Restoration of TFPI2 by LSD1 inhibition suppresses tumor progression and potentiates antitumor immunity in breast cancer.

Histone lysine-specific demethylase 1 (LSD1) is frequently overexpressed in triple negative breast cancer (TNBC), which is associated with worse clinical outcome in TNBC patients. However, the underlying mechanisms by which LSD1 promotes TNBC progression remain to be identified. We recently established a genetically engineered murine model by crossing mammary gland conditional LSD1 knockout mice with Brca1-deficient mice to explore the role of LSD1 in TNBC pathogenesis. Cre-mediated Brca1 loss led to higher incidence of tumor formation in mouse mammary glands, which was hindered by concurrent depletion of LSD1, indicating a critical role of LSD1 in promoting Brca1-deficient tumors. We also demonstrated that the silencing of a tumor suppressor gene, Tissue Factor Pathway Inhibitor 2 (TFPI2), is functionally associated with LSD1-mediated TNBC progression. Mouse Brca1-deficient tumors exhibited elevated LSD1 expression and decreased TFPI2 level compared to normal mammary tissues. Analysis of TCGA database revealed that TFPI2 expression is significantly lower in aggressive ER-negative or basal-like BC. Restoration of TFPI2 through LSD1 inhibition increased H3K4me2 enrichment at the TFPI2 promoter, suppressed tumor progression, and enhanced antitumor efficacy of chemotherapeutic agent. Induction of TFPI2 by LSD1 ablation downregulates activity of matrix metalloproteinases (MMPs) that in turn increases the level of cytotoxic T lymphocyte attracting chemokines in tumor environment, leading to enhanced tumor infiltration of CD8+ T cells. Moreover, induction of TFPI2 potentiates antitumor effect of LSD1 inhibitor and immune checkpoint blockade in poorly immunogenic TNBC. Together, our study identifies previously unrecognized roles of TFPI2 in LSD1-mediated TNBC progression, therapeutic response, and immunogenic effects.

WNT5B promotes the malignant phenotype of non-small cell lung cancer via the FZD3-DVL3-RAC1-PCP-JNK pathway.

The WNT5B ligand regulates the non-canonical wingless-related integration site (WNT)-planar cell polarity (PCP) pathway. However, the detailed mechanism underlying the activity of WNT5B in the WNT-PCP pathway in non-small cell lung cancer (NSCLC) is unclear. In this study, we assessed the clinicopathological significance of WNT5B expression in NSCLC specimens. WNT5B-overexpression and -knockdown NSCLC cell lines were generated in vivo and in vitro, respectively. WNT5B overexpression in NSCLC specimens correlates with advanced tumor node metastasis (TNM) stage, lymph node metastasis, and poor prognosis in patients with NSCLC. Additionally, WNT5B promotes the malignant phenotype of NSCLC cells in vivo and in vitro. Interactions were identified among WNT5B, frizzled3 (FZD3), and disheveled3 (DVL3) in NSCLC cells, leading to the activation of WNT-PCP signaling. The FZD3 receptor initiates DVL3 recruitment to the membrane for phosphorylation in a WNT5B ligand-dependent manner and activates c-Jun N-terminal kinase (JNK) signaling via the small GTPase RAC1. Furthermore, the deletion of the DEP domain of DVL3 abrogated these effects. Overall, we demonstrated a novel signal transduction pathway in which WNT5B recruits DVL3 to the membrane via its DEP domain through interaction with FZD3 to promote RAC1-PCP-JNK signaling, providing a potential target for clinical intervention in NSCLC treatment.

Decreased PANK1 expression in kidney renal clear cell carcinoma: impact on cell apoptosis, invasion, migration, and epithelial-mesenchymal transition.

