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Ovarian cancer (OC) manifests as a complex disease characterized by inter- and intra-patient heterogeneity. Despite enhanced biological and genetic insights, OC remains a recalcitrant malignancy with minimal survival improvement. Based on multi-site sampling and a multi-lineage patient-derived xenograft (PDX) establishment strategy, we present herein the establishment of a comprehensive PDX biobank from histologically and molecularly heterogeneous OC patients. Comprehensive profiling of matched PDX and patient samples demonstrates that PDXs closely recapitulate parental tumors. By leveraging multi-lineage models, we reveal that the previously reported genomic disparities of PDX could be mainly attributed to intra-patient spatial heterogeneity instead of substantial model-independent genomic evolution. Moreover, DNA damage response pathway inhibitor (DDRi) screening uncovers heterogeneous responses across models. Prolonged iterative drug exposure recapitulates acquired drug resistance in initially sensitive models. Meanwhile, interrogation of induced drug-resistant (IDR) models reveals that suppressed interferon (IFN) response and activated Wnt/ß-catenin signaling contribute to acquired DDRi drug resistance.
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Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Animais , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Via de Sinalização Wnt/genética , Resistencia a Medicamentos Antineoplásicos/genética , Genômica/métodos , Bancos de Espécimes Biológicos , Heterogeneidade Genética , Dano ao DNA/genética , Interferons/metabolismo , Interferons/genética , Linhagem da Célula/genéticaRESUMO
BACKGROUND: Frozen embryo transfer (FET) has become a widely employed assisted reproductive technology technique. There have historically been concerns regarding the long-term metabolic safety of FET technology in offspring due to pregnancy-induced hypertension and large for gestational age, both of which are well-recognized factors for metabolic dysfunction of children. Therefore, we aimed to compare the metabolic profiles of children born after frozen versus fresh embryo transfer at 2 to 5 years of age. METHODS AND FINDINGS: This was a prospective cohort study. Using data from the "Assisted Reproductive Technology borned KIDs (ARTKID)," a birth cohort of offspring born from assisted reproductive technology at the Institute of Women, Children and Reproductive Health, Shandong University, China. We included 4,246 singletons born after FET (n = 2,181) and fresh embryo transfer (n = 2,065) enrolled between 2008 and 2019 and assessed the glucose and lipid variables until the age of 2 to 5 years. During a mean follow-up of 3.6 years, no significant differences were observed in fasting blood glucose, fasting insulin, Homeostatic Model Assessment of Insulin Resistance Index, total cholesterol, triglycerides, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol levels between offspring conceived by fresh and frozen embryo transfer in the crude model and adjusted model (adjusted for parental age, parental body mass index, parental education level, paternal smoking, parity, offspring age and sex). These results remained consistent across subgroup analyses considering offspring age, the stage of embryo transfer, and the mode of fertilization. Results from sensitivity analysis on children matched for age within the cohort remains the same. The main limitation of our study is the young age of the offspring. CONCLUSIONS: In this study, the impact of FET on glucose and lipid profiles during early childhood was comparable to fresh embryo transfer. Long-term studies are needed to evaluate the metabolic health of offspring born after FET.
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Criopreservação , Transferência Embrionária , Humanos , Transferência Embrionária/métodos , Feminino , Pré-Escolar , Masculino , China/epidemiologia , Estudos Prospectivos , Metaboloma , Gravidez , Glicemia/metabolismo , Adulto , Estudos de Coortes , População do Leste AsiáticoRESUMO
Hyperthermic intraperitoneal chemotherapy's role in ovarian cancer remains controversial, hindered by limited understanding of hyperthermia-induced tumor cellular changes. This limits developing potent combinatory strategies anchored in hyperthermic intraperitoneal therapy (HIPET). Here, we perform a comprehensive multi-omics study on ovarian cancer cells under hyperthermia, unveiling a distinct molecular panorama, primarily characterized by rapid protein phosphorylation changes. Based on the phospho-signature, we pinpoint CDK1 kinase is hyperactivated during hyperthermia, influencing the global signaling landscape. We observe dynamic, reversible CDK1 activity, causing replication arrest and early mitotic entry post-hyperthermia. Subsequent drug screening shows WEE1 inhibition synergistically destroys cancer cells with hyperthermia. An in-house developed miniaturized device confirms hyperthermia and WEE1 inhibitor combination significantly reduces tumors in vivo. These findings offer additional insights into HIPET, detailing molecular mechanisms of hyperthermia and identifying precise drug combinations for targeted treatment. This research propels the concept of precise hyperthermic intraperitoneal therapy, highlighting its potential against ovarian cancer.
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Hipertermia Induzida , Neoplasias Ovarianas , Feminino , Humanos , Proteína Quinase CDC2/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas Tirosina Quinases/metabolismo , Multiômica , Mitose , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/patologiaRESUMO
This study aims to explore the relationship between serum iron by inductively coupled plasma-mass spectrometry (ICP-MS) and the efficacy of immune checkpoint inhibitors (ICIs) and potential mechanism. Totally 113 patients from 233 patients with advanced metastatic lung cancer, esophageal cancer, gastric cancer and colorectal cancer who treated with immunotherapy in Shandong Provincial Hospital were divided into training group (n=68) and validation group (n=45), whose patients were divided into clinical benefit response (CBR) and non-clinical benefit (NCB) by RECIST (v1.1) respectively. We found for the first time that high serum iron level (>1036 µg/L) was a novel biomarker of better PFS (10.13 months vs 7.37 months; p = 0.0015) and OS(16.00 months vs 11.00 months; p = 0.0235) by ROC curve (sensitivity: 78.13 %; Specificity: 80.56 %; p < 0.0001) of CBR (n=32) and NCB (n=36) patients in training group. Interestingly, consistently stable and high serum iron level predicted better efficacy during immunotherapy. Noteworthy, the predictive efficacy of PD-L1 expression was significantly inferior than serum iron (accuracy:63.49% vs 79.41%, p=0.0432), while serum iron detected by spectrophotometry did not predict the efficacy of immunotherapy (p=0.0671) indicating higher sensitivity of ICP-MS. Bioinformatics analysis showed that serum iron could enhance innate immunity and cytokine release and was verified by proteomics that KEGG and GO analysis enriched innate immune and cytokine signaling pathways. Flow cytometry showed that IL-17 (p=0.0002) increased and IL-6 (p=0.