RESUMEN
Interorganelle contacts facilitate material exchanges and sustain the structural and functional integrity of organelles. Lipid droplets (LDs) of adipocytes are responsible for energy storage and mobilization responding to body needs. LD biogenesis defects compromise the lipid-storing capacity of adipocytes, resulting in ectopic lipid deposition and metabolic disorders, yet how the uniquely large LDs in adipocytes attain structural and functional maturation is incompletely understood. Here we show that the mammalian adipocyte-specific protein CLSTN3B is crucial for adipocyte LD maturation. CLSTN3B employs an arginine-rich segment to promote extensive contact and hemifusion-like structure formation between the endoplasmic reticulum (ER) and LD, allowing ER-to-LD phospholipid diffusion during LD expansion. CLSTN3B ablation results in reduced LD surface phospholipid density, increased turnover of LD-surface proteins, and impaired LD functions. Our results establish the central role of CLSTN3B in the adipocyte-specific LD maturation pathway that enhances lipid storage and maintenance of metabolic health under caloric overload in mice of both sexes.
Asunto(s)
Adipocitos , Retículo Endoplásmico , Gotas Lipídicas , Metabolismo de los Lípidos , Animales , Gotas Lipídicas/metabolismo , Adipocitos/metabolismo , Ratones , Retículo Endoplásmico/metabolismo , Masculino , Femenino , Ratones Endogámicos C57BL , Ratones Noqueados , Fosfolípidos/metabolismo , Células 3T3-L1 , Proteínas de la Membrana/metabolismoRESUMEN
High-grade serous cancer is the most common type of ovarian cancer and is usually diagnosed at advanced stages with high mortality due to recurrence and eventual resistance to standard platinum therapy. The aim of this study was to compare two-dimensional (2D) versus tridimensional (3D) cell culture as a preclinical model of response to carboplatin, paclitaxel and niraparib using PEO1, PEO4 and PEO6 cell lines, which were generated from the same patient along disease progression. Morphologically, cells formed flat adherent layers versus spheroidal structures with different compaction patterns in 2D and 3D respectively. In 2D, apoptosis was rare whereas in 3D cells formed a multilayered structure with an outer layer of live proliferating cells and an inner core of apoptotic cells. Furthermore, a differential capacity to produce ATP was observed among the cell lines in 3D but not in 2D. While response to carboplatin, paclitaxel and niraparib in both settings followed a similar trend, a lower sensitivity was observed in 3D with respect to 2D. Overall, 3D cell culture is likely more reflective of the in vivo cellular tumor behavior and more suitable of therapeutic evaluation given its added complexity absent in 2D.
RESUMEN
Uterine leiomyosarcoma (LMS) represents a rare yet highly aggressive tumor, comprising approximately 1% of uterine malignancies. First-line regimens involving doxorubicin or gemcitabine and docetaxel demonstrate modest response rates. Notably, the combination of doxorubicin plus trabectedin has emerged as a preferred first-line option following the LMS-04 study, showing superior progression-free survival compared to doxorubicin alone. Second-line therapy for recurrent LMS poses greater challenges, with single-agent treatments exhibiting limited efficacy. Herein, we present a case of a 65-year-old woman with stage 1B uterine leiomyosarcoma, previously treated with surgical resection and adjuvant gemcitabine/docetaxel, due to surgical morcellation. Despite initially achieving disease-free status, she experienced a first recurrence 5 years later, treated with surgery and radiation, and a second recurrence 4 years after, necessitating second-line therapy with doxorubicin and trabectedin. The patient exhibited a remarkable response to this regimen, achieving partial response after 6 cycles of doxorubicin and trabectedin chemotherapy. She maintained stable disease over 13 cycles of maintenance trabectedin and 6 months off treatment, for a total of 16 months of progression-free survival. This case underscores the potential efficacy of combination chemotherapy with doxorubicin and trabectedin as a second-line treatment option for recurrent uterine leiomyosarcoma.
