OBJECTIVE: To summarize the clinical features and management of two brothers affected with X-linked inhibitor of apoptosis protein (XIAP) deficiency. METHODS: This study retrospectively analyzed the clinical presentations, treatment, and follow-up of two brothers with XIAP deficiency diagnosed at Shanghai Children's Hospital in 2020, and summarized similar cases recorded in databases such as PubMed, Wanfang, Chinese Medical Association Journals, and WIP from January 2006 to November 2024. This study was approved by the Medical Ethics Committee of our hospital (Ethics No.: 2025R128-E01). RESULTS: Patient 1 was the younger brother, who presented at 8 years of age with growth retardation, folliculitis, erythema nodosum, and perineal abscess. Sequencing revealed that he has carried a hemizygous c.566T>C (p.Leu189Pro) variant of the XIAP gene, which was inherited from his mother. He was allergic to infliximab treatment and underwent allogeneic stem cell transplantation (HSCT) in January 2021. During a follow-up of 3 years and 10 months post-transplantation, he showed no gastrointestinal symptoms and had a good outcome. Patient 2 was the elder brother, who presented at 10 years and 6 months of age with growth retardation, rash, and anal fistula. Genetic testing revealed the same variant. He was treated with oral azathioprine but did not have regular follow-ups. At 14-years-and-6-months of age, he had developed severe gastrointestinal infection and hemophagocytic lymphohistiocytosis, which was alleviated after treatment with antibiotics, glucocorticoids, immunoglobulin, and rituximab. He is currently being prepared for HSCT. A total of 13 publications were retrieved, which involved 64 patients from 23 families, with 23 different variants identified. The main clinical manifestations included splenomegaly (34 cases, 53.1%), hemophagocytic lymphohistiocytosis (27 cases, 42.2%), and inflammatory bowel disease or colitis (20 cases, 31.8%). There were significant phenotypic differences among patients from the same family. Thirteen patients (20.3%) underwent HSCT, with a survival rate of 61.5%. CONCLUSION For male children with early onset, poor treatment response, especially those with unexplained splenomegaly and IBD-like symptoms, early genetic testing is recommended. HSCT is a safe and effective treatment for XIAP deficiency. For patients with developmental delay, early onset, and severe IBD phenotype, early transplantation is recommended.
Humans ; Male ; X-Linked Inhibitor of Apoptosis Protein/deficiency* ; Child ; Genetic Diseases, X-Linked/therapy* ; Phenotype ; Siblings ; Retrospective Studies ; Hematopoietic Stem Cell Transplantation

BACKGROUND: In the interim analysis of MONARCH plus, adding abemaciclib to endocrine therapy (ET) improved progression-free survival (PFS) and objective response rate (ORR) in predominantly Chinese postmenopausal women with HR+/HER2- advanced breast cancer (ABC). This study presents the final pre-planned PFS analysis. METHODS: In the phase III MONARCH plus study, postmenopausal women in China, India, Brazil, and South Africa with HR+/HER2- ABC without prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) were randomized (2:1) to abemaciclib (150 mg twice daily [BID]) or placebo plus: anastrozole (1.0 mg/day) or letrozole (2.5 mg/day) (cohort A) or fulvestrant (500 mg on days 1 and 15 of cycle 1 and then on day 1 of each subsequent cycle) (cohort B). The primary endpoint was PFS of cohort A. Secondary endpoints included cohort B PFS (key secondary endpoint), ORR, overall survival (OS), safety, and health-related quality of life (HRQoL). RESULTS: In cohort A (abemaciclib: n  = 207; placebo: n  = 99), abemaciclib plus a non-steroidal aromatase inhibitor improved median PFS vs . placebo (28.27 months vs . 14.73 months, hazard ratio [HR]: 0.476; 95% confidence interval [95% CI]: 0.348-0.649). In cohort B (abemaciclib: n  = 104; placebo: n  = 53), abemaciclib plus fulvestrant improved median PFS vs . placebo (11.41 months vs . 5.59 months, HR: 0.480; 95% CI: 0.322-0.715). Abemaciclib numerically improved ORR. Although immature, a trend toward OS benefit with abemaciclib was observed (cohort A: HR: 0.893, 95% CI: 0.553-1.443; cohort B: HR: 0.512, 95% CI: 0.281-0.931). The most frequent grade ≥3 adverse events in the abemaciclib arms were neutropenia, leukopenia, anemia (both cohorts), and lymphocytopenia (cohort B). Abemaciclib did not cause clinically meaningful changes in patient-reported global health, functioning, or most symptoms vs . placebo. CONCLUSIONS: Abemaciclib plus ET led to improvements in PFS and ORR, a manageable safety profile, and sustained HRQoL, providing clinical benefit without a high toxicity burden or reduced quality of life. TRIAL REGISTRATION ClinicalTrials.gov (NCT02763566).
Humans ; Female ; Fulvestrant/therapeutic use* ; Breast Neoplasms/metabolism* ; Aminopyridines/therapeutic use* ; Benzimidazoles/therapeutic use* ; Middle Aged ; Aromatase Inhibitors/therapeutic use* ; Aged ; Receptor, ErbB-2/metabolism* ; Adult ; Letrozole/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Anastrozole/therapeutic use*

