Triple-negative breast cancer (TNBC) remains a refractory subtype of breast cancer due to its resistance to various therapeutic strategies. In this study, we introduce a "brake-release and accelerator-pressing" approach to engineer a microneedle patch embedded with copper-doped Prussian blue nanoparticles (Cu-PB) and the ferroptosis inducer sorafenib (SRF) for raised chemodynamic (CDT)/photothermal (PTT) combination therapy against TNBC. Upon transdermal insertion, the dissolving microneedles swiftly disintegrate and facilitate the release of SRF. Under gentle external light exposure, copper ions (Cu²⁺) and iron ions (Fe³⁺) were liberated from Cu-PB. The direct chelation of Cu²⁺ and the indirect suppression by SRF, collectively attenuate glutathione peroxidase 4 (GPX4) enzymatic function, destabilizing the cellular redox equilibrium (referred to as the "brake-release" strategy). The release of Cu²⁺ and Fe³⁺ ions instigates a Fenton/Fenton-like reaction within tumor cells, further yielding hydroxyl radicals and elevating reactive oxygen species (ROS) concentrations (referred to as the "accelerator-pressing" strategy). This overwhelming ROS accumulation, coupled with the impaired clearance of resultant lipid peroxides (LPO), ultimately triggers a robust ferroptosis cell death response. In summary, this study presents an innovative combinatorial therapeutic strategy based on dual-ferroptosis induction for TNBC, implying a promising therapeutic platform for developing ferroptosis-centered treatments for this aggressive breast cancer subtype.

Objective To investigate the mechanism of Sanguisorbae Radix(SR)in the treatment of ulcerative colitis(UC).Methods Using the GSE92415 dataset from the Gene Expression Omnibus database,we analyzed differentially expressed genes and carried out weighted gene correlation network analysis and FerrDb analysis.Core genes were identified through protein-protein interaction(PPI)network and correlation analysis.UC mouse model induced by dextran sulfate sodium(DSS)was constructed and treated with SR via intragastric administration for 9 days.Disease activity index(DAI)and colon length were recorded.Pathological changes in colon tissue were observed using the HE staining.Levels of inflammatory cytokines such as tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6)were detected by enzyme linked immunosorbent assay(ELISA).Lipid peroxidantion factors such as malondialdehyde(MDA)and glutathione(GSH)were detected using biochemical test kits.Protein expression levels of zonula occludens protein-1(ZO-1)tight junction protein,peroxisome proliferator-activated receptor gamma(PPARG),solute carrier family 7 member 11(SCL7A11),and glutathione peroxidase 4(GPX4)were examined by Western blot or immunofluorescence labeling.Results Nine differentially expressed genes associated with ferroptosis were screened and PPARG was identified as a key gene.Correlation analysis showed a strong correlation between PPARG and ferroptosis.Subsequently,the potential mechanism of SR in improving UC in mice was discussed according to the bioinformatics screening results.The experimental results demonstrated that SR significantly reduced the DAI,prevented colon shortening and improved intestinal mucosal barrier function in the colon.SR decreased TNF-α and IL-6 levels,MDA content and GSH levels in colon tissues.SR also enhanced the expression of PPARG,SLC7A11 and GPX4,which reversed the effect of DSS in mice with colitis.Conclusions Ferroptosis is closely related to UC.SR can inhibit ferroptosis by regulating PPARG and SCL7A11/GPX4 expression,thereby improving colon epithelial injury and dysfunction in UC mice.This provides ideas and directions for UC treatment strategies.

