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1.
Transplant Cell Ther ; 2024 Jul 04.
Article in English | MEDLINE | ID: mdl-38971463

ABSTRACT

Steroid-refractory (SR) acute graft-versus-host disease (aGVHD) is a major cause of mortality after allogeneic stem cell transplantation (allo-HSCT). We aimed to evaluate the effectiveness and safety of ruxolitinib plus basiliximab for treating SR-aGVHD after unrelated cord blood transplantation (UCBT). Among the 1154 patients with hematological malignancies who underwent UCBT between February 2014 and May 2022, 198 patients with grade II to IV SR-aGVHD were enrolled, 112 of whom were treated with basiliximab alone (basiliximab group) and 86 of whom received basiliximab plus ruxolitinib (combined therapy group). The combined therapy group demonstrated a significantly higher complete response rate (CRR) on day 28 (36.0%) than did the basiliximab group (12.5%, P < 0.001). SR-aGVHD patients were further stratified into standard-risk and high-risk groups using the refined Minnesota aGVHD risk score. For standard-risk patients, combined therapy significantly improved the CRR (51.1% versus 13.6%, P < 0.001) and 3-year overall survival (74.5% versus 52.4%, P = 0.033). However, high-risk patients did not exhibit the same benefits. Compared with basiliximab monotherapy, ruxolitinib plus basiliximab therapy was an effective therapy for patients with standard-risk SR-aGVHD following UCBT. The effectiveness of combined therapy in high-risk patients was not apparent, indicating the need for other treatments.

3.
Nucleic Acids Res ; 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38967000

ABSTRACT

Mitochondrial transcripts in Trypanosoma brucei require extensive uridine insertion/deletion RNA editing to generate translatable open reading frames. The RNA editing substrate binding complex (RESC) serves as the scaffold that coordinates the protein-protein and protein-RNA interactions during editing. RESC broadly contains two modules termed the guide RNA binding complex (GRBC) and the RNA editing mediator complex (REMC), as well as organizer proteins. How the protein and RNA components of RESC dynamically interact to facilitate editing is not well understood. Here, we examine the roles of organizer proteins, RESC8 and RESC14, in facilitating RESC dynamics. High-throughput sequencing of editing intermediates reveals an overlapping RESC8 and RESC14 function during editing progression across multiple transcripts. Blue native PAGE analysis demonstrates that RESC14 is essential for incorporation of RESC8 into a large RNA-containing complex, while RESC8 is important in recruiting a smaller ribonucleoprotein complex (RNP) to this large complex. Proximity labeling shows that RESC14 is important for stable RESC protein-protein interactions, as well as RESC-RECC associations. Together, our data support a model in which RESC14 is necessary for assembly of editing competent RESC through recruitment of an RNP containing RESC8, GRBC and gRNA to REMC and mRNA.

