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Resistance to neoadjuvant chemotherapy leads to poor prognosis of locally advanced rectal cancer (LARC), representing an unmet clinical need that demands further exploration of therapeutic strategies to improve clinical outcomes. Here, we identified a noncanonical role of RB1 for modulating chromatin activity that contributes to oxaliplatin resistance in colorectal cancer (CRC). We demonstrate that oxaliplatin induces RB1 phosphorylation, which is associated with the resistance to neoadjuvant oxaliplatin-based chemotherapy in LARC. Inhibition of RB1 phosphorylation by CDK4/6 inhibitor results in vulnerability to oxaliplatin in both intrinsic and acquired chemoresistant CRC. Mechanistically, we show that RB1 modulates chromatin activity through the TEAD4/HDAC1 complex to epigenetically suppress the expression of DNA repair genes. Antagonizing RB1 phosphorylation through CDK4/6 inhibition enforces RB1/TEAD4/HDAC1 repressor activity, leading to DNA repair defects, thus sensitizing oxaliplatin treatment in LARC. Our study identifies a RB1 function in regulating chromatin activity through TEAD4/HDAC1. It also provides the combination of CDK4/6 inhibitor with oxaliplatin as a potential synthetic lethality strategy to mitigate oxaliplatin resistance in LARC, whereby phosphorylated RB1/TEAD4 can serve as potential biomarkers to guide the patient stratification.
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Terapia Neoadyuvante , Neoplasias del Recto , Humanos , Oxaliplatino/farmacología , Terapia Neoadyuvante/métodos , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/genética , Quimioradioterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cromatina , Resultado del Tratamiento , Factores de Transcripción de Dominio TEA , Ubiquitina-Proteína Ligasas , Proteínas de Unión a RetinoblastomaRESUMEN
Whereas the actions of enhancers in gene transcriptional regulation are well established, roles of JmjC-domain-containing proteins in mediating enhancer activation remain poorly understood. Here, we report that recruitment of the JmjC-domain-containing protein 6 (JMJD6) to estrogen receptor alpha (ERα)-bound active enhancers is required for RNA polymerase II recruitment and enhancer RNA production on enhancers, resulting in transcriptional pause release of cognate estrogen target genes. JMJD6 is found to interact with MED12 in the mediator complex to regulate its recruitment. Unexpectedly, JMJD6 is necessary for MED12 to interact with CARM1, which methylates MED12 at multiple arginine sites and regulates its chromatin binding. Consistent with its role in transcriptional activation, JMJD6 is required for estrogen/ERα-induced breast cancer cell growth and tumorigenesis. Our data have uncovered a critical regulator of estrogen/ERα-induced enhancer coding gene activation and breast cancer cell potency, providing a potential therapeutic target of ER-positive breast cancers.
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Neoplasias de la Mama/enzimología , Proliferación Celular , Receptor alfa de Estrógeno/metabolismo , Histona Demetilasas con Dominio de Jumonji/metabolismo , Complejo Mediador/metabolismo , Proteína-Arginina N-Metiltransferasas/metabolismo , Activación Transcripcional , Animales , Sitios de Unión , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Estradiol/farmacología , Receptor alfa de Estrógeno/agonistas , Receptor alfa de Estrógeno/genética , Femenino , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Histona Demetilasas con Dominio de Jumonji/genética , Células MCF-7 , Complejo Mediador/genética , Ratones Endogámicos BALB C , Ratones Desnudos , Unión Proteica , Transporte de Proteínas , Proteína-Arginina N-Metiltransferasas/genética , Transducción de Señal , Activación Transcripcional/efectos de los fármacosRESUMEN
Heart failure and cardiac remodeling are both characterized by mitochondrial dysfunction. Healthy mitochondria are required for adequate contractile activity and appropriate regulation of cell survival. In the mammalian heart, enhancement of the mitochondrial unfolded protein response (UPRmt) is cardioprotective under pressure overload conditions. We explored the UPRmt and the underlying regulatory mechanism in terms of hypertension-induced cardiac remodeling and the cardioprotective effect of metformin. Male spontaneously hypertensive rats and angiotensin II-treated neonatal rat cardiomyocytes were used to induce cardiac hypertrophy. The results showed that hypertension induced the formation of aberrant mitochondria, characterized by a reduced mtDNA/nDNA ratio and swelling, as well as lower levels of mitochondrial complexes I to V and inhibition of the expression of one protein subunit of each of complexes I to IV. Such changes eventually enlarged cardiomyocytes and increased cardiac fibrosis. Metformin treatment increased the mtDNA/nDNA ratio and regulated the UPRmt, as indicated by increased expression of activating transcription factor 5, Lon protease 1, and heat shock protein 60, and decreased expression of C/EBP homologous protein. Thus, metformin improved mitochondrial ultrastructure and function in spontaneously hypertensive rats. In vitro analyses revealed that metformin reduced the high levels of angiotensin II-induced mitochondrial reactive oxygen species in such animals and stimulated nuclear translocation of heat shock factor 1 (HSF1). Moreover, HSF1 small-interfering RNA reduced the metformin-mediated improvements in mitochondrial morphology and the UPRmt by suppressing hypertrophic signals and cardiomyocyte apoptosis. These results suggest that HSF1/UPRmt signaling contributes to the beneficial effects of metformin. Metformin-mediated targeting of mitochondrial protein homeostasis and modulation of HSF1 levels have potential therapeutic implications in terms of cardiac remodeling.