Objective:To analyze the genetic variations and clinical phenotypic characteristics of epilepsy associated with CSNK2B gene mutations. Methods:A case series summary study.Clinical data of 15 epileptic children with CSNK2B gene mutations diagnosed and treated at the Third Affiliated Hospital of Zhengzhou University and the Peking University First Hospital from February 2016 to October 2023 were retrospectively analyzed.The clinical manifestations, genotypes, and electroencephalography (EEG) results were summarized. Results:Among the 15 children (8 boys and 7 girls), 14 cases had de novo mutations in the CSNK2B gene, and 1 case had hereditary variations.There were 5 missense variants, 4 splice-site variants, 3 frameshift variants, and 3 nonsense variants.Ten mutation sites had not been previously reported (c.326G>A/p.Cys109Tyr, c.485A>G/p.His162Arg, c.368-1G>A, c.464A>C/p.Asp155Ala, c.301T>G/p.Tyr101Asp, c.342T>A/p.Cys114*, c.198del/p.Asn67Thrfs*5, c.292-10T>G, c.573-574del/p.Lys191Asnfs*54, and c. 11C>G/p.Ser4*).The age of onset of seizures ranged from 14 days to 6 years, with 13 cases starting within 2 years old.The types of seizures included focal seizures in 9 cases, generalized tonic-clonic seizure (GTCS) in 5 cases, myoclonic seizures in 1 case, atonic seizures in 1 case, atypical absence seizures in 1 case, and epileptic seizures in 1 case.Three cases had multiple seizures, and 4 cases had cluster seizures.The EEG showed slow background activity in 1 case.Epileptiform discharges were observed in 13 cases during the interictal phase, including generalized discharges in 6 cases, multifocal discharges in 3 cases, and focal discharges in 5 cases.Two cases had normal EEG findings.Brain magnetic resonance imaging results were normal in 10 cases.The age of the last follow-up ranged from 1 year and 1 month to 13 years and 10 months.Seizures were controlled in 12 cases treated with 1 or 2 antiepileptic drugs, while seizures persisted in 2 cases treated with multiple antiepileptic drugs, and 1 case suffered no seizures for 1 year and 3 months, without antiepileptic drug treatment.Oxcarbazepine was effective in 5 cases (5/7), Valproate sodium was effective in 6 cases (6/8), and Levetiracetam was effective in 3 cases (3/9). Conclusions:CSNK2B gene mutations are mainly de novo mutations, and epilepsy triggered by them typically starts within 2 years of age.GTCS and focal seizures are the most common types.The seizures of most children are easily controlled with the effective treatment of Oxcarbazepine, Valproate sodium, and Levetiracetam.

Objective To investigate the significance of intratumoral and peritumoral radiomics models in predicting occult lymph node metastasis in stage T1 non-small cell lung cancer(NSCLC)and to compare the predictive accuracy in different peritumoral radiomics models.Methods The CT images and clinical data of 211 patients without lymph node metastasis on preoperative CT examination and pathologically confirmed NSCLC after surgery were collected.The radiomics features were derived from the three-dimensional volume of interest(VOI)of the intratumoral and peritumoral at 3-,5-,and 10-mm following lesion segmentation on CT images of each patient.The feature data of all nidus were radomly divide into training set and validation set with a ratio of 7︰3.The Pearson or Spearman correlation test was performed to remove redundancy.Dimensionality was reduced by the least absolute shrinkage and selection operator(LASSO)regression analysis.The linear combination of selected features and corresponding coefficients were used to construct the Radiomics score(Radscore).The clinical model and comprehensive model were constructed by logistic regression analysis.The conprehensive model was visualized with the nomogram,and its performance was evaluated.Results Among the peritumoral radiomics models,the peritumoral 5-mm model showed the best predictive efficacy[validation set,area under the curve(AUC)0.771].The comprehensive model containing Radscore,CT image features and CEA exhibited the best performance(validation set,AUC 0.850).Conclusion Intratumoral and peritumoral radiomics models perform efficiently in predicting occult lymph node metastasis in stage T1 NSCLC,and nomogram can effectively and noninvasively predict occult lymph node metastasis in NSCLC.