RESUMEN
Prostate cancer presents as an immunologically "cold" malignancy, characterized by a lack of response to immunotherapy in the majority of patients. The dysfunction of prostate tumor metabolism is recognized as a critical factor in immune evasion, resulting in reduced effectiveness of immunotherapeutic interventions. Despite this awareness, the precise molecular mechanisms underpinning metabolic dysregulation in prostate cancer and its intricate relationship with immune evasion remain incompletely elucidated. In this study, we introduce the multi-drug resistance protein ABCC4/MRP4 as a key player prominently expressed in prostate cancer, exerting a pivotal role in suppressing the activity of intratumoral CD8+ T cells. Depletion of ABCC4 in prostate cancer cells halts the release of prostaglandin E2 (PGE2), a molecule that diminishes the population of CD8+ T cells and curtails their cytotoxic capabilities. Conversely, constraining the activation of PGE2 signaling in CD8+ T cells effectively improved the efficacy of prostate cancer treatment with PD-1 blockade. During this process, downregulation of the JAK1-STAT3 pathway and depolarization of mitochondria emerge as crucial factors contributing to T cell anergy. Collectively, our research identifies the ABCC4-PGE2 axis as a promising target for reversing dysfunction within tumor-infiltrating lymphocytes (TILs) and augmenting the suboptimal responsiveness to immunotherapy in prostate cancer.
Asunto(s)
Linfocitos T CD8-positivos , Dinoprostona , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Neoplasias de la Próstata , Masculino , Neoplasias de la Próstata/metabolismo , Linfocitos T CD8-positivos/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Dinoprostona/metabolismo , Humanos , Receptor de Muerte Celular Programada 1/metabolismo , Línea Celular Tumoral , Animales , RatonesRESUMEN
Background: Multiparametric magnetic resonance imaging (mpMRI) is a commonly used method to diagnose pelvic lymph node metastasis (PLNM) in prostate cancer (PCa) patients, but there are few comparative studies on mpMRI and 68Ga-prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) in locally advanced PCa (LAPC) patients. Therefore, we designed a retrospective study to compare the diagnostic value of 68Ga-PSMA PET/CT and mpMRI for PLNM of LAPC. Methods: A retrospective study was performed on 50 patients with LAPC who underwent radical prostatectomy (RP) in Tongji Hospital from 2021 to 2023. All patients underwent PET/CT and mpMRI examination, and were diagnosed as LAPC before surgery, followed by robot-assisted laparoscopic prostatectomy or laparoscopic RP and extended pelvic lymph node dissection (ePLND). Routine postoperative pathological examination was performed. According to the results, the sensitivity, specificity, positive predictive value, and negative predictive value of 68Ga-PSMA PET/CT and mpMRI for the diagnosis of PLNM of LAPC were compared. Results: Among the 50 patients, the mean age was 65.5±10.3 years, the preoperative total serum prostate-specific antigen (PSA) was 30.7±12.3 ng/mL, and the Gleason score was 7 [7, 8]. The difference in diagnostic efficacy between 68Ga-PSMA PET/CT and mpMRI in the preoperative diagnosis of PLNM of PCa was determined by postoperative pathological results. Based on the number of patients who developed PLNM, the sensitivity, specificity, positive predictive value, and negative predictive value of 68Ga-PSMA PET/CT were as follows: 93.75%, 100.00%, 100.00%, 97.14%, and 68.75%, 97.06%, 91.67%, 86.84% for mpMRI, respectively. Based on the number of pelvic metastatic lymph nodes, the sensitivity, specificity, positive predictive value, and negative predictive value of 68Ga-PSMA PET/CT were 95.24%, 100.00%, 100.00%, 99.48%, and 65.08%, 99.13%, 89.13%, 96.30% for mpMRI, respectively. It turned out that PET/CT was more sensitive than mpMRI in detecting PLNM of PCa, and the difference was statistically significant. Conclusions: 68Ga-PSMA PET/CT is more sensitive than mpMRI in the detection of PLNM in patients with LAPC. It is a promising method in the diagnosis and preoperative assessment of PLNM in LAPC.