4.
Front Nutr ; 11: 1358651, 2024.
Article in English | MEDLINE | ID: mdl-38938667

ABSTRACT

Phospholipids (PLs) and long-chain polyunsaturated fatty acids (LCPUFAs) are naturally present in breast milk and play important roles in promoting the growth of the infant. Several studies have investigated the effects of the combination of PLs and LCPUFAs on neurodevelopment. However, data on the effectiveness of infant formula containing both PLs and LCPUFAs on the neurodevelopment of infants is still scarce. This randomized, double-blind, controlled clinical study was designed to evaluate the effect of an infant formula enriched with PLs and LCPUFAs on growth parameters and neurodevelopmental outcomes in term infants up to 365 days of age. Infants were enrolled within 30 days of birth who were then randomly assigned to either a control group (n = 150) or an investigational group (n = 150). Both groups consist of cow's milk-based formula which were generally identical in terms of composition, except that the investigational formula was additionally supplemented with PLs and LCPUFAs. The infants were followed for the first year of life. Breastfed infants were the reference (n = 150). Bayley Scales of Infant Development [3rd edition (Bayley-III)], Carey Toddler Temperament Scales (TTS), MacArthur-Bates Communicative Development Inventories (CDI), Single Object Attention and Free Play Tasks were used to evaluate neurodevelopmental outcomes of infant at 365 days of age. In addition, Ages and Stages Questionnaires (ASQ) were also conducted at 120, 180, and 275 days of age. Compared to breastfeeding, both infant formulas were well-tolerated and provided adequate growth, with no adverse events being reported throughout the study. Infants of the investigational group showed higher mean scores in Bayley-III cognitive performance (104.3 vs. 99.0, p < 0.05), language (106.9 vs. 104.5, p < 0.05), and motor skills (109.2 vs. 103.9, p < 0.05) compared the control group. Similar results were being reported for other developmental scales including TTS and ASQ. Notably, the test scores of infants fed the investigational formula were similar to those who were breastfed. Our results indicate that PL and LCPUFA supplementation may be beneficial for neurodevelopment of infants throughout the first year of life. Further studies are needed to investigation long-term effects PL and LCPUFA on neurodevelopment in early life.

5.
J Autoimmun ; 147: 103274, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38936148

ABSTRACT

Chronic graft-versus-host disease (cGVHD) is the most common long-term complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The patients with pulmonary cGVHD in particular have a very poor prognosis. NK cells are the first reconstituted lymphocyte subset after allo-HSCT; however, the impact of reconstituted NK cells on cGVHD is unclear. Here, we found allogeneic recipients showed obvious pulmonary cGVHD. Surprisingly, deletion of reconstituted NK cells resulted in maximal relief of pulmonary cGVHD. Mechanistically, reconstituted NK cells with donor profiles modulated the pulmonary inflammatory microenvironment to trigger cGVHD. Reconstituted NK cells secreted IFN-γ and TNF-α to induce CXCL10 production by epithelial cells, which recruited macrophages and CD4+ T cells to the lungs. Then macrophages and CD4+ T cells were activated by the inflammatory microenvironment, thereby mediating lung injury. Through assessment of differences in cellular energy, we found that CD74+ NK cells with high mitochondrial potential and pro-inflammatory activity triggered pulmonary cGVHD. Furthermore, targeted elimination of CD74+ NK cells using the anti-CD74 antibody significantly alleviated pulmonary cGVHD but preserved the CD74- NK cells to exert graft-versus-leukemia (GVL) effects. Data from human samples corroborated our findings in mouse models. Collectively, our results reveal that reconstituted CD74+ NK cells trigger pulmonary cGVHD and suggest that administration of CD74 antibody was a potential therapeutic for patients with cGVHD.


Subject(s)
Bone Marrow Transplantation , Graft vs Host Disease , Killer Cells, Natural , Transplantation, Homologous , Graft vs Host Disease/etiology , Graft vs Host Disease/immunology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Animals , Mice , Humans , Bone Marrow Transplantation/adverse effects , Chronic Disease , Male , Female , Histocompatibility Antigens Class II/immunology , Histocompatibility Antigens Class II/metabolism , Disease Models, Animal , Hematopoietic Stem Cell Transplantation/adverse effects , Mice, Inbred C57BL , Immune Reconstitution , Bronchiolitis Obliterans Syndrome
6.
Article in English | MEDLINE | ID: mdl-38839035

