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Tumor-derived factors are thought to regulate thrombocytosis and erythrocytopenia in individuals with cancer; however, such factors have not yet been identified. Here we show that tumor cell-released kynurenine (Kyn) biases megakaryocytic-erythroid progenitor cell (MEP) differentiation into megakaryocytes in individuals with cancer by activating the aryl hydrocarbon receptor-Runt-related transcription factor 1 (AhR-RUNX1) axis. During tumor growth, large amounts of Kyn from tumor cells are released into the periphery, where they are taken up by MEPs via the transporter SLC7A8. In the cytosol, Kyn binds to and activates AhR, leading to its translocation into the nucleus where AhR transactivates RUNX1, thus regulating MEP differentiation into megakaryocytes. In addition, activated AhR upregulates SLC7A8 in MEPs to induce positive feedback. Importantly, Kyn-AhR-RUNX1-regulated MEP differentiation was demonstrated in both humanized mice and individuals with cancer, providing potential strategies for the prevention of thrombocytosis and erythrocytopenia.
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Neoplasias , Trombocitosis , Animales , Ratones , Quinurenina/metabolismo , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Megacariocitos/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Células Precursoras Eritroides/metabolismo , Diferenciación Celular/fisiología , Neoplasias/metabolismo , Trombocitosis/metabolismo , SesgoRESUMEN
Memories are believed to be encoded by sparse ensembles of neurons in the brain. However, it remains unclear whether there is functional heterogeneity within individual memory engrams, i.e., if separate neuronal subpopulations encode distinct aspects of the memory and drive memory expression differently. Here, we show that contextual fear memory engrams in the mouse dentate gyrus contain functionally distinct neuronal ensembles, genetically defined by the Fos- or Npas4-dependent transcriptional pathways. The Fos-dependent ensemble promotes memory generalization and receives enhanced excitatory synaptic inputs from the medial entorhinal cortex, which we find itself also mediates generalization. The Npas4-dependent ensemble promotes memory discrimination and receives enhanced inhibitory drive from local cholecystokinin-expressing interneurons, the activity of which is required for discrimination. Our study provides causal evidence for functional heterogeneity within the memory engram and reveals synaptic and circuit mechanisms used by each ensemble to regulate the memory discrimination-generalization balance.
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Miedo/fisiología , Memoria/fisiología , Neuronas/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Encéfalo/fisiología , Giro Dentado/fisiología , Interneuronas/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/fisiología , Proteínas Proto-Oncogénicas c-fos/metabolismoRESUMEN
CRISPR-Cas systems are bacterial anti-viral systems, and phages use anti-CRISPR proteins (Acrs) to inactivate these systems. Here, we report a novel mechanism by which AcrIF11 inhibits the type I-F CRISPR system. Our structural and biochemical studies demonstrate that AcrIF11 functions as a novel mono-ADP-ribosyltransferase (mART) to modify N250 of the Cas8f subunit, a residue required for recognition of the protospacer-adjacent motif, within the crRNA-guided surveillance (Csy) complex from Pseudomonas aeruginosa. The AcrIF11-mediated ADP-ribosylation of the Csy complex results in complete loss of its double-stranded DNA (dsDNA) binding activity. Biochemical studies show that AcrIF11 requires, besides Cas8f, the Cas7.6f subunit for binding to and modifying the Csy complex. Our study not only reveals an unprecedented mechanism of type I CRISPR-Cas inhibition and the evolutionary arms race between phages and bacteria but also suggests an approach for designing highly potent regulatory tools in the future applications of type I CRISPR-Cas systems.
