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

Objective:To investigate the changes of left ventricular systolic function in patients after pacing in differ-ent sites of right ventricle.Methods:The clinical data of 95 patients requiring right ventricular pacing who were ad-mitted to our hospital from February 2018 to May 2020 were collected.According to pacing site,they were divided into right ventricular apex pacing(RVAP)group(n=47)and right ventricular outflow tract septal pacing(RVSP)group(n=48).The pacing threshold,perception threshold,electrode impedance,left ventricular end-diastolic volume(LVEDV),left ventricular end-systolic volume(LVESV),stroke volume(SV),left ventricular ejection fraction(LVEF)were compared between the two groups.According to incidence of cardiac insufficiency on one year after pacing,patients were divided into cardiac insufficiency group(n=18)and normal cardiac function group(n=77).Influencing factors of cardiac insufficiency in patients requiring right ventricular pacing were analyzed.Results:Compared with one week after pacing,on one year after pacing,perception threshold[(11.51±1.21)mV vs.(12.11±0.81)mV]significantly increased in RVAP group,P=0.004.Compared with RVAP group on one year after pacing,there were significant rise in LVESV[(25.32±7.63)ml vs.(29.77±12.36)ml],LVEDV[(58.30±15.71)ml vs.(68.33±25.31)ml],SV[(31.36±10.73)ml vs.(41.29±16.15)ml],and significant reductions in LVEF[(60.55±8.76)％vs.(54.10±6.44)％]and proportion of cardiac insufficiency(27.66％vs.10.42％)in RVSP group,P＜0.05 or＜0.01.Non-conditional multivariate Logistic regression model analysis indicated that LVEF was inde-pendent protective factor for cardiac insufficiency in patients requiring right ventricular pacing(OR=0.854,P=0.003),while RVAP and age ≥60 years were its independent risk factors(OR=9.041,4.145,P=0.003,0.024).Conclusion:Compared with right ventricular apex pacing,right ventricular outflow tract septal pacing can significantly improve stroke volume,and incidence rate of cardiac insufficiency significantly reduces.

Objectives: Osteoblast is known to regulate hematopoiesis according to preclinical studies but the causal rela tionship in human remains uncertain. We aimed to evaluate causal relationships of bone mineral density (BMD) with blood cell traits using genetic data. Methods: Summary statistics from the largest available genome-wide association study were retrieved for total body BMD (TBBMD), lumbar spine BMD (LSBMD), femoral neck BMD (FNBMD) and 29 blood cell traits including red blood cell, white blood cell and platelet-related traits. Using two-sample Mendelian randomization (MR) approach, inverse-variance weighted method was adopted as main univariable MR analysis. Multivariable MR (MVMR) analysis was conducted to evaluate whether the casual effect is independent of confounders. Results: BMD was positively associated with reticulocyte-related traits, including high light scatter reticulocyte count and percentage, immature reticulocyte fraction, reticulocyte count and percentage, with causal effect estimate (beta) ranging from 0.023 to 0.064. Conversely, inverse association of BMD with hematocrit, hemo globin, and red blood cell count was observed, with beta ranging from − 0.038 to − 0.019. The association remained significant in MVMR analysis after adjustment for confounders. For white blood cells, BMD was inversely associated with neutrophil count (beta: 0.029 to − 0.019) and white blood cell count (beta: 0.024 to − 0.02). Results across TBBMD, LSBMD, and FNBMD were consistent. Conclusions This study suggested bone metabolism had a causal effect on hematopoietic system in humans. Its causal effect on red blood cell traits was independent of confounders. Further studies on how improving bone health can reduce risk of hematological disorders are warranted.

