Analytical validation of the DropXpert S6 system for diagnosis of chronic myelocytic leukemia.

Digital PCR is a powerful method for absolute nucleic acid quantification and is widely used in the absolute quantification of viral copy numbers, tumor marker detection, and prenatal diagnosis. However, for most of the existing droplet-based dPCR systems, the droplet generation, PCR reaction, and droplet detection are performed separately using different instruments. Making digital PCR both easy to use and practical by integrating the qPCR workflow into a superior all-in-one walkaway solution is one of the core ideas. A new innovative and integrated digital droplet PCR platform was developed that utilizes cutting-edge microfluidics to integrate dPCR workflows onto a single consumable chip. This makes previously complex workflows fast and simple; the whole process of droplet generation, PCR amplification, and droplet detection is completed on one chip, which meets the clinical requirement of "sample in, result out". It provides high multiplexing capabilities and strong sensitivity while all measurements were within the 95% confidence interval. This study is the first validation of the DropXpert S6 system and focuses primarily on verifying its reliability, repeatability, and consistency. In addition, the accuracy, detection limit, linearity, and precision of the system were evaluated after sample collection. Among them, the accuracy assessment by calculating the absolute bias of each target gene yielded a range from -0.1 to 0.08, all within ±0.5 logarithmic orders of magnitude; the LOB for the assay was set at 0, and the LoD value calculated using probit curves is MR4.7 (0.002%); the linearity evaluation showed that the R2 value of the BCR-ABL was 0.9996, and the R2 value of the ABL metrics calculated using the ERM standard was 0.9999; and the precision evaluation showed that all samples had a CV of less than 4% for intra-day, inter-day, and inter-instrument variation. The CV of inter-batch variation was less than 7%. The total CV was less than 5%. The results of the study demonstrate that dd-PCR can be applied to molecular detection and the clinical evaluation of CML patients and provide more precise personal treatment guidance, and its reproducibility predicts the future development of a wide range of clinical applications.

Injectable hydrogels activated with copper sulfide nanoparticles for enhancing spatiotemporal sterilization and osteogenesis in periodontal therapy.

Developing biomaterials capable of promoting bone regeneration in bacteria-infected sites is of utmost urgency for periodontal disease therapies. Here we produce a hybrid hydrogel by integrating CuS nanoparticles (CuSNPs), which could kill bacteria through photothermal therapy (PTT) triggered by a near infrared (NIR) light, and a gelatin methacryloyl (GelMA) hydrogel, which is injectable and biocompatible. Specifically, CuSNPs were precipitated by chitosan (CS) firstly, then grafted with methacrylic anhydride (MA) to form CuSNP@CS-MA, which was photo-crosslinked with GelMA to synthesize hybrid hydrogels (GelMA/CuSNP). The hybrid hydrogels exhibited a broad-spectrum antibacterial property that could be spatiotemprorally manipulated through applying a NIR light. Their mechanical properties were adjustable by controlling the concentration of CuSNPs, enabling the hydrogels to become more adapted to the oral diseases. Meanwhile, the hybrid hydrogels showed good cytocompatibility in vitro and improved hemostasis in vivo. Moreover, they accelerated alveolar osteogenesis and vascular genesis, successfully treating periodontis in four weeks in a rat model. GelMA/CuSNP hydrogels showed a broad-spectrum sterilization ability via PTT in vitro and outstanding antibacterial property in vivo, suggesting that the hybrid hydrogels could function in the challenging, bacteria-rich, oral environment. Such injectable hybrid hydrogels, capable of achieving both facilitated osteogenesis and NIR-inducible sterilization, represent a new biomaterial for treating periodontitis.

Heightened neural reward responsiveness functions as a plasticity factor moderating the association between childhood emotional abuse and young adult depressive symptoms: Evidence of differential susceptibility.

