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Maternal age is one of the most important factors affecting the success of maternal pregnancy. Uterine aging is the leading cause of pregnancy failure in older women. However, how uterine aging affects uterine receptivity and decidualization is unclear. In this study, naturally aged one-year-old female mice were used to investigate effects of maternal age on embryo implantation during early pregnancy. In our study, we found abnormal uterine receptivity in aged mice. Aged mouse uterus indicates a decrease in nuclear LAMIN A, and an increase in PRELAMIN A and PROGERIN. In aged mouse uterus, double-stranded DNA (dsDNA) in cytoplasmic fraction is significantly increased. PROGERIN overexpression in mouse uterine epithelial cells and epithelial organoids leads to nuclear DNA leakage and impaired uterine receptivity. DNase I, DNase II, and TREX1 are obviously reduced in aged mouse uterus. Treatments with foreign DNA or STING agonist significantly downregulate uterine receptivity markers and activate cGAS-STING pathway. Uterine estrogen (E2) concentration is significantly increased in aged mice. After ovariectomized mice are treated with a high level of E2, there are significant increase of PROGERIN and cytoplasmic DNA, and activation of cGAS-STING pathway. CD14 is significantly increased in aged uterus. Intrauterine CD14 injection inhibits embryo implantation. In vitro CD14 treatment of cultured epithelial cells or epithelial organoids decreases uterine receptivity. Uterine abnormality in aged mouse can be partially rescued by STING inhibitor. In conclusion, uterine PROGERIN increase in aged mouse uterus results in cytoplasmic DNA accumulation and cGAS-STING pathway activation. CD14 secretion in aged uterus impairs uterine receptivity.
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Family with sequence similarity 135 member B (FAM135B) is a novel driver gene in esophageal squamous cell carcinoma (ESCC). However, little is known regarding its biological functions and mechanisms in ESCC. Here, we identified that the high expression of FAM135B was associated with lymph node metastasis and infiltrating development of ESCC. Elevated FAM135B expression promoted ESCC migration and invasion in vitro and lung metastasis in vivo. Furthermore, epithelial-mesenchymal transition (EMT)-related pathways were enriched in ESCC samples with high levels of FAM135B and FAM135B positively regulated EMT markers. Mechanistically, we observed that FAM135B interacted with the intermediate domain of TRAF2 and NCK-interacting kinase (TNIK), activating the Wnt/ß-catenin signaling pathway. The facilitation of TNIK on ESCC migration and invasion was reversed by FAM135B siRNA. In addition, the N6-methyladenosine (m6A) modification positively regulated FAM135B expression, with methyltransferase like 3 (METTL3) acting as its substantial m6A writer. The pro-EMT effects of METTL3 overexpression were reversed by silencing FAM135B. Collectively, these findings illustrate the critical role of ABCDE in ESCC progression and provide new insights into the upstream and downstream mechanisms of FAM135B.NEW & NOTEWORTHY This study reveals for the first time that the novel cancer-related gene, FAM135B, promotes ESCC metastasis both in vitro and in vivo. Besides, we substantiate FAM135B's action on the ß-catenin pathway through interacting with TNIK, thereby elucidating the promotional effect of FAM135B on ESCC EMT. Furthermore, we provide initial evidence demonstrating that METTL3-mediated m6A modification upregulates the expression of FAM135B in ESCC cells.
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Movimento Celular , Transição Epitelial-Mesenquimal , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Regulação Neoplásica da Expressão Gênica , Metiltransferases , Regulação para Cima , Via de Sinalização Wnt , Humanos , Via de Sinalização Wnt/genética , Transição Epitelial-Mesenquimal/genética , Metiltransferases/genética , Metiltransferases/metabolismo , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/metabolismo , Linhagem Celular Tumoral , Animais , Masculino , Feminino , Camundongos Nus , Camundongos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , beta Catenina/metabolismo , beta Catenina/genética , Invasividade Neoplásica , Camundongos Endogâmicos BALB C , Metástase Linfática , Pessoa de Meia-Idade , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/genéticaRESUMO
The first systematic acylated diversification of naturally scarce premyrsinane diterpenes, together with their biosynthetic precursors lathyrane diterpene were carried out. Two new series of premyrsinane derivates (1a-32a) and lathyrane derivates (1-32) were synthesized from the naturally abundant lathyrane diterpene Euphorbia factor L3 through a bioinspired approach. The cholinesterase inhibitory and neuroprotective activities of these diterpenes were investigated to explore potential anti-Alzheimer's disease (AD) bioactive lead compounds. In general, the lathyrane diterpenes showed the better acetylcholinesterase (AChE) inhibitory activity than that of premyrsinanes. The lathyrane derivative 17 bearing a 3-dimethylaminobenzoyl moiety showed the best AChE inhibition effect with the IC50 value of 7.1 µM. Molecular docking demonstrated that 17 could bond with AChE well (-8 kal/mol). On the other hand, premyrsinanes showed a better neuroprotection profile against H2O2-induced injury in SH-SY5Y cells. Among them, the premyrsinane diterpene 16a had significant neuroprotective effect with the cell viability rate of 113.5 % at 12.5 µM (the model group with 51.2 %). The immunofluorescence, western blot and reactive oxygen species (ROS) analysis were conducted to demonstrate the mechanism of 16a. Furthermore, a preliminary SAR analysis of the two categories of diterpenes was performed to provide the insights for anti-AD drug development.
