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This study investigates the therapeutic potential of electroacupuncture (EA) on obesity, focusing on its influence on autophagy and energy metabolism, utilizing a high-fat diet (HFD)-induced mouse model. Treatment with EA significantly reduces body weight, fat deposition, and lipid accumulation in HFD-fed mice. Additionally, EA effectively ameliorates metabolic imbalances, reducing blood glucose levels and plasma markers of liver function. At the molecular level, EA enhances the expression of thermogenesis-associated genes in brown adipose tissue and decreases p53 expression, suggesting a decrease in apoptosis. Autophagy in white adipose tissue is inhibited by EA, as demonstrated by the suppression of key autophagy-related proteins. Further experiments highlight the critical role of Sirtuin 3 (Sirt3) in EA's anti-obesity effects. Sirt3 supplementation combined with EA results in reduced body weight, fat deposition, and lipid accumulation, along with modulations in key metabolic indicators. Moreover, EA's modulatory effect on uncoupling protein 1 (Ucp1), Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc-1α), and p53 is found to be Sirt3 dependent. In conclusion, EA exerts beneficial effects against obesity through Sirt3-dependent modulation of autophagy and energy metabolism, indicating a potential therapeutic approach for obesity and related metabolic disorders.
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Electroacupuntura , Sirtuina 3 , Ratones , Animales , Sirtuina 3/genética , Sirtuina 3/metabolismo , Sirtuina 3/uso terapéutico , Dieta Alta en Grasa/efectos adversos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/uso terapéutico , Obesidad/terapia , Obesidad/genética , Obesidad/metabolismo , Peso Corporal , Autofagia/genética , Lípidos/uso terapéuticoRESUMEN
Recurrent endometrial cancer (EC) remains a therapeutic challenge despite advancements in personalized medicine. SIENDO trial showed the potential clinical benefit of selinexor in patients with TP53 wild-type advanced/recurrent EC. The quest for novel therapeutic avenues and approaches continues as researchers seek a glimmer of hope in an area of uncertainty.
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Neoplasias Endometriales , Recurrencia Local de Neoplasia , Femenino , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Hidrazinas/farmacología , Hidrazinas/uso terapéutico , Triazoles/uso terapéutico , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/uso terapéuticoRESUMEN
Tumoral microRNAs, such as miR-125b and miR-155b, are important gene expression regulators with complex pathogenetic mechanisms. However, their role in DLBCL, especially when cell-of-origin classification is considered, are still to be elucidated. In a series of 139 DLBCL cases considering germinal center (GC) versus nonGC subtypes, we investigated miR-125b and miR-155b expression by in situ hibridization and their association with some immunophenotypic presentations, including MYC, BCL2 and TP53 expression, MYC, BCL2 and BCL6 translocation status, as well as clinicopathological features and outcomes. miR-125b detection was positively correlated to the Ki-67 index (P = 0.035) in the nGC. Considering the GC subgroup, the percentage of miR-125b positive cells was also correlated to either MYC and MYC/BCL2 double expression (P = 0.047 and P = 0.049, respectively). When it comes to nGC patients, miR-155b percentage and intensity, as well as Allred score, were positively correlated to disease progression (P = 0.038, P = 0.057 and P = 0.039, respectively). In a multivariate analysis, GC phenotype was a significant independent factor associated with higher OS (P = 0.007) and, considering the nGC group, although not significant, the expression of TP53, miR-125b and miR-155b seems to be potential prognostic biomarkers in these tumors. This study demonstrated different pathways based on cell-of-origin classification and highlighted different clinical outcomes. miR-125b, miR-155b and TP53 expression may also represent potential prognostic factors in nGC-DLBCL.
