Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3), represents the most common autosomal dominant cerebellar ataxia worldwide. Despite its progressive and debilitating nature, disease-modifying therapies remain elusive. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising non-invasive intervention; however, its clinical application has been hindered by inconsistent protocols and a lack of mechanistic understanding. A recent landmark study published in Brain Stimulation by Chen et al. addressed these challenges by combining a high-dose intermittent theta-burst stimulation (iTBS) protocol with concurrent transcranial magnetic stimulation-electroencephalography (TMS-EEG). This commentary provides an in-depth analysis of their findings, highlighting the restoration of cerebello-cortical inhibition (CBI) as a key therapeutic mechanism. Furthermore, we discuss the broader implications of this work, proposing that future translational research should integrate accelerated iTBS (aiTBS) paradigms, cortical response measurements (CRM), and individualized neuro-navigation to establish a new era of precision neuromodulation for ataxia.

Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3), represents the most common autosomal dominant cerebellar ataxia worldwide. Despite its progressive and debilitating nature, disease-modifying therapies remain elusive. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising non-invasive intervention; however, its clinical application has been hindered by inconsistent protocols and a lack of mechanistic understanding. A recent landmark study published in Brain Stimulation by Chen et al. addressed these challenges by combining a high-dose intermittent theta-burst stimulation (iTBS) protocol with concurrent transcranial magnetic stimulation-electroencephalography (TMS-EEG). This commentary provides an in-depth analysis of their findings, highlighting the restoration of cerebello-cortical inhibition (CBI) as a key therapeutic mechanism. Furthermore, we discuss the broader implications of this work, proposing that future translational research should integrate accelerated iTBS (aiTBS) paradigms, cortical response measurements (CRM), and individualized neuro-navigation to establish a new era of precision neuromodulation for ataxia.

This study aims to investigate the protective effects and mechanisms of polysaccharide extract PCP1 from Polygonatum cyrtonema in ameliorating cerebral ischemia-reperfusion(I/R) injury in rats through modulation of the Toll-like receptor 4(TLR4)/NOD-like receptor protein 3(NLRP3) signaling pathway. In vivo, SD rats were randomly divided into the sham group, model group, PCP1 group, nimodipine(NMDP) group, and TLR4 signaling inhibitor(TAK-242) group. A middle cerebral artery occlusion/reperfusion(MCAO/R) model was established, and neurological deficit scores and infarct size were evaluated 24 hours after reperfusion. Hematoxylin-eosin(HE) and Nissl staining were used to observe pathological changes in ischemic brain tissue. Transmission electron microscopy(TEM) assessed ultrastructural damage in cortical neurons. Enzyme-linked immunosorbent assay(ELISA) was used to measure the levels of interleukin-1β(IL-1β), interleukin-6(IL-6), interleukin-18(IL-18), tumor necrosis factor-α(TNF-α), interleukin-10(IL-10), and nitric oxide(NO) in serum. Immunofluorescence was used to analyze the expression of TLR4 and NLRP3 proteins. In vitro, a BV2 microglial cell oxygen-glucose deprivation/reperfusion(OGD/R) model was established, and cells were divided into the control, OGD/R, PCP1, TAK-242, and PCP1 + TLR4 activator lipopolysaccharide(LPS) groups. The CCK-8 assay evaluated BV2 cell viability, and ELISA determined NO release. Western blot was used to analyze the expression of TLR4, NLRP3, and downstream pathway-related proteins. The results indicated that, compared with the model group, PCP1 significantly reduced neurological deficit scores, infarct size, ischemic tissue pathology, cortical cell damage, and the levels of inflammatory factors IL-1β, IL-6, IL-18, TNF-α, and NO(P<0.01). It also elevated IL-10 levels(P<0.01) and decreased the expression of TLR4 and NLRP3 proteins(P<0.05, P<0.01). Moreover, in vitro results showed that, compared with the OGD/R group, PCP1 significantly improved BV2 cell viability(P<0.05, P<0.01), reduced cell NO levels induced by OGD/R(P<0.01), and inhibited the expression of TLR4-related inflammatory pathway proteins, including TLR4, myeloid differentiation factor 88(MyD88), tumor necrosis factor receptor-associated factor 6(TRAF6), phosphorylated nuclear factor-kappaB dimer RelA(p-p65)/nuclear factor-kappaB dimer RelA(p65), NLRP3, cleaved-caspase-1, apoptosis-associated speck-like protein(ASC), GSDMD-N, IL-1β, and IL-18(P<0.05, P<0.01). The protective effects of PCP1 were reversed by LPS stimulation. In conclusion, PCP1 ameliorates cerebral I/R injury by modulating the TLR4/NLRP3 signaling pathway, exerting anti-inflammatory and anti-pyroptotic effects.
Animals ; Toll-Like Receptor 4/genetics* ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics* ; Rats, Sprague-Dawley ; Rats ; Reperfusion Injury/genetics* ; Male ; Signal Transduction/drug effects* ; Polysaccharides/isolation & purification* ; Polygonatum/chemistry* ; Brain Ischemia/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Mice ; Humans