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Factores de Transcripción del Choque Térmico , Metformina , Miocitos Cardíacos , Respuesta de Proteína Desplegada , Animales , Masculino , Ratas , Angiotensina II/farmacología , Cardiomegalia/metabolismo , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/patología , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Factores de Transcripción del Choque Térmico/efectos de los fármacos , Factores de Transcripción del Choque Térmico/metabolismo , Hipertensión/metabolismo , Hipertensión/tratamiento farmacológico , Metformina/farmacología , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Respuesta de Proteína Desplegada/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacosRESUMEN
The effector potential of NK cells is counterbalanced by their sensitivity to inhibition by "self" MHC class I molecules in a process called "education." In humans, interactions between inhibitory killer immunoglobulin-like receptors (KIR) and human MHC (HLA) mediate NK cell education. In HLA-B(∗)27:05(+) transgenic mice and in patients undergoing HLA-mismatched hematopoietic cell transplantation (HCT), NK cells derived from human CD34(+) stem cells were educated by HLA from both donor hematopoietic cells and host stromal cells. Furthermore, mature human KIR3DL1(+) NK cells gained reactivity after adoptive transfer to HLA-B(∗)27:05(+) mice or bone marrow chimeric mice where HLA-B(∗)27:05 was restricted to either the hematopoietic or stromal compartment. Silencing of HLA in primary NK cells diminished NK cell reactivity, while acquisition of HLA from neighboring cells increased NK cell reactivity. Altogether, these findings reveal roles for cell-extrinsic HLA in driving NK cell reactivity upward, and cell-intrinsic HLA in maintaining NK cell education.
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Autoantígenos/metabolismo , Trasplante de Células Madre de Sangre del Cordón Umbilical , Antígeno HLA-B27/metabolismo , Neoplasias Hematológicas/terapia , Células Asesinas Naturales/inmunología , Receptores KIR3DL1/metabolismo , Células del Estroma/inmunología , Animales , Antígenos CD34/metabolismo , Diferenciación Celular , Células Cultivadas , Quimerismo , Espacio Extracelular/metabolismo , Antígeno HLA-B27/genética , Neoplasias Hematológicas/inmunología , Humanos , Isoantígenos/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , ARN Interferente Pequeño/genéticaRESUMEN
USP25 encodes ubiquitin-specific proteases 25, a key member of deubiquitinating enzyme family and is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown etiology. Five heterozygous USP25 variants including two de novo and three co-segregated variants were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared to the East Asian population and all populations in the gnomAD database. The mean onset ages of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom except one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability. Usp25 was ubiquitously expressed in mouse brain with two peaks on embryonic days (E14âE16) and postnatal day 21, respectively. Similarly, USP25 expressed in fetus/early childhood stage with a second peak at approximately 12â20 years old in human brain, consistent with the seizure onset age at infancy and juvenile in the patients. To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knock-out mice, which showed increased seizure susceptibility compared to wild-type mice in pentylenetetrazol-induced seizure test. To explore the impact of USP25 variants, we employed multiple functional detections. In HEK293T cells, the severe phenotype associated variant (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed a stable truncated dimers with increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del increased neuronal excitability in mice brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating USP25 is potentially a predisposing gene for epilepsy. Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain.
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Adaptation to the environment and extraction of energy are essential for survival. Some species have found niches and specialized in using a particular source of energy, whereas others-including humans and several other mammals-have developed a high degree of flexibility1. A lot is known about the general metabolic fates of different substrates but we still lack a detailed mechanistic understanding of how cells adapt in their use of basic nutrients2. Here we show that the closely related fasting/starvation-induced forkhead transcription factors FOXK1 and FOXK2 induce aerobic glycolysis by upregulating the enzymatic machinery required for this (for example, hexokinase-2, phosphofructokinase, pyruvate kinase, and lactate dehydrogenase), while at the same time suppressing further oxidation of pyruvate in the mitochondria by increasing the activity of pyruvate dehydrogenase kinases 1 and 4. Together with suppression of the catalytic subunit of pyruvate dehydrogenase phosphatase 1 this leads to increased phosphorylation of the E1α regulatory subunit of the pyruvate dehydrogenase complex, which in turn inhibits further oxidation of pyruvate in the mitochondria-instead, pyruvate is reduced to lactate. Suppression of FOXK1 and FOXK2 induce the opposite phenotype. Both in vitro and in vivo experiments, including studies of primary human cells, show how FOXK1 and/or FOXK2 are likely to act as important regulators that reprogram cellular metabolism to induce aerobic glycolysis.
