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1.
Cell ; 187(6): 1422-1439.e24, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38447573

RESUMEN

Neutrophils, the most abundant and efficient defenders against pathogens, exert opposing functions across cancer types. However, given their short half-life, it remains challenging to explore how neutrophils adopt specific fates in cancer. Here, we generated and integrated single-cell neutrophil transcriptomes from 17 cancer types (225 samples from 143 patients). Neutrophils exhibited extraordinary complexity, with 10 distinct states including inflammation, angiogenesis, and antigen presentation. Notably, the antigen-presenting program was associated with favorable survival in most cancers and could be evoked by leucine metabolism and subsequent histone H3K27ac modification. These neutrophils could further invoke both (neo)antigen-specific and antigen-independent T cell responses. Neutrophil delivery or a leucine diet fine-tuned the immune balance to enhance anti-PD-1 therapy in various murine cancer models. In summary, these data not only indicate the neutrophil divergence across cancers but also suggest therapeutic opportunities such as antigen-presenting neutrophil delivery.


Asunto(s)
Presentación de Antígeno , Neoplasias , Neutrófilos , Animales , Humanos , Ratones , Antígenos de Neoplasias , Leucina/metabolismo , Neoplasias/inmunología , Neoplasias/patología , Neutrófilos/metabolismo , Linfocitos T , Análisis de Expresión Génica de una Sola Célula
2.
Cell ; 179(2): 561-577.e22, 2019 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-31585088

RESUMEN

We performed the first proteogenomic characterization of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) using paired tumor and adjacent liver tissues from 159 patients. Integrated proteogenomic analyses revealed consistency and discordance among multi-omics, activation status of key signaling pathways, and liver-specific metabolic reprogramming in HBV-related HCC. Proteomic profiling identified three subgroups associated with clinical and molecular attributes including patient survival, tumor thrombus, genetic profile, and the liver-specific proteome. These proteomic subgroups have distinct features in metabolic reprogramming, microenvironment dysregulation, cell proliferation, and potential therapeutics. Two prognostic biomarkers, PYCR2 and ADH1A, related to proteomic subgrouping and involved in HCC metabolic reprogramming, were identified. CTNNB1 and TP53 mutation-associated signaling and metabolic profiles were revealed, among which mutated CTNNB1-associated ALDOA phosphorylation was validated to promote glycolysis and cell proliferation. Our study provides a valuable resource that significantly expands the knowledge of HBV-related HCC and may eventually benefit clinical practice.


Asunto(s)
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virología , Fructosa-Bifosfato Aldolasa/genética , Virus de la Hepatitis B , Hepatitis B Crónica/complicaciones , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virología , Proteogenómica/métodos , beta Catenina/genética , Animales , Proliferación Celular , Estudios de Cohortes , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Células Hep G2 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Microambiente Tumoral/genética
4.
Hum Mol Genet ; 32(10): 1622-1633, 2023 05 05.
Artículo en Inglés | MEDLINE | ID: mdl-36617157

RESUMEN

As the auditory and balance receptor cells in the inner ear, hair cells are responsible for converting mechanical stimuli into electrical signals, a process referred to as mechano-electrical transduction. Hair cell development and function are tightly regulated, and hair cell deficits are the main reasons for hearing loss and balance disorders. TMCC2 is an endoplasmic reticulum (ER)-residing transmembrane protein whose physiological function largely remains unknown. In the present work, we show that Tmcc2 is specifically expressed in the auditory hair cells of mouse inner ear. Tmcc2 knockout mice were then established to investigate its physiological role in hearing. Auditory brainstem responses measurements show that Tmcc2 knockout mice suffer from congenital hearing loss. Further investigations reveal progressive auditory hair cell loss in the Tmcc2 knockout mice. The general morphology and function of ER are unaffected in Tmcc2 knockout hair cells. However, increased ER stress was observed in Tmcc2 knockout mice and knockdown cells, suggesting that loss of TMCC2 leads to auditory hair cell death through elevated ER stress.


Asunto(s)
Sordera , Pérdida Auditiva , Animales , Ratones , Sordera/metabolismo , Estrés del Retículo Endoplásmico/genética , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas Internas , Audición , Pérdida Auditiva/metabolismo , Ratones Noqueados
5.
J Virol ; 98(5): e0006024, 2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38557170

