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.

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.

Objective:To design two kinds of intensity modulated radiotherapy (IMRT) plans with different radiation field distributions,and to compare the dose differences of that at the dose of target region and organs at risk (OAR) for middle and lower esophageal cancer,so as to provide a reference for the design of IMRT plan. Methods:The data of 17 patients with middle and lower esophageal cancer who received IMRT at Shangluo Central Hospital from November 2022 to May 2023 were retrospectively analyzed. IMRT plans with different radiation fields for Plan 1 and Plan 2 were designed for each patient. The angles of radiation field for Plan 1 were 0°,80°,120°,160° and 200°,and those for Plan 2 were 30°,130°,180°,230° and 330°,respectively. The prescribed dose to the planning target volume (PTV) was 60 Gy/30 F. The differences in dosimetric parameters between the two plans were compared. Results:There were no statistically significant differences in the dose parameters of 2％,98％,50％ target dose (D2％,D98％,D50％),homogeneity index (HI),conformity index (CI) and monitor unit between the two groups (P>0.05). There were no significant differences in V5 of dual lungs,the mean dose (Dmean) of heart,and the maximum dose (Dmax) of spinal-cord between two groups (P>0.05). The volume percentage (V10,V20,V30) of dual lungs received radiation doses of 10,20 and 30 Gy,and the mean dose (Vmean) of lung in the Plan1 group reduced respectively 7.44％,21.16％,10.09％ and 5.31％ than those in the Plan2 group,and the differences of them were statistically significant (t=-5.845,-7.729,-2.247,-3.960,P<0.05). Heart V10 and V20 in the Plan1 group decreased respectively by 7.23％ and 5.78％,with statistical significance (t=-4.376,-3.523,P<0.01),while V30 and V40 of Plan 1 increased respectively by 2.7％ and 4.92％,without statistical significance (P>0.05). There was no significant difference in heart Dmean between the Plan1 group and the Plan2 group (P>0.05). Conclusion:Both two methods of distribution field can meet the clinical requirements,and Plan1 has more advantages in protecting organs at risk under the premise of meeting the requirements of target region.

Objective:To design two kinds of intensity modulated radiotherapy (IMRT) plans with different radiation field distributions,and to compare the dose differences of that at the dose of target region and organs at risk (OAR) for middle and lower esophageal cancer,so as to provide a reference for the design of IMRT plan. Methods:The data of 17 patients with middle and lower esophageal cancer who received IMRT at Shangluo Central Hospital from November 2022 to May 2023 were retrospectively analyzed. IMRT plans with different radiation fields for Plan 1 and Plan 2 were designed for each patient. The angles of radiation field for Plan 1 were 0°,80°,120°,160° and 200°,and those for Plan 2 were 30°,130°,180°,230° and 330°,respectively. The prescribed dose to the planning target volume (PTV) was 60 Gy/30 F. The differences in dosimetric parameters between the two plans were compared. Results:There were no statistically significant differences in the dose parameters of 2％,98％,50％ target dose (D2％,D98％,D50％),homogeneity index (HI),conformity index (CI) and monitor unit between the two groups (P>0.05). There were no significant differences in V5 of dual lungs,the mean dose (Dmean) of heart,and the maximum dose (Dmax) of spinal-cord between two groups (P>0.05). The volume percentage (V10,V20,V30) of dual lungs received radiation doses of 10,20 and 30 Gy,and the mean dose (Vmean) of lung in the Plan1 group reduced respectively 7.44％,21.16％,10.09％ and 5.31％ than those in the Plan2 group,and the differences of them were statistically significant (t=-5.845,-7.729,-2.247,-3.960,P<0.05). Heart V10 and V20 in the Plan1 group decreased respectively by 7.23％ and 5.78％,with statistical significance (t=-4.376,-3.523,P<0.01),while V30 and V40 of Plan 1 increased respectively by 2.7％ and 4.92％,without statistical significance (P>0.05). There was no significant difference in heart Dmean between the Plan1 group and the Plan2 group (P>0.05). Conclusion:Both two methods of distribution field can meet the clinical requirements,and Plan1 has more advantages in protecting organs at risk under the premise of meeting the requirements of target region.