As a neural indicator of reward responsiveness (RR), reward positivity (RewP) has been demonstrated to moderate the association between stress exposure and depressive symptoms. However, extant research has primarily (a) focused on life stress rather than early maltreatment, (b) ignored the time-frequency components, and (c) has been based on a traditional perspective of diathesis stress. The present study aimed to comprehensively examine whether and how neurophysiological (RewP and its time-frequency decomposition components) and self-reported measures of RR interact with childhood emotional abuse on young adult depressive symptoms. The sample of 192 Chinese university students aged 18-25 (Mage = 21.08 ± 1.91 years; 59.4% girls) completed self-reported questionnaires of emotional abuse, depressive symptoms and RR. The RewP and its time-frequency components delta and theta were elicited via a monetary reward task. The results demonstrated that RewP significantly moderated the association between emotional abuse and young adult depressive symptoms in a differential susceptibility but not diathesis-stress manner. However, gain-related delta, loss-related theta, or self-reported RR did not drive such moderation effects. These findings were robust and survived a series of rigorous sensitivity analyses. The current findings provide preliminary evidence that heightened RewP may function as a plasticity factor moderating the association between early maltreatment exposure and depression, and highlight the effect specific to emotional abuse. However, caution should be paid to the generalizability of these findings in high-risk clinical samples, in light of the current high-functioning sample features and low rates of high symptom and abuse levels. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Injectable Phage-Loaded Microparticles Effectively Release Phages to Kill Methicillin-Resistant Staphylococcus aureus.

The increasing prevalence of bacterial multidrug antibiotic resistance has led to a serious threat to public health, emphasizing the urgent need for alternative antibacterial therapeutics. Lytic phages, a class of viruses that selectively infect and kill bacteria, offer promising potential as alternatives to antibiotics. However, injectable carriers with a desired release profile remain to be developed to deliver them to infection sites. To address this challenge, phage-loaded microparticles (Phage-MPs) have been developed to deliver phages to the infection site and release phages for an optimal therapeutic effect. The Phage-MPs are synthesized by allowing phages to be electrostatically attached onto the porous polyethylenimine-modified silk fibroin microparticles (SF-MPs). The high specific surface area of SF-MPs allows them to efficiently load phages, reaching about 1.25 × 1010 pfu per mg of microparticles. The Phage-MPs could release phages in a controlled manner to achieve potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Unlike the diffuse biodistribution of free phages post-intraperitoneal injection, Phage-MPs could continuously release phages to effectively boost the local phage concentration at the bacterial infection site after they are intraperitoneally injected into an abdominal MRSA-infected mouse model. In a mouse abdominal MRSA infection model, Phage-MPs significantly reduce the bacterial load in major organs, achieving an efficient therapeutic effect. Furthermore, Phage-MPs demonstrate outstanding biocompatibility both in vitro and in vivo. Overall, our research lays the foundation for a new generation of phage-based therapies to combat antibiotic-resistant bacterial infections.

Microglial activation in spaceflight and microgravity: potential risk of cognitive dysfunction and poor neural health.

Due to the increased crewed spaceflights in recent years, it is vital to understand how the space environment affects human health. A lack of gravitational force is known to risk multiple physiological functions of astronauts, particularly damage to the central nervous system (CNS). As innate immune cells of the CNS, microglia can transition from a quiescent state to a pathological state, releasing pro-inflammatory cytokines that contribute to neuroinflammation. There are reports indicating that microglia can be activated by simulating microgravity or exposure to galactic cosmic rays (GCR). Consequently, microglia may play a role in the development of neuroinflammation during spaceflight. Prolonged spaceflight sessions raise concerns about the chronic activation of microglia, which could give rise to various neurological disorders, posing concealed risks to the neural health of astronauts. This review summarizes the risks associated with neural health owing to microglial activation and explores the stressors that trigger microglial activation in the space environment. These stressors include GCR, microgravity, and exposure to isolation and stress. Of particular focus is the activation of microglia under microgravity conditions, along with the proposal of a potential mechanism.

Modulation of adipose tissue metabolism by exosomes in obesity.

