Exercise therapy during cancer treatment reduces symptom burden and improves quality of life (QoL). Polycythemia vera (PV) is a myeloproliferative neoplasia associated with good overall survival (up to decades) but a significant symptom burden, including thromboembolic events and dysesthesias. There are no specific exercise recommendations for patients with PV. Thus, we aimed to determine the exercise preferences of patients with PV and to derive specific recommendations based on the most commonly reported symptoms.This multicenter survey included patients with PV ≥18 years old. Demographic, clinical, and disease burden data were collected. The severity of selected symptoms was assessed using the adapted Myeloproliferative Neoplasms Symptom Assessment Form: 0 (absent), 1–30 (mild), 31–70 (moderate), or 71–100 (severe). The patients' information needs about physical activity (PA) and exercise preferences were recorded depending on their motivation and analyzed with regard to demographic aspects.p < 0.001). Higher sport‐inactiveness was observed in patients with lower educational level compared to patients with higher educational level . For beginners, combined resistance‐endurance (circuit) training two times/week, which can be performed outdoors or at home, should be recommended. In the case of splenomegaly or bleeding symptoms, exercises with a low injury risk should be chosen.The sample comprised 182 patients . The prevalence of moderate‐to‐severe symptoms was 60% for fatigue, 44% for concentration problems, and 35% for bone/muscle pain. Other commonly reported symptoms included skin reactions (49%), splenomegaly (35%), and increased bleeding tendency (28%). Overall, 67% of respondents requested more information regarding PA. Patients with PV preferred individual training (79%) located outdoors (79%) or at home (56%). Regarding the amount of training, sports‐inactive patients preferred a frequency of 1–2 times/week and session durations of 15–45 min, whereas sports‐active patients preferred 3–4 times/week and 30–60 min (PA is important for patients with PV; therefore, counseling should be integrated into the treatment plan. Specifically, patients with low educational level should be addressed. Prospective studies are warranted to evaluate the effects of the novel exercise recommendations. Several studies have shown that exercise therapy decreases mortality in patients with cancer.Currently, there are no specific evidence‐based recommendations for patients with polycythemia vera (PV) nor for patients with other myeloproliferative neoplasms (MPN). In Europe, the incidence of PV ranges from 0.4 to 2.8 per 100,000 people.In a large multicenter survey, performed within the framework of the East German Study Group for Hematology and Oncology, we analyzed the exercise behavior of patients with MPN.We conducted the current study to gain insights into (i) the level of information and request for more information regarding exercise therapy options for patients with PV and (ii) to learn more about exercise preferences. Subsequently, (iii) we developed symptom‐based exercise recommendations for patients with PV.22.1The design of the study has been published in detail earlier, see Felser et al.2.22.2.12]) and classified as <18.5, 18.5–24.9, 25.0–29.9, and ≥30.0, representing, underweight, normal weight, overweight, and obesity, respectively.The self‐administered survey comprised questions about gender, age, weight and height, school education, family, and professional status. The body mass index (BMI) was calculated 2.2.4The patients' level of information regarding the importance of and opportunities for PA and their need for information about this topic were recorded.2.2.5The five stages of the transtheoretical model of behavioral change were used to determine the motivation to participate regularly in sports.2.2.6The patients were asked to indicate their physical exercise preferences: the kind of training, location, frequency, and time per session.2.3integrative decision making was chosen.To identify symptom‐based exercise recommendations for PV patients the method of 2.4p‐values <0.05.Continuous data are reported as the mean ± standard deviation, and categorical variables are presented as numbers and percentages. Mean differences were tested using the chi‐squared test (Fisher's exact test). All data were analyzed using SPSS . Statistical significance was assumed for 33.1n = 315) were completed in the hardcopy format and 59% (n = 451) were completed online. Due to missing information regarding diagnosis or too many missing details, we excluded 8% (n = 60) of the questionnaires. Thus, we included 706 questionnaires in the analysis. The PV cohort comprised 182 questionnaires, 26% (n = 48) in the hardcopy format and 74% (n = 134) in the online format. The demographic and clinical data of the patients are presented in Table n = 124) women. The mean age of patients with PV was 61 ± 12 years . According to the BMI calculation, 39% (n = 70) of the participants were overweight or obese. At the time of the survey, 48% (n = 87) of patients were with PV were working, of whom 14% (n = 12) were on sick leave. The first diagnosis of PV was a mean of 7.9 ± 7.5 years ago at the time of the survey (diagnosed between 1981 and 2021). The average age at diagnosis was 53 ± 13 years. The most frequently mentioned therapies were phlebotomy and anticoagulation, each reported by 40% (n = 72) of the patients, followed by cytostatics .In total, we received 766 questionnaires, of which 41% (3.2n = 88), splenomegaly , and increased bleeding tendency . Figure The frequencies of typical symptoms are shown in Table 3.3n = 77) of the patients with PV said no. No significant group differences depending on demographic data were observed. Regardless of the level of information, 67% (n = 108) of the patients with PV stated they would like to receive more information about PA. The proportion of patients who would like to receive more information about PA was particularly high among patients with high levels of education  and age ≤60 years (73%). However, the difference was not significant compared to patients with low educational level  or patients >60 years .When asked whether they felt sufficiently informed about the importance and opportunities of PA in regards to their disease, 47% (3.4n = 157) of the patients with PV. The analysis of the stages of behavioral change revealed that 38% (n = 60) of them were not action oriented (precontemplation stage), and 20% (n = 31) were in the contemplation or preparation stage. In total, 42% (n = 66) patients with PV reported regular participation in sports (action and maintenance stages). The proportion of those who felt adequately informed about the importance of and opportunities for PA was significantly higher among those who were active in sports than among those who were not active in sports .The question about motivation to participate regularly in sports was answered by 86% (3.5n = 126) of patients with PV, and group training was preferred by 40% (n = 64). The preferred training locations were outdoors , followed by at home  and an indoor swimming pool . Group differences of training type or location were found depending on BMI, school education, and professional status. While 64% of normal‐weight PV patients reported preferring training at home, the proportion in overweight/obese patients was 45% (p = 0.032). Among the higher educated patients, 88% indicated a preference for individual training. In comparison, among the patients with lower education level this was 69% (p = 0.005). Employed PV patients prefered significantly higher individual (85%) and outdoor training (89%) compared to retired patients .Table p < 0.001). Regarding the training time per session, sports‐inactive patients with PV preferred 15–45 min; in contrast, sports‐active patients with PV preferred 30–60 min (p < 0.001). It should be mentioned that the proportion of patients who are sports‐inactive is significantly higher in patients with lower educational level compared to patients with higher educational level . In addition, the analyses showed that patients with lower educational level are more often overweight/obese compared to patients with higher educational level . The proportion of overweight/obese patients among sports‐inactive patients is significantly higher than among sports‐active patients .Regarding the amount of training, significant group differences were observed, especially between sports‐active and sports‐inactive patients with PV. Of the sports‐inactive patients with PV, 74% indicated a preference for an exercise frequency of 1–2 times/week, with 3–4 times/week preferred by 21%. In contrast, 26% of the sports‐active patients with PV preferred a frequency of 1–2 times/week and 54% preferred 3–4 times/week  and aim for at least 150 min/week. Combined resistance‐endurance training can be done independently outdoors or at home using their own body weight and/or small equipment. Outdoors, stairs, benches, or railings could be used for exercises. Patients with PV who prefer group exercise have many options: They could use a sports hall, a gym, or an indoor swimming pool. In principle, patients with PV can participate in all sports, except that in cases of splenomegaly and increased bleeding tendency , ball and contact sports or sports with a high risk of falling or injury should be avoided. Because there is no evidence to date on whether free‐weight training is safe and feasible for patients with PV and splenomegaly, low‐injury training on equipment (weight training machines and ergometers) is advised. Patients with PV experiencing skin reactions should refrain from activities in water (chlorinated water) or avoid direct sunlight, depending on the trigger. Generally, adequate sun protection should be used during outdoor activities to prevent melanoma.Because fatigue and concentration problems are independent risk factors for falls in patients with MPN,4Here, we present the first study to investigate the level of information and information needs about PA and exercise preferences of patients with PV. Further, novel‐specific PA training recommendations for patients with PV were developed.A key finding is that patients with PV have a high need for information on PA, regardless on the level of motivation to exercise regularly. The relevance of this topic is strengthened by the relatively young age of the patients with PV at diagnosis, accompanied with a high proportion of employees.Another finding of this study is that exercise preferences in terms of volume among sports‐inactive patients with PV are significantly below the general exercise recommendations of major health organizations.Because there have been few (feasibility) studies to date regarding the effects of exercise interventions in patients with PV or MPN,4.1A strength of the study is that despite the low incidence, we recruited a large cohort of patients with PV in German‐speaking regions. Due to the survey design, there are unavoidable limitations that must be considered when interpreting the data. First, as the survey was voluntary and offered online, primarily younger patients with PV and those with an affinity for sports might have participated. Consequently, the proportion of sports‐inactive patients with PV in the population could be higher than the data indicate. Second, the majority of the participants are women, who are known to often report a higher symptom burden.5The current study has shown how important information about PA is for patients with PV. Because these patients benefit from PA in many ways, PA counseling should become an integral part of the treatment plan for patients with PV. This includes regular screening of symptoms. Regarding PA counseling and support for inducing behavioral changes, special attendence should be given to patients with low educational levels. For the first time, we have outlined exercise recommendations based on symptoms to provide specific guidance for patients with PV. Prospective studies evaluating the feasibility, safety, and efficacy of the proposed exercise recommendations are needed to ultimately provide evidence‐based exercise recommendations for patients with PV. In addition, it should be investigated whether providing knowledge about the opportunities and effects of PA leads to a change in the PA behavior of patients with PV.Sabine Felser: Conceptualization ; data curation ; formal analysis ; funding acquisition ; project administration ; writing – original draft (lead). Julia Rogahn: Formal analysis ; writing – original draft (supporting). Lina Hollenbach: Formal analysis ; writing – original draft (supporting). Julia Gruen: Data curation . Philipp le Coutre: Data curation ; writing – review and editing . Haifa Kathrin Al‐Ali: Data curation ; writing – review and editing . Susann Schulze: Data curation ; writing – review and editing . Lars‐Olof Muegge: Data curation ; writing – review and editing . Veronika Kraze‐Kliebhahn: Data curation ; writing – review and editing . Christian Junghanss: Conceptualization ; data curation ; supervision ; writing – review and editing .The study was supported by the East German Study Group Hematology and Oncology (OSHO #97).The authors declare that they have no competing interests.This study was approved by the Ethics Committee of the University of Rostock (A2020‐0274), and registered with the German Registry of Clinical Trials (DRKS00023698).Data S1.Click here for additional data file.Data S2.Click here for additional data file.


