PARP1-TRIM44-MRN loop dictates the response to PARP inhibitors.

PARP inhibitors (PARPi) show selective efficacy in tumors with homologous recombination repair (HRR)-defects but the activation mechanism of HRR pathway in PARPi-treated cells remains enigmatic. To unveil it, we searched for the mediator bridging PARP1 to ATM pathways by screening 211 human ubiquitin-related proteins. We discovered TRIM44 as a crucial mediator that recruits the MRN complex to damaged chromatin, independent of PARP1 activity. TRIM44 binds PARP1 and regulates the ubiquitination-PARylation balance of PARP1, which facilitates timely recruitment of the MRN complex for DSB repair. Upon exposure to PARPi, TRIM44 shifts its binding from PARP1 to the MRN complex via its ZnF UBP domain. Knockdown of TRIM44 in cells significantly enhances the sensitivity to olaparib and overcomes the resistance to olaparib induced by 53BP1 deficiency. These observations emphasize the central role of TRIM44 in tethering PARP1 to the ATM-mediated repair pathway. Suppression of TRIM44 may enhance PARPi effectiveness and broaden their use even to HR-proficient tumors.

HER4 is a high-affinity dimerization partner for all EGFR/HER/ErbB family proteins.

Human epidermal growth factor receptors (HER)-also known as EGFR or ErbB receptors-are a subfamily of receptor tyrosine kinases (RTKs) that play crucial roles in cell growth, division, and differentiation. HER4 (ErbB4) is the least studied member of this family, partly because its expression is lower in later stages of development. Recent work has suggested that HER4 can play a role in metastasis by regulating cell migration and invasiveness; however, unlike EGFR and HER2, the precise role that HER4 plays in tumorigenesis is still unresolved. Early work on HER family proteins suggested that there are direct interactions between the four members, but to date, there has been no single study of all four receptors in the same cell line with the same biophysical method. Here, we quantitatively measure the degree of association between HER4 and the other HER family proteins in live cells with a time-resolved fluorescence technique called pulsed interleaved excitation fluorescence cross-correlation spectroscopy (PIE-FCCS). PIE-FCCS is sensitive to the oligomerization state of membrane proteins in live cells, while simultaneously measuring single-cell protein expression levels and diffusion coefficients. Our PIE-FCCS results demonstrate that HER4 interacts directly with all HER family members in the cell plasma membrane. The interaction between HER4 and other HER family members intensified in the presence of a HER4-specific ligand. Our work suggests that HER4 is a preferred dimerization partner for all HER family proteins, even in the absence of ligands.

Transcriptomic heterogeneity of EGFR-mutant non-small cell lung cancer evolution towards small cell lung cancer.

PURPOSE: Histological transformation from epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a key mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs). However, transcriptomic changes between NSCLC and transformed SCLC (t-SCLC) remain unexplored. EXPERIMENTAL DESIGN: We conducted whole transcriptome analysis of 59 regions of interest (ROIs) through the spatial profiling of FFPE tissues obtained from ten patients (lung adenocarcinoma, 22; combined SCLC/NSCLC, 7; t-SCLC, 30 ROIs). Transcriptomic profiles and differentially expressed genes (DEGs) were compared between pre- and post-transformed tumors. RESULTS: Following EGFR-TKI treatment, 93.7% (15/16) of transformed-SCLC (t-SCLC) components evolved into neuroendocrine-high subtypes (SCLC-A or SCLC-N). The transition to t-SCLC occurred regardless of EGFR-TKI treatment and EGFR mutational status, with a notable decrease in EGFR expression (P < 0.001) at both mRNA and protein levels. Pathway analysis revealed that gene overexpression was related to epigenetic alterations in t-SCLC. Interestingly, Histone deacetylase (HDAC) inhibitors restored EGFR expression in SNU-2962A cells and their organoid model. The synergistic effects of third-generation EGFR-TKI osimertinib and the HDAC inhibitor fimepinostat were validated in both in vitro and in vivo models. CONCLUSIONS: Our study demonstrated most t-SCLC showed neuronal subtypes with low EGFR expression. DEGs analysis and t-SCLC preclinical models identified an epigenetic modifier as a promising treatment strategy for t-SCLC.

