Sex-determining region Y-box 2 (SOX2), a well-known stemness biomarker, is highly expressed in a variety of cancers, including human highly invasive bladder cancer (BC). However, the role of SOX2 may vary in different kinds of malignancy. In the present study, we discovered that ChlA-F, a novel conformation derivative of isolate Cheliensisin A (Chel A), remarkably inhibits the invasive ability of human invasive BC cells through downregulation of SOX2 protein expression. We found that ChlA-F treatment dramatically decreases SOX2 protein expression in human high-grade invasive BC cells. Ectopic expression of SOX2 reversed ChlA-F inhibition of cell invasion ability in human bladder cancer cells, suggesting that SOX2 is a major target of ChlA-F during its inhibition of human BC invasion. Mechanistic studies revealed that ChlA-F downregulates SOX2 at both the protein degradation and protein translation levels. Further studies revealed that ChlA-F treatment induces HuR protein expression and that the increased HuR interacts with USP8 mRNA, resulting in elevation of USP8 mRNA stability and protein expression. Elevated USP8 subsequently acts as an E3 ligase to promote SOX2 ubiquitination and protein degradation. We also found that ChlA-F treatment substantially increases c-Jun phosphorylation at Ser63 and Ser73, initiating miR-200c transcription. The increased miR-200c directly binds to the 3′-UTR of SOX2 mRNA to suppress SOX2 protein translation. These results present novel mechanistic insight into understanding SOX2 inhibition upon ChlA-F treatment and provide important information for further exploration of ChlA-F as a new therapeutic compound for the treatment of highly invasive/metastatic human BC patients.

Knee osteoarthritis (KOA) is a common, chronic, degenerative disease. Platelet-rich plasma (PRP) can significantly relieve KOA pain; however, the mechanism of PRP-induced analgesia remains to be studied. Macrophages are closely related to KOA pain, and regulating macrophage polarization may be an effective way to relieve KOA pain. Therefore, the aim of this study is: First, to explore whether PRP can effectively relieve pain in a KOA animal model and whether it relieves pain by regulating macrophage polarization. Second, to explore the mechanism by which PRP regulates macrophage polarization. Thirty-six healthy male SD rats were randomly divided into sham group, MIA group and PRP group. The KOA rat model was established by injecting 1 mg of MIA into the joint cavity. Behavioral tests, including weight-bearing asymmetry, hot plate, and von Frey hairs tests, were performed. The positive expression rates of inducible nitric oxide synthase (iNOS) and CD163 in the synovium were detected via immunohistochemical staining. Meanwhile, RAW 264.7 cells induced by lipopolysaccharide were treated with PRP in vitro. The production levels of the nuclear factor kappa-B (NF-κB) pathway-related proteins NF-κB p65, inhibitor-κ binding protein α (IκBα), p-NF-κB p65, p-IκBα and the iNOS and CD163 proteins were measured via western blotting. An enzyme-linked immunosorbent assay was used to detect the release of tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1β), interleukin-10 (IL-10), and nerve growth factor (NGF). The behavioral results revealed that PRP relieved pain. PRP reduced the proportion of M1/M2 macrophages among synovial macrophages, significantly inhibited the secretion of TNF-α and IL-1β in the synovium, and increased the secretion of IL-10. In addition, in vivo experiments revealed that PRP decreased the protein expression of iNOS, p-IκBα/IκBα, and p-p65/p65 and increased the protein expression of CD163. Furthermore, PRP decreased TNF-α, IL-1β, and NGF levels in RAW 264.7 cells and increased the secretion of IL-10. Our findings indicate that PRP can improve long-term relief from KOA pain. The analgesic mechanism promotes the transformation of M1 macrophages to M2 macrophages by inhibiting the NF-κB signaling pathway, which reduces the release of downstream pain-causing factors, thus relieving inflammation and pain.