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Aerobiosis , Factores de Transcripción Forkhead/metabolismo , Glucólisis , Células 3T3 , Animales , Células Cultivadas , Femenino , Factores de Transcripción Forkhead/deficiencia , Factores de Transcripción Forkhead/genética , Humanos , Ácido Láctico/biosíntesis , Ácido Láctico/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/enzimología , Mitocondrias/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Oxidación-Reducción , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Piruvato Deshidrogenasa (Lipoamida)-Fosfatasa/metabolismo , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Complejo Piruvato Deshidrogenasa/química , Complejo Piruvato Deshidrogenasa/metabolismo , Ácido Pirúvico/metabolismoRESUMEN
BACKGROUND: IFIH1 variants have been reported to be associated with immune-related disorders with/without seizures. It is unknown whether IFIH1 variants are associated with common epilepsy without acquired causes and the mechanism underlying phenotypic variation remains elusive. METHODS: Trio-based whole-exome sequencing was performed on patients with febrile seizures or epilepsy with antecedent febrile seizures. Previously reported variants were systematically reviewed to investigate genotype-phenotype associations. RESULTS: Two de novo heterozygous and three biallelic missense variants were identified in five patients with generalised epilepsy with antecedent febrile seizures. The variants were predicted to be damaging by in silico tools and were associated with hydrogen bonding changes to neighbouring amino acids or decreased protein stability. Patients exhibited an early onset age and became seizure-free with favourable outcome. Further analysis revealed that de novo missense variants located in the Hel region resulted in seizures with multiple neurological abnormalities, while those in the pincer domain or C-terminal domain led to seizures with normal neurodevelopment, suggesting a sub-molecular effect. Biallelic missense variants, which were inherited from unaffected parents and presented low allele frequencies in general populations, were associated with seizures without neurological abnormalities. Truncation variants were related to refractory epilepsy and severe developmental delay, suggesting a genotype-phenotype correlation. IFIH1 is predominantly expressed in the neonatal stage and decreases dramatically in the adulthood, which is consistent with the early onset age and favourable outcome of the patients. CONCLUSIONS: IFIH1 variants are potentially associated with generalised epilepsy with antecedent febrile seizures. The sub-molecular implication and genotype-phenotype association help explain phenotype variations of IFIH1 variants.
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BACKGROUND: The ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and neuronal death. This study aims to explore the relationship between ZFHX3 variants and epilepsy. METHODS: Whole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A Drosophila Zfh2 knockdown model was used to validate the association between ZFHX3 and epilepsy. RESULTS: Compound heterozygous ZFHX3 variants were identified in eight unrelated cases. The burden of ZFHX3 variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. In Zfh2 knockdown flies, the incidence and duration of seizure-like behaviour were significantly greater than those in the controls. The Zfh2 knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent non-convulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated that ZFHX3 orthologous were highly expressed in the embryonic stage and decreased dramatically after birth. CONCLUSION: ZFHX3 is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness.
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Epilepsias Parciales , Proteínas de Homeodominio , Espasmos Infantiles , Animales , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Epilepsias Parciales/genética , Epilepsias Parciales/tratamiento farmacológico , Secuenciación del Exoma , Predisposición Genética a la Enfermedad , Proteínas de Homeodominio/genética , Mutación , Espasmos Infantiles/genética , DrosophilaRESUMEN
Jumonji C-domain-containing protein 6 (JMJD6), an iron (Fe2+) and α-ketoglutarate (α-KG)-dependent oxygenase, is expressed at high levels, correlated with poor prognosis, and considered as a therapeutic target in multiple cancer types. However, specific JMJD6 inhibitors that are potent in suppressing tumorigenesis have not been reported so far. We herein report that iJMJD6, a specific small-molecule inhibitor of JMJD6 with favorable physiochemical properties, inhibits the enzymatic activity of JMJD6 protein both in vitro and in cultured cells. iJMJD6 is effective in suppressing cell proliferation, migration, and invasion in multiple types of cancer cells in a JMJD6-dependent manner, while it exhibits minimal toxicity in normal cells. Mechanistically, iJMJD6 represses the expression of oncogenes, including Myc and CCND1, in accordance with JMJD6 function in promoting the transcription of these genes. iJMJD6 exhibits suitable pharmacokinetic properties and suppresses tumor growth in multiple cancer cell line- and patient-derived xenograft models safely. Furthermore, combination therapy with iJMJD6 and BET protein inhibitor (BETi) JQ1 or estrogen receptor antagonist fulvestrant exhibits synergistic effects in suppressing tumor growth. Taken together, we demonstrate that inhibition of JMJD6 enzymatic activity by using iJMJD6 is effective in suppressing oncogene expression and cancer development, providing a therapeutic avenue for treating cancers that are dependent on JMJD6 in the clinic.