Multiple prognostic biomarkers, including circulating tumour cell (CTC) counts, exist in metastatic castration‐resistant prostate cancer (mCRPC) patients, but none of them have been implemented into daily clinical care. The modified fast aneuploidy screening test‐sequencing system (mFast‐SeqS), which yields a genome‐wide aneuploidy score, is able to reflect the fraction of cell‐free tumour DNA (ctDNA) within cell‐free DNA (cfDNA) and may be a promising biomarker in mCRPC. In this study, we investigated the prognostic value of dichotomized aneuploidy scores (< 5 vs. ≥ 5) as well as CTC counts (< 5 vs. ≥ 5) in 131 mCRPC patients prior to treatment with cabazitaxel. We validated our findings in an independent cohort of 50 similarly treated mCRPC patients. We observed that, similar to the dichotomized CTC count , dichotomized aneuploidy scores  significantly correlated with overall survival in mCRPC patients. We conclude that a dichotomized aneuploidy score from cfDNA is a prognostic marker for survival in mCRPC patients within our discovery cohort and in an independent mCRPC validation cohort. Therefore, this easy and robust minimally‐invasive assay can be readily implemented as a prognostic marker in mCRPC. A dichotomized aneuploidy score might also be used as a stratification factor in clinical studies to account for tumour load. The dichotomized mFast‐SeqS‐based aneuploidy score from cfDNA is a prognostic marker for survival in mCRPC patients. This easy, robust, low‐cost, and minimally invasive assay can be readily implemented as a prognostic marker in mCRPC. This assay represents an attractive stand‐alone stratification tool for use in daily clinical practice, and could also aid as a stratification factor in clinical studies. ALBalbumin levelsANCabsolute neutrophil countcfDNAcell‐free DNACIconfidence intervalctDNAcell‐free tumour DNAEpCamepithelial cell adhesion moleculeHBGhemoglobin levelsHRhazard ratioLDHlactate dehydrogenase levelsmCRPCmetastatic castration‐resistant prostate cancermFast‐SeqSmodified Fast Aneuploidy Screening Test‐Sequencing SystemNIPTnoninvasive prenatal testOSoverall survival1The daily clinical care of metastatic castration‐resistant prostate cancer (mCRPC) patients could be improved by utilizing non‐invasively derived prognostic markers. Circulating tumour cells (CTCs) and circulating tumour‐derived DNA (ctDNA) comprise two minimally invasive and safely obtainable biomarkers from liquid biopsies . ExtensiIn this manuscript, we investigated the prognostic value of mFast‐SeqS‐derived dichotomized aneuploidy scores for mCRPC patients and compared their performance to dichotomized CTC counts.22.1et al. [For our discovery cohort, we included 131 out of 137 mCRPC patients with known CTC counts from the CABA‐V7 trial (MEC16‐703), as previously detailed by Isebia et al. . Six patn = 50) with known CTC counts from the CABARESC trial , as previously detailed by Nieuweboer et al. [U test and Fisher's exact test) where we used P > 0.1 to propose no difference.As an independent validation cohort, we selected mCRPC patients  contained sufficient events.The outcome of interest was overall survival (OS), as measured from the inclusion of the study until death from any cause. Based on results in our discovery cohort, we calculated that in order to have 80% power to detect a similar HR in the validation cohort given a two‐sided α of 5%, a minimum of 32 events (i.e. deaths) needed to be observed. The included validation cohort  according to the manufacturer's instructions. Briefly, CTC enumeration was performed on 7.5 mL of CS blood using the Circulating Epithelial Cell Kit on the CellSearch system. Using ferrofluid labelled anti‐EpCAM antibodies, immunomagnetically captured cells are characterized using different combinations of staining reagents.As previously detailed by Isebia et al.  and Onst [et al.  for the 2.3et al. [g, respectively. EDTA tubes were processed within 24 h and CS tubes within 96 h, respectively. Plasma was then immediately stored at −80 C in 2 mL aliquots until cfDNA isolation. Next, cfDNA was isolated using the QIAamp® Circulating Nucleic Acid kit  and Maxwell® RSC ccfDNA Plasma Kit  according to the manufacturer's instructions.Per included patient (CABA‐V7 and CABARESC), collected blood was centrifuged twice to obtain plasma, as detailed by van Dessel et al. , and pla2.4et al. [Z‐score that serves as an estimate for overall aneuploidy. As described by Belic et al. [m) and supplemented with a 5% PhiX control library. The libraries were sequenced single‐ended for 150 bp reads on a MiSeq‐sequencer . Samples yielding < 90 000 reads were sequenced again, and resulting reads were combined [We employed the mFast‐SeqS platform on 1 ng of cfDNA to obtain low‐resolution copy‐number profiles. Aneuploidy scores per chromosome arm were determined using the mFast‐SeqS method. The original Fast‐SeqS  was deveet al.  to estimc et al. , we usedcombined .trimmomatic [Z‐score  from Belic et al.) [Z‐scores per chromosome arm were squared and summed into a genome‐wide aneuploidy score per patient. Samples with a genome‐wide Z‐score ≥ 5   trimmoma2.5et al. [Using the maximum variant allele frequencies per sample as derived from our targeted QIASeq panel as detailed by Isebia et al. , we perf2.6cutpointr package (version 1.1.2) [n = 131) based on their survival status ; using 10.000 bootstrap iterations.We utilized the n 1.1.2)  to estab2.7n = 131) for predicting OS, as measured from inclusion of study until death from any cause, were studied in a univariate Cox proportional hazards regression analysis. The following characteristics were investigated: age at registration, total Gleason‐score, PSA at primary diagnosis, dichotomized WHO‐status (0 vs. 1–2), albumin levels (ALB), absolute neutrophil count (ANC), haemoglobin levels (HBG), number of white blood cells (WBC), alkaline phosphatase levels (ALP), lactate dehydrogenase levels (LDH), dichotomized aneuploidy scores at baseline (aneuploidy score < 5 vs. ≥ 5) and dichotomized number of CTCs (per 7.5 mL) at baseline (< 5 vs. ≥ 5 CTCs). We only retained characteristics with P < 0.1 for subsequent multivariable Cox proportional hazards regression where backward selection was applied with a threshold of P < 0.1. In addition, sample‐specific dichotomized aneuploidy scores and dichotomized CTC counts were combined to identify potential complimentary effects. Kaplan–Meier curves were generated for dichotomized aneuploidy score, dichotomized CTC count and dichotomized WHO status and obtained curves were tested using the log‐rank test.The most relevant baseline characteristics from the discovery cohort (r (version 4.2.1).All analyses were performed on the statistical language platform 33.1n = 131; 92 deaths; Fig. n = 50) and the complete CABARESC study group (n = 224) from which the validation cohort was drawn  and dichotomized CTC counts (< 5 or ≥ 5) were analysed for predicting OS using Cox proportional hazards regression analysis including all relevant clinical characteristics (based on backward selection). This revealed that dichotomized aneuploidy scores and dichotomized CTC counts both independently served as significant non‐invasive biomarkers predicting OS (Our previous threshold for the dichotomization of mFast‐SeqS scores (< 5 or ≥ 5) was based on previous studies , 11, 21.4Numerous efforts and studies have been undertaken to study and improve the prognostic value of non‐invasively derived markers in mCRPC patients , 24, 25.et al. [Different methods exist for detecting ctDNA within the total pool of cfDNA. These ctDNA analyses are variable in their design; some focusing on single tumour‐specific gene alterations, whilst others, for example, quantify ctDNA by utilizing aneuploidy detection based on copy number alterations  or singlet al.  showed tThe exploitation of dichotomized aneuploidy scores as prognostic markers for mCRPC patients has not yet been investigated, whilst it could complement CTC enumeration. In this analysis, we investigated the prognostic value of aneuploidy scores for mCRPC patients and compared their performance to dichotomized CTC counts.We observed a prognostic value for OS for cfDNA‐based dichotomized aneuploidy scores. These findings were significant in our discovery cohort (CABA‐V7) and were replicated in our comparable mCRPC validation cohort (CABARESC). Dichotomized aneuploidy scores and their combination with dichotomized CTC counts hold complementary benefits in identifying the mCRPC patients with the worst outcome. Additionally, we revealed that dichotomized aneuploidy scores and dichotomized CTC counts both independently serve as significant non‐invasive biomarkers for predicting OS.Despite these significant observations, this work has limitations. Our employed thresholds for dichotomization of CTC counts and aneuploidy scores are currently based on the previously employed threshold , 8, whic5In conclusion, the mFast‐SeqS‐derived aneuploidy score is a global, minimally invasive and user‐friendly assay that can be employed unrestrictedly without the use of specialized equipment such as CellSearch. In this study, we showed that a dichotomized aneuploidy score is a clinically relevant stratification marker, akin to an established CTC count. The mFast‐SeqS method can be used for an estimation of ctDNA percentage, since it correlates with tumour content and can be easily used for monitoring disease progression without prior knowledge of the genetic composition of the malignancy. The mFAST‐SeqS assay provides an intuitive low‐resolution copy number profile, requiring only a low input of 1 ng cfDNA and results can typically be obtained within 2 days. Therefore, this affordable assay represents an attractive stand‐alone stratification tool for usage in daily clinical practice, which could also aid as a stratification factor in clinical studies. Whether mFast‐SeqS‐derived aneuploidy score could also serve as a predictive biomarker for therapy response or longitudinal therapy monitoring should be further investigated.Ronald de Wit has acted in a consulting or advisory role for Sanofi, Merck, and Bayer and has received research funding from Bayer, Sanofi.Martijn P. Lolkema has acted in a consulting or advisory role for Sanofi, Johnson & Johnson, Merck, Astellas, Incyte, Amgen, Janssen Cilag, Bayer, Servier and Pfizer; and has received research funding from Sanofi, Astellas, Janssen Cilag and MSD.John. W. M. Martens has acted in a consulting or advisory role for Novartis and Roche; and has received research funding from Philips, Therawis, Pamgene, Cergentis, Cytotrack.Bianca Mostert has acted in a consulting or advisory role for Servier, Lilly and BMS; and has received research funding from Sanofi, Pfizer and BMS.Ron H.J. Mathijssen received research funding from Astellas, Bayer, Cristal Therapeutics, Novartis, Pamgene, Pfizer, Roche, Sanofi, Boehringer‐Ingelheim and Servier.All authors certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript , are the following:The remaining authors have nothing to disclose.KTI, JvR, JWMM and MPL had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: MPL, JWMM, BM, SMW, RdW. Acquisition of data: KTI, BM, TD, JK, VdW, EOH, PH, BCMH, HHH, RdW, RHJM, MPL, SMW, JvR, JWMM. Analysis and interpretation of data: KTI, JvR, MPL, SMW, TD, BM, EOH, RHJM, JWMM. Drafting of the manuscript: KTI, JvR, MPL. Critical revision of the manuscript for important intellectual content: KTI, BM, TD, JK, VdW, EOH, PH, BCMH, HHH, RdW, RHJM, MPL, SMW, JvR, JWMM. Statistical analysis: KTI, JvR, EOH. Obtaining funding: MPL, RdW, BM. Administrative, technical, or material support: KTI, JvR, SMW, TD, VdW, JK, BCMH, PH, HHH. Supervision: JWMM.https://www.webofscience.com/api/gateway/wos/peer‐review/10.1002/1878‐0261.13449.The peer review history for this article is available at Fig. S1. Association of aneuploidy scores with other molecular characteristics. (a) Aneuploidy scores  per dichotomized aneuploidy group. Boxplots represent the median and first and third quantile whilst error bars depict the interquartile range (IQR)x1.5. (b) Aneuploidy scores  versus sample‐specific maximum variant allele frequency derived from a targeted QIASeq panel of 57 genes . Spearman correlation coefficient (ρ) and statistical significance of observed association (p), together with a linear model equation as depicted by a blue line with 95% confidence level interval as gray background, is shown in top. (c) Same a b) but for CTC counts .Click here for additional data file.Fig. S2. Overall survival versus alternative dichotomized aneuploidy scores. Survival probability (OS), as measured from inclusion of study until death from any cause, using univariate analysis of all patients per cohort (y‐axis), stratified and colored by varying dichotomized categories at baseline, depicted in months (x‐axis); censoring is shown by crosses (+). The bottom table represents the total number of remaining cases per depicted time‐point. The log‐rank p‐value, hazard ratio (death) with 95% CI and Akaike information criterion (AIC) is shown on the right‐hand top‐side. The 50% survival probabilities per strata as indicated by dashed lines whilst the confidence interval per stratum is indicated by transparent backgrounds. a) Discovery cohort (CABA‐V7), b) Validation cohort (CABARESC).Click here for additional data file.Fig. S3. Overall survival for all included patients in the discovery cohort, full CABARESC cohort and the included CABARESC cohort as validation cohort. Survival probability (OS) using univariate analysis of all included patients per cohort (y‐axis), stratified and colored by cohort, depicted in months (x‐axis); censoring is shown by crosses (+). The bottom table represents the total number of remaining cases per depicted time‐point. Hazard ratios with 95% confidence interval (CI) from multivariate Cox proportional hazards regression within the discovery cohort (n = 131). The p‐values for each multivariate assessment are presented on the right‐hand side of each comparison.Click here for additional data file.Table S1. Baseline characteristics of the complete CABARESC cohort and the included subset used for validation.Click here for additional data file.Table S2. Overview of included patients and data presented in figures. Overview of all data as presented and quantified in this manuscript.Click here for additional data file.


Previous studies reported that patients with asthma showed higher levels of interleukin (IL)‐33 in peripheral blood, compared to healthy control (HCs). However, we also noticed that there were no significant differences of IL‐33 levels between controls and asthma patients in a recent study. We aim to conduct this meta‐analysis and evaluate the feasibility of IL‐33 in peripheral blood that may act as a promising biomarker in asthma.Articles published before December 2022 were searched in these databases . We used STATA 12.0 software to compute the results.I2 = 98.4%, p < .001; plasma: SMD 3.67, 95% CI 2.32−5.03, I2 = 86.0%, p < .001). Subgroup analysis indicated that asthma adults showed higher IL‐33 level in serum, compared to HCs, whereas no significant difference in IL‐33 level in serum was showed between asthma children and HCs . The study indicated that moderate and severe asthmatics showed higher IL‐33 level in serum, compared to mild asthmatics .The study showed that asthmatics showed higher IL‐33 level in serum and plasma, compared to HCs ‐33 levels and the severity of asthma. Therefore, the IL‐33 levels of either serum or plasma may be regarded as a useful biomarker of asthma or the degree of disease. However, we can not ignore the influences of ethnic and age factors on the IL‐33 levels. It is encouraged that data from multi‐center, well‐designed and large sample size studies should be conducted for validating the clinical value of IL‐33 on asthma. Ideally, samples should be collected using quick, cost‐efficient and noninvasive methods. Thus, some serum/plasma biomarkers change in asthma have been searched in recent years. Interleukin‐4 (IL‐4), IL‐5, and IL‐13 are involved in asthma pathogenesis by synthesis of immunoglobulin E (IgE), activation of eosinophils, and by inducing hypersecretion of mucus resulting in hyperresponsiveness of airways.IL‐33 is a member of the IL‐1 cytokine family and abundantly expressed by fibroblasts, endothelial and epithelial cells.Previous studies reported that patients with asthma showed higher levels of IL‐33 in peripheral blood, compared to HCs.2The study was made according to the Preferred Reporting Items for Systematic reviews and Meta‐Analysis (PRISMA) guideline.2.1N = 3143 duplicates, N = 1262 studies were included in the study. Two independent investigators (Ranran Zhao and Yun Shi) decided study eligibility after reading the scanned abstracts and citations. We resolved discrepancies through consultation.Articles published before December 2022 were searched in these databases . These search terms were used: (“Interleukin‐33” OR “Interleukin 33” OR “IL33” OR “IL‐33”) AND (“asthma”). After excluding 2.2We included studies according to the following inclusion criteria: (1) studies explored IL‐33 in peripheral blood; (2) studies focused on asthma. Exclusion criteria were showed as follows: (1) reviews, meta‐analyses studies and case reports; (2) published articles written in languages other than English; (3) studies which did not provide sufficient information for IL‐33 level in the peripheral blood in both asthmatics and HC.2.3The following data were collected from included articles using Excel by two independent investigators (Ranran Zhao and Yun Shi): author, publication year, located country, ethnicity, sample size, gender, mean age, specimen, detection method and results . If data of these items were not reported in primary studies, the item was marked as “not reported (NR).”2.4I2 were used to assess heterogeneity among studies. With low heterogeneity , fixed effects models were used; with high heterogeneity , random effects models were used. Meta‐regression analyses were made to evaluate the source of the heterogeneity. Subgroup analyses  were made to investigate the source of the heterogeneity. In addition, sensitivity analysis was made by removing 1 individual study each time to assess the stability of the meta‐analysis. Publication bias was evaluated by Begg's test, Egger's test and funnel plots.We used STATA 12.0 software to compute the results. The SMD and a 95% confidence interval (CI) regarding comparison in IL‐33 level in the peripheral blood between asthmatics and HC were computed. Q test and 33.1N = 13 studiesN = 3 studiesN = 4 studiesTable 3.2I2 = 98.4%, p < .001; Figure p = .152; gender: p = .987). N = 9 studiesN = 4 studiesp = .180; Egger's tests: p = .216; Supporting Information: Figure The study showed that asthmatics showed higher IL‐33 level in serum, compared to HCs . Sensitivity analyses showed no changes in the direction of effect while anyone study was excluded for meta‐analysis . Subgroup analysis indicated that moderate asthmatics showed higher IL‐33 level in serum, compared to mild asthmatics . Subgroup analysis revealed that the difference of serum IL‐33 existed among adults, while not among children . However, Wang et al. reported that there was an association between asthma patients and higher serum levels of IL‐33 among children .In this meta‐analysis, we included 17 studies with a total of over 2600 participants (1427 asthma patients and 1205 HCs). Our findings showed that asthma patients were likely to have higher serum levels of IL‐33, compared to HCs . This result was analogous to previous meta‐analysis conducted by Li et al.Meanwhile, this meta‐analysis revealed that the serum levels of IL‐33 were higher in moderate and severe asthma patients compared to that in mild asthma patients . This result was inconsistent with finding from Wang et al.IL‐33 plays important roles in type 2 inflammatory responses and linking innate and adaptive immunity.There were some limitations in this study. First, we only included the published articles in English. The findings may be biased owing to the exclusion of unpublished and non‐English literatures. Second, several confounding factors were not adjusted for all included studies, including gender, family history, diet differences and cigarette smoking, which may influence the results. Thirdly, the study did not explore IL‐33 levels in the airways  or other biological samples) in asthma.5In conclusion, the main findings of present meta‐analysis suggested that there was a significant correlation between IL‐33 levels and the severity of asthma. Therefore, IL‐33 levels of either serum or plasma may be regarded as a useful biomarker of asthma or the degree of disease. However, we can not ignore the influences of ethnic and age factors on the IL‐33 levels. It is encouraged that data from multi‐center, well‐designed and large sample size studies should be conducted for validating the clinical value of IL‐33 on asthma.Ranran Zhao: Conceptualization; data curation; formal analysis; investigation; methodology; software; writing—original draft. Na Liu: Data curation; investigation; methodology; software. Bin Li: Data curation; investigation; methodology.The authors declare no conflict of interest.Supporting information.Click here for additional data file.Supporting information.Click here for additional data file.Supporting information.Click here for additional data file.Supporting information.Click here for additional data file.Supporting information.Click here for additional data file.Supporting information.Click here for additional data file.Supporting information.Click here for additional data file.Supporting information.Click here for additional data file.Supporting information.Click here for additional data file.Supporting information.Click here for additional data file.