OBJECTIVE: To investigate pantothenate kinases 1 (PANK1) expression in kidney renal clear cell carcinoma (KIRC) tissues, analyze its correlation with clinicopathological features and prognosis, and explore its impact on invasion, migration, and apoptosis in KIRC cells. METHODS: GEPIA (gene expression profiling interactive analysis), UALCAN and LinkedOmics, were employed to analyze PANK1 expression in KIRC tissues and its correlation with clinical characteristics. Comparative analyses were performed between KIRC (Caki-1 and 786-O) and noncancerous renal cells (HK-2 and RPTEC). Transfection with PANK1 activation particles was conducted, followed by Wound healing, Transwell assay, Annexin V-fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI) staining, quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and Western blotting. RESULTS: PANK1 was down-regulated in KIRC tissues and cells compared to normal tissues and noncancerous cells. Correlation analyses linked PANK1 expression with clinicopathological features in KIRC, with high PANK1 expression associated with a favorable outcome. High PANK1 expression correlated positively with E-cadherin (CDH1), tight junction protein 1 (TJP1), Fas cell surface death receptor (FAS), caspase-8 (CASP8), and CASP9, while showing a negative correlation with vimentin (VIM), snail family transcriptional repressor 1 (SNAIL1), twist family BHLH transcription factor 1 (TWIST1), and TWIST2. PANK1 overexpression increased CDH1, TJP1, FAS, CASP8, and CASP9 while downregulating SNAIL1, VIM, TWIST1, and TWIST2, inhibiting invasion and migration, and promoting apoptosis in KIRC cells. CONCLUSION: PANK1 down-regulation in KIRC tissues correlated with clinicopathological features and prognosis. Its overexpression modulated epithelial-mesenchymal transition (EMT)-related gene, inhibited invasion, promoted apoptosis in KIRC cells, highlighting its role in disease progression and therapeutic potential.

Citrus polymethoxyflavones degrade estrogen receptor-alpha (ERα) and combine with tamoxifen for the treatment of estrogen receptor-positive breast cancer.

Estrogen receptor-positive (ER+) breast cancer seriously endangers the women's physical and mental health worldwide and ER targeting therapy is vital. Here, we found that a citrus polymethoxyflavones (PMFs)-rich hydrolysate (C-H) and its major components (nobiletin and 3-methoxynobiletin) potently degrade ERα protein via the ubiquitin-proteasome pathway, thereby impairing the proliferation of ER+ breast cancer cells. Moreover, our study exhibited that C-H combined with tamoxifen (TAM) inhibited the cell proliferation of ER+ breast cancer in vitro. It was further confirmed that C-H decreased tumor growth of ER+ breast cancer in tumor-bearing 129 mice in vivo and improved the efficacy of tamoxifen. Our study revealed that the citrus PMFs have potential applications as pharmaceutical and healthcare products in breast cancer treatment by targeting ERα protein degradation.

The Role of HSP90 Molecular Chaperones in Depression: Potential Mechanisms.

Major depressive disorder (MDD) is characterized by high rates of disability and death and has become a public health problem that threatens human life and health worldwide. HPA axis disorder and neuroinflammation are two common biological abnormalities in MDD patients. Hsp90 is an important molecular chaperone that is widely distributed in the organism. Hsp90 binds to the co-chaperone and goes through a molecular chaperone cycle to complete its regulation of the client protein. Numerous studies have demonstrated that Hsp90 regulates how the HPA axis reacts to stress and how GR, the HPA axis' responsive substrate, matures. In addition, Hsp90 exhibits pro-inflammatory effects that are closely related to neuroinflammation in MDD. Currently, Hsp90 inhibitors have made some progress in the treatment of a variety of human diseases, but they still need to be improved. Further insight into the role of Hsp90 in MDD provides new ideas for the development of new antidepressant drugs targeting Hsp90.

Systematic Structural Modification of Squaraine Dye for Near-Infrared Window One and Two Multiplexed In Vivo Imaging and Photothermal Therapy.

Due to the wide application of reporter gene-related visible/NIR-I bioluminescent imaging, multiplexed fluorescence imaging across visible/NIR-I/NIR-II has excellent potential in biomedical research. However, in vivo multiplexed imaging applications across those regions have rarely been reported due to the lack of proper fluorophores. Herein, nine squaraine dyes, which exhibit diverse adsorption and emission wavelengths, were synthesized. Among them, water-soluble SQ 710-5k and SQ 905 were found to have significant absorption differences, which allowed the tumor and lymph nodes to be identified. Then, for the first time, six-channel multiplexed fluorescence imaging across visible/NIR-I/II was achieved by coordination with reporter gene-related bioluminescent phosphors. Additional research revealed that SQ 710-5k exhibited higher-quality blood vessels and tumor imaging in NIR-II. H-aggregates SQ 905 demonstrated a high photothermal conversion efficiency for photothermal therapy. This study proposed an approach to creating small molecular dyes that coordinate with reporter gene-related bioluminescent phosphors for six-color fluorescence imaging.