Objectives:Coronary slow flow(CSF)has long been regarded as a marker of coronary microvascular dysfunction(CMD).This study aims to evaluate the diagnostic value of CSF for CMD in patients with angina and nonobstructive coronary arteries(ANOCA).Methods:The study data were derived from the ANOCA-CMD prospective cohort study.All enrolled patients underwent coronary angiography and concurrent coronary physiological assessments in the left anterior descending artery using pressure-wire and thermodilution techniques to obtain coronary flow reserve(CFR)and the index of microcirculatory resistance(IMR).Based on the results,CMD was classified into four subtypes:CMD with elevated IMR(IMR≥25),CMD with reduced CFR(CFR<2.5),CMD with either reduced CFR or elevated IMR(CFR<2.5 or IMR≥25),and CMD with both reduced CFR and elevated IMR(CFR<2.5 and IMR≥25).The corrected thrombolysis in myocardial infarction(TIMI)frame count(CTFC)in the left anterior descending artery was calculated from coronary angiography images,with CSF defined as CTFC>27.This study evaluated the correlation between CTFC,CFR,and IMR,and investigated the diagnostic value of CSF for CMD in ANOCA patients.Results:A total of 103 ANOCA patients were enrolled in this study,with a mean age of(64.2±10.6)years,and 53.4％were female.Among them,57 patients(55.3％)were diagnosed with coronary slow flow.Patients with slow flow had higher IMR(P<0.001)and CFR(P=0.041).Similarly,the proportion of CMD with elevated IMR was higher in the slow flow group(P<0.001),while the proportion of CMD with reduced CFR was lower(P=0.044).There was no significant difference between the groups in the proportions of CMD with either reduced CFR or elevated IMR or CMD with both reduced CFR and elevated IMR(all P>0.05).CTFC was positively correlated with hyperemic mean transit time(r=0.424,P<0.001),IMR(r=0.430,P<0.001),and CFR(r=0.211,P=0.032).The area under the curve(AUC)of CTFC for diagnosing CMD with elevated IMR was 0.721(95％CI:0.623-0.819)with an accuracy of 67％(57％,76％),for diagnosing CMD with reduced CFR was 0.610(95％CI:0.499-0.720)with an accuracy of 60％(50％,70％),for diagnosing CMD with either reduced CFR or elevated IMR was 0.549(95％CI:0.425-0.673)with an accuracy of 47％(37％,57％),and for diagnosing CMD with both reduced CFR and elevated IMR was 0.582(95％CI:0.471-0.693)with an accuracy of 47％(37％,57％).Thus,CSF demonstrated limited diagnostic values across all subtypes of CMD.Conclusions:In ANOCA patients,CSF cannot serve as an effective diagnostic marker for CMD.Therefore,in clinical practice,the slow flow phenomenon should not be directly equated with the presence of coronary microvascular dysfunction in ANOCA patients.

Hepatocellular carcinoma(HCC)is the third leading cause of cancer-related deaths,and al-though considerable progress has been made in the clinical diagnosis and treatment of HCC,the prognosis for patients remains poor,with a 5-year survival rate of only about 18％.The development of HCC is driven by the occurrence of mutations in driver genes that can directly promote cell proliferation,survival and metastasis.With the development of molecular biology and genomics technologies,researchers have elucidated that driver mutations that give HCC cells a selective growth advantage,the ability of the cells to resist apoptosis,maintain proliferative signals,initiate invasion and metastasis,induce angiogenesis,enable metabolic remodeling and immune escape.Exploring the key drivers of HCC development to fur-ther elucidate the pathogenesis of HCC may provide new directions for the diagnosis and treatment of HCC as well as improving the prognosis.In this paper,we summarize the driver gene mutations in HCC from various biological pathways such as telomere maintenance,cell cycle,the Wnt signaling pathway,oxida-tive stress,and epigenetic modifications.We also summarize the application prospects of driver gene mu-tations in the diagnosis and treatment of HCC.We aim to provide a reference for the diagnosis,treatment and research of HCC.