Abstract Background NUP98-rearranged AML has a dismal prognosis with a 2-year OS of less than 35% with current therapies. The combination of hypomethylating agents and BCL-2 inhibitors venetoclax shows promise in some AML patients, and CDK6 inhibitor palbociclib has demonstrated potential anti-leukemia activity in preclinical models. Thus, a multi-center, phase 2 cohort study was conducted to evaluate the efficacy and safety of this combination therapy (palbociclib, venetoclax and azacitidine, VAP) in these patients. Methods This multi-center, single-arm, phase 2 cohort study was conducted across 34 hospitals of China. Eligible patients were aged 0 to 18 years with newly diagnosed NUP98- rearranged AML after induction chemotherapy, or those with refractory or relapsed AML with NUP98 fusions. Patients received azacitidine 75mg/m2 via subcutaneous injection on day 1-7, palbociclib 50mg/m2 via oral administration on day 8-28, and venetoclax 50mg/m2 on day 1, 100mg/m2 on day 2, and 200mg/m2 on day 3-28 via oral administration (VAP regimen). The primary endpoint was the composite of complete remission (CR) and complete remission with incomplete hematologic recovery (CRi), as defined by the International Working Group (IWG) criteria. The secondary endpoints included the overall response rate, minimal residual disease (MRD) status, relapse rate, 2-year overall survival (OS), 2-year event-free survival (EFS), duration of response, and safety. The trial is registered with the Chinese Clinical Trial Registry (ChiCTR2300074396) and conducted in accordance with Good Clinical Practice guidelines. Findings From December 2022 to March 2024, nine patients were enrolled, including six (66.7%) patients with NUP98-NSD1 fusions, two (22.2%) patients with NUP98-KDM5A fusions, and one (11.1%) patient with NUP98-TOP1 fusion. Six patients achieved CR with MRD negativity. All patients with NUP98-NSD1 fusions demonstrated complete molecular remission eventually, while those with NUP98-KDM5A or NUP98-TOP1 fusions had persistent positivity. The median OS and EFS were 21 months and 13 months, respectively. The 2-year OS and EFS rates were 88.9% and 77.8%. Treatment-related adverse events were uncommon, including cytopenia, febrile neutropenia, tumor lysis syndrome and pneumonia. No treatment-related deaths were reported. Conclusion The combination of palbociclib, venetoclax and azacitidine is a safe and effective treatment for pediatric patients with NUP98-rearranged AML. It achieved high rates of durable remission at morphological, immunophenotypic, and molecular levels, offering promising long-term survival outcomes. This regimen could become a new standard of care for this high-risk subgroup, potentially redefining frontline therapy, although larger studies with longer follow-up are needed to confirm these findings.

Objective To investigate the analgesic effect of transcranial direct current stimulation (tDCS) on chronic pain in a rat model of monosodium iodoacetate (MIA)-induced osteoarthritis (OA) and its mechanism. Methods Healthy male Sprague-Dawley rats were randomly divided into sham-operation group, MIA group, tDCS group, and sham-tDCS group, with 9 rats in each group. The rats in the sham-operation group were given intra-articular injection of normal saline into the left knee joint, and those in the MIA group, the tDCS group, and the sham-tDCS group were given MIA injection at the same site to establish a model of chronic pain in OA. On day 21 after MIA injection, the rats in the tDCS group and the sham-tDCS group were treated with real or sham tDCS, respectively, for 8 d. The pain behavioral test was performed for the rats in each group on day 1, 2, and 7 after treatment; the periaqueductal gray (PAG) of rats were collected on day 2 after treatment and Western blot was used to measure the expression of brain-derived neurotrophic factor (BDNF). Results The pain behavioral test showed that compared with the sham-tDCS group, the tDCS group had a significantly longer thermal paw withdrawal latency at each time point after treatment (F=11.25-21.48,P<0.01) and a significantly higher mechanical paw withdrawal threshold at each time point after treatment (F=54.42-186.40,P<0.01). Western blot showed that compared with the sham-tDCS group, the tDCS group had a significant reduction in the protein expression of BDNF in PAG tissue (F=24.70,P<0.01). Conclusion This study shows that tDCS can effectively alleviate chronic pain in rats with MIA-induced OA, and such therapeutic effect can last till day 7 after treatment; tDCS exerts an analgesic effect possibly by downregulating the expression of BDNF and reducing neuronal excitability in PAG tissue of rats with MIA-induced OA.