BACKGROUND:Cerebral ischemic stroke is one of the main fatal and disabling diseases in the clinic,but only a few patients benefit from vascular recanalization in time,so it is urgent to explore new and effective therapy.As one of the critical pathological changes of ischemic stroke,the glial scar formed mainly by astrocytes is one major cause that hinders axonal regeneration and neurological recovery at the late stage of stroke. OBJECTIVE:To elucidate the pathological process and crucial signal regulatory mechanism of astrocytes in the formation of glial scar after ischemic stroke,as well as the potential therapeutic targets,to provide a theoretical reference for intervening astrocytic scar formation against ischemic stroke effectively,and novel strategies for promoting post-stroke rehabilitation. METHODS:The relevant articles published in CNKI,PubMed and Web of Science databases from 2010 to 2022 were retrieved.The search terms were"Ischemic stroke,Brain ischemi*,Cerebral ischemi*,Astrocyt*,Astroglia*,Glial scar,Gliosis,Astrogliosis"in Chinese and English.Finally,78 articles were included after screening and summarized. RESULTS AND CONCLUSION:(1)Astrocytes play an important role in the maintenance of central nervous system homeostasis.After ischemic stroke,astrocytes change from a resting state to an active state.According to the different severities of cerebral ischemic injury,astrocyte activation changes dynamically from swelling and proliferation to glial scar formation.(2)Mature astrocytes are stimulated to restart the cell cycle,then proliferate and migrate to lesions,which is the main source of the glial scar.Neural stem cells in the subventricular zone,neuron-glial antigen 2 precursor cells and ependymal precursor cells in the brain parenchyma can also differentiate into astrocytes.Endothelin-1,aquaporin 4,ciliary neurotrophic factor and connexins are involved in this process.In addition,chondroitin sulfate proteoglycan,as the main component of the extracellular matrix,forms the dense glial scar barrier with proliferated astrocytes,which hinders the polarization and extension of axons.(3)Activation or inhibition of crucial signal molecules involved in astrocyte activation,proliferation,migration and pro-inflammation functions regulate the glial scar formation.Transforming growth factor beta 1/Smad and Janus kinase/signal transducer and activator of transcription 3 are classical pathways related to astrogliosis,while receptor-interacting protein 1 kinase and glycogen synthase kinase 3β are significant molecules regulating the inflammatory response.However,there are relatively few studies on Smad ubiquitination regulatory factor 2 and Interleukin-17 and their downstream signaling pathways in glial scar formation,which are worthy of further exploration.(4)Drugs targeting astrogliosis-related signaling pathways,cell proliferation regulatory proteins and inflammatory factors effectively inhibit the formation of glial scar after cerebral ischemic stroke.Among them,the role of commonly used clinical drugs such as melatonin and valproic acid in regulating glial scar formation has been verified,which makes it possible to use drugs that inhibit glial scar formation to promote the recovery of neurological function in patients with stroke.(5)Considering the protective effects of glial scar in the acute phase,how to choose the appropriate intervention chance of drugs to maintain the protective effect of the glial scar while promoting nerve regeneration and repair in the local microenvironment is the direction of future efforts.

Objective To analyze the correlation between T lymphocyte subsets,neutrophil/lymphocyte ratio(NLR),procalcitonin(PCT)and the severity of sepsis.Methods A prospective research method was adopted.A total of 78 sepsis patients admitted to the department of intensive care medicine of Zibo Central Hospital from January 2021 to December 2022 were selected as the research subjects.Patients were divided into a septic shock group(37 cases)and a sepsis group(41 cases)based on the severity of their condition,with 40 healthy examinees from our hospital as the healthy control group.Using flow cytometry to measure the levels of CD4+ T lymphocytes count(CD4+ T)and CD8+ T lymphocytes count(CD8+ T)in three groups of subjects,calculate the CD4+ T/CD8+ T lymphocyte ratio(CD4+ T/CD8+ T)and NLR.The levels of PCT and interleukin-6(IL-6)were measured using electrochemiluminescence immunoassay,and the levels of C-reactive protein(CRP)were measured using immunoassay turbidimetry.Acute physiology and chronic health evaluationⅡ(APACHEⅡ)score within 24 hours was recorded for the two groups of patients,and the differences in lymphocyte subsets and various inflammatory indicators were compared between the groups.Pearson correlation analysis was used to analyze the