INTRODUCTION: Trastuzumab deruxtecan (T-DXd) has revolutionised treatment for metastatic breast cancer (MBC). While effective, its high cost and toxicities, such as fatigue and nausea, pose challenges. METHOD: Medical records from the Joint Breast Cancer Registry in Singapore were used to study MBC patients treated with T-DXd (February 2021-June 2024). This study was conducted to address whether reducing dose intensity and density may have an adverse effect on treatment outcomes. RESULTS: Eighty-seven MBC patients were treated with T-DXd, with a median age of 59 years. At the time of data cutoff, 32.1% of patients were still receiving T-DXd. Over half (54%) of the patients received treatment with an initial relative dose intensity (RDI) of <;85%. Overall median real-world progression-free survival (rwPFS) was 8.1 months. rwPFS was similar between RDI groups (<85%: 8.7 months, <85%: 8.1 months, P=0.62). However, human epidermal growth receptor 2 (HER2)-positive patients showed significantly better rwPFS outcomes compared to HER2-low patients (8.8 versus 2.5 months, P<0.001). Only 16% with central nervous system (CNS) involvement had CNS progressive disease on treatment. No significant progression-free survival (PFS) differences were found between patients with or without CNS disease, regardless of RDI groups. Five patients (5.7%) developed interstitial lung disease (ILD), with 3 (3.4%) having grade 3 events. Two required high-dose steroids and none were rechallenged after ILD. There were no fatalities. CONCLUSION Our study demonstrated that reduced dose intensity and density had no significant impact on rwPFS or treatment-related toxicities. Furthermore, only 5.7% of patients developed ILD. T-Dxd provided good control of CNS disease, with 82% of patients achieving CNS disease control.
Humans ; Female ; Breast Neoplasms/mortality* ; Middle Aged ; Trastuzumab/adverse effects* ; Aged ; Adult ; Singapore/epidemiology* ; Antineoplastic Agents, Immunological/adverse effects* ; Camptothecin/adverse effects* ; Immunoconjugates/adverse effects* ; Retrospective Studies ; Progression-Free Survival ; Receptor, ErbB-2/metabolism* ; Neoplasm Metastasis ; Dose-Response Relationship, Drug ; Treatment Outcome ; Registries

OBJECTIVES: To study the clinical characteristics of pediatric Behçet syndrome (BS). METHODS: A retrospective review was conducted on the medical records of children hospitalized in the Department of Pediatrics at the Second Hospital of Hebei Medical University between December 2014 and December 2024 who met diagnostic criteria for BS. RESULTS: Among 45 children with BS, 26 (58%) were male. Oral aphthous ulcers were the most common manifestation (43/45, 96%), followed by genital ulcers (23/45, 51%) and gastrointestinal involvement (18/45, 40%). Genital ulcers were more frequent in girls, whereas ocular involvement was more common in boys (P<0.05). The pathergy test was positive in 10 (22%), and HLA-B51 was positive in 13 (29%). Fecal calprotectin (FC) was elevated in 16 (36%); gastrointestinal involvement was more frequent in children with elevated FC than in those with normal FC (P<0.05). According to the respective criteria, 17 (38%) patients met the International Study Group criteria (1990), 33 (73%) met the International Criteria for Behçet Disease (2014), and 13 (29%) met the Pediatric Behçet Disease criteria (2015). CONCLUSIONS Pediatric BS shows marked clinical heterogeneity. HLA-B51 is associated with disease susceptibility.
Humans ; Behcet Syndrome/genetics* ; Male ; Female ; Child ; Retrospective Studies ; Adolescent ; Child, Preschool ; Leukocyte L1 Antigen Complex/analysis* ; HLA-B51 Antigen