RESUMEN

As obligate parasites, viruses have evolved multiple strategies to evade the host immune defense. Manipulation of the host proteasome system to degrade specific detrimental factors is a common viral countermeasure. To identify host proteins targeted for proteasomal degradation by porcine reproductive and respiratory syndrome virus (PRRSV), we conducted a quantitative proteomics screen of PRRSV-infected Marc-145 cells under the treatment with proteasome inhibitor MG132. The data revealed that the expression levels of programmed cell death 4 (PDCD4) were strongly downregulated by PRRSV and significantly rescued by MG132. Further investigation confirmed that PRRSV infection induced the translocation of PDCD4 from the nucleus to the cytoplasm, and the viral nonstructural protein 9 (Nsp9) promoted PDCD4 proteasomal degradation in the cytoplasm by activating the Akt-mTOR-S6K1 pathway. The C-terminal domain of Nsp9 was responsible for PDCD4 degradation. As for the role of PDCD4 during PRRSV infection, we demonstrated that PDCD4 knockdown favored viral replication, while its overexpression significantly attenuated replication, suggesting that PDCD4 acts as a restriction factor for PRRSV. Mechanistically, we discovered eukaryotic translation initiation factor 4A (eIF4A) was required for PRRSV. PDCD4 interacted with eIF4A through four sites (E249, D253, D414, and D418) within its two MA3 domains, disrupting eIF4A-mediated translation initiation in the 5'-untranslated region of PRRSV, thereby inhibiting PRRSV infection. Together, our study reveals the antiviral function of PDCD4 and the viral strategy to antagonize PDCD4. These results will contribute to our understanding of the immune evasion strategies employed by PRRSV and offer valuable insights for developing new antiviral targets.IMPORTANCEPorcine reproductive and respiratory syndrome virus (PRRSV) infection results in major economic losses in the global swine industry and is difficult to control effectively. Here, using a quantitative proteomics screen, we identified programmed cell death 4 (PDCD4) as a host protein targeted for proteasomal degradation by PRRSV. We demonstrated that PDCD4 restricts PRRSV replication by interacting with eukaryotic translation initiation factor 4A, which is required for translation initiation in the viral 5'-untranslated region. Additionally, four sites within two MA3 domains of PDCD4 are identified to be responsible for its antiviral function. Conversely, PRRSV nonstructural protein 9 promotes PDCD4 proteasomal degradation in the cytoplasm by activating the Akt-mTOR-S6K1 pathway, thus weakening the anti-PRRSV function. Our work unveils PDCD4 as a previously unrecognized host restriction factor for PRRSV and reveals that PRRSV develops countermeasures to overcome PDCD4. This will provide new insights into virus-host interactions and the development of new antiviral targets.


Asunto(s)
Proteínas Reguladoras de la Apoptosis , Factor 4A Eucariótico de Iniciación , Virus del Síndrome Respiratorio y Reproductivo Porcino , Proteínas de Unión al ARN , Proteínas no Estructurales Virales , Replicación Viral , Virus del Síndrome Respiratorio y Reproductivo Porcino/fisiología , Animales , Proteínas no Estructurales Virales/metabolismo , Proteínas no Estructurales Virales/genética , Factor 4A Eucariótico de Iniciación/metabolismo , Factor 4A Eucariótico de Iniciación/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Porcinos , Línea Celular , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Interacciones Huésped-Patógeno , Proteolisis , Humanos , Síndrome Respiratorio y de la Reproducción Porcina/metabolismo , Síndrome Respiratorio y de la Reproducción Porcina/virología , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal
6.
FASEB J ; 38(15): e23868, 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-39102213

RESUMEN

Glycolysis is a major determinant of pulmonary artery smooth muscle cell (PASMC) proliferation in pulmonary hypertension (PH). Circular RNAs (circRNAs) are powerful regulators of glycolysis in multiple diseases; however, the role of circRNAs in glycolysis in PH has been poorly characterized. The aim of this study was to uncover the regulatory mechanism of a new circRNA, circNAP1L4, in human pulmonary artery smooth muscle cell (HPASMC) proliferation through the host protein NAP1L4 to regulate the super-enhancer-driven glycolysis gene hexokinase II (HK II). CircNAP1L4 was downregulated in hypoxic HPASMCs and plasma of PH patients. Functionally, circNAP1L4 overexpression inhibited glycolysis and proliferation in hypoxic HPASMCs. Mechanistically, circNAP1L4 directly bound to its host protein NAP1L4 and affected the ability of NAP1L4 to move into the nucleus to regulate the epigenomic signals of the super-enhancer of HK II. Intriguingly, circNAP1L4 overexpression inhibited the proliferation but not the migration of human pulmonary arterial endothelial cells (HPAECs) cocultured with HPASMCs. Furthermore, pre-mRNA-processing-splicing Factor 8 (PRP8) was found to regulate the production ratio of circNAP1L4 and linear NAP1L4. In vivo, targeting circNAP1L4 alleviates SU5416 combined with hypoxia (SuHx)-induced PH. Overall, these findings reveal a new circRNA that inhibits PASMC proliferation and serves as a therapeutic target for PH.