Thyroid cancer (TC) is becoming an increasing public health problem worldwide. TikTok is a global video-sharing social media app, which can be a source of information on TC. However, the information quality of these videos remains unknown.A search of TikTok was performed with the term “甲状腺癌”and “甲状腺肿瘤” (“thyroid cancer” and “thyroid neoplasm” in Chinese). Videos included were independently assessed using six predefined questions for content scores and DISCERN scale for information quality, while the video popularity index (VPI) was also calculated. A correlation analysis was performed among duration, presence of animation, VPI, DISCERN scores, and content scores.A total of 56 videos were finally included, of which 49 were uploaded by physicians, 4 by health organizations, and 3 by hospitals. While 43 were real content videos, 13 were animated. The mean of DISCERN score and content score was 3.44 ± 0.72 and 5.19 ± 0.95, respectively. Good consistency was found between the two reviewers in terms of both DISCERN scores and content scores. The video duration and presence of animation were positively correlated with VPI, while DISCERN scores and content scores were not correlated with VPI.The overall quality of TC-related videos was satisfactory, although the quality varies greatly depending on the type of source. Patients should be cautious when using TikTok as a source of TC-related information. Thyroid cancer is the most common malignancy of the endocrine system, with the differentiated thyroid cancers papillary and follicular accounting for the majority of new cases . FurtherDue to an increase in health awareness, people have a greater demand for health information, especially for patients suffering from cancer. Patients are increasingly demanding to be involved in decision-making process . Health Social media is an important way to disseminate information. However, social media is also a major source of misinformation, especially health relevant information. Misinformation tends to spread faster and more broadly than verified information due to the diversity of users and lack of monitoring and censorship mechanisms. Several studies have shown the potential for social media to be misleading in disseminating health information . TikTok Although TC is a disease with a good prognosis, receiving a cancer diagnosis is a sensational event for the general person. Correct dissemination of TC-related health information plays an important role in enhancing patient belief and maintaining good patient–physician relationships. However, to our knowledge, the quality of short video content regarding to TC has not yet been analyzed. To address this gap, this study aims to assess the quality of the short videos about TC from TikTok.n = 8), duplicated (n = 36), as shown in the Keywords “甲状腺癌” and “甲状腺肿瘤” (“Thyroid cancer” and “thyroid neoplasm” in Chinese) was searched within TikTok app on March 20, 2022. The first 100 videos that appeared on each search were reviewed. A total of 56 videos were finally included for analyzing in this study after excluding videos with advertising content , and health organizations (for-profit organizations). In order to confirm the authenticity of the included videos, we not only carefully checked the registration information of the video uploader’s account, but also accessed the official website of the hospital where the video author worked to confirm the author’s real identity. Information of videos was extracted and coded, including source of video, the content of the videos, the presence of animation, duration (in seconds), the upload date, and other viewer interactive quality markers including number of views, likes, and comments. The VPI was calculated using the formula “(number of likes/number of views) × 100)” .Videos were assessed from two aspects: the quality of information and their contents. The quality of information was rated using an adapted DISCERN tool by Singh et al.  considerContent score was rated in terms of six predefined questions . To facilitate statistical analysis, we recorded the basic information of each video  and basic information of the video publisher . Two reviewers independently appraised the quality of the included videos.This study focused on the quality assessment of TikTok videos contributed and viewed by the public, so ethics committee approval was not required.p < 0.05 was considered statistically significant.Statistical analysis was made using IBM SPSS Statistics for Windows, version 19.0. The statistical analysis methods used include descriptive statistical analysis, Pearson correlation analysis, and one-way ANOVA. The continuous variables were expressed as mean ± standard deviation, median (min-max), while nominal variables were given as frequency and percentage. Of the 56 videos included in this study, 49 (87.5%) were uploaded by physicians, 4 (7.1%) by health organizations, and 3 (5.4%) by hospital channels. There wasn’t video from patients or their relatives. Forty three (76.8%) videos were real content videos, 13 (23.2%) were videos with animation.p = 0.002), physicians (p < 0.001).The duration of the videos varied from 5 to 111 s. The least online days of video were 2 days prior to data collection, whereas the most online days were nearly 3 years. Median (min-max) number of views, likes, comments, collection, sharing, and VPI were 46,211 , 1378.5 , 83 , 82.5 (1–1775), 130.5  and 2.5 (2–8.82) prior to data collection. There were no significant differences among different sources of video  regarding such video characteristics mentioned above except for VPI between health organization and hospital channel (κ = 0.72 (p < 0.001). Regarding the source of videos, the videos contributed by hospital (4.0 ± 0.12) and physicians (3.4 ± 0.7) had higher DISCERN scores than the one by the health organization (2.3 ± 0.5). Significant quality difference was observed between health organizations and hospitals (p = 0.014), physicians (p = 0.006). More than 85% of videos have a DISCERN score greater than 3 (κ-coefficient for content scores was 0.781 (p < 0.001), which indicated a good consistency between the two reviewers. The results also showed that most of videos sufficiently addressed definition , signs and symptoms , management , evaluation  and outcomes , while risk factors  were absent in 42.9% videos.The average DISCERN score given by the two reviewers was 3.44 ± 0.72, while the DISCERN score for individual reviewers was 3.5 ± 0.71 and 3.38 ± 0.73, respectively. A good agreement was observed, r than 3 . In addiThe top 10 videos, the source of videos, the video content, the upload date, and VPI values are given in r = 0.40, p = 0.002; animation: r = 0.52, p < 0.001). Both DISCERN score and content score were not correlated with VPI, and no correlation was noted between DISCERN score and content score, as shown in The duration of the video and presence of animation were positively correlated with VPI of videos  . The mosTikTok app has a strict audit system for video publishers of health knowledge sharing . TherefoFor videos found on TikTok, the video popularity attributes to many factors, such as the rules set by TikTok and common social interactions, even the psychological effects of the audience , which cAnimated videos in previous study  were repLimitations to this study should be mentioned. First, the search results on TikTok are dynamic over time; the results thus might vary with the use of different search dates and time. Second, the research results may vary according to the geographical location of the viewer. Third, video sampling retrieves only the first 100 in each search which can lead to inadequate coverage.In this study, we analyzed the quality of information provided by TikTok video regarding TC. The overall quality of information based on DISCERN scores and content scores was satisfactory. Our finding also supports TikTok as a new source of information on TC, and therefore, physicians and hospitals should embrace this evolving technology and provide videos with higher quality to improve patients’ awareness about TC. Patients should also be cautious when watching TC relevant videos on TikTok due to the complexity of VPI.The original contributions presented in the study are included in the article/LW and YL: Conceptualization and Methodology. JG and LX: Experiments and Data analysis. LW and YL: Writing. All authors contributed to the article and approved the submitted version.This work was supported by Science and Technology Department of Zhejiang Province (LGC21H200001) and Huzhou Science and Technology Bureau (2020GZ29).