ABSTRACT

BACKGROUND: Internet Gaming Disorder (IGD) involves an imbalance in the brain's dual-system, characterized by heightened reward-seeking and diminished cognitive control, which leads to decision-making challenges. The exploration-exploitation strategy is key to decision-making, but how IGD affects this process is unclear. METHODS: To investigate the impact of IGD on decision-making, a modified version of the two-armed bandit task was employed. Participants included 41 IGD individuals and 44 healthy control (HC) individuals. The study assessed the strategies used by participants in the task, particularly focusing on the exploitation-exploration strategy. Additionally, functional magnetic resonance imaging (fMRI) was used to examine brain activation patterns during decision-making and estimation phasess. RESULTS: The study found that individuals with IGD demonstrated a higher reliance on exploitative strategies in decision-making due to their elevated value-seeking tendencies and decreased cognitive control. IGD individuals also displayed heightened activation in the pre-supplementary motor area (preSMA) and the ventral striatum (VS) compared to the HC group in both decision-making and estimation phases. Meanwhile, the prefrontal cortex (PFC) showed more inhibition in IGD individuals than in the HC group during exploitative strategies. This inhibition was found to decrease as cognitive control diminished. CONCLUSION: The study concludes that the imbalance in the development of the dual-system in individuals with IGD may lead to an over-reliance on exploitative strategies. This imbalance, marked by increased reward-seeking and reduced cognitive control, contributes to difficulties in decision-making and value-related behavioral processes in IGD individuals.

7.
Nat Microbiol ; 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38862603

ABSTRACT

Dimethylsulfoniopropionate (DMSP) is an abundant marine organosulfur compound with roles in stress protection, chemotaxis, nutrient and sulfur cycling and climate regulation. Here we report the discovery of a bifunctional DMSP biosynthesis enzyme, DsyGD, in the transamination pathway of the rhizobacterium Gynuella sunshinyii and some filamentous cyanobacteria not previously known to produce DMSP. DsyGD produces DMSP through its N-terminal DsyG methylthiohydroxybutyrate S-methyltransferase and C-terminal DsyD dimethylsulfoniohydroxybutyrate decarboxylase domains. Phylogenetically distinct DsyG-like proteins, termed DSYE, with methylthiohydroxybutyrate S-methyltransferase activity were found in diverse and environmentally abundant algae, comprising a mix of low, high and previously unknown DMSP producers. Algae containing DSYE, particularly bloom-forming Pelagophyceae species, were globally more abundant DMSP producers than those with previously described DMSP synthesis genes. This work greatly increases the number and diversity of predicted DMSP-producing organisms and highlights the importance of Pelagophyceae and other DSYE-containing algae in global DMSP production and sulfur cycling.

8.
Biomed Pharmacother ; 176: 116832, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38850659

ABSTRACT

Berberine (BBR) is a compound derived from Chinese herbal medicine, known for its anticancer properties through multiple signaling pathways. However, whether BBR can inhibit tumor growth by participating in ferroptosis remains unconfirmed. In this study, we demonstrated that berberine synergistically inhibited NSCLC in combination with multiple ferroptosis inducers, and this combination synergistically down-regulated the mRNA and protein expression of SLC7A11, GPX4, and NRF2, resulting in ferroptosis accompanied by significant depletion of GSH, and aberrant accumulation of reactive oxygen species and malondialdehyde. In a lung cancer allograft model, the combination treatment exhibited enhanced anticancer effects compared to using either drug alone. Notably, p53 is critical in determining the ferroptosis sensitivity. We found that the combination treatment did not elicit a synergistic anticancer effect in cells with a p53 mutation or with exogenous expression of mutant p53. These findings provide insight into the mechanism by which combination induces ferroptosis and the regulatory role of p53 in this process. It may guide the development of new strategies for treating NSCLC, offering great medical potential for personal diagnosis and treatment.


Subject(s)
Amino Acid Transport System y+ , Berberine , Carcinoma, Non-Small-Cell Lung , Drug Synergism , Ferroptosis , Lung Neoplasms , Phospholipid Hydroperoxide Glutathione Peroxidase , Signal Transduction , Tumor Suppressor Protein p53 , Ferroptosis/drug effects , Berberine/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/genetics , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Humans , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/metabolism , Lung Neoplasms/genetics , Amino Acid Transport System y+/metabolism , Amino Acid Transport System y+/genetics , Animals , Signal Transduction/drug effects , Cell Line, Tumor , Reactive Oxygen Species/metabolism , Mice , Mice, Nude , Mice, Inbred BALB C , NF-E2-Related Factor 2/metabolism , A549 Cells
9.
J Clin Oncol ; : JCO2302044, 2024 Jun 20.
Article in English | MEDLINE | ID: mdl-38900984