Approximately 60% of colorectal cancer (CRC) patients exhibit TP53 mutations, which are strongly associated with tumor progression, chemotherapy resistance, and an unfavorable prognosis. However, targeting p53 has historically been challenging, and currently, there are no approved p53-based therapeutics for clinical use worldwide. In this study, we discovered that ubiquitin carboxyl terminal hydrolase L3 (UCHL3) plays a crucial role in high-level glycolysis, enhanced stem-like properties, and 5-fluorouracil (5-FU) chemoresistance in TP53-mutant CRC by exerting its deubiquitinating enzyme activity to stabilize α-enolase (ENO1) protein. Notably, we identified a newly Food and Drug Administration (FDA)-approved drug, pacritinib, that potently suppresses UCHL3 expression by blocking the janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway in TP53-mutant CRC. Furthermore, Pacritinib was demonstrated to effectively inhibit glycolysis and improve the sensitivity to 5-FU chemotherapy in TP53-mutant CRC. Our findings suggest that targeting the JAK2-STAT3-UCHL3-ENO1 axis is a promising strategy to suppress glycolysis and enhance the efficacy of 5-FU chemotherapy in TP53-mutant CRC. Pacritinib shows potential for clinical application in the treatment of TP53-mutant CRC.

Radiochemotherapy-induced oral mucositis (OM) is a common oral complication in patients with tumors following head and neck radiotherapy or chemotherapy. Erosion and ulcers are the main features of OM that seriously affect the quality of life of patients and even the progress of tumor treatment. To date, differences in clinical prevention and treatment plans for OM have been noted among doctors of various specialties, which has increased the uncertainty of treatment effects. On the basis of current research evidence, this expert consensus outlines risk factors, clinical manifestations, clinical grading, ancillary examinations, diagnostic basis, prevention and treatment strategies and efficacy indicators for OM. In addition to strategies such as basic oral care, anti-inflammatory and analgesic agents, anti-infective agents, pro-healing agents, and photobiotherapy recommended in previous guidelines, we also emphasize the role of traditional Chinese medicine in OM prevention and treatment. This expert consensus aims to provide references and guidance for dental physicians and oncologists in formulating strategies for OM prevention, diagnosis, and treatment, standardizing clinical practice, reducing OM occurrence, promoting healing, and improving the quality of life of patients.
Humans ; Chemoradiotherapy/adverse effects* ; Consensus ; Risk Factors ; Stomatitis/etiology*