RESUMEN
OBJECTIVE: Serological and molecular biology methods were used to identify the blood type of a patient with forward and reverse ABO typing inconsistency, and to explore the genetic characteristics of this blood type. METHODS: The ABO phenotype of the proband was identified by tube method, and the ABO blood group genotype of the proband and her parents was determined by fluorescent PCR. The 7 exons of the ABO gene were directly sequenced and analyzed. RESULTS: According to preliminary serological identification, the ABO phenotype of this patient was Bel subtype. Genotyping tests showed that the ABO genotype of the proband and her father was B/O1 , and her mother was O1/O1. Sequencing of exons revealed novel heterozygous variations in exon 1: c.16_17delinsTGTTGCA. CONCLUSION: The Novel variations in exon 1 led to Bel subtype in the ABO blood group of the proband, and these variations are heritable.
Asunto(s)
Sistema del Grupo Sanguíneo ABO , Exones , Genotipo , Humanos , Sistema del Grupo Sanguíneo ABO/genética , Femenino , Tipificación y Pruebas Cruzadas Sanguíneas , Fenotipo , Variación Genética , HeterocigotoRESUMEN
Constipation is a common gastrointestinal disorder characterized by infrequent bowel movements and difficulty in passing stools. It can significantly affect an individual's quality of life and overall well-being. Understanding the causes of constipation is important for its effective management and treatment. In this paper, we have reviewed the primary causes of constipation or functional constipation. Primary constipation is a bowel disorder associated with colonic or anorectal sensorimotor or neuromuscular dysfunction. As per the literature, it is multifactorial and involves factors such as decreased interstitial cells of Cajal, altered colonic motility, enteric nervous system dysfunction, intestinal flora disturbances, and psychological influences. Clinical symptoms include difficulty in defecation, decreased frequency of defecation, or a feeling of incomplete evacuation. A comprehensive evaluation and management of constipation require an interdisciplinary approach incorporating dietary modifications, lifestyle changes, pharmacotherapy, and psychological interventions. Further research is imperative to explain the intricate mechanisms underlying constipation and develop targeted therapies for improved patient outcomes.
RESUMEN
PURPOSES: To explore the characteristics of PSMA PET/CT and FDG PET/CT images in prostatic ductal adenocarcinoma (DA) patients. METHODS: We retrospectively enrolled prostatic DA patients with PET/CT scans at Tongji Hospital from 2018 to 2022. Patients with prostatic acinar adenocarcinoma (AA) and benign pathology (BP) were enrolled by 1:1 matching. Differences in the uptake of primary and metastatic foci on PET among the groups were analyzed. RESULTS: A total of 42 patients were enrolled: 14 in each group. In primary foci, the mean PSMA uptake in the DA group was lower than that in the AA group (14.2 ± 9.6 vs. 27.1 ± 14.3, Pâ¯=â¯0.009) and greater than that in the BP group (14.2 ± 9.6 vs. 4.7 ± 1.3, Pâ¯=â¯0.003). The AUCs of the DA-AA ROC curve and DA-BP ROC curve were 0.781 and 0.872, respectively. The median PSMA uptake of metastatic lymph nodes in the DA group was lower than that in the AA group (5.6 vs. 14.2, Pâ¯=â¯0.033), with no significant difference in metastatic bone lesions (9.5 vs 19.1, Pâ¯=â¯0.485). No significant difference was found in the FDG uptake of primary and metastatic foci between the DA and AA groups (P > 0.05). CONCLUSION: Prostatic DA has greater PSMA uptake than BP diseases, but lower uptake in both primary foci and metastatic lymph nodes than AA on PSMA PET/CT, aiding in the differential diagnosis of DA, AA and BP diseases. Clinicians should combine traditional imaging with PSMA PET/CT to avoid underestimating the clinical stage of DA patients.