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Antineoplásicos , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Neoplasias , Antineoplásicos/farmacología , Carcinogénesis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
BACKGROUND & AIMS: Natural killer (NK) cell-based anti-hepatocellular carcinoma (HCC) therapy is an increasingly attractive approach that warrants further study. Siglec-9 interacts with its ligand (Siglec-9L) and restrains NK cell functions, suggesting it is a potential therapeutic target. However, in situ Siglec-9/Siglec-9L interactions in HCC have not been reported, and a relevant interventional strategy is lacking. Herein, we aim to illustrate Siglec-9/Siglec-9L-mediated cell sociology and identify small-molecule inhibitors targeting Siglec-9 that could improve the efficacy of NK cell-based immunotherapy for HCC. METHODS: Multiplexed immunofluorescence staining was performed to analyze the expression pattern of Siglec-7, -9 and their ligands in HCC tissues. Then we conducted docking-based virtual screening combined with bio-layer interferometry assays to identify a potent small-molecule Siglec-9 inhibitor. The therapeutic potential was further evaluated in vitro and in hepatoma-bearing NCG mice. RESULTS: Siglec-9 expression, rather than Siglec-7, was markedly upregulated on tumor-infiltrating NK cells, which correlated significantly with reduced survival of patients with HCC. Moreover, the number of Siglec-9L+ cells neighboring Siglec-9+ NK cells was increased in HCC tissues and was also associated with tumor recurrence and reduced survival, further suggesting that Siglec-9/Siglec-9L interactions are a potential therapeutic target in HCC. In addition, we identified a small-molecule Siglec-9 inhibitor MTX-3937 which inhibited phosphorylation of Siglec-9 and downstream SHP1 and SHP2. Accordingly, MTX-3937 led to considerable improvement in NK cell function. Notably, MTX-3937 enhanced cytotoxicity of both human peripheral and tumor-infiltrating NK cells. Furthermore, transfer of MTX-3937-treated NK92 cells greatly suppressed the growth of hepatoma xenografts in NCG mice. CONCLUSIONS: Our study provides the rationale for HCC treatment by targeting Siglec-9 on NK cells and identifies a promising small-molecule inhibitor against Siglec-9 that enhances NK cell-mediated HCC surveillance. IMPACT AND IMPLICATIONS: Herein, we found that Siglec-9 expression is markedly upregulated on tumor-infiltrating natural killer (TINK) cells and correlates with reduced survival in patients with hepatocellular carcinoma (HCC). Moreover, the number of Siglec-9L+ cells neighboring Siglec-9+ NK cells was increased in HCC tissues and was also associated with tumor recurrence and reduced survival. More importantly, we identified a small-molecule inhibitor targeting Siglec-9 that augments NK cell functions, revealing a novel immunotherapy strategy for liver cancer that warrants further clinical investigation.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animales , Ratones , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Recurrencia Local de Neoplasia/metabolismo , Células Asesinas Naturales/patología , Inmunoterapia , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/metabolismo , Ligandos , PronósticoRESUMEN
BACKGROUNDS: There is little evidence on the safety, efficacy, and survival benefit of restarting immune checkpoint inhibitors (ICI) in patients with cancer after discontinuation due to immune-related adverse events (irAEs) or progressive disease (PD). Here, we performed a meta-analysis to elucidate the possible benefits of ICI rechallenge in patients with cancer. METHODS: Systematic searches were conducted using PubMed, Embase, and Cochrane Library databases. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and incidence of irAEs were the outcomes of interest. RESULTS: Thirty-six studies involving 2026 patients were analyzed. ICI rechallenge was associated with a lower incidence of all-grade (OR, 0.05; 95%CI, 0.02-0.13, Pâ <â .05) and high-grade irAEs (OR, 0.37; 95%CI, 0.21-0.64, Pâ <â .05) when compared with initial ICI treatment. Though no significant difference was observed between rechallenge and initial treatment regarding ORR (OR, 0.69; 95%CI, 0.39-1.20, Pâ =â .29) and DCR (OR, 0.85; 95%CI, 0.51-1.40, Pâ =â 0.52), patients receiving rechallenge had improved PFS (HR, 0.56; 95%CI, 0.43-0.73, Pâ <â .05) and OS (HR, 0.55; 95%CI, 0.43-0.72, Pâ <â .05) than those who discontinued ICI therapy permanently. Subgroup analysis revealed that for patients who stopped initial ICI treatment because of irAEs, rechallenge showed similar safety and efficacy with initial treatment, while for patients who discontinued ICI treatment due to PD, rechallenge caused a significant increase in the incidence of high-grade irAEs (OR, 4.97; 95%CI, 1.98-12.5, Pâ <â .05) and a decrease in ORR (OR, 0.48; 95%CI, 0.24-0.95, Pâ <â .05). CONCLUSION: ICI rechallenge is generally an active and feasible strategy that is associated with relative safety, similar efficacy, and improved survival outcomes. Rechallenge should be considered individually with circumspection, and randomized controlled trials are required to confirm these findings.