Resistance mechanisms of EGFR tyrosine kinase inhibitors, in EGFR exon 20 insertion-mutant lung cancer.

BACKGROUND: Mobocertinib, an EGFR exon 20 insertion (Ex20ins)-specific tyrosine kinase inhibitor has been used for treatment of advanced/metastatic EGFR Ex20ins-mutant non-small cell lung cancer (NSCLC). However, resistance mechanisms to EGFR Ex20ins-specific inhibitors and the efficacy of subsequent amivantamab treatment is unknown. METHODS: To investigate resistance mechanisms, tissue and cfDNA samples were collected before treatment initiation and upon development of resistance from NSCLC patients with EGFR Ex20ins mutations received mobocertinib, poziotinib, and amivantamab treatments. Genetic alterations were analyzed using whole-genome and targeted sequencing, and in vitro resistant cell lines were generated for validation. RESULTS: EGFR amplification (n = 6, including 2 broad copy number gain) and EGFR secondary mutation (n = 3) were observed at the resistance of mobocertinib. One patient had both EGFR secondary mutation and high EGFR focal amplification. In vitro models harboring EGFR alterations were constructed to validate resistance mechanisms and identify overcoming strategies to resistance. Acquired EGFR-dependent alterations were found to mediate resistance to mobocertinib in patients and in vitro models. Furthermore, two of six patients who received sequential amivantamab followed by an EGFR tyrosine kinase inhibitor had MET amplification and showed partial response. CONCLUSIONS: Our study revealed EGFR-dependent and -independent mechanisms of mobocertinib resistance in patients with advanced EGFR Ex20ins-mutant NSCLC.

Smoking-attributable Mortality in Korea, 2020: A Meta-analysis of 4 Databases.

OBJECTIVES: Estimating the number of deaths caused by smoking is crucial for developing and evaluating tobacco control and smoking cessation policies. This study aimed to determine smoking-attributable mortality (SAM) in Korea in 2020. METHODS: Four large-scale cohorts from Korea were analyzed. A Cox proportional-hazards model was used to determine the hazard ratios (HRs) of smoking-related death. By conducting a meta-analysis of these HRs, the pooled HRs of smoking-related death for 41 diseases were estimated. Population-attributable fractions (PAFs) were calculated based on the smoking prevalence for 1995 in conjunction with the pooled HRs. Subsequently, SAM was derived using the PAF and the number of deaths recorded for each disease in 2020. RESULTS: The pooled HR for all-cause mortality attributable to smoking was 1.73 for current men smokers (95% confidence interval [CI], 1.53 to 1.95) and 1.63 for current women smokers (95% CI, 1.37 to 1.94). Smoking accounted for 33.2% of all-cause deaths in men and 4.6% in women. Additionally, it was a factor in 71.8% of men lung cancer deaths and 11.9% of women lung cancer deaths. In 2020, smoking was responsible for 53 930 men deaths and 6283 women deaths, totaling 60 213 deaths. CONCLUSIONS: Cigarette smoking was responsible for a significant number of deaths in Korea in 2020. Monitoring the impact and societal burden of smoking is essential for effective tobacco control and harm prevention policies.

A phase II study of osimertinib in patients with NSCLC harboring EGFR exon 20 insertion: A multicenter trial of the Korean Cancer Study Group (LU17-19).

BACKGROUND: Epidermal growth factor receptor (EGFR) exon 20 insertions account for up to 10% of all EGFR mutations. Clinical outcomes in patients receiving approved EGFR exon 20 insertion-specific inhibitors have been variable. Although osimertinib has demonstrated antitumor activity in clinical trials, its clinical efficacy and translational potential remain to be determined in non-small cell lung carcinoma (NSCLC) with EGFR exon 20 insertion. METHODS: In this multicenter phase II study, patients with advanced NSCLC harboring EGFR exon 20 insertions for whom the standard chemotherapy failed received 80 mg osimertinib once daily. The primary endpoint was the investigator-assessed objective response rate (ORR) as defined by Response Evaluation Criteria in Solid Tumors version 1.1. The secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety profile. RESULTS: Among 15 patients enrolled at stage 1, the best response was most commonly disease stabilization (73.3 %), which did not meet the stage 1 threshold (objective response ≥ 2/15). As of data cutoff, two patients remained on the treatment. The median PFS and OS were 3.8 (95 % confidence interval [CI] = 1.7-5.5) months and 6.5 (95 % CI = 3.9-not reached) months, respectively. Adverse events (≥grade 3) were anemia, hypercalcemia, and pneumonia (13.3 % each), and asthenia, femur fracture, increased alkaline phosphate, hyperkalemia, bone pain, and azotemia (6.7 % each). Pre-existing EGFR C797S mutation detected in plasma limited the efficacy of osimertinib. CONCLUSION: Osimertinib at 80 mg once daily had limited efficacy and mostly showed disease stabilization with an acceptable safety profile in advanced NSCLC harboring EGFR exon 20 insertions. CLINICALTRIALS: govIdentifier: NCT03414814.

