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

BACKGROUND: The optimal antidepressant dosages remain controversial. This study aimed to analyze the efficacy of antidepressants and characterize their dose-response relationships in the treatments of major depressive disorders (MDD). METHODS: We searched multiple databases, including the Embase, Cochrane Central Register of Controlled Trials, PubMed, and Web of Science, for the studies that were conducted between January 8, 2016, and April 30, 2023. The studies are double-blinded, randomized controlled trials (RCTs) involving the adults (≥18 years) with MDD. The primary outcomes were efficacy of antidepressant and the dose-response relationships. A frequentist network meta-analysis was conducted, treating participants with various dosages of the same antidepressant as a single therapy. We also implemented the model-based meta-analysis (MBMA) using a Bayesian method to explore the dose-response relationships. RESULTS: The network meta-analysis comprised 135,180 participants from 602 studies. All the antidepressants were more effective than the placebo; toludesvenlafaxine had the highest odds ratio (OR) of 4.52 (95% confidence interval [CI]: 2.65-7.72), and reboxetine had the lowest OR of 1.34 (95%CI: 1.14-1.57). Moreover, amitriptyline, clomipramine, and reboxetine showed a linear increase in effect size from low to high doses. The effect size of toludesvenlafaxine increased significantly up to 80 mg/day and subsequently maintained the maximal dose up to 160 mg/day while the predictive curves of nefazodone were fairly flat in different dosages. CONCLUSIONS: Although most antidepressants were more efficacious than placebo in treating MDD, no consistent dose-response relationship between any antidepressants was observed. For most antidepressants, the maximum efficacy was achieved at lower or middle prescribed doses, rather than at the upper limit. REGISTRATION No. CRD42023427480; https://www.crd.york.ac.uk/prospero/display_record.php?
Humans ; Antidepressive Agents/therapeutic use* ; Depressive Disorder, Major/drug therapy* ; Dose-Response Relationship, Drug ; Randomized Controlled Trials as Topic

Hormesis effect has been observed in the secondary metabolite synthesis of microorganisms induced by rare earth elements. However, the underlying molecular mechanism remains unclear. To analyze the molecular mechanism of the regulatory effect of Rhodotorula mucilaginosa in the presence of lanthanum chloride, different concentrations of lanthanum chloride were added to the fermentation medium of Rhodotorula mucilaginosa, and the carotenoid content was subsequently measured. It was found that the concentrations of La³⁺ exerting the promotional and inhibitory effects were 0-100 mg/L and 100-400 mg/L, respectively. Furthermore, the expression of 33 genes and the synthesis of 55 metabolites were observed to be up-regulated, while the expression of 85 genes and the synthesis of 123 metabolites were found to be down-regulated at the concentration range of the promotional effect. Notably, the expression of carotenoid synthesis-related genes except AL1 was up-regulated. Additionally, the content of β-carotene, lycopene, and astaxanthin demonstrated increases of 10.74%, 5.02%, and 3.22%, respectively. The expression of 5 genes and the synthesis of 91 metabolites were up-regulated, while the expression of 35 genes and the synthesis of 138 metabolites were down-regulated at the concentration range of the inhibitory effect. Meanwhile, the content of β-carotene, lycopene, and astaxanthin decreased by 21.73%, 34.81%, and 35.51%, respectively. In summary, appropriate concentrations of rare earth ions can regulate the synthesis of secondary metabolites by modulating the activities of various enzymes involved in metabolic pathways, thereby exerting the hormesis effect. The findings of this study not only contribute to our comprehension for the mechanism of rare earth elements in organisms but also offer a promising avenue for the utilization of rare earth elements in diverse fields, including agriculture, pharmaceuticals, and healthcare.
Lanthanum/pharmacology* ; Rhodotorula/genetics* ; Carotenoids/metabolism* ; Hormesis/drug effects* ; Fermentation ; Multiomics

Objective: To investigate the safety and efficacy of troxatabine in advanced or relapsed malignant tumors resistant to standard therapy in China. Methods: This is a phase Ⅰ prospective study. During dose escalation, patients in Cancer Hospital, Chinese Academy of Medical Sciences received a single-dose intravenous infusion of troxacitabine. The planned dosing groups were 1.8, 3.6, 4.8, 6.4 and 8.0 mg/m(2) on days 1 and 8 every 3 weeks. The data of all patients were collected for safety analyses. Safety and tolerability were evaluated by monitoring adverse events. Results: Nineteen patients were enrolled from April 2018 to May 2019. The major adverse events were fatigue (89.5%, 17/19), leukopenia (84.2%, 16/19) and neutropenia (78.9%, 15/19). The dose limiting toxicity was neutropenia. The maximum tolerated dose was 6.4 mg/m(2). The best effect was stable disease (43.8%). The half-life of elimination phase from 15.91 hours to 76.63 hours in each dose group. Conclusions: The toxicity of troxacitabine is well tolerant. We recommend that the dose for Phase Ⅱ clinical trial should be 6.4 mg/m(2).
Humans ; Antineoplastic Agents/adverse effects* ; Maximum Tolerated Dose ; Neoplasms/drug therapy* ; Neutropenia/chemically induced* ; Prospective Studies