Abstract Background Infection is the most common adverse event of acute lymphoblastic leukemia (ALL) treatment and is also one of the main causes of death. Methods To investigate the clinical characteristics and risk factors of severe infections during the maintenance phase of ALL treatment, we conducted a retrospective study. Results A total of 181 children were eligible and 46 patients (25.4%) suffered from 51 events of severe infection, most of which occurred in the first half year of the maintenance phase (52.9%). The most common infection was pulmonary infection (86.3%) followed by bloodstream infection (19.6%). The main symptoms of ALL patients with pulmonary infection were fever, cough, and shortness of breath. The main manifestations of computer tomography (CT) were ground glass shadow (56.8%), consolidation shadow (27.3%), and streak shadow (25%). Multivariate binary logistic regression analysis showed that agranulocytosis, agranulocytosis ≥7 days, anemia, and low globulin level were independent risk factors for severe infection during the maintenance phase (all p < 0.05). Conclusions Taken together, blood routine examinations and protein levels should be monitored regularly for ALL patients in the maintenance phase, especially in the first 6 months. For ALL patients with risk factors, preventive anti‐infective or supportive therapies can be given as appropriate to reduce the occurrence of severe infections.

BACKGROUNDAcute megakaryoblastic leukemia (AMKL) without Down syndrome (non-DS-AMKL) usually a worse outcome than DS-AMKL. Acquired trisomy 21(+21) was one of the most common cytogenetic abnormalities in non-DS-AMKL. Knowledge of the difference in the clinical characteristics and prognosis between non-DS-AMKL with +21 and those without +21 is limited.OBJECTIVEVerify the clinical characteristics and prognosis of non-DS-AMKL with +21.METHODWe retrospectively analyzed 33 non-DS-AMKL pediatric patients and 118 other types of AML, along with their clinical manifestations, laboratory data, and treatment response.RESULTSCompared with AMKL without +21, AMKL with +21 has a lower platelet count (44.04 ± 5.01G/L) at onset (P > 0.05). Differences in remission rates between AMKL and other types of AML were not significant. Acquired trisomy 8 in AMKL was negatively correlated with the long-term OS rate (P < 0.05), while +21 may not be an impact factor. Compared with the other types of AML, AMKL has a younger onset age (P < 0.05), with a mean of 22.27 months. Anemia, hemorrhage, lymph node enlargement, lower white blood cell, and complex karyotype were more common in AMKL (P < 0.05). AMKL has a longer time interval between onset to diagnosis (53.61 ± 71.15 days) (P < 0.05), and patients with a diagnosis delay ≥3 months always presented as thrombocytopenia or pancytopenia initially.CONCLUSIONSDue to high heterogeneity, high misdiagnosis rate, and myelofibrosis, parts of AMKL may take a long time to be diagnosed, requiring repeated bone marrow punctures. Complex karyotype was common in AMKL. +21 may not be a promising indicator of a poor prognosis.

Hypothyroidism as a long-term complication in cancer survivors has been an issue, but few studies have focused on changes in thyroid hormone levels during chemotherapy for leukaemia. This retrospective study was conducted to assess the characteristics of children with acute lymphoblastic leukaemia (ALL) and hypothyroidism during induction chemotherapy and to investigate the prognostic value of hypothyroidism in ALL. Patients with a detailed thyroid hormone profile at ALL diagnosis were enrolled. Hypothyroidism was defined as low serum levels of free tetraiodothyronine (FT4) and/or free triiodothyronine (FT3). The Kaplan-Meier method was used to create survival curves, and multivariate Cox regression analysis was used to screen prognostic factors associated with progression-free survival (PFS) and overall survival (OS). There were 276 children eligible for the study, and 184 patients (66.67%) were diagnosed with hypothyroidism, including 90 cases (48.91%) with functional central hypothyroidism and 82 cases (44.57%) with low T3 syndrome. Hypothyroidism was correlated with the dosages of L-Asparaginase (L-Asp) (P = .004) and glucocorticoids (P = .010), central nervous system (CNS) status (P = .012), number of severe infections (grade 3, 4 or 5) (P = .026) and serum albumin level (P = .032). Hypothyroidism was an independent prognostic factor for PFS in ALL children (P = .024, 95% CI: 1.1-4.1). We conclude that hypothyroidism is commonly present in ALL children during induction remission, which is related to chemotherapy drugs and severe infections. Hypothyroidism was a predictor of poor prognosis in childhood ALL.

