ObjectiveTo explore the effect of transcutaneous electrical acupoint stimulation （TEAS） on stress response in patients undergoing unilateral biportal endoscopy （UBE） and to identify optimal TEAS parameters. MethodsA total of 96 patients undergoing UBE were randomly grouped into total intravenous anesthesia （TIVA） group， acupuncture-assisted anesthesia with continuous waves （AACW） group， and acupuncture-assisted anesthesia with sparse-dense waves （AASDW） group， with 32 patients per group. All groups were given a standardized TIVA protocol. In the AACW group （100 Hz continuous wave stimulation） and the AASDW group （2/100 Hz sparse-dense wave stimulation）， TEAS intervention was applied to both bilateral Zusanli （ST36） and Sanyinjiao （SP6） 30 minutes before TIVA induction and continued until the end of the surgery. In the TIVA group， electrodes were only connected without electrical stimulation. The stress response indicators including cortisol （Cor） and adrenocorticotropic hormone （ACTH）， heart rate （HR）， mean arterial pressure （MAP）， and bispectral index （BIS） at before anesthesia induction （T0）， after tracheal intubation （T1）， during laminectomy （T2）， and 1 hour after surgery （T3） were compared across groups. The operation duration， anesthesia duration， extubation and recovery duration were recorded， as well as pain intensity including visual analogue scale （VAS）， and sedation level （by Ramsay sedation score） at 2， 6， 12 hours after surgery， and postoperative complications. ResultsThe AACW group and AASDW group had lower ACTH and COR levels at T1， T2 and T3， as well as lower HR and MAP levels at T1 and T2 than TIVA group， with AASDW group being lower than AACW group （P＜0.05）. At T3， the AASDW group had higher BIS than TIVA group and AACW group （P＜0.05）. No significant difference in operation duration was observed （P＞0.05）. The AACW group and AASDW group had shorter anesthesia， extubation and recovery duration than TIVA group， with AASDW group being the shortest （P＜0.05）. The VAS scores at 2 h， 6 h， and 12 h after surgery in the AACW and AASDW groups were lower than those in the TIVA group， with the AASDW group showing significantly lower scores than the AACW group （P＜0.05）. The Ramsay sedation scores in the AASDW group were lower than those in the AACW group at 2 h and 6 h after surgery （P＜0.05）. The total incidence of complications in the AASDW group was 6.25% （2/32）， significantly lower than 28.13% （9/32） in the TIVA group （P＜0.05）. ConclusionTEAS can effectively suppresses stress response in patients undergoing UBE， with the 2/100 Hz sparse-dense wave parameter being most effective， which can stabilize hemodynamics， accelerate recovery， improve postoperative sedation and analgesia quality， and reduces complications.

ObjectiveThis paper aims to observe the syndrome improvement and negative antigen conversion rate of Qingxuan Daozhi formula in the treatment of influenza in children （heat accumulation in the lung and stomach syndrome）. MethodsThrough a multi-center randomized controlled methodology design，confirmed influenza cases were collected from October 2022 to April 2023 in the pediatrics department of eight hospitals，such as Dongfang Hospital of Beijing University of Chinese Medicine. A total of 180 children with influenza and heat accumulation in the lung and stomach syndrome conforming to the standard were recruited through the clinic. The sick children meeting the inclusion criteria were randomly divided into groups by a block-randomized method. The children in the experimental group were treated with Qingxuan Daozhi formula for five days，and those in the control group were treated with Oseltamivir Phosphate Granules for five days. The primary efficacy indicator was the negative conversion rate of influenza antigen detection. Secondary efficacy indicators were the Canadian acute respiratory illness and flu scale （CARIFS） and the incidence of complications，severe cases， and critical cases. Follow-up observation was conducted on the day of enrollment，48 hours after medication，72 hours after medication， and （6+1） d after medication. ResultsOne hundred and eighty participants were randomly assigned to the experimental group （90 cases） or the control group （90 cases）. All participants were followed up during the study. Comparison of influenza antigen detection results in the primary efficacy indicators showed that the average time of negative influenza antigen conversion in the experimental group was （5.29±1.25） d，and that in the control group was （5.40±1.68） d，without a statistically significant difference. After five days of intervention，52 cases in the experimental group and 51 cases in the control group converted to negative，without a statistically significant difference. CARIFS score results in the secondary efficacy indicators showed that during 72 hours after intervention，there were statistically significant differences between the experimental group and the control group in three dimensions， including headache，muscle soreness， and the need for extra care （P<0.05）. On the （6+1） days after the intervention，the differences in both the experimental group and the control group were statistically significant in 10 dimensions， including sore throat，bad sleep，uncomfortable feeling，poor spirit and fatigue，crying