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Proteínas Asociadas a CRISPR/antagonistas & inhibidores , Sistemas CRISPR-Cas/fisiología , Proteínas Virales/metabolismo , ADP-Ribosilación/fisiología , Proteínas Bacterianas/genética , Bacteriófagos/genética , Proteínas Asociadas a CRISPR/genética , Proteínas Asociadas a CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Microscopía por Crioelectrón/métodos , ADN/metabolismo , Modelos Moleculares , ARN Bacteriano/metabolismo , Proteínas Virales/genéticaRESUMEN
Aberrant mitophagy has been implicated in a broad spectrum of disorders. PINK1, Parkin, and ubiquitin have pivotal roles in priming mitophagy. However, the entire regulatory landscape and the precise control mechanisms of mitophagy remain to be elucidated. Here, we uncover fundamental mitophagy regulation involving PINK1 and a non-canonical role of the mitochondrial Tu translation elongation factor (TUFm). The mitochondrion-cytosol dual-localized TUFm interacts with PINK1 biochemically and genetically, which is an evolutionarily conserved Parkin-independent route toward mitophagy. A PINK1-dependent TUFm phosphoswitch at Ser222 determines conversion from activating to suppressing mitophagy. PINK1 modulates differential translocation of TUFm because p-S222-TUFm is restricted predominantly to the cytosol, where it inhibits mitophagy by impeding Atg5-Atg12 formation. The self-antagonizing feature of PINK1/TUFm is critical for the robustness of mitophagy regulation, achieved by the unique kinetic parameters of p-S222-TUFm, p-S65-ubiquitin, and their common kinase PINK1. Our findings provide new mechanistic insights into mitophagy and mitophagy-associated disorders.
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Drosophila melanogaster/crecimiento & desarrollo , Mitocondrias/patología , Proteínas Mitocondriales/metabolismo , Mitofagia , Factor Tu de Elongación Peptídica/metabolismo , Proteínas Quinasas/metabolismo , Animales , Citosol/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Femenino , Células HeLa , Humanos , Masculino , Mitocondrias/genética , Mitocondrias/metabolismo , Proteínas Mitocondriales/genética , Factor Tu de Elongación Peptídica/genética , Fosforilación , Dominios y Motivos de Interacción de Proteínas , Proteínas Quinasas/genética , Transporte de Proteínas , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Synthetic chemistry is built around the formation of carbon-carbon bonds. However, the development of methods for selective carbon-carbon bond cleavage is a largely unmet challenge1-6. Such methods will have promising applications in synthesis, coal liquefaction, petroleum cracking, polymer degradation and biomass conversion. For example, aromatic rings are ubiquitous skeletal features in inert chemical feedstocks, but are inert to many reaction conditions owing to their aromaticity and low polarity. Over the past century, only a few methods under harsh conditions have achieved direct arene-ring modifications involving the cleavage of inert aromatic carbon-carbon bonds7,8, and arene-ring-cleavage reactions using stoichiometric transition-metal complexes or enzymes in bacteria are still limited9-11. Here we report a copper-catalysed selective arene-ring-opening reaction strategy. Our aerobic oxidative copper catalyst converts anilines, arylboronic acids, aryl azides, aryl halides, aryl triflates, aryl trimethylsiloxanes, aryl hydroxamic acids and aryl diazonium salts into alkenyl nitriles through selective carbon-carbon bond cleavage of arene rings. This chemistry was applied to the modification of polycyclic aromatics and the preparation of industrially important hexamethylenediamine and adipic acid derivatives. Several examples of the late-stage modification of complex molecules and fused ring compounds further support the potential broad utility of this methodology.
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Genetically encoded calcium indicators (GECIs) are indispensable tools for real-time monitoring of intracellular calcium signals and cellular activities in living organisms. Current GECIs face the challenge of suboptimal peak signal-to-baseline ratio (SBR) with limited resolution for reporting subtle calcium transients. We report herein the development of a suite of calcium sensors, designated NEMO, with fast kinetics and wide dynamic ranges (>100-fold). NEMO indicators report Ca2+ transients with peak SBRs around 20-fold larger than the top-of-the-range GCaMP6 series. NEMO sensors further enable the quantification of absolution calcium concentration with ratiometric or photochromic imaging. Compared with GCaMP6s, NEMOs could detect single action potentials in neurons with a peak SBR two times higher and a median peak SBR four times larger in vivo, thereby outperforming most existing state-of-the-art GECIs. Given their high sensitivity and resolution to report intracellular Ca2+ signals, NEMO sensors may find broad applications in monitoring neuronal activities and other Ca2+-modulated physiological processes in both mammals and plants.
