Mechanistic Insights into Oxidation of Benzaldehyde by Co-Peroxo Complexes.

Transition metal-peroxide complexes play a crucial role as intermediates in oxidation reactions. To unravel the mechanism of benzaldehyde oxidation by the Co-peroxo complex, we conducted density functional theory (DFT) calculations. The identified competing mechanisms include nucleophilic attack and hydrogen atom transfer (HAT). The nucleophilic attack pathway involves Co-O cleavage and nucleophilic attack, leading to the formation of the benzoate product. And the HAT pathway comprises O-O cleavage and HAT, ultimately resulting in the benzoate product. DFT calculations revealed that the formation of the end-on Co-superoxo complex 2 through Co-O cleavage, starting from the side-on Co-peroxo complex 1, is much more favorable than the formation of the two-terminal oxyl-radical intermediate 3 through O-O cleavage. Compared with the nucleophilic attack of benzaldehyde by 2, the abstraction of a hydrogen atom from benzaldehyde by 3 requires higher energy. The nature of the nucleophilicity of 2 and 3 accounts for the reactivity of the reaction.

Blocking the TRAIL-DR5 Pathway Reduces Cardiac Ischemia-Reperfusion Injury by Decreasing Neutrophil Infiltration and Neutrophil Extracellular Traps Formation.

PURPOSE: Acute myocardial infarction (AMI) is a leading cause of mortality. Neutrophils penetrate injured heart tissue during AMI or ischemia-reperfusion (I/R) injury and produce inflammatory factors, chemokines, and extracellular traps that exacerbate heart injury. Inhibition of the TRAIL-DR5 pathway has been demonstrated to alleviate cardiac ischemia-reperfusion injury in a leukocyte-dependent manner. However, it remains unknown whether TRAIL-DR5 signaling is involved in regulating neutrophil extracellular traps (NETs) release. METHODS: This study used various models to examine the effects of activating the TRAIL-DR5 pathway with soluble mouse TRAIL protein and inhibiting the TRAIL-DR5 signaling pathway using DR5 knockout mice or mDR5-Fc fusion protein on NETs formation and cardiac injury. The models used included a co-culture model involving bone marrow-derived neutrophils and primary cardiomyocytes and a model of myocardial I/R in mice. RESULTS: NETs formation is suppressed by TRAIL-DR5 signaling pathway inhibition, which can lessen cardiac I/R injury. This intervention reduces the release of adhesion molecules and chemokines, resulting in decreased neutrophil infiltration and inhibiting NETs production by downregulating PAD4 in neutrophils. CONCLUSION: This work clarifies how the TRAIL-DR5 signaling pathway regulates the neutrophil response during myocardial I/R damage, thereby providing a scientific basis for therapeutic intervention targeting the TRAIL-DR5 signaling pathway in myocardial infarction.

Asiatic acid ameliorates doxorubicin-induced cardiotoxicity by promoting FPN-mediated iron export and inhibiting ferroptosis.

Doxorubicin (DOX), a common chemotherapeutic agent in cancer therapy, is accompanied by pronounced cardiotoxicity. Ferroptosis has been implicated in the pathogenesis and therapeutics of DOX-induced cardiotoxicity (DIC). Asiatic acid (AA), a pentacyclic triterpene from the Chinese medicinal herb Centella asiatica, displays antioxidant, anti-inflammatory, and antiapoptotic activities. In this study, we investigated the beneficial effects of AA against DOX-induced ferroptosis and cardiotoxicity and the underlying mechanisms. A chronic DIC model was established by challenging mice with DOX (5 mg/kg, i.p.) once per week for 4 weeks. Concurrent with DOX insult, the mice were administered AA (25 mg·kg-1·d-1, i.g.). Cardiac function and mechanical properties of isolated cardiomyocytes were evaluated at the end of treatment. We showed that AA administration preserved cardiac function, significantly reduced cardiac injury, and improved cardiomyocyte contractile function in DIC mice. The beneficial effects of AA were causally linked to the inhibition of DOX-induced ferroptosis both in vivo and in vitro. We revealed that AA attenuated DOX-induced iron accumulation in HL-1 cells by increasing FPN-mediated iron export, in a Nrf2-dependent manner. AA upregulated Nrf2 expression and promoted Nrf2 nuclear translocation in DOX-treated HL-1 cells. Moreover, AA-offered benefits against DOX-induced cardiac dysfunction and ferroptosis were abolished by Nrf2 inhibitor ML385 (30 mg·kg-1·d-1, i.p.) administrated 30 min before AA in DIC mice. Our data favor that AA promotes FPN-mediated iron export to inhibit iron overload and ferroptosis in DIC, suggesting its therapeutic potential in the treatment of DIC.