Objective To explore the diagnostic and prognostic values of procalcitonin(PCT),interleukin 6(IL-6)and cystatin C(CysC)combined detection in sepsis acute kidney injury(AKI).Methods A total of 100 patients with sepsis were divided into the AKI group(n=56)and the non AKI group(n=44)according to the occurrence of AKI.The prognosis of AKI patients was followed up,and patients were divided into the survival group(n=32)and the death group(n=24)according to the presence or absence of death.Enzyme-linked immunosorbent assay(ELISA)was used to detect PCT,IL-6 and CysC in different groups of patients.The Acute Physiological Function and Chronic Health Status Score(APACHEⅡ)was used to assess the condition of illness.ROC curve was used to analyze the predictive values of PCT,IL-6 and CysC in the diagnosis and death of sepsis combined with AKI.Results The male ratio,age,hypertension with diabetes ratio,APACHE Ⅱ score,serum creatinine(Scr),PCT,IL-6 and CysC levels were higher in the AKI group than those in the non AKI group,and the ratio of complications and onset time were lower in the AKI group than those in the non AKI group(P＜0.05).The ROC curve results showed that the area under the curve(AUC)of PCT,IL-6,and CysC combined for the diagnosis of sepsis complicated with AKI was 0.859,with a sensitivity of 91.07%and a specificity of 90.91%.The combined diagnostic efficacy was better than that of a single indicator.The APACHE Ⅱ score,PCT,IL-6 and CysC levels were higher in the death group than those in the survival group(P＜0.05).The ROC curve results showed that the AUC,sensitivity and specificity of PCT,IL-6 and CysC combined in predicting mortality in sepsis patients with AKI were 0.847,91.67%and 87.50%,respectively.The combined predictive efficacy was better than that of single indicator.Conclusion The combination of PCT,CysC and IL-6 indicators is more valuable in diagnosing and predicting prognosis of sepsis with AKI.

Objective To investigate the influencing factor of prognosis of symptomatic intracranial large artery occlusive(ILAO)cerebral infarction in nonacute phase.Methods According to the prognosis,86 patients with symptomatic ILAO cerebral infarction in nonacute phase were divided into good prognosis group and poor prognosis group,and the clinical data of the two groups were compared.Multifactorial Logistic regression analysis was used to screen out the factors that influence prognosis.The related factors were combined to construct a nomogram for predicting poor prognosis of ILAO cerebral infarction in nonacute phase,validated by calibration curves and decision curve analysis.Results Compared with those in the good prognosis group,age,admission mRS,admission NIHSS score,globulin level and medication ratio in the poor prognosis group were significantly higher,and triacylglycerol level,albumin-globulin ratio in the poor prognosis group were significantly lower(P＜0.05-0.01).Multifactorial Logistic regression analysis showed that admission mRS was positively associated with poor 3-month prognosis of patients with ILAO cerebral infarction in nonacute phase(OR=2.551,95％CI:1.134-5.738,P=0.024);endovascular opening therapy was negatively associated with poor 3-month prognosis of patients with ILAO cerebral infarction in the nonacute phase(OR=0.132,95％CI:0.027-0.634,P=0.011).Incorporating admission mRS and endovascular opening treatment to establish a nomogram had good predictive efficacy.Conclusions Admission mRS and endovascular recanalization treatment increased and decreased the risk of poor prognosis at 3 months in patients with ILAO cerebral infarction in nonacute phase,respectively.The nomogram established by combining the two has good application value in predicting the poor prognosis of patients.

Objective To understand the current situation and influencing factors of work-related musculoskeletal disorders (WMSDs) in medical staff in Beijing City. Methods A total of 2 687 medical staff were selected as the research subjects using the multi-stage sampling method. The current situation of WMSDs and occupational stress, anxiety symptoms, depressive symptoms, and insomnia symptoms were investigated using the Musculoskeletal Disorders Questionnaire, the Core Occupational Stress Scale, the Generalized Anxiety Disorder Scale, the Patient Health Questionnaire Depression Scale, and the Self-Sleep Management Questionnaire. The Max-Min Hill-Climbing algorithm was used to construct a Bayesian network model to analyze the influencing factors and internal relationships of WMSDs and to conduct reasoning and prediction of the model. Results The prevalence of WMSDs among the research subjects was 88.9%. Binary logistic regression analysis was used to identify age, educational level, personal monthly income, anxiety symptoms, depressive symptoms, insomnia symptoms, prolonged forward-head desk work, and prolonged static posture work to construct the Bayesian network model. The model consisted of nine nodes and eleven directed edges. Prolonged static posture work, prolonged forward-head desk work, and anxiety symptoms were directly related to WMSDs. Age and educational level were indirectly related to WMSDs through their influence on prolonged forward-head desk work. Depression symptoms were indirectly associated with WMSDs through their influence on anxiety symptoms. The model's prediction accuracy was 90.5%. Conclusion The prevalence of WMSDs among medical staff in Beijing City is relatively high. Prolonged static posture work, prolonged forward-head desk work, and anxiety symptoms may directly increase the risk of developing WMSDs.

