The Nampt amplitude, measured both relatively and absolutely, was significantly higher in females than in males. Meals did not influence Nampt serum levels, whereas physical exercise and an OGTT did significantly influence Nampt serum levels. In conclusion, we found gender specific differences in Nampt amplitude and coefficient variation with both being higher in females. The circadian rhythm of Nampt was independent of gender in healthy lean individuals, whereas it was disturbed in men with obesity. [ABSTRACT FROM AUTHOR]

Developmental and epileptic encephalopathies are severe neurological conditions in clinical practice, among which loss-of-function mutations in brain-enriched serine-threonine kinase cyclin dependent kinase like-5 (CDKL5) exists as one of the most common types. It is unknown, therefore, how precisely CDKL5 mutations lead to neuronal hyper-excitation. A recent study that looked at the connection between voltage-gated calcium channel Cav2.3 and CDKL5 in an experimental context was published in Nature Communications. This study has revealed that Cav2.3, a physiological phosphorylation target of CDKL5, would show delayed inactivation and increased cholinergic stimulation in CDKL5 knock out conditions. This would in turn cause neuronal hyperexcitability and related enhanced seizure susceptibility. This work, in our opinion, provided fresh insight into the epileptic encephalopathies linked to CDKL5 and highlighted Cav2.3 as a possible target for it. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of berberine (BBR) combined with XAV939 on the migration and apoptosis of osteosarcoma MG-63 cells and its possible mechanisms. Methods: MG-63 cells were cultured, and 20~120 µmol/L of BBR and 5~60 µmol/L of XAV939 were added, respectively. The cytotoxicity of BBR and XAV939 was determined by CCK-8 assay, and the combined index of the two was clarified using Chou-Talalay analysis to determine the intervention dose for the subsequent experiments. MG-63 cells were randomly divided into the blank control (NC) group, the BBR group, the XAV939 group, and the BBR+XAV939 combined group. The effects of BBR and XAV939 treatment alone or in combination on the migratory ability of MG-63 cells were detected by the scratch healing assay and the Transwell assay. Hoechst 33258 staining, JC-1 staining and Annexin V-FITC/PI double staining flow cytometry were used to detect the effects on cell mitochondrial membrane potential and apoptosis. Immunofluorescence was used to datect the expression of BAX protein, WB assay was used to detect the effects on the expression of MMP-2 and BAX in the cells, and qPCR was used to detect the effects on the expression of the MMP-2 gene. Results: BBR and XAV939 inhibited the proliferation of MG-63 cells in a dose-dependent manner, and 30 µmol/L BBR, 7.5 µmol/L XAV939 were selected for subsequent experiments. Compared with the NC group, 24 h after the cells were treated with BBR (30 µmol/L), XAV939 (7.5 µmol/L) and BBR+ XAV939 combination, the migration ability of MG-63 cells was significantly reduced; apoptotic cells were significantly increased (all P <0.05); the mitochondrial membrane potential was decreased (P<0.01); the gene expression of MMP-2, and MMP-2, BAX protein levels were all reduced (all P<0.05). In addition, the effect of the combination group was significantly stronger than that of the monotherapy group (P<0.05 or P<0.01). Conclusion: BBR and XAV939 alone or in combination can inhibit the migration and promote the apoptosis of MG-63 cells. The mechanism may be related to the decreased expression of migration-related protein MMP-2 and increased level of apoptosis-related protein BAX. [ABSTRACT FROM AUTHOR]