Engineered Extracellular Vesicles for Delivery of an IL-1 Receptor Antagonist Promote Targeted Repair of Retinal Degeneration.

Retinal degeneration (RD) is an irreversible blinding disease that seriously affects patients' daily activities and mental health. Targeting hyperactivated microglia and regulating polarization are promising strategies for treating the disease. Mesenchymal stem cell (MSC) transplantation is proven to be an effective treatment due to its immunomodulatory and regenerative properties. However, the low efficiency of cell migration and integration of MSCs remains a major obstacle to clinical use. The goal of this study is to develop a nanodelivery system that targets hyperactivated microglia and inhibits their release of proinflammatory factors, to achieve durable neuroprotection. This approach is to engineer extracellular vesicles (EVs) isolated from MSC, modify them with a cyclic RGD (cRGD) peptide on their surface, and load them with an antagonist of the IL-1 receptor, anakinra. Comparing with non-engineered EVs, it is observed that engineered cRGD-EVs exhibit an increased targeting efficiency against hyperactivated microglia and strongly protected photoreceptors in experimental RD cells and animal models. This study provides a strategy to improve drug delivery to degenerated retinas and offers a promising approach to improve the treatment of RD through targeted modulation of the immune microenvironment via engineered cRGD-EVs.

The FACT-targeted drug CBL0137 enhances the effects of rituximab to inhibit B-cell non-Hodgkin's lymphoma tumor growth by promoting apoptosis and autophagy.

BACKGROUND: Aggressive B-cell non-Hodgkin's lymphoma (B-NHL) patients often develop drug resistance and tumor recurrence after conventional immunochemotherapy, for which new treatments are needed. METHODS: We investigated the antitumor effects of CBL0137. In vitro, cell proliferation was assessed by CCK-8 and colony formation assay. Flow cytometry was performed to analyze cell cycle progression, apoptosis, mitochondrial depolarization, and reactive oxygen species (ROS) production. Autophagy was detected by transmission electron microscopy and mGFP-RFP-LC3 assay, while western blotting was employed to detect proteins involved in apoptosis and autophagy. RNA-sequencing was conducted to analyze the transcription perturbation after CBL0137 treatment in B-NHL cell lines. Finally, the efficacy and safety of CBL0137, rituximab, and their combination were tested in vivo. RESULTS: CBL0137, a small molecule anticancer agent that has significant antitumor effects in B-NHL. CBL0137 sequesters the FACT (facilitates chromatin transcription) complex from chromatin to produce cytotoxic effects in B-NHL cells. In addition, we discovered novel anticancer mechanisms of CBL0137. CBL0137 inhibited human B-NHL cell proliferation by inducing cell cycle arrest in S phase via the c-MYC/p53/p21 pathway. Furthermore, CBL0137 triggers ROS generation and induces apoptosis and autophagy in B-NHL cells through the ROS-mediated PI3K/Akt/mTOR and MAPK signaling pathways. Notably, a combination of CBL0137 and rituximab significantly suppressed B-NHL tumor growth in subcutaneous models, consistent with results at the cellular level in vitro. CONCLUSIONS: CBL0137 has potential as a novel approach for aggressive B-NHL, and its combination with rituximab can provide new therapeutic options for patients with aggressive B-NHL. Video Abstract.

VLX1570 regulates the proliferation and apoptosis of human lung cancer cells through modulating ER stress and the AKT pathway.

The ubiquitin-proteasome system (UPS) possesses unique functions in tumorigenesis and has great potential for targeting tumours. The effectiveness of inhibitors targeting UPS in solid tumours remains to be studied. We screened a library of inhibitors targeting the ubiquitination system and found the highly potent, low-concentration inhibitor molecule VLX1570 that specifically killed lung cancer cells. VLX1570 is an inhibitor of deubiquitinating enzyme activity and has also shown potential for preclinical cancer treatment. We found that VLX1570 significantly inhibited lung cancer cells proliferation and colony formation. VLX1570 induced a G2/M cell cycle arrest by downregulating CDK1 and CyclinB1. Moreover, VLX1570 significantly promoted the mitochondrial-associated apoptosis. Mechanistically speaking, VLX1570 activated the PERK/IRE1/ATF6 pathway and induced ER stress in lung cancer cell lines. The inhibition of ER stress by tauroursodeoxycholic acid sodium or 4-phenylbutyric acid enhanced VLX1570-induced apoptosis. In addition, VLX1570 treatment led to the inactivation of Akt signalling and inhibited the proliferation of lung cancer cells by downregulating the Akt pathway. Moreover, combined treatment with VLX1570 and Afatinib or Gefitinib induced synergistic anti-lung cancer activity. Our present study demonstrated a novel therapy using VLX1570, which inhibited the proliferation and increased apoptosis in human lung cancer.