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Linfoma de Células B Grandes Difuso , MicroARNs , Humanos , Pronóstico , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , MicroARNs/genética , MicroARNs/uso terapéutico , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/uso terapéuticoRESUMEN
The emergence of drug-resistant cells, most of which have a mutated TP53 gene, prevents curative treatment in most advanced and common metastatic cancers of adults. Yet, a few, rarer malignancies, all of which are TP53 wild type, have high cure rates. In this Perspective, we discuss how common features of curable cancers offer insights into the evolutionary and developmental determinants of drug resistance. Acquired loss of TP53 protein function is the most common genetic change in cancer. This probably reflects positive selection in the context of strong ecosystem pressures including microenvironmental hypoxia. Loss of TP53's functions results in multiple fitness benefits and enhanced evolvability of cancer cells. TP53-null cells survive apoptosis, and tolerate potent oncogenic signalling, DNA damage and genetic instability. In addition, critically, they provide an expanded pool of self-renewing, or stem, cells, the primary units of evolutionary selection in cancer, making subsequent adaptation to therapeutic challenge by drug resistance highly probable. The exceptional malignancies that are curable, including the common genetic subtype of childhood acute lymphoblastic leukaemia and testicular seminoma, differ from the common adult cancers in originating prenatally from embryonic or fetal cells that are developmentally primed for TP53-dependent apoptosis. Plus, they have other genetic and phenotypic features that enable dissemination without exposure to selective pressures for TP53 loss, retaining their intrinsic drug hypersensitivity.
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Ecosistema , Neoplasias , Adulto , Humanos , Neoplasias/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/uso terapéutico , Evolución BiológicaRESUMEN
The aims of this study were to assess the effect of known gene alterations (RAS, TP53, APC, SMAD4, BRAF, and FBXW7) on pathologic response (PR) and their combined association with survival in patients with colorectal liver metastases (CLM). From a prospectively maintained database, we collected data on 458 patients who underwent curative-intent hepatectomy after receiving the first-line preoperative chemotherapy between 2004 and 2020. Major PR was defined as tumor viability of less than 50% in all tumors. Multivariate logistic regression revealed that oxaliplatin-containing regimen (OR: 2.54, 95% CI: 1.58-4.07, P < 0.001), bevacizumab-containing regimen (OR: 2.15, 95%CI: 1.36-3.39, P = 0.001), and TP53 alteration (OR: 0.42, 95%CI: 0.27-0.66, P < 0.001) were independently associated with major PR. Multivariate Cox regression also revealed that patients with TP53 wild-type and major PR (HR: 0.49, 95%CI: 0.31-0.77, P = 0.002) and those with TP53 alteration and major PR (HR: 0.70, 95%CI: 0.49-1.00, P = 0.048) had significantly better overall survival compared to those with minor PR. Further studies targeting the association of TP53 with PR and survival can help clarify the role of TP53 in CLM.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Neoplasias Colorrectales/patología , Pronóstico , Hepatectomía , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/secundario , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/uso terapéuticoRESUMEN
High levels of reactive oxygen species (ROS) lead to progressive deterioration of mitochondrial function, resulting in tissue degeneration. In this study, ROS accumulation induced nucleus pulposus cells (NPCs) senescence is observed in degenerative human and rat intervertebral disc, suggesting senescence as a new therapeutic target to reverse intervertebral disc degeneration (IVDD). By targeting this, dual-functional greigite nanozyme is successfully constructed, which shows the ability to release abundant polysulfides and presents strong superoxide dismutase and catalase activities, both of which function to scavenge ROS and maintain the tissue at physical redox level. By significantly lowering the ROS level, greigite nanozyme rescues damaged mitochondrial function in IVDD models both in vitro and in vivo, rescues NPCs from senescence and alleviated the inflammatory response. Furthermore, RNA-sequencing reveals ROS-p53-p21 axis is responsible for cellular senescence-induced IVDD. Activation of the axis abolishes greigite nanozyme rescued NPCs senescence phenotype, as well as the alleviated inflammatory response to greigite nanozyme, which confirms the role of ROS-p53-p21 axis in greigite nanozyme's function to reverse IVDD. In conclusion, this study demonstrates that ROS-induced NPCs senescence leads to IVDD and the dual-functional greigite nanozyme holds strong potential to reverse this process, providing a novel strategy for IVDD management.