Objectives: Osteoblast is known to regulate hematopoiesis according to preclinical studies but the causal rela tionship in human remains uncertain. We aimed to evaluate causal relationships of bone mineral density (BMD) with blood cell traits using genetic data. Methods: Summary statistics from the largest available genome-wide association study were retrieved for total body BMD (TBBMD), lumbar spine BMD (LSBMD), femoral neck BMD (FNBMD) and 29 blood cell traits including red blood cell, white blood cell and platelet-related traits. Using two-sample Mendelian randomization (MR) approach, inverse-variance weighted method was adopted as main univariable MR analysis. Multivariable MR (MVMR) analysis was conducted to evaluate whether the casual effect is independent of confounders. Results: BMD was positively associated with reticulocyte-related traits, including high light scatter reticulocyte count and percentage, immature reticulocyte fraction, reticulocyte count and percentage, with causal effect estimate (beta) ranging from 0.023 to 0.064. Conversely, inverse association of BMD with hematocrit, hemo globin, and red blood cell count was observed, with beta ranging from − 0.038 to − 0.019. The association remained significant in MVMR analysis after adjustment for confounders. For white blood cells, BMD was inversely associated with neutrophil count (beta: 0.029 to − 0.019) and white blood cell count (beta: 0.024 to − 0.02). Results across TBBMD, LSBMD, and FNBMD were consistent. Conclusions This study suggested bone metabolism had a causal effect on hematopoietic system in humans. Its causal effect on red blood cell traits was independent of confounders. Further studies on how improving bone health can reduce risk of hematological disorders are warranted.

Objectives: Osteoblast is known to regulate hematopoiesis according to preclinical studies but the causal rela tionship in human remains uncertain. We aimed to evaluate causal relationships of bone mineral density (BMD) with blood cell traits using genetic data. Methods: Summary statistics from the largest available genome-wide association study were retrieved for total body BMD (TBBMD), lumbar spine BMD (LSBMD), femoral neck BMD (FNBMD) and 29 blood cell traits including red blood cell, white blood cell and platelet-related traits. Using two-sample Mendelian randomization (MR) approach, inverse-variance weighted method was adopted as main univariable MR analysis. Multivariable MR (MVMR) analysis was conducted to evaluate whether the casual effect is independent of confounders. Results: BMD was positively associated with reticulocyte-related traits, including high light scatter reticulocyte count and percentage, immature reticulocyte fraction, reticulocyte count and percentage, with causal effect estimate (beta) ranging from 0.023 to 0.064. Conversely, inverse association of BMD with hematocrit, hemo globin, and red blood cell count was observed, with beta ranging from − 0.038 to − 0.019. The association remained significant in MVMR analysis after adjustment for confounders. For white blood cells, BMD was inversely associated with neutrophil count (beta: 0.029 to − 0.019) and white blood cell count (beta: 0.024 to − 0.02). Results across TBBMD, LSBMD, and FNBMD were consistent. Conclusions This study suggested bone metabolism had a causal effect on hematopoietic system in humans. Its causal effect on red blood cell traits was independent of confounders. Further studies on how improving bone health can reduce risk of hematological disorders are warranted.

Objectives: Osteoblast is known to regulate hematopoiesis according to preclinical studies but the causal rela tionship in human remains uncertain. We aimed to evaluate causal relationships of bone mineral density (BMD) with blood cell traits using genetic data. Methods: Summary statistics from the largest available genome-wide association study were retrieved for total body BMD (TBBMD), lumbar spine BMD (LSBMD), femoral neck BMD (FNBMD) and 29 blood cell traits including red blood cell, white blood cell and platelet-related traits. Using two-sample Mendelian randomization (MR) approach, inverse-variance weighted method was adopted as main univariable MR analysis. Multivariable MR (MVMR) analysis was conducted to evaluate whether the casual effect is independent of confounders. Results: BMD was positively associated with reticulocyte-related traits, including high light scatter reticulocyte count and percentage, immature reticulocyte fraction, reticulocyte count and percentage, with causal effect estimate (beta) ranging from 0.023 to 0.064. Conversely, inverse association of BMD with hematocrit, hemo globin, and red blood cell count was observed, with beta ranging from − 0.038 to − 0.019. The association remained significant in MVMR analysis after adjustment for confounders. For white blood cells, BMD was inversely associated with neutrophil count (beta: 0.029 to − 0.019) and white blood cell count (beta: 0.024 to − 0.02). Results across TBBMD, LSBMD, and FNBMD were consistent. Conclusions This study suggested bone metabolism had a causal effect on hematopoietic system in humans. Its causal effect on red blood cell traits was independent of confounders. Further studies on how improving bone health can reduce risk of hematological disorders are warranted.