Joint models for recurrent event and terminating event data are increasingly used for the analysis of clinical trials. However, few methods have been proposed for designing clinical trials using these models. In this article, we develop a Bayesian clinical trial design methodology focused on evaluating the effect of an investigational product (IP) on both recurrent event and terminating event processes considered as multiple primary endpoints, using a multifrailty joint model. Dependence between the recurrent and terminating event processes is accounted for using a shared frailty. Inferences for the multiple primary outcomes are based on posterior model probabilities corresponding to mutually exclusive hypotheses regarding the benefit of IP with respect to the recurrent and terminating event processes. We propose an approach for sample size determination to ensure the trial design has a high power and a well-controlled type I error rate, with both operating characteristics defined from a Bayesian perspective. We also consider a generalization of the proposed parametric model that uses a nonparametric mixture of Dirichlet processes to model the frailty distributions and compare its performance to the proposed approach. We demonstrate the methodology by designing a colorectal cancer clinical trial with a goal of demonstrating that the IP causes a favorable effect on at least one of the two outcomes but no harm on either.

Pediatric Blood & CancerEarly View e30021 LETTER TO THE EDITOR Refractory pediatric acute myeloid leukemia expressing NUP98-NSD1 fusion gene responsive to chemotherapy combined with venetoclax and decitabine Huan Xu, Huan Xu Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorHui Yu, Hui Yu Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorJiawei Xu, Jiawei Xu orcid.org/0000-0002-0173-698X Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorFen Zhou, Fen Zhou Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorShuo Tang, Shuo Tang Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorXingxing Feng, Xingxing Feng Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorQuan Luo, Quan Luo Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorBingyu Zhang, Bingyu Zhang Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorXiaoyan Wu, Xiaoyan Wu Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorRunming Jin, Corresponding Author Runming Jin rmjin@hust.edu.cn Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Correspondence Hongbo Chen, Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Email: hbchen@hust.edu.cn Runming Jin, Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Email: rmjin@hust.edu.cnSearch for more papers by this authorHongbo Chen, Corresponding Author Hongbo Chen hbchen@hust.edu.cn orcid.org/0000-0002-9084-7277 Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Correspondence Hongbo Chen, Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Email: hbchen@hust.edu.cn Runming Jin, Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Email: rmjin@hust.edu.cnSearch for more papers by this author Huan Xu, Huan Xu Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorHui Yu, Hui Yu Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorJiawei Xu, Jiawei Xu orcid.org/0000-0002-0173-698X Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorFen Zhou, Fen Zhou Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorShuo Tang, Shuo Tang Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorXingxing Feng, Xingxing Feng Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorQuan Luo, Quan Luo Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorBingyu Zhang, Bingyu Zhang Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorXiaoyan Wu, Xiaoyan Wu Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorRunming Jin, Corresponding Author Runming Jin rmjin@hust.edu.cn Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Correspondence Hongbo Chen, Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Email: hbchen@hust.edu.cn Runming Jin, Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Email: rmjin@hust.edu.cnSearch for more papers by this authorHongbo Chen, Corresponding Author Hongbo Chen hbchen@hust.edu.cn orcid.org/0000-0002-9084-7277 Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Correspondence Hongbo Chen, Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Email: hbchen@hust.edu.cn Runming Jin, Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Email: rmjin@hust.edu.cnSearch for more papers by this author First published: 02 October 2022 https://doi.org/10.1002/pbc.30021Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Early ViewOnline Version of Record before inclusion in an issuee30021 RelatedInformation