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Acetilcolinesterase , Doença de Alzheimer , Inibidores da Colinesterase , Diterpenos , Euphorbia , Fármacos Neuroprotetores , Diterpenos/farmacologia , Diterpenos/química , Diterpenos/síntese química , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/síntese química , Euphorbia/química , Humanos , Acetilcolinesterase/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular , Simulação de Acoplamento Molecular , Relação Dose-Resposta a Droga , Sobrevivência Celular/efeitos dos fármacosRESUMO
Esophageal cancer ranks among the most prevalent malignant tumors globally, primarily due to its highly aggressive nature and poor survival rates. According to the 2020 global cancer statistics, there were approximately 604000 new cases of esophageal cancer, resulting in 544000 deaths. The 5-year survival rate hovers around a mere 15%-25%. Notably, distinct variations exist in the risk factors associated with the two primary histological types, influencing their worldwide incidence and distribution. Squamous cell carcinoma displays a high incidence in specific regions, such as certain areas in China, where it meets the cost-effectiveness criteria for widespread endoscopy-based early diagnosis within the local population. Conversely, adenocarcinoma (EAC) represents the most common histological subtype of esophageal cancer in Europe and the United States. The role of early diagnosis in cases of EAC originating from Barrett's esophagus (BE) remains a subject of controversy. The effectiveness of early detection for EAC, particularly those arising from BE, continues to be a debated topic. The variations in how early-stage esophageal carcinoma is treated in different regions are largely due to the differing rates of early-stage cancer diagnoses. In areas with higher incidences, such as China and Japan, early diagnosis is more common, which has led to the advancement of endoscopic methods as definitive treatments. These techniques have demonstrated remarkable efficacy with minimal complications while preserving esophageal functionality. Early screening, prompt diagnosis, and timely treatment are key strategies that can significantly lower both the occurrence and death rates associated with esophageal cancer.
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BACKGROUND: Dental anxiety is a widespread complication occurring in pediatric patients during dental visits and may lead to undesirable complications. Esketamine may be effective in anxiety. OBJECTIVE: The objective of this study was to investigate the effect of premedication with a dexmedetomidine-esketamine combination compared with dexmedetomidine alone on dental anxiety in preschool children undergoing dental treatment under general anesthesia. METHODS: This is a prospective, double-blinded, randomized controlled trial. A total of 84 patients were scheduled for elective outpatient dental caries treatment under general anesthesia. Patients were randomly premedicated with intranasal dexmedetomidine (group D) or intranasal dexmedetomidine-esketamine (group DS). The primary outcome was the level of dental anxiety assessed by the Modified Child Dental Anxiety Scale (MCDAS) at 2 h after surgery. Secondary outcomes included level of dental anxiety at 1 day and 7 days after surgery, the incidence of dental anxiety at 2 h, 1 day, and 7 days after surgery, sedation onset time, overall success of sedation, acceptance of mask induction, postoperative pain intensity, incidence of emergence agitation in PACU, adverse reactions, HR, and SpO2 before premedication (baseline) and at 10, 20, and 30 min after the end of study drug delivery. RESULTS: The dental anxiety in group DS was lower than that in group D at 2 h, 1 day, and 7 days postoperatively (P = 0.04, 0.004, and 0.006, respectively). The incidences of dental anxiety in group DS were lower than those in group D at 2 h (53 % vs 76 %, P = 0.03), 1 day (47 % vs 71 %, P = 0.04), and 7 days (44 % vs 71 %, P = 0.02) after surgery. Group DS had a higher success rate of sedation (P = 0.03) but showed a lower MAS score (P = 0.005) and smoother hemodynamics (P < 0.01) after drug administration than group D. Group DS showed a significantly lower incidence rate of emergence agitation (P = 0.03) and postoperative pain intensity (P = 0.006) than that in group D during the anesthesia recovery time. The occurrence of adverse reactions was similar in both groups (P > 0.05). LIMITATIONS: We did not analyze and correct for the learning effect caused by repeated applications of the MCDAS and MCDAS scores on the 1 day after surgery were obtained by telephone follow-up. CONCLUSIONS: Compared to premedication with dexmedetomidine alone, premedication with intranasal dexmedetomidine combined with esketamine could significantly improve dental anxiety in preschool children undergoing dental treatment under general anesthesia.