Obesity and its related metabolic complications represent a significant global health challenge. Central to this is the dysregulation of glucolipid metabolism, with a predominant focus on glucose metabolic dysfunction in the current research, whereas adipose metabolism impairment garners less attention. Exosomes (EXs), small extracellular vesicles (EVs) secreted by various cells, have emerged as important mediators of intercellular communication and have the potential to be biomarkers, targets, and therapeutic tools for diverse diseases. In particular, EXs have been found to play a role in adipose metabolism by transporting cargoes such as noncoding RNAs (ncRNA), proteins, and other factors. This review article summarizes the current understanding of the role of EXs in mediating adipose metabolism disorders in obesity. It highlights their roles in adipogenesis (encompassing adipogenic differentiation and lipid synthesis), lipid catabolism, lipid transport, and white adipose browning. The insights provided by this review offer new avenues for developing exosome-based therapies to treat obesity and its associated comorbidities.

Correlation between symptoms and cognitive function changes in patients with primary insomnia and pathways in gut microbiota.

Background: Primary insomnia (PI) refers to syndromes of difficulty falling asleep, poor sleep quality, early awakening, and difficulty falling asleep after waking up. Although there have been numerous studies, the specific etiology and pathogenesis of PI are still misunderstanding. In recent years, the gut microbiota has been proved to be involved in the metabolism of many mental disorders. But the specific mechanisms of its involvement in PI have not been fully elucidated. This study aims to explore the relationship between the gut microbiota and the symptoms, cognitive function changes in PI. Methods: In this study, the gut microbiota of PI patients and healthy controls was profiled by performing stool 16s rRNA gene sequencing. The co-occurrence network was constructed by using Weight Gene Co-expression Network Analysis (WGCNA) algorithm. The correlation between gut microbiota associated pathways and traits in PI were predicted. Results: WGCNA results demonstrated several Operational Taxonomic Units (OTU) modules are correlated to symptoms. By using PICRUSt2 software, we predicted the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of microbiota in modules. For instance, sleep efficiency may be correlated with the presence of Insulin signaling pathway, Flavonoid biosynthesis, Ascorbate and aldarate metabolism, Nitrotoluene degradation, Biotin metabolism, RNA polymerase and Chlorocyclohexane and chlorobenzene degradation. Total sleep time may be correlated with the presence of Tyrosine metabolism, Propanoate metabolism, Carbon fixation pathways in prokaryotes, Carotenoid biosynthesis, Systemic lupus erythematosus, Nitrotoluene degradation and Biosynthesis of unsaturated fatty acids. The severity of insomnia may be correlated with Insulin signaling pathway, Flavonoid biosynthesis, Ascorbate and aldarate metabolism, Nitrotoluene degradation, Biotin metabolism and RNA polymerase. Change of name score in Montreal Cognitive Assessment (MoCA) may be correlated with Tyrosine metabolism, Propanoate metabolism, Carbon fixation pathways in prokaryotes, Carotenoid biosynthesis, Systemic lupus erythematosus, Nitrotoluene degradation, Biosynthesis of unsaturated fatty acids, Apoptosis, Steroid hormone biosynthesis, Geraniol degradation, Protein digestion and absorption and Bisphenol degradation in Gut Microbiota (GM). Conclusion: This study revealed the potential relationships between gut microbiota and PI. By using pathway prediction and enrichment analysis, we concluded many metabolic pathways may associated with some important traits of insomnia patients, including sleep efficiency, severe insomnia, total sleep time and change of name score in MoCA. The metabolic pathways include Insulin signaling pathway, Flavonoid biosynthesis, Ascorbate and aldarate metabolism, Nitrotoluene degradation, Biotin metabolism, RNA polymerase and Chlorocyclohexane, chlorobenzene degradation, Tyrosine metabolism, Propanoate metabolism, Carbon fixation pathways in prokaryotes, Carotenoid biosynthesis, Systemic lupus erythematosus, Biosynthesis of unsaturated fatty acids, Apoptosis, Steroid hormone biosynthesis, Geraniol degradation, Protein digestion and absorption and Bisphenol degradation.Our study demonstrated that PI patients demonstrate significant changes in gut microbiota, which will help delineate the relationship between gut microbiota and syndromes of PI.