Background The combined use of radiotherapy (RT) and immune checkpoint inhibitors (ICIs) is a promising strategy in the treatment of cancer patients. We sought to comprehensively summarize the characteristics of oncological trials investigating the synergistic effect of RT and ICIs registered at ClinicalTrials.gov. Methods In this cross-sectional study, oncological trials investigating the synergistic effect of RT and ICIs registered at ClinicalTrials.gov from database inception to November 30, 2021 were retrieved. The characteristics of the included trials were assessed. Results Overall, 403 registered trials were identified for analysis. Of these trials, 393 (97.5%) were interventional trials and 10 (2.5%) were observational trials. The top 3 most-studied conditions were gastrointestinal cancer (25.8%), head and neck cancer (18.6%), and non-small cell lung cancer (NSCLC) (17.9%). Approximately, 60.0% of the trials comprised ≤50 participants and 22.6% of the trials comprised >100 participants. More than half of the registered trials were prospective phase 2 trials (54.3%). In relation to trial location, 39.7% of the trials were conducted in the United States, which was the most common registered area, followed by China (33.7%) and Europe (19.4%). In relation to the radiation fractionation, the conventional fractionation size of 1.8–2.0 Gy was comparable to the ultra-hypofractionation size of ≥5 Gy (46.4% vs. 32.8%), and the most commonly used ultra-hypofractionation regimen was 24 Gy/3 Fx (24%), followed by 25 Gy/5 Fx (11%) and 30 Gy/5 Fx (11%). Additionally, the most commonly used ICI in the registered trials was pembrolizumab (20.1%), followed by durvalumab (11.4%) and nivolumab (9.2%). Among all the registered trials, only 4% of the trials had been completed, but 61.5% of the completed trials had reported their results on ClinicalTrials.gov. The conventional fractionation trials were more likely to be phase 3 trials, located in China, and performed in patients with head and neck cancer or gynecological cancer (all P values <0.05), while the ultra-hypofractionation trials were more likely to be phase 1 trials, stopped early, located in the United States, and performed in patients with lung cancer (all P values <0.05). Conclusions The number of prospective trials investigating the synergistic effect of RT and ICIs registered at ClinicalTrials.gov has increased significantly over the past decade. The ultra-hypofractionation size of the registered trials varies, but the 24 Gy/3 Fx regimen is commonly used. The clinical results of registered trials examining the synergistic effect of RT in combination with ICIs, specifically in terms of ultra-hypofractionation, remain limited.

Study Objectives Opioid-related adverse events (OAEs), including opioid use disorders, overdose, and death, are serious public health concerns. OAEs are often associated with disrupted sleep, but the long-term relationship between poor sleep and subsequent OAE risk remains unknown. This study investigates whether sleep behavior traits are associated with incident OAEs in a large population cohort. Methods 444 039 participants (mean age +/- SD 57 +/- 8 years) from the UK Biobank reported their sleep behavior traits (sleep duration, daytime sleepiness, insomnia-like complaints, napping, and chronotype) between 2006 and 2010. The frequency/severity of these traits determined a poor sleep behavior impacts score (0-9). Incident OAEs were obtained from hospitalization records during 12-year median follow-up. Cox proportional hazards models examined the association between sleep and OAEs. Results Short and long sleep duration, frequent daytime sleepiness, insomnia symptoms, and napping, but not chronotype, were associated with increased OAE risk in fully adjusted models. Compared to the minimal poor sleep behavior impacts group (scores of 0-1), the moderate (4-5) and significant (6-9) groups had hazard ratios of 1.47 (95% confidence interval [1.27, 1.71]), p < 0.001, and 2.19 ([1.82, 2.64], p < 0.001), respectively. The latter risk magnitude is greater than the risk associated with preexisting psychiatric illness or sedative-hypnotic medication use. In participants with moderate/significant poor sleep impacts (vs. minimal), subgroup analysis revealed that age Conclusions Certain sleep behavior traits and overall poor sleep impacts are associated with an increased risk for opioid-related adverse events.

巨细胞病毒(cytomegalovirus,CMV)感染在免疫功能受损患儿,尤其是接受异基因造血干细 胞移植(allogeneic hematopoietic stem cell transplantation,allo-HSCT)患儿中易引起严重的危害.近年来,随着造血干细胞移植(HSCT)工作在各大移植中心陆续开展,CMV感染的防治备受关注且有利于提高allo-HSCT的成功率和存活率.本文通过对儿童allo-HSCT后CMV感染的流行病学、危险因素、诊断、预防和治疗以及新型抗CMV药物的文献综述对与CMV感染相关的最新研究进展作一介绍.