Effect of local ozone treatment on rats with anterior rectal resection and the possible mechanisms.

BACKGROUND: Anterior resection syndrome (ARS) is characterized by the diverse and interchangeable evacuatory symptoms that may occur following distal colorectal resection. We aimed to investigate the effect and potential mechanisms of ozone perfusion on rats with anterior rectal resection (ARR). MATERIAL AND METHODS: After establishment of rat ARR model, 20, 40 and 80 ug/ml ozone was used to treat rats by enema administration. The pathological examination of intestinal tissue was detected using hematoxylin-eosin staining. The rate of loose stools, minimum threshold volume of abdominal withdrawal reflex (AWR) and Bristol grade were used to evaluate the degree of abnormal defecation function. Subsequently, the levels of oxidative stress- and inflammation-related markers, 5-hydroxytryptamine (5-HT), inducible nitric oxide synthase (iNOS) and nitric oxide (NO) in the serum and intestinal tissue were determined with the corresponding kits. Meanwhile, the expression of nuclear factor kappa B (NF-κB) p65, transient receptor potential vanilloid (TRPV)1, TRPV4, iNOS and 5-HT receptor 3A (5-HTR3A) was determined with RT-qPCR and western blotting. RESULTS: Ozone administration (20 and 40 ug/ml) significantly alleviated the pathological changes of intestinal tissue-induced by ARR, accompanied by the decreased loose stools rate, Bristol score and increased abdominal withdraw reflex. However, 80 ug/ml of ozone intervention played opposite roles in the aforementioned changes with 20 and 40 ug/ml of ozone. Additionally, remarkably elevated reactive oxygen species (ROS), malonaldehyde (MDA), superoxide dismutase (SOD), 5-HT, iNOS and NO levels were observed in the ozone-treated groups (20 and 40 ug/ml), while high dose of ozone drastically improved ROS, MDA, 5-HT, iNOS and NO levels but reduced the activity of SOD. Consistently, the contents of inflammatory factors were decreased after low and middle doses of ozone administration. However, high dose of ozone aggravated the inflammatory injury. Moreover, 20 and 40 ug/ml ozone upregulated TRPV1 and TRPV4 expression but downregulated 5-HTR3A expression, which was restored after 80 ug/ml of ozone intervention. Remarkably, the levels of NF-κB p65 and iNOS were dose-dependently enhanced following ozone treatment. CONCLUSIONS: Taken together, low concentration of ozone attenuated intestinal injury induced by ARR via balancing oxidative stress and inflammation, but high concentration of ozone exacerbated the intestinal injury, which might be related to the 5-HT and TRPV signaling.

Water-cooled microwave ablation array for bloodless rapid transection of the liver.

BACKGROUND: Microwaves (MWs) deliver relatively high temperatures into biological tissue and cover a large ablation zone. This study aims to evaluate the efficacy and effectiveness of water-cooled double-needle MW ablation arrays in assisting the hepatic transection of an in vivo pig model. METHODS: Our research program comprised computer modeling, tissue-mimicking phantom experiments, and in vivo pig liver experiments. Computer modeling was based on the finite element method (FEM) to evaluate ablation temperature distributions. In tissue-mimicking phantom and in vivo pig liver ablation experiments, the performances of the water-cooled MW ablation array and conventional clamp crushing liver resection were compared. RESULTS: FEM showed that the maximum lateral ablation diameter at 100 W output and a duration of 60 s was 3 cm (assessed at 50 °C isotherm). In the phantom, the maximum transverse ablation diameter of the double-needle MW ablation increased rapidly to 3 cm in 60 s at 50 W. The blood loss and blood loss per transection area in Group A were significantly lower than those in Group B (18 (7-26) ml vs. 34 (19-57) ml, and 2.4 (2-3.1) ml/cm2 vs. 6.9 (3.2-8.3) ml/cm2, respectively) (p < 0.05). The transection speed in Group A (2.6(1.9-3.8) cm2/min) was significantly faster than that in Group B (1.7(1.1-2.2) cm2/min) (p < 0.05). CONCLUSION: In this experimental model, the new water-cooled MW array-assisted liver resection (LR) has the potential advantage of less blood loss and rapid removal than the conventional LR.