Childhood maltreatment, multilocus HPA-axis genetic variation and adolescent comorbidity profiles of depressive and anxiety symptoms.

BACKGROUND: Despite a growing body of evidence showing both genetic and environmental influences on adolescent depression and anxiety, the involved comorbid mechanisms regarding gene-by-environment (G × E) interaction remain unclear. OBJECTIVE: The current study was the first to investigate the extent to which multilocus hypothalamic-pituitary-adrenal (HPA)-axis genetic variants moderated the association between childhood maltreatment and adolescent comorbid depression and anxiety. METHODS: The participants were 827 Chinese Han adolescents (Mage = 16.45 ± 1.37 years; 50.2 % girls). A theory-driven multilocus genetic profile score (MGPS) was computed by calculating alleles of core HPA-axis genes (CRHR1, NR3C1, NR3C2, and FKBP5) associated with heightened stress reactivity. Childhood maltreatment was retrospectively collected using Childhood Trauma Questionnaire. Comorbidity profiles of self-reported adolescent depressive and anxiety symptoms were constructed via person-centered latent profile analysis. RESULTS: Three heterogeneous comorbidity profiles of depressive and anxiety symptoms were identified: comorbid severe symptoms (9.7 %), comorbid moderate symptoms (46.4 %) and comorbid mild symptoms (43.9 %). The HPA-axis related MGPS significantly interacted with childhood maltreatment, especially emotional maltreatment (emotional abuse: OR = 1.14, 95 % CI [1.03, 1.26], p < .01; emotional neglect: OR = 1.07, 95 % CI [1.01, 1.13], p < .05), to distinguish the comorbid severe symptoms profile from the comorbid mild symptoms profile (OR = 1.03, 95 % CI [1.01, 1.06], p < .05). CONCLUSION: The HPA-axis related genes showed an additive polygenic sensitivity toward childhood maltreatment, which might be one of the polygenic G × E mechanisms underlying adolescent comorbid depression and anxiety.

Proteotranscriptomic analyses of the midgut and Malpighian tubules after a sublethal concentration of Cry1Ab exposure on Spodoptera litura.

BACKGROUND: Cry1Ab has emerged as a bio-insecticide to control Spodoptera litura (Lepidoptera: Noctuidae). However, the sublethal effects of Cry1Ab on the physiological changes and molecular level of S. litura have not been well documented. Our aims in this study were to assess the sublethal effect of Cry1Ab on S. litura, including midgut and Malpighian tubules as targets. RESULTS: After sublethal Cry1Ab exposure, distinct histological alterations were mainly observed in the midgut. Furthermore, the results of comparative RNA sequencing and tandem mass tag-based proteomics showed that, in the midgut, most differential expression genes (DEGs) were up-regulated and significantly enriched in the serine protease activity pathway, and up-regulated differential expression proteins (DEPs) were mainly associated with the oxidative phosphorylation pathway, whereas the down-regulated involved in the ribosome pathways. In the Malpighian tubules, DEGs and DEPs were significantly enriched in the ribosome pathway. We proposed that ribosome may act as a universal target in energy metabolism with other pathways via the results of protein-protein interaction analysis. Further, by verification of the mRNA expression of some Cry protein receptor and detoxification genes after Cry1Ab treatment, it was suggested that the ribosomal proteins (RPs) possibly participate in influencing the Bt-resistance of S. litura larvae under sublethal Cry1Ab exposure. CONCLUSION: Under sublethal Cry1Ab exposure, the midgut of S. litura was damaged, and the proteotranscriptomic analysis elucidated that Cry1Ab disrupted the energy homeostasis of larvae. Furthermore, we emphasized the potential role of ribosomes in sublethal Cry1Ab exposure. © 2024 Society of Chemical Industry.

Microglial Refinement of A-Fiber Projections in the Postnatal Spinal Cord Dorsal Horn Is Required for Normal Maturation of Dynamic Touch.