OBJECTIVE: To evaluate the molluscicidal activity of surfactin against Oncomelania hupensis, so as to provide the experimental basis for use of Bacillus for killing O. hupensis. METHODS: O. hupensis snails were collected from schistosomiasisendemic foci of Wuhu City on September 2022, and Schistosoma japonicum-infected snails were removed. Then, 60 snails were immersed in surfactin at concentrations of 2, 1, 0.5, 0.25, 0.125 mg/mL and 0.062 5 mg/mL for 24, 48, 72 hours at 26 °C, while ultrapure water-treated snails served as controls. The median lethal concentration (LC₅₀) of surfactin against O. hupensis snails was estimated. O. hupensis snails were immersed in surfactin at a concentration of 24 h LC₅₀ and ultrapure water, and then stained with propidium iodide (PI). The PI uptake in haemocyte was observed in O. hupensis snails using fluorescence microscopy. RESULTS: The mortality of O. hupensis was 5.0% following immersion in surfactin at a concentration of 0.062 5 mg/mL for 24 h, and the mortality was 100.0% following immersion in surfactin at a concentration of 2 mg/mL for 72 h, while no snail mortality was observed in the control group. There were significant differences in the mortality of O. hupensis in each surfactin treatment groups at 24 (χ² = 180.150, P < 0.05), 48 h (χ² = 176.786, P < 0.05) and 72 h (χ² = 216.487, P < 0.05), respectively. The average mortality rates of O. hupensis were 38.9% (140/360), 62.2% (224/360) and 83.3% (300/360) 24, 48 h and 72 h post-immersion in surfactin, respectively (χ² = 150.264, P < 0.05), and the 24, 48 h and 72 h LC₅₀ values of surfactin were 0.591, 0.191 mg/mL and 0.054 mg/mL against O. hupensis snails. Fluorescence microscopy showed more numbers of haemocytes with PI uptake in 0.5 mg/mL surfactintreated O. hupensis snails than in ultrapure water-treated snails for 24 h, and there was a significant difference in the proportion of PI uptake in haemocytes between surfactin-and ultrapure water-treated snails (χ² = 6.690, P < 0.05). CONCLUSIONS Surfactin is active against O. hupensis snails, which may be associated with the alteration in the integrity of haemocyte membrane.
Animals ; Molluscacides/pharmacology* ; Snails ; Schistosoma japonicum ; Lethal Dose 50 ; Water

Humans ; Warfarin/therapeutic use* ; Cytochrome P-450 CYP2C9/genetics* ; Anticoagulants/therapeutic use* ; Genotype ; Heart Valves ; China ; Apolipoproteins E/genetics* ; Dose-Response Relationship, Drug ; Receptors, Calcitriol/genetics*

Animals ; Caffeine/adverse effects* ; Central Nervous System Stimulants/adverse effects* ; Dose-Response Relationship, Drug ; Female ; Fetal Growth Retardation/chemically induced* ; Immune System Diseases/chemically induced* ; Male ; Organ Size/drug effects* ; Pregnancy ; Pregnancy Complications/immunology* ; Rats ; Spleen/growth & development*

To explore interleukin-6 (IL-6) production and characterize lipid accumulation in L02 hepatocytes induced by sodium oleate. L02 hepatocytes were incubated with 0, 37.5, 75, 150, 300, 600, or 1,200 μmol/L sodium oleate for 24 h, and the supernatant was collected to detect the concentration of IL-6. L02 hepatocytes were incubated with 300, 150, 75, or 0 μmol/L sodium oleate for 0-24 h. The supernatant was collected for detection of IL-6 and free fatty acids. L02 hepatocytes treated with 300 μmol/L sodium oleate for 0-24 h were stained with Oil Red O. With extended sodium oleate incubation time, IL-6 levels increased, and free fatty acids decreased. After 24 h incubation, IL-6 levels increased as sodium oleate increased from 37.5 to 300 μmol/L (
Dose-Response Relationship, Drug ; Hepatocytes/metabolism* ; Humans ; Interleukin-6/metabolism* ; Lipid Metabolism ; Oleic Acid/administration & dosage* ; Time Factors

A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (M
Antiviral Agents/therapeutic use* ; Binding Sites ; COVID-19/virology* ; Coronavirus Papain-Like Proteases/metabolism* ; Crystallography, X-Ray ; Drug Evaluation, Preclinical ; Drug Repositioning ; High-Throughput Screening Assays/methods* ; Humans ; Imidazoles/therapeutic use* ; Inhibitory Concentration 50 ; Molecular Dynamics Simulation ; Mutagenesis, Site-Directed ; Naphthoquinones/therapeutic use* ; Protease Inhibitors/therapeutic use* ; Protein Structure, Tertiary ; Recombinant Proteins/isolation & purification* ; SARS-CoV-2/isolation & purification*

High levels (> 100 ug/L) of arsenic are known to cause lung cancer; however, whether low (≤ 10 ug/L) and medium (10 to 100 ug/L) doses of arsenic will cause lung cancer or other lung diseases, and whether arsenic has dose-dependent or threshold effects, remains unknown. Summarizing the results of previous studies, we infer that low- and medium-concentration arsenic cause lung diseases in a dose-dependent manner. Arsenic trioxide (ATO) is recognized as a chemotherapeutic drug for acute promyelocytic leukemia (APL), also having a significant effect on lung cancer. The anti-lung cancer mechanisms of ATO include inhibition of proliferation, promotion of apoptosis, anti-angiogenesis, and inhibition of tumor metastasis. In this review, we summarized the role of arsenic in lung disease from both pathogenic and therapeutic perspectives. Understanding the paradoxical effects of arsenic in the lungs may provide some ideas for further research on the occurrence and treatment of lung diseases.
Animals ; Arsenic/toxicity* ; Dose-Response Relationship, Drug ; Humans ; Lung/pathology* ; Lung Neoplasms/drug therapy* ; Mice