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Degeneración del Disco Intervertebral , Núcleo Pulposo , Ratas , Humanos , Animales , Degeneración del Disco Intervertebral/tratamiento farmacológico , Degeneración del Disco Intervertebral/genética , Núcleo Pulposo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteína p53 Supresora de Tumor/uso terapéuticoRESUMEN
INTRODUCTION: Although epithelial-mesenchymal transition (EMT) and p53 have been established to play a pivotal role in the aggressiveness of muscle-invasive bladder cancer (MIBC), its pathological correlation to cisplatin treatment in the Malaysian patient cohort is lacking. This study aimed to evaluate the association of EMT markers, e-cadherin, vimentin and actin, as well as tumour suppressor gene, p53, in cisplatin-receiving MIBC patients. MATERIALS AND METHODS: Formalin-fixed paraffinembedded (FFPE) blocks of muscle-invasive bladder cancer patients receiving cisplatin-based chemotherapy between January 2010 to December 2020 were traced. Immunohistochemistry staining was performed on traced blocks using antibodies to e-cadherin, vimentin and actin, and p53. RESULTS: p53 and e-cadherin were stained positive in most cases (p=0.515 and 0.242 respectively), although e-cadherin showed stronger positive expression in pre-cisplatin receiving MIBC cases. All the cases stained negative for actin and vimentin except for faint staining observed in one pre-cisplatin case. CONCLUSION: Although this study does not show a significant correlation between EMT markers and p53 with cisplatin-responsiveness in MIBC patients, the results serve as preliminary findings on the heterogeneous outcomes of molecular staining in the Malaysian MIBC patient cohort.
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Cisplatino , Neoplasias de la Vejiga Urinaria , Humanos , Cisplatino/uso terapéutico , Cisplatino/metabolismo , Vimentina/metabolismo , Vimentina/uso terapéutico , Proteína p53 Supresora de Tumor/uso terapéutico , Transición Epitelial-Mesenquimal , Actinas/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Cadherinas/metabolismo , Cadherinas/uso terapéutico , Músculos/metabolismo , Músculos/patología , Biomarcadores de Tumor/metabolismoRESUMEN
BACKGROUND: Mesenteric ischemia is a frequently encountered disease in surgical clinics, difficult to diagnose, and very mortal if not treated. Our study investigated the effects of astaxanthin, which is known to have potent antioxidant properties and is also known to have anti-inflammatory effects on ischemia-reperfusion (I/R) injury. METHODS: A total of 32 healthy Wistar albino female rats were used in our study. Subjects were randomized and equally divided into 4 groups; control (laparotomy group only), I/R (transient mesenteric ischemia group only), astaxanthin 1 mg/kg and 10 mg/kg doses. The transient ischemia time was 60 minutes and the reperfusion time was 120 minutes. Tissue samples were taken from intracardiac blood and terminal ileum after reperfusion. Superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA) from blood samples, interleukin-1 (IL-1), IL-6, tumor necrosis factor-α (TNFα), Caspase-3, P53 tests from terminal ileum were studied. Tissue samples were also taken for histopathological evaluation. RESULTS: At the end of the study, both doses of astaxanthin were found to significantly reduce MDA level, CAT, and SOD enzymatic activity, whereas higher doses of astaxanthin significantly reduced MDA level, CAT, and SOD enzyme activities. In addition, cytokines such as TNFα, IL-1 and IL-6 were found to be reduced at both doses of astaxanthin, but only significantly inhibited at higher doses. We observed that inhibition of apoptosis reduced caspase-3 activity and P53 and deoxyribonucleic acid (DNA) fragmentation. CONCLUSION: Astaxanthin, a potent antioxidant, and anti-inflammatory, significantly reduces ischemia and reperfusion injury, especially when used at a dose of 10 mg/kg. These data need to be confirmed by larger animal series and clinical studies.
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Isquemia Mesentérica , Daño por Reperfusión , Humanos , Ratas , Animales , Antioxidantes/uso terapéutico , Ratas Wistar , Caspasa 3/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6 , Proteína p53 Supresora de Tumor/uso terapéutico , Isquemia , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/etiología , Daño por Reperfusión/prevención & control , Interleucina-1/uso terapéutico , Superóxido Dismutasa/metabolismo , Antiinflamatorios/uso terapéutico , MalondialdehídoRESUMEN
The tumor suppressor p53 is the most frequently mutated protein in human cancer and tops the list of high-value precision oncology targets. p53 prevents initiation and progression of cancer by inducing cell-cycle arrest and various forms of cell death. Tumors have thus evolved ways to inactivate p53, mainly by TP53 mutations or by hyperactive p53 degradation. This review focuses on two types of p53 targeting compounds, MDM2 antagonists and mutant p53 correctors. MDM2 inhibitors prevent p53 protein degradation, while correctors restore tumor suppressor activity of p53 mutants by enhancing thermodynamic stability. Herein we explore both novel and repurposed p53 targeting compounds, discuss their mode of action, and examine the challenges in advancing them to the clinic.