Objective:To investigate the causal correlation between depression and stress urinary incontinence(SUI)using Mendelian randomization(MR)analysis.Methods:We searched the FinnGen Consortium database for genome-wide association studies(GWAS)on depression and obtained 23 424 case samples and 192 220 control samples,with the GWAS data on SUI provided by the UK Biobank,including 4 340 case samples and 458 670 control samples.We investigated the correlation between depression and SUI based on the depression data collected from the Psychiatric Genomics Consortium(PGC).We employed inverse-variance weighting as the main method for the MR study,and performed sensitivity analysis to verify the accuracy and stability of the findings.Results:Analysis of the data from the UK Biobank and FinnGen Consortium showed that depression was significantly correlated with an increased risk of SUI(P=0.005),but not SUI with the risk of depression(P=0.927).And analysis of the PGC data verified the correlation of depression with the increased risk of SUI(P=0.043).Conclusion:Depression is associated with an increased risk of SUI,while SUI does not increase the risk of depression.

ObjectiveTo observe the effects of Xibining （XBN） and adipose stem cell exosome （ADSC-Exos） in the cases of separate or joint application on cartilage degeneration and mitochondrial autophagy and explore its mechanism of action to improve knee osteoarthritis （KOA）. MethodSD rats were divided into a sham operation group （sham group）， a model group， an ADSC-Exos group （Exos group）， an XBN group， and an ADSC-Exos+XBN group （Exos+XBN group）. KOA model was established by using anterior cruciate ligament transection （ACLT）. The pain sensitivity status of rats was evaluated， and the degeneration degree of the knee joint and cartilage tissue was detected by Micro-CT and pathological staining. The expression of p62 and LC3B was observed by immunofluorescence， and the serum levels of TNF-α， IL-1β， IL-6， and IL-15 in rats were detected by ELISA. The Western blot was used to detect the protein expression levels of MMP-3， MMP-13， ADAMTS5， ColⅡ， TIMP， ACAN， PINK1， Parkin， p62， and LC3A/B. ResultCompared with the sham group， rats in the model group showed decreased cold-stimulated foot-shrinkage thresholds and mechanical pain sensitivity thresholds， varying degrees of abrasion and loss of cartilage tissue， degeneration of cartilage tissue， elevated serum IL-1β， IL-6， IL-15， and TNF-α levels （P<0.01）， and increased protein expression of MMP-3， MMP-13， and ADAMTS5 in cartilage tissue. In addition， the protein expression of ColⅡ， TIMP1， and ACAN was decreased （P<0.01）. Compared with the model group， rats in each treatment group showed higher cold-stimulated foot-shrinkage thresholds and mechanical pain sensitivity thresholds， reduced cartilage tissue degeneration， lower serum levels of IL-1β， IL-6， IL-15， and TNF-α （P<0.05，P<0.01）， decreased protein expression of MMP-3， MMP-13， and ADAMTS5， and higher protein expression of Cold， TIMP1， and ACAN in cartilage tissue （P<0.05，P<0.01）. Moreover， the changes were the most obvious in the Exos+XBN group. ConclusionBoth ADSCs-Exos and XBN can increase the level of mitochondrial autophagy in chondrocytes and delay cartilage tissue degeneration by promoting the expression of the PINK1/Parkin signaling pathway， and the combination of the two can enhance the therapeutic effect.

Osteoporotic proximal humeral fracture (OPHF) is one of the common osteoporotic fractures in the aged, with an incidence only lower than vertebral compression fracture, hip fracture, and distal radius fracture. OPHF, secondary to osteoporosis and characterized by poor bone quality, comminuted fracture pattern, slow healing, and severely impaired shoulder joint function, poses a big challenge to the current clinical diagnosis and treatment. In the field of diagnosis, treatment, and rehabilitation of OPHF, traditional Chinese and Western medicine have accumulated rich experience and evidence from evidence-based medicine and achieved favorable outcomes. However, there is still a lack of guidance from a relevant consensus as to how to integrate the advantages of the two medical systems and achieve the integrated diagnosis and treatment. To promote the diagnosis and treatment of OPHF with integrated traditional Chinese and Western medicine, relevant experts from Orthopedic Expert Committee of Geriatric Branch of Chinese Association of Gerontology and Geriatrics, Youth Osteoporosis Group of Orthopedic Branch of Chinese Medical Association, Osteoporosis Group of Orthopedic Surgeon Branch of Chinese Medical Doctor Association, and Osteoporosis Committee of Shanghai Association of Integrated Traditional Chinese and Western Medicine have been organized to formulate Expert consensus on the diagnosis and treatment of osteoporotic proximal humeral fracture with integrated traditional Chinese and Western medicine ( version 2024) by searching related literatures and based on the evidences from evidence-based medicine. This consensus consists of 13 recommendations about the diagnosis, treatment and rehabilitation of OPHF with integrated traditional Chinese medicine and Western medicine, aimed at standardizing, systematizing, and personalizing the diagnosis and treatment of OPHF with integrated traditional Chinse and Western medicine to improve the patients ′ function.