Triphenylphosphonium-functionalized dimeric BODIPY-based nanoparticles for mitochondria-targeting photodynamic therapy.

The dimerization of boron dipyrromethene (BODIPY) moieties is an appealing molecular design approach for developing heavy-atom-free triplet photosensitizers (PSs). However, BODIPY dimer-based PSs generally lack target specificity, which limits their clinical use for photodynamic therapy. This study reports the synthesis of two mitochondria-targeting triphenylphosphonium (TPP)-functionalized meso-ß directly linked BODIPY dimers (BTPP and BeTPP). Both BODIPY dimers exhibited solvent-polarity-dependent singlet oxygen (1O2) quantum yields, with maximum values of 0.84 and 0.55 for BTPP and BeTPP, respectively, in tetrahydrofuran. The compact orthogonal geometry of the BODIPY dimers facilitated the generation of triplet excited states via photoinduced charge separation (CS) and subsequent spin-orbit charge-transfer intersystem crossing (SOCT-ISC) processes and their rates were dependent on the energetic configuration between the frontier molecular orbitals of the two BODIPY subunits. The as-synthesized compounds were amphiphilic and hence formed stable nanoparticles (∼36 nm in diameter) in aqueous solutions, with a zeta potential of ∼33 mV beneficial for mitochondrial targeting. In vitro experiments with MCF-7 and HeLa cancer cells indicated the effective localization of BTPP and BeTPP within cancer-cell mitochondria. Under light irradiation, BTPP and BeTPP exhibited robust photo-induced therapeutic effects in both cell lines, with half-maximal inhibitory concentration (IC50) values of ∼30 and ∼55 nM, respectively.

64Cu-Labeled Boron-Containing Cyclic RGD Peptides for BNCT and PET Imaging.

The burgeoning interest in developing boron neutron capture therapy (BNCT) tracers and their accompanying diagnostics for the treatment of recalcitrant tumors has prompted this investigation. Our study aims to devise a tumor treatment strategy utilizing BNCT to target the αvß3 integrin. To this end, we propose a pioneering boron-infused cyclic Arg-Gly-Asp (RGD) peptide, cRGD(d-BPA)K, designed as an efficacious BNCT tracer. Additionally, we introduce its diagnostic complement, DOTA-cRGD(d-BPA)K, tailored for positron emission tomography (PET) to visualize αvß3 expressed tumors. Radiolabeling [64Cu]Cu-DOTA-cRGD(d-BPA)K (64Cu-1) resulted in a high radiochemical yield and purity. The radiotracer exhibited exceptional in vitro stability and demonstrated significant uptake in U87MG tumors via PET imaging. Biodistribution analysis using compound 2 showed a 7.0 ppm accumulation of boron in the U87MG tumor 1 h post-intravenous injection. Furthermore, compound 2 displayed superior tumor/blood (2.41) and tumor/muscle (2.46) ratios compared to the clinically approved l-BPA-fructose. Both compound 2 and its diagnostic counterpart 64Cu-1 hold potential for BNCT and cancer diagnosis, respectively, via molecular imaging.

Oral subacute polypropylene microplastics administration effect on potential immunotoxicity in ICR mice.