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Calcio , Neuronas , Animales , Calcio/metabolismo , Neuronas/fisiología , Señalización del Calcio/fisiología , Indicadores y Reactivos , Mamíferos/metabolismoRESUMEN
Significant advances have been made in reprogramming various somatic cells into induced pluripotent stem cells (iPSCs) and in multi-lineage differentiation (transdifferentiation) into different tissues. These manipulable transdifferentiating techniques may be applied in cancer therapy. Limited works have been reported that cancer cell malignancy can be switched to benign phenotypes through reprogramming techniques. Here, we reported that two colorectal cancer (CRC) cell lines (DLD1, HT29) could be reprogrammed into iPSCs (D-iPSCs, H-iPSCs). D- and H-iPSCs showed reduced tumorigenesis. Furthermore, we successfully induced D- and H-iPSCs differentiation into terminally differentiated cell types such as cardiomyocyte, neuron, and adipocyte-like cells. Impressively, the differentiated cells exhibited further attenuated tumorigenesis in vitro and in vivo. RNA-Seq further indicated that epigenetic changes occurred after reprogramming and transdifferentiation that caused reduced tumorigenicity. Overall, our study indicated that CRC cells can be reprogrammed and further differentiated into terminally differentiated lineages with attenuation of their malignancy in vitro and in vivo. The current work sheds light on a potential multi-lineage differentiation therapeutic strategy for colorectal cancer.
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Carcinogénesis , Transdiferenciación Celular , Técnicas de Reprogramación Celular , Neoplasias Colorrectales , Células Madre Pluripotentes Inducidas , Humanos , Carcinogénesis/patología , Diferenciación Celular/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapiaRESUMEN
Chemotherapy is still the main therapeutic strategy for gastric cancer (GC). However, most patients eventually acquire multidrug resistance (MDR). Hyperactivation of the EGFR signaling pathway contributes to MDR by promoting cancer cell proliferation and inhibiting apoptosis. We previously identified the secreted protein CGA as a novel ligand of EGFR and revealed a CGA/EGFR/GATA2 positive feedback circuit that confers MDR in GC. Herein, we outline a microRNA-based treatment approach for MDR reversal that targets both CGA and GATA2. We observed increased expression of CGA and GATA2 and increased activation of EGFR in GC samples. Bioinformatic analysis revealed that miR-107 could simultaneously target CGA and GATA2, and the low expression of miR-107 was correlated with poor prognosis in GC patients. The direct interactions between miR-107 and CGA or GATA2 were validated by luciferase reporter assays and Western blot analysis. Overexpression of miR-107 in MDR GC cells increased their susceptibility to chemotherapeutic agents, including fluorouracil, adriamycin, and vincristine, in vitro. Notably, intratumor injection of the miR-107 prodrug enhanced MDR xenograft sensitivity to chemotherapies in vivo. Molecularly, targeting CGA and GATA2 with miR-107 inhibited EGFR downstream signaling, as evidenced by the reduced phosphorylation of ERK and AKT. These results suggest that miR-107 may contribute to the development of a promising therapeutic approach for the treatment of MDR in GC.
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The perinuclear theca (PT) is a cytoskeletal element encapsulating the sperm nucleus; however, the physiological roles of the PT in sperm are largely uncertain. Here, we reveal that ACTRT1, ACTRT2, ACTL7A and ACTL9 proteins interact to form a multimeric complex and localize to the subacrosomal region of spermatids. Furthermore, we engineered Actrt1-knockout (KO) mice to define the functions of ACTRT1. Despite normal sperm count and motility, Actrt1-KO males were severely subfertile owing to a deficiency in fertilization. Loss of ACTRT1 caused a high incidence of malformed heads and detachment of acrosomes from sperm nuclei, caused by loosened acroplaxome structure during spermiogenesis. Furthermore, Actrt1-KO sperm showed reduced ACTL7A and PLCζ protein content as a potential cause of fertilization defects. Moreover, we reveal that ACTRT1 anchors developing acrosomes to the nucleus, likely by interacting with the inner acrosomal membrane protein SPACA1 and the nuclear envelope proteins PARP11 and SPATA46. Loss of ACTRT1 weakened the interaction between ACTL7A and SPACA1. Our study and recent findings of ACTL7A/ACTL9-deficient sperm together reveal that the sperm PT-specific ARP complex mediates the acrosome-nucleus connection.