Celastrol and wilforlide A are the main active triterpenoids of the traditional Chinese medicine Lei Gong Teng, which have anti-tumour, anti-inflammatory and immunosuppressive activities, and are the material basis for the clinical efficacy of Lei Gong Teng-related Chinese medicinal preparations. By analysing the biosynthetic pathway of active ingredients, optimizing genetic elements and utilizing "cell factory" to produce triterpenoids heterologously will be an effective way to obtain from Tripterygium wilfordii in the future in a "low-cost and high-efficient" manner. CYP712Ks are the first cytochrome P450s involved in the skeleton modification of friedelane-type and oleanane-type triterpenoids in T. wilfordii, and they can catalyse the generation of polpunonic acid from friedelin and 3-epi-katonic acid from β-amyrin by carboxylation at C-29 position. In this study, four multifunctional TwCYP712K1/2/3/5 were used to clarify the catalytic function and substrate selection preference using in vivo functional characterization in Saccharomyces cerevisiae. The spatial structure of the protein-substrate binding was clarified through homology modeling and molecular docking, and then the differential amino acids in the active pocket of the protein were mutated to clarify the crucial amino acids determining the catalytic function and the selection of substrate structure. A total of 63 mutant elements were constructed, and the amino acid sites affecting the carboxylation function of TwCYP712Ks were analyzed. In particular, the key amino acids affecting the substrate selectivity of TwCYP712K2 towards oleanane-type and friedelane-type triterpenoids were revealed and the TwCYP712K2^F127I and TwCYP712K2^A227T mutants would result in a reversal of the product ratio. In conclusion, four proteins of TwCYP712Ks were semi-rationally designed by homologous protein alignment and mutual mutation to elucidate multiple amino acid sites determining the catalytic function of the proteins, and a series of activity-enhancing or altering mutants were obtained, which provide abundant catalytic elements for the biosynthesis of active triterpenoids from T. wilfordii, and the mechanism of carboxylation in the C-29 position was initially elucidated.

Stem cell exosome therapy has shown significant potential in treating hair loss, but its safety profile has not been thoroughly studied. This paper reported a case of a 32-year-old female patient who experienced an allergic reaction following adipose-derived stem cell exosomes injection for hair loss treatment at the Plastic Surgery Hospital, Chinese Academy of Medical Sciences in June 2023. Within 24 hours post-injection, the patient developed swelling of the forehead and right postauricular lymph nodes, accompanied by mild pain, and left posterior ear lymph nodes 48 hours later. Ultrasound examination revealed thickening of the local soft tissue and enlarged lymph nodes. The condition was diagnosed as an injection-induced allergic reaction. The symptoms gradually subsided after combined treatment with lidocaine, 5-fluorouracil, and triamcinolone acetonide injections. During a 6-month follow-up period, the patient did not experience any recurrence of allergic reactions, and the therapeutic effects remained stable. This case report highlights the potential risk of allergic reactions associated with stem cell exosome therapy for hair loss, underscoring the need for close monitoring and timely intervention in clinical applications to ensure both safety and efficacy.