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Antineoplásicos , Neoplasias , Humanos , Neoplasias/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/uso terapéutico , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Medicina de Precisión , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
Age is associated with the decline of multiple organ systems. In older patients, hematological toxicities associated with chemotherapy are often dose limiting, impairing dose intensity and treatment efficacy. Contrary to the classical path using growth factors to activate tissue regeneration, a novel strategy is emerging to prevent chemotherapy toxicity that involves temporary cell-cycle arrest of normal cells, such as hematopoietic or epithelial precursors. This proactive approach may allow the sparing of the stem cell reserve of these tissues. Two molecules are included in this new category, trilaciclib and ALRN-6924, which induce cell-cycle arrest by two different pathways. Previous approaches, such as the use of myelopoietic growth factors, were reactive and they might even have accelerated the depletion of stem cells by enhancing the commitment of these elements. Trilaciclib causes cell-cycle arrest by CDK 4/6 inhibition and ALRN-6924 by p53 activation. In a pooled analysis of three randomized phase II studies of patients with small cell lung cancer, trilaciclib prevented neutropenia, thrombocytopenia, and anemia. Similar chemoprotective results were observed with ALRN-6924 in an open-label phase Ib study of patients with p53-mutated small cell lung cancer. Trilaciclib is now approved as a myelopreservation agent in patients with extensive-stage small cell lung cancer. ALRN-6924 is currently in phase Ib clinical development in patients with p53-mutated cancer. In addition to preserving the normal hemopoietic pool, these drugs promise to preserve the stem cell reserve of other normal tissues with high turnover, preventing potentially other dose-limiting toxicities, such as mucositis and diarrhea. An "ex vivo" study provided early evidence that ALRN-6924 may prevent chemotherapy-induced alopecia. By affording protection from multiple toxicities with a single drug, trilaciclib and ALRN-6924 have the potential to transform the current standards of supportive care for oncology patients and may prevent the depletion of tissue stem cells already compromised with age.
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Antineoplásicos , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Anciano , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/etiología , Proteína p53 Supresora de Tumor/uso terapéutico , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Puntos de Control del Ciclo Celular , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Ensayos Clínicos Fase I como AsuntoRESUMEN
PURPOSE: To explore the mechanism of jatrorrhizine on apoptosis and fibrosis induced by myocardial infarction (MI) in an animal model. METHODS: The left anterior descending branch of coronary artery was surgically ligated to duplicate the mouse model of MI. The sham and infarcted mice were treated with normal saline once a day, while mice in experimental groups received low-dose (LD) and high-dose (HD) jatrorrhizine once a day respectively. Two weeks later, cardiac function was detected by echocardiography, and histopathological examination was performed using hematoxylin and eosin (H&E) and Masson staining. The expressions of p53, TGF-ß1, Smad/2/3, Bax, Bcl-2, collagen I and collagen III were quantified using qRT-PCR and western blot assays. RESULTS: Jatrorrhizine significantly improved left ventricular ejection fraction (LVEF) and left ventricle end-systolic (LVES) in mice. Histopathological, administration of jatrorrhizine weakened infiltration of inflammatory cells and cardiac fibrosis in myocardium of mice caused by MI. Additionally, jatrorrhizine suppressed cardiomyocyte apoptosis exhibited as its capability to reverse changes of Bax and Bcl-2 levels in myocardium caused by MI. Jatrorrhizine statistically significantly downregulated expression of collagen I and collagen III, as well as TGF-ß1, Smad2/3 and p53. CONCLUSIONS: Jatrorrhizine reduce cardiomyocyte apoptosis and fibrosis through inhibiting p53/Bax/Bcl-2 and TGF-ß1/Smad2/3 signaling pathways.