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PURPOSE: The significance of postmastectomy radiotherapy (PMRT) in breast cancer patients who initially have clinically node-positive (cN +) status but achieve downstaging to ypN0 following neoadjuvant chemotherapy (NAC) remains uncertain. This study aims to assess the impact of PMRT in this patient subset. METHODS: Patients were enrolled from West China Hospital, Sichuan University from 2008 to 2019. Overall survival (OS), Locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and breast cancer-specific survival (BCSS) were estimated using the Kaplan-Meier method and assessed with the log-rank test. The impact of PMRT was further analyzed by the Cox proportional hazards model. Propensity score matching (PSM) was performed to reduce the selection bias. RESULTS: Of the 333 eligible patients, 189 (56.8%) received PMRT, and 144 (43.2%) did not. At a median follow-up period of 71 months, the five-year LRFS, DMFS, BCSS, and OS rates were 99.1%, 93.4%, 96.4%, and 94.3% for the entire cohort, respectively. Additionally, the 5-year LRFS, DMFS, BCSS, and OS rates were 98.9%, 93.8%, 96.7%, and 94.5% with PMRT and 99.2%, 91.3%, 94.9%, and 92.0% without PMRT, respectively (all p-values not statistically significant). After multivariate analysis, PMRT was not a significant risk factor for any of the endpoints. When further stratified by stage, PMRT did not show any survival benefit for patients with stage II-III diseases. CONCLUSION: In the context of comprehensive treatments, PMRT might be exempted in ypN0 breast cancer patients. Further large-scale, randomized controlled studies are required to investigate the significance of PMRT in this patient subset.
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Neoplasias de la Mama , Mastectomía , Terapia Neoadyuvante , Estadificación de Neoplasias , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/radioterapia , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Adulto , Anciano , Estudios Retrospectivos , Radioterapia Adyuvante/métodos , Quimioterapia Adyuvante/métodos , Metástasis Linfática , Recurrencia Local de Neoplasia/patologíaRESUMEN
BACKGROUND: There is some evidence to suggest that there may be a link between body mass index (BMI) and the development of kidney stones, it remains unclear whether weight change was associated with the presence of kidney stone. AIMS: The objective of this study was to investigate the potential association between changes patterns in weight during adulthood and the incidence of kidney stone. METHODS: This study included 14472 participants aged 30-75 years, whose BMI was recorded at both baseline and 10 years prior to the survey. We categorized individuals into five weight change patterns: stable healthy, non-obesity to obesity, obesity to non-obesity, stable obesity, and maximum overweight. Odds ratios (OR) and 95% confidence intervals (CI) relating weight change to incident kidney stone were calculated using logistic regression models adjusting for covariates. The non-linear association between absolute weight change was investigated using the restricted cubic spline (RCS) regression. The supposed population attributable fraction (PAF) for the weight change patterns was calculated. RESULTS: After adjusting for all confounders, participants changing from non-obesity to obesity, obesity to non-obesity, and stable obesity had significantly higher risks of kidney stone than those with healthy weight during adulthood (OR = 1.59, 95% CI:1.18-2.13; OR = 1.78, 95% CI: 1.47-2.16; OR = 1.80, 95% CI: 1.48-2.19, respectively). A U-shaped association was observed, and the risk of kidney stone was lowest in participants with stable healthy BMI. If the population had maintained a healthy BMI, a 28.7% (95% CI: 18.6%-37.5%) lower incidence of kidney stones was observed. CONCLUSIONS: This study found that changes in weight during adulthood are linked to the risk of developing kidney stones. Maintaining healthy weight during adulthood is important for reducing the risk of developing kidney stones.