Background The prognosis of malignant primary high-grade brain tumors, predominantly glioblastomas, is poor despite intensive multimodality treatment options. In more than 50% of patients with glioblastomas, potentially targetable mutations are present, including rearrangements, altered splicing, and/or focal amplifications of epidermal growth factor receptor (EGFR) by signaling through the RAF / RAS pathway. We studied whether treatment with the clinically available anti- EGFR monoclonal antibody panitumumab provides clinical benefit for patients with RAF/RAS -wild-type (wt) glioblastomas in the Drug Rediscovery Protocol (DRUP). Methods Patients with progression of treatment refractory RAF / RASwt glioblastoma were included for treatment with panitumumab in DRUP when measurable according to RANO criteria. The primary endpoints of this study are clinical benefit (CB: defined as confirmed objective response [OR] or stable disease [SD] ≥ 16 weeks) and safety. Patients were enrolled using a Simon-like 2-stage model, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 in 8 patients had CB in stage 1. Results Between 03-2018 and 02-2022, 24 evaluable patients were treated. CB was observed in 5 patients (21%), including 2 patients with partial response (8.3%) and 3 patients with SD ≥ 16 weeks (12.5%). After median follow-up of 15 months, median progression-free survival and overall survival were 1.7 months (95% CI 1.6-2.1 months) and 4.5 months (95% CI 2.9-8.6 months), respectively. No unexpected toxicities were observed. Conclusions Panitumumab treatment provides limited CB in patients with recurrent RAF / RAS wt glioblastoma precluding further development of this therapeutic strategy. [ABSTRACT FROM AUTHOR]

Background: Studies have shown that visfatin is an inflammatory factor closely related to periodontitis. We examined the levels of visfatin in gingival crevicular fluid (GCF) and gingival tissues under different periodontal conditions, in order to provide more theoretical basis for exploring the role of visfatin in the pathogenesis of periodontitis. Methods: We enrolled 87 subjects, with 43 in the chronic periodontitis (CP) group, 21 in the chronic gingivitis (CG) group, and 23 in the periodontal health (PH) group. Periodontal indexes (PD, AL, PLI, and BI) were recorded. GCF samples were collected for visfatin quantification, and gingival tissues were assessed via immunohistochemical staining. Results: Visfatin levels in GCF decreased sequentially from CP to CG and PH groups, with statistically significant differences (P < 0.05). The CP group exhibited the highest visfatin levels, while the PH group had the lowest. Gingival tissues showed a similar trend, with significant differences between groups (P < 0.001). Periodontal indexes were positively correlated with visfatin levels in both GCF and gingival tissues (P < 0.001). A strong positive correlation was observed between visfatin levels in GCF and gingival tissues (rs = 0.772, P < 0.001). Conclusion: Greater periodontal destruction corresponded to higher visfatin levels in GCF and gingival tissues, indicating their potential collaboration in damaging periodontal tissues. Visfatin emerges as a promising biomarker for periodontitis and may play a role in its pathogenesis. [ABSTRACT FROM AUTHOR]

Poria sini decoction (PSD), a significant traditional Chinese herbal formula, is effective in liver cancer (LC) and chronic heart failure (CHF); however, little is known about its concurrent targeting mechanism. Methods. This study analyzed the potential molecular mechanism of PSD against the two distinct diseases using network pharmacology approaches, including multidatabase search, pharmacokinetic screening, network construction analysis, Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and molecular docking to elaborate the active components, signaling pathways, and potential mechanisms of PSD in the treatment of both LC and CHF. Results. A total of 155 active components and 193 potential targets in PSD were identified. Bioinformatics analysis revealed that quercetin, isorhamnetin, and naringenin, etc. may be potential candidate agents. TNF, AKT1, and IL6, etc. could become potential therapeutic targets. TNF-α, NF-κB, PI3K-AKT, and TRP signaling pathways might play an important role in PSD against LC and CHF. Molecular docking results showed that most screened active compounds could embed itself into target proteins with a high binding affinity, and the hydrogen bonds number ≥3 indicated a more stable conformation of the compounds and target proteins. Overall, quercetin and isorhamnetin were the main active components, and TNF and AKT1 were the primary targets for PSD treatment of LC and CHF. Conclusions. This study illustrated that quercetin contained in PSD played an important role in the treatment of LC and CHF by acting on the key gene of TP53 and downregulating the PI3K-AKT signaling pathway. [ABSTRACT FROM AUTHOR]