Objective:To explore the mechanism of Danxing Zhishuang Prescription in the treatment of Parkinson's disease (PD) by combining network pharmacology with animal models.Methods:TCMSP, BATMAN database, Genecards, and OMIM databases were retrieved to obtain the active components and action targets of Danxing Zhishuang Prescription. Venny 2.1.0 was used to intersect drug targets and PD related genes, and a protein interaction network of the intersection targets was constructed using the STRING 12.0 platform. Topology analysis was performed using Cytoscape 3.10.0 software to identify the key targets of Danxing Zhishuang Prescription on PD; GO functional and KEGG pathway enrichment analysis was performed on key targets using the WeChat platform, and molecular docking was validated through AutoDockTools 1.5.7. Using a random number table method, mice were divided into a blank control group, a model group, and a Danxing Zhishuang Prescription group, with 20 mice in each group; except for the blank group, all other groups of mice were orally administered fisetin to prepare PD models; Danxing Zhishuang Prescription group was orally administered with concentrated Danxing Zhishuang Prescription at a dosage of 10.5 g/kg, while the blank group and model group were orally administered with 0.2 ml of physiological saline for 21 days; Western blot was used to detect the expressions of Akt1, Bcl-2, Bax, and α-Syn proteins.Results:359 intersection targets, 69 core targets, and 185 active components were obtained the treatment of PD with Danxing Zhishuang Prescription. The main active components included quercetin, kaempferol, phenylalanine, etc., and the key targets were AKT1, TP53, TNF, ESR1, etc. KEGG analysis revealed several key signaling pathways, such as AGE-RAGE, PI3K-Akt, fluid shear stress and atherosclerosis signaling pathways. The validation experiment results showed that compared with the model group, the expression of Bcl-2 protein was up-regulated ( P<0.01), and the expressions of Bax, Akt1, and α-Syn proteins were down-regulated in the Danxing Zhishuang Prescription group ( P<0.01). Conclusions:Danxing Zhishuang Prescription has the advantages of multi target and multi pathway treatment for PD. Its mechanism may be related to down-regulating the expressions of Bax, Akt1, and α-Syn proteins, improving brain blood supply, regulating neurotransmitter balance, inhibiting oxidative stress response, and promoting nerve regeneration.