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Cálculos Renales , Obesidad , Humanos , Adulto , Incidencia , Factores de Riesgo , Obesidad/complicaciones , Obesidad/epidemiología , Sobrepeso/epidemiología , Índice de Masa Corporal , Cálculos Renales/epidemiología , Cálculos Renales/etiologíaRESUMEN
BACKGROUND: The effects of gut microbiota and metabolites on the responses to immune checkpoint inhibitors (ICIs) in advanced epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) have been studied. However, their effects on EGFR-mutated (EGFR +) NSCLC remain unknown. METHODS: We prospectively recorded the clinicopathological characteristics of patients with advanced EGFR + NSCLC and assessed potential associations between the use of antibiotics or probiotics and immunotherapy efficacy. Fecal samples were collected at baseline, early on-treatment, response and progression status and were subjected to metagenomic next-generation sequencing and ultra-high-performance liquid chromatography-mass spectrometry analyses to assess the effects of gut microbiota and metabolites on immunotherapy efficacy. RESULTS: The clinical data of 74 advanced EGFR + NSCLC patients were complete and 18 patients' fecal samples were dynamically collected. Patients that used antibiotics had shorter progression-free survival (PFS) (mPFS, 4.8 vs. 6.7 months; P = 0.037); probiotics had no impact on PFS. Two dynamic types of gut microbiota during immunotherapy were identified: one type showed the lowest relative abundance at the response time point, whereas the other type showed the highest abundance at the response time point. Metabolomics revealed significant differences in metabolites distribution between responders and non-responders. Deoxycholic acid, glycerol, and quinolinic acid were enriched in responders, whereas L-citrulline was enriched in non-responders. There was a significant correlation between gut microbiota and metabolites. CONCLUSIONS: The use of antibiotics weakens immunotherapy efficacy in patients with advanced EGFR + NSCLC. The distribution characteristics and dynamic changes of gut microbiota and metabolites may indicate the efficacy of immunotherapy in advanced EGFR + NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Microbioma Gastrointestinal , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/tratamiento farmacológico , Inmunoterapia , Receptores ErbB/genética , Antibacterianos/uso terapéuticoRESUMEN
Lupus erythematosus (LE) is a heterogeneous, antibody-mediated autoimmune disease. Isolate discoid LE (IDLE) and systematic LE (SLE) are traditionally regarded as the two ends of the spectrum, ranging from skin-limited damage to life-threatening multi-organ involvement. Both belong to LE, but IDLE and SLE differ in appearance of skin lesions, autoantibody panels, pathological changes, treatments, and immunopathogenesis. Is discoid lupus truly a form of LE or is it a completely separate entity? This question has not been fully elucidated. We compared the clinical data of IDLE and SLE from our center, applied multi-omics technology, such as immune repertoire sequencing, high-resolution HLA alleles sequencing and multi-spectrum pathological system to explore cellular and molecular phenotypes in skin and peripheral blood from LE patients. Based on the data from 136 LE patients from 8 hospitals in China, we observed higher damage scores and fewer LE specific autoantibodies in IDLE than SLE patients, more uCDR3 sharing between PBMCs and skin lesion from SLE than IDLE patients, elevated diversity of V-J recombination in IDLE skin lesion and SLE PBMCs, increased SHM frequency and class switch ratio in IDLE skin lesion, decreased SHM frequency but increased class switch ratio in SLE PBMCs, HLA-DRB1*03:01:01:01, HLA-B*58:01:01:01, HLA-C*03:02:02:01, and HLA-DQB1*02:01:01:01 positively associated with SLE patients, and expanded Tfh-like cells with ectopic germinal center structures in IDLE skin lesions. These findings suggest a significant difference in the immunopathogenesis of skin lesions between SLE and IDLE patients. SLE is a B cell-predominate systemic immune disorder, while IDLE appears limited to the skin. Our findings provide novel insights into the pathogenesis of IDLE and other types of LE, which may direct more accurate diagnosis and novel therapeutic strategies.
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Autoanticuerpos , Lupus Eritematoso Discoide , Lupus Eritematoso Sistémico , Piel , Humanos , Lupus Eritematoso Discoide/inmunología , Lupus Eritematoso Discoide/patología , Femenino , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/diagnóstico , Masculino , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Piel/patología , Piel/inmunología , Piel/metabolismo , Adulto , Persona de Mediana Edad , Alelos , Antígenos HLA/genética , Antígenos HLA/inmunología , Adulto Joven , MultiómicaRESUMEN
CCDC88C gene, which encodes coiled-coil domain containing 88C, is essential for cell communication during neural development. Variants in the CCDC88C caused congenital hydrocephalus, some accompanied by seizures. In patients with epilepsy without acquired etiologies, we performed whole-exome sequencing (trio-based). Two de novo and two biallelic CCDC88C variants were identified in four cases with focal (partial) epilepsy. These variants did not present or had low frequencies in the gnomAD populations and were predicted to be damaging by multiple computational algorithms. Patients with de novo variants presented with adult-onset epilepsy, whereas patients with biallelic variants displayed infant-onset epilepsy. They all responded well to anti-seizure medications and were seizure-free. Further analysis showed that de novo variants were located at crucial domains, whereas one paired biallelic variants were located outside the crucial domains, and the other paired variant had a non-classical splicing and a variant located at crucial domain, suggesting a sub-molecular effect. CCDC88C variants associated with congenital hydrocephalus were all truncated, whereas epilepsy-associated variants were mainly missense, the proportion of which was significantly higher than that of congenital hydrocephalus-associated variants. CCDC88C is potentially associated with focal epilepsy with favorable outcome. The underlying mechanisms of phenotypic variation may correlation between genotype and phenotype.