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Cárie Dentária , Dexmedetomidina , Delírio do Despertar , Criança , Humanos , Pré-Escolar , Dexmedetomidina/efeitos adversos , Hipnóticos e Sedativos/efeitos adversos , Delírio do Despertar/epidemiologia , Delírio do Despertar/prevenção & controle , Delírio do Despertar/induzido quimicamente , Estudos Prospectivos , Ansiedade ao Tratamento Odontológico/prevenção & controle , Cárie Dentária/induzido quimicamente , Cárie Dentária/tratamento farmacológico , Anestesia Geral/efeitos adversos , Dor Pós-Operatória/induzido quimicamente , Assistência Odontológica , Método Duplo-CegoRESUMO
Microglia aggregate in regions of active inflammation and demyelination in the CNS of multiple sclerosis (MS) patients and are considered pivotal in the disease process. Targeting microglia is a promising therapeutic approach for myelin repair. Previously, we identified two candidates for microglial modulation and remyelination using a Connectivity Map (CMAP)-based screening strategy. Interestingly, with results that overlapped, sanguinarine (SAN) emerged as a potential drug candidate to modulate microglial polarization and promote remyelination. In the current study, we demonstrate the efficacy of SAN in mitigating the MS-like experimental autoimmune encephalomyelitis (EAE) in a dose-dependent manner. Meanwhile, prophylactic administration of a medium dose (2.5 mg/kg) significantly reduces disease incidence and ameliorates clinical signs in EAE mice. At the cellular level, SAN reduces the accumulation of microglia in the spinal cord. Morphological analyses and immunophenotyping reveal a less activated state of microglia following SAN administration, supported by decreased inflammatory cytokine production in the spinal cord. Mechanistically, SAN skews primary microglia towards an immunoregulatory state and mitigates proinflammatory response through PPARγ activation. This creates a favorable milieu for the differentiation of oligodendrocyte progenitor cells (OPCs) when OPCs are incubated with conditioned medium from SAN-treated microglia. We further extend our investigation into the cuprizone-induced demyelinating model, confirming that SAN treatment upregulates oligodendrocyte lineage genes and increases myelin content, further suggesting its pro-myelination effect. In conclusion, our data propose SAN as a promising candidate adding to the preclinical therapeutic arsenal for regulating microglial function and promoting myelin repair in CNS demyelinating diseases such as MS.
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Benzofenantridinas , Encefalomielite Autoimune Experimental , Isoquinolinas , Esclerose Múltipla , Humanos , Camundongos , Animais , Microglia , PPAR gama , Encefalomielite Autoimune Experimental/tratamento farmacológico , Bainha de Mielina/fisiologia , Esclerose Múltipla/tratamento farmacológico , Camundongos Endogâmicos C57BL , Modelos Animais de DoençasRESUMO
The primary objective of this investigation was to examine the evolving trajectories and pivotal focal points within the domain of research on intestinal barriers with regard to inflammatory bowel disease (IBD). Publications germane to the intestinal barrier in the context of IBD were procured from the Science Citation Index Expanded within the Web of Science Core Collection database. Bibliometric scrutiny and visualization were executed employing the R package "bibliometrix" through the R software platform (version: 4.3.0). A comprehensive compilation of 7344 English-language articles spanning from January 1, 2001 to December 31, 2021 was meticulously identified and included in the analysis. Remarkably, China emerged as the preeminent force in the realm of intestinal barrier research in relation to IBD. The significance of the intestinal barrier in the context of IBD has been progressively and comprehensively acknowledged. This recognition has ushered in a fresh therapeutic perspective that offers the promise of enhancing the management of inflammation and prognostication.