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Infarto del Miocardio , Factor de Crecimiento Transformador beta1 , Animales , Ratones , Apoptosis , Proteína X Asociada a bcl-2/metabolismo , Colágeno Tipo I/metabolismo , Modelos Animales de Enfermedad , Fibrosis , Infarto del Miocardio/patología , Miocardio/patología , Volumen Sistólico , Factor de Crecimiento Transformador beta1/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/uso terapéutico , Función Ventricular IzquierdaRESUMEN
BACKGROUND: The mechanism of Heat Shock Protein 90 (HSP90) in Ulcerative Colitis (UC) has been studied, and mitogenic-activated protein kinases (MAPK) also contribute to the pathogenesis of UC. However, the effect of the HSP90/MAPK pathway in UC is still unclear. Therefore, the mainstay of this research is to explore the mechanism of action of this pathway in UC. Compound sophorae decoction (CSD), as a Chinese herbal decoction, can synergistically affect the above process. OBJECTIVE: This study aimed to uncover the synergistic effects of HSP90 inhibitors regulating the MAPK pathway for treating DSS-induced colitis in mice and the synergistic effects of CSD. METHODS: This experiment used oral administration of standard diets containing 3% dextran sodium sulfate (DSS) to establish an experimental colitis model in mice. The model was treated with HSP90 inhibitor, CSD, or dexamethasone. Mouse feces, mobility, body weight, colon length, and colon histopathology scores were recorded daily to assess the degree of colitis inflammation. Expression levels of HSP90 and MAPK pathway-related genes and proteins were evaluated by Western blot and qPCR. The evaluation of intestinal mucosal permeability was measured by enzyme-linked immunosorbent assay (ELISA), which could detect the protein level of D-Amino Acid Oxidase (DAO) and D-lactic acid (D-LA). The same went for downstream molecules AFT-2, p53, and apoptosis-related proteins BAX, BCL-2, Caspase3, and survivin in the MAPK pathway. Immunohistochemical measured p-38, p-JNK, and p-ERK expressions. JAM-A and claudin-1 connexin were tested by immunofluorescence staining. The TUNEL method was for measuring the apoptosis rate of colonic epithelial cells. CBA kit determined the level of inflammatory factors of colons. RESULTS: HSP90 inhibitor can improve the degree of pathological damage in the colon of mice treated with DSS, increase the mice's weight and the length of the colon, and significantly reduce the disease activity index (DAI) score. Intraperitoneal injection of HSP90 inhibitor can reduce the expression of MAPK pathway markers P38, JNK, ERK, and their phosphorylation and decrease the content of AFT-2 and p53, which is downstream of the MAPK pathway. In addition, treatment of the HSP90 inhibitor up-regulated the expression of anti-apoptotic proteins BCL-2 and survivin, as well as down-regulated apoptotic protein caspase3, BAX in the colon of mice with colitis. Lower levels of inflammatory factors such as IL-6, MCP-1, IFN-γ, TNF, IL-12p70, and increased IL-10 were observed after HSP90 inhibitor therapy. Furthermore, the combination treatment of CSD can enhance the effect of the single HSP90 inhibitor treatment and play a synergistic effect. CONCLUSION: These data suggest that an HSP90 inhibitor is available to treat UC by inhibiting the MAPK signaling pathway. This axis can restore the intestinal mucosa barrier's function by reducing intestinal mucosa's permeability and inhibiting apoptosis of intestinal epithelial cells. The specific mechanism is that HSP90 inhibitor can reduce the pathological damage and inflammation levels of colitis mice, and reduce the apoptosis rate of colonic epithelial cells and the mucosal permeability, thereby restoring the mucosal barrier function. During this process, CSD works synergistically to improve the therapeutic effect of the HSP90 inhibitor.