Sensory systems are shaped in postnatal life by the refinement of synaptic connectivity. In the dorsal horn of the spinal cord, somatosensory circuits undergo postnatal activity-dependent reorganization, including the refinement of primary afferent A-fiber terminals from superficial to deeper spinal dorsal horn laminae which is accompanied by decreases in cutaneous sensitivity. Here, we show in the mouse that microglia, the resident immune cells in the CNS, phagocytose A-fiber terminals in superficial laminae in the first weeks of life. Genetic perturbation of microglial engulfment during the initial postnatal period in either sex prevents the normal process of A-fiber refinement and elimination, resulting in an altered sensitivity of dorsal horn cells to dynamic tactile cutaneous stimulation, and behavioral hypersensitivity to dynamic touch. Thus, functional microglia are necessary for the normal postnatal development of dorsal horn sensory circuits. In the absence of microglial engulfment, superfluous A-fiber projections remain in the dorsal horn, and the balance of sensory connectivity is disrupted, leading to lifelong hypersensitivity to dynamic touch.

Regulatory mechanism of the six-method massage antipyretic process on lipopolysaccharide-induced fever in juvenile rabbits: A targeted metabolomics approach.

Objective: To investigate the mechanism of the six-method massage antipyretic process (SMAP) and its influence on the body's metabolic state. Methods: The random number table method was used to divide 24 New Zealand 2-month-old rabbits with qualified basal body temperature into a control group, model group and massage group (n = 8 per group). The model group and massage groups were injected with 0.5 µg/ml lipopolysaccharide (1 ml/kg) into the auricular vein, and the control group was injected with the same amount of normal saline at the same temperature. One hour after modelling, the massage group was given SMAP (opening Tianmen, pushing Kangong, rubbing Taiyang, rubbing Erhougaogu, clearing the Tianheshui and pushing the spine). The change of anal temperature 5 h after moulding was recorded to clarify the antipyretic effect. Results: After modelling, the rectal temperature of the juvenile rabbits in the three groups increased. The rectal temperature of the model group was higher than that of the control group 5 h after modelling, and the rectal temperature of the massage group was lower than that of the model group (P < 0.05). The antipyretic mechanism is related to the regulation of the synthesis of phenylalanine, tyrosine and tryptophan, as well as the pentose phosphate pathway. Compared with the model group, the plasma interleukin (IL)-1, IL-6, interferon-gamma, toll-like receptor 4, nuclear factor κB, the mechanistic target of rapamycin complex 1, indoleamine 2,3-dioxygenase 1, aryl hydrocarbon receptor, liver aspartate transaminase (AST), alanine transaminase (ALT) and l-glutamate dehydrogenase (L-GLDH) expression in the massage group were significantly decreased (P < 0.05). Compared with the model group, the massage group had significantly reduced AST, ALT and L-GLDH expression in plasma (P < 0.05). Conclusion: The mechanism of SMAP therapy is related to regulating the expression of peripheral inflammatory factors and metabolic pathways.

Matrix metalloproteinase 2 contributes to adult eclosion and immune response in the small hive beetle, Aethina tumida.

During the pupal-adult eclosion process of holometabolous insects, the old cuticle is shed and replaced by a completely different new cuticle that requires tanning and expansion, along with extensive extracellular matrix (ECM) remodeling. In vertebrates, matrix metalloproteinases (MMPs), a class of zinc-dependent endopeptidases, play key roles in regulating the ECM that surrounds cells. However, little is known about these extracellular proteinases available in insects. The small hive beetle (SHB), Aethina tumida, is a widespread invasive parasite of honey bees. In this study, 6 MMP homologs were identified in the SHB genome. RNA interference experiments showed that all 6 AtMmps are not required for the larval-pupal transition, only AtMmp2 was essential for pupal-adult eclosion in SHB. Knockdown of AtMmp2 resulted in eclosion defects and wing expansion failure, as well as mortality within 3 d of adult eclosion. Transcriptomic analysis revealed that knockdown of AtMmp2 significantly increased expression of the Toll and Imd pathways, chitin metabolism, and cross-linking (such as the pro-phenoloxidase activating cascade pathway and the tyrosine-mediated cuticle sclerotization and pigmentation pathway). These data revealed evolutionarily conserved functions of Mmp2 in controlling adult eclosion and wing expansion, also provided a preliminary exploration of the novel function of regulating Toll and Imd pathways, as well as new insights into how MMPs regulate insect development and defense barriers.