ABSTRACT

PURPOSE: SHR-A1811 is an antibody-drug conjugate composed of an anti-human epidermal growth factor receptor 2 (HER2) antibody trastuzumab, a cleavable linker, and a topoisomerase I inhibitor payload. We assessed the safety, tolerability, antitumor activity, and pharmacokinetics of SHR-A1811 in heavily pretreated HER2-expressing or mutated advanced solid tumors. METHODS: This global, multi-center, first-in-human, phase I trial was conducted at 33 centers. Patients who had HER2-expressing or mutated unresectable, advanced, or metastatic solid tumors and were refractory or intolerant to standard therapies were enrolled. SHR-A1811 was administered intravenously at doses ranging from 1.0 to 8.0 mg/kg once every 3 weeks. The primary end points were dose-limiting toxicity, safety, and the recommended phase II dose. RESULTS: From September 7, 2020, to February 27, 2023, 307 patients who had undergone a median of three (IQR, 2-5) previous treatment regimens in the metastatic setting received SHR-A1811 treatment. As of data cutoff (February 28, 2023), one patient from the 6.4 mg/kg group experienced dose-limiting toxicities (pancytopenia and colitis). The most common grade 3 or higher adverse events (AEs) included decreased neutrophil count (119 [38.8%]) and decreased WBC count (70 [22.8%]). Interstitial lung disease occurred in only eight (2.6%) patients. Serious AEs and deaths occurred in 70 (22.8%) and 13 (4.2%) patients, respectively. SHR-A1811 led to objective responses in 59.9% (184/307) of all patients, 76.3% (90/118) of HER2-positive breast cancer, 60.4% (55/91) of HER2 low-expressing breast cancer, and 45.9% (39/85 with evaluable tumor responses) of the 98 nonbreast tumors. CONCLUSION: SHR-A1811 exhibited acceptable tolerability, promising antitumor activity, and a favorable pharmacokinetic profile in heavily pretreated advanced solid tumors. The recommended phase II dose of 4.8 or 6.4 mg/kg was selected for various tumor types.

11.
Future Microbiol ; : 1-16, 2024 Jun 24.
Article in English | MEDLINE | ID: mdl-38913747

ABSTRACT

Aim: Animal models of fatal pneumonia caused by Streptococcus pneumoniae (Spn) have not been reliably generated using many strains of less virulent serotypes. Materials & methods: Pulmonary infection of a less virulent Spn serotype1 strain in the immunocompetent mice was established via the intratracheal aerosolization (ITA) route. The survival, local and systemic bacterial spread, pathological changes and inflammatory responses of this model were compared with those of mice challenged via the intratracheal instillation, intranasal instillation and intraperitoneal injection routes. Results: ITA and intratracheal instillation both induced fatal pneumonia; however, ITA resulted in better lung bacterial deposition and distribution, pathological homogeneity and delivery efficiency. Conclusion: ITA is an optimal route for developing animal models of severe pulmonary infections.


What is this article about? Streptococcus pneumoniae (Spn), a type of bacteria, can cause serious illness and death in otherwise healthy people. One way that we study pneumonia is using animals. However, pneumonia in animals infected with Spn in the laboratory does not mimic that in humans very well. To study this illness, we need a new way to set up a proper animal model.What were the results? This study set up a method called intratracheal aerosolization (ITA). In ITA, bacteria can form small droplets called aerosols and reach the deepest parts of a mouse's lung. ITA can cause deadly illness in mice infected with Spn, even if the mice are healthy.What do the results of the study mean? The ITA method could be a useful tool to set up animal models of serious pneumonia with less virulent bacteria.