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Acrosoma , Infertilidad Masculina , Acrosoma/metabolismo , Animales , Humanos , Infertilidad Masculina/genética , Infertilidad Masculina/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Proteínas de Microfilamentos/metabolismo , Espermátides/metabolismo , Espermatogénesis/genética , Espermatozoides/metabolismoRESUMEN
Adenine base editors (ABEs) catalyze A-to-G transitions showing broad applications, but their bystander mutations and off-target editing effects raise safety concerns. Through structure-guided engineering, we found ABE8e with an N108Q mutation reduced both adenine and cytosine bystander editing, and introduction of an additional L145T mutation (ABE9), further refined the editing window to 1-2 nucleotides with eliminated cytosine editing. Importantly, ABE9 induced very minimal RNA and undetectable Cas9-independent DNA off-target effects, which mainly installed desired single A-to-G conversion in mouse and rat embryos to efficiently generate disease models. Moreover, ABE9 accurately edited the A5 position of the protospacer sequence in pathogenic homopolymeric adenosine sites (up to 342.5-fold precision over ABE8e) and was further confirmed through a library of guide RNA-target sequence pairs. Owing to the minimized editing window, ABE9 could further broaden the targeting scope for precise correction of pathogenic single-nucleotide variants when fused to Cas9 variants with expanded protospacer adjacent motif compatibility. bpNLS, bipartite nuclear localization signals.
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Adenina , Edición Génica , Animales , Ratones , Ratas , Mutación , Citosina , Sistemas CRISPR-Cas/genética , ARN Guía de Sistemas CRISPR-CasRESUMEN
Idiopathic granulomatous mastitis (IGM), a recurrent inflammation disease of the non-lactating breast, has had an increasing clinical morbidity rate in recent years, and its complicated symptoms and unclear etiology make it challenging to treat. This rare benign inflammatory breast disease, centered on the lobules, represents the most challenging type of non-puerperal mastitis (NPM), also known as non-lactating mastitis. In this study, patients diagnosed with IGM (M, n = 23) were recruited as cases, and patients with benign control breast disease (C, n = 17) were enrolled as controls. Cytokine microarray detection measured and analyzed the differentially expressed cytokine factors between IGM and control patients. Then, we verified the mRNA and protein expression levels of the significantly changed cytokine factors using Q-RT-PCR, ELISA, western blot, and IHC experiments. The cytokine factor expression levels significantly changed compared to the control group. We observed a significant increase between IGM and control patients in cytokine factors expression, such as interleukin-1ß (IL-1ß), monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-1α, MIP-1ß, tumor necrosis factor receptor 2 (TNF RII). Then, we verified the expression of these top five dysregulated factors in both mRNA and protein levels. Our results demonstrated the cytokine map in IGM and indicated that several cytokines, especially chemokines, were associated with and significantly dysregulated in IGM tissues compared to the control group. The chemokine factors involved might be essential in developing and treating IGM. These findings would be helpful for a better understanding of IGM and offer valuable insights for devising novel diagnostic and therapeutic strategies.