Objectives: Osteoblast is known to regulate hematopoiesis according to preclinical studies but the causal rela tionship in human remains uncertain. We aimed to evaluate causal relationships of bone mineral density (BMD) with blood cell traits using genetic data. Methods: Summary statistics from the largest available genome-wide association study were retrieved for total body BMD (TBBMD), lumbar spine BMD (LSBMD), femoral neck BMD (FNBMD) and 29 blood cell traits including red blood cell, white blood cell and platelet-related traits. Using two-sample Mendelian randomization (MR) approach, inverse-variance weighted method was adopted as main univariable MR analysis. Multivariable MR (MVMR) analysis was conducted to evaluate whether the casual effect is independent of confounders. Results: BMD was positively associated with reticulocyte-related traits, including high light scatter reticulocyte count and percentage, immature reticulocyte fraction, reticulocyte count and percentage, with causal effect estimate (beta) ranging from 0.023 to 0.064. Conversely, inverse association of BMD with hematocrit, hemo globin, and red blood cell count was observed, with beta ranging from − 0.038 to − 0.019. The association remained significant in MVMR analysis after adjustment for confounders. For white blood cells, BMD was inversely associated with neutrophil count (beta: 0.029 to − 0.019) and white blood cell count (beta: 0.024 to − 0.02). Results across TBBMD, LSBMD, and FNBMD were consistent. Conclusions This study suggested bone metabolism had a causal effect on hematopoietic system in humans. Its causal effect on red blood cell traits was independent of confounders. Further studies on how improving bone health can reduce risk of hematological disorders are warranted.

ObjectiveTo evaluate the expression level of DNA damage repair gene FANCI in hepatocellular carcinoma （HCC） and its relationship with prognosis， clinical stage and immune infiltration. MethodsIn this study， TCGA， GTEx， TIMER2.0， HPA database and qRT-PCR， western blot and immunohistochemistry were used to analyze the expression of FANCI in HCC and its correlation with different clinical stages； Kaplan-Meier Plotter database was used to explore the relationship between FANCI and the prognosis of HCC； the TISIDB database was used to analyze the relationship between FANCI and immune cell infiltration and immune checkpoints in HCC； the STRING database was used to detect the protein binding with FANCI； the TCGA and GTEx databases were used for GO and KEGG enrichment analysis； Cell experiments were used to explore the role of FANCI in HCC. ResultsCompared with normal tissues， the mRNA and protein expression levels of FANCI in tumor tissues were up-regulated （P<0.001）； and HCC patients with high expression of FANCI had poor prognosis （P<0.001）； the expression of FANCI in tumor tissues was positively correlated with the number of activated CD4⁺ T cells， the number of Th2 cells and the expression of immune checkpoints， and B-cell and macrophage infiltration was significantly lower in the FANCI high expression group （P<0.01）； GO and KEGG enrichment analysis showed that FANCI-related genes were enriched in various biological processes such as amino acid transmembrane transporter activity； Cell experiments showed that knockdown of FANCI could inhibit the proliferation， invasion and migration of HCC （P<0.05）. ConclusionsFANCI is highly expressed in hepatocellular carcinoma tissues， which may play a role in suppressing anti-tumor immunity and acting on pathways such as amino acid transmembrane transport， and is associated with poor prognosis. The proliferation， invasion and migration ability of hepatocellular carcinoma are inhibited after knocking down FANCI.