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Vacinas Anticâncer , Doenças Inflamatórias Intestinais , Humanos , Doenças Inflamatórias Intestinais/terapia , Intestinos , Inflamação , BibliometriaRESUMO
There are inconsistencies in treatment outcomes, measurement instruments, and criteria for assessing clinical effectiveness in studies related to distal radius fractures (DRF), resulting in potential biases and failing to provide high-quality clinical evidence. To address these challenges, international researchers have reached a consensus on developing the core outcome indicator set for distal radius fractures(COS-DRF). However, it's important to note that the existing COS-DRF framework could not reflect the unique characteristics of Traditional Chinese Medicine (TCM) treatment. Currently, there are no established standards for treatment outcomes and measurement instruments specific to TCM clinical research, nor has a COS-DRF been established for TCM clinical studies in China. In light of these gaps, our research team aims to construct a core set of treatment outcomes for TCM clinical research on distal radius fractures. This involves compiling a comprehensive list of treatment outcomes and measurement instruments, initially derived from a thorough literature review and expert consensus, which will then undergo further refinement and updates based on real-world clinical experiences, incorporating feedback from 2 to 3 rounds of expert consensus or Delphi questionnaire surveys. Our goal is to establish a COS-DRF or CMS-DRF that aligns with the principles and practices of TCM, and provide high-quality evidence for clinical practice.
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Fixação de Fratura , Medicina Tradicional Chinesa , Fraturas do Punho , Humanos , China , Consenso , População do Leste Asiático , Avaliação de Resultados em Cuidados de Saúde , Fraturas do Punho/terapia , Literatura de Revisão como Assunto , Fixação de Fratura/métodos , Fixação de Fratura/normasRESUMO
Hiptagestenopterum K.Tan & M.X.Ren, a new species of Hiptage collected from a deep valley close to the Nujiang Gorge, northwest of Yunnan Province, China, is described and illustrated based on molecular and morphological data. The new species was found isolated in an entrenched valley of the Laowo River, a tributary of the Nujiang River, at the northern edge of the distribution range of the genus. H.stenopterum shares some morphological similarities with the narrowly endemic H.incurvatum and H.lushuiensis. However, H.stenopterum is easily distinguished by its oblanceolate lateral wing of winged mericarp, 10 to 12 calyx glands, and branchlets densely rusty tomentose. The new species status is also supported by molecular phylogenetic analyses based on nuclear ribosome internal transcribed spacer (nrITS), which showed distinct systematic boundaries from the most morphologically similar species, H.incurvatum and their morphological relatives, H.lushuiensis.
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OBJECTIVES: Venetoclax has shown synergism with BCR-ABL1 tyrosine kinase inhibitors (TKIs) in preclinical studies for patients with Philadelphia chromosome-positive (Ph+) leukemias. This combination may suggest a novel treatment strategy for Ph + leukemias. METHODS: We conducted a retrospective study to summarize the activity of combining venetoclax and BCR-ABL1 TKI-based therapies in Ph + leukemias. RESULT: A total of 18 patients with Ph + leukemias were enrolled in this study. At the time of venetoclax and TKI-based therapy, 5 patients were initially diagnosed, with Ph + acute myeloid leukemia (AML) (n = 1) and mixed phenotype acute leukemia (MPAL) (n = 4), 7 patients had chronic myeloid leukemia at blastic phase (CML-BP), and the remaining 6 patients had relapsed or refractory to prior therapy. The overall response rate (ORR) was 88.9% (9 CR, 2 CRi, 4 MLFS, 1 PR), and a major molecular response (MMR) (or better) was achieved in 7 (38.8%) of all patients. With a median follow-up of 7.0 months (range, 2.3-15.6), 15 (83.3%) were in continuous CR at the time of this analysis, with a 1-year OS of 85.6%, 1-year LFS of 76.7%, and 1-year CIR of 22.4%. Moreover, 10 of 18 patients were treated with venetoclax, TKI and hypomethylating agent (HMA) regimens, which also associated with a high ORR rate (6 CR, 1 CRi, 3 MLFS), and can be used for induction or salvage therapy. CONCLUSION: Venetoclax and TKI-based combination regimens may be a feasible approach for Ph + leukemias, and prospective studies are needed to properly assess the safety, tolerability and efficacy of this regimen.