Potent human neutralizing antibodies against Nipah virus derived from two ancestral antibody heavy chains.

Nipah virus (NiV) is a World Health Organization priority pathogen and there are currently no approved drugs for clinical immunotherapy. Through the use of a naïve human phage-displayed Fab library, two neutralizing antibodies (NiV41 and NiV42) targeting the NiV receptor binding protein (RBP) were identified. Following affinity maturation, antibodies derived from NiV41 display cross-reactivity against both NiV and Hendra virus (HeV), whereas the antibody based on NiV42 is only specific to NiV. Results of immunogenetic analysis reveal a correlation between the maturation of antibodies and their antiviral activity. In vivo testing of NiV41 and its mature form (41-6) show protective efficacy against a lethal NiV challenge in hamsters. Furthermore, a 2.88 Å Cryo-EM structure of the tetrameric RBP and antibody complex demonstrates that 41-6 blocks the receptor binding interface. These findings can be beneficial for the development of antiviral drugs and the design of vaccines with broad spectrum against henipaviruses.

Spatiotemporal dual-periodic soliton pulsation in a multimode fiber laser.

Spatiotemporal mode-locked (STML) fiber lasers have become a new platform for investigating nonlinear phenomena. In this work, spatiotemporal dual-periodic soliton pulsation (SDSP) is firstly observed in an STML fiber laser. It is found that in the SDSP, the long-period pulsations (LPPs) of different transverse modes are synchronous, while the short-period pulsations (SPPs) exhibit asynchronous modulations. The numerical simulation confirms the experimental results and further reveals that the proportion of transverse mode components can manipulate the periods of the LPP and SPP but does not affect the synchronous and asynchronous pulsations of different transverse modes. The obtained results bring the study of spatiotemporal dissipative soliton pulsation into the multi-period modulation stage, which helps to understand the complex spatiotemporal dynamics in STML fiber lasers and discover new dynamics in high-dimensional nonlinear systems.

Dehydrocurvularin-loaded mPEG-PLGA nanoparticles for targeted breast cancer drug delivery: preparation, characterization, in vitro, and in vivo evaluation.

Dehydrocurvularin (DCV) is a promising lead compound for anti-cancer therapy. Unfortunately, the development of DCV-based drugs has been hampered by its poor solubility and bioavailability. Herein, we prepared a DCV-loaded mPEG-PLGA nanoparticles (DCV-NPs) with improved drug properties and therapeutic efficacy. The spherical and discrete particles of DCV-NPs had a uniform diameter of 101.8 ± 0.45 nm and negative zeta potential of -22.5 ± 1.12 mV (pH = 7.4), and its entrapment efficiency (EE) and drug loading (DL) were ∼53.28 ± 1.12 and 10.23 ± 0.30%, respectively. In vitro the release of DCV-NPs lasted for more than 120 h in a sustained-release pattern, its antiproliferation efficacy towards breast cancer cell lines (MCF-7, MDA-MB-231, and 4T1) was better than that of starting drug DCV, and it could be efficiently and rapidly internalised by breast cancer cells. In vivo DCV-NPs were gradually accumulated in tumour areas of mice and significantly suppressed tumour growth. In summary, loading water-insoluble DCV onto nanoparticles has the potential to be an effective agent for breast cancer therapy with injectable property and tumour targeting capacity.

[Monkeypox transmission and oral prevention].

Monkeypox is becoming a viral infectious disease of global concern. WHO has reported monkeypox outbreaks in more than 50 countries. Since the first imported case has been confirmed and reported by Taiwan, China, in June 2022, the monkeypox has draw high attention from the national public health and epidemic prevention department. Among the key tasks of Shanghai high-quality healthcare development in 2023, monkeypox has been identified as one of the key infectious diseases that need to be under strict prevention and control. The diagnosis and treatment in dental department are mainly performed face-to-face, with patients' masks taken-off. Large amount of aerosol spray will be generated during the operation. At the same time, dental diagnosis and treatment is in outpatient department, where the patient flow is large. Once monkeypox patients have been diagnosed and treated in the dental diagnosis and treatment area, and the preventive measures are not implemented, it will provide convenience for monkeypox to transmit. In order to avoid this kind of situation, this article made a review of monkey-pox from the following 3 aspects: epidemic transmission history of monkeypox, systemic and oral symptoms of monkeypox, and oral prevention of monkeypox, to improve the knowledge and prevention ability of dental medical staff on monkeypox for early recognition and prevention.