Asunto(s)
Proliferación Celular , Glucólisis , Hexoquinasa , Hipertensión Pulmonar , Miocitos del Músculo Liso , Arteria Pulmonar , ARN Circular , Humanos , Hexoquinasa/metabolismo , Hexoquinasa/genética , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/genética , Miocitos del Músculo Liso/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , Animales , Ratones , Masculino , Células Cultivadas , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/citología
7.
J Neurosci ; 43(5): 812-826, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-36596697

RESUMEN

Distributed cortical regions show differential responses to visual objects belonging to different domains varying by animacy (e.g., animals vs tools), yet it remains unclear whether this is an organization principle also applying to the subcortical structures. Combining multiple fMRI activation experiments (two main experiments and six validation datasets; 12 females and 9 males in the main Experiment 1; 10 females and 10 males in the main Experiment 2), resting-state functional connectivity, and task-based dynamic causal modeling analysis in human subjects, we found that visual processing of images of animals and tools elicited different patterns of response in the pulvinar, with robust left lateralization for tools, and distinct, bilateral (with rightward tendency) clusters for animals. Such domain-preferring activity distribution in the pulvinar was associated with the magnitude with which the voxels were intrinsically connected with the corresponding domain-preferring regions in the cortex. The pulvinar-to-right-amygdala path showed a one-way shortcut supporting the perception of animals, and the modulation connection from pulvinar to parietal showed an advantage to the perception of tools. These results incorporate the subcortical regions into the object processing network and highlight that domain organization appears to be an overarching principle across various processing stages in the brain.SIGNIFICANCE STATEMENT Viewing objects belonging to different domains elicited different cortical regions, but whether the domain organization applied to the subcortical structures (e.g., pulvinar) was unknown. Multiple fMRI activation experiments revealed that object pictures belonging to different domains elicited differential patterns of response in the pulvinar, with robust left lateralization for tool pictures, and distinct, bilateral (with rightward tendency) clusters for animals. Combining the resting-state functional connectivity and dynamic causal modeling analysis on task-based fMRI data, we found domain-preferring activity distribution in the pulvinar aligned with that in cortical regions. These results highlight the need for coherent visual theories that explain the mechanisms underlying the domain organization across various processing stages.


Asunto(s)
Pulvinar , Masculino , Femenino , Animales , Humanos , Pulvinar/diagnóstico por imagen , Pulvinar/fisiología , Imagen por Resonancia Magnética/métodos , Encéfalo , Mapeo Encefálico , Amígdala del Cerebelo/fisiología
8.
J Neurosci ; 43(2): 319-332, 2023 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-36446585

RESUMEN

Mechanical impact-induced primary injury after traumatic brain injury (TBI) leads to acute microglial pro-inflammatory activation and consequently mediates neurodegeneration, which is a major secondary brain injury mechanism. However, the detailed pathologic cascades have not been fully elucidated, partially because of the pathologic complexity in animal TBI models. Although there are several in vitro TBI models, none of them closely mimic post-TBI microglial activation. In the present study, we aimed to establish an in vitro TBI model, specifically reconstituting the pro-inflammatory activation and associated neurodegeneration following TBI. We proposed three sets of experiments. First, we established a needle scratch injured neuron-induced microglial activation and neurodegeneration in vitro model of TBI. Second, we compared microglial pro-inflammatory cytokines profiles between the in vitro TBI model and TBI in male mice. Additionally, we validated the role of injured neurons-derived damage-associated molecular patterns in amplifying microglial pro-inflammatory pathways using the in vitro TBI model. Third, we applied the in vitro model for the first time to characterize the cellular metabolic profile of needle scratch injured-neuron-activated microglia, and define the role of metabolic reprogramming in mediating pro-inflammatory microglial activation and mediated neurodegeneration. Our results showed that we successfully established a novel in vitro TBI model, which closely mimics primary neuronal injury-triggered microglial pro-inflammatory activation and mediated neurodegeneration after TBI. This in vitro model provides an advanced and highly translational platform for dissecting interactions in the pathologic processes of neuronal injury-microglial activation-neuronal degeneration cascade, and elucidating the detailed underlying cellular and molecular insights after TBI.SIGNIFICANCE STATEMENT Microglial activation is a key component of acute neuroinflammation that leads to neurodegeneration and long-term neurologic outcome deficits after TBI. However, it is not feasible to truly dissect primary neuronal injury-induced microglia activation, and consequently mediated neurodegeneration in vivo Furthermore, there is currently lacking of in vitro TBI models closely mimicking the TBI primary injury-mediated microglial activation. In this study, we successfully established and validated a novel in vitro TBI model of microglial activation, and for the first time, characterized the cellular metabolic profile of microglia in this model. This novel microglial activation in vitro TBI model will help in elucidating microglial inflammatory activation and consequently associated neurodegeneration after TBI.