Exposure to microplastics may be associated with damage of immune system. Polypropylene microplastics (PP-MPs) with a wide range of beneficial applications have not been extensively studied with respect to the immune system. The aim of this investigation is to examine the influence of two different sizes of PP-MPs (5.2 and 23.9 µm diameter) on immune system components in ICR mice. PP-MPs were administered orally to female and male mice at 0 (corn oil vehicle), 500, 1000, or 2000 mg/kg/d for single and daily for 4-week repeated toxicity test, respectively. No significant differences were observed in number of thymic CD4+, CD8+, CD4+CD8+ T lymphocytes, splenic helper T cells, cytotoxic T cells, and B cells. The ratio of interferon-γ to interleukin-4 in culture supernatants from activated splenocytes ex vivo (48 hr) was lower in females which were repeatedly administered with PP-MPs compared to vehicle irrespective of PP-MPs size and dose. In contrast, the opposite trend was observed in males. Production of tumor necrosis factor-α was upregulated in females that were repeatedly exposed to PP-MPs. The serum IgG2a/IgG1 ratio was lowered in female receiving large-size PP-MPs. Data suggest that immune disturbances resulting in predominant type-2 helper T cell reactivity may occur in mice, especially in females, when repeatedly exposed to PP-MPs. Further investigations with longer exposure periods are necessary to determine the immunotoxicities attributed to PP-MPs.

Comparison of computed tomography perfusion and magnetic resonance dynamic susceptibility contrast perfusion-weighted imaging in canine brain.

Brain perfusion allows for the evaluation of cerebral hemodynamics, particularly in brain infarcts and tumors. Computed tomography (CT) perfusion (CTP) provides reliable data; however, it has a limited scan field of view and radiation exposure. Magnetic resonance (MR) perfusion provides detailed imaging of small structures and a wide scan field of view. However, no study has compared CTP and MR perfusion and assessed the correlation between the perfusion parameters measured using CTP and MR perfusion. The aim of the present study was to assess the correlation and agreement of the cerebral perfusion derived from dynamic susceptibility contrast (DSC)-MRI and CTP in dogs. In this crossover design study, the cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time, and time to peak were measured in the temporal cerebral cortex, caudate nucleus, thalamus, piriform lobe, and hippocampus using CTP and DSC-MRI in six healthy beagle dogs and a dog with a pituitary tumor. On the color map of healthy beagles, blood vessels and the perivascular brain parenchyma appeared as red-green, indicating high perfusion, and the areas distant from the vessels appeared as green-blue, indicating low perfusion levels in CTP and DSC-MRI. CTP parameters were highest in the piriform lobe (CBF = 121.11 ± 12.78 mL/100 g/min and CBV = 8.70 ± 2.04 mL/100 g) and lowest in the thalamus (CBF = 63.75 ± 25.24 mL/100 g/min and CBV = 4.02 ± 0.55 mL/100 g). DSC-MRI parameters were also highest in the piriform lobe (CBF = 102.31 ± 14.73 mL/100 g/min and CBV = 3.17 ± 1.23 mL/100 g) and lowest in the thalamus (CBF = 37.73 ± 25.11 mL/100 g/min and CBV = 0.81 ± 0.44 mL/100 g) although there was no statistical correlation in the quantitative perfusion parameters between CTP and DSC-MRI. In a dog with a pituitary tumor, the color map of the tumor appeared as a red scale, indicating high perfusion and higher CBF and CBV on CTP (149 mL/100 g and 20 mL/100 g/min) and on DSC-MRI (116.3 mL/100 g and 15.32 mL/100 g/min) compared to those measured in healthy dogs. These findings indicate that DSC-MRI and CTP maps exhibit comparability and interchangeability in the assessment of canine brain perfusion.

LC3B drives transcription-associated homologous recombination via direct interaction with R-loops.

Exploring the connection between ubiquitin-like modifiers (ULMs) and the DNA damage response (DDR), we employed several advanced DNA damage and repair assay techniques and identified a crucial role for LC3B. Notably, its RNA recognition motif (RRM) plays a pivotal role in the context of transcription-associated homologous recombination (HR) repair (TA-HRR), a particular subset of HRR pathways. Surprisingly, independent of autophagy flux, LC3B interacts directly with R-loops at DNA lesions within transcriptionally active sites via its RRM, promoting TA-HRR. Using native RNA immunoprecipitation (nRIP) coupled with high-throughput sequencing (nRIP-seq), we discovered that LC3B also directly interacts with the 3'UTR AU-rich elements (AREs) of BRCA1 via its RRM, influencing its stability. This suggests that LC3B regulates TA-HRR both proximal to and distal from DNA lesions. Data from our LC3B depletion experiments showed that LC3B knockdown disrupts end-resection for TA-HRR, redirecting it towards the non-homologous end joining (NHEJ) pathway and leading to chromosomal instability, as evidenced by alterations in sister chromatid exchange (SCE) and interchromosomal fusion (ICF). Thus, our findings unveil autophagy-independent functions of LC3B in DNA damage and repair pathways, highlighting its importance. This could reshape our understanding of TA-HRR and the interaction between autophagy and DDR.