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The response of CQP at poly(DHRPCo)/GCE was not influenced by the presence of amoxicillin, ciprofloxacillin and paracetamol in addition to its high stability and reproducibility. It was applied for detection of CQP in various real samples, including three brands of tablets, human blood serum, and urine samples. The detected amount in tablets were in the range 98.4–103.2 % of their labeled value. Spike recovery results in human blood serum, urine, and tablet samples were 99.35–100.28 %, 99.03–100.32 %, and 98.40–100.41 %, respectively. Interference recovery results with less than 4.60 % error, the lower limit of detection and the wider dynamic range than most of the previously reported methods validate the potential applicability of the proposed method for CQP determination in various real samples with complex matrices.Chloroquine phosphate (CQP) is used for malaria treatment. As it is facing increasing resistance, it needs continuous monitoring using sensitive and specific detection methods. In this work, a voltammetric sensor was prepared by electropolymerization of a diresorcinate‐1,10‐phenanthrolinecobalt(II) complex on a glassy carbon electrode (poly(DHRPCo)/GCE) which was followingly characterized. Compared with a bare GCE, CQP showed single well shaped irreversible oxidative peak at the poly(DHRPCo)/GCE. The peak current showed excellent linearity with CQP concentration in the range of 0.005–300.0 μ The synthesis, characterization and electrochemical application of a novel mixed ligand Co(II) complex for SWV determination of Chloroquine phosphate CQP in biological and pharmaceutical formulations samples are reported. The developed sensor is validated by recovery, interference, and long‐term stability and reproducibility tests. The method showed excellent performance, making it an excellent candidate for determination of CQP in real samples. Chloroquine phosphate (7‐chloro‐4‐4‐diethylamino‐1‐methylbutyl amino‐quinoline diphosphate) ,2),Limited studies on the electrochemical determination of CQP in pharmaceutical and biological fluid samples have been reported using modified electrodes such as DNA modified carbon paste electrode,2) and requires one step for its production in comparison to other electrodes. By monitoring the non‐formation of white precipitate when the aqueous solution of the complex was treated with an aqueous silver nitrate solution, it was possible to verify that the modifier complex did not include counter chloride.Hence, in this work, a sensitive stripping electrochemical method was employed for the CQP determination in tablets and biological samples with GCE modified with diresorcinate‐1,10‐phenanthrolinecobalt(II) complex, which was synthesized using non‐toxic reagents , 1,10‐phenanthroline monohydrate , silver nitrate , potassium hexacyanoferrate(II) and potassium hexacyanoferrate(III) , resorcinol , potassium chloride  Ltd), sodium monohydrogen phosphate and sodium dihydrogen phosphate  Ltd), sulfuric acid , hydrochloric acid , and sodium hydroxide  were used without further purification.CH Instruments 760E potentiostat , pH meter , deionizer , centrifuge , electronic balance  were among the instruments used.m KCl) as reference electrode and Pt coil as counter electrode. Prior to every measurement, the working electrode was regenerated by scanning in blank solution until stable voltammogram was obtained. While electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) were used to characterize the modified electrode and/or investigate the electrochemical behavior of CQP at poly(DHRPCo), AdSSWV was employed for quantitative determination of CQP in the analyzed human blood serum, human urine, and three brands of tablet formulation samples.Electrochemical measurements were performed using a conventional three electrode system whereby poly(DHRPCo)/GCE or unmodified GCE as working electrode, Ag/AgCl (3.0 m DHRPCo in 0.1 m PBS of pH 7.0 between −0.8 and +1.8 V for 20 cycles at a scan rate of 100 mV s−1. The resulting modified electrode was rinsed with distilled water and scanned in monomer‐free 0.5 m H2SO4 between −0.8 and +0.8 V until a steady‐state CV was obtained.Poly(DHRPCo)/GCE was prepared following the reported electropolymerization procedure with substantial modification.m) of CQP was prepared by dissolving 257.95 mg of CQP in deionized water 100 mL of a volumetric flask. The working solution was prepared from the stock solution through serial dilution with 0.1 m PBS of the appropriate pH.A stock solution (5.0 mm) of the tablet were prepared by dissolving  tablet powder into a 100 mL volumetric flask and filled up to the mark with deionized water. Working solutions of CQP were further prepared from stock solution of each brand in pH 7.5 PBS.Three commercially available CQP tablets were purchased from local drug stores in Bahir Dar city, Ethiopia. Five weighed CQP tablets from each of the three tablet brands including; Addis pharmaceutical factory (APF), Ethiopia; Bayer Zydus Pharma Pvt Ltd (Resochin), India; and IPCA Laboratories Ltd (Lariago), India, with an average tablet mass of 307.60, 315.16, and 297.54 mg/tablet, respectively were ground and homogenized using a mortar and pestle. Stock solutions  for 15 cycles. From the Figure m CQP was recorded within the potential range of −0.8 to +1.8 V. Hence, due to current and over‐potential advantages, the optimized potential window for the electropolymerization of DHRPCo at GCE was between −0.8 to +1.8 V.The electropolymerization of 1.0 mm CQP was increased with the increasing number of cycles, which may be due to the increase in effective surface area of GCE as a result of modification /GCE displayed distinct redox peaks 6]3−/4− solution in 0.1 m KCl using CV. As can be seen in Figure 6]3−/4− at poly(DHRPCo)/GCE (curve b) were about three times higher than the currents recorded at the unmodified GCE (curve a). Besides, the peak‐to‐peak separations of GCE (ΔE=228.9 mV) and poly(DHRPCo)/GCE (ΔE=104.5 mV). This could be attributed to faster electron transfer kinetics and high electroactive surface area of the modified electrode compared with bare GCE.The electrochemical behavior of the modified electrode was examined in 10.0 mThe electroactive surface area of the electrodes was calculated from the slope value of the plot of current versus square root of scan rate of Figure 6]3−/4− (n=1), Ip is the peak current, A is the effective surface area, D is the diffusion coefficient of [Fe(CN)6]3−/4− (D=7.6×10−6 cm2 s−1), v is the scan rate, C is the concentration of the [Fe(CN)6]3−/4− (10.0 mm).Where n is the number of electrons transferred for 3−/4− in 0.1 m KCl over the frequency range of 0.01 to 10,000 Hz. As illustrated in Figure ct) of the electrode and the linear portion at the lower frequency region is an indicator of diffusion process of the electroactive species from the bulk to the solution‐electrode interface, all ruled by the recommended equivalent circuit /GCE and unmodified GCE.16, 18ct value of poly(DHRPCo)/GCE (206.6 Ω) was smaller than unmodified GCE (5427 Ω), indicating the surface of GCE greatly improved at poly(DHRPCo)/GCE and hence the electron transfer rate between the substrate and the analyte increase. The result obtained in EIS is in agreement with the results obtained in CV , Rct, and double layer capacitance (Cdl) for each studied electrode as calculated from the respective Nyquist plot using Equation (2), and the apparent heterogeneous electron transfer rate constant (k0) calculated using eq. 3,3−/4− (10.0 mm).Where C0 value for the poly(DHRPCo)/GCE than the unmodified GCE clearly indicates the electrocatalytic property of the modified electrode towards the probe.As can be seen from Table ct) values of the poly(DHRPCo)/GCE confirmed excellent catalytic property of an electrode surface, its catalytic effect towards CQP was examined. The electrochemical behavior of 1.0 mm CQP in pH 7.0 PBS at GCE and poly(DHRPCo)/GCE was studied using CV /GCE, indicated the catalytic effect of the poly(DHRPCo)/GCE towards oxidation of CQP. The absence of any reduction peak on the reverse scan indicated that the oxidation of CQP is irreversible at both the unmodified GCE and poly(DHRPCo)/GCE.−1    Figure  than wit) Figure , suggest) Figure , which iWhile the observed peak potential shift of CQP with increasing the scan rate Figure  confirmeThe number of electron transferred during the electrochemical oxidation of CQP was calculated using Equation p and Ep1/2 obtained from the cyclic voltammogram of CQP at 100 mV s−1 scan rate were 1029 and 974 mV Ep and Ep1/2, respectively. The calculated value of an was 0.87. Since the value of a is 0.5 for a totally irreversible process,The values of E(an) of the electrode process during the electrochemical oxidation of CQP at poly(DHRPCo)/GCE was determined from the plot of Epa versus ln(v) using Equation The charge transferred coefficient p ‐ oxidation peak potential, E0 – formal potential, α ‐ electron transfer coefficient, n ‐ number of electrons, k0 ‐ standard constant rate of the reaction, DR – diffusion coefficient, ν – scan rate, T – temperature (298 K), R – molar gas constant (8.314 J mol−1 K−1), and F – Faraday constant .Epa versus RT/2n(1‐α)Fln(ν) for the linear fit  was 0.351. Taking the two electrons for oxidation of CQP calculated using Equation (5), the value of a was estimated to be 0.82, indicating the irreversibility of the oxidation of CQP at poly(DHRPCo)/GCE.From the slope of the plot of Et Figure , the calKa: 8.4),Ka values of 4.86&9.15, respectively).[The effect of pH on the peak current and peak potential of CQP was investigated to evaluate the participation of proton, proton:electron ratio, and rationalize the type of interaction between CQP and surface of the electrode (poly(DHRPCo)/GCE) in the pH range of 5.0–8.5 PBS Figure . The oxiThe peak potential shift to the negative direction with pH values from 5.0 to 8.5 indicated proton participation in the oxidation process,Based on the calculated kinetic parameters (number of electrons and protons), and the electron to proton ratio, a reaction mechanism was proposed Scheme , which iacc) and accumulation time (tacc) on the oxidation peak current for 1.0 mm CQP were investigated.Since the electrochemical oxidation of CQP at poly(DHRPCo)/GCE is governed predominantly by adsorption controlled process, the effects of accumulation potential /GCE. Appearance of a well‐shaped oxidative peak with much improved current at a reduced potential at poly(DHRPCo)/GCE (curve b of inset) than at the bare GCE (curve a of inset). These effects are a clear indication of the electro‐catalytic effect of the poly(DHRPCo) film for the oxidation of CQP.Adsorptive stripping square wave voltammetric (AdSSWV) method, which is effective and rapid electroanalytical technique due to its ability to discriminate against back ground currents, good sensitivity and low detection limits,29, 30To develop the AdSSWV method for CQP analysis, square wave parameters  were optimized. The effects of step potential, amplitude, and frequency on the peak current response were studied in the range from 2 to 12 mV, 15 to 45 mV and 10 to 35 Hz, respectively. Although the increase of peak current with increasing step potential, amplitude and square wave frequency are implicit, the parameters were optimized by making a compromise between the peak current increment and the shape of the peaks  