Computer modeling and in vitro experimental study of water-cooled microwave ablation array.

INTRODUCTION: Microwaves (MWs) quickly deliver relatively high temperatures into tumors and cover a large ablation zone. We present a research protocol for using water-cooled double-needle MW ablation arrays for tumor ablation here. MATERIAL AND METHODS: Our research program includes computer modeling, tissue-mimicking phantom experiments, and in vitro swine liver experiments. The computer modeling is based on the finite element method (FEM) to evaluate ablation temperature distributions. In tissue-mimicking phantom and in vitro swine liver ablation experiments, the performances of the new device and the single-needle MW device currently used in clinical practice are compared. RESULTS: FEM shows that the maximum transverse ablation diameter (MTAD) is 4.2 cm at 100 W output and 300 s (assessed at the 50 °C isotherm). In the tissue-mimicking phantom, the MTDA is 2.6 cm at 50 W and 300 s in single-needle MW ablation, and 4 cm in double needle MW ablation array. In in vitro swine liver experiments, the MTAD is 2.820 ± 0.127 cm at 100 W and 300 s in single-needle MW ablation, and 3.847 ± 0.103 cm in MW ablation array. CONCLUSION: A new type of water-cooled MW ablation array is designed and tested, and has potential advantages over currently used devices.

Comprehensive epigenetic analyses reveal master regulators driving lung metastasis of breast cancer.

The lung metastasis of breast cancer involves complicated regulatory changes driven by chromatin remodelling. However, the epigenetic reprogramming and regulatory mechanisms in lung metastasis of breast cancer remain unclear. Here, we generated and analysed genome-wide profiles of multiple histone modifications (H3K4me3, H3K27ac, H3K27me3, H3K4me1 and H3K9me3), as well as transcriptome data in lung-metastatic and non-lung-metastatic breast cancer cells. Our results showed that the expression changes were correlated with the enrichment of specific histone modifications in promoters and enhancers. Promoter and enhancer reprogramming regulated gene expression in a synergetic way, and involved in multiple important biological processes and pathways. In addition, lots of gained super-enhancers were identified in lung-metastatic cells. We also identified master regulators driving differential gene expression during lung metastasis of breast cancer. We found that the cooperations between regulators were much closer in lung-metastatic cells. Moreover, regulators such as TFAP2C, GTF2I and LMO4 were found to have potential prognostic value for lung metastasis free (LMF) survival of breast cancer. Functional studies motivated by our data analyses uncovered an important role of LMO4 in regulating metastasis. This study provided comprehensive insights into regulatory mechanisms, as well as potential prognostic markers for lung metastasis of breast cancer.

CEBPE expression is an independent prognostic factor for acute myeloid leukemia.

BACKGROUND: Identifying reliable predictive markers is important to make therapeutic decisions, and determine the prognosis for acute myeloid leukemia (AML) patients. However, approximately 50% patients could not be accurately predicted by existing risk factors. It is necessary to identify novel prognostic factors to subdivide the intermediate-risk group or patients without any cytogenetic and molecular abnormalities. METHODS: Kaplan-Meier and Cox regression were used for survival analyses in three independent AML datasets. Analyses integrating both bioinformatics and ChIP-qPCR experiments were performed to explore the role of CEBPE in regulating the expression of known prognostic factors. RESULTS: CEBPE expression was an independent predictor for both overall survival (OS) and event-free survival (EFS) of AML patients. Moreover, low-expression of CEBPE was found to be associated with high relapse rate. We also proved that differential expression of CEBPE stratified the wild-type patients of multiple genes into good and poor outcomes. In addition, the results showed that no obvious improvement was achieved by allogeneic transplantation in CEBPE high-expressed group, while the survival rate (both OS and EFS) was significantly increased in transplanted patients that with low expression of CEBPE. Finally, we found that CEBPE might regulate the expression of known prognostic factors by localizing on their promoters. CONCLUSION: Our findings indicated that CEBPE expression was an independent prognostic factor for AML survival, relapse and allogeneic transplantation, which will provide useful information for outcome prediction and therapeutic decisions.