Objective To evaluate the effect of cytochrome P450 3A5(CYP3A5)genetic polymorphism on the blood drug concentration of tacrolimus(TAC)in patients with lupus nephritis(LN),to determine the appropriate initial dose for LN patients of different genotypes and the differences in time to remission,and to analyze factors associated with LN prognosis.Methods Patients with active LN attending the outpatient clinic of the Department of Rheumatology and Immunology,West China Hospital,Sichuan University were enrolled.Their CYP3A5 genotypes were determined.According to the different genotypes,the patients were assigned to two groups,the AA+GA group,or the rapid metabolism group with the genotype CYP3A5*1/*1,i.e.,AA+CYP3A5*1/*3,and the GG group,or the slow metabolism group with the genotype CYP3A5*3/*3.The basic information,clinical manifestations,history of other diseases,and medication history of the enrolled patients were collected.According to the principle of simple random grouping,patients in each group were randomly divided into two subgroups,receiving TAC at initial doses of 0.05 mg/(kg·d)and 0.075 mg/(kg·d),respectively.Data on laboratory test indicators,including TAC blood drug concentration,blood pressure,and other relevant clinical follow-up indicators,were collected each month from each group.Patients were also evaluated each month for their clinical remission status.When patients in the 0.05 mg/(kg·d)initial dose group did not achieve clinical remission after 2 months,the TAC dose was increased to 0.075 mg/(kg·d),and the patients were observed until the end of the 6th month.Patients in the 0.075 mg/(kg·d)initial dose group were observed for 6 months,regardless of their remission status.Results In the LN patient subgroups receiving TAC at the same initial dose,the cumulative remission rate of patients with the GG genotype was higher than that of patients with the AA+GA genotype,but only in the 0.05 mg/(kg·d)initial dose group,the difference in cumulative remission rate between the two genotypes was statistically significant(P<0.05).According to a comparison of patients with the same genotype who received TAC at different initial doses,the remission rate of patients receiving 0.075 mg/(kg·d)initial dose was higher than that of the 0.05 mg/(kg·d)initial dose group,but only in patients with AA+GA genotype,the difference in remission rate between the two initial dose groups was statistically significant(P<0.05).Whether it was different genotypes in the same TAC initial dose group or different TAC initial doses of the same genotype,there was no statistically significant difference in the time to achieve complete remission(P>0.05).Regardless of the different initial TAC doses,patients with the GG genotype maintained higher TAC blood concentrations than those with the AA+GA genotype throughout the course of treatment.TAC blood concentration during treatment(OR=1.941;95%CI,1.47-2.563;P<0.001),CYP3A5*1 genotype carrier status(OR=0.161;95%CI,0.053-0.492;P=0.001),and the initial TAC dose(OR=0.205;95%CI,0.113-0.371;P<0.001)were all significant factors influencing treatment efficacy.When TAC blood concentration was higher,patients with the GG genotype receiving TAC at an initial dose of 0.075 mg/(kg·d)were more likely to achieve clinical remission.There were no statistically significant differences in the incidence of adverse reactions between subgroups with the same genotype but receiving TAC at different initial doses(P>0.05).Conclusion The efficacy of TAC in treating LN patients is correlated with CYP3A5 genotypes,TAC blood drug concentration,and TAC initial dose.The blood drug concentration of TAC is influenced by CYP3A5 genotypes,with the TAC blood drug concentrations of the slow metabolism group being higher than that of the fast metabolism group.When the TAC blood drug concentration reaches 6-10 ng/mL,it is more likely for LN patients to achieve clinical remission.

Objective:To summarize the clinical features, laboratory findings, treatment and prognosis of children confirmed as Mycoplasma pneumoniae-induced rash and mucositis (MIRM) in children. Methods:This retrospective study concluded 6 children diagnosed as MIRM in Department of Gastroenterology and Infectious Diseases, Shanghai Children′s Hospital, School of Medicine, Shanghai Jiao Tong University from August 2023 to April 2024. This paper described the characteristics of MIRM and analyzed the therapeutic strategy and prognosis.Results:A total of 6 children were diagnosed as MIRM including 2 boys and 4 girls with an age of onset was 6.4 (3.1, 7.5) years. Among the 6 patients, 4 patients had oral mucosal involvement among whom 2 showed crusting of the lips. Four patients had ocular involvement manifesting as conjunctival congestion and increased secretion. All patients presented with skin lesions, manifesting as target-shaped damage in 4 cases, herpes herpetiformis in 1 case and purpura-like rash in 1 case. Serological tests for Mycoplasma pneumoniae IgM and Mycoplasma pneumoniae nucleic acid test were positive in all 6 cases. Two cases received intravenous immunogloblin infusion combined with methylprednisolone, monotherapy of methylprednisolone in 4 cases. The course of glucocorticoids was 1-7 weeks, and the initial dose was 2-4 mg/(kg·d), which was gradually reduced according to the rash. The children were followed up for 3 to 9 months, no case suffered from long term ocular or cutaneous complications or recurrence of rash. All cases had good prognosis. Conclusions:Children diagnosed as MIRM present with mild symptoms and usually have good prognosis with early identification and appropriate intervention. Individualized therapy should be applied based on the severity of skin involvement.