12.
Eur J Pharm Sci ; 198: 106796, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38735400

ABSTRACT

Polysorbate 80, commonly abbreviated as PS80, is a widely used pharmaceutical excipient renowned for its role as a solubilizer and stabilizer in drug formulations. Although PS80 is essential for various pharmaceutical applications, particularly in the formulation of injectable drugs, it has been implicated in a range of adverse reactions. However, due to the complexity of the composition of PS80, the differences in the types and contents of the constituents of PS80 from different manufacturers increase the probability or likelihood of their uneven quality. Addressing the complete spectrum of PS80's components is challenging; thus, most studies to date have examined PS80 as a singular entity. This approach, however, carries a degree of uncertainty, as it overlooks the unique composition and concentration of components within the PS80 used in experiments, which may not reflect the actual diversity in commercially available PS80 products. Recognizing the critical need to understand how PS80's composition influences biological effects and toxicity, our study aims to bridge this knowledge gap. By doing so, we can clarify how different PS80 compositions from various manufacturers might affect the quality of pharmaceutical formulations, and also guide excipient manufacturers toward producing higher-quality PS80. Such insights could further facilitate a more targeted application of PS80 in drug development. Building on our previous work, we isolated and prepared two key components of PS80-polyoxyethylene sorbitan monooleate (PSM) and polyoxyethylene isosorbide monooleate (PIM)-and conducted a systematic comparison. We evaluated the acute, hemolytic, and target organ toxicity of two different PS80 samples, as well as PSM and PIM, using a zebrafish model. Our research also delved into the potential mechanisms behind the observed toxicological effects, providing an in-depth understanding of PS80's impact on biological systems.The results show that PS80, PSM, and PIM resulted in developmental anomalies in larval zebrafish. The primary organs of acute toxicity in zebrafish exposed to PS80 and its typical components PSM and PIM include the cardiovascular system, kidneys, intestines, skin, and liver. Notably, PIM further induced severe pericardial edema and erythrocyte hemolysis, thereby affecting blood flow. The samples also instigated oxidative damage by disrupting the redox equilibrium in the larvae. Compared to PS80, both PSM and PIM induced greater oxidative damage, with PIM notably causing significantly higher lipid oxidation, suggesting that oxidative stress may play a crucial role in polysorbate80-induced toxicity. Furthermore, our study found that PS80 could induce alterations in DNA conformation. The findings underscore the necessity for excipient regulators to establish comprehensive quality standards for Polysorbate 80 (PS80). By implementing such standards, it is possible to minimize the clinical risks associated with the variability in PS80 composition, ensuring safer pharmaceutical products for patients.


Subject(s)
Excipients , Polysorbates , Zebrafish , Animals , Polysorbates/toxicity , Polysorbates/chemistry , Excipients/toxicity , Excipients/chemistry
13.
Water Sci Technol ; 89(9): 2523-2537, 2024 May.
Article in English | MEDLINE | ID: mdl-38747965

ABSTRACT

Miscanthus sacchariflorus is previously demonstrated to be a potential candidate for remediation of cadmium (Cd) pollution. To explore its resistance strategy to Cd, a hydroponic experiment was conducted to determine the variations of photosynthetic activity in leaves and physiological response in roots of this plant. Results showed that the root of M. sacchariflorus was the primary location for Cd accumulation. The bioconcentration factor in the roots and rhizomes was >1, and the translocation factor from underground to aboveground was <1. Throughout the experimental period, treatment with 0.06 mM Cd2+ did not significantly alter the contents of chlorophyll a, chlorophyll b, or carotenoid. By contrast, treatment with 0.15 and 0.30 mM Cd2+ decreased the contents of chlorophyll a, chlorophyll b, and carotenoid; caused the deformation of the chlorophyll fluorescence transient curve; reduced the photochemical efficiency of photosystem II; and increased the contents of non-protein thiols, total flavone, and total phenol. These results indicate that M. sacchariflorus has good adaptability to 0.06 mM Cd2+. Moreover, the accumulation of the non-protein thiols, total flavone, and total phenol in roots may promote the chelation of Cd2+, thus alleviating Cd toxicity. This study provides theoretical support for using M. sacchariflorus to remediate Cd-polluted wetlands.