Avatrombopag for adult chronic primary immune thrombocytopenia: a randomized phase 3 trial in China.

Background: Immune thrombocytopenia (ITP) is an autoimmune disorder with decreased platelet counts and increased bleeding risk. Objectives: To evaluate the efficacy and safety of avatrombopag, a second-generation oral thrombopoietin receptor agonist, for the treatment of Chinese patients with chronic primary ITP. Methods: This multicenter, randomized, double-blind, placebo-controlled phase 3 study (CTR20210431) consisted of a 6-week double-blind core treatment phase followed by a 20-week, open-label extension phase. Chinese adults with chronic primary ITP for at least 12 months and a platelet count <30 × 109/L were randomized (2:1) to receive avatrombopag (initial dose of 20 mg/day) or matched placebo. The primary endpoint was the proportion of subjects with a platelet count ≥50 × 109/L at week 6 of the core treatment phase in absence of rescue therapy. Results: In total, 74 patients were randomized (avatrombopag: N = 48; placebo: N = 26) between March 5, 2021, and August 6, 2021; all of whom entered the extension phase (72 received avatrombopag up to 26 weeks). At week 6 of the core study, the platelet response (≥50 x 109/L) rate was significantly higher in the avatrombopag group (77.1%; 95% CI, 62.7, 88.0) vs placebo (7.7%; 95% CI, 1.0, 25.1); the treatment difference was 69.4% (95% CI, 56.2, 86.3; P < .0001). During the 6-week core study, treatment-emergent adverse events were reported in 41 (85.4%) and 20 (76.9%) patients in the avatrombopag and placebo groups, respectively. The most common avatrombopag-related treatment-emergent adverse events were upper respiratory tract infection (14/48 [29.2%]), increased platelet count (13/48 [27.1%]) and headache (7/48 [14.6%]). Conclusion: Avatrombopag was efficacious and generally well tolerated in Chinese patients with chronic primary ITP, with comparable efficacy and safety to previous reports in Western patients.

Impact of genetic patterns on sorafenib efficacy in patients with FLT3-ITD acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation: a multi-center, cohort study.

Sorafenib therapy improves overall survival (OS) in patients with FLT3 internal tandem duplication (ITD) acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation. We explored the efficacy of sorafenib therapy in this population with different concomitant genetic patterns. In this multi-center, cohort study, we enrolled patients with FLT3-ITD AML undergoing allogenic hematopoietic cell transplantation. Patients with sorafenib maintenance post-transplantation for at least four weeks were allocated to the sorafenib group, and otherwise to the control group. Endpoints were OS, disease-free survival, and relapse for the whole cohort and OS for genetic pattern subgroups. Among 613 patients enrolled, 275 were in the sorafenib and 338 the control group. Median follow-up was 36.5 (interquartile range (IQR), 25.2-44.7) months post-transplantation. The 3-year OS post-transplantation was 79.6% (95% confidential interval (CI) 74.8%-84.6%) and 65.2% (95% CI 60.3%-70.6%) (Hazard ratio (HR) 0.50, 95% CI 0.37-0.69; P < 0.0001) in both groups. Sorafenib maintenance post-transplantation improved OS in the favorable (HR 0.33, 95% CI 0.14-0.77; P = 0.011) and adverse (HR 0.56, 95% CI 0.33-0.93; P = 0.026) ELN 2017 risk subgroups. Patients with mutated NPM1, DNMT3A, co-occurring NPM1/DNMT3A, "activated signaling" and "DNA methylation" genes benefited in OS from sorafenib maintenance, while those carrying CEBPA, "tumor suppressors" and "myeloid transcription factors" genes did not. Patients with FLT3-ITDhigh and FLT3-ITDlow AML both benefited in OS from sorafenib maintenance. Our results identify the response of genetic patterns to sorafenib maintenance, providing new viewpoints for the optimal use of sorafenib in FLT3-ITD AML in the transplantation setting.