more than usual，the need for extra care，symptom，function，influence on parents，and total score （P<0.05）. The comparison results within the group in the dimensional scores of symptom， function， and influence on parents，as well as the CARIFS total score showed that with the delay of follow-up time，scores of both groups decreased significantly，with a statistically significant difference （P<0.01）. Inter-group comparison results showed that the mean score of the experimental group was higher than that of the control group at the time of enrollment. With the progress of intervention，the score of the experimental group was significantly decreased compared with that of the control group. At the end of follow-up，the mean score of the experimental group was lower than that of the control group，with no statistically significant difference. In terms of the incidence of complications，severe cases， and critical cases， there were no complications，severe cases， and critical cases in the two groups，without a statistically significant difference. ConclusionThe symptom improvement effect and negative antigen conversion rate of Qingxuan Daozhi formula in the treatment of influenza in children （heat accumulation in the lung and stomach syndrome） are not inferior to Oseltamivir Phosphate granules， and children's acceptance is better. It can be more widely used in clinical treatment of influenza in children （heat accumulation in the lung and stomach syndrome）.

ObjectiveTo reveal the molecular mechanism by which the traditional Chinese medicine compound prescription Qiangjing tablets regulate the aging of the testicular tissue and Leydig cells in rats through the cyclin-dependent kinase 4 （CDK4）-early 2 factor （E2F） signaling pathway. MethodsFor the cell experiment， 2-month-old SPF-grade SD male rats were selected and randomly assigned into a blank control group （administrated with an equal volume of 0.9% sodium chloride injection） and a Qiangjing tablets group （20 rats in each group） according to body weight. The Leydig cell model of aging was established by treatment of TM3 cells with 100 μmol·L^-1 H₂O₂， and the modeling performance was evaluated based on the levels of p16 and p21 determined by Western blot. The antioxidant NAC （1 mmol·L^-1） was used as the positive control for eliminating reactive oxygen species （ROS）. Cells were intervened with Qiangjing tablets-containing serum at low （2.5%）， medium （5%）， and high （10%） concentrations. The testosterone level in the cell supernatant was determined by enzyme-linked immunosorbent assay （ELISA）， and the protein levels of CDK4， E2F1， and E2F2 were analyzed by Western blot. In the animal experiment， 19-month-old naturally aging rats were used as the model group， and 2-month-old rats as the young control group. The positive control group was subcutaneously injected with 5.21 mg·kg^-1·d^-1 testosterone propionate. Qiangjing tablets were administered by gavage at low， medium， and high doses of 0.72， 1.44， 2.88 g·kg^-1·d^-1， respectively. The general conditions of rats were observed， and the protein levels of CDK4， E2F1， and E2F2 in the testicular tissue were determined by Western blot. ResultsIn the cell experiment， compared with the blank control group， the model group showed upregulated expression of CDK4 and E2F1 （P<0.05） and slightly downregulated expression of E2F2. Compared with that in the model group， the expression of CDK4 was upregulated in the NAC group and the low-dose Qiangjing tablets group （P<0.05）， slightly upregulated in the medium-dose Qiangjing tablets group， and downregulated in the high-dose Qiangjing tablets group （P<0.05）. The NAC group showed downregulated expression of E2F1 （P<0.05） and E2F2， and the low-， medium-， and high-dose Qiangjing tablets groups showed downregulated expression of both E2F1 and E2F2 （P<0.05）. Compared with that in the NAC group， the expression of CDK4 was upregulated in the low-dose Qiangjing tablets group and downregulated in the medium-dose and high dose （P<0.05） groups. The expression of E2F1 was down-regulated in all the three dose groups， with statistically significance in the high dose group （P<0.05）， and that of E2F2 were downregulated in all the three dose groups （P<0.05）. In the animal experiment， compared with the young control group， the model group exhibited downregulated expression of CDK4 （P<0.05） and slightly upregulated expression of E2F1 and E2F2. Compared with that in the model group， the expression of CDK4 decreased in the testosterone propionate group and the low-dose Qiangjing tablets group （P<0.05） but increased in the medium-dose （P<0.05） and high-dose groups. In addition， the expression of E2F1 decreased （P<0.05）， and that of E2F2 was slightly elevated. Compared with that in the NAC group， CDK4 expression was elevated in the Qiangjing tablets groups， with statistical significance in the medium- and high-dose groups （P<0.05）. Similarly， the E2F1 expression was also upregulated in the Qiangjing tablets groups， with statistical significance in the medium-dose group （P<0.05）. The expression of E2F2 was downregulated in all the Qiangjing tablets groups. ConclusionQiangjing tablets delay the aging process of Leydig cells and testicular tissue by up-regulating the expression of CDK4 and lowering the levels of E2F1 and E2F2.