Targeting the Mitochondrial Chaperone TRAP1 Alleviates Vascular Pathologies in Ischemic Retinopathy.

Activation of hypoxia-inducible factor 1α (HIF1α) contributes to blood-retinal barrier (BRB) breakdown and pathological neovascularization responsible for vision loss in ischemic retinal diseases. During disease progression, mitochondrial biology is altered to adapt to the ischemic environment created by initial vascular dysfunction, but the mitochondrial adaptive mechanisms, which ultimately contribute to the pathogenesis of ischemic retinopathy, remain incompletely understood. In the present study, it is identified that expression of mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) is essential for BRB breakdown and pathologic retinal neovascularization in mouse models mimicking ischemic retinopathies. Genetic Trap1 ablation or treatment with small molecule TRAP1 inhibitors, such as mitoquinone (MitoQ) and SB-U015, alleviate retinal pathologies via proteolytic HIF1α degradation, which is mediated by opening of the mitochondrial permeability transition pore and activation of calcium-dependent protease calpain-1. These findings suggest that TRAP1 can be a promising target for the development of new treatments against ischemic retinopathy, such as retinopathy of prematurity and proliferative diabetic retinopathy.

Evaluating the agreement between different substance use recall periods in multiple HIV cohorts.

BACKGROUND: This study aims to evaluate the agreement in substance use on both binary and ordinal scales between 3-month and 6-month recall periods with samples from different communities, demographic backgrounds, and HIV status. METHODS: We administered the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) to 799 participants from three different North American cohorts focused on substance use and HIV. We conducted a within-person agreement analysis by calculating the agreement levels and Kappa statistic between data collected using the 3-month recall ASSIST and 6-month custom substance use surveys as well as different terminology for each substance in multiple cohorts. RESULTS: For all drugs studied, the agreement on the binary use or ordinal frequency of use metrics showed a high agreement level between 80.4% and 97.9% and an adequate adjusted kappa value between 0.61 and 0.96, suggesting substantial agreement. According to the agreement criteria we proposed, substance use data collected using different recall periods and with variation in drug names can be harmonized across cohorts. CONCLUSIONS: This study is the first to evaluate the feasibility of data harmonization of substance use by demonstrating high level of agreement between different recall periods in different cohorts. The results can inform data harmonization efforts in consortia where data are collected from cohorts using different questions and recall periods.

Glucose-mediated mitochondrial reprogramming by cholesterol export at TM4SF5-enriched mitochondria-lysosome contact sites.

BACKGROUND: Transmembrane 4 L six family member 5 (TM4SF5) translocates subcellularly and functions metabolically, although it is unclear how intracellular TM4SF5 translocation is linked to metabolic contexts. It is thus of interests to understand how the traffic dynamics of TM4SF5 to subcellular endosomal membranes are correlated to regulatory roles of metabolisms. METHODS: Here, we explored the metabolic significance of TM4SF5 localization at mitochondria-lysosome contact sites (MLCSs), using in vitro cells and in vivo animal systems, via approaches by immunofluorescence, proximity labelling based proteomics analysis, organelle reconstitution etc. RESULTS: Upon extracellular glucose repletion following depletion, TM4SF5 became enriched at MLCSs via an interaction between mitochondrial FK506-binding protein 8 (FKBP8) and lysosomal TM4SF5. Proximity labeling showed molecular clustering of phospho-dynamic-related protein I (DRP1) and certain mitophagy receptors at TM4SF5-enriched MLCSs, leading to mitochondrial fission and autophagy. TM4SF5 bound NPC intracellular cholesterol transporter 1 (NPC1) and free cholesterol, and mediated export of lysosomal cholesterol to mitochondria, leading to impaired oxidative phosphorylation but intact tricarboxylic acid (TCA) cycle and ß-oxidation. In mouse models, hepatocyte Tm4sf5 promoted mitophagy and cholesterol transport to mitochondria, both with positive relations to liver malignancy. CONCLUSIONS: Our findings suggested that TM4SF5-enriched MLCSs regulate glucose catabolism by facilitating cholesterol export for mitochondrial reprogramming, presumably while hepatocellular carcinogenesis, recapitulating aspects for hepatocellular carcinoma metabolism with mitochondrial reprogramming to support biomolecule synthesis in addition to glycolytic energetics.