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Epilepsias Parciales , Epilepsia , Hidrocefalia , Lactante , Adulto , Humanos , Epilepsias Parciales/genética , Epilepsia/genética , Hidrocefalia/genética , Genotipo , Estudios de Asociación Genética , Proteínas de Microfilamentos/genética , Péptidos y Proteínas de Señalización Intracelular/genéticaRESUMEN
As a chronic relapsing disease, psoriasis is characterized by widespread skin lesions. The Psoriasis Area and Severity Index (PASI) is the most frequently utilized tool for evaluating the severity of psoriasis in clinical practice. Nevertheless, long-term monitoring and precise evaluation pose difficulties for dermatologists and patients, which is time-consuming, subjective and prone to evaluation bias. To develop a deep learning system with high accuracy and speed to assist PASI evaluation, we collected 2657 high-quality images from 1486 psoriasis patients, and images were segmented and annotated. Then, we utilized the YOLO-v4 algorithm to establish the model via four modules, we also conducted a human-computer comparison through quadratic weighted Kappa (QWK) coefficients and intra-class correlation coefficients (ICC). The YOLO-v4 algorithm was selected for model training and optimization compared with the YOLOv3, RetinaNet, EfficientDet and Faster_rcnn. The model evaluation results of mean average precision (mAP) for various lesion features were as follows: erythema, mAP = 0.903; scale, mAP = 0.908; and induration, mAP = 0.882. In addition, the results of human-computer comparison also showed a median consistency for the skin lesion severity and an excellent consistency for the area and PASI score. Finally, an intelligent PASI app was established for remote disease assessment and course management, with a pleasurable agreement with dermatologists. Taken together, we proposed an intelligent PASI app based on the image YOLO-v4 algorithm that can assist dermatologists in long-term and objective PASI scoring, shedding light on similar clinical assessments that can be assisted by computers in a time-saving and objective manner.
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Algoritmos , Aprendizaje Profundo , Psoriasis , Índice de Severidad de la Enfermedad , Psoriasis/patología , Humanos , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
BACKGROUND: This study aimed to identify metabolic subtypes in ESCA, explore their relationship with immune landscapes, and establish a metabolic index for accurate prognosis assessment. METHODS: Clinical, SNP, and RNA-seq data were collected from 80 ESCA patients from the TCGA database and RNA-seq data from the GSE19417 dataset. Metabolic genes associated with overall survival (OS) and progression-free survival (PFS) were selected, and k-means clustering was performed. Immune-related pathways, immune infiltration, and response to immunotherapy were predicted using bioinformatic algorithms. Weighted gene co-expression network analysis (WGCNA) was conducted to identify metabolic genes associated with co-expression modules. Lastly, cell culture and functional analysis were performed using patient tissue samples and ESCA cell lines to verify the identified genes and their roles. RESULTS: Molecular subtypes were identified based on the expression profiles of metabolic genes, and univariate survival analysis revealed 163 metabolic genes associated with ESCA prognosis. Consensus clustering analysis classified ESCA samples into three distinct subtypes, with MC1 showing the poorest prognosis and MC3 having the best prognosis. The subtypes also exhibited significant differences in immune cell infiltration, with MC3 showing the highest scores. Additionally, the MC3 subtype demonstrated the poorest response to immunotherapy, while the MC1 subtype was the most sensitive. WGCNA analysis identified gene modules associated with the metabolic index, with SLC5A1, NT5DC4, and MTHFD2 emerging as prognostic markers. Gene and protein expression analysis validated the upregulation of MTHFD2 in ESCA. MTHFD2 promotes the progression of ESCA and may be a potential therapeutic target for ESCA. CONCLUSION: The established metabolic index and identified metabolic genes offer potential for prognostic assessment and personalized therapeutic interventions for ESCA, underscoring the importance of targeting metabolism-immune interactions in ESCA. MTHFD2 promotes the progression of ESCA and may be a potential therapeutic target for ESCA.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Pronóstico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/terapia , Inmunoterapia , Regulación hacia ArribaRESUMEN