Tumors continue to be a major challenge in human survival that we have yet to overcome. Despite the variety of treatment options available, we have not yet found an effective method. As more and more research is conducted, attention has been turned to a new field for tumor treatment—the tumor microenvironment (TME). This is a dynamic and complex environment consisting of various matrix cells surrounding cancer cells, including surrounding immune cells, blood vessels, extracellular matrix, fibroblasts, bone marrow-derived inflammatory cells, signaling molecules, and some specific cell types. Firstly, endothelial cells play a key role in tumor development and the immune system’s protection of tumor cells. Secondly, immune cells, such as macrophages, Treg cells, Th17 cells, are widely involved in various immune responses and activities in the human body, such as inflammation responses promoting survival carefully orchestrated by the tumor. Even though many studies have extensively researched the TME and found many research schemes, so far, no key effective method has been found to treat tumors by affecting the TME. The TME is a key interaction area between the host immune system and the tumor. Cells within the TME influence each other and interact with cancer cells to affect cancer cell invasion, tumor growth, and metastasis. This is a new direction for cancer treatment. In the complex environment of the TME, post-translational modifications (PTMs) of proteins have been proven to play an important role in the TME. PTMs are dynamic, strictly regulated changes to proteins that control their function by regulating their structure, spatial location, and interaction. Among PTMs, a reversible post-translational modification called SUMOylation is a common regulatory mechanism in cellular processes. It is a post-translational modification that targets lysine residues with a small ubiquitin-like modifier (SUMO) in a reversible post-translational modification manner. SUMOylation is widely involved in carcinogenesis, DNA damage response, cancer cell proliferation, metastasis, and apoptosis, playing a pivotal role in the TME, such as DNA damage repair, tumor metastasis, and also participates in immune cell differentiation, activation, and inhibition of immune cells. On the other hand, SUMO or sentrin-specific protease (SENP) inhibitors can interfere with the SUMOylation process, thereby affecting many biological processes, including immune response, carcinogenesis, cell cycle progression, and cell apoptosis, etc. In summary, this review aims to introduce the dynamic modification of protein SUMOylation on various immune cells and the application of various inhibitors, thereby exploring its role in the TME. This is a challenging but hopeful field, and we look forward to future research that can bring more breakthroughs. In conclusion, the TME is a complex and dynamic environment that plays a crucial role in the development and progression of tumors. Understanding the intricate interactions within the TME and the role of PTMs, particularly SUMOylation, could provide valuable insights into the mechanisms of tumor development and potentially lead to the development of novel therapeutic strategies. The study of SUMOylation and its effects on various immune cells in the TME is an exciting and promising area of research that could significantly advance our understanding of tumor biology and potentially lead to the development of more effective treatments for cancer. This is a challenging but hopeful field, and we look forward to future research that can bring more breakthroughs.

Tumor metastasis is the main cause of death in clinical patients. The proposal of the pre-metastatic microenvironment hypothesis offers a new research direction for tumor metastasis. Targeting and inhibiting the activation of the stimulator of interferon genes(STING) signals by tumor cell-derived microparticles may help reduce tumor metastasis. This study constructed a pre-metastatic microenvironment and pulmonary metastasis model using recombinant adeno-associated virus vector-mediated short hairpin RNA interference of STING(rAAV STING shRNA) to investigate the effects of STING interference on the pre-metastatic microenvironment and the impact of total Epimedium flavonoids(EFs) as an intervention. Drug-containing microparticles were prepared by incubating mouse Lewis lung cancer(LLC) cells with the total EFs(EFs-LLC-MPs), and EFs-LLC-MPs were characterized by measuring the average particle size, polydispersity index, zeta potential, and release profile. Western blot was used to examine changes in pre-metastatic microenvironment markers in mouse alveolar epithelial cells(MLE-12) after treatment with microparticles or total EFs. Drug loading capacity and the uptake of microparticles by MLE-12 and mouse alveolar macrophages(MH-S) cells were determined using HPLC and flow cytometry. The uptake experiments showed that after nasal administration of rAAV STING shRNA, STING expression was significantly inhibited, and the markers of the pre-metastatic microenvironment were markedly reduced. Micro-CT results indicated a reduction in lung metastases and nodules, and the anti-metastatic effect of total EFs was affected. The results showed that the microparticles were membrane vesicles with a particle size of(373.17±3.18)nm, a Zeta potential of(-35.40±1.08)mV, a protein concentration of 562.62 μg·mL~(-1), and a drug loading of 0.060 9 μg per microgram of protein. These microparticles were effectively taken up by MLE-12 and MH-S cells. Treatment of MLE-12 and MH-S cells with EFs-LLC-MPs reduced the expression of pre-metastatic microenvironment markers such as fibronectin and lysyl oxidase(LOX). Based on these findings, it was confirmed that STING was involved in the regulation of the formation of the pre-metastatic microenvironment in the lungs. Furthermore, total EFs microparticles were successfully prepared, showing potential to intervene in the inflammatory pre-metastatic microenvironment, which could be promising for controlling tumor metastasis.
Animals ; Flavonoids/chemistry* ; Mice ; Tumor Microenvironment/drug effects* ; Epimedium/chemistry* ; Lung Neoplasms/metabolism* ; Humans ; Mice, Inbred C57BL ; Neoplasm Metastasis ; Cell Line, Tumor ; Particle Size ; Drugs, Chinese Herbal/pharmacology* ; Membrane Proteins/metabolism*