Screening tumor stage-specific candidate neoantigens in thyroid adenocarcinoma using integrated exome and transcriptome sequencing.

Background: The incidence of thyroid carcinoma (THCA), the most common endocrine tumor, is continuously increasing worldwide. Although the overall prognosis of THCA is good, patients with distant metastases exhibit a mortality rate of 5-20%. Methods: To improve the diagnosis and overall prognosis of patients with thyroid cancer, we screened specific candidate neoantigen genes in early- and late-stage THCA by analyzing the transcriptome and somatic cell mutations in this study. Results: The top five early-stage neoantigen-related genes (NRGs) were G protein-coupled receptor 4 [GPR4], chondroitin sulfate proteoglycan 4 [CSPG4], teneurin transmembrane protein 1 [TENM1], protein S 1 [PROS1], and thymidine kinase 1 [TK1], whereas the top five late-stage NRGs were cadherin 6 [CDH6], semaphorin 6B [SEMA6B], dysferlin [DYSF], xenotropic and polytropic retrovirus receptor 1 [XPR1], and ABR activator of RhoGEF and GTPase [ABR]. Subsequently, we used machine learning models to verify their ability to screen NRGs and analyze the correlations among NRGs, immune cell types, and immune checkpoint regulators. The use of candidate antigen genes resulted in a better diagnostic model (the area under the curve [AUC] value of the early-stage group [0.979] was higher than that of the late-stage group [0.959]). Then, a prognostic model was constructed to predict NRG survival, and the 1-, 3- and 5-year AUC values were 0.83, 0.87, and 0.86, respectively, which were closely related to different immune cell types. Comparison of the expression trends and mutation frequencies of NRGs in multiple tumors revealed their potential for the development of broad spectrum therapeutic drugs. Conclusion: In conclusion, the candidate NRGs identified in this study could potentially be used as therapeutic targets and diagnostic biomarkers for the development of novel broad spectrum therapeutic agents.

Sleep Deprivation Impairs Human Cognitive Reappraisal Ability: A Randomized Controlled Trial.

Purpose: This study aims to examine the impact of sleep deprivation on individual cognitive reappraisal ability using a standardized behavioral paradigm. Methods: A randomized pretest-posttest control group design was conducted. Thirty-nine participants were eventually enrolled and randomly assigned to receive either the sleep control (SC: n = 17) or the sleep deprivation (SD: n = 22). Both of them were required to perform a standardized behavioral paradigm of measuring cognitive reappraisal ability one time under sleep-rested condition and another time under the condition of different sleep manipulation a week later. Results: Mean valence ratings of SD group were more negative than SC group's (p < 0.05) and mean arousal ratings of SD group were higher than SC group's (p < 0.01). Conclusion: Sleep deprivation may impair individual cognitive reappraisal ability and could potentially undermine the efficacy of cognitive therapy in terms of emotion regulation.

Targeting LSD1 in tumor immunotherapy: rationale, challenges and potential.

Lysine-specific demethylase 1 (LSD1) is an enzyme that removes lysine methylation marks from nucleosome histone tails and plays an important role in cancer initiation, progression, metastasis, and recurrence. Recent research shows that LSD1 regulates tumor cells and immune cells through multiple upstream and downstream pathways, enabling tumor cells to adapt to the tumor microenvironment (TME). As a potential anti-tumor treatment strategy, immunotherapy has developed rapidly in the past few years. However, most patients have a low response rate to available immune checkpoint inhibitors (ICIs), including anti-PD-(L)1 therapy and CAR-T cell therapy, due to a broad array of immunosuppressive mechanisms. Notably, inhibition of LSD1 turns "cold tumors" into "hot tumors" and subsequently enhances tumor cell sensitivity to ICIs. This review focuses on recent advances in LSD1 and tumor immunity and discusses a potential therapeutic strategy for combining LSD1 inhibition with immunotherapy.

Semantic Segmentation of Gastric Polyps in Endoscopic Images Based on Convolutional Neural Networks and an Integrated Evaluation Approach.