Edge detection based on Retinex theory and wavelet multiscale product for mine images.

The application of visual technology to mine robots has become a hot topic in the development of coal mine automatic production. Key techniques of robot control are the feature recognition of sampled videos and the perception of complex surroundings. However, it is difficult for features in underground images with dark hue and low target discrimination to be recognized and extracted, especially for reasons of the nonuniform illumination and heavy dust concentration in mines. Hence, an edge detection algorithm based on the Retinex theory and wavelet multiscale product is proposed in this paper for low-light-level mine image feature extraction, which employs a modified multiscale Retinex method to deal with the low frequency subplot after the wavelet decomposition, an improved fuzzy enhancement approach to handle high frequency components, and finally a revised multiscale product edge detection algorithm to obtain the ultima edge image. Compared with a variety of algorithms by detecting edges of both normal illuminated and underground images, experimental results show that with characteristics of high real-time performance and detection accuracy, the proposed algorithm can exactly meet the needs of surrounding environment perception for mine robots, which applies well to image edge detection in low illumination mines.

Inhibition of METTL3 ameliorates doxorubicin-induced cardiotoxicity through suppression of TFRC-mediated ferroptosis.

BACKGROUND: Doxorubicin (DOX) is a chemotherapeutic drug, while its clinical use is greatly limited by the life-threatening cardiotoxicity. N6-methyladenosine (m6A) RNA modification participates in varieties of cellular processes. Nonetheless, it remains elusive whether m6A modification and its methyltransferase METTL3 are involved in the progression of DOX-induced cardiotoxicity (DIC). METHODS: Mice were administrated with DOX (accumulative dosage of 20 mg/kg) repeatedly to establish a chronic DIC model. Cardiomyocyte-specific conditional METTL3 knockout mice were employed to evaluate the effects of altered m6A RNA modification on DIC. The effects of METTL3 on cardiomyocyte ferroptosis were also examined in response to DOX stimulation. RESULTS: DOX led to increased levels in m6A modification and METTL3 expression in cardiomyocytes in a c-Jun-dependent manner. METTL3-knockout mice exhibited improved cardiac function, remodeling and injury following DOX insult. Besides, inhibition of METTL3 alleviated DOX-induced iron accumulation and ferroptosis in cardiomyocytes, whereas METTL3 overexpression exerted the opposite effects. Mechanistically, METTL3 promoted m6A modification of TFRC mRNA, a critical gene governing iron uptake, and enhanced its stability through recognition of the m6A reader protein, IGF2BP2. Moreover, pharmacological administration of a highly selective METTL3 inhibitor STM2457 effectively ameliorated DIC in mice. CONCLUSION: METTL3 plays a cardinal role in the etiology of DIC by regulating cardiac iron metabolism and ferroptosis through TFRC m6A modification. Inhibition of METTL3 might be a potential therapeutic avenue for DIC.

The green tide causative-species Ulva prolifera responding to exposure to oil and dispersant.

In order to study the role of oil spills in the occurrence of green tide in the Yellow Sea, the physiological characteristics and photosynthetic activities of green tide causative-species Ulva prolifera was monitored under different conditions including two oil water-accommodated fractions (WAFs) of diesel oil and crude oil, dispersed water-accommodated fractions (DWAFs) and dispersant GM-2. The results showed that, the physiological parameters of U. prolifera including the growth, pigment, carbohydrate and protein contents decreased with the increased diesel oil WAF (WAFDO) concentration, while crude oil WAF (WAFCO) showed low concentration induction and high concentration inhibition effect. In addition, with the increase of WAFs concentration, two antioxidant activities were activated. However, compared with WAFDO alone and WAFCO alone, the mixture of oil and dispersant enhanced the toxicity on the above physiological characteristics of U. prolifera. On the other hand, the photosynthetic efficiency of U. prolifera showed a similar trend. Two WAFs showed significant concentration effects on the chlorophyll-a fluorescence transients and JIP-test. The addition of dispersant further blocked the electron flow beyond QA and from plastoquinone (PQ) to PSI acceptor side, damaged the active OEC centers at the PSII donor side, suppressed the pool size and the reduction rate of PSI acceptor side, and reduced the energy transfer efficiency between PSII functional units. These results implied that the crude oil spills may induce the formation of U. prolifera green tide, and the oil dispersant GM-2 used after the oil spills is unlikely to further stimulate the scale of bloom, while the diesel oil spills is always not conducive to the outbreak of green tide of U. prolifera.