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Quimiocinas , Mastitis Granulomatosa , Humanos , Femenino , Mastitis Granulomatosa/metabolismo , Mastitis Granulomatosa/genética , Adulto , Quimiocinas/metabolismo , Quimiocinas/genética , Persona de Mediana Edad , Citocinas/metabolismo , Citocinas/genética , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Estudios de Casos y Controles , Quimiocina CXCL9/metabolismo , Quimiocina CXCL9/genéticaRESUMEN
Ovarian endometriosis is a common gynecological disease, and one of its most significant symptoms is infertility. In patients with endometriosis, defects in endometrial decidualization lead to impaired endometrial receptivity and embryo implantation, thus affecting early pregnancy and women's desire to have children. However, the mechanisms underlying the development of endometriosis and its associated defective decidualization are unclear. We find that NEK2 expression is increased in the ectopic and eutopic endometrium of patients with endometriosis. Meanwhile, NEK2 interacts with FOXO1 and phosphorylates FOXO1 at Ser184, inhibiting the stability of the FOXO1 protein. Importantly, NEK2-mediated phosphorylation of FOXO1 at Ser184 promotes cell proliferation, migration, invasion and impairs decidualization. Furthermore, INH1, an inhibitor of NEK2, inhibits the growth of ectopic lesions in mouse models of endometriosis and promotes endometrial decidualization in mouse models of artificially induced decidualization. Taken together, these findings indicate that NEK2 regulates the development of endometriosis and associated disorders of decidualization through the phosphorylation of FOXO1, providing a new therapeutic target for its treatment.
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Proliferación Celular , Endometriosis , Endometrio , Proteína Forkhead Box O1 , Quinasas Relacionadas con NIMA , Femenino , Endometriosis/metabolismo , Endometriosis/patología , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Humanos , Animales , Fosforilación , Ratones , Quinasas Relacionadas con NIMA/metabolismo , Quinasas Relacionadas con NIMA/genética , Endometrio/metabolismo , Endometrio/patología , Movimiento Celular , Decidua/metabolismo , Decidua/patología , Adulto , Modelos Animales de EnfermedadRESUMEN
Polyploidy and the subsequent ploidy reduction and genome shuffling are the major driving forces of genome evolution. Here, we revealed short-term allopolyploid genome evolution by sequencing a synthetic intergeneric hybrid (Raphanobrassica, RRCC). In this allotetraploid, the genome deletion was quick, while rearrangement was slow. The core and high-frequency genes tended to be retained while the specific and low-frequency genes tended to be deleted in the hybrid. The large-fragment deletions were enriched in the heterochromatin region and probably derived from chromosome breaks. The intergeneric translocations were primarily of short fragments dependent on homoeology, indicating a gene conversion origin. To accelerate genome shuffling, we developed an efficient genome editing platform for Raphanobrassica. By editing Fanconi Anemia Complementation Group M (FANCM) genes, homoeologous recombination, chromosome deletion and secondary meiosis with additional ploidy reduction were accelerated. FANCM was shown to be a checkpoint of meiosis and controller of ploidy stability. By simultaneously editing FLIP genes, gene conversion was precisely introduced, and mosaic genes were produced around the target site. This intergeneric hybrid and genome editing platform not only provides models that facilitate experimental evolution research by speeding up genome shuffling and conversion but also accelerates plant breeding by enhancing intergeneric genetic exchange and creating new genes.
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Brassica , Barajamiento de ADN , Poliploidía , Raphanus , Humanos , ADN Helicasas , Genoma de Planta , Raphanus/genética , Brassica/genéticaRESUMEN
BACKGROUND: The global resurgence of syphilis necessitates vaccine development. METHODS: We collected ulcer exudates and blood from 17 primary syphilis (PS) participants and skin biopsies and blood from 51 secondary syphilis (SS) participants in Guangzhou, China for Treponema pallidum subsp. pallidum (TPA) qPCR, whole genome sequencing (WGS), and isolation of TPA in rabbits. RESULTS: TPA DNA was detected in 15 of 17 ulcer exudates and 3 of 17 blood PS specimens. TPA DNA was detected in 50 of 51 SS skin biopsies and 27 of 51 blood specimens. TPA was isolated from 47 rabbits with success rates of 71% (12/17) and 69% (35/51), respectively, from ulcer exudates and SS bloods. We obtained paired genomic sequences from 24 clinical samples and corresponding rabbit isolates. Six SS14- and two Nichols-clade genome pairs contained rare discordances. Forty-one of the 51 unique TPA genomes clustered within SS14 subgroups largely from East Asia, while 10 fell into Nichols C and E subgroups. CONCLUSIONS: Our TPA detection rate was high from PS ulcer exudates and SS skin biopsies and over 50% from SS blood, with TPA isolation in over two-thirds of samples. Our results support the use of WGS from rabbit isolates to inform vaccine development.