Subject(s)
Cadmium , Photosynthesis , Poaceae , Sulfhydryl Compounds , Cadmium/toxicity , Cadmium/metabolism , Photosynthesis/drug effects , Poaceae/metabolism , Poaceae/drug effects , Sulfhydryl Compounds/metabolism , Chlorophyll/metabolism , Plant Roots/metabolism , Plant Roots/drug effects , Biodegradation, Environmental
14.
Gynecol Endocrinol ; 40(1): 2351525, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38726683

ABSTRACT

OBJECTIVE: Stable luteal cell function is an important prerequisite for reproductive ability and embryonic development. However, luteal insufficiency seriously harms couples who have the desire to have a pregnancy, and the most important thing is that there is no complete solution. In addition, Vaspin has been shown to have regulatory effects on luteal cells, but the complex mechanisms involved have not been fully elucidated. Therefore, this study aimed to explore the effect of Vaspin on rat luteal cells and its mechanism. METHODS: Granulosa lutein cells separated from the ovary of female rats were incubated for 24h with gradient concentrations of Vaspin, and granulosa lutein cells incubated with 0.5% bovine serum albumin were used as controls. The proliferation, apoptosis, angiogenesis, progesterone (P4) and estradiol (E2) were detected by CCK-8, Anneixn-FITC/PI staining, angiogenesis experiment and ELISA. Western blot was applied to observe the expression levels of proteins related to cell proliferation, apoptosis, angiogenesis and MEK/MAPK signaling pathway. RESULTS: Compared with the Control group, Vaspin could significantly up-regulate the proliferation of granulosa lutein cells and reduce the apoptosis. Moreover, Vaspin promoted the angiogenesis of granulosa lutein cells and the production of P4 and E2 in a concentration-dependent manner. Furthermore, Vaspin up-regulated the CyclinD1, CyclinB1, Bcl2, VEGFA and FGF-2 expression in granulosa lutein cells, and down-regulated the level of Bax. Also, Vaspin increased the p-MEK1 and p-p38 levels. CONCLUSION: Vaspin can up-regulate the proliferation and steroidogenesis of rat luteal cells and reduce apoptosis, which may be related to the influence of MEK/MAPK activity.


Subject(s)
Apoptosis , Cell Proliferation , Luteal Cells , Progesterone , Serpins , Animals , Female , Cell Proliferation/drug effects , Serpins/metabolism , Serpins/pharmacology , Rats , Luteal Cells/drug effects , Luteal Cells/metabolism , Apoptosis/drug effects , Progesterone/pharmacology , Estradiol/pharmacology , Cells, Cultured , Rats, Sprague-Dawley , MAP Kinase Signaling System/drug effects , Neovascularization, Physiologic/drug effects
15.
Plant Cell ; 36(7): 2729-2745, 2024 Jul 02.
Article in English | MEDLINE | ID: mdl-38652680

ABSTRACT

Flowering is a key developmental transition in the plant life cycle. In temperate climates, flowering often occurs in response to the perception of seasonal cues such as changes in day-length and temperature. However, the mechanisms that have evolved to control the timing of flowering in temperate grasses are not fully understood. We identified a Brachypodium distachyon mutant whose flowering is delayed under inductive long-day conditions due to a mutation in the JMJ1 gene, which encodes a Jumonji domain-containing protein. JMJ1 is a histone demethylase that mainly demethylates H3K4me2 and H3K4me3 in vitro and in vivo. Analysis of the genome-wide distribution of H3K4me1, H3K4me2, and H3K4me3 in wild-type plants by chromatin immunoprecipitation and sequencing combined with RNA sequencing revealed that H3K4m1 and H3K4me3 are positively associated with gene transcript levels, whereas H3K4me2 is negatively correlated with transcript levels. Furthermore, JMJ1 directly binds to the chromatin of the flowering regulator genes VRN1 and ID1 and affects their transcription by modifying their H3K4me2 and H3K4me3 levels. Genetic analyses indicated that JMJ1 promotes flowering by activating VRN1 expression. Our study reveals a role for JMJ1-mediated chromatin modification in the proper timing of flowering in B. distachyon.