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Colitis Ulcerosa , Colitis , Sophora , Animales , Ratones , Proteína X Asociada a bcl-2/metabolismo , Proteína X Asociada a bcl-2/farmacología , Proteína X Asociada a bcl-2/uso terapéutico , Colitis/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colon/metabolismo , Modelos Animales de Enfermedad , Inflamación/metabolismo , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Sophora/metabolismo , Survivin/metabolismo , Survivin/farmacología , Survivin/uso terapéutico , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/farmacología , Proteína p53 Supresora de Tumor/uso terapéutico , Proteínas HSP90 de Choque Térmico/metabolismoRESUMEN
BACKGROUND: TP53 is frequently mutated in solid tumors, but its basic mutation mapping is mixed, particularly in aggressive-stage lung cancer. EXPERIMENTAL DESIGN: We curated a total of 139 advanced non-small cell lung cancer (NSCLC) patients who harbored wild-type TP53 (TP53wt) or mutated TP53 (TP53mut) based on next-generation sequencing (NGS) to analyze multiple-dimensional data types, including tumor mutation burden (TMB), programmed death receptor ligand 1 (PD-L1) expression, co-mutant alterations, hotspot mutations distribution, and therapy response. RESULTS: TP53 was evident in 125 mutations and significantly associated with male sex, adenocarcinoma differentiation, smoking history, PD-L1 tumor proportion score, and TMB level. The most frequent mutations were distributed on exon 8, but there were no distinct hotspot mutations. After outlining the co-mutation genes, it is interesting to note that DNA damage repair (DDR) genes were frequent alterations in the mutated TP53 cohort. Even though there was no significant difference between the TP53wt and TP53mut cohorts on therapy response, patients with nucleotide variation in G>T achieved a relatively higher durable clinical benefit (DCB) rate. CONCLUSIONS: This real-world retrospective study suggests that molecular stratification on the basis of TP53 mutations should be deeply explored for NSCLC to optimize and modify clinical therapy choices.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Masculino , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Antígeno B7-H1 , Estudios Retrospectivos , Neoplasias Pulmonares/patología , Ligandos , Mutación , Biomarcadores de Tumor/genética , Nucleótidos/uso terapéutico , Receptores de Muerte Celular/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/uso terapéuticoRESUMEN
This real-world cohort analysis assessed the efficacy of alpelisib and endocrine treatment (ET) combinations in a post-everolimus setting. Thirteen women who started alpelisib and ET at standard doses between 2018 and 2022 for advanced breast cancer (ABC), after undergoing CDK4/6i and everolimus treatment, were eligible for the study entry. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were the objective response rate (ORR) and clinical benefit rate (CBR), with different molecular profiling. The patients had previously received a median of four (range 3-8) systemic treatments, including CDK4/6i and everolimus. The median PFS on alpelisib was 5.5 months (range 0.5-10), and four women each had an ORR and three (23%) had a stable disease. The 6-month CBR was 46.1%, similar to the BYLeive study cohort C (47.8%). Notably, our cohort included patients with a long CBR under everolimus treatment (median 6 months, range 1-18); however, the responses to alpelisib and everolimus were not correlated (Pearson r = -0.23, p = 0.44). The PIK3CA, P53, ARID, GATA3, and ESR1 mutations were not associated with the 6-month CBR. Despite heavy pre-treatments, including everolimus, alpelisib was clinically relevant in our cohort, even among patients with an ESR1 mutation. The best treatment sequence for PIK3CA/mTOR inhibitors warrants examination in future trials on PIK3CA-mutant inpatients with luminal ABC.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Everolimus/uso terapéutico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Proteína p53 Supresora de Tumor/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Fosfatidilinositol 3-Quinasa Clase I/genéticaRESUMEN
Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK)/receptor tyrosine kinase inhibitor (ROS1), demonstrated efficacy in ROS1 positive (ROS1+) non-small cell lung cancer (NSCLC), although approval is currently limited to the treatment of ALK+ patients. However, lorlatinib-induced resistance mechanisms, and its efficacy against the resistance mutation G2032R in ROS1, respectively, have not yet been fully understood. Furthermore, concomitant tumor suppressor gene p53 (TP53) mutations occur in driver alteration positive NSCLC, but their prognostic contribution in the context of ROS1 inhibition remains unclear. Here we report a ROS1+ NSCLC patient who developed an on target G2032R resistance mutation during second-line lorlatinib treatment, indicating the lack of activity of lorlatinib against ROS1 G2032R. The resistance mutation was detected in plasma-derived ctDNA, signifying the clinical utility of liquid biopsies.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Aminopiridinas , Quinasa de Linfoma Anaplásico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Resistencia a Antineoplásicos/genética , Humanos , Lactamas , Lactamas Macrocíclicas/farmacología , Lactamas Macrocíclicas/uso terapéutico , Biopsia Líquida , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Pirazoles , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/uso terapéuticoRESUMEN
OBJECTIVE: This study aims to examine the synergetic augmentation of calycosin-7-O-ß-D-glucoside (CG) on cisplatin (CDDP) to induce apoptosis of human epithelial ovarian SK-OV-3 cancer cells. METHODS: The SK-OV-3 cells were divided into four groups: control, CDDP monotherapy, CG monotherapy, and combined CDDP and CG treatment. The cell counting kit-8 method detected cell proliferation at different times and under different treatments. Hoechst 33258 staining and annexin V-FITC/propidium iodide double staining methods were used to observe the apoptosis of the SK-OV-3 cells. The caspase-3 enzyme activity detection method, quantitative reverse transcription-polymerase chain reaction, and western blot were used to detect the apoptosis-related factors and the activities of the enzyme in SK-OV-3 cells. RESULTS: The inhibition rates of SK-OV-3 cell proliferation when exposed to 10 µM of CDDP, 50 µM of CG, and a combination of 10 µM of CDDP and 50 µM of CG were 23.2% ± 1.1%, 26.7% ± 2.0%, and 46.7% ± 1.3% after 48 h, respectively. Following the use of the drug combination, the apoptosis rate and caspase-3 enzyme activity were significantly higher than in the single-drug treatment group; the data differences were also significant (p < 0.05). At the protein and ribonucleic acid levels, CG significantly enhanced the effect of CDDP on p53, caspase-3, caspase-9, Bax, and Bcl-2. CONCLUSION: In vitro, CG significantly increases the CDDP-induced apoptosis of the SK-OV-3 cells through the p53 pathway at the cellular level. In addition, using the drugs in combination reduces the toxicity and side effects caused by using CDDP alone.