Knee osteoarthritis (KOA) is the most common cause of chronic pain, but its pain mechanisms are complex and may be closely related to the descending pain modulation system. Transcranial direct current stimulation (tDCS) is used for relieving pain, but its analgesic mechanisms are still being explored. The purpose of this study was to investigate the role of BDNF/TrkB signaling in chronic pain in KOA and to investigate whether this signaling is related to the analgesic effect of tDCS. Rats were injected with monosodium iodoacetate (MIA) into the left knee joint to establish a chronic pain model and then received 20 min of tDCS for 8 days. Rats were respectively administered the TrkB inhibitor ANA-12 after MIA modeling and exogenous BDNF after tDCS treatment. Behaviors testing was assessed by hot plate and von Frey hairs using the up-down method. In addition, the expression levels of BDNF and TrkB on the periaqueductal gray (PAG)-the rostral ventromedial medulla (RVM)-the spinal dorsal horn (SDH) axis were detected by Western blot and Immunohistochemistry staining. Behavioral results show that tDCS treatment and ANA-12 injection reversed MIA-induced allodynia while reducing BDNF and TrkB expression levels. Furthermore, injection of exogenous BDNF reversed the therapeutic effect of tDCS on pain. These results indicate that upregulation of the BDNF/TrkB signaling in the descending pain modulation system may play an important role in KOA-induced chronic pain in rats, and tDCS may reduce KOA-induced chronic pain by inhibiting the BDNF/TrkB signaling in the descending pain modulation system.

IntroductionNeuronal surface antibody syndromes (NSAS) encompass a growing set of autoimmune neurological disorders, with their predominant clinical presentation being autoimmune encephalitis (AE). The most extensively documented form within NSAS is anti-N-methyl-D-aspartate receptor (NMDAR) autoimmunity. In contrast, other NSAS, such as anti-metabotropic glutamate receptor-5 (mGluR5) autoimmunity, are less common and less comprehensively characterized, particularly in pediatric cases.Case descriptionIn this instance, we present the case of a 7-year-old girl who exhibited abnormal behaviors following hematopoietic stem cell transplantation (HSCT). She received a diagnosis of anti-mGluR5 AE, and her Electroencephalogram (EEG) displayed an increased number of generalized slow waves during wakefulness. Treatment involved intravenous administration of gamma globulin and methylprednisolone, followed by oral prednisone tablets. Levetiracetam was introduced as an antiepileptic therapy during the pulse steroid therapy. Notably, the abnormal behaviors exhibited significant improvement after treatment.ConclusionsTo the best of our knowledge, this is the first report of rare pediatric NSAS involving anti-mGluR5 AE following HSCT. Enhancing our understanding and characterization of this condition may facilitate its recognition and treatment in children. Serum antibody testing could enable early identification and treatment of anti-mGluR5 AE.

Data regarding the epidemiologic characteristics and clinical features of pediatric hematologic patients are limited in this corona virus disease 2019 (COVID-19) crisis. We investigated the status of 113 pediatric hematologic patients in Wuhan union hospital during the COVID-19 pandemic from January 23 to March 10, 2020. All the patients had routine blood and biochemical examination, as well as chest computed tomography scans, and the nucleic acid, immunoglobulin G-immunoglobulin M combined antibodies tests for SARS-CoV-2. After admission, all patients were single-room isolated for 5 to 7 days. The results showed that only 1 (0.88%) child with leukemia was confirmed to have SARS-CoV-2 infection and 15 (13.2%) children were considered as suspected cases. Comparing to the nonsuspected patients, the suspected cases had lower white blood cell count, hemoglobin level, neutrophil count, serum calcium ion level and serum albumin concentration, as well as higher levels of C-reactive protein. All the suspected cases were ruled out of SARS-CoV-2 infection by twice negative tests for the virus. Therefore, the incidence of SARS-CoV-2 infection in hematologic malignancy children was low during the COVID-19 pandemic in China. COVID-19 got early detected and the virus spread out in the ward was effectively blocked by increasing test frequency and using single-room isolation for 5 to 7 days after admission.

We develop a Bayesian design method for a clinical program where an investigational product is to be studied concurrently in a set of clinical trials involving related diseases with the goal of demonstrating superiority to a control in each. The approach borrows information on treatment effectiveness using correlated mixture priors using an analysis procedure that is closely related Bayesian model averaging. Mixture priors are constructed by eliciting conjugate priors based on pessimistic and enthusiastic predictions for the data to be observed for each disease and then by eliciting mixture weights for all possible configurations of the pessimistic and enthusiastic priors across the diseases to be studied. The proposed approach provides a robust framework for information borrowing in settings where the diseases may have endpoints based on different data types. We show via simulation that operating characteristics based on the proposed design framework are favorable compared to those based on information borrowing designs using the Bayesian hierarchical model which is poorly suited for information borrowing when there are different data types underpinning the endpoints across which information is to be borrowed.