A life-threatening bleeding prediction model for immune thrombocytopenia based on personalized machine learning: a nationwide prospective cohort study.

Rare but critical bleeding events in primary immune thrombocytopenia (ITP) present life-threatening complications in patients with ITP, which severely affect their prognosis, quality of life, and treatment decisions. Although several studies have investigated the risk factors related to critical bleeding in ITP, large sample size data, consistent definitions, large-scale multicenter findings, and prediction models for critical bleeding events in patients with ITP are unavailable. For the first time, in this study, we applied the newly proposed critical ITP bleeding criteria by the International Society on Thrombosis and Hemostasis for large sample size data and developed the first machine learning (ML)-based online application for predict critical ITP bleeding. In this research, we developed and externally tested an ML-based model for determining the risk of critical bleeding events in patients with ITP using large multicenter data across China. Retrospective data from 8 medical centers across the country were obtained for model development and prospectively tested in 39 medical centers across the country over a year. This system exhibited good predictive capabilities for training, validation, and test datasets. This convenient web-based tool based on a novel algorithm can rapidly identify the bleeding risk profile of patients with ITP and facilitate clinical decision-making and reduce the occurrence of adversities.

Interpersonal Stress and Late Adolescent Depressive Symptoms: Moderation by Perceptual Sensitivity to Facial Expression of Anger.

The interpersonal theories of depression highlight the role of interpersonal stress and individual's sensitivity to social rejection in the development of depression. However, previous research has tested their respective effects, whereas whether or not these two factors interact to affect depression, especially in ways of differential susceptibility or diathesis-stress, remains unknown. By adopting a morphed facial expressions recognition paradigm, the current study investigated the potential moderating role of perceptual sensitivity to facial expressions, especially that to angry expression which signaled social rejection, in the association between interpersonal stress and adolescent depressive symptoms. A total of 186 Chinese late adolescents (Mage = 21.16 ± 1.81 years; 73.7% females) participated in this study. The results demonstrated that perceptual sensitivity for angry faces, but not sad or happy faces, functioned as a plasticity factor significantly moderating the effect of interpersonal stress on depressive symptoms, which was consistent with hypothesis of differential susceptibility rather than diathesis-stress. No interactions were observed regarding non-interpersonal dimensions. These results were robust and survived a series of sensitivity analyses, including k-fold cross-validation test. The current findings highlight the crucial role of perceptual sensitivity to angry expression in explaining individual differences behind the links between interpersonal stress and adolescent depressive symptoms.