ObjectiveTo explore the mechanism by which Qiangjing tablets （QJT） alleviate the spermatogenic function damage caused by varicocele （VC） based on the Kelch-like ECH-associated protein 1 （Keap1）/nuclear factor erythroid 2-related factor 2 （Nrf2） signaling pathway-mediated oxidative stress. MethodsTen Sprague-Dawley （SD） rats were randomly assigned into a control group and a model group. Pathological examination confirmed the stability of the model. Thirty-six SD rats were randomized into control， model， low-dose （0.23 g·kg^-1） QJT， medium-dose （0.46 g·kg^-1） QJT， high-dose （0.92 g·kg^-1） QJT， and mazhilin （61.7 mg·kg^-1） groups， with 6 rats in each group. A rat model of experimental left varicocele （ELV） was established by partially ligating the left renal vein to simulate the human nutcracker syndrome. The rats were administrated with corresponding agents once a day for 28 consecutive days. The in vitro testicular culture model of rats was established through the Transwell chamber method and intervened with QJT-containing sera （2.3， 4.6， and 9.2 g·kg^-1）. Microscopic observation was carried out for the morphology of the left kidney. A micrometer was used to measure the diameter of the left spermatic vein （LSV）. The body weights of rats were recorded weekly， and the epididymis and testis weights were measured. The pathological changes of the testicular tissue was observed via hematoxylin-eosin （HE） staining. The levels of testosterone （T） in the cell culture supernatant and reactive oxygen species （ROS） in the rat testicular tissue were measured by enzyme-linked immunosorbent assay （ELISA）. Flow cytometry was employed to determine the ROS content. Immunohistochemical staining was conducted to analyze Keap1， Nrf2， 3β-hydroxysteroid dehydrogenase （3β-Hsd）， GATA-binding protein-4 （Gata-4）， and proto-oncogene receptor tyrosine kinase （C-kit）. The ultrastructure of the tissue was observed by transmission electron microscopy （TEM）. Cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling （TUNEL） staining. The expression of Keap1， Nrf2， glutathione S-transferase α2 （Gsta2）， glutathione S-transferase μ1 （Gstm1）， heme oxygenase-1 （HO-1）， quinone oxidoreductase 1 （Nqo1）， and thioredoxin reductase 1 （Txnrd1） was quantified by Real-time quantitative polymerase chain reaction（Real-time PCR） and Western blot. ResultsCompared with the control group， the ROS content and the percentage of apoptotic cells in the model group were significantly increased （P<0.01）， the T concentration was significantly decreased （P<0.01）， the mRNA and protein expressions of Keap1 were significantly increased （P<0.01）， and the mRNA and protein expressions of Nrf2， Gsta2， Gstm1， HO-1， Nqo1 and Txnrd1 were significantly decreased （P<0.05）. Compared with the model group， the ROS content and the percentage of apoptotic cells in each dose group of the Qiangjing Tablets were significantly reduced （P<0.05）， and the mRNA and protein expressions of Keap1 were significantly decreased （P<0.05）， while the mRNA and protein expressions of Nrf2， Gsta2， Gstm1， HO-1， Nqo1 and Txnrd1 were significantly increased （P<0.05）. ConclusionQJT improves sperm motility in the rat model of VC by modulating the Keap1/Nrf2 signaling pathway and reducing oxidative stress injury.