Hepatocellular carcinoma(HCC)is the third leading cause of cancer-related deaths,and al-though considerable progress has been made in the clinical diagnosis and treatment of HCC,the prognosis for patients remains poor,with a 5-year survival rate of only about 18％.The development of HCC is driven by the occurrence of mutations in driver genes that can directly promote cell proliferation,survival and metastasis.With the development of molecular biology and genomics technologies,researchers have elucidated that driver mutations that give HCC cells a selective growth advantage,the ability of the cells to resist apoptosis,maintain proliferative signals,initiate invasion and metastasis,induce angiogenesis,enable metabolic remodeling and immune escape.Exploring the key drivers of HCC development to fur-ther elucidate the pathogenesis of HCC may provide new directions for the diagnosis and treatment of HCC as well as improving the prognosis.In this paper,we summarize the driver gene mutations in HCC from various biological pathways such as telomere maintenance,cell cycle,the Wnt signaling pathway,oxida-tive stress,and epigenetic modifications.We also summarize the application prospects of driver gene mu-tations in the diagnosis and treatment of HCC.We aim to provide a reference for the diagnosis,treatment and research of HCC.

Objectives:Coronary slow flow(CSF)has long been regarded as a marker of coronary microvascular dysfunction(CMD).This study aims to evaluate the diagnostic value of CSF for CMD in patients with angina and nonobstructive coronary arteries(ANOCA).Methods:The study data were derived from the ANOCA-CMD prospective cohort study.All enrolled patients underwent coronary angiography and concurrent coronary physiological assessments in the left anterior descending artery using pressure-wire and thermodilution techniques to obtain coronary flow reserve(CFR)and the index of microcirculatory resistance(IMR).Based on the results,CMD was classified into four subtypes:CMD with elevated IMR(IMR≥25),CMD with reduced CFR(CFR<2.5),CMD with either reduced CFR or elevated IMR(CFR<2.5 or IMR≥25),and CMD with both reduced CFR and elevated IMR(CFR<2.5 and IMR≥25).The corrected thrombolysis in myocardial infarction(TIMI)frame count(CTFC)in the left anterior descending artery was calculated from coronary angiography images,with CSF defined as CTFC>27.This study evaluated the correlation between CTFC,CFR,and IMR,and investigated the diagnostic value of CSF for CMD in ANOCA patients.Results:A total of 103 ANOCA patients were enrolled in this study,with a mean age of(64.2±10.6)years,and 53.4％were female.Among them,57 patients(55.3％)were diagnosed with coronary slow flow.Patients with slow flow had higher IMR(P<0.001)and CFR(P=0.041).Similarly,the proportion of CMD with elevated IMR was higher in the slow flow group(P<0.001),while the proportion of CMD with reduced CFR was lower(P=0.044).There was no significant difference between the groups in the proportions of CMD with either reduced CFR or elevated IMR or CMD with both reduced CFR and elevated IMR(all P>0.05).CTFC was positively correlated with hyperemic mean transit time(r=0.424,P<0.001),IMR(r=0.430,P<0.001),and CFR(r=0.211,P=0.032).The area under the curve(AUC)of CTFC for diagnosing CMD with elevated IMR was 0.721(95％CI:0.623-0.819)with an accuracy of 67％(57％,76％),for diagnosing CMD with reduced CFR was 0.610(95％CI:0.499-0.720)with an accuracy of 60％(50％,70％),for diagnosing CMD with either reduced CFR or elevated IMR was 0.549(95％CI:0.425-0.673)with an accuracy of 47％(37％,57％),and for diagnosing CMD with both reduced CFR and elevated IMR was 0.582(95％CI:0.471-0.693)with an accuracy of 47％(37％,57％).Thus,CSF demonstrated limited diagnostic values across all subtypes of CMD.Conclusions:In ANOCA patients,CSF cannot serve as an effective diagnostic marker for CMD.Therefore,in clinical practice,the slow flow phenomenon should not be directly equated with the presence of coronary microvascular dysfunction in ANOCA patients.