Drug Interactions between Traditional Chinese Medicines and Cardiovascular Drugs.

Cardiovascular disease (CVD) is one of the leading causes of death worldwide, and its internal medicine treatments are mostly single/few-target chemical drugs. Long-term use of cardiovascular drugs for complex chronic diseases may lead to serious adverse drug reactions. Traditional Chinese medicine (TCM) has been used to treat heart diseases for thousands of years, helping to ease symptoms and prolong patients' lifespan in ancient China. TCM has the pharmacological characteristics of being multi-component, multi-target and multi-pathway, and the combined application of TCM and western medicine can be an alternative treatment for chronic and intractable diseases with high safety levels. This article reviewed the interactions and synergistic effect of TCM and cardiovascular drugs. In the treatment of arrhythmia, TCM combined with western medicine can more effectively regulate patients' cardiac electrophysiological characteristics, reduce the onsets of premature beat and heart rate variability, lower the levels of QT interval dispersion and serum inflammatory factors, alleviate clinical symptoms and TCM syndromes, and improve cardiac function with good safety levels. In the treatment of hypertension, integrative medicine can more steadily reduce blood pressure and levels of serum inflammatory factors and improve hemodynamic indexes and exercise tolerance, and it has high safety levels, especially for pregnant women. As for coronary heart disease, the combination of TCM and antiplatelet drugs may promote the absorption of each other. However, the interaction risk of pharmacokinetic mechanism between them is low at the dose of efficacy. Integrative medicine can reduce the level of N-terminal pro-brain natriuretic peptide, delay cardiac remodeling and improve heart function and quality of life for patients with heart failure with high safety levels.

Survival outcome and optimal candidates of primary tumor resection for patients with metastatic medullary thyroid cancer.

CONTEXT: Medullary thyroid cancer (MTC) often exhibits aggressive growth with distant organ metastasis, leading to poor survival. OBJECTIVE: The question of whether primary tumor resection (PTR) is beneficial for patients with metastatic MTC remains a subject of debate. In this study, we evaluated the prognostic significance of organ-specific metastases and the number of metastatic organs in these patients, and we also conducted an analysis to determine the therapeutic value of PTR in managing this rare malignancy. MATERIALS AND METHODS: Patients initially diagnosed with metastatic MTC were identified within the Surveillance, Epidemiology, and End Results (SEER) database. Univariable and multivariable Cox proportional hazards regression models were performed to identify survival predictors. Survival outcomes were calculated using the Kaplan-Meier method and compared using the log-rank tests. RESULTS: A total of 186 patients with metastatic MTC at initial diagnosis from 2010 to 2020 were included. Bone, lung and liver were the most common metastatic organs. Patients with brain metastasis had significantly worse overall survival (OS) (p = 0.007) and cancer-specific survival (CSS) (p = 0.0013). Among all patients, 105 (56.45%) underwent PTR, and this group showed reduced overall mortality (OM) and cancer-specific mortality (CSM) (all p < 0.05). When analyzing different metastatic patterns, PTR significantly lowered the risk of OM and CSM for patients with bone, lung, liver, or distant lymph node (DLN) involvement (all p < 0.05). Additionally, among patients with one or two metastases, those undergoing surgical resection were significantly associated with favorable OS (p = 0.008) and CSS (p = 0.0247). CONCLUSIONS: PTR may confer therapeutic benefits for carefully selected individuals with metastatic MTCs. To integrate these insights into clinical decision-making settings, it is imperative to undertake multicenter prospective studies in the future.

Comprehensive DNA Methylation Profiling of Medullary Thyroid Carcinoma: Molecular Classification, Potential Therapeutic Target, and Classifier System.