and limit of quantification (LoQ=10s/m) were 0.39 and 1.36 nm, respectively.In order to assess the applicability of the developed sensor (poly(DHRPCo)/GCE) for the determination of CQP in tablet formulations, human blood serum, and urine samples. The calibration curve was constructed in the CQP concentration range of 0.005–300.0 μM under optimized SWV parameters and solution pH Figure  with %RSm of CQP for each tablet brand are presented in Figure Under the optimum conditions (adsorption and SWV parameters and solution pH), the applicability of the developed sensor for determination of CQP amount in each tablet brand samples listed under section 2.5 were investigated. The detected levels of each brand were compared with the labeled CQP amount in the samples. The AdSSWVs for 20.0 and 40.0 μThe analysis content in the range between 98.40–103.2 %, which is in excellent agreement with the labeled content of the tablets with RSD 3.3 %. Therefore, the developed method could be successfully applied for the determination of CQP in pharmaceutical formulations.A small peak exist at the characteristic potential of CQP /GCE. The experiment was performed by spiking 20.0, 40.0 and 80.0 μs Figure  and B. Am Resochin brand CQP tablet sample. As shown in Table m CPF, indicating the selectivity of the developed method (poly(DHRPCo)/GCE) for determination of CQP in real samples with the presence of potential interferents.To further elaborate the applicability of the proposed method, the selectivity of the poly(DHRPCo)/GCE for the determination of CQP was evaluated in the presence of interferents amoxicillin (AMX), ciprofloxacillin (CPF), and paracetamol (Parac). The effect of each selected interferent was investigated at various concentrations of the interferents Figure −C added m CQP in pH 7.5 of PBS for five separate electrodes prepared using similar fabrication process, very good reproducibility result was obtained which showed the %RSD below 3.46 %  stability of poly(DHRPCo)/GCE was examined by five successive AdSSWV measurements recorded at an interval of 1 week for 5 weeks with an error of only 2.50 % (%RSD) Figure . Similar% Figure . Hence, The performance of the present sensor was compared with previous reports for the determination of CQP in terms of modifier used, linear dynamic range, and LoD Table . Along wThe present study established a simple, nontoxic, cost‐effective, highly sensitive and selective method for the fabrication of voltammetric sensors for CQP based on the potentiodynamic electropolymerization of diresorcinate‐1,10‐phenanthrolinecobalt(II) complex on GCE. The fabricated sensor showed significant peaks current enhancement and over potential reduction as compared to the bare GCE. Poly(DHRPCo)/GCE was successfully utilized for AdSSWV determination of CQP with a promising wide linear dynamic range and lowest limit of detection. The sensor was successfully applied for determining CQP in human blood serum, urine, and tablet formulations of three brands with excellent recovery values. The effect of potential interferents such as AMX, CPF and Parac on the determination of CQP using the proposed sensor was also examined. Besides the simplicity of electrode modification process, stability and repeatability, excellent recovery results for pharmaceutical analysis suggest the potential of poly(DHRPCo)/GCE for direct determination of CQP in various real samples.The authors declare no conflict of interest.1


We aimed to validate the predictive factors for tumor response and the prognostic impact of conversion therapy aimed at cancer‐ and drug‐free states in patients with unresectable hepatocellular carcinoma (u‐HCC) undergoing atezolizumab plus bevacizumab (Atez/Bev) therapy.This retrospective study enrolled 156 patients who were Child‐Pugh class A with u‐HCC treated using Atez/Beva. The profile of objective response was investigated using decision‐tree analysis. Progression‐free, recurrence‐free, and overall survival were assessed.p = 0.008, Atez/Bev discontinuation; 3.9 months, p = 0.048, respectively) groups.The progression‐free and overall survival were 6.1 and 18.0 months, respectively. Objective response and disease control rates were 32.0% and 84.0%, respectively. Decision‐tree analysis revealed that neutrophil‐to‐lymphocyte ratio (NLR) <3, modified albumin‐bilirubin grade (m‐ALBI) 1 or 2a, and age < 75 were sequential splitting variables for the objective response, respectively. In the multivariate analysis, NLR <3 and m‐ALBI grade 1 or 2a were identified as predictive factors for objective response. We successfully achieved eligibility for conversion therapy in 17 patients after Atez/Bev therapy significant response. Following conversion therapy, the curative therapy group, including surgical resection or radiofrequency ablation (RFA), had significantly higher recurrence‐free survival than did the transcatheter arterial chemoembolization (TACE) and Atez/Bev discontinuation (surgical resection or RFA; not reached vs. TACE; 5.3 months, NLR <3 and m‐ALBI grade 1 or 2a were predictive factors for conversion therapy, leading to cancer‐ and drug‐free states in patients with u‐HCC undergoing Atez/Bev therapy. Moreover, surgery or RFA may be suitable for conversion therapy for cancer‐free status. Overall survival duration in patients with HCC treated with Atez/Bev according to treatment response by RECIST. The black, dotted, and thin line indicates the PR, SD, and PD group, respectively. Additionally, we aimed to evaluate the impact of conversion therapy aimed at cancer‐ and drug‐free states after an effective response to Atez/Bev treatment.22.1Between 2020 and October 31, 2022, this multicenter retrospective cohort study enrolled 177 consecutive u‐HCC patients treated with Atez/Bev at seven Japanese institutions. The following eligibility criteria were used: (i) age > 18 years; (ii) Eastern Cooperative Oncology Group performance status (PS) <2; and (iii) clinical data were available and it could follow‐up until study cessation  or death. Exclusion criteria were as follows: (i) Child‐Pugh class B or C; (ii) history of autoimmune disease; and (iii) active esophageal varices. Thus, 21 patients were excluded. Finally, this study enrolled 156 patients Figure .This research was conducted according to the Helsinki Declaration and approved by the Ethics Committee of the Kurume University School of Medicine . An opt‐out approach was used to obtain informed consent from patients.2.2HCC confirmation was based on hypervascularization in the arterial phase and washout in the portal venous phase or delayed phase on CT or MRI examination. Additionally, in MRI, focal areas with a suspicious hypointense signal in the hepatobiliary phase were used to detect HCC. For the cutoff of tumor marker level, AFP ≥7 was considered positive in this study. HCC was diagnosed using a combination of serum markers and imaging following recommendations of The Japan Society of Hepatology.2.3The patient was administrated Atez/Bev according to the recommended dosage (1200 mg of Atez and 15 mg/kg of Bev intravenously every 3 weeks). The clinical guidelines for Atez/Bev created by the manufacturer were used for the discontinuation of each component agent if a treatment‐related adverse event occurred. Atezolizumab therapy was interrupted when any unacceptable grade 2 or over grade 3 immune‐related AEs occurred such as liver injury, skin disorder, and drug‐induced pneumonia.2.4The Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1).2.5We defined eligibility for conversion therapy as follows: (1) no viable lesion on CT or MRI (such as necrotic cases) scans and range within normal values for tumor markers; AFP was the independent risk factor for early recurrence after surgical resection for HCC,2.6A decision‐tree algorithm was constructed to reveal the profiles' relationship with conversion therapy and objective response (OR) following the instructions provided with the R software package as described previously.2.7p < 0.05. Statistical analyses were performed using JMP software .All provided data were described as medians (ranges). Between‐group comparisons were carried out using the Mann–Whitney U test, the Kruskal–Wallis test, and a nonparametric analysis of variance. If the one‐way analysis of variance was significant, differences between individual groups were analyzed using the Fisher least significant difference test. Evaluation of PFS, recurrence‐free survival (RFS), and OS was carried out using the Kaplan–Meier method, and statistical differences were evaluated with the log‐rank test or Bonferroni method. A decision‐tree analysis was carried out to investigate the factors of conversion therapy and objective response (OR), as previously described.33.1The characteristics of the 156 patients are listed in Table 3.2The median PFS and median survival time (MST) were 6.1 and 18.0 months Figure . In the 3.3In the present study, the conversion therapy rate in all participants was 10.9% . In addition, the SD group had a significantly higher MST than the PD group .The MST was not reached, 15.7 months, and 8.4 months among patients who achieved PR, SD, and PD, respectively Figure . The PR 3.5In the present study, the OR rate in all participants was 32.0% . Five, three, and three patients underwent surgery, RFA, and transarterial chemoembolization, respectively, as a treatment for conversion therapy. The prevalence of curative therapy as surgery and RFA was 47.1% (Table 3.9p < 0.001)  Figure .3.10The characteristics of patients at the time of receipt of conversion therapy are listed in Table 3.11Figure 3.12Table 4In this multicenter investigation, we demonstrated that NLR <3 and m‐ALBI grade 1 or 2a were significant predictive factors for therapeutic response and conversion therapy, leading to cancer‐ and drug‐free patients treated with Atez/Bev. Moreover, we found that curative conversion therapy may be important in achieving long‐term RFS after Atez/Bev significant response.We revealed that NLR <3 and m‐ALBI grade 1 or 2a