Asunto(s)
Lesiones Traumáticas del Encéfalo , Microglía , Ratones , Masculino , Animales , Microglía/metabolismo , Lesiones Traumáticas del Encéfalo/patología , Macrófagos/metabolismo , Neuronas/metabolismo , Ratones Endogámicos C57BL
9.
J Neurosci ; 43(18): 3219-3231, 2023 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-37001993

RESUMEN

The mechanoelectrical transduction (MET) protein complex in the inner-ear hair cells is essential for hearing and balance perception. Calcium and integrin-binding protein 2 (CIB2) has been reported to be a component of MET complex, and loss of CIB2 completely abolishes MET currents in auditory hair cells, causing profound congenital hearing loss. However, loss of CIB2 does not affect MET currents in vestibular hair cells (VHCs) as well as general balance function. Here, we show that CIB2 and CIB3 act redundantly to regulate MET in VHCs, as MET currents are completely abolished in the VHCs of Cib2/Cib3 double knock-out mice of either sex. Furthermore, we show that Cib2 and Cib3 transcripts have complementary expression patterns in the vestibular maculae, and that they play different roles in stereocilia maintenance in VHCs. Cib2 transcripts are highly expressed in the striolar region, and knock-out of Cib2 affects stereocilia maintenance in striolar VHCs. In contrast, Cib3 transcripts are highly expressed in the extrastriolar region, and knock-out of Cib3 mainly affects stereocilia maintenance in extrastriolar VHCs. Simultaneous knock-out of Cib2 and Cib3 affects stereocilia maintenance in all VHCs and leads to severe balance deficits. Taken together, our present work reveals that CIB2 and CIB3 are important for stereocilia maintenance as well as MET in mouse VHCs.SIGNIFICANCE STATEMENT Calcium and integrin-binding protein 2 (CIB2) is an important component of mechanoelectrical transduction (MET) complex, and loss of CIB2 completely abolishes MET in auditory hair cells. However, MET is unaffected in Cib2 knock-out vestibular hair cells (VHCs). In the present work, we show that CIB3 could compensate for the loss of CIB2 in VHCs, and Cib2/Cib3 double knock-out completely abolishes MET in VHCs. Interestingly, CIB2 and CIB3 could also regulate VHC stereocilia maintenance in a nonredundant way. Cib2 and Cib3 transcripts are highly expressed in the striolar and extrastriolar regions, respectively. Stereocilia maintenance and balance function are differently affected in Cib2 or Cib3 knock-out mice. In conclusion, our data suggest that CIB2 and CIB3 are important for stereocilia maintenance and MET in mouse VHCs.


Asunto(s)
Células Ciliadas Vestibulares , Animales , Ratones , Calcio/metabolismo , Células Ciliadas Vestibulares/metabolismo , Integrinas , Ratones Noqueados , Estereocilios/metabolismo
10.
Ann Surg ; 279(2): 297-305, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-37485989

RESUMEN

OBJECTIVE: The purpose of this study was to compare the outcomes of robotic limited liver resections (RLLR) versus laparoscopic limited liver resections (LLLR) of the posterosuperior segments. BACKGROUND: Both laparoscopic and robotic liver resections have been used for tumors in the posterosuperior liver segments. However, the comparative performance and safety of both approaches have not been well examined in the existing literature. METHODS: This is a post hoc analysis of a multicenter database of 5446 patients who underwent RLLR or LLLR of the posterosuperior segments (I, IVa, VII, and VIII) at 60 international centers between 2008 and 2021. Data on baseline demographics, center experience and volume, tumor features, and perioperative characteristics were collected and analyzed. Propensity score-matching (PSM) analysis (in both 1:1 and 1:2 ratios) was performed to minimize selection bias. RESULTS: A total of 3510 cases met the study criteria, of whom 3049 underwent LLLR (87%), and 461 underwent RLLR (13%). After PSM (1:1: and 1:2), RLLR was associated with a lower open conversion rate [10 of 449 (2.2%) vs 54 of 898 (6.0%); P =0.002], less blood loss [100 mL [IQR: 50-200) days vs 150 mL (IQR: 50-350); P <0.001] and a shorter operative time (188 min (IQR: 140-270) vs 222 min (IQR: 158-300); P <0.001]. These improved perioperative outcomes associated with RLLR were similarly seen in a subset analysis of patients with cirrhosis-lower open conversion rate [1 of 136 (0.7%) vs 17 of 272 (6.2%); P =0.009], less blood loss [100 mL (IQR: 48-200) vs 160 mL (IQR: 50-400); P <0.001], and shorter operative time [190 min (IQR: 141-258) vs 230 min (IQR: 160-312); P =0.003]. Postoperative outcomes in terms of readmission, morbidity and mortality were similar between RLLR and LLLR in both the overall PSM cohort and cirrhosis patient subset. CONCLUSIONS: RLLR for the posterosuperior segments was associated with superior perioperative outcomes in terms of decreased operative time, blood loss, and open conversion rate when compared with LLLR.