PURPOSE: Medullary thyroid carcinoma (MTC) presents a distinct biological context from other thyroid cancers due to its specific cellular origin. This heterogeneous and rare tumor has a high prevalence of advanced diseases, making it crucial to address the limited therapeutic options and enhance complex clinical management. Given the high clinical accessibility of methylation information, we construct the largest MTC methylation cohort to date. EXPERIMENTAL DESIGN: Seventy-eight fresh-frozen MTC samples constituted our methylation cohort. The comprehensive study process incorporated machine learning, statistical analysis, and in vitro experiments. RESULTS: Our study pioneered the identification of a three-class clustering system for risk stratification, exhibiting pronounced epigenomic heterogeneity. The elevated overall methylation status in MTC-B, combined with the "mutual exclusivity" of hypomethylated sites displayed by MTC-A and MTC-C, distinctively characterized the MTC-specific methylation pattern. Integrating with the transcriptome, we further depicted the features of these three clusters to scrutinize biological properties. Several MTC-specific aberrant DNA methylation events were emphasized in our study. NNAT expression was found to be notably reduced in poor-prognostic MTC-C, with its promoter region overlapping with an upregulated differentially methylated region. In vitro experiments further affirmed NNAT's therapeutic potential. Moreover, we built an elastic-net logistic regression model with a relatively high AUC encompassing 68 probes, intended for future validation and systematic clinical application. CONCLUSIONS: Conducting research on diseases with low incidence poses significant challenges, and we provide a robust resource and comprehensive research framework to assist in ongoing MTC case inclusion and facilitate in-depth dissection of its molecular biological features.

iSCORE-PD: an isogenic stem cell collection to research Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder caused by complex genetic and environmental factors. Genome-edited human pluripotent stem cells (hPSCs) offer the uniique potential to advance our understanding of PD etiology by providing disease-relevant cell-types carrying patient mutations along with isogenic control cells. To facilitate this experimental approach, we generated a collection of 55 cell lines genetically engineered to harbor mutations in genes associated with monogenic PD (SNCA A53T, SNCA A30P, PRKN Ex3del, PINK1 Q129X, DJ1/PARK7 Ex1-5del, LRRK2 G2019S, ATP13A2 FS, FBXO7 R498X/FS, DNAJC6 c.801 A>G+FS, SYNJ1 R258Q/FS, VPS13C A444P, VPS13C W395C, GBA1 IVS2+1). All mutations were generated in a fully characterized and sequenced female human embryonic stem cell (hESC) line (WIBR3; NIH approval number NIHhESC-10-0079) using CRISPR/Cas9 or prime editing-based approaches. We implemented rigorous quality controls, including high density genotyping to detect structural variants and confirm the genomic integrity of each cell line. This systematic approach ensures the high quality of our stem cell collection, highlights differences between conventional CRISPR/Cas9 and prime editing and provides a roadmap for how to generate gene-edited hPSCs collections at scale in an academic setting. We expect that our isogenic stem cell collection will become an accessible platform for the study of PD, which can be used by investigators to understand the molecular pathophysiology of PD in a human cellular setting.

Mitochondrial quality control mechanisms as therapeutic targets in doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is a chemotherapeutic drug that is utilized for solid tumors and hematologic malignancies, but its clinical application is hampered by life-threatening cardiotoxicity including cardiac dilation and heart failure. Mitochondrial quality control processes, including mitochondrial proteostasis, mitophagy, and mitochondrial dynamics and biogenesis, serve to maintain mitochondrial homeostasis in the cardiovascular system. Importantly, recent advances have unveiled a major role for defective mitochondrial quality control in the etiology of DOX cardiomyopathy. Moreover, specific interventions targeting these quality control mechanisms to preserve mitochondrial function have emerged as potential therapeutic strategies to attenuate DOX cardiotoxicity. However, clinical translation is challenging because of obscure mechanisms of action and potential adverse effects. The purpose of this review is to provide new insights regarding the role of mitochondrial quality control in the pathogenesis of DOX cardiotoxicity, and to explore promising therapeutic approaches targeting these mechanisms to aid clinical management.

A new emerging target in cancer immunotherapy: Galectin-9 (LGALS9).

Over the past few decades, advances in immunological knowledge have led to the identification of novel immune checkpoints, reinvigorating cancer immunotherapy. Immunotherapy, represented by immune checkpoint inhibitors, has become the leader in the precision treatment of cancer, bringing a new dawn to the treatment of most cancer patients. Galectin-9 (LGALS9), a member of the galectin family, is a widely expressed protein involved in immune regulation and tumor pathogenesis, and affects the prognosis of various types of cancer. Galectin-9 regulates immune homeostasis and tumor cell survival through its interaction with its receptor Tim-3. In the review, based on a brief description of the signaling mechanisms and immunomodulatory activities of galectin-9 and Tim-3, we summarize the targeted expression patterns of galectin-9 in a variety of malignancies and the promising mechanisms of anti-galectin-9 therapy in stimulating anti-tumor immune responses.