[MR-Guided Targeted Prostate Biopsy from Radiologists' Perspective]. / 영상의학과 의사의 시각에서 본 ìžê¸°ê³µëª ì˜ìƒ 기반 ì „ë¦½ì„ í‘œì  생검.

The prostate cancer diagnosis has traditionally been based on a systematic biopsy method in which tissue samples are randomly obtained from the prostate 10-12 sites. However, there are concerns as the method can fail to diagnose all prostate cancers or lead to over-detection of clinically insignificant cancers. MRI-guided prostate targeted biopsy has been proposed to address these shortcomings. This method involves identifying suspicious lesions using MRI and performing targeted biopsies under ultrasound or MRI guidance. We review the methods of MRI-based targeted biopsy and discuss recent guidelines and trends in prostate cancer diagnosis.

Time-resolved live-cell spectroscopy reveals EphA2 multimeric assembly.

Ephrin type-A receptor 2 (EphA2) is a receptor tyrosine kinase that initiates both ligand-dependent tumor-suppressive and ligand-independent oncogenic signaling. We used time-resolved, live-cell fluorescence spectroscopy to show that the ligand-free EphA2 assembles into multimers driven by two types of intermolecular interactions in the ectodomain. The first type entails extended symmetric interactions required for ligand-induced receptor clustering and tumor-suppressive signaling that inhibits activity of the oncogenic extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) protein kinases and suppresses cell migration. The second type is an asymmetric interaction between the amino terminus and the membrane proximal domain of the neighboring receptors, which supports oncogenic signaling and promotes migration in vitro and tumor invasiveness in vivo. Our results identify the molecular interactions that drive the formation of the EphA2 multimeric signaling clusters and reveal the pivotal role of EphA2 assembly in dictating its opposing functions in oncogenesis.

Alismol Purified from the Tuber of Alisma orientale Relieves Acute Lung Injury in Mice via Nrf2 Activation.

Since the ethanol extract of Alisma orientale Juzepzuk (EEAO) suppresses lung inflammation by suppressing Nuclear Factor-kappa B (NF-κB) and activating Nuclear Factor Erythroid 2-related Factor 2 (Nrf2), we set out to identify chemicals constituting EEAO that suppress lung inflammation. Here, we provide evidence that among the five most abundant chemical constituents identified by Ultra Performance Liquid Chromatography (UPLC) and Nuclear Magnetic Resonance (NMR), alismol is one of the candidate constituents that suppresses lung inflammation in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model and protects mice from ALI-like symptoms. Alismol did not induce cytotoxicity or reactive oxygen species (ROS). When administered to the lung of LPS-induced ALI mice (n = 5/group), alismol decreased the level of neutrophils and of the pro-inflammatory molecules, including Tumor Necrosis Factor-alpha (TNF-α), Interleukin-1 beta (IL-1ß), Interleukin-6 (IL-6), Monocyte Chemoattractant Protein-1 (MCP-1), Interferon-gamma (IFN-γ), and Cyclooxygenase-2 (COX-2), suggesting an anti-inflammatory activity of alismol. Consistent with these findings, alismol ameliorated the key features of the inflamed lung of ALI, such as high cellularity due to infiltrated inflammatory cells, the development of hyaline membrane structure, and capillary destruction. Unlike EEAO, alismol did not suppress NF-κB activity but rather activated Nrf2. Consequently, alismol induced the expression of prototypic genes regulated by Nrf2, including Heme Oxygenase-1 (HO-1), NAD(P)H: quinine oxidoreductase-1 (NQO-1), and glutamyl cysteine ligase catalytic units (GCLC). Alismol activating Nrf2 appears to be associated with a decrease in the ubiquitination of Nrf2, a key suppressive mechanism for Nrf2 activity. Together, our results suggest that alismol is a chemical constituent of EEAO that contributes at least in part to suppressing some of the key features of ALI by activating Nrf2.