Asunto(s)
Laparoscopía , Neoplasias Hepáticas , Procedimientos Quirúrgicos Robotizados , Humanos , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/patología , Puntaje de Propensión , Estudios Retrospectivos , Cirrosis Hepática/cirugía , Hepatectomía , Tiempo de Internación , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/cirugía
11.
Ann Surg ; 2024 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-38939972

RESUMEN

OBJECTIVE: We aimed to establish global benchmark outcomes indicators for L-RPS/H67. BACKGROUND: Minimally invasive liver resections has seen an increase in uptake in recent years. Over time, challenging procedures as laparoscopic right posterior sectionectomies (L-RPS)/H67 are also increasingly adopted. METHODS: This is a post hoc analysis of a multicenter database of 854 patients undergoing minimally invasive RPS (MI-RPS) in 57 international centers in 4 continents between 2015 and 2021. There were 651 pure L-RPS and 160 robotic RPS (R-RPS). Sixteen outcome indicators of low-risk L-RPS cases were selected to establish benchmark cutoffs. The 75th percentile of individual center medians for a given outcome indicator was set as the benchmark cutoff. RESULTS: There were 573 L-RPS/H67 performed in 43 expert centers, of which 254 L-RPS/H67 (44.3%) cases qualified as low risk benchmark cases. The benchmark outcomes established for operation time, open conversion rate, blood loss ≥500 mL, blood transfusion rate, postoperative morbidity, major morbidity, 90-day mortality and textbook outcome after L-RPS were 350.8 minutes, 12.5%, 53.8%, 22.9%, 23.8%, 2.8%, 0% and 4% respectively. CONCLUSIONS: The present study established the first global benchmark values for L-RPS/H6/7. The benchmark provided an up-to-date reference of best achievable outcomes for surgical auditing and benchmarking.

12.
Biochem Biophys Res Commun ; 737: 150467, 2024 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-39133984

RESUMEN

In general, Cu(II) is the critical factor in catalyzing reactive oxygen species (ROS) production and accelerating amyloid-ß (Aß) oligomer formation in Alzheimer's disease (AD). Natural chelating agents with good biocompatibility and appropriate binding affinity with Cu(II) have emerged as potential candidates for AD therapy. Herein, we tested the capability of guluronic acid disaccharide (Di-GA), a natural chelating agent with the moderate association affinity to Cu(II), in inhibiting ROS production and Aß oligomer formation. The results showed that Di-GA was capable of chelating with Cu(II) and reducing ROS production, even in solutions containing Fe(II), Zn(II), and Aß. In addition, Di-GA can also capture Cu(II) from Cu-Aß complexes and decrease Aß oligomer formation. The cellular results confirmed that Di-GA prevented SH-SY5Y cells from ROS and Aß oligomer damage by reducing the injury of ROS and Aß oligomers on cell membrane and decreasing their intracellular damage on mitochondria. Notably, the slightly higher efficiency of Di-GA in chelating with Cu(I) than Cu(II) can be benefit for its in vivo applications, as Cu(I) is not only the most active but also the special intermediate specie during ROS production process. All of these results proved that Di-GA could be a promising marine drug candidate in reducing copper-related ROS damage and Aß oligomer toxicity associated with AD.

13.
BMC Med ; 22(1): 282, 2024 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-38972973

RESUMEN

BACKGROUND: The advances in deep learning-based pathological image analysis have invoked tremendous insights into cancer prognostication. Still, lack of interpretability remains a significant barrier to clinical application. METHODS: We established an integrative prognostic neural network for intrahepatic cholangiocarcinoma (iCCA), towards a comprehensive evaluation of both architectural and fine-grained information from whole-slide images. Then, leveraging on multi-modal data, we conducted extensive interrogative approaches to the models, to extract and visualize the morphological features that most correlated with clinical outcome and underlying molecular alterations. RESULTS: The models were developed and optimized on 373 iCCA patients from our center and demonstrated consistent accuracy and robustness on both internal (n = 213) and external (n = 168) cohorts. The occlusion sensitivity map revealed that the distribution of tertiary lymphoid structures, the geometric traits of the invasive margin, the relative composition of tumor parenchyma and stroma, the extent of necrosis, the presence of the disseminated foci, and the tumor-adjacent micro-vessels were the determining architectural features that impacted on prognosis. Quantifiable morphological vector extracted by CellProfiler demonstrated that tumor nuclei from high-risk patients exhibited significant larger size, more distorted shape, with less prominent nuclear envelope and textural contrast. The multi-omics data (n = 187) further revealed key molecular alterations left morphological imprints that could be attended by the network, including glycolysis, hypoxia, apical junction, mTORC1 signaling, and immune infiltration. CONCLUSIONS: We proposed an interpretable deep-learning framework to gain insights into the biological behavior of iCCA. Most of the significant morphological prognosticators perceived by the network are comprehensible to human minds.


Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Aprendizaje Profundo , Humanos , Colangiocarcinoma/patología , Pronóstico , Neoplasias de los Conductos Biliares/patología , Masculino , Femenino , Persona de Mediana Edad , Procesamiento de Imagen Asistido por Computador/métodos , Anciano
14.
Biol Reprod ; 110(3): 536-547, 2024 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-38011671

RESUMEN

Recurrent implantation failure (RIF) patients exhibit poor endometrial receptivity and abnormal decidualization with reduced effectiveness and exposure to progesterone, which is an intractable clinical problem. However, the associated molecular mechanisms remain elusive. We found that EH domain containing 1 (EHD1) expression was abnormally elevated in RIF and linked to aberrant endometrial decidualization. Here we show that EHD1 overexpressed in human endometrial stromal cells significantly inhibited progesterone receptor (PGR) transcriptional activity and the responsiveness to progesterone. No significant changes were observed in PGR mRNA levels, while a significant decrease in progesterone receptor B (PRB) protein level. Indeed, EHD1 binds to the PRB protein, with the K388 site crucial for this interaction. Overexpression of EHD1 promotes the SUMOylation and ubiquitination of PRB, leading to the degradation of the PRB protein. Supplementation with the de-SUMOylated protease SENP1 ameliorated EHD1-repressed PRB transcriptional activity. To establish a functional link between EHD1 and the PGR signalling pathway, sg-EHD1 were utilized to suppress EHD1 expression in HESCs from RIF patients. A significant increase in the expression of prolactin and insulin-like growth factor-binding protein 1 was detected by interfering with the EHD1. In conclusion, we demonstrated that abnormally high expression of EHD1 in endometrial stromal cells attenuated the activity of PRB associated with progesterone resistance in a subset of women with RIF.


Asunto(s)
Decidua , Progesterona , Humanos , Femenino , Progesterona/farmacología , Progesterona/metabolismo , Decidua/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Endometrio/metabolismo , Células del Estroma/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Cisteína Endopeptidasas
15.
J Transl Med ; 22(1): 289, 2024 03 17.
Artículo en Inglés | MEDLINE | ID: mdl-38494492

RESUMEN

BACKGROUND: Global myopia prevalence poses a substantial public health burden with vision-threatening complications, necessitating effective prevention and control strategies. Precise prediction of spherical equivalent (SE), myopia, and high myopia onset is vital for proactive clinical interventions. METHODS: We reviewed electronic medical records of pediatric and adolescent patients who underwent cycloplegic refraction measurements at the Eye & Ear, Nose, and Throat Hospital of Fudan University between January 2005 and December 2019. Patients aged 3-18 years who met the inclusion criteria were enrolled in this study. To predict the SE and onset of myopia and high myopia in a specific year, two distinct models, random forest (RF) and the gradient boosted tree algorithm (XGBoost), were trained and validated based on variables such as age at baseline, and SE at various intervals. Outputs included SE, the onset of myopia, and high myopia up to 15 years post-initial examination. Age-stratified analyses and feature importance assessments were conducted to augment the clinical significance of the models. RESULTS: The study enrolled 88,250 individuals with 408,255 refraction records. The XGBoost-based SE prediction model consistently demonstrated robust and better performance than RF over 15 years, maintaining an R2 exceeding 0.729, and a Mean Absolute Error ranging from 0.078 to 1.802 in the test set. Myopia onset prediction exhibited strong area under the curve (AUC) values between 0.845 and 0.953 over 15 years, and high myopia onset prediction showed robust AUC values (0.807-0.997 over 13 years, with the 14th year at 0.765), emphasizing the models' effectiveness across age groups and temporal dimensions on the test set. Additionally, our classification models exhibited excellent calibration, as evidenced by consistently low brier score values, all falling below 0.25. Moreover, our findings underscore the importance of commencing regular examinations at an early age to predict high myopia. CONCLUSIONS: The XGBoost predictive models exhibited high accuracy in predicting SE, onset of myopia, and high myopia among children and adolescents aged 3-18 years. Our findings emphasize the importance of early and regular examinations at a young age for predicting high myopia, thereby providing valuable insights for clinical practice.


Asunto(s)
Miopía , Refracción Ocular , Adolescente , Niño , Preescolar , Humanos , Miopía/diagnóstico , Miopía/epidemiología
16.
Hepatology ; 77(3): 745-759, 2023 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-35243663