Purpose: To compare the anatomical and clinical outcomes based on the distance from the corneal limbus to the scleral tunnel in flanged intrascleral intraocular lens (IOL) fixation. Methods: We retrospectively analyzed the medical records of patients who underwent scleral fixation of flanged IOLs. Group 1 (54 eyes) had a distance of 2.1 mm from the corneal limbus to the scleral tunnel, and Group 2 (48 eyes) had a distance of 2.8 mm. We evaluated the best corrected visual acuity (BCVA), postoperative complications, IOL tilt and decentration, refractive prediction error (RPE), effective lens position, and iris-IOL distance. Results: The BCVA, postoperative complications, IOL tilt, and IOL decentration did not differ between the two groups (p > 0.05). The RPE showed a hyperopic shift in Group 1 and a myopic shift in Group 2 (Group 1: +0.24 ± 0.68 D, Group 2: -0.03 ± 0.43 D, p = 0.03). The iris-IOL distance was statistically longer in Group 1 compared to Group 2 (Group 1: 1.02 ± 0.40 mm, Group 2: 0.57 ± 0.32 mm, p = 0.02). The incidence of pupillary optic capture was significantly higher in Group 2 compared to Group 1 (Group 1; 0%, Group 2; 8.3%, p = 0.03). Conclusions It should be considered that a shorter distance from the corneal limbus to the scleral tunnel results in a postoperative hyperopic shift and reduces the incidence of pupillary optic capture when performing flanged intrascleral IOLs fixation.

A unified consensus statement on medication-related osteonecrosis of the jaw (MRONJ) has not yet been established among the Asian member countries or regions of the Asian Federation of Osteoporosis Societies (AFOS). This study aimed to develop a consensus on MRONJ in patients with osteoporosis across these countries and regions. In this study, the term “Asia-Pacific” refers specifically to the Asian member countries and regions of AFOS. A structured survey consisting of nine MRONJ-related questions was distributed across 10 countries and regions to assess the level of agreement and summarize regional perspectives. In addition, a manual literature review and voting were conducted to evaluate the current evidence on MRONJ. The key aspects of MRONJ, including definition, staging, diagnosis, pathogenesis, risk factors, management, and prevention, were generally consistent among the AFOS countries and regions. The annual incidence and incidence rate of MRONJ associated with low-dose antiresorptive therapy in patients with osteoporosis ranged from 0.025% to 0.136% and 21 to 283 cases per 100,000 person-years, respectively. However, evidence regarding the benefits of drug discontinuation before dental surgery, such as tooth extraction, remains insufficient. Large-scale, multinational studies across AFOS countries and regions are warranted to determine the incidence of MRONJ better and evaluate the impact of antiresorptive drug discontinuation before dental procedures. These findings may contribute to the devel opment of effective evidence-based strategies for preventing MRONJ in patients with osteoporosis.

BACKGROUND:Spondylolisthesis is a common disease,and there is a lack of effective drugs to treat it.There is still a need to further define the pathogenesis and screen out more suitable therapeutic targets for spondylolisthesis.Mendelian randomization analysis can be used to explore the drugable genes associated with spondylolisthesis and provide valuable guidance for the development of more effective and targeted therapeutic drugs.OBJECTIVE:To explore potential therapeutic targets and effective drugs for spondylolisthesis by means of pharmaceutically available genome-wide Mendelian randomization analysis.METHODS:Using the Finnish database,eQTLGen consortium,drug signature database,drug-gene interaction database,protein-protein interaction database,organic small molecule biological activity database and protein structure database,which contains genome and health information of half a million Finns,data on druggable genes were subjected to two-sample Mendelian randomization analysis and co-localization analysis with data from genome-wide association studies of spondylolisthesis to identify genes highly associated with spondylolisthesis.In addition,GO and KEGG enrichment analysis,protein network construction,drug prediction and molecular docking were performed to provide valuable guidance for the development of more effective and targeted therapeutic agents.RESULTS AND CONCLUSION:In this study,we identified 34 potential drug target genes that were significantly associated with spondylolisthesis,particularly the gene APOBEC3G.This gene showed a significant association with spondylolisthesis outcomes through Mendelian analysis and co-localization analysis,suggesting that APOBEC3G may be a priority therapeutic target.As for other potential mechanisms and drugs,we still need to conduct more in-depth research to determine their roles.This study used a database from a European population,which can be used as a reference for the study of population genetics in China.