For clinical trial design and analysis, there has been extensive work related to using joint models for longitudinal and time-to-event data without a cure fraction (i.e., when all patients are at risk for the event of interest), but comparatively little treatment has been given to design and analysis of clinical trials using joint models that incorporate a cure fraction. In this paper, we develop a Bayesian clinical trial design methodology focused on evaluating the treatment’s effect on a time-to-event endpoint using a promotion time cure rate model, where the longitudinal process is incorporated into the hazard model for the promotion times. A piecewise linear hazard model for the period after assessment of the longitudinal measure ends is proposed as an alternative to extrapolating the longitudinal trajectory. This may be advantageous in scenarios where the period of time from the end of longitudinal measurements until the end of observation is substantial. Inference for the time-to-event endpoint is based on a novel estimand which combines the treatment’s effect on the probability of cure and its effect on the promotion time distribution, mediated by the longitudinal outcome. We propose an approach for sample size determination such that the design has a high power and a well-controlled type I error rate with both operating characteristics defined from a Bayesian perspective. We demonstrate the methodology by designing a breast cancer clinical trial with a primary time-to-event endpoint where longitudinal outcomes are measured periodically during follow up.

Pediatric Blood & CancerVolume 68, Issue 1 e28563 LETTER TO THE EDITOR A flowchart strategy for children with leukemia during COVID-19: A nondesignated hospital's experience Hongbo Chen, Hongbo Chen orcid.org/0000-0002-9084-7277 Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorHui Li, Hui Li Department of Oncology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorYining Qiu, Yining Qiu Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorZhujun Wang, Zhujun Wang Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorHui Yu, Hui Yu Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorJiawei Xu, Jiawei Xu Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorYun Peng, Yun Peng Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorXia Wan, Xia Wan Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorBingyu Zhang, Bingyu Zhang Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorTiantian Song, Tiantian Song Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorFen Zhou, Fen Zhou Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorRunming Jin, Corresponding Author Runming Jin [email protected] orcid.org/0000-0002-7233-0354 Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Correspondence Xiaoyan Wu and Runming Jin, Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan, 430022 Hubei, China. Email: [email protected]; [email protected]Search for more papers by this authorXiaoyan Wu, Corresponding Author Xiaoyan Wu [email protected] Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Correspondence Xiaoyan Wu and Runming Jin, Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan, 430022 Hubei, China. Email: [email protected]; [email protected]Search for more papers by this author Hongbo Chen, Hongbo Chen orcid.org/0000-0002-9084-7277 Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorHui Li, Hui Li Department of Oncology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorYining Qiu, Yining Qiu Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorZhujun Wang, Zhujun Wang Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorHui Yu, Hui Yu Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorJiawei Xu, Jiawei Xu Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorYun Peng, Yun Peng Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorXia Wan, Xia Wan Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorBingyu Zhang, Bingyu Zhang Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorTiantian Song, Tiantian Song Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorFen Zhou, Fen Zhou Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaSearch for more papers by this authorRunming Jin, Corresponding Author Runming Jin [email protected] orcid.org/0000-0002-7233-0354 Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Correspondence Xiaoyan Wu and Runming Jin, Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan, 430022 Hubei, China. Email: [email protected]; [email protected]Search for more papers by this authorXiaoyan Wu, Corresponding Author Xiaoyan Wu [email protected] Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Correspondence Xiaoyan Wu and Runming Jin, Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan, 430022 Hubei, China. Email: [email protected]; [email protected]Search for more papers by this author First published: 25 July 2020 https://doi.org/10.1002/pbc.28563Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. CONFLICT OF INTEREST The authors declare that there is no conflict of interest. REFERENCES 1Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395: 497-506. 10.1016/S0140-6736(20)30183-5 CASPubMedWeb of Science®Google Scholar 2Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020; 382: 727-733. 10.1056/NEJMoa2001017 CASPubMedWeb of Science®Google Scholar 3Wang C, Horby P, Hayden F, et al. A novel coronavirus outbreak of global health concern. Lancet. 2020; 395: 470-473. 10.1016/S0140-6736(20)30185-9 CASPubMedWeb of Science®Google Scholar 4Holshue M, DeBolt C, Lindquist S, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020; 382: 929-936. 10.1056/NEJMoa2001191 CASPubMedWeb of Science®Google Scholar 5Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet. 2008; 371: 1030-1043. 10.1016/S0140-6736(08)60457-2 CASPubMedWeb of Science®Google Scholar 6Taub J, Ge Y, Xavier A. COVID-19 and childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2020; 67(7):e28400. 10.1002/pbc.28400 CASPubMedWeb of Science®Google Scholar 7Bouffet E, Challinor J, Sullivan M, Biondi A, Rodriguez-Galindo C, Pritchard-Jones K. Early advice on managing children with cancer during the COVID-19 pandemic and a call for sharing experiences. Pediatr Blood Cancer. 2020; 67(7):e28327. 10.1002/pbc.28327 CASPubMedWeb of Science®Google Scholar 8Lu X, Zhang L, Du H, et al. SARS-CoV-2 infection in children. N Engl J Med. 2020; 382: 1663-1665. 10.1056/NEJMc2005073 PubMedWeb of Science®Google Scholar 9Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 among children in China. Pediatrics. 2020; 145(6):e20200702. 10.1542/peds.2020-0702 PubMedWeb of Science®Google Scholar 10Gilbert M, Pullano G, Pinotti F, et al. Preparedness and vulnerability of African countries against importations of COVID-19: a modelling study. Lancet. 2020; 395: 871-877. 10.1016/S0140-6736(20)30411-6 CASPubMedWeb of Science®Google Scholar Citing Literature Volume68, Issue1January 2021e28563 ReferencesRelatedInformation