RESUMEN

BACKGROUND AND AIMS: IL-10-producing regulatory B cells (IL-10 + B cells), a dominant regulatory B cell (Breg) subset, foster tumor progression. However, the mechanisms underlying their generation in HCC are poorly understood. Ten-eleven translocation-2 (TET2), a predominant epigenetic regulatory enzyme in B cells, regulates gene expression by catalyzing demethylation of 5-methylcytosine into 5-hydroxymethyl cytosine (5hmC). In this study, we investigated the role of TET2 in IL-10 + B cell generation in HCC and its prospects for clinical application. APPROACH AND RESULTS: TET2 activation in B cells triggered by oxidative stress from the HCC microenvironment promoted IL-10 expression, whereas adoptive transfer of Tet2 -deficient B cells suppressed HCC progression. The aryl hydrocarbon receptor is required for TET2 to hydroxylate Il10 . In addition, high levels of IL-10, TET2, and 5hmc in B cells indicate poor prognosis in patients with HCC. Moreover, we determined TET2 activity using 5hmc in B cells to evaluate the efficacy of anti-programmed death 1 (anti-PD-1) therapy. Notably, TET2 inhibition in B cells facilitates antitumor immunity to improve anti-PD-1 therapy for HCC. CONCLUSIONS: Our findings propose a TET2-dependent epigenetic intervention targeting IL-10 + B cell generation during HCC progression and identify the inhibition of TET2 activity as a promising combination therapy with immune checkpoint inhibitors for HCC.


Asunto(s)
Linfocitos B Reguladores , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , 5-Metilcitosina , Linfocitos B Reguladores/metabolismo , Linfocitos B Reguladores/patología , Carcinoma Hepatocelular/patología , Interleucina-10 , Neoplasias Hepáticas/patología , Microambiente Tumoral
17.
Ann Surg Oncol ; 31(1): 97-114, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37936020

RESUMEN

BACKGROUND: Minimally invasive liver resections (MILR) offer potential benefits such as reduced blood loss and morbidity compared with open liver resections. Several studies have suggested that the impact of cirrhosis differs according to the extent and complexity of resection. Our aim was to investigate the impact of cirrhosis on the difficulty and outcomes of MILR, focusing on major hepatectomies. METHODS: A total of 2534 patients undergoing minimally invasive major hepatectomies (MIMH) for primary malignancies across 58 centers worldwide were retrospectively reviewed. Propensity score (PSM) and coarsened exact matching (CEM) were used to compare patients with and without cirrhosis. RESULTS: A total of 1353 patients (53%) had no cirrhosis, 1065 (42%) had Child-Pugh A and 116 (4%) had Child-Pugh B cirrhosis. Matched comparison between non-cirrhotics vs Child-Pugh A cirrhosis demonstrated comparable blood loss. However, after PSM, postoperative morbidity and length of hospitalization was significantly greater in Child-Pugh A cirrhosis, but these were not statistically significant with CEM. Comparison between Child-Pugh A and Child-Pugh B cirrhosis demonstrated the latter had significantly higher transfusion rates and longer hospitalization after PSM, but not after CEM. Comparison of patients with cirrhosis of all grades with and without portal hypertension demonstrated no significant difference in all major perioperative outcomes after PSM and CEM. CONCLUSIONS: The presence and severity of cirrhosis affected the difficulty and impacted the outcomes of MIMH, resulting in higher blood transfusion rates, increased postoperative morbidity, and longer hospitalization in patients with more advanced cirrhosis. As such, future difficulty scoring systems for MIMH should incorporate liver cirrhosis and its severity as variables.


Asunto(s)
Hipertensión Portal , Laparoscopía , Neoplasias Hepáticas , Procedimientos Quirúrgicos Robotizados , Humanos , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/cirugía , Hepatectomía/métodos , Estudios Retrospectivos , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugía , Cirrosis Hepática/complicaciones , Cirrosis Hepática/cirugía , Cirrosis Hepática/patología , Laparoscopía/métodos , Hipertensión Portal/etiología , Hipertensión Portal/cirugía , Tiempo de Internación , Puntaje de Propensión
18.
Ann Surg Oncol ; 31(9): 5615-5630, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38879668

RESUMEN

INTRODUCTION: Despite the increasing widespread adoption and experience in minimally invasive liver resections (MILR), open conversion occurs not uncommonly even with minor resections and as been reported to be associated with inferior outcomes. We aimed to identify risk factors for and outcomes of open conversion in patients undergoing minor hepatectomies. We also studied the impact of approach (laparoscopic or robotic) on outcomes. METHODS: This is a post-hoc analysis of 20,019 patients who underwent RLR and LLR across 50 international centers between 2004-2020. Risk factors for and perioperative outcomes of open conversion were analysed. Multivariate and propensity score-matched analysis were performed to control for confounding factors. RESULTS: Finally, 10,541 patients undergoing either laparoscopic (LLR; 89.1%) or robotic (RLR; 10.9%) minor liver resections (wedge resections, segmentectomies) were included. Multivariate analysis identified LLR, earlier period of MILR, malignant pathology, cirrhosis, portal hypertension, previous abdominal surgery, larger tumor size, and posterosuperior location as significant independent predictors of open conversion. The most common reason for conversion was technical issues (44.7%), followed by bleeding (27.2%), and oncological reasons (22.3%). After propensity score matching (PSM) of baseline characteristics, patients requiring open conversion had poorer outcomes compared with successful MILR cases as evidenced by longer operative times, more blood loss, higher requirement for perioperative transfusion, longer duration of hospitalization and higher morbidity, reoperation, and 90-day mortality rates. CONCLUSIONS: Multiple risk factors were associated with conversion of MILR even for minor hepatectomies, and open conversion was associated with significantly poorer perioperative outcomes.