RESUMEN
Hybrid plants are found extensively in the wild, and they often demonstrate superior performance of complex traits over their parents and other selfing plants. This phenomenon, known as heterosis, has been extensively applied in plant breeding for decades. However, the process of decoding hybrid plant genomes has seriously lagged due to the challenges associated with genome assembly and the lack of appropriate methodologies for their subsequent representation and analysis. Here, we present the assembly and analysis of 2 hybrids, an intraspecific hybrid between 2 maize (Zea mays ssp. mays) inbred lines and an interspecific hybrid between maize and its wild relative teosinte (Z. mays ssp. parviglumis), utilizing a combination of PacBio High Fidelity sequencing and chromatin conformation capture sequencing data. The haplotypic assemblies are well phased at chromosomal scale, successfully resolving the complex loci with extensive parental structural variations (SVs). By integrating into a biparental genome graph, the haplotypic assemblies can facilitate downstream short-read-based SV calling and allele-specific gene expression analysis, demonstrating outstanding advantages over a single linear genome. Our work offers a comprehensive workflow that aims to facilitate the decoding of numerous hybrid plant genomes, particularly those with unknown or inaccessible parentage, thereby enhancing our understanding of genome evolution and heterosis.
Asunto(s)
Genoma de Planta , Hibridación Genética , Zea mays , Genoma de Planta/genética , Zea mays/genética , Vigor Híbrido/genética , Fitomejoramiento/métodosRESUMEN
KEY MESSAGE: The exploration and dissection of a set of QTLs and candidate genes for gray leaf spot disease resistance using two fully assembled parental genomes may help expedite maize resistance breeding. The fungal disease of maize known as gray leaf spot (GLS), caused by Cercospora zeae-maydis and Cercospora zeina, is a significant concern in China, Southern Africa, and the USA. Resistance to GLS is governed by multiple genes with an additive effect and is influenced by both genotype and environment. The most effective way to reduce the cost of production is to develop resistant hybrids. In this study, we utilized the IBM Syn 10 Doubled Haploid (IBM Syn10 DH) population to identify quantitative trait loci (QTLs) associated with resistance to gray leaf spot (GLS) in multiple locations. Analysis of seven distinct environments revealed a total of 58 QTLs, 49 of which formed 12 discrete clusters distributed across chromosomes 1, 2, 3, 4, 8 and 10. By comparing these findings with published research, we identified colocalized QTLs or GWAS loci within eleven clustering intervals. By integrating transcriptome data with genomic structural variations between parental individuals, we identified a total of 110 genes that exhibit both robust disparities in gene expression and structural alterations. Further analysis revealed 19 potential candidate genes encoding conserved resistance gene domains, including putative leucine-rich repeat receptors, NLP transcription factors, fucosyltransferases, and putative xyloglucan galactosyltransferases. Our results provide a valuable resource and linked loci for GLS marker resistance selection breeding in maize.