correlation between various indicators and APACHEⅡscore.Results The CD4+ T,CD8+ T,and CD4+T/CD8+T levels in the septic shock and sepsis groups were significantly lower than those in the healthy control group[CD4+ T(×106/L):168.27±76.68,266.08±131.57 vs.789.60±173.78,CD8+ T(×106/L):156.50±68.37,205.81±75.60 vs.636.42±90.59,CD4+ T/CD8+ T:1.09±0.39,1.27±0.34 vs.1.44±0.38,all P<0.01],NLR,PCT,CRP and IL-6 were significantly higher than those in the healthy control group[NLR:25.85±11.62,15.94±8.72 vs.2.68±1.31,PCT(μg/L):21.82±15.28,9.09±4.96 vs.0.13±0.10,CRP(mg/L):158.65±62.33,106.97±51.49 vs.6.48±2.08,IL-6(ng/L):1 344.64±899.21,245.31±176.99 vs.3.25±1.83,all P<0.01].The APACHEⅡscore in the septic shock group was significantly higher than that in the sepsis group(32.00±1.00 vs.22.01±1.09,P<0.05).Correlation analysis showed that the levels of CD4+ T,CD8+ T,CD4+ T/CD8+ T in two groups of sepsis patients were negatively correlated with the APACHEⅡscore(r values were-0.571,-0.506,and-0.555,respectively,all P<0.01),while the levels of NLR,PCT,CRP,and IL-6 were positively correlated with the APACHEⅡscore(r values were 0.711,0.709,0.777,and 0.707,respectively,all P<0.01).Conclusions As the levels of T lymphocyte subsets decrease,inflammatory indicators like NLR and PCT rise,indicating a more severe sepsis condition.Therefore,T lymphocyte subsets and levels of various inflammatory indicators can serve as markers for evaluating the severity of sepsis.

Objective:To investigate the safety and efficacy of total pelvic exenteration (TPE) for treating late complications of radiation-induced pelvic injury.Methods:This was a descriptive case series study. The inclusion criteria were as follows: (1) confirmed radiation-induced pelvic injury after radiotherapy for pelvic malignancies; (2) late complications of radiation-induced pelvic injury, such as bleeding, perforation, fistula, and obstruction, involving multiple pelvic organs; (3) TPE recommended by a multidisciplinary team; (4) patient in good preoperative condition and considered fit enough to tolerate TPE; and (5) patient extremely willing to undergo the procedure and accept the associated risks. The exclusion criteria were as follows: (1) preoperative or intraoperative diagnosis of tumor recurrence or metastasis; (2) had only undergone diversion or bypass surgery after laparoscopic exploration; and (3) incomplete medical records. Clinical and follow-up data of patients who had undergone TPE for late complications of radiation-induced pelvic injury between March 2020 and September 2022 at the Sixth Affiliated Hospital of Sun Yat-sen University were analyzed. Perioperative recovery, postoperative complications, perioperative deaths, and quality of life 1 year postoperatively were recorded.Results:The study cohort comprised 14 women, nine of whom had recto-vagino-vesical fistulas, two vesicovaginal fistulas, one ileo-vesical fistula and rectal necrosis, one ileo-vesical and rectovaginal fistulas, and one rectal ulcer and bilateral ureteral stenosis. The mean duration of surgery was 592.1±167.6 minutes and the median blood loss 550 (100–6000) mL. Ten patients underwent intestinal reconstruction, and four the Hartmann procedure. Ten patients underwent urinary reconstruction using Bricker's procedure and 7 underwent pelvic floor reconstruction. The mean postoperative hospital stay was 23.6±14.9 days. Seven patients (7/14) had serious postoperative complications (Clavien-Dindo IIIa to IVb), including surgical site infections in eight, abdominopelvic abscesses in five, pulmonary infections in five, intestinal obstruction in four, and urinary leakage in two. Empty pelvis syndrome (EPS) was diagnosed in five patients, none of whom had undergone pelvic floor reconstruction. Five of the seven patients who had not undergone pelvic floor reconstruction developed EPS, compared with none of those who had undergone pelvic floor reconstruction. One patient with EPS underwent reoperation because of a pelvic abscess, pelvic hemorrhage, and intestinal obstruction. There were no perioperative deaths. During 18.9±10.1 months of follow-up, three patients died, two of renal failure, which was a preoperative comorbidity, and one of COVID-19. The remaining patients had gradual and significant relief of symptoms during follow-up. QLQ-C30 assessment of postoperative quality of life showed gradual improvement in all functional domains and general health at 1, 3, and 6 months postoperatively (all P<0.05). Conclusions:TPE is a feasible procedure for treating late complications of radiation-induced pelvic injury combined with complex pelvic fistulas. TPE is effective in alleviating symptoms and improving quality of life. However, the indications for this procedure should be strictly controlled and the surgery carried out only by experienced surgeons.