Asunto(s)
Conversión a Cirugía Abierta , Hepatectomía , Laparoscopía , Neoplasias Hepáticas , Procedimientos Quirúrgicos Robotizados , Humanos , Masculino , Femenino , Hepatectomía/métodos , Hepatectomía/mortalidad , Laparoscopía/métodos , Persona de Mediana Edad , Conversión a Cirugía Abierta/estadística & datos numéricos , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/patología , Anciano , Estudios de Seguimiento , Complicaciones Posoperatorias/epidemiología , Factores de Riesgo , Tempo Operativo , Pronóstico , Tiempo de Internación/estadística & datos numéricos , Estudios Retrospectivos
19.
Clin Proteomics ; 21(1): 32, 2024 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-38735925

RESUMEN

BACKGROUND: Traumatic brain injury (TBI) often results in diverse molecular responses, challenging traditional proteomic studies that measure average changes at tissue levels and fail to capture the complexity and heterogeneity of the affected tissues. Spatial proteomics offers a solution by providing insights into sub-region-specific alterations within tissues. This study focuses on the hippocampal sub-regions, analyzing proteomic expression profiles in mice at the acute (1 day) and subacute (7 days) phases of post-TBI to understand subregion-specific vulnerabilities and long-term consequences. METHODS: Three mice brains were collected from each group, including Sham, 1-day post-TBI and 7-day post-TBI. Hippocampal subregions were extracted using Laser Microdissection (LMD) and subsequently analyzed by label-free quantitative proteomics. RESULTS: The spatial analysis reveals region-specific protein abundance changes, highlighting the elevation of FN1, LGALS3BP, HP, and MUG-1 in the stratum moleculare (SM), suggesting potential immune cell enrichment post-TBI. Notably, established markers of chronic traumatic encephalopathy, IGHM and B2M, exhibit specific upregulation in the dentate gyrus bottom (DG2) independent of direct mechanical injury. Metabolic pathway analysis identifies disturbances in glucose and lipid metabolism, coupled with activated cholesterol synthesis pathways enriched in SM at 7-Day post-TBI and subsequently in deeper DG1 and DG2 suggesting a role in neurogenesis and the onset of recovery. Coordinated activation of neuroglia and microtubule dynamics in DG2 suggest recovery mechanisms in less affected regions. Cluster analysis revealed spatial variations post-TBI, indicative of dysregulated neuronal plasticity and neurogenesis and further predisposition to neurological disorders. TBI-induced protein upregulation (MUG-1, PZP, GFAP, TJP, STAT-1, and CD44) across hippocampal sub-regions indicates shared molecular responses and links to neurological disorders. Spatial variations were demonstrated by proteins dysregulated in both or either of the time-points exclusively in each subregion (ELAVL2, CLIC1 in PL, CD44 and MUG-1 in SM, and SHOC2, LGALS3 in DG). CONCLUSIONS: Utilizing advanced spatial proteomics techniques, the study unveils the dynamic molecular responses in distinct hippocampal subregions post-TBI. It uncovers region-specific vulnerabilities and dysregulated neuronal processes, and potential recovery-related pathways that contribute to our understanding of TBI's neurological consequences and provides valuable insights for biomarker discovery and therapeutic targets.

20.
Exp Eye Res ; 238: 109726, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37979904

RESUMEN

This study aimed to investigate the underlying pathophysiology of high myopia by analyzing the proteome of human corneal stromal lenticule samples obtained through small incision lenticule extraction (SMILE). A total of thirty-two patients who underwent SMILE were included in the study. Label-free quantitative proteomic analysis was performed on corneal stromal lenticule samples, equally representing high myopia (n = 10) and low myopia (n = 10) groups. The identified and profiled lenticule proteomes were analyzed using in silico tools to explore biological characteristics of differentially expressed proteins (DEPs). Additionally, LASSO regression and random forest model were employed to identify key proteins associated with the pathophysiology of high myopia. The DEPs were found to be closely linked to immune activation, extracellular matrix, and cell adhesion-related pathways according to gene ontology analysis. Specifically, decreased expression of COL1A1 and increased expression of CDH11 were associated with the pathogenesis of high myopia and validated by western blotting (n = 6) and quantitative real time polymerase chain reaction (n = 6). Overall, this study provides evidence that COL1A1 and CDH11 may contribute to the pathophysiology of high myopia based on comparative proteomic profiling of human corneal stromal lenticules obtained through SMILE.


Asunto(s)
Cirugía Laser de Córnea , Miopía , Humanos , Proteómica , Sustancia Propia/metabolismo , Miopía/metabolismo , Láseres de Excímeros
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