Asunto(s)
Cercospora , Mapeo Cromosómico , Resistencia a la Enfermedad , Enfermedades de las Plantas , Sitios de Carácter Cuantitativo , Zea mays , Zea mays/genética , Zea mays/microbiología , Resistencia a la Enfermedad/genética , Enfermedades de las Plantas/genética , Enfermedades de las Plantas/microbiología , Cercospora/genética , Fitomejoramiento , Fenotipo , Haploidia , Genotipo , Genes de PlantasAsunto(s)
Neoplasias Ováricas , Tromboflebitis , Humanos , Femenino , Neoplasias Ováricas/patología , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/cirugía , Neoplasias Ováricas/diagnóstico por imagen , Tromboflebitis/etiología , Tromboflebitis/diagnóstico , Tromboflebitis/diagnóstico por imagen , Persona de Mediana EdadRESUMEN
To understand the status of sedentary behaviour in elderly patients after total knee arthroplasty and analyse its influencing factors so as to provide a reference for developing targeted interventions. Conveniently selected elderly patients undergoing total knee arthroplasty (> 6 months) in a tertiary hospital in Jiangsu Province were investigated using a general information questionnaire, the Charlson Comorbidity Index, patients' self-reported sedentary behaviour information, the WOMAC Score, The Groningen Orthopaedic Social Support Scale, and Lee's Fatigue. The median daily sedentary time was 5.5 h (4.5 h, 6.625 h) in 166 elderly patients after total knee arthroplasty, of whom 82 (49.40%) showed sedentary behaviour (≥ 6 h per day). Logistic regression analysis showed that being retired/unemployed (OR = 8.550, 95% CI 1.732-42.207, P = 0.0084), having a CCI score ≥ 3 (OR = 9.018, 95% CI 1.288-63.119, P < 0.0001), having high WOMAC scores (OR = 1.783, 95% CI 1.419-2.238, P < 0.0001), having a high social support score (OR = 1.155, 95% CI 1.031-1.294, P = 0.0130), and having a fatigue score ≥ 5 (OR = 4.848, 95% CI 1.084-21.682, P = 0.0389) made patients more likely to be sedentary. The sedentary time of elderly patients after total knee arthroplasty is long, and sedentary behaviour is common among them. Healthcare professionals should develop targeted sedentary behaviour interventions based on the influencing factors of sedentary behaviour in order to reduce the occurrence of sedentary behaviour in elderly patients after total knee arthroplasty.
Asunto(s)
Artroplastia de Reemplazo de Rodilla , Conducta Sedentaria , Humanos , Masculino , Femenino , Anciano , Encuestas y Cuestionarios , Anciano de 80 o más Años , Persona de Mediana Edad , Factores de Riesgo , Apoyo SocialRESUMEN
BACKGROUND: Maintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, has been shown to extend progression-free survival in patients with newly diagnosed advanced ovarian cancer who responded to first-line platinum-based chemotherapy, regardless of biomarker status. However, there are limited data on niraparib's efficacy and safety in the neoadjuvant setting. The objective of Cohort C of the OPAL trial (OPAL-C) is to evaluate the efficacy, safety, and tolerability of neoadjuvant niraparib treatment compared with neoadjuvant platinum-taxane doublet chemotherapy in patients with newly diagnosed stage III/IV ovarian cancer with confirmed homologous recombination-deficient tumors. METHODS: OPAL is an ongoing global, multicenter, randomized, open-label, phase 2 trial. In OPAL-C, patients will