Anthracycline-associated cardiotoxicity is frequently seen in cancer survivors years after treatment, but it is rare in patients on chemotherapy. This study aimed to investigate the clinical characteristics of cardiac disorders in children with acute lymphoblastic leukemia (ALL) during chemotherapy. A retrospective case study was conducted in children with ALL, for whom electrocardiogram (ECG) and echocardiography (Echo) were regularly assessed before each course of chemotherapy. The cardiac disorders were diagnosed according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Binary logistic regression analysis was used to identify risk factors associated with cardiac disorders. There were 171 children eligible for the study, and 78 patients (45.61%) were confirmed as having cardiac disorders. The incidence of cardiac disorders was dependent upon the cumulative dose of daunorubicin (DNR) (p = 0.030, OR = 1.553, 95% CI: 1.005–3.108). Four patients (2.34%) presented with palpitation, chest pain, and persistent tachycardia, and they were cured or improved after medical intervention. A total of 74 patients (43.27%) had subclinical cardiac disorders confirmed by ECG or Echo. ECG abnormalities were commonly seen in the induction and continuation treatments, including arrhythmias (26, 15.20%), ST changes (24, 14.04%) and conduction disorders (4, 2.34%). Pericardial effusion (14, 8.19%), left ventricular hypertrophy (11, 6.43%), a widened pulmonary artery (5, 2.92%) and valvular insufficiency (5, 2.92%) suggested by Echo occurred after induction chemotherapy. Therefore, cardiac disorders with clinical manifestations are rare and need early intervention. Subclinical cardiac disorders are common but very hidden in children during ALL chemotherapy. Regular ECG and Echo could help paediatricians to identify and monitor patients with asymptomatic cardiac disorders earlier.

In this article, we develop a Bayesian adaptive design methodology for oncology basket trials with binary endpoints using a Bayesian model averaging framework. Most existing methods seek to borrow information based on the degree of homogeneity of estimated response rates across all baskets. In reality, an investigational product may only demonstrate activity for a subset of baskets, and the degree of activity may vary across the subset. A key benefit of our Bayesian model averaging approach is that it explicitly accounts for the possibility that any subset of baskets may have similar activity and that some may not. Our proposed approach performs inference on the basket-specific response rates by averaging over the complete model space for the response rates, which can include thousands of models. We present results that demonstrate that this computationally feasible Bayesian approach performs favorably compared to existing state-of-the-art approaches, even when held to stringent requirements regarding false positive rates.