Objective To investigate the effects of Chaihuang Yishen Granules on renal fibrosis in unilateral ureteral obstruction(UUO)mice and its underlying mechanisms.Methods Twenty-four 8-week-old male C57BL/6 mice were randomly divided into control group,model group,and low and high dose groups of Chaihuang Yishen Granules(6 in each group).In control group,only right kidney ureter was exposed and dissected.In model group,the UUO animal model was established by UUO.In low and high dose groups,mice were administered intragastrically at doses of 3.8 and 7.6 g/kg of Chaihuang Yishen Granules respectively,following the model group's method to establish the UUO model.After 7 days,the mice were euthanized and renal samples were collected.HE and Masson staining were used to observe pathological changes and fibrosis degree of the kidneys in each group,Sirius red staining was used to observe collagen deposition.The expression levels of α-smooth muscle actin(α-SMA),fibronectin(FN),type Ⅰ collagen(Col-Ⅰ),glycogen synthase kinase 3β(GSK-3β),and β-catenin related proteins were detected using Western blotting.Changes in A33 and GSK-3β,β-catenin mRNA levels were measured by RT-PCR.Additionally,a normal transformed C3H mouse kidney-1(TCMK1)was used as control(normal group);an in vitro fibrosis model was established using TCMK1 stimulated with Transforming Growth Factor-β(TGF-β);and an in vitro drug model was established using TCMK1 treated with serum containing Chaihuang Yishen Granules.A33 was overexpressed in TCMK1 cells using a transfection with an A33 overexpression plasmid,and changes in fibrosis-related indicators and the expression of A33 and GSK-3β,β-catenin mRNA were observed.Results RT-PCR results showed that,compared with control group,A33 level was significantly increased in model group,while it was significantly reduced in both low and high dose groups of Chaihuang Yishen Granules(P＜0.05).Western blotting showed that the expression levels of fibrosis-related factors such as α-SMA,FN,Col-Ⅰ in model group were significantly higher than those in control group(P＜0.05);while compared with model group,the expression levels of α-SMA,FN,Col-Ⅰ in low and high dose groups of Chaihuang Yishen Granules were significantly lower(P＜0.05).HE,Masson,immunohistochemical staining results showed that model group had severe kidney structural damage,significant increase in collagen deposition,and significantly higher expression levels of GSK-3β and β-catenin proteins compared with those in control group(P＜0.01).In contrast,low and high dose groups of Chaihuang Yishen Granules had good kidney structure,significant improvement in kidney damage and fibrosis,and significantly lower expression levels of GSK-3β and β-catenin proteins compared with those in model group(P＜0.05).In vitro experiment results confirmed that,compared with normal group,A33 overexpression promoted the upregulation of fibrosis-related factors in TCMK1 cells,significantly increase the expression of downstream target genes GSK-3β and β-catenin mRNA in the Wnt/β-catenin signaling pathway(P＜0.05),and A33 overexpression reversed the cellular fibrosis changes downregulated by the serum containing Chaihuang Yishen Granules(P＜0.01).Conclusion Chaihuang Yishen Granules significantly improve renal fibrosis in UUO mice by downregulating the A33/Wnt/β-catenin signaling pathway,suggesting that A33 may be a potential therapeutic target for renal fibrosis.

Objective To explore the distribution and localization of dopamine receptor D3-D5 in the small intestine of different species.Methods The distribution and expression of D3-D5 in the small intestine of mice,rats and rhesus monkeys were detected by immunohistochemistry and Western blotting.The expression of D3-D5 in immunoglobulin A positive plasma cells(IgA+PC)located in the lamina propria(LP)were detected by immunofluorescence double labeling.Results D3 and D5 were widely distributed in the epithelium,LP,submucosal plexus(SMP)and intermuscular plexus(MP)of the small intestine in mice,rats and rhesus monkeys.The distribution of D4 in the small intestinal of mice and rhesus monkeys were consistent with the result of D3 and D5.D4 was distributed only within the epithelium and LP of rat small intestine.D3 and D5 were expressed in the IgA+PC in the LP of mice and rats,whereas D4 was not.Conclusion The distribution and localization pattern of D3 and D5 are similar in the small intestine of mice,rats and rhesus monkeys,whereas those of D4 vary between different species.Dopamine may be involved in regulating the functions of IgA+PC.