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Leucemia Mielogênica Crônica BCR-ABL Positiva , Cromossomo Filadélfia , Humanos , Estudos Retrospectivos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Proteínas de Fusão bcr-abl/genética , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
The treatment of B-cell acute lymphoblastic leukemia (B-ALL) with central nervous system (CNS) involvement poses a significant clinical challenge because most chemotherapeutic agents exhibit weak permeability to the blood-brain barrier (BBB). In addition, current anti-CNS leukemia treatments often bring short or long-term complications. Immunotherapy including chimeric antigen T-cell therapy and bispecific antibody have shown profound treatment responses in relapsed/refractory B-ALL. However, there is a lack of data on the efficacy of bispecific antibody in treating B-ALL with CNS involvement. Here, we report two ALL patients with CNS leukemia who received blinatumomab. Case 1 was diagnosed with chronic myeloid leukemia in lymphoid blast phase. The patient developed CNS leukemia and bone marrow relapse during the treatment with dasatinib. Case 2 was diagnosed with B-ALL and suffered early hematologic relapse and cerebral parenchyma involvement. After treatment with one cycle of blinatumomab, both patients achieved complete remission in the bone marrow and CNS. Furthermore, this is the first report on the efficacy of blinatumomab in treating CNS leukemia with both of the cerebral spinal fluid and the cerebral parenchymal involvement. Our results suggest that blinatumomab might be a potential option for the treatment of CNS leukemia.
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Antineoplásicos , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Antineoplásicos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Recidiva , Sistema Nervoso CentralRESUMO
To avoid wasting blueberry pomace resources, deep eutectic solvents (DESs) were combined with ultrasound technology to establish an efficient green method for the recovery of anthocyanins and polyphenols from plant-derived by-products. Choline chloride:1,4-butanediol (molar ratio of 1:3) was chosen as the optimal solvent based on the screening of eight solvents and single-factor experiments. Response surface methodology was applied to optimize the extraction parameters: water content, 29%; extraction temperature, 63 °C; liquid-solid ratio, 36:1 (v/w). The yields of total anthocyanins and total polyphenols from the optimized extraction were 11.40 ± 0.14 mg cyanidin-3-glucoside equiv./g and 41.56 ± 0.17 mg gallic acid equiv./g, respectively, which were both significantly better than the yields achieved with 70% ethanol. The purified anthocyanins showed excellent inhibition of α-glucosidase (IC50 = 16.57 µg/mL). The physicochemical parameters of DES suggest that it can be used for the extraction of bioactive substances.
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Mirtilos Azuis (Planta) , Polifenóis , Solventes/química , Antocianinas , Mirtilos Azuis (Planta)/química , Solventes Eutéticos Profundos , Extratos Vegetais/química , EtanolRESUMO
A Gram-staining-negative, non-motile, rod-shaped or curved rod-shaped, moderately halophilic bacterium, designated C176T, was isolated from Yuncheng Salt Lake in Shanxi Province, P.R. China. The optimal temperature, salinity and pH for growth of strain C176T was 37 °C, 6% (w/v) NaCl and 7.5. Phylogenetic analysis using 16S rRNA gene sequences indicated strain C176T has the highest similarity with Spiribacter salinus LMG 27464 T (97.7%), following by the S. halobius E85T (97.6%), S. curvatus DSM 28542 T (97.2%), S. roseus CECT 9117 T (97.0%) and S. vilamensis DSM 21056 T (96.9%). The ANI and dDDH values between strain C176T and S. salinus LMG 27464 T were 69.8 and 17.7%, respectively. The DNA G + C content of genome for strain C176T was 54.1%. Summed feature 8 (C18:1 ω7c and/or C18:1 ω6c) and C16:0 were detected as its major fatty acids, with content of 38.7 and 28.6% respectively, while Q-8 was the predominant ubiquinone. The major polar lipids of strain C176T contained phospholipid, phosphatidylglycerol and phosphoglycolipid. In accordance with results of polyphasic taxonomy, strain C176T is considered as a novel species of the genus Spiribacter, for which the name Spiribacter salilacus sp. nov. is proposed. The type strain is C176T (= MCCC 1H00417T = KCTC 72692 T).