Objective:To investigate the safety and efficacy of total pelvic exenteration (TPE) for treating late complications of radiation-induced pelvic injury.Methods:This was a descriptive case series study. The inclusion criteria were as follows: (1) confirmed radiation-induced pelvic injury after radiotherapy for pelvic malignancies; (2) late complications of radiation-induced pelvic injury, such as bleeding, perforation, fistula, and obstruction, involving multiple pelvic organs; (3) TPE recommended by a multidisciplinary team; (4) patient in good preoperative condition and considered fit enough to tolerate TPE; and (5) patient extremely willing to undergo the procedure and accept the associated risks. The exclusion criteria were as follows: (1) preoperative or intraoperative diagnosis of tumor recurrence or metastasis; (2) had only undergone diversion or bypass surgery after laparoscopic exploration; and (3) incomplete medical records. Clinical and follow-up data of patients who had undergone TPE for late complications of radiation-induced pelvic injury between March 2020 and September 2022 at the Sixth Affiliated Hospital of Sun Yat-sen University were analyzed. Perioperative recovery, postoperative complications, perioperative deaths, and quality of life 1 year postoperatively were recorded.Results:The study cohort comprised 14 women, nine of whom had recto-vagino-vesical fistulas, two vesicovaginal fistulas, one ileo-vesical fistula and rectal necrosis, one ileo-vesical and rectovaginal fistulas, and one rectal ulcer and bilateral ureteral stenosis. The mean duration of surgery was 592.1±167.6 minutes and the median blood loss 550 (100–6000) mL. Ten patients underwent intestinal reconstruction, and four the Hartmann procedure. Ten patients underwent urinary reconstruction using Bricker's procedure and 7 underwent pelvic floor reconstruction. The mean postoperative hospital stay was 23.6±14.9 days. Seven patients (7/14) had serious postoperative complications (Clavien-Dindo IIIa to IVb), including surgical site infections in eight, abdominopelvic abscesses in five, pulmonary infections in five, intestinal obstruction in four, and urinary leakage in two. Empty pelvis syndrome (EPS) was diagnosed in five patients, none of whom had undergone pelvic floor reconstruction. Five of the seven patients who had not undergone pelvic floor reconstruction developed EPS, compared with none of those who had undergone pelvic floor reconstruction. One patient with EPS underwent reoperation because of a pelvic abscess, pelvic hemorrhage, and intestinal obstruction. There were no perioperative deaths. During 18.9±10.1 months of follow-up, three patients died, two of renal failure, which was a preoperative comorbidity, and one of COVID-19. The remaining patients had gradual and significant relief of symptoms during follow-up. QLQ-C30 assessment of postoperative quality of life showed gradual improvement in all functional domains and general health at 1, 3, and 6 months postoperatively (all P<0.05). Conclusions:TPE is a feasible procedure for treating late complications of radiation-induced pelvic injury combined with complex pelvic fistulas. TPE is effective in alleviating symptoms and improving quality of life. However, the indications for this procedure should be strictly controlled and the surgery carried out only by experienced surgeons.

OBJECTIVE To evaluate the cost-effectiveness of regorafenib in the treatment of hepatocellular carcinoma after failure of sorafenib from the perspective of Chinese health system. METHODS Based on a phase Ⅲ trial（RESORCE）， the partition survival model （PSM） and Markov model were constructed. The cycle was set as four weeks， the duration of the study lasted for lifetime， the annual discount rate was 5%. Drug cost data was obtained from yaozhi.com， other cost data were obtained from Anhui Provincial Medical Insurance Bureau and related literature， and utility values were obtained from literature. The incremental cost-effectiveness ratio （ICER） was used as the evaluation index， and the value of willingness to pay （WTP） was three times of China’s gross domestic product （GDP） per capita in 2022； one-way sensitivity analysis and probabilistic sensitivity analysis were used to verify the robustness of the basic analysis results. RESULTS The incremental cost of regorafenib group versus placebo group in PSM and Markov model was 112 116.95 yuan and 96 617.19 yuan， respectively. The incremental effectiveness was 0.31 QALYs and 0.32 QALYs， respectively. The ICERs were 360 751.01 yuan/QALY and 301 114.45 yuan/QALY， which were both greater than the value of WTP； regorafenib was not cost-effective. Results of one-way sensitivity analysis showed that the utility of progression-free survival and progressive disease， the unit cost of regorafenib had the greatest influence on the results， but ICER was always greater than the WTP within the floating range of each parameter. Under the WTP of 3 times China’s per capita GDP in 2022， the probabilities of regorafenib with cost-effectiveness were 0.8% （PSM） and 11.4% （Markov）. CONCLUSIONS Under the WTP of 3 times the per capita GDP of China， regorafenib is not cost-effective in the treatment of hepatocellular carcinoma after failure of sorafenib treatment， compared with placebo.

