Mesenchymal stem cell-derived extracellular vesicles mitigate neuronal damage from intracerebral hemorrhage by modulating ferroptosis.

BACKGROUND: Hemorrhagic stroke is a devastating cerebrovascular event with a high rate of early mortality and long-term disability. The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) for neurological conditions, such as intracerebral hemorrhage (ICH), has garnered considerable interest, has garnered considerable interest, though their mechanisms of action remain poorly understood. METHODS: EVs were isolated from human umbilical cord MSCs, and SPECT/CT was used to track the 99mTc-labeled EVs in a mouse model of ICH. A series of comprehensive evaluations, including magnetic resonance imaging (MRI), histological study, RNA sequencing (RNA-Seq), or miRNA microarray, were performed to investigate the therapeutic action and mechanisms of MSC-EVs in both cellular and animal models of ICH. RESULTS: Our findings show that intravenous injection of MSC-EVs exhibits a marked affinity for the ICH-affected brain regions and cortical neurons. EV infusion alleviates the pathological changes observed in MRI due to ICH and reduces damage to ipsilateral cortical neurons. RNA-Seq analysis reveals that EV treatment modulates key pathways involved in the neuronal system and metal ion transport in mice subjected to ICH. These data were supported by the attenuation of neuronal ferroptosis in neurons treated with Hemin and in ICH mice following EV therapy. Additionally, miRNA microarray analysis depicted the EV-miRNAs targeting genes associated with ferroptosis, and miR-214-3p was identified as a regulator of neuronal ferroptosis in the ICH cellular model. CONCLUSIONS: MSC-EVs offer neuroprotective effects against ICH-induced neuronal damage by modulating ferroptosis highlighting their therapeutic potential for combating neuronal ferroptosis in brain disorders.

Combined UTMD-Nanoplatform for the Effective Delivery of Drugs to Treat Renal Cell Carcinoma.

Introduction: The effective accumulation of nanoparticles (NPs) in the tumour area is an important goals of current nanotechnology research, and a targeted nanoplatform is an effective solution. So we designed a multifunctional sound-sensitive targeted NP that combines a sonosensitizer to enable precisely targeted, deep-penetration sonodynamic therapy (SDT) in combination with multimodal imaging for the diagnosis and monitoring of renal cell carcinoma (RCC). Methods: ZnPP@PP NPs (ZnPP@PLGA- PFP NPs) were prepared via a double emulsion method, and G250 was covalently attached to the NPs shell via the carbon diimide method. Physicochemical property tests were conducted on the ZnPP@G-PP NPs, including tests of particle size, potential distribution, encapsulation efficiency and drug loading capability. We assessed the targeting ability, the production of reactive oxygen species (ROS) and permeability of the NPs in vitro. Moreover, we evaluated the nanoparticle's multimodal imaging capabilities and therapeutic ability against RCC, both in vitro and in vivo. Results: The Znpp@G-PP NPs were successfully constructed, and their general properties showed uniform particle size, negative potential and good stability. The nanoparticles were successfully loaded with ZnPP and connected with G250, showing tumor-specific targeting ability. Under LIFU irradiation, the nanoparticles produced 1O2 by SDT. For RCC, PA/US multi-modal imaging of Znpp@G-PP NPs provide diagnostic information and monitor therapies in real time in 786-O RCC xenografts, with good biocompatibility. With the UTMD, nanoparticles can be effectively targeted into the tumor cells and penetrate into the tumor interior, significantly improving the SDT effect. Experiments in vitro and in vivo showed that the combination of the nanoparticles and LIFU could suppress the tumor, and the therapeutic effect was confirmed by immunohistochemistry. Conclusion: ZnPP@G-PP NPs provide a promising theranostic strategy for RCC and a platform for further research on improving the efficacy of diagnosis and treatment.

Carrier cascade target delivery of 5-aminolevulinic acid nanoplatform to enhance antitumor efficiency of photodynamic therapy against lung cancer.