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Antineoplásicos , Neoplasias Ováricas , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Caspasa 3/metabolismo , Caspasa 3/farmacología , Caspasa 3/uso terapéutico , Línea Celular Tumoral , Cisplatino/farmacología , Cisplatino/uso terapéutico , Femenino , Glucósidos , Humanos , Isoflavonas , Neoplasias Ováricas/tratamiento farmacológico , Proteína p53 Supresora de Tumor/farmacología , Proteína p53 Supresora de Tumor/uso terapéuticoRESUMEN
BACKGROUND: Targeted drugs have greatly improved the therapeutic outcome of non-small cell lung cancer (NSCLC) patients compared with conventional chemotherapy, whereas about one-third of patients are so far not suitable for targeted therapy due to lack of known driver oncogenes such as a mutated receptor tyrosine kinase (RTK) genes. In this study, we aimed to identify therapeutic targets for this subgroup of NSCLC patients. METHODS: We performed genome-wide CRISPR/Cas9 screens in two NSCLC cell lines carrying wild-type TP53 and receptor tyrosine kinase (wtTP53-RTK) genes using a GeCKO v2.0 lentiviral library (containing 123411 sgRNAs and targeting 19050 genes). MAGeCKFlute was used to analyse and identify candidate genes. Genetic perturbation and pharmacological inhibition were used to validate the result in vitro and in vivo. RESULTS: The Genome-wide CRISPR/Cas9 screening identified MDM2 as a potential therapeutic target for wtTP53-RTK NSCLC. Genetic and pharmacological inhibition of MDM2 reduced cell proliferation and impaired tumour growth in the xenograft model, thus confirming the finding of the CRISPR/Cas9 screening. Moreover, treatment by a selective MDM2 inhibitor RG7388 triggered both cell cycle arrest and apoptosis in several NSCLC cell lines. Additionally, RG7388 and pemetrexed synergistically blocked the cell proliferation and growth of wtTP53-RTK tumours but had limited effects for other genotypes. CONCLUSIONS: We identified MDM2 as an essential gene and a potential therapeutic target in wtTP53-RTK NSCLC via a genome-wide CRISPR/Cas9 screening. For this subgroup, treatment by RG7388 alone or by its combination with pemetrexed resulted in significant tumour inhibition.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Sistemas CRISPR-Cas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Pemetrexed/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/uso terapéutico , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/uso terapéuticoRESUMEN
Chlamydia (C.) abortus is an emerging zoonotic pathogen. Since data on its antimicrobial susceptibility are lacking, we aimed to determine minimal inhibitory (MIC) and minimal bactericidal concentrations (MBC) for azithromycin and doxycycline in HeLa-cells and primary human macrophages (M1). We also examined the MDM2-p53-inhibitor nutlin-3, an anti-infective imidazoline analog. Azithromycin and doxycycline demonstrated MICs and MBCs equal or below their peak serum concentrations (PSC) after standard dosing in both cell types. While doxycycline exhibited an MIC 64-fold and an MBC 4-fold below its PSC in HeLa-cells, the MIC of azithromycin was 4-fold below, the MBC equal to the PSC. However, azithromycin revealed lower MBCs in M1. The pharmacological advantage of azithromycin accumulation in phagocytes and their role as chlamydial reservoirs remain uncertain. However, our data suggest possible therapeutic advantages of doxycycline in epithelial cells and we provide first evidence for an anti-C. abortus effect of nutlin-3 in M1.