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Ácidos Graxos , Lagos , Filogenia , Lagos/microbiologia , RNA Ribossômico 16S/genética , DNA Bacteriano/genética , Hibridização de Ácido Nucleico , Ácidos Graxos/análise , China , Análise de Sequência de DNA , Técnicas de Tipagem BacterianaRESUMO
We conducted a single-arm, open-label, single-center phase 1 study to assess the safety and efficacy of multicycle-sequential anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in combination with autologous CD19+ feeding T cells (FTCs) and tyrosine kinase inhibitor (TKI) as consolidation therapy in patients under the age of 65 years with de novo Ph-positive CD19+ B-cell acute lymphoblastic leukemia. Participants were given induction chemotherapy as well as systemic chemotherapy with TKI. Afterward, they received a single cycle of CD19 CAR T-cell infusion and another 3 cycles of CD19 CAR T-cell and CD19+ FTC infusions, followed by TKI as consolidation therapy. CD19+ FTCs were given at 3 different doses. The phase 1 results of the first 15 patients, including 2 withdrawals, are presented. The most common adverse events were cytopenia (13/13) and hypogammaglobinemia (12/13). There was no incidence of cytokine release syndrome above grade 2 or immune effector cell-associated neurotoxicity syndrome or grade 4 nonhematological toxicities. All 13 patients achieved complete remission, including 12 patients with a complete molecular response (CMR) at the data cutoff. The relapse-free survival was 84%, and the overall survival was 83% with a median follow-up of 27 months. The total number of CD19-expressing cells decreased with an increasing CMR rate. CD19 CAR T cells survived for up to 40 months, whereas CD19+ FTCs vanished in 8 patients 3 months after the last infusion. These findings could form the basis for the development of an allo-HSCT-free consolidation paradigm. This trial was registered at www.clinicaltrials.gov as #NCT03984968.
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Antígenos CD19 , Imunoterapia Adotiva , Linfoma de Células B , Síndromes Neurotóxicas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Idoso , Humanos , Antígenos CD19/imunologia , Antígenos CD19/uso terapêutico , Quimioterapia de Consolidação , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Linfócitos T , Imunoterapia Adotiva/métodosRESUMO
Decidualization is necessary for the successful establishment of early pregnancy in rodents and humans. Disturbed decidualization results in recurrent implantation failure, recurrent spontaneous abortion, and preeclampsia. Tryptophan (Trp), one of the essential amino acids in humans, has a positive effect on mammalian pregnancy. Interleukin 4-induced gene 1 (IL4I1) is a recently identified enzyme that can metabolize L-Trp to activate aryl hydrocarbon receptor (AHR). Although IDO1-catalyzed kynurenine (Kyn) from Trp has been shown to enhance human in vitro decidualization via activating AHR, whether IL4I1-catalyzed metabolites of Trp are involved in human decidualization is still unknown. In our study, human chorionic gonadotropin stimulates IL4I1 expression and secretion from human endometrial epithelial cells through ornithine decarboxylase-induced putrescine production. Either IL4I1-catalyzed indole-3-pyruvic acid (I3P) or its metabolite indole-3-aldehyde (I3A) from Trp is able to induce human in vitro decidualization by activating AHR. As a target gene of AHR, Epiregulin induced by I3P and I3A promotes human in vitro decidualization. Our study indicates that IL4I1-catalyzed metabolites from Trp can enhance human in vitro decidualization through AHR-Epiregulin pathway.
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Interleucina-4 , Receptores de Hidrocarboneto Arílico , Animais , Humanos , Epirregulina , Receptores de Hidrocarboneto Arílico/metabolismo , Triptofano/metabolismo , Cinurenina/metabolismo , Gonadotropina Coriônica , Mamíferos/metabolismo , L-Aminoácido OxidaseRESUMO
Philadelphia chromosome-positive acute myeloid leukemia (Ph + AML) is a rare type of AML with a low survival rate and poor prognosis. We first report a Ph + AML patient who remained in long-term remission after the combination of flumatinib and venetoclax, which could provide corresponding treatment ideas for clinical practice.