Effect of In Vitro Gastrointestinal Digestion on Phytochemicals and Antioxidant Activities in Cherry Tomatoes (Solanum lycopersicum var. cerasiforme).

We investigated the impact of simulated in vitro gastrointestinal digestion on the levels of total polyphenols, total flavonoids, carotenoids, and antioxidant capacity in cherry tomatoes. The initial total polyphenol content of fresh tomatoes was 220.51 µg GAE/g, which decreased to 203.24 µg GAE/g after 120 min of stomach treatment and further decreased to 138.23 µg GAE/g after 120 min of small intestine treatment. Similarly, the initial total flavonoid content in fresh tomatoes was 43.28 µg QE/g, but after 120 min of small intestine digestion, it decreased by approximately 50.72% to 21.33 µg QE/g. Lycopene, lutein, and ß-carotene also experienced a decrease of 69.71∼78.38% during the digestion process compared to fresh tomatoes. The antioxidant activity exhibited a reduction of 34.95∼37.67% compared to fresh tomatoes after digestion in the stomach and intestines. The bioactive compounds present in tomatoes undergo decomposition and conversion into other substances during digestion, and these degradation products are believed to inhibit the growth of SK-Hep1 human hepatoma cells while enhancing antioxidant activity within the intracellular environment.

Porphyrin-Based Brain Tumor-Targeting Agents: [64Cu]Cu-porphyrin and [64Cu]Cu-TDAP.

The aim of this study is to evaluate a radioactive metal complex platform for brain tumor targeting. Herein, we introduce a new porphyrin derivative, 5,10,15,20-(tetra-N,N-dimethyl-4-aminophenyl)porphyrin (TDAP), in which four N,N-dimethyl-4-p-phenylenediamine (DMPD) moieties are conjugated to the porphyrin labeled with the radiometal 64Cu. DMPD affected the pharmacokinetics of porphyrin in terms of retention time in vivo and tumor-targeting ability relative to those of unmodified porphyrin. [64Cu]Cu-TDAP showed stronger enhancement than [64Cu]Cu-porphyrin in U87MG glioblastoma cells, especially in the cytoplasm and nucleus, indicating its tumor-targeting properties and potential use as a therapeutic agent. In the subcutaneous and orthotopic models of brain-tumor-bearing mice, [64Cu]Cu-TDAP was clearly visualized in the tumor site via positron emission tomography imaging and showed a tumor-to-brain ratio as high as 13. [64Cu]Cu-TDAP deserves attention as a new diagnostic agent that is suitable for the early diagnosis and treatment of brain tumors.

The Digastric Muscle: Its Anatomy and Functions Revisited / El Músculo Digástrico: Revisión de su Anatomía y Funciones

SUMMARY: As one of the suprahyoid muscles, the digastric muscle is characterized by two separate bellies of different embryologic origins. The origin of the anterior belly is the digastric fossa, while the origin of the posterior belly is the mastoid notch. They share a common insertion: the intermediate tendon. When the digastric muscle contracts, the hyoid bone is raised. Opening of the jaw and swallowing of food boli are associated with digastric muscle activity. This review discusses the general anatomic features of the digastric muscle and its variation, primary functions, and clinical implications focused on surgical reconstruction and rejuvenation.

Como uno de los músculos suprahioideos, el músculo digástrico se caracteriza por dos vientres separados, de diferentes orígenes embriológicos. El origen del vientre anterior es la fosa digástrica, mientras que el origen del vientre posterior es la incisura mastoidea. Comparten una inserción común, El tendón intermedio. Cuando el músculo digástrico se contrae, el hueso hioides se eleva. La apertura de la mandíbula y la deglución del bolo alimenticio se asocian con la actividad del músculo digástrico. Esta revisión analiza las características anatómicas generales del músculo digástrico y su variación, funciones primarias e implicaciones clínicas centradas en la reconstrucción y el rejuvenecimiento quirúrgico.