The incidence of new cases of syphilis has skyrocketed globally in the twenty-first century. This global resurgence requires new strategies, including vaccine development. As part of an NIH funded Cooperative Research Center to develop a syphilis vaccine, we established a clinical research site in Guangzhou, China to better define the local syphilis epidemic and obtain samples from patients with primary and secondary syphilis for whole genome sequencing (WGS) of circulating Treponema pallidum strains. Inoculation of rabbits enabled us to obtain T. pallidum genomic sequences from spirochetes disseminating in blood, a compartment of immense importance for syphilis pathogenesis. Collectively, our results further clarify the molecular epidemiology of syphilis in southern China, enrich our understanding of the manifestations of early syphilis, and demonstrate that the genomic sequences of spirochetes obtained by rabbit inoculation accurately represent those of the spirochetes infecting the corresponding patients.
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Myelodysplastic syndromes (MDS) are a group of heterogeneous myeloid clonal disorders characterized by ineffective hematopoiesis. Accumulating evidence has shown that macrophages (MΦs) are important components in the regulation of tumor progression and hematopoietic stem cells (HSCs). However, the roles of bone marrow (BM) MΦs in regulating normal and malignant hematopoiesis in different clinical stages of MDS are largely unknown. Age-paired patients with lower-risk MDS (N = 15), higher-risk MDS (N = 15), de novo acute myeloid leukemia (AML) (N = 15), and healthy donors (HDs) (N = 15) were enrolled. Flow cytometry analysis showed increased pro-inflammatory monocyte subsets and a decreased classically activated (M1) MΦs/alternatively activated (M2) MΦs ratio in the BM of patients with higher-risk MDS compared to lower-risk MDS. BM MФs from patients with higher-risk MDS and AML showed impaired phagocytosis activity but increased migration compared with lower-risk MDS group. AML BM MΦs showed markedly higher S100A8/A9 levels than lower-risk MDS BM MΦs. More importantly, coculture experiments suggested that the HSC supporting abilities of BM MΦs from patients with higher-risk MDS decreased, whereas the malignant cell supporting abilities increased compared with lower-risk MDS. Gene Ontology enrichment comparing BM MΦs from lower-risk MDS and higher-risk MDS for genes was involved in hematopoiesis- and immunity-related pathways. Our results suggest that BM MΦs are involved in ineffective hematopoiesis in patients with MDS, which indicates that repairing aberrant BM MΦs may represent a promising therapeutic approach for patients with MDS.
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Infecciones , Macrófagos , Síndromes Mielodisplásicos , Humanos , Médula Ósea/patología , Hematopoyesis , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Macrófagos/patología , Síndromes Mielodisplásicos/genética , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Infecciones/patologíaRESUMEN
Polyolefins are recognized as fundamental plastic materials that are manufactured in the largest quantities among all synthetic polymers. The chemical inertness of the saturated hydrocarbon chains is crucial for storing and using polyolefin plastics, but poses significant environmental challenges related to plastic pollution. Here, we report a versatile approach to creating polyethylene materials with tunable degradability by incorporating in-chain mechanophores. Through palladium-catalyzed coordination/insertion copolymerization of ethylene with cyclobutene-fused comonomers, several cyclobutane-fused mechanophores were successfully incorporated with varied insertion ratios (0.35-26 mol %). The resulting polyethylene materials with in-chain mechanophores exhibit both high thermal stability and remarkable acid resistance. Upon mechanochemical activation by ultrasonication or ball-milling, degradable functional units (imide and ester groups) are introduced into the main polymer chain. The synergy of mechanochemical activation and acid hydrolysis facilitates the efficient degradation of high molecular weight polyethylene materials into telechelic oligomers.