Sorafenib maintenance after allogeneic haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid leukaemia: long-term follow-up of an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: Our open-label, multicentre, randomised, phase 3 trial showed that sorafenib maintenance after haematopoietic stem-cell transplantation (HSCT) improved overall survival and reduced relapse for patients with FLT3 internal tandem duplication (FLT3-ITD) acute myeloid leukaemia undergoing allogeneic HSCT. Here, we present a post-hoc analysis on the 5-year follow-up data of this trial. METHODS: This phase 3 trial, done in seven hospitals in China, included patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic HSCT, who were aged 18-60 years, had an Eastern Cooperative Oncology Group performance status of 0-2, had composite complete remission before and after transplantation, and had haematopoietic recovery within 60 days after transplantation. Patients were randomly assigned (1:1) to receive sorafenib maintenance (400 mg orally twice daily) or non-maintenance (control) at 30-60 days after transplantation. Randomisation was done with permuted blocks (block size four) via an interactive web-based system. Investigators and participants were not masked to group assignment. The primary endpoint was the 1-year cumulative incidence of relapse, which was reported previously. For this updated analysis, the 5-year endpoints were overall survival; cumulative incidence of relapse; non-relapse mortality; leukaemia-free survival; graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS); cumulative incidence of chronic GVHD; and late effects in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT02474290, and is complete. FINDINGS: Between June 20, 2015, and July 21, 2018, 202 patients were randomly assigned to sorafenib maintenance (n=100) or non-maintenance (n=102). Median follow-up was 60·4 months (IQR 16·7-73·3). Extended follow-up showed improved overall survival (72·0% [95% CI 62·1-79·7] vs 55·9% [45·7-64·9]; hazard ratio [HR] 0·55, 95% CI 0·34-0·88; p=0·011), leukaemia-free survival (70·0% [60·0-78·0] vs 49·0% [39·0-58·3]; 0·47, 0·30-0·73; p=0·0007), and GRFS (58·0% [47·7-67·0] vs 39·2% [29·8-48·5]; 0·56, 0·38-0·83; p=0·0030), lower cumulative incidence of relapse (15·0% [8·8-22·7] vs 36·3% [27·0-45·6]; 0·33, 0·18-0·60; p=0·0003), and no increase in non-relapse mortality (15·0% [8·8-22·7] vs 14·7% [8·6-22·3]; 0·79, 0·39-1·62; p=0·98) for patients in the sorafenib group compared with those in the control group. The 5-year cumulative incidence of chronic GVHD (54·0% [43·7-63·2] vs 51·0% [40·8-60·3]; 0·82, 0·56-1·19; p=0·73) did not differ significantly between the two groups and we did not find substantial differences in late effects between the two groups. There were no treatment-related deaths. INTERPRETATION: With extended follow-up, sorafenib maintenance after transplantation is associated with improved long-term survival and reduced relapse rates compared with non-maintenance, further supporting this strategy as a standard of care for patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic HSCT. FUNDING: None. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Potential of Copper and Copper Compounds for Anticancer Applications.

Inducing cancer cell death has always been a research hotspot in life sciences. With the continuous deepening and diversification of related research, the potential value of metal elements in inducing cell death has been explored. Taking iron as an example, ferroptosis, mainly characterized by increasing iron load and driving the production of large amounts of lipid peroxides and eventually leading to cell death, has recently attracted great interest in the cancer research community. After iron, copper, a trace element, has received extensive attention in cell death, especially in inducing tumor cell death. Copper and its complexes can induce autophagy or apoptosis in tumor cells through a variety of different mechanisms of action (activation of stress pathways, arrest of cell cycle, inhibition of angiogenesis, cuproptosis, and paraptosis), which are promising in cancer therapy and have become new hotspots in cancer treatment research. This article reviews the main mechanisms and potential applications of novel copper and copper compound-induced cell death, focusing on copper compounds and their anticancer applications.

Impact of a novel prognostic model on allogeneic hematopoietic stem cell transplantation outcomes in patients with CMML.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell malignancy, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curable treatment. The outcomes after transplant are influenced by both disease characteristics and patient comorbidities. To develop a novel prognostic model to predict the post-transplant survival of CMML patients, we identified risk factors by applying univariable and multivariable Cox proportional hazards regression to a derivation cohort. In multivariable analysis, advanced age (hazard ratio [HR] 3.583), leukocyte count (HR 3.499), anemia (HR 3.439), bone marrow blast cell count (HR 2.095), and no chronic graft versus host disease (cGVHD; HR 4.799) were independently associated with worse survival. A novel prognostic model termed ABLAG (Age, Blast, Leukocyte, Anemia, cGVHD) was developed and the points were assigned according to the regression equation. The patients were categorized into low risk (0-1), intermediate risk (2, 3), and high risk (4-6) three groups and the 3-year overall survival (OS) were 93.3% (95%CI, 61%-99%), 78.9% (95%CI, 60%-90%), and 51.6% (95%CI, 32%-68%; p < .001), respectively. In internal and external validation cohort, the area under the receiver operating characteristic (ROC) curves of the ABLAG model were 0.829 (95% CI, 0.776-0.902) and 0.749 (95% CI, 0.684-0.854). Compared with existing models designed for the nontransplant setting, calibration plots, and decision curve analysis showed that the ABLAG model revealed a high consistency between predicted and observed outcomes and patients could benefit from this model. In conclusion, combining disease and patient characteristic, the ABLAG model provides better survival stratification for CMML patients receiving allo-HSCT.