Simple Summary: Epidemiologic evidence and previous research have established obesity, diabetes and the metabolic syndrome as risk factors for pancreatic cancer in humans, while the precise mechanisms remain incompletely characterized. The concept that these metabolic diseases may be driven by diet implies that many cancers could be prevented or delayed through lifestyle modifications. By design, genetically engineered mouse models expressing oncogenic mutants of KRAS protein within the epithelial cells of the pancreas closely recapitulate the human disease. Research on diet-induced obesity in such mice implies the involvement of diverse factors including elevated insulin/insulin-like growth factors, inflammation, and genetic/epigenetic alterations and has revealed dramatic acceleration of cancer incidence that was more marked in males than females. The present research uses proteomic and phosphoproteomic analysis as a foundation to assess differentially expressed proteins and associated signal transduction pathways, yielding further novel mechanistic insights into the influence of tumor microenvironment on diet-induced obesity-associated pancreatic cancer. Diet-induced obesity (DIO) promotes pancreatic ductal adenocarcinoma (PDAC) in mice expressing KRasG12D in the pancreas (KC mice), but the precise mechanisms remain unclear. Here, we performed multiplex quantitative proteomic and phosphoproteomic analysis by liquid chromatography–tandem mass spectrometry and further bioinformatic and spatial analysis of pancreas tissues from control-fed versus DIO KC mice after 3, 6, and 9 months. Normal pancreatic parenchyma and associated proteins were steadily eliminated and the novel proteins, phosphoproteins, and signaling pathways associated with PDAC tumorigenesis increased until 6 months, when most males exhibited cancer, but females did not. Differentially expressed proteins and phosphoproteins induced by DIO revealed the crucial functional role of matrisomal proteins, which implies the roles of upstream regulation by TGFβ, extracellular matrix-receptor signaling to downstream PI3K-Akt-mTOR-, MAPK-, and Yap/Taz activation, and crucial effects in the tumor microenvironment such as metabolic alterations and signaling crosstalk between immune cells, cancer-associated fibroblasts (CAFs), and tumor cells. Staining tissues from KC mice localized the expression of several prognostic PDAC biomarkers and elucidated tumorigenic features, such as robust macrophage infiltration, acinar–ductal metaplasia, mucinous PanIN, distinct nonmucinous atypical flat lesions (AFLs) surrounded by smooth muscle actin-positive CAFs, invasive tumors with epithelial–mesenchymal transition arising close to AFLs, and expanding deserted areas by 9 months. We next used Nanostring GeoMX to characterize the early spatial distribution of specific immune cell subtypes in distinct normal, stromal, and PanIN areas. Taken together, these data richly contextualize DIO promotion of Kras-driven PDAC tumorigenesis and provide many novel insights into the signaling pathways and processes involved. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is the most common malignant brain cancer and is associated with poor prognosis, with an average survival after diagnosis of less than 18 months. Hundreds of clinical trials have been conducted, with more underway to make progress in treating glioblastoma. This review details conventional and emergent targeted therapies for glioblastoma. Glioblastoma is most commonly a primary brain tumor and the utmost malignant one, with a survival rate of approximately 12–18 months. Glioblastoma is highly heterogeneous, demonstrating that different types of cells from the same tumor can manifest distinct gene expression patterns and biological behaviors. Conventional therapies such as temozolomide, radiation, and surgery have limitations. As of now, there is no cure for glioblastoma. Alternative treatment methods to eradicate glioblastoma are discussed in this review, including targeted therapies to PI3K, NFKβ, JAK-STAT, CK2, WNT, NOTCH, Hedgehog, and TGFβ pathways. The highly novel application of oncolytic viruses and nanomaterials in combating glioblastoma are also discussed. Despite scores of clinical trials for glioblastoma, the prognosis remains poor. Progress in breaching the blood–brain barrier with nanomaterials and novel avenues for targeted and combination treatments hold promise for the future development of efficacious glioblastoma therapies. [ABSTRACT FROM AUTHOR]