be randomized 1:1 to receive three 21-day cycles of either neoadjuvant niraparib or platinum-taxane doublet neoadjuvant chemotherapy per standard of care. Patients with a complete or partial response per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) will then undergo interval debulking surgery; patients with stable disease may proceed to interval debulking surgery or alternative therapy at the investigator's discretion. Patients with disease progression will exit the study treatment and proceed to alternative therapy at the investigator's discretion. After interval debulking surgery, all patients will receive up to three 21-day cycles of platinum-taxane doublet chemotherapy followed by niraparib maintenance therapy for up to 36 months. Adult patients with newly diagnosed stage III/IV ovarian cancer eligible to receive neoadjuvant platinum-taxane doublet chemotherapy followed by interval debulking surgery may be enrolled. Patients must have tumors that are homologous recombination-deficient. The primary endpoint is the pre-interval debulking surgery unconfirmed overall response rate, defined as the investigator-assessed percentage of patients with unconfirmed complete or partial response on study treatment before interval debulking surgery per RECIST v1.1. DISCUSSION: OPAL-C explores the use of niraparib in the neoadjuvant setting as an alternative to neoadjuvant platinum-taxane doublet chemotherapy to improve postsurgical residual disease outcomes for patients with ovarian cancer with homologous recombination-deficient tumors. Positive findings from this approach could significantly impact preoperative ovarian cancer therapy, particularly for patients who are ineligible for primary debulking surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT03574779. Registered on February 28, 2022.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Indazoles , Terapia Neoadyuvante , Estadificación de Neoplasias , Neoplasias Ováricas , Piperidinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Terapia Neoadyuvante/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Piperidinas/efectos adversos , Piperidinas/administración & dosificación , Piperidinas/uso terapéutico , Indazoles/efectos adversos , Indazoles/uso terapéutico , Indazoles/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Supervivencia sin Progresión , Ensayos Clínicos Fase II como Asunto , Recombinación Homóloga , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Hidrocarburos Aromáticos con Puentes/efectos adversos , Piperazinas/efectos adversos , Piperazinas/administración & dosificación , Piperazinas/uso terapéutico , Factores de TiempoRESUMEN
A scheme is proposed to achieve significantly enhanced quantum estimation of optorotational-coupling (ORC) strength by coupling a driven auxiliary cavity to a Laguerre-Gaussian (L-G) rotational cavity, where the ORC originates from the exchange of orbital angular momentum between a L-G light and rotational mirror. The results indicate that, by appropriately designing the auxiliary-cavity mechanism, the estimation error of the ORC parameter is significantly reduced, and revealing the estimation precision has a much stronger thermal noise and dissipation robustness in comparison with the unassisted case. Our study paves the way toward achieving high-precision quantum sensors.