Asunto(s)
Antibacterianos , Infecciones por Chlamydia , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Azitromicina/farmacología , Chlamydia , Chlamydia trachomatis , Doxiciclina/farmacología , Doxiciclina/uso terapéutico , Células Epiteliales , Humanos , Imidazoles , Macrófagos , Piperazinas , Proteínas Proto-Oncogénicas c-mdm2/farmacología , Proteína p53 Supresora de Tumor/farmacología , Proteína p53 Supresora de Tumor/uso terapéuticoRESUMEN
BACKGROUND: Low back pain is a common symptom of intervertebral disc degeneration (IDD), which seriously affects the quality of life of patients. The abnormal apoptosis and senescence of nucleus pulposus (NP) cells play important roles in the pathogenesis of IDD. Proanthocyanidins (PACs) are polyphenolic compounds with anti-apoptosis and anti-aging effects. However, their functions in NP cells are not yet clear. Therefore, this study was performed to explore the effects of PACs on NP cell apoptosis and aging and the underlying mechanisms of action. METHODS: Cell viability was evaluated by cell counting kit-8 (CCK-8) assay. The apoptosis rate was determined TUNEL assays. Levels of apoptosis-associated molecules (Bcl-2, Bax, C-caspase-3 and Caspase-9) were evaluated via western blot. The senescence was observed through SA-ß-gal staining and western blotting analysis was performed to observe the expression of senescence-related molecules (p-P53, P53, P21 and P16). RESULTS: Pretreatment with PACs exhibited protective effects against IL-1ß-induced NP cell apoptosis including apoptosis rate, expressions of proapoptosis and antiapoptosis related genes and protein. PACs could also alleviate the increase of p-p53, P21, and P16 in IL-1ß-treated NP cells. SA-ß-gal staining showed that IL-1ß-induced senescence of NP cells was prevented by PACs pertreatment. In addition, PACs activated PI3K/Akt pathway in IL-1ß-stimulated NP cells. However, these protected effects were inhibited after LY294002 treatment. CONCLUSION: The results of the present study showed that PACs inhibit IL-1ß-induced apoptosis and aging of NP cells by activating the PI3K/Akt pathway, and suggested that PACs have therapeutic potential for IDD.
Asunto(s)
Degeneración del Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , Proantocianidinas , Envejecimiento , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Caspasa 9/farmacología , Células Cultivadas , Humanos , Disco Intervertebral/patología , Degeneración del Disco Intervertebral/patología , Núcleo Pulposo/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Proantocianidinas/metabolismo , Proantocianidinas/farmacología , Proantocianidinas/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Calidad de Vida , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/farmacología , Proteína p53 Supresora de Tumor/uso terapéutico , Proteína X Asociada a bcl-2/metabolismo , Proteína X Asociada a bcl-2/farmacologíaRESUMEN
This case report concerns a 31-year-old male with an aggressive pituitary tumor who presented initially with bitemporal hemianopsia and slightly elevated prolactin. On magnetic resonance imaging of the brain, there was a sellar mass with parasellar invasion to the lateral aspects of the internal carotid arteries, compressing the optic chiasm. On histopathological analysis, the diagnosis was made of a densely granulated lactotroph pituitary tumor with a Ki67 proliferation rate of 15%, a mitotic count of 6/10 high-power fields, and p53 positivity. Based on these features, the tumor was classified as a grade 2b tumor according to the Trouillas classification, and a more aggressive behavior of the tumor could be expected. In order to anticipate a future need for alternative drug treatments, the following analyses were undertaken: MGMT methylation (present) as well as the expression of estrogen receptor (negative), programmed-death ligand 1 (60 - 70% positive tumor cells), vascular endothelial growth factor-A and somatostatin receptor 2 (both positive). There was regrowth of residual tumor tissue, and the treatment consisted thus far of repeat surgery, cabergoline, pasireotide, and radiotherapy. Chemotherapy with temozolomide could not yet be initiated due to a concurrent infertility treatment. This case is unique because the tumor displays atypical characteristics, both in terms of morphology and behavior. It also illustrates how pathologists can play an important role in determining the diagnosis, prognosis, and possibilities for targeted therapy.