5-Aminolevulinic acid (5-ALA) is a prodrug of porphyrin IX (PpIX). Disadvantages of 5-ALA include poor stability, rapid elimination, poor bioavailability, and weak cell penetration, which greatly reduce the clinical effect of 5-ALA based photodynamic therapy (PDT). Presently, a novel targeting nanosystem was constructed using gold nanoparticles (AuNPs) as carriers loaded with a CSNIDARAC (CC9)-targeting peptide and 5-ALA via Au-sulphur and ionic bonds, respectively, and then wrapped in polylactic glycolic acid (PLGA) NPs via self-assembly to improve the antitumor effects and reduce the side effect. The successful preparation of ALA/CC9@ AuNPs-PLGA NPs was verified using ultraviolet-visible, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The analyses revealed good sphericity with a particle size of approximately140 nm, Zeta potential of 10.11 mV, and slow-controlled release characteristic in a weak acid environment. Confocal microscopy revealed targeting of NCL-H460 cells by NPs by actively internalising CC9 and avoiding the phagocytic action of RAW264.7 cells, and live fluorescence imaging revealed targeting of tumours in tumour-bearing mice. Compared to free 5-ALA, the nanosystem displayed amplified anticancer activity by increasing production of PpIX and reactive oxygen species to induce mitochondrial pathway apoptosis. Antitumor efficacy was consistently observed in three-dimensionally cultured cells as the loss of integrity of tumour balls. More potent anti-tumour efficacy was demonstrated in xenograft tumour models by decreased growth rate and increased tumour apoptosis. Histological analysis showed that this system was not toxic, with lowered liver toxicity of 5-ALA. Thus, ALA/CC9@AuNPs-PLGA NPs deliver 5-ALA via a carrier cascade, with excellent effects on tumour accumulation and PDT through passive enhanced permeability and retention action and active targeting. This innovative strategy for cancer therapy requires more clinical trials before being implemented.

Global status of research on fertility preservation in male patients with cancer: A bibliometric and visual analysis.

Background: Recently, male fertility preservation before cancer treatment has become more prevalent. The research in this field has progressed over time, with some studies having a major impact and providing guidance for further research. However, the trends and hotspots of research on fertility preservation in male cancer patients may have changed; exploring them is essential for relevant research progress. Design: We extracted relevant studies from the Web of Science Core Collection database, capturing information on the countries of study, affiliations, authors, keywords, as well as co-citations of references and journals. To identify publication trends, research strengths, key subjects, prominent topics, and emerging areas, we conducted a bibliometric analysis using CiteSpace. Results: We included 3201 articles on fertility preservation in male cancer patients published over January 1999 to December 2023 were included. Although the relevant research growth rate was slow initially, the number of publications increased annually. Of all study countries, the United States, Germany, and Japan reported the earliest studies; the United States published the highest number of relevant studies. The US institutions remained at the forefront for all 25 years, and the US researcher Ashok Agarwal published the most articles. Literature co-citation analyses indicated a transformation in the study participants; they comprised a younger demographic (i.e., a large number of adolescent male patients underwent fertility preservation); moreover, fertility preservation techniques evolved from sperm cryopreservation to testicular tissue cryopreservation. Research on reproductive outcomes of sperm cryopreservation was the recent hotspot in male fertility preservation research, and the impact of immunotherapy and checkpoint inhibitors on male fertility requires further research. Conclusions: Male fertility preservation will be a major future research focus, with closer connections and collaborations between countries and organizations. Our results present the historical data on the development of research on male fertility preservation in cancer patients, providing relevant insights for future research and development in this study area.

Pan-cancer Analysis Reveals m6A Variation and Cell-specific Regulatory Network in Different Cancer Types.

As the most abundant messenger RNA (mRNA) modification in mRNA, N  6-methyladenosine (m6A) plays a crucial role in RNA fate, impacting cellular and physiological processes in various tumor types. However, our understanding of the function and role of the m6A methylome in tumor heterogeneity remains limited. Herein, we collected and analyzed m6A methylomes across nine human tissues from 97 m6A sequencing (m6A-seq) and RNA sequencing samples. Our findings demonstrate that m6A exhibits different heterogeneity in most tumor tissues compared to normal tissues, which contributes to the diverse clinical outcomes in different cancer types. We also found that the cancer type-specific m6A level regulated the expression of different cancer-related genes in distinct cancer types. Utilizing a novel and reliable method called "m6A-express", we predicted m6A-regulated genes and revealed that cancer type-specific m6A-regulated genes contributed to the prognosis, tumor origin, and infiltration level of immune cells in diverse patient populations. Furthermore, we identified cell-specific m6A regulators that regulate cancer-specific m6A and constructed a regulatory network. Experimental validation was performed, confirming that the cell-specific m6A regulator CAPRIN1 controls the m6A level of TP53. Overall, our work reveals the clinical relevance of m6A in various tumor tissues and explains how such heterogeneity is established. These results further suggest the potential of m6A for cancer precision medicine for patients with different cancer types.