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Mixed phenotype acute leukemia (MPAL) is a subtype of leukemia in which lymphoid and myeloid markers are co-expressed. Knowledge regarding the genetic features of MPAL is lacking due to its rarity and heterogeneity. Here, we applied an integrated genomic and transcriptomic approach to explore the molecular characteristics of 176 adult patients with MPAL, including 86 patients with T-lymphoid/myeloid MPAL (T/My MPAL-NOS), 42 with Ph+ MPAL, 36 with B-lymphoid/myeloid MPAL (B/My MPAL-NOS), 4 with t(v;11q23), and 8 with MPAL, NOS, rare types. Genetically, T/My MPAL-NOS was similar to B/T MPAL-NOS but differed from Ph+ MPAL and B/My MPAL-NOS. T/My MPAL-NOS exhibited higher CEBPA, DNMT3A, and NOTCH1 mutations. Ph+ MPAL demonstrated higher RUNX1 mutations. B/T MPAL-NOS showed higher NOTCH1 mutations. By integrating next-generation sequencing and RNA sequencing data of 89 MPAL patients, we defined eight molecular subgroups (G1-G8) with distinct mutational and gene expression characteristics. G1 was associated with CEBPA mutations, G2 and G3 with NOTCH1 mutations, G4 with BCL11B rearrangement and FLT3 mutations, G5 and G8 with BCR::ABL1 fusion, G6 with KMT2A rearrangement/KMT2A rearrangement-like features, and G7 with ZNF384 rearrangement/ZNF384 rearrangement-like characteristics. Subsequently, we analyzed single-cell RNA sequencing data from five patients. Groups G1, G2, G3, and G4 exhibited overexpression of hematopoietic stem cell disease-like and common myeloid progenitor disease-like signatures, G5 and G6 had high expression of granulocyte-monocyte progenitor disease-like and monocyte disease-like signatures, and G7 and G8 had common lymphoid progenitor disease-like signatures. Collectively, our findings indicate that integrative genomic and transcriptomic profiling may facilitate more precise diagnosis and develop better treatment options for MPAL.
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Leucemia Mieloide Aguda , Transcriptoma , Humanos , Doença Aguda , Fenótipo , GenômicaRESUMO
BACKGROUND: To evaluate the prognostic value of DNAJB6, KIAA1522, and p-mTOR expression for colorectal cancer (CRC) and to develop effective prognostic models for CRC patients. METHODS: The expression of DNAJB6, KIAA1522, and p-mTOR (Ser2448) was detected using immunohistochemistry in 329 CRC specimens. The prognostic values of the three proteins in the training cohort were assessed using Kaplan-Meier curves and univariate and multivariate Cox proportional hazards models. Prediction nomogram models integrating the three proteins and TNM stage were constructed. Subsequently, calibration curves, receiver operating characteristic (ROC) curves, the concordance index (C-index), and decision curve analysis (DCA) were used to evaluate the performance of the nomograms in the training and validation cohorts. RESULTS: The three proteins DNAJB6, KIAA1522, and p-mTOR were significantly overexpressed in CRC tissues (each P < 0.01), and their expression was an independent prognostic factor for overall survival (OS) and disease-free survival (DFS) (each P < 0.05). The area under the ROC curves (AUC) and C-index values were approximately 0.7. Additionally, the calibration curves showed that the predicted values and the actual values fit well. Furthermore, DCA curves indicated that the clinical value of the nomogram models was higher than that of TNM stage. Overall, the novel prediction models have good discriminability, sensitivity, specificity and clinical utility. CONCLUSION: The nomograms containing DNAJB6, KIAA1522, and p-mTOR may be promising models for predicting postoperative survival in CRC.
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In the recent decades, obesity rates among children and adolescents, especially males, have increased significantly. This worldwide phenomenon is thought to significantly affect the levels of sex hormones. However, the association between waist circumference (a marker of abdominal obesity) and sex hormone levels in children and adolescents is unknown. In this study, 4031 participants aged 6-19 years from the United States National Health and Nutrition Examination Survey (NHANES) in the USA were enrolled in this study. The common confounders of age, race, body mass index, educational level, family income, diabetes, and time of sample collection were also collected. The participants missing any of the above information were excluded from the study. We used multiple linear regression and other multiple statistics to assess the associations between waist circumference and serum testosterone, estradiol, sex hormone-binding globulin (SHBG), free androgen index (FAI), and testosterone/estradiol ratio (T/E2). Waist circumference remained associated with sex hormone levels in children and adolescents after controlling for covariates. As waist circumference increases, testosterone levels in children and adolescents show an overall decline after a brief increase, with the inflection point for waist circumference of 65-66 cm. In addition, waist circumference positively correlates with estradiol levels in male children (ß = 0.007, 95% confidence interval: 0.004-0.009). Moreover, circulating SHBG decreases in children and adolescents as waist circumference increases. In conclusion, this study highlighted waist circumference as a vital indicator affecting sex hormone levels in children and adolescents.