Subject(s)
Brachypodium , Flowers , Gene Expression Regulation, Plant , Histones , Plant Proteins , Brachypodium/genetics , Brachypodium/physiology , Flowers/genetics , Flowers/physiology , Flowers/growth & development , Plant Proteins/genetics , Plant Proteins/metabolism , Histones/metabolism , Mutation/genetics , Jumonji Domain-Containing Histone Demethylases/genetics , Jumonji Domain-Containing Histone Demethylases/metabolism , Chromatin/metabolism , Chromatin/genetics
16.
Sci Bull (Beijing) ; 69(12): 1866-1874, 2024 Jun 30.
Article in English | MEDLINE | ID: mdl-38670850

ABSTRACT

The merging of transition metal catalysis with electrochemistry has become a powerful tool for organic synthesis because catalysts can govern the reactivity and selectivity. However, coupling catalysts with alkyl radical species generated by anodic oxidation remains challenging because of electrode passivation, dimerization, and overoxidation. In this study, we developed convergent paired electrolysis for the coupling of nickel catalysts with alkyl radicals derived from photoinduced ligand-to-metal charge-transfer of cyclic alcohols and iron catalysts, providing a practical method for site-specific and remote arylation of ketones. The synergistic use of photocatalysis with convergent paired electrolysis can provide alternative avenues for metal-catalyzed radical coupling reactions.

17.
Br J Haematol ; 204(6): 2378-2389, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38581290

ABSTRACT

To explore the impact of letermovir (LET) prophylaxis on cytomegalovirus (CMV) reactivation and resistance in both adult and paediatric umbilical cord blood transplantation (UCBT) patients, we retrospectively compared 43 UCBT patients who received LET as CMV prophylaxis with a historical cohort of 207 UCBT patients without LET usage. LET was administered from Day +1 to Day +100. The 180-day cumulative incidence of CMV reactivation (47.3% vs. 74.4%, p < 0.001) and the proportion of refractory CMV reactivation (15.0% vs. 42.9%, p = 0.016) were significantly lower than those in the control group. However, more frequent late CMV infection (31.0% vs. 4.3%, p = 0.002) and the 180-day cumulative incidence of Epstein-Barr virus (EBV) reactivation (9.3% vs. 3.4%, p = 0.087) were observed in UCBT patients with LET prophylaxis. Meanwhile, older age (>15 years old) and the occurrence of pre-engraftment syndrome were identified as the significant risk factors for CMV reactivation, and in patients at high risk, the incidence of CMV reactivation in the LET group was lower than that in the control group (46.7% vs. 86.5%, p < 0.001), while this decline was less pronounced among patients at low risk (47.8% vs. 62.1%, p = 0.120).


Subject(s)
Antiviral Agents , Cord Blood Stem Cell Transplantation , Cytomegalovirus Infections , Cytomegalovirus , Quinazolines , Virus Activation , Humans , Cord Blood Stem Cell Transplantation/adverse effects , Cord Blood Stem Cell Transplantation/methods , Male , Cytomegalovirus Infections/prevention & control , Cytomegalovirus Infections/etiology , Female , Cytomegalovirus/drug effects , Cytomegalovirus/physiology , Adult , Retrospective Studies , Adolescent , Middle Aged , Child , Virus Activation/drug effects , Antiviral Agents/therapeutic use , Quinazolines/therapeutic use , Quinazolines/pharmacology , Child, Preschool , Drug Resistance, Viral , Young Adult , Infant , Aged , Acetates
18.
Br J Haematol ; 204(6): 2390-2399, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38664918