Objective: To analyze the associations of physical activity with overweight/obesity, depressive symptoms, and their co-occurrence among junior and senior high school students, so as to provide reference for optimizing physical activity intervention strategies and promoting healthy lifestyles. Methods: From March to November 2023, a cross sectional survey was conducted among 90 457 junior and senior high school students aged 11-18 years in Zhejiang Province using a stratified cluster random sampling method. Data on physical activity and dietary behavior were collected through questionnaires, height and weight were measured. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). The Chi-square test was used to examine differences, and Logistic regression was applied to evaluate the associations of physical activity characteristics with overweight/obesity, depressive symptoms, and their co-occurrence. Additionally, the effectiveness of physical activity performed on rest days versus work days was examined. Results: The prevalence of overweight/obesity, depressive symptoms, and their co-occurrence among junior and senior high school students were 25.1%, 27.9%, and 6.7%, respectively, with significant sex differences ( χ 2=2 005.3, 587.7, 99.6, all P <0.01). Logistic regression analysis showed that students with insufficient physical activity had a higher risk of overweight/obesity compared with those with sufficient physical activity ( OR=1.12, 95%CI=1.06-1.17, P <0.01). Comparing to students who exercised 0-1 day per week, those who exercised 5-7 days per week were associated with a reduced risk of overweight/obesity and depressive symptoms ( OR=0.93, 95%CI =0.90-0.97; OR=0.95, 95%CI =0.91-0.99, both P <0.05). When total activity volume and frequency were held constant, students with sufficient rest day physical activity had lower risks of overweight/obesity, depressive symptoms, and their co-occurrence than those with insufficient rest day activity (all P < 0.01). Conclusions Sufficient amount of physical activity and higher frequency of rest day physical activity are significantly associated with lower risks of overweight/obesity, depressive symptoms, and their co-occurrence in adolescents. Physical activity performed on rest days may confer greater health benefits than activity performed on work days.

ObjectiveTaking the cuproptosis/oxidative stress pathway as the entry point， this study investigated the effect and mechanism of Liangyi Paste on hepatic lipid deposition in naturally aged mice fed with a high-fat diet. MethodsAfter adaptive feeding， 80 ten-week-old male C57BL/6 mice were used. Thirty of them were randomly divided into three groups （10 mice per group）： The 12-month-old control group （12MCON）， the 15-month-old control group （15MCON）， and the 15-month-old group with a high-fat diet （15MHFD）. The 12MCON and 15MCON groups were continuously fed a standard diet， while the 15MHFD group started receiving a high-fat diet at 12 months of age. Tissue samples were collected at the corresponding time points for each group. The remaining 50 mice were randomly divided into five groups （10 mice per group）： the 20-month-old control group （20MCON）， the model group， and the low-， medium-， and high-dose Liangyi Paste groups （2.91 ， 5.82 ， 11.64 g·kg^-1·d^-1， respectively）. The 20MCON group was continuously fed a standard diet， while the other groups started receiving a high-fat diet at 15 months of age. At 18 months of age， the Liangyi Paste groups were administered the corresponding doses of Liangyi Paste by gavage， while the 20MCON and model groups were given an equal volume of saline by gavage. After 8 weeks of continuous gavage （when the mice reached 20 months of age）， tissue samples were collected. Hepatic TG levels were measured using assay kits； liver histology and lipid deposition were observed via hematoxylin-eosin （HE） and oil red O staining； reactive oxygen species （ROS） were detected by enzyme-linked immunosorbent assay （ELISA）； Cu²⁺， superoxide dismutase （SOD）， and malondialdehyde （MDA） levels were measured by colorimetry； mRNA and protein expression of genes related to cuproptosis and oxidative stress pathways were analyzed by Real-time polymerase chain reaction（Real-time PCR） and Wes automated protein expression system. ResultsCompared with 12MCON， the 15MCON group showed significantly increased hepatic TG， Cu²⁺， ROS， and MDA levels （P<0.01）， decreased SOD （P<0.01）， hepatocyte swelling， and disordered arrangement. The