Convolutional neural networks (CNNs) have received increased attention in endoscopic images due to their outstanding advantages. Clinically, some gastric polyps are related to gastric cancer, and accurate identification and timely removal are critical. CNN-based semantic segmentation can delineate each polyp region precisely, which is beneficial to endoscopists in the diagnosis and treatment of gastric polyps. At present, just a few studies have used CNN to automatically diagnose gastric polyps, and studies on their semantic segmentation are lacking. Therefore, we contribute pioneering research on gastric polyp segmentation in endoscopic images based on CNN. Seven classical semantic segmentation models, including U-Net, UNet++, DeepLabv3, DeepLabv3+, Pyramid Attention Network (PAN), LinkNet, and Muti-scale Attention Net (MA-Net), with the encoders of ResNet50, MobineNetV2, or EfficientNet-B1, are constructed and compared based on the collected dataset. The integrated evaluation approach to ascertaining the optimal CNN model combining both subjective considerations and objective information is proposed since the selection from several CNN models is difficult in a complex problem with conflicting multiple criteria. UNet++ with the MobineNet v2 encoder obtains the best scores in the proposed integrated evaluation method and is selected to build the automated polyp-segmentation system. This study discovered that the semantic segmentation model has a high clinical value in the diagnosis of gastric polyps, and the integrated evaluation approach can provide an impartial and objective tool for the selection of numerous models. Our study can further advance the development of endoscopic gastrointestinal disease identification techniques, and the proposed evaluation technique has implications for mathematical model-based selection methods for clinical technologies.

Mouse Abdominal Aortic Aneurysm Model Induced by Periarterial Incubation of Papain.

For decades, numerous experimental animal models have been developed to examine the pathophysiologic mechanisms and potential treatments for abdominal aortic aneurysms (AAAs) in diverse species with varying chemical or surgical approaches. This study aimed to create an AAA mouse model by the periarterial incubation with papain, which can mimic human AAA with advantages such as simplicity, convenience, and high efficiency. Eighty C57BL/6J male mice were randomly assigned to 1 of the 4 groups: papain (1.0 or 2.0 mg), porcine pancreatic elastase, and phosphate-buffered solution. The aortic segment was wrapped for 20 minutes, and the diameter was measured using ultrasound preoperatively and postoperative days 7 and 14. Then, the mice were killed for histomorphometric and immunohistochemical analyses. According to ultrasound measurements and histomorphometric analyses, on postoperative day 7, 65% of mice in the 1.0-mg papain group and 60% of mice in the 2.0-mg papain group developed AAA. In both papain groups, 100% of mice developed AAA, and 65% of mice in the porcine pancreatic elastase group developed AAA on postoperative day 14. Furthermore, hematoxylin/eosin, elastin van Gieson, and Masson staining of tissues from the papain group revealed thickened media and intimal hyperplasia, collagen sediments, and elastin destruction, indicating that AAA histochemical alteration was similar to that of humans. In addition, the immunohistochemical analysis was conducted to detect infiltrated inflammatory cells, such as macrophages and leukocytes, in the aortic wall and hyperplasic adventitia. The expression of matrix metalloproteinase 2 and 9 was significantly upregulated in papain and human AAA tissues. Periarterial incubation with 1.0 mg of papain for 20 minutes can successfully create an experimental AAA model in mice for 14 days, which can be used to explore the mechanism and treatment of human AAA.

Boosting Activity and Selectivity of UiO-66 through Acidity/Alkalinity Functionalization in Dimethyl Carbonate Catalysis.

The acid-base properties of supports have an enormous impact on catalytic reactions to regulate the selectivity and activity of supported catalysts. Herein, a train of Pd-X-UiO-66 (X = NO2 , NH2 , and CH3 ) catalysts with different acidity/alkalinity functional groups and encapsulated Pd(II) species is first developed, whose activities in dimethyl carbonate (DMC) catalysis are then investigated in details. Thereinto, the Pd-NO2 -UiO-66 catalyst with acidity functionalization exhibits the best catalytic behavior: the DMC selectivity stemmed from methyl nitrite (MN) is up to 68%, the conversion of CO is 73.4%. The obtained experimental results demonstrate that the NO2 group not only affected the interaction between X-UiO-66 and Pd(II) active sites but also play an indispensable role in the adsorption and activation of MN and CO, which remarkably promote the formation of the COOCH3 * intermediate and DMC product.