ABSTRACT

In this multicentre, real-world study, we aimed to identify the clinical outcomes and safety of allogeneic haematopoietic stem cell transplantation (allo-HSCT) in T-lymphoblastic lymphoma (T-LBL). A total of 130 Ann Arbor stage III or IV T-LBL patients (>16 years) treated with allo-HSCT across five transplant centres were enrolled. The 2-year cumulative incidence of disease progression, the probabilities of progression-free survival (PFS), overall survival (OS) and non-relapse mortality (NRM) after allo-HSCT were 21.0%, 69.8%, 79.5% and 9.2% respectively. Patients with central nervous system (CNS) involvement had a higher cumulative incidence of disease progression compared with those without CNS involvement (57.1% vs. 18.9%, HR 3.78, p = 0.014). Patients receiving allo-HSCT in non-remission (NR) had a poorer PFS compared with those receiving allo-HSCT in complete remission (CR) or partial remission (49.2% vs. 72.7%, HR 2.21, p = 0.041). Particularly for patients with bone marrow involvement and achieving CR before allo-HSCT, measurable residual disease (MRD) positivity before allo-HSCT was associated with a poorer PFS compared with MRD negativity (62.7% vs. 86.8%, HR 1.94, p = 0.036). On multivariate analysis, CNS involvement at diagnosis and receiving allo-HSCT in NR were associated with disease progression. Thus, our real-world data suggested that allo-HSCT appeared to be an effective therapy for adult T-LBL patients with Ann Arbor stage III or IV disease.


Subject(s)
Hematopoietic Stem Cell Transplantation , Humans , Adult , Male , Female , Middle Aged , China/epidemiology , Adolescent , Young Adult , Transplantation, Homologous , Transplantation Conditioning/methods , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/therapy , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Disease-Free Survival
19.
Bioorg Med Chem Lett ; 107: 129769, 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-38670537

ABSTRACT

Among small-molecule CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) approved for metastatic breast cancers, abemaciclib has a more tolerable adverse effects in clinic. This is attributable to preferential inhibition of CDK4 over CDK6. In our search for a biased CDK4 inhibitor, we discovered a series of pyrimidine-indazole inhibitors. SAR studies led us to TQB3616 as a preferential CDK4 inhibitor. TQB3616 exhibited improvements in both enzymatic and cellular proliferation inhibitory potency when tested side-by-side with the FDA approved palbociclib and abemaciclib. TQB3616 also possessed favorable PK profile in multiple species. These differentiated properties, together with excellent GLP safety profile warranted TQB3616 moving to clinic. TQB3616 entered into clinical development in 2019 and currently in phase III clinical trials (NCT05375461, NCT05365178).


Subject(s)
Cell Proliferation , Cyclin-Dependent Kinase 4 , Protein Kinase Inhibitors , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 4/metabolism , Humans , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Structure-Activity Relationship , Molecular Structure , Cell Proliferation/drug effects , Animals , Drug Discovery , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Dose-Response Relationship, Drug , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrimidines/chemical synthesis , Rats , Drug Screening Assays, Antitumor , Drug Evaluation, Preclinical
20.
Sci Rep ; 14(1): 9149, 2024 Apr 21.
Article in English | MEDLINE | ID: mdl-38644401

ABSTRACT

Taking thin gauge strip as an example, the deformation process of metal strip in bending roll straightening was studied. Based on the theory of discrete, curvature integral and elastic-plastic mechanics, the strip travel trajectory of the bending roll straightening process is analyzed, and the numerical analytical calculation method of the continuous straightening process of the strip bending roll is established. The results are verified by establishing MARC finite element simulation and designing straightening experiment. The effects of yield strength, plastic rate and bending amount on residual stress after straightening were studied. In the straightening process, with the increase of the amount of bending roll, the residual strain converges to the region Γ, and with the increase of the yield strength, the region Γ decreases. With the increase of the yield strength, the amount of bending roll and the plastic rate, the wave height increases. The results of the calculation of residual stress, finite element simulation and experiment are close and the trend is consistent. The results show that the logic of the calculation method is reasonable, and the prediction error is within the scope of engineering application, which is helpful to the realization of process intelligence in the process of bending roller straightening.

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