The study aims to observe the effects and explore the mechanisms of Buyang Huanwu Decoction and Astragali Radix-Angelicae Sinensis Radix combination in the treatment of the inflammatory response of mice with atherosclerosis(AS) via the Toll-like receptor 4(TLR4)/myeloid differentiation primary response protein 88(MyD88)/nuclear factor-κB(NF-κB) signaling pathway. Male ApoE~(-/-) mice were randomly assigned into a model group, a Buyang Huanwu Decoction group, an Astragali Radix-Angelicae Sinensis Radix combination group, and an atorvastatin group, and male C57BL/6J mice of the same weeks old were used as the control group. Other groups except the control group were given high-fat diets for 12 weeks to establish the AS model, and drugs were administrated by gavage. Aortic intimal hyperplasia thickness, blood lipid level, plasma inflammatory cytokine levels, M1/M2 macrophage markers, and expression levels of proteins in TLR4/MyD88/NF-κB pathway in the vessel wall were measured to evaluate the effects of drugs on AS lesions and inflammatory responses. The results showed that the AS model was successfully established with the ApoE~(-/-) mice fed with high-fat diets. Compared with the control group, the model group showed elevated plasma total cholesterol(TC), triglyceride(TG), and low-density lipoprotein cholesterol(LDL-c) levels(P<0.05), thickened intima(P<0.01), and increased plasma tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6) levels(P<0.01). Moreover, the model group showed increased expression of vascular cell adhesion molecule-1(VCAM-1) and inducible nitric oxide synthase(iNOS)(P<0.01), inhibited expression of endothelial nitric oxide synthase(eNOS) and cluster of differentiation 206(CD206)(P<0.01), and up-regulated mRNA and protein levels of TLR4, MyD88, NF-κB inhibitor alpha(IκBα), and NF-κB in the vessel wall(P<0.05). Compared with the model group, Buyang Huanwu Decoction and Astragali Radix-Angelicae Sinensis Radix combination lowered the plasma TC and LDL-c levels(P<0.01), alleviated the intimal hyperplasia(P<0.01), and reduced the plasma TNF-α and IL-6 levels(P<0.05). Moreover, the two interventions promoted the expression of eNOS and CD206(P<0.05), inhibited the expression of VCAM-1 and iNOS(P<0.01), and down-regulated the mRNA and protein levels of TLR4, MyD88, IκBα, and NF-κB(P<0.05) in the vessel wall. This study indicated that Buyang Huanwu Decoction and Astragali Radix-Angelicae Sinensis Radix combination could delay the progression of AS, inhibit the polarization of vascular wall macrophages toward M1 type, and attenuate vascular inflammatory response by inhibiting the activation of TLR4/MyD88/NF-κB signaling pathway in the vascular wall. Astragali Radix and Angelicae Sinensis Radix were the main pharmacological substances in Buyang Huanwu Decoction for alleviating the AS vascular inflammatory response.
Mice ; Male ; Animals ; NF-kappa B/metabolism* ; Toll-Like Receptor 4/metabolism* ; NF-KappaB Inhibitor alpha/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Interleukin-6/metabolism* ; Myeloid Differentiation Factor 88/metabolism* ; Vascular Cell Adhesion Molecule-1/metabolism* ; Cholesterol, LDL ; Hyperplasia ; Mice, Inbred C57BL ; Atherosclerosis/genetics* ; Apolipoproteins E/therapeutic use* ; RNA, Messenger

This study investigated the differences in excretion kinetics of three alkaloids and their four metabolites from Simiao Pills in normal and type 2 diabetic rats. The diabetes model was established in rats by injection of streptozotocin, and the alkaloids in urine, feces, and bile of normal and diabetic rats were detected by LC-MS/MS to explore the effect of diabetes on alkaloid excretion of Simiao Pills. The results showed that 72 h after intragastric administration of the extract of Simiao Pills, feces were the main excretion route of alkaloids from Simiao Pills. The total excretion rates of magnoflorine and berberine in normal rats were 4.87% and 56.54%, which decreased to 2.35% and 35.53% in diabetic rats, which had statistical significance(P<0.05). The total excretion rates of phellodendrine, magnoflorine, and berberine in the urine of diabetic rats decreased significantly, which were 53.57%, 60.84%, and 52.78% of those in normal rats, respectively. After 12 h of intragastric administration, the excretion rate of berberine in the bile of diabetic rats increased significantly, which was 253.33% of that of normal rats. In the condition of diabetes, the excretion rate of berberine metabolite, thalifendine significantly decreased in urine and feces, but significantly increased in bile. The total excretion rates of jateorrhizine and palmatine in the urine increased significantly, and t_(1/2) and K_e changed significantly. The results showed that diabetes affected the in vivo process of alkaloids from Simiao Pills, reducing their excretion in the form of prototype drug, affecting the biotransformation of berberine, and ultimately increasing the exposure of alkaloids in vivo, which would be conducive to the hypoglycemic effect of alkaloids. This study provides references for the clinical application and drug development of Simiao Pills in diabetes.
Rats ; Animals ; Bile/metabolism* ; Chromatography, Liquid/methods* ; Berberine ; Diabetes Mellitus, Experimental/metabolism* ; Chromatography, High Pressure Liquid/methods* ; Tandem Mass Spectrometry/methods* ; Feces ; Alkaloids/metabolism* ; Diabetes Mellitus, Type 2/metabolism*