Objective:To study the dosimetry effects of differently selected values of control point(CP)in Monaco radiotherapy planning system on dynamic intensity modulated radiation therapy(dIMRT)for esophageal cancer of middle and lower segment.Methods:Thirteen patients with esophageal cancer at middle and lower segment who received dIMRT in Shangluo Central Hospital from January to June 2023 were selected.In the Monaco radiotherapy planning system,nine groups of dIMRT plans were designed for each patient according to the 9 kinds of CP limit values(10,20,30,40,50,60,70,80 and 90).There were not changes in other optimized parameters except CP parameter.The differences of the dosimetry between target region and organs at risk(OAR)included lung,heart and spinal cord were analyzed.Results:With the increase of the CP limit value,the maximum dose of the target region which was radiation dose(D2%)of 2%volume of target region,the mean dose,which was radiation dose(D50%)of 50%volume of target region,and the homogeneity index(HI)appeared a trend of gradual stability after reduction,and the radiation dose(D98%)of 98%volume of target region which was the minimum dose of target region and the conformance index(CI)appeared a trend of gradual stability after increase.There was not significant in each dose indicator of OAR(P>0.05).The variation ranges of lung at 5,10,20,30 Gy dose(V5,V10,V20 and V30)were respectively 1.13%,0.75%,0.29%and 0.19%,and the maximum deviation of mean dose(Vmean)of lung was 18.7 cGy.The variation ranges of V10,V20,V30 and V40 in the heart were respectively 2.2%,1.23%,1.39%and 1.12%,and the maximum deviation of Vmean in the heart was 63.85 cGy,and the maximum deviation of Dmax in the spinal-cord was 70.78 cGy.There were statistically significant differences in the actual CP number(CPs),execution time(DT)of plan,and ratio value of machine unit(MU)of the complexity of plan to CPs(MU/CPs)among the plans of 9 groups(F=2.857,25.145,135.467,P<0.05),respectively.Conclusion:In the dIMRT plan of esophageal cancer of middle and lower segment,the maximum CP value is set at between 40-50,which can reduce the optimization time of the plan,the number of subfields and the treatment time of patients under the premise of meeting the dose of the target region and the OAR.

Objective: Individuals with dementia are at a substantially elevated risk for mortality; however, few studies have examined multimorbidity patterns and determined the inter-relationship between these comorbidities in predicting mortality risk. Methods: This is a prospective cohort study. Data from 6,556 patients who were diagnosed with dementia between 1997 and 2012 using the Taiwan National Health Insurance Research Database were analyzed. Latent class analysis was performed using 16 common chronic conditions to identify mortality risk among potentially different latent classes. Logistic regression was performed to determine the adjusted association of the determined latent classes with the 5-year mortality rate. Results: With adjustment for age, a three-class model was identified, with 42.7% of participants classified as “low comorbidity class (cluster 1)”, 44.2% as “cardiometabolic multimorbidity class (cluster 2)”, and 13.1% as “FRINGED class (cluster 3, characterized by FRacture, Infection, NasoGastric feeding, and bleEDing over upper gastrointestinal tract).” The incidence of 5-year mortality was 17.6% in cluster 1, 26.7% in cluster 2, and 59.6% in cluster 3. Compared with cluster 1, the odds ratio for mortality was 9.828 (95% confidence interval [CI]=6.708–14.401; p<0.001) in cluster 2 and 1.582 (95% CI=1.281–1.953; p<0.001) in cluster 3. Conclusion Among patients with dementia, the risk for 5-year mortality was highest in the subpopulation characterized by fracture, urinary and pulmonary infection, upper gastrointestinal bleeding, and nasogastric intubation, rather than cancer or cardiometabolic comorbidities. These findings may improve decision-making and advance care planning for patients with dementia.