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The global pandemic has resulted in the common occurrence of SARS-CoV-2 infection in the population. In the post-pandemic era, it is imperative to understand the influence of donor SARS-CoV-2 infection on outcomes after allogeneic haematopoietic stem cell transplantation (allo-HSCT). We retrospectively analysed allo-HSCTs from donors with mild SARS-CoV-2 infection or early recovery stage (ERS) (group 1, n = 65) and late recovery stage (group 2, n = 120). Additionally, we included allo-HSCT from donors without prior SARS-CoV-2 infection as group 0 (n = 194). Transplants from donors with different SARS-CoV-2 infection status had comparable primary engraftment and survival rates. However, group 1 had higher incidences of acute graft-versus-host disease (aGvHD), grade II-IV (41.5% vs. 28.1% in group 0 [p = 0.014] and 30.6% in group 2 [p = 0.067]) and grade III-IV (22.2% vs. 9.6% [p = 0.004] in group 0 and 12.2% in group 2 [p = 0.049]). Conversely, the risk of aGvHD in group 2 was similar to that in group 0 (p > 0.5). Multivariable analysis identified group 1 associated with grade II-IV (hazard ratio [HR] 2.307, p = 0.010) and grade III-IV (HR 2.962, p = 0.001) aGvHD, which yielded no significant risk factors for survival. In conclusion, we preliminarily demonstrated donors in the active infection state or ERS of mild SARS-CoV-2 infection were associated with higher incidences of aGvHD in transplants from related donors.
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COVID-19 , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , SARS-CoV-2 , Donantes de Tejidos , Humanos , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , COVID-19/epidemiología , Masculino , Adulto , Femenino , Persona de Mediana Edad , Incidencia , Estudios Retrospectivos , Trasplante Homólogo/efectos adversos , Enfermedad Aguda , Adolescente , Anciano , Adulto JovenRESUMEN
The objective of this study was to identify independent prognostic factors of viral encephalitis (VE) after allogeneic haematopoietic stem cell transplantation (allo-HSCT) and establish a prognostic model to identify post-transplant VE patients with a greater likelihood of mortality. Among 5380 patients in our centre from 2014 to 2022, 211 patients who developed VE after allo-HSCT were reviewed in this retrospective study. Prognostic factors were selected, and a prognostic model was constructed using Cox regression analysis. The model was subsequently validated and estimated using the area under the receiver operating characteristic curve (AUC), a calibration plot and decision curve analysis (DCA). Glasgow Coma Scale score <9, lesions >3 lobes on magnetic resonance imaging and severe thrombocytopenia were identified as independent prognostic risk factors for VE patients who underwent allo-HSCT. The prognostic model GTM (GTM is an abbreviation for a model composed of three risk factors: GCS score <9, severe thrombocytopenia [platelet count <20 000 per microliter], and lesions >3 lobes on MRI) was established according to the regression coefficients. The validated internal AUC was 0.862 (95% confidence interval [CI], 0.773-0.950), and the external AUC was 0.815 (95% CI, 0.708-0.922), indicating strong discriminatory ability. Furthermore, we constructed calibration plots that demonstrated good consistency between the predicted outcomes and the observed outcomes. DCA exhibited high accuracy in this system, leading to potential benefits for patients.
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Intestinal ischaemiaâreperfusion (I/R) injury is a surgical emergency. This condition is associated with a high mortality rate. At present, there are limited number of efficient therapeutic measures for this injury, and the prognosis is poor. Therefore, the pathophysiological mechanisms of intestinal I/R injury must be elucidated to develop a rapid and specific diagnostic and treatment protocol. Numerous studies have indicated the involvement of endoplasmic reticulum (ER) stress in the development of intestinal I/R injury. Specifically, the levels of unfolded and misfolded proteins in the ER lumen are increased due to unfolded protein response. However, persistent ER stress promotes apoptosis of intestinal mucosal epithelial cells through three signalling pathways in the ER, impairing intestinal mucosal barrier function and leading to the dysfunction of intestinal tissues and distant organ compartments. This review summarises the mechanisms of ER stress in intestinal I/R injury, diagnostic indicators, and related treatment strategies with the objective of providing novel insights into future therapies for this condition.