mRNA and protein levels of ferredoxin 1 （FDX1）， dihydrolipoamide S-acetyltransferase （DLAT）， heat shock protein 70 （HSP70）， dihydrolipoamide dehydrogenase （DLD）， pyruvate dehydrogenase E1 subunit-β （PDHB）， nuclear factor erythroid 2-related factor 2 （Nrf2）， and peroxisome proliferator-activated receptor γ （PPARγ） were significantly elevated （P<0.05， P<0.01）. Compared with 15MCON group， the 15MHFD and 20MCON groups exhibited further increases in TG， Cu²⁺， ROS， and MDA （P<0.01）， reduced SOD （P<0.01）， and aggravated hepatocyte swelling and disorder. There were increased lipid droplets with mild vacuolization in the 15MHFD group， and no significant lipid deposition was observed in the 20MCON group. FDX1， DLAT， HSP70， DLD， PDHB， Nrf2， and PPARγ mRNA and protein levels were significantly increased （P<0.05， P<0.01）. Compared with 20MCON group， the model group demonstrated markedly elevated TG， Cu²⁺， ROS， and MDA （P<0.01）， reduced SOD （P<0.01）， severe hepatic steatosis， and upregulated expression of FDX1， DLAT， HSP70， DLD， PDHB， Nrf2， and PPARγ mRNA and proteins （P<0.05， P<0.01）. All abnormalities were significantly reversed after Liangyi Paste treatment. ConclusionLiangyi paste can ameliorate hepatic lipid deposition in naturally aged mice with a high-fat diet by modulating the cuproptosis/oxidative stress pathway.

ObjectiveTo investigate the epigenetic mechanism of Diwu Yanggan Capsule in improving liver regeneration microenvironment in a rat model of liver cancer by regulating DNA methylation， and to provide a basis for scientific clinical medication. MethodsA total of 48 specific pathogen-free Sprague-Dawley rats were divided into normal group， model group， and Diwu Yanggan Capsule group using a random number table， with 16 rats in each group. The Solt-Farber two-step method was used to establish a rat model of liver cancer. The rats in the Diwu Yanggan Capsule group were given Diwu Yanggan Capsule at a dose of 750 mg/kg/d by gavage， and those in the normal group and the model group were given an equal volume of normal saline by gavage. Liver tissue samples were collected from each group of rats after 16 weeks of continuous intervention； DNA methylation chips were used to analyze the change in DNA methylation in liver tissue， and gene ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） analyses were used for data analysis. In addition， the MeDIP-PCR technique was used to detect the changes in candidate differentially methylated genes such as YWHAB， ADCK2， ERLIN2， SEMA3B， and TPH2 in the liver tissue of rats， and Western blot and RT-qPCR were used to verify the expression of key methylated genes. The independent-samples t test was used for comparison of continuous data between two groups， and a one-way analysis of variance was used for comparison between multiple groups， while the least significant difference t-test was used for further comparison between two groups. ResultsThe DNA methylation chip analysis showed that compared with the normal group， the model group had significant methylation changes in the promoter region of 2 422 genes in liver tissue of rats. The GO functional enrichment analysis and the KEGG pathway enrichment analysis showed that these differentially methylated genes were significantly enriched in metabolic pathways such as steroid hormone biosynthesis and drug metabolism-cytochrome P450. Compared with the model group， the Diwu Yanggan Capsule group had significant reversal of promoter methylation in 1 650 genes， and the KEGG enrichment analysis showed that these genes were mainly involved in the pathways closely associated with cell proliferation， apoptosis， and microenvironment regulation， such as the calcium ion signaling pathway， the cAMP signaling pathway， and the extracellular factor signaling pathway. Compared with the model group， the Diwu Yanggan Capsule group had a significant increase in the promoter methylation level of the ADCK2 gene （P<0.05） and significant reductions in the promoter methylation levels of the ERLIN2 and TPH2 genes （all P<0.05）. Compared with the model group， the Diwu Yanggan Capsule group had significant reductions in the mRNA expression levels and the protein expression levels of the ADCK2 （all P<0.05）. ConclusionAbnormal DNA methylation in liver tissue participates in the development and progression of liver cancer. The effect of Diwu Yanggan Capsule on DNA methylation level is an important epigenetic mechanism for its effect in the prevention and treatment of liver cancer.