were significant predictive factors for therapeutic response and conversion therapy leading to cancer‐ and drug‐free status in u‐HCC patients treated with Atez/Bev. Ochi et al. reported that low NLR can predict therapeutic response in patients with m‐ALBI grade 1 or 2a treated with Atez/Bev.Conversion therapy aims to reduce tumor volume and provide a chance at curative surgery for unresectable cancer patients.In this study, our findings demonstrated that the curative therapy group had a significantly higher RFS than the non‐curative therapy group after Atez/Bev significant response. To our knowledge, this is the first study to show the importance of curative conversion therapy after Atez/Bev significant response. Recently, Xiao et al. reported that RFS was 75% at 12 months in HCC patients who underwent hepatectomy after treatment with tyrosine kinase inhibitor and anti‐PD‐1 Antibody combination therapy.The present study had several limitations. First, it was a retrospective study. Second, the study included approximately 40% of patients who were treated with Atez/Bev as second‐line or later treatment. Third, HCC was not evaluated using The Liver Imaging Reporting and Data System.In conclusion, NLR <3 and m‐ALBI grade 1 or 2a were significant predictive factors for therapeutic response and conversion therapy, leading to cancer‐ and drug‐free patients with u‐HCC treated with Atez/Bev. Moreover, curative conversion therapy may be important in achieving long‐term RFS after Atez/Bev significant response.This study has nothing to report.Shigeo Shimose: Conceptualization (lead); investigation ; project administration ; writing – original draft (lead). Hideki Iwamoto: Conceptualization ; formal analysis . Tomotake Shirono: Data curation (supporting). Masatoshi Tanaka: Data curation (supporting). Takashi Niizeki: Data curation . Masahiko Kajiwara: Data curation . Satoshi Itano: Data curation . Yoichi Yano: Data curation . Satoru Matsugaki: Data curation . Etsuko Moriyama: Data curation . Yu Noda: Data curation . Masahito Nakano: Data curation . Ryoko Kuromatsu: Data curation . Hironori Koga: Writing – review and editing (lead). Takumi Kawaguchi: Writing – review and editing (lead).This study has nothing to report.Takumi Kawaguchi received honoraria (lecture fees) from Janssen Pharmaceutical K.K., Otsuka Pharmaceutical Co., Ltd, Taisho Pharmaceutical Co., Ltd., and EA Pharma Co., Ltd. The other authors declare no conflicts of interest.The present study was approved by the Ethics Committee of Kurume University .Figure S1.Click here for additional data file.Figure S2.Click here for additional data file.Figure S3.Click here for additional data file.Table S1–S4.Click here for additional data file.


Myotis myotis) in relation to changes of the ambient temperature. For this purpose, we investigated the effect of ambient temperature on the phenology of the greater mouse‐eared bat by using activity data of the bats collected using light barriers at the maternity roosts. The light barrier used in this study is a system that detects the interruption of two light beams, for example, by a flying bat, and displays it as an electrical signal.In order to assess the consequences of climate change and evaluate its impacts on wildlife, it is essential to do so on a species‐specific level. It is assumed that changes in the ambient temperature influence energy consumption as well as food availability and thus foraging behavior, reproduction, survival, and therefore population dynamics in bats. Based on this assumption, the present study aims to gain insights into the roosting and breeding behavior of the greater mouse‐eared bat  in relation to the ambient temperature (Ta). This study highlights, that in order to understand the impact of climate change on biodiversity it is necessary to investigate in detail effects on a species‐specific level and also to consider effects of Ta on different life history stages.The present study aims to gain insights into the roosting and breeding behavior of the greater mouse‐eared bat ( Numerous studies have shown that climate change alters the phenology of both plant and animal species. Spring events such as flowering, reproduction, emergence after hibernation, and migration have occurred earlier in the last few years for numerous species, vegetation periods lengthen and, in extreme cases, geographical ranges of species change  below their thermoneutral zone  to Ta. If the torpid state lasts only a few hours, this is called daily torpor  are a species‐rich, globally distributed group of mammals with different feeding and reproductive strategies. They perform key ecological services, such as pest suppression, pollinating plants, or dispersing seeds  .A relationship has been found between spring temperature and reproductive success in bats  that had higher body mass after warmer‐than‐average periods . This is because it increases with increasing Ta and Tb, because of a higher frequency of energy consuming arousals, but also due to the Q10 effect, which describes the temperature dependence of biochemical reaction rates  in relation to changes in Ta. We investigated the influence of Ta for three annually key events that represent important aspects of bat phenology. Therefore, we analyzed whether Ta during hibernation, spring and lactation has an influence on the following events:the timing of the formation of the maternity colony,the beginning of the birth season and,the dissolution of the maternity roost.As shown above, changes in Tas in winter lead to an earlier emergence from hibernation in greater mouse‐eared bats and an earlier formation of the maternity colony. In maternity roosts, a high Ta in spring reduces the time spent in torpor and lowers thermoregulation costs for the mothers and improves insect availability, which leads to faster embryonic development  were used. For this purpose, the weather station with the shortest distance to the respective maternity roost was selected  and the daily maximum Ta (Tamax), which were both measured at 2 m above the ground. The daily mean temperature (Tamean) results from the daily mean of 24‐hourly values. The reference period for a day lasts from 23:51 UTC of the previous day to 23:50 UTC.For the statistical analyses of the data, we used the following T2.62.6.1a on the three key events. To analyze the effect of winter Ta on the timing of the formation of the maternity colony, we used the mean daily minimum temperature during hibernation (Taminhib) which lasts from 1st November of the previous year until 31st March of the respective study year. Tamin was used because it has a decisive influence on energy consumption during hibernation. Temperatures in the winter roosts of the greater mouse‐eared bats are assumed to be quite constant and buffered against daily fluctuations of the Ta outside  fluctuations.Time periods were defined to analyze the influence of Te Perry, . For thia on gestation length, the mean daily maximum Ta in spring (Tamaxspring) lasting from 1st April until 31st June of a respective year was used, as this is the period when females are pregnant. To analyze the effect of Ta on the timing of the dissolution of the maternity roost, the mean daily maximum Ta during lactation (Tamaxlac) lasting from 15th May to 31st July was used, as this period covers the time period when females are lactating. Tamax was included into the models concerning the timing of the birth season and of the dissolution of the maternity roosts, as thermoregulatory costs and insect availability is assumed to depend mainly on Tamax.To analyze the effect of T2.6.2a on the different key events, we used linear mixed effects models, function ‘lmer’ from the lme4 package  represented the dependent variables and Ta as covariable, including the maternity colony as random effect. Dates of key events are given as Julian date, defined as the continuous count of days in the year. We chose a Taminhib of 0.5°C as a cutoff for the timing of the maternity colony formation due to visual inspection of the figure  and conditional (R2c) pseudo‐R2s for generalized mixed effects models : Estimate = −3.17, SD = 1.44, t‐value = −2.20, p‐value = .03). When Taminhib was above 0.5°C, there was no temperature effect on the formation date (Table >0.5°C: FM = Taminhib + (1|colony): Estimate = 0.88, SD = 1.52, t‐value = 0.58, p‐value = .57).With a T3.2amaxspring showed a highly significant effect on the beginning of births : Estimate = −4.89, SD = 0.43, t‐value = −11.32, p‐value = <.0001). The higher Tamaxspring, the earlier the births started in the respective study year. For each degree of temperature increase (Tamaxspring), greater mouse‐eared bat births occurred almost 5 days earlier (Table amaxspring + FM + (1|colony): EstimateFM = −0.03, SDFM = 0.07, t‐valueFM = −0.40, p‐valueFM = .69).Ter Table . Althoug3.3amaxlac + BB + (1|colony): EstimateBB = 0.39, SDBB = 0.11, t‐valueBB = 3.63, p‐valueBB = .0007). The earlier the births occurred in a year, the earlier the dissolution of the maternity roosts could be observed. For each day the birth season started earlier, the dissolution advanced by nearly 0.4 days : EstimateTamaxlac = −1.71, SDTamaxlac = 0.80, t‐valueTamaxlac = −2.15, p‐valueTamaxlac = .04). The analyses showed that for each degree of higher Tamaxlac, the maternity colony population dissolved up to 1.7 days earlier  and Natterer's bat (Myotis nattereri) ; data curation ; formal analysis (lead); investigation (lead); methodology (lead); validation (lead); visualization (lead); writing – original draft (lead); writing – review and editing (lead). Karl Kugelschafter: Data curation ; investigation (supporting); resources (lead); software ; writing – review and editing (supporting). Joanna Fietz: Conceptualization (supporting); formal analysis (supporting); methodology (supporting); supervision (lead); validation (supporting); visualization (supporting); writing – review and editing (supporting).No funding has been received.The authors declare no conflict of interest.