BACKGROUND: Both functional brain imaging studies and autopsy reports have indicated the presence of synaptic loss in the brains of depressed patients. The activated microglia may dysfunctionally engulf neuronal synapses, leading to synaptic loss and behavioral impairments in depression. However, the mechanisms of microglial-synaptic interaction under depressive conditions remain unclear. METHODS: We utilized lipopolysaccharide (LPS) to induce a mouse model of depression, examining the effects of LPS on behaviors, synapses, microglia, microglial phagocytosis of synapses, and the C1q/C3-CR3 complement signaling pathway. Additionally, a C1q neutralizing antibody was employed to inhibit the C1q/C3-CR3 signaling pathway and assess its impact on microglial phagocytosis of synapses and behaviors in the mice. RESULTS: LPS administration resulted in depressive and anxiety-like behaviors, synaptic loss, and abnormal microglial phagocytosis of synapses in the hippocampal dentate gyrus (DG) of mice. We found that the C1q/C3-CR3 signaling pathway plays a crucial role in this abnormal microglial activity. Treatment with the C1q neutralizing antibody moderated the C1q/C3-CR3 pathway, leading to a decrease in abnormal microglial phagocytosis, reduced synaptic loss, and improved behavioral impairments in the mice. CONCLUSIONS: The study suggests that the C1q/C3-CR3 complement signaling pathway, which mediates abnormal microglial phagocytosis of synapses, presents a novel potential therapeutic target for depression treatment.
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Complemento C1q , Complemento C3 , Depresión , Modelos Animales de Enfermedad , Microglía , Fagocitosis , Transducción de Señal , Sinapsis , Animales , Complemento C1q/metabolismo , Microglía/metabolismo , Sinapsis/metabolismo , Ratones , Transducción de Señal/fisiología , Depresión/metabolismo , Fagocitosis/fisiología , Complemento C3/metabolismo , Masculino , Lipopolisacáridos/farmacología , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Xeligekimab (GR1501) is a fully human monoclonal antibody that selectively neutralizes interleukin (IL)-17A and has shown potential efficacy in treating moderate-to-severe psoriasis in preliminary trials. OBJECTIVES: To evaluate the efficacy and safety of xeligekimab in Chinese patients with moderate-to-severe psoriasis. METHODS: A total of 420 Chinese patients were randomized to 200â mg xeligekimab every 2 weeks (n = 281) or placebo (n = 139) for the first 12 weeks, followed by an extension of the treatment schedule to xeligekimab every 4 weeks for a further 40 weeks. Efficacy was assessed by evaluating achievement of Physician Global Assessment (PGA) 0/1 and 75%, 90% and 100% improvement in Psoriasis Area and Severity Index (PASI 75, PASI 90 and PASI 100, respectively). The safety profile was also evaluated. RESULTS: At week 12, PASI 75, PASI 90 and PASI 100 were achieved in 90.7%, 74.4% and 30.2% of patients in the xeligekimab group vs. 8.6%, 1.4% and 0% of patients in the placebo group, respectively. PGA 0/1 was achieved in 74.4% patients in the xeligekimab group and 3.6% of patients in the placebo group. PASI 75 and PGA 0/1 were maintained until week 52. No unexpected adverse events were recorded. CONCLUSIONS: Xeligekimab showed high efficacy and was well tolerated in Chinese patients with moderate-to-severe plaque psoriasis.
Psoriasis is a skin disease characterized by scaly and raised patches of skin on any part of the body. The condition can be caused by a combination of how a person's immune system works, their genes and their environment. A cytokine is a substance secreted by certain cells of the immune system that have an effect on other cells. One such cytokine, called IL-17A, has been associated with different inflammatory diseases, including psoriasis. We conducted a large trial in Chinese people with moderate-to-severe psoriasis to look at the efficacy (ability to produce the intended result) and safety of a medicine called xeligekimab (known as a 'monoclonal antibody') which works by targeting IL-17A. We randomly assigned 420 Chinese patients to receive 200â mg of xeligekimab every 2 weeks or a 'placebo' (no active medicine) for the first 12 weeks. We extended the treatment schedule of xeligekimab to every 4 weeks for a further 40 weeks. To assess how the medicine worked, we measured people's psoriasis symptoms and severity. To assess how safe the medicine was, we looked at the side-effects (or 'adverse events'). The results of this trial showed that xeligekimab improved people's psoriasis and itching starting at week 4 of receiving treatment, and more than 60% of people achieved improvement or remission by week 6, which was sustained up to week 52. The safety of xeligekimab was similar to another medicine classed as a monoclonal antibody (called secukinumab) and there were no new or unexpected adverse events reported. Overall, our findings suggest that xeligekimab is a safe and effective medicine for the treatment of psoriasis in Chinese people.