RESUMEN
Novel components in the noncanonical Hippo pathway that mediate the growth, metastasis, and drug resistance of breast cancer (BC) cells need to be identified. Here, we showed that expression of SAM and SH3 domain-containing protein 1 (SASH1) is negatively correlated with expression of mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) in a subpopulation of patients with luminal-subtype BC. Downregulated SASH1 and upregulated MAP4K4 synergistically regulated the proliferation, migration, and invasion of luminal-subtype BC cells. The expression of LATS2, SASH1, and YAP1 and the phosphorylation of YAP1 were negatively regulated by MAP4K4, and LATS2 then phosphorylated SASH1 to form a novel MAP4K4-LATS2-SASH1-YAP1 cascade. Dephosphorylation of Yes1 associated transcriptional regulator (YAP1), YAP1/TAZ nuclear translocation, and downstream transcriptional regulation of YAP1 were promoted by the combined effects of ectopic MAP4K4 expression and SASH1 silencing. Targeted inhibition of MAP4K4 blocked proliferation, cell migration, and ER signaling both in vitro and in vivo. Our findings reveal a novel MAP4K4-LATS2-SASH1-YAP1 phosphorylation cascade, a noncanonical Hippo pathway that mediates ER signaling, tumorigenesis, and metastasis in breast cancer. Targeted intervention with this noncanonical Hippo pathway may constitute a novel alternative therapeutic approach for endocrine-resistant BC.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Neoplasias de la Mama , Péptidos y Proteínas de Señalización Intracelular , Proteínas Serina-Treonina Quinasas , Factores de Transcripción , Proteínas Supresoras de Tumor , Proteínas Señalizadoras YAP , Humanos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Femenino , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Señalizadoras YAP/metabolismo , Proteínas Señalizadoras YAP/genética , Proteínas Supresoras de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Animales , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Ratones , Transducción de Señal , Metástasis de la Neoplasia , Movimiento Celular , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Fosforilación , Ratones Desnudos , Carcinogénesis/genética , Carcinogénesis/metabolismoRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) are the standard of care for metastatic renal cell carcinoma (RCC); however, most patients develop de novo or acquired resistance to ICIs. Oxidative phosphorylation (OXPHOS) has been rarely explored as a potential target for correcting ICI resistance. METHODS: We systematically analyzed RNA sequencing and clinical data from CheckMate, JAVELIN Renal 101, and NCT01358721 clinical trials, and clinicopathological data of 25 patients from Tongji Hospital to investigate the relationship between OXPHOS and ICI resistance. The Ndufb8-knockdown Renca cell line was derived to determine the effect of OXPHOS on RCC immunotherapy in vivo. RESULTS: An analysis of the CheckMate series data revealed that high OXPHOS levels are risk factors for ICI in patients with RCC, but are affected by thevon Hippel-Lindau protein (VHL) and hypoxia-inducible factor-1α status. This result is consistent with correlation between clinicopathological characteristics and prognostic observations at our institute. Knockdown of the mitochondrial complex I subunit Ndufb8 of the Renca cell line had no effect on cell growth and migration in vitro, but slowed down cell growth in vivo. Among anti-programmed death ligand 1 (PD-L1)-treated BALB/c mice, shNdufb8 Renca tumors grew slower than shControl Renca tumors and the corresponding mice survived longer. Flow cytometry revealed that CD8+ T cells in shNdufb8 Renca tumors, which were exposed to a lower degree of hypoxia and expressed less programmed death-1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3), secreted more interferon-γ after stimulation. Immunofluorescence demonstrated that the shNdufb8 Renca tumors had a higher proportion of CD8+ T cells and the proportion of these cells was lower in the hypoxic area. CONCLUSIONS: OXPHOS is a reliable predictor of immunotherapy response in RCC and is more pronounced in metastatic lesions. RCC cells generate a hypoxic tumor microenvironment and inhibit T-cell function through oxidative metabolism, thereby leading to immunotherapy resistance.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Animales , Ratones , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Linfocitos T CD8-positivos , Fosforilación Oxidativa , Línea Celular Tumoral , Microambiente TumoralRESUMEN
CONTEXT: Polyporus polysaccharide (PPS), the leading bioactive ingredient extracted from Polyporus umbellatus (Pers.) Fr. (Polyporaceae), has been demonstrated to exert anti-bladder cancer and immunomodulatory functions in macrophages. OBJECTIVE: To explore the effects of homogeneous Polyporus polysaccharide (HPP) on the proliferation and autophagy of bladder cancer cells co-cultured with macrophages. MATERIALS AND METHODS: MB49 bladder cancer cells and RAW264.7 macrophages were co-cultured with or without HPP intervention (50, 100, or 200 µg/mL) for 24 h. The cell counting kit-8 (CCK-8) assay and 5-ethynyl-2â³-deoxyuridine (EdU) staining evaluated MB49 cell proliferation. Monodansylcadaverine (MDC) staining and transmission electron microscopy (TEM) observed autophagosomes. Western blotting detected the expression levels of autophagy-related proteins and PI3K/Akt/mTOR pathway proteins. RESULTS: HPP inhibited the proliferation of MB49 cells co-cultured with RAW264.7 cells but not MB49 cells alone. HPP altered the expression of autophagy-related proteins and promoted the formation of autophagosomes in MB49 cells in the co-culture system. Autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) not only antagonized HPP-induced autophagy but also attenuated the inhibitory effects of HPP on MB49 cell proliferation in the co-culture system. HPP or RAW264.7 alone was not sufficient to induce autophagy in MB49 cells. In addition, HPP suppressed the protein expression of the PI3K/Akt/mTOR pathway in MB49 cells in the co-culture system. DISCUSSION AND CONCLUSIONS: HPP induced bladder cancer cell autophagy by regulating macrophages in the co-culture system, resulting in the inhibition of cancer cell proliferation. The PI3K/Akt/mTOR pathway was involved in HPP-induced autophagy in the co-culture system.