Sex differences of signal complexity at resting-state functional magnetic resonance imaging and their associations with the estrogen-signaling pathway in the brain.

Sex differences in the brain have been widely reported and may hold the key to elucidating sex differences in many medical conditions and drug response. However, the molecular correlates of these sex differences in structural and functional brain measures in the human brain remain unclear. Herein, we used sample entropy (SampEn) to quantify the signal complexity of resting-state functional magnetic resonance imaging (rsfMRI) in a large neuroimaging cohort (N = 1,642). The frontoparietal control network and the cingulo-opercular network had high signal complexity while the cerebellar and sensory motor networks had low signal complexity in both men and women. Compared with those in male brains, we found greater signal complexity in all functional brain networks in female brains with the default mode network exhibiting the largest sex difference. Using the gene expression data in brain tissues, we identified genes that were significantly associated with sex differences in brain signal complexity. The significant genes were enriched in the gene sets that were differentially expressed between the brain cortex and other tissues, the estrogen-signaling pathway, and the biological function of neural plasticity. In particular, the G-protein-coupled estrogen receptor 1 gene in the estrogen-signaling pathway was expressed more in brain regions with greater sex differences in SampEn. In conclusion, greater complexity in female brains may reflect the interactions between sex hormone fluctuations and neuromodulation of estrogen in women. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-023-09954-y.

Plakophilin 1 in carcinogenesis.

Plakophilin 1 (PKP1) belongs to the desmosome family as an anchoring junction protein in cellular junctions. It localizes at the interface of the cell membrane and cytoplasm. Although PKP1 is a non-transmembrane protein, it may become associated with the cell membrane via transmembrane proteins such as desmocollins and desmogleins. Homozygous deletion of PKP1 results in ectodermal dysplasia-skin fragility syndrome (EDSF) and complete knockout of PKP1 in mice produces comparable symptoms to EDSF in humans, although mice do not survive more than 24 h. PKP1 is not limited to expression in desmosomal structures, but is rather widely expressed in cytoplasm and nucleus, where it assumes important cellular functions. This review will summarize distinct roles of PKP1 in the cell membrane, cytoplasm, and nucleus with an overview of relevant studies on its function in diverse types of cancer.

Butylparaben induced zebrafish (Danio rerio) kidney injury by down-regulating the PI3K-AKT pathway.

Butylparaben, a common endocrine disruptor in the environment, is known to be toxic to the reproductive system, heart, and intestines, but its nephrotoxicity has rarely been reported. In order to study the nephrotoxicity and mechanism of butylparaben, we examined the acute and chronic effects on human embryonic kidney cells (HEK293T) and zebrafish. Additionally, we assessed the potential remedial effects of salidroside against butylparaben-induced nephrotoxicity. Our in vitro findings demonstrated oxidative stress and cytotoxicity to HEK293T cells caused by butylparaben. In the zebrafish model, the concentration of butylparaben exposure ranged from 0.5 to 15 µM. An assortment of experimental techniques was employed, including the assessment of kidney tissue morphology using Hematoxylin-Eosin staining, kidney function analysis via fluorescent dextran injection, and gene expression studies related to kidney injury, development, and function. Additionally, butylparaben caused lipid peroxidation in the kidney, thereby damaging glomeruli and renal tubules, which resulted from the downregulation of the PI3K-AKT signaling pathway. Furthermore, salidroside ameliorated butylparaben-induced nephrotoxicity through the PI3K-AKT signaling pathway. This study reveals the seldom-reported kidney toxicity of butylparaben and the protective effect of salidroside against toxicological reactions related to nephrotoxicity. It offers valuable insights into the risks to kidney health posed by environmental toxins.

Complete idiopathic resorption of distobuccal root of a maxillary first molar: A case report.

Key Clinical Message: This case report provides a rare case of idiopathic root resorption in maxillary first molar and suggests the importance of CBCT in the diagnosis and treatment outcome of complex endodontic diseases. Endodontic surgery is an effective method for treating teeth with persistent apical periodontitis. Abstract: Idiopathic root resorption is an unexplained root resorption when the patient experiences root resorption without any local or systemic factors. Early diagnosis and appropriate treatment are crucial for long-term outcomes.

First-line treatment of driver gene-negative metastatic lung adenocarcinoma with malignant pleural effusion: Should chemotherapy be combined with an immune checkpoint inhibitor or bevacizumab?

Patients with metastatic lung adenocarcinoma (MLA) and malignant pleural effusion (MPE) without driver gene mutations have a poor prognosis. None of the standard treatment strategies is recommended for such patients. We retrospectively analyzed the efficacy of the first-line treatment for this specific population: standard platinum-based doublet chemotherapy (CT), CT plus an immune checkpoint inhibitor (CT plus ICI), and CT plus bevacizumab (CT plus Bev). A total of 323 eligible patients were enrolled: CT alone (n = 166), CT plus Bev (n = 72), and CT plus ICI (n = 85). Treatment efficacy assessments were performed every two cycles according to the RECIST guidelines. The endpoints were overall survival (OS) and progression-free survival (PFS). Kaplan-Meier (K‒M) curves and the log-rank test were used to compare OS and PFS. p < 0.05 was the threshold of significance (statistical software: SPSS). The median follow-up was 11.4 months (range, 2.1-49.6 months). PFS and OS in the CT plus ICI/CT plus Bev cohort were significantly longer than those in the CT group (PFS: 7.8/6.4/3.9 months, p < 0.0001; OS: 16.4/15.6/9.6 months, p < 0.0001, respectively). CT plus Bev had better PFS and OS than CT plus ICI/CT in PD-L1 < 1% patients (PFS: 8.4/5.0/3.8 months, p < 0.0001; OS: 15.6/12.9/9.3 months, p < 0.0001). Among patients with PD-L1 1-49%, CT plus ICI led to a longer PFS and OS (PFS: 8.9/5.8/4.2 months, p = 0.009; OS: 24.2/18.8/11.5 months, p = 0.03). In the cohort with PD-L1 ≥ 50%, CT plus ICI was still the best first-line treatment (PFS: 19.7/13.8/9.6 months, p = 0.033; OS: 27.2/19.6/14.9 months, p = 0.047). In driver gene-negative MLA with MPE, CT plus Bev or ICI better controlled MPE and significantly prolonged survival compared to CT alone. PD-L1 expression (negative/positive) may be a key factor influencing the choice of CT plus Bev or ICI.

Tumor-Microenvironment-Responsive Cerium-Enriched Copper Nanozyme with O2 Supply and Oxidative Stress Amplification for In Situ Disulfiram Chemotherapy and Chemodynamic Therapy Intensification.

Traditional chemotherapy has faced tough challenges of systemic toxicity, hypoxia resistance, and inadequacy of monotherapy. Developing the tumor-specific O2-supply-enhanced chemotherapy without toxic drugs while combing other precise treatments can substantially improve therapeutic efficacy. Herein, a CeO2-enriched CuO nanozyme with O2 supply and oxidative stress amplification for tumor-specific disulfiram (DSF) chemotherapy and intensified chemodynamic therapy by synergistic in situ "nontoxicity-toxicity" activation is developed. Notably, CeO2 can not only act as a morphological "regulator," but also serve as a cascaded enzyme-mimetic catalyst via tumor-microenvironment-responsive cascaded-logical programmable valence conversion. Once internalized inside tumor cells, the nanozyme can be degraded by lysosomal acidity to release nontoxic DSF and Cu2+, which can trigger in situ "Cu2+-DSF" chelation, generating a highly toxic Cu(DTC)2 for in situ chemotherapy. Moreover, the enriched CeO2 with catalase-mimetic activity can decompose the endogenous H2O2 into O2, which can relieve the hypoxia to enhance the chemotherapeutic efficacy. Furthermore, the simultaneously generated Ce3+ can exert peroxidase-mimetic activity to catalyze H2O2 into hydroxyl radicals (•OH) for chemodynamic therapy. This Fenton-like chemistry is accompanied by the regeneration of Ce4+, which can deplete the intracellular overproduced GSH to amplify the oxidative stress. Therefore, this nanozyme can provide an alternative to precise cancer treatment.

Prenatal substance exposure and child health: Understanding the role of environmental factors, genetics, and brain development.

Prenatal substance exposure (PSE) has been linked to adverse health outcomes, but its interactions with environmental and genetic factors remain unclear. Using data from the adolescent brain cognitive development cohort (n = 9,838; baseline age: 9.92 ± 0.62 years), we tested for the robust associations of PSE-caffeine/alcohol/tobacco/marijuana with children's health, cognition, and brain metrics after controlling for the environmental and genetic contexts. The environmental context involved birth, familial, and societal risk factors, while the genetic context included family histories and polygenic risk scores (PRSs) of mental disorders. In this sample, PSE-caffeine was observed in 59.8%, PSE-alcohol in 25.7%, PSE-tobacco in 13.2%, and PSE-marijuana in 5.6% of children. PSE-tobacco/marijuana was associated with higher environmental risks, PSE-alcohol was associated with lower familial risks, and all PSEs were associated with higher genetic risks. Controlling for these contexts reduced the number of significant health associations by 100, 91, 84, and 18% for PSE-tobacco/marijuana/caffeine/alcohol. Compared to the baseline, PSE-alcohol had the most health associations that were persistent over a 2-year period from preadolescence to adolescence, including associations with more sleep and mental health problems, improved cognitive functions, and larger brain volumes. These persistent associations with mental health problems and crystallized cognition were mediated by the surface areas of the frontal and the parietal cortices, respectively. Lower risk scores of the familial contexts attenuated associations between PSE-alcohol/marijuana and mental health problems. Higher PRS for substance use disorders enhanced late-onset associations of PSE-marijuana with externalizing problems. Results support the "health in context" concept, emphasizing modifiable factors mitigating adverse PSE effects.

Long-term efficacy of microwave ablation for multifocal papillary thyroid microcarcinoma: a 5-year follow-up study.

OBJECTIVES: Microwave ablation (MWA) has achieved excellent long-term efficacy in treating unifocal papillary thyroid microcarcinoma (UPTMC). The therapeutic effect of this treatment on multifocal papillary thyroid microcarcinoma (MPTMC) is unknown. Therefore, we evaluated the long-term efficacy of MWA for low-risk MPTMC and to provide evidence-based medicine for the revision of clinical guidelines. METHODS: This study included 66 MPTMC patients with a total of 158 lesions, all of whom received MWA. We collected and retrospectively analyzed the patients' follow-up data before MWA, at 1, 3, 6, and 12 months posttreatment and every 6 months thereafter until 5 years posttreatment. We evaluated the MWA complication rate, technical success rate (TSR), lesion volume reduction rate (VRR), and complete disappearance rate (CDR) during follow-up and in those patients with tumor progression and delayed surgery. RESULTS: After 60 months of follow-up, all 158 lesions disappeared in 66 patients, and the volume was reduced from 43.82 mm3 to 0.00 mm3. The TSR and VRR were both 100%. The CDRs at 1 year, 2 years, and 3 years were 57.59%, 93.67%, and 100%, respectively. The complication rate was 3.03% (2/66), and the incidence of tumor progression was 3.03% (2/66), including one new intrathyroidal lesion and one cervical lymph node metastasis (LNM). These lesions were retreated with MWA, and the lesions disappeared during the follow-up period. CONCLUSIONS: Ultrasound-guided MWA for low-risk MPTMC is safe and effective and may serve as an alternative option for patients who refuse surgery or active surveillance (AS). CLINICAL RELEVANCE STATEMENT: This study concludes that ultrasound-guided microwave ablation for low-risk multifocal papillary thyroid microcarcinoma is safe and effective and may serve as an alternative option for patients who refuse surgery or active surveillance. KEY POINTS: • Ultrasound-guided microwave ablation for low-risk multifocal papillary thyroid microcarcinoma is safe and effective. • During 5 years of follow-up, multifocal papillary thyroid microcarcinoma patients treated with microwave ablation had a favorable prognosis. • To provide evidence-based medicine for the revision of clinical guidelines.

Injectable alginate hydrogel promotes antitumor immunity through glucose oxidase and Fe3+ amplified RSL3-induced ferroptosis.

Ferroptosis induced by RAS-selective lethal small molecule 3 (RSL3) can trigger anti-tumor immune responses by reversing the immunosuppressive tumor microenvironment (TME). However, it is challenging to achieve sufficient ferroptosis in the tumor via RSL3 alone. Because of the excellent reactive oxygen species (ROS) production capacity of glucose oxidase (GOx) and Fe3+, we hypothesized that GOx and Fe3+ could increase intracellular lipid peroxidation (LPO) accumulation, and strengthen RSL3-induced ferroptosis in tumor cells. Herein we designed an in-situ gelation strategy based on sodium alginate (SA) to realize localized transport and specific retention of GOx, RSL3, and Fe3+ in tumor tissues. We loaded hydrophobic RSL3 with the tannic acid (TA)/Fe3+ complexes to form nanoparticles (RTF NPs). GOx diluted in the SA solution was blended with RTF NPs to obtain a homogeneous solution. The solution could form hydrogels in the tumor site (RTFG@SA) upon injection. The retained GOx and Fe3+ amplified the induction of ferroptosis by RSL3, augmented immunogenic cell death (ICD) and promoted antitumor immunity. The RTFG@SA hydrogel presented a significant restraint of tumor growth and metastasis in the 4T1 tumor model. This hydrogel could offer an effective means of co-delivery of hydrophilic drugs, hydrophobic drugs, and metal ions.

Long-term survival after stereotactic body radiotherapy combined with immunotherapy plus anti-angiogenesis therapy in patients with advanced non-small cell lung cancer and EGFR exon 20 insertion mutation: a report of two cases.

Background: Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutation is the third most common EGFR-mutant form, accounting for 10-12% of all EGFR mutations in non-small cell lung cancer (NSCLC). Chemotherapy was the first-line treatment for patients with EGFR ex20ins mutation in the era when EGFR ex20ins tyrosine kinase inhibitors (EGFR ex20ins-TKIs) were inaccessible. Although EGFR ex20ins-TKIs have since then demonstrated certain efficacy, the population benefit rate is not high due to the high cost of the drug and limited benefit to the population. Therefore, the choice of treatment modality when a patient does not have access to EGFR ex20ins-TKIs or are resistant to them remains an avenue worth exploring. Case Description: In this report, we present two cases of patients with lung adenocarcinoma and EGFR ex20ins mutation. The two patients were middle-aged Asian women with no smoking history, and both had one or more metastatic lesions. Both achieved long-term clinical benefit (progression-free survival ≥12 months) after receiving combined treatment, suggesting that this is a promising treatment modality. Conclusions: To the best of our knowledge, this is the first report supporting the combination of stereotactic body radiotherapy and apatinib and camrelizumab as an effective treatment strategy in patients with advanced EGFR ex20ins-positive NSCLC who have been previously treated with chemotherapy. The therapy described in this report might serve as a potential alternative approach for clinical oncologists.

Stimuli-activatable nanomedicine meets cancer theranostics.

Stimuli-activatable strategies prevail in the design of nanomedicine for cancer theranostics. Upon exposure to endogenous/exogenous stimuli, the stimuli-activatable nanomedicine could be self-assembled, disassembled, or functionally activated to improve its biosafety and diagnostic/therapeutic potency. A myriad of tumor-specific features, including a low pH, a high redox level, and overexpressed enzymes, along with exogenous physical stimulation sources (light, ultrasound, magnet, and radiation) have been considered for the design of stimuli-activatable nano-medicinal products. Recently, novel stimuli sources have been explored and elegant designs emerged for stimuli-activatable nanomedicine. In addition, multi-functional theranostic nanomedicine has been employed for imaging-guided or image-assisted antitumor therapy. In this review, we rationalize the development of theranostic nanomedicine for clinical pressing needs. Stimuli-activatable self-assembly, disassembly or functional activation approaches for developing theranostic nanomedicine to realize a better diagnostic/therapeutic efficacy are elaborated and state-of-the-art advances in their structural designs are detailed. A reflection, clinical status, and future perspectives in the stimuli-activatable nanomedicine are provided.

Convergent evolution of allele-specific gene expression that leads to non-small cell lung cancer in different human populations.

Phenotypical innovations during evolution are caused by novel mutations, which are usually heterozygous at the beginning. The gene expressions on two alleles of these mutation sites are not necessarily identical, leading to flexible allele-specific regulation in cell systems. We retrieve the transcriptome data of normal and non-small cell lung cancer (NSCLC) tissues from 47 African Americans (AA) and 50 European Americans (EA). We analyze the differentially expressed genes (DEGs) in NSCLC as well as the tumor-specific mutations. Expression and mutation profiles show convergent evolution in AA and EA populations. The tumor-specific mutations are poorly overlapped, but many of them are located in the same genes, mainly oncogenes and tumor suppressor genes. The DEGs in tumors are majorly caused by the mutated alleles rather than normal alleles. The relative expressions of mutated alleles are highly correlated between AA and EA. The differential expression in NSCLC is predominantly mediated by the mutated alleles on heterozygous sites. This molecular mechanism underlying NSCLC oncogenesis is conserved across different human populations, exhibiting convergent evolution. We present this novel angle that differential expression analysis should be performed separately for different alleles. Our ideas should greatly benefit the cancer community.

Endogenous H2O2 Self-Replenishment and Sustainable Cascades Enhance the Efficacy of Sonodynamic Therapy.

Purpose: Sonodynamic therapy (SDT), with its high tissue penetration and noninvasive advantages, represents an emerging approach to eradicating solid tumors. However, the outcomes of SDT are typically hampered by the low oxygen content and immunosuppression in the tumor microenvironment (TME). Accordingly, we constructed a cascade nanoplatform to regulate the TME and improve the anti-tumor efficiency of SDT. Methods: In this study, we rationally design cascade nanoplatform by incorporating immunostimulant hyaluronic acid (HA) and sonosensitizer chlorin e6 (Ce6) on the polydopamine nanocarrier that is pre-doped with platinum nanozymes (designated Ce6/Pt@PDA-HA, PPCH). Results: The cascade reactions of PPCH are evidenced by the results that HA exhibits reversing immunosuppressive that converts M2 macrophages into M1 macrophages in situ, while producing H2O2, and then platinum nanozymes further catalyze the H2O2 to produce O2, and O2 produces abundant singlet oxygen (1O2) under the action of Ce6 and low-intensity focused ultrasound (LIFU), resulting in a domino effect and further amplifying the efficacy of SDT. Due to its pH responsiveness and mitochondrial targeting, PPCH effectively accumulates in tumor cells. Under LIFU irradiation, PPCH effectively reverses immunosuppression, alleviates hypoxia in the TME, enhances reactive oxygen species (ROS) generation, and enhances SDT efficacy for eliminating tumor cells in vivo and in vitro. Meanwhile, an in vivo dual-modal imaging including fluorescence and photoacoustic imaging achieves precise tumor diagnosis. Conclusion: This cascade nanoplatform will provide a promising strategy for enhancing SDT eradication against tumors by modulating immunosuppression and relieving hypoxia.

Talaromyces marneffei suppresses macrophage inflammation by regulating host alternative splicing.

Talaromyces marneffei (T. marneffei) immune escape is essential in the pathogenesis of talaromycosis. It is currently known that T. marneffei achieves immune escape through various strategies. However, the role of cellular alternative splicing (AS) in immune escape remains unclear. Here, we depict the AS landscape in macrophages upon T. marneffei infection via high-throughput RNA sequencing and detect a truncated protein of NCOR2 / SMRT, named NCOR2-013, which is significantly upregulated after T. marneffei infection. Mechanistic analysis indicates that NCOR2-013 forms a co-repression complex with TBL1XR1 / TBLR1 and HDAC3, thereby inhibiting JunB-mediated transcriptional activation of pro-inflammatory cytokines via the inhibition of histone acetylation. Furthermore, we identify TUT1 as the AS regulator that regulates NCOR2-013 production and promotes T. marneffei immune evasion. Collectively, these findings indicate that T. marneffei escapes macrophage killing through TUT1-mediated alternative splicing of NCOR2 / SMRT, providing insight into the molecular mechanisms of T. marneffei immune evasion and potential targets for talaromycosis therapy.

Identification and functional regulation of three alternative splicing isoforms of the fthl27 gene in miiuy croaker, Miichthys miiuy.

Alternative splicing is an important basic mechanism for eukaryotes to control gene expression. Different forms of alternative splicing may lead to the production of protein subtypes with different functions, leading to the expansion of protein diversity in organisms, affecting cell production and metabolism, and is even related to the occurrence of many diseases. Many studies have shown that ferritin is usually associated with inflammation, vascular proliferation, and tumors, which is the focus of immunological research. It not only plays a role in iron metabolism and storage in the body, but also plays an important regulatory role in pathways related to immune and inflammatory regulation. However, there are few studies on alternative splicing events of the ferritin gene nowadays. Therefore, this study identified three different splicing isoforms in its ferritin gene fthl27 of Miichthys miiuy through Sanger sequencing, qRT-PCR, and other experimental techniques, and we found that three different splicing isoforms of the ferritin gene fthl27 in M. Miiuy cells showed an upregulation trend after being stimulated by Lipopolysaccharide (LPS) and poly (I: C). The experiment also found that the three isoforms may have different regulatory effects on the expression of inflammatory factors and antiviral immune factors, playing an important role in the innate immune response of fish.