However, the CD2–CD58 axis, an important component of the immunological synapse, remains unknown in LGG.Low‐grade gliomas (LGGs) are currently considered a premalignant condition for high‐grade gliomas (HGGs) and are characterized by a relatively intact immune system. Immunotherapeutic modalities may offer a safe and effective treatment option for these patients. RNA‐seq data from TCGA databases were analyzed. Immune cell infiltration was determined using a single‐sample gene set enrichment analysis (ssGSEA) based on integrated immune gene sets from published studies. Kaplan–Meier survival analysis, univariate and multivariate logistic analysis, and the ESTIMATE algorithm were employed to evaluate the impact of the CD2–CD58 axis on adult LGG patients.p < .05). Uni‐ and multi‐variable logistic analysis demonstrated that age, WHO grade, and CD58 levels were associated with poor prognosis in LGG patients with (p < .01). MetaSape pathways analysis revealed the involvement of CD58 in regulating T cell activation, leukocyte‐mediated immunity, and the positive regulation of cell activation in WHO grade II and III. CD58 expression correlated with infiltrations of CD4+ lymphocytes, NK cells, and macrophages cells. The ESTIMATE algorithm indicated that patients with high CD58 expression had significantly higher immune scores compared with low CD58 expression in WHO grade II/III, but no statistical difference was observed in WHO grade IV (p < .05). Furthermore, correlation analysis demonstrated the significant association between CD58 and CD274 , HAVCR2 , and LGALS9 . Immunohistochemical staining further confirmed the relationship of CD58, HAVCR2, WHO grade, and prognosis in grade II and III patients.The expression of the CD2–CD58 axis was found to be elevated with increasing of WHO grade (Overall, our findings highlight the significant association between the CD2–CD58 axis and poor survival in LGG patients. High CD58 expression is implicated in T cell‐mediated immune responses as an immunosuppressive factor and affect inhibitory immune checkpoint genes. CD2‐CD58 axis is notably related to poor survival of LGGs, and high CD58 expression is involved in T cell‐mediated immune responses as an immunosuppressive factor by affecting inhibitory immune checkpoint genes. The dataset included 216 grade II, 241 grade III, and 152 grade IV patients. Two patients were excluded due to age (<18 years). Raw RNA‐seq data were normalized using the LIMMA package in the R platform. The infiltration cell types and the levels of immune cell were determined using Cibersort with default parameters.A total of 609 expression profiles were acquired from the TCGA database . The low expression group for CD2, CD48, CD58, and CD59 was used as the reference, with adjustment for tumor stage. A P‐value of <0.05 indicated a statistically significant difference, designating the respective gene as a prognostic gene.Normalized mRNA gene levels of CD2, CD48, CD58, CD59, and clinical outcomes were used for survival analysis. Patients were categorized into high and low expression groups based on the median value of genes. Multivariate logistic regressive analysis evaluated the prognostic values of CD2, CD48, CD59, and CD59 using the survival package in the R platform (2.3https://github.com/GuangchuangYu/enrichplot). Additionally, GSEA (http://software.broadinstitute.org/gsea/index.jsp) was conducted to assess the biological pathways associated with the prognostic CD2–CD58 axis. GSEA utilized the Molecular Signatures Database  c2 .The LIMMA package was used for differential analysis, and the GO and KEEG analyses of DEGs were performed using the clusterProfiler and enrichplot packages (2.4The “GSVA” package was used for single‐sample GSEA (ssGSEA) to quantify immune cell infiltration kinds and levels based on the TPM values of each sample. The R package “ESTIMATE” was used to evaluate the immune score, stromal score, and ESTIMATEScore of different groups. Moreover, Spearman's correlation analysis was conducted to evaluate the correlations between the 28 immune cell types in tumor samples.2.5The study included 32 patients  enrolled at Qinzhou First People's Hospital from February 2010 to August 2020. The study protocols adhered to the ethical guidelines of the Declaration of Helsinki and were approved by the Internal Review Board of Qinzhou First People's Hospital. Tissue sections of 4‐μm were incubated with primary antibodies against CD58 , HAVCR2 , and LGALS9 . An H‐score was calculated based on the staining intensity and positive ratio, ranging from 0 to 12.2.6https://www.r-project.org). The median TPM value of the CD2–CD58 axis served as the cutoff value to separate patients into the high and low groups. Survival analyses were performed using the Kaplan–Meier method and the Cox proportional hazard regression model. A value of p < .05 was considered to indicate a statistically significant difference.Statistical analyses were conducted using SPSS version 19.0 software (IBM Corp.) and R3.3.1 (33.1p < .001). However, there was no statistical difference regarding sex among patients with grades II–IV (p = .14).A total of 607 glioma patients were included in the transcriptomic analysis, consisting of 352 males and 255 females, with average age of 47.43 ± 0.62 years (range: 18–89 years). The analysis revealed a correlation between the WHO classification and various clinical and pathological features. Elderly patients had a higher representation of higher WHO grades, along with increased death incidence and wild‐type IDH status in Table 3.2p < .001), while there was no significant difference in CD59 expression between the WHO II–IV groups. Gene expression profiling interactive analysis (GEPIA) revealed that CD2, CD48, and CD58 were associated with the poor OS in LGG patients in Figure p < .001), followed by CD2  and CD48 . Pearson's correlation analysis demonstrated the positive correlation between CD2 and CD48 in WHO II , WHO III , and WHO IV . Similarly, CD2 showed a positive correlation with CD58 in WHO II , WHO III , and WHO IV  gliomas in Figure p < .001), WHO grade , and CD58 levels  as independent risk factors for poor prognosis, as seen in in Table The expression levels of CD2, CD48, and CD58 were the lowest in the WHO II gliomas, and the highest in the WHO IV group, as shown in Table 3.3n = 597). Differential analysis identified 81 upregulated genes and 61 downregulated genes in the high CD58 group compared to the low CD58 group , as seen in Figure Based on the median mRNA level of CD58, the patients were divided into high‐ and low‐CD58 groups (3.4p < .05), as shown in Figure p < .001), while no difference was observed in WHO grade IV gliomas (p > .05), as shown in Figure A heatmap analysis was performed to uncover the types and ratios of immune cells in LGG patients, as shown in Figure 3.5p < .001). Uni‐ and multivariable logistic regression analyses identified HAVCR2 and LGALS9 as independent risk factors for poor prognosis in LGG patients in Table We examined the correlation between CD58 and stimulatory or inhibitory immune checkpoint genes in LGG patients, as shown in Figure 3.6t‐test revealed higher H‐scores of CD58, HAVCR2, and LGALS9 in WHO grade III compared to WHO grade II gliomas (p < .05), as shown in Figure p = .027), as shown in Figure A total of 32 LGG patients  were included in this study, including 17 grade II and 15 grade III cases. Immunohistochemistry (IHC) analysis was performed to measure the expression of CD58, HAVCR2, and LGALS9, as shown in Figure 4Gliomas, the most common primary malignant brain tumors, present a therapeutic challenge due to their heterogeneity in clinical behavior.The tumor immune microenvironment plays a crucial role in tumorigenesis, tumor progression, and recurrence.Furthermore, our study highlighted the critical role of the tumor immune microenvironment in glioma progression and recurrence. Our findings from the TCGA database and our cohort demonstrated that CD2–CD58 axis expression levels are associated with WHO grades in LGG patients. Cox's regression analysis identified CD58 as an independent prognostic marker for poor prognosis in LGG patients. Recent findings in the molecular landscape of adult LGG have refined the understanding of the heterogenous tumor populations. Notably, CD58 is implicated in immune cell infiltration in WHO grade II and III but not in WHO grade IV patients. CD58 enhances immune escape by affecting T cell activation and leukocyte‐mediated immunity, potentially contributing to poor prognosis in tumors.The immune competence in cancer has a significant impact on the efficacy of conventional medical therapy. Immune checkpoint inhibitors, such as those targeting cytotoxic T lymphocyte‐associated molecule 4 (CTLA‐4), programmed cell death receptor 1 , and programmed cell death ligand 1 , have revolutionized cancer treatment.Additionally, our study demonstrated a close association between CD58 and the TIM‐3/GAL9 immune checkpoint, rather than CTLA‐4 or PD‐1/PDL‐1 signaling, in LGG patients. Uni‐variable and multi‐variable logistic analyses identified TIM‐3 and GAL9 as independent risk factors for poor prognosis in LGG patients. IHC experiments supported the correlation between TIM‐3 expression (measured by H‐score) and poor prognosis. We speculate that the disruption of the CD2–CD58–TIM‐3 axis contributes to immune evasion in LGG patients, potentially leading to intrinsic resistance to CAR T cell therapy. This finding highlights the heterogeneity within LGGs and suggests that CD58 may play a role in immune escape mechanisms and contribute to poor prognosis in these tumors. Understanding the immune landscape and the interactions between tumor cells and immune cells is crucial for developing effective immunotherapeutic strategies tailored to individual patients. These findings expand the repertoire of immune checkpoints that can be targeted to enhance anticancer immune responses and overcome treatment resistance in LGGs patients.In summary, immune checkpoint modulators have become integral to immunotherapy in the field of oncology. Our study highlights the CD2–CD58 axis‐related immune signature as a valuable prognostic biomarker in LGG patients, with increased CD58 expression potentially serving as an immune evasion mechanism. Considering the heterogeneity across patients and WHO grades, individualized combination strategies targeting TIM‐3/GAL9 could enhance the efficacy of immunomodulatory approaches and overcome treatment resistance in LGG patients.mingwei Wu: Data curation; Resources; Writing—original draft. yiyuan Chen: Formal analysis; Methodology. Gao Hua: Investigation; Validation. Liu Chunhui: Project administration; Writing—review & editing.The authors declare no conflict of interest.