Objective:To investigate the impact of peak pressure upon different bone densities during autonomous puncture by orthopedic robot on puncture path deviation and bone cement leakage.Methods:A spinal surgery robot system was designed for autonomous vertebral puncture and bone cement injection, and six porcine spine specimens were used for single-segment or double-segment simulated percutaneous vertebral augmentation surgery. The accuracy of puncture path (Gertzbein-Robbins grading), bone cement leakage classification, and peak bone drill pressure were measured to assess the accuracy of autonomous vertebral puncture and bone cement leakage in vertebral cortical and cancellous bone of different densities.Results:A total of 64 porcine vertebrae were simulated for puncture, among which 53 vertebrae were classified as Grade A, 8 as Grade B, and 3 as Grade C according to the Gertzbein-Robbins grading. The cortical bone pressure of Grade A vertebrae was 6.663±0.319 N which was lower than that of Grade B (8.348±0.418 N) and Grade C (11.500±0.600 N), with significant differences ( F=341.000, P<0.001). The cancellous bone pressure of Grade A, B, and C vertebrae were 3.660±0.317, 3.594±0.608, and 4.117±0.257 N, respectively, with no significant difference ( F=2.496, P=0.091). There were 40 cases of no leakage, 20 cases of Type I leakage (leakage into the surrounding vertebrae), and 3 cases of Type II leakage (leakage into the vertebral canal), with an overall leakage rate of 36% (23/64). The peak cortical bone pressure for no leakage, Type I, and Type II leakage was 6.638±0.301, 6.792±0.404, and 6.753±0.473 N, respectively, and the peak cancellous bone pressure was 3.634±0.279, 3.783±0.423, and 3.920±0.255 N, respectively, with no significant difference ( F=1.521, P=0.227; F=2.106, P=0.131). Conclusion:During the autonomous puncture process of the novel orthopedic robot, the accuracy of autonomous puncture path decreased when the puncture pressure through the cortical bone was high, and the probability of invading the pedicle increased. The puncture pressure of cortical and cancellous bone had no significant effect on the occurrence rate of bone cement leakage.

Dihydroorotate dehydrogenase (DHODH) is a flavin-dependent metabolic enzyme that oxidizes dihydroorotate acid to orotic acid in the de novo synthesis pathway of pyrimidine metabolism. DHODH is located in mitochondria, closely related to cellular oxidative phosphorylation, and an important suppressor of the ferroptosis pathway. This study investigates the influence of DHODH on the progression of malignant tumors, including its important role in the de novo synthesis of pyrimidine, oxidative phosphorylation, and ferroptosis. The objective is to present evidence that DHODH is a potential target for the clinical treatment of tumors.

Objective:To investigate the relationship between preoperative plasma fibrin degradation products (FDP) level and clinicopathological features of patients with completely resected non-small cell lung cancer (NSCLC).Methods:A retrospective case series study was performed. The clinical data of 521 patients who were pathologically diagnosed with NSCLC in Beijing Friendship Hospital Affiliated to Capital Medical University from January 2016 to December 2017 were retrospectively analyzed. Among 521 cases, 406 cases were postoperatively pathologically confirmed as non-lymph node and non-distant metastasis (non-metastasis group) and 115 cases were postoperatively pathologically confirmed as lymph node or distant metastasis (metastasis group). The preoperative FDP level and clinicopathological characteristics as well as the clinicopathological characteristics of NSCLC patients with different FDP levels were compared between the two groups. The correlation between preoperative FDP level and TNM staging was analyzed by using Spearman correlation analysis.Results:Among 521 NSCLC patients, 266 cases were female, 255 cases were male; the age [ M( Q1, Q3)] was 59 years (54 years, 65 years); 441 cases were adenocarcinoma and 70 cases were squamous cell carcinoma. The preoperative median FDP level was 2.78 mg/L (2.35 mg/L, 3.13 mg/L) and 2.99 mg/L (2.56 mg/L, 4.16 mg/L), respectively of NSCLC patients in non-metastasis group and metastasis group, and the difference was statistically significant ( Z = 6.13, P < 0.001). The preoperative FDP level was 2.56 mg/L (2.35 mg/L, 3.20 mg/L) and 2.99 mg/L (2.56 mg/L, 3.20 mg/L), respectively in the early-stage NSCLC (stage Ⅰ-Ⅱ) and advanced NSCLC (stage Ⅲ-Ⅳ) patients, and the difference was statistically significant ( Z = 8.42, P < 0.001). Spearman correlation analysis showed that preoperative FDP level was positively correlated with tumor diameter ( r = 0.287, P < 0.001). There was a positive correlation between preoperative FDP level and the number of metastatic lymph nodes in 115 patients with lymph node metastasis ( r = 0.679, P < 0.001). According to the preoperative median FDP (2.78 mg/L), all patients were divided into FDP ≤2.78 mg/L group and FDP >2.78 mg/L, and there were statistically significant differences in age, metastasis, tumor staging, tumor diameter, the metastatic number of lymph node and histological types of NSCLC patients in both groups (all P < 0.05). Conclusions:The increase of preoperative plasma FDP level may be related to the tumor metastasis and clinical stage of NSCLC patients