Objective:To investigate the clinical efficacy of redo rectal resection and coloanal anastomosis.Methods:The retrospective and descriptive study was conducted. The clinicopatholo-gical data of 49 patients who underwent redo rectal resection and coloanal anastomosis for the treatment of local recurrence of tumors and failure of colorectal or coloanal anastomosis after rectal resection in the Sixth Affiliated Hospital of Sun Yat-sen University from November 2012 to December 2021 were collected. There were 32 males and 17 females, aged 57(range,31-87)years. Redo rectal resection and coloanal anastomosis was performed according to the patient′s situations. Observa-tion indicators: (1) surgical situations; (2) postoperative situations; (3) follow-up. Measurement data with normal distribution were represented as Mean± SD, and measurement data with skewed distri-bution were represented as M( Q1, Q3) or M(range). Count data were described as absolute numbers or percentages. Results:(1) Surgical situations. All 49 patients underwent redo rectal resection and coloanal anastomosis successfully, with the interval between the initial surgery and the reopera-tion as 14.2(7.1,24.3)months. The operation time and volume of intraoperative bold loss of 49 patients in the redo rectal resection and coloanal anastomosis was 313(251,398)minutes and 125(50,400)mL, respectively. Of the 49 patients, there were 38 cases receiving laparoscopic surgery including 12 cases with transanoscopic laparoscopic assisted surgery, 11 cases receiving open surgery including 2 cases as conversion to open surgery, there were 20 cases undergoing Bacon surgery, 14 cases undergoing Dixon surgery, 12 cases undergoing Parks surgery, 2 cases undergoing intersphincter resection and 1 case undergoing Kraske surgery, there were 20 cases undergoing rectum dragging out excision and secondary colonic anastomosis, 13 cases undergoing dragging out excision single anastomosis, 12 cases undergoing rectum dragging out excision double anastomosis, 4 cases undergoing first-stage manual anastomosis, there were 21 cases with enterostomy before surgery, 16 cases with prophylactic enterostomy after surgery, 12 cases without prophylactic enterostomy after surgery. The duration of postoperative hospital stay of 49 patients was (14±7)days. (2) Postoperative situations. Fifteen of 49 patients underwent postoperative complications, including 8 cases with grade Ⅱ Clevien-Dindo complications and 7 cases with ≥grade Ⅲ Clevien-Dindo complications. None of 49 patient underwent postoperative transferring to intensive care unit and no patient died during hospitalization. Results of postoperative histopathological examination in 23 patients with tumor local recurrence showed negative incision margin of the surgical specimen. (3) Follow-up. All 49 patients underwent post-operative follow-up of 90 days. There were 42 cases undergoing redo rectal resection and coloanal anastomosis successfully and 7 cases failed. Of the 37 patients with enterostomy, 20 cases failed in closing fistula, and 17 cases succeed. There were 46 patients receiving follow-up with the median time as 16.1(7.5,34.6)months. The questionnaire response rate for low anterior resection syndrome (LARS) score was 48.3%(14/29). Of the patients who underwent redo coloanal anastomosis and closure of stoma successfully, there were 9 cases with mild-to-moderate LARS.Conclusion:Redo rectal resection and coloanal anastomosis is safe and feasible for patients undergoing local recurr-ence of tumors and failure of colorectal or coloanal anastomosis after rectal resection, which can successfully restore intestinal continuity in patients and avoid permanent enterostomy.