Asunto(s)
Polyporus , Neoplasias de la Vejiga Urinaria , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Apoptosis , Polyporus/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Autofagia , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Proliferación Celular , Polisacáridos/farmacología , Proteínas Relacionadas con la Autofagia/farmacologíaRESUMEN
Different aromatic components do indeed give different tea flavors. There is still little research on whether there is a certain regularity in the combination and content of aromatic components in different aroma types of Phoenix Dancong (PDC) tea. This potential regularity may be a key factor in unraveling the relationship between reproduction and evolution in PDC tea. Here, the 5 kinds of these 4 aroma types PDC tea (Zhuye, Tuofu, Jianghuaxiang, Juduo, Yashixiang) were used as research materials in this study, the headspace solid-phase microextraction combined with gas chromatography-mass spectrometry was used to analyze the aromatic components of these PDC teas. The results showed a total of 36 aromatic components identified in this study. When conducting cluster analysis, it was found that similarity degree arrangement sequence of 5 PDC teas was Juduo, Tuofu, Yashixiang, Zhuye and Jianghuaxiang. Among these aromatic components, the 7,9-Di-tert-butyl-1-oxaspiro(4,5)deca-6,9-diene-2,8-dione, the 2-Cyclopenten-1-one, 3-methyl-2-(2-pentenyl)-,(Z)-, the 2,4-Di-tert-butylphenol, the 3,7-dimethyl-1,5,7-Octatrien-3-ol, and the 2-Furanmethanol,5-ethenyltetrahydro-.alpha.,.alpha.,5-trimethyl-,cis- are common to 5 PDC teas. This study aims to elucidate the similarities in the aromatic components of 5 PDC teas, revealing the major aroma-endowed substances of various aroma, and providing theoretical reference for further exploring the relationship between aroma type discrimination, variety selection, and evolution of PDC teas.
Asunto(s)
Odorantes , Compuestos Orgánicos Volátiles , Odorantes/análisis , Té/química , Cromatografía de Gases y Espectrometría de Masas/métodos , Microextracción en Fase Sólida/métodos , Análisis por Conglomerados , Compuestos Orgánicos Volátiles/análisisRESUMEN
Objective: To evaluate the use of manipulators on the outcome of women who had minimally invasive surgery for endometrial cancer. Methods: Retrospective analysis of patients operated with or without an intrauterine manipulator. Results: Six hundred ninety-nine patients were included. The median follow-up was 44 months (range, 29-67). Nineteen (8.8%) patients had positive cytology in the manipulator group versus 21 (4.4%) in the comparison group (p = 0.02). Total recurrence rate was similar between the groups (12.3% vs. 11.9%; p = 0.8). Vaginal vault recurrence was the most common site of recurrence with higher incidence in the manipulator group (4.5% vs. 1.3%; p = 0.007). Subgroup analysis of low-risk patients who did not receive adjuvant treatment showed higher recurrence rate (8.3% vs. 3%; p = 0.023) and worse disease-free survival (p = 0.01) for the manipulator group. After controlling for other variables, the use of a manipulator did not affect the risk of recurrence for the whole cohort (hazard ratio [HR], 1.28; confidence interval [95% CI], 0.7-2.1, p = 0.3) and for the low-risk subgroup of patients who did not receive adjuvant treatment (HR, 2.47; 95% CI, 0.8-7, p = 0.08). Conclusion: The use of a manipulator increases the risk of positive cytology as well as vaginal vault recurrences, but it does not reduce the overall survival of patients.
Asunto(s)
Neoplasias Endometriales , Histerectomía , Humanos , Femenino , Estudios Retrospectivos , Neoplasias Endometriales/cirugía , Procedimientos Quirúrgicos Mínimamente Invasivos , Recurrencia Local de Neoplasia/epidemiología , Estadificación de NeoplasiasRESUMEN
Interorganelle contacts facilitate material exchanges and sustain the structural and functional integrity of organelles. Lipid droplets (LDs) of adipocytes are responsible for energy storage and mobilization responding to body needs. LD biogenesis defects compromise the lipid-storing capacity of adipocytes, resulting in ectopic lipid deposition and metabolic disorders, yet how the uniquely large LDs in adipocytes attain structural and functional maturation is incompletely understood. Here we show that the mammalian adipocyte-specific protein CLSTN3B is crucial for adipocyte LD maturation. CLSTN3B employs an arginine-rich segment to promote extensive contact and hemifusion-like structure formation between the endoplasmic reticulum (ER) and LD, allowing ER-to-LD phospholipid diffusion during LD expansion. CLSTN3B ablation results in reduced LD surface phospholipid density, increased turnover of LD-surface proteins, and impaired LD functions. Our results establish the central role of CLSTN3B in the adipocyte-specific LD maturation pathway that enhances lipid storage and maintenance of metabolic health under caloric overload.