Corrigendum: Case report: Potential predictive value of MMR/MSI status and PD-1 expression in immunotherapy for urothelial carcinoma.

[This corrects the article DOI: 10.3389/pore.2022.1610638.].

Effects of Holliday Junction-Recognition Protein-Mediated C-Jun N-Terminal Kinase/ Signal Transducer and Activator of Transcription 3 Signaling Pathway on Cell Proliferation, Cell Cycle and Cell Apoptosis in Bladder Urothelial Carcinoma.

The Holliday Junction-Recognition Protein (HJURP) was upregulated in several tumors, which was associated with poor outcome. This study investigated the effects of the HJURP-mediated c-Jun N-terminal kinase (JNK)/ signal transducer and activator of transcription 3 (STAT3) pathway on bladder urothelial carcinoma (BLUC). Online databases were used to analyze HJURP expression in BLUC and the correlation of HJURP to JNK1 [mitogen-activated protein kinase 8 (MAPK8)], JNK2 (MAPK9), STAT3, marker of proliferation Ki-67 (MKI67), proliferating cell nuclear antigen (PCNA), cyclin dependent kinase 2 (CDK2), CDK4 and CDK6. HJURP expression was detected in BLUC cells and human normal primary bladder epithelial cells (BdECs). BLUC cells were treated with HJURP lentivirus activation /shRNA lentivirus particles or JNK inhibitor SP600125. HJURP was upregulated in BLUC tissues and correlated with poor prognosis of patients (all P < 0.05). HJURP in tumor positively correlated with MAPK8 (R = 0.30), MAPK9 (R = 0.30), STAT3 (R = 0.15), MKI67 (R = 0.60), PCNA (R = 0.46), CDK2 (R = 0.39), CDK4 (R = 0.24) and CDK6 (R = 0.21). The JNK inhibitor SP600125 decreased p-JNK/JNK and p-STAT3/STAT3 in BLUC cells, which was reversed by HJURP overexpression (P < 0.05). The HJURP-mediated JNK/STAT3 pathway promoted BLUC cell proliferation and inhibited cell apoptosis (P < 0.05). HJURP reversed the arrested G0/G1 phase of BLUC cells by SP600125. HJURP acted as an oncogene to regulate BLUC cell proliferation, apoptosis and the cell cycle by mediating the JNK/STAT3 pathway. Therefore, HJURP targeting might be an attractive novel therapeutic target for early diagnosis and treatment in BLUC.

Case Report: Potential Predictive Value of MMR/MSI Status and PD-1 Expression in Immunotherapy for Urothelial Carcinoma.

Immune checkpoint inhibitors (ICIs) have shown encouraging outcomes against Lynch syndrome (LS)-associated colorectal cancer (CRC) and endometrial cancer with mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H). However, there is as yet no clarity on the safety and efficacy of immunotherapy combined with chemotherapy in LS-associated urothelial carcinoma (UC). Here, we report a patient with recurrent and metastatic LS-associated UC who achieved sustained response to programmed death protein 1 (PD-1) inhibitor combined with chemotherapy over 31 months, during which the side effects of immunotherapy could be controlled and managed. Our findings indicate that the dMMR/MSI status and PD-1 expression in UC may have potential predictive value for the response to PD-1-targeted immunotherapy. Our case supports the inclusion of such combination and/or monotherapy for UC in clinical studies and using dMMR/MSI status and PD-1 expression as potential predictive biomarkers for assessment of the therapeutic response.

Processing speed mediates the relationship between brain structure and semantic fluency in aging.

The present study has investigated how brain structure and processing speed contribute to age-related changes in semantic fluency. Groups of younger (N = 37) and older healthy participants (N = 40) completed a semantic fluency test and digit symbol test, and rested while diffusion tensor imaging (DTI) was performed. Group comparisons and correlational analysis revealed that age-related decline in semantic fluency was associated with reduction in gray matter volume in widespread fronto-temporal regions. Age-related decline in semantic fluency was also associated with decline in white matter integrity in brain tracts connecting these brain regions. Critically, hierarchical regression analysis suggested that low processing speed fully mediated the negative effects of lower gray matter volume and white matter integrity on semantic fluency. The present findings provide a support for the processing speed theory in relation to age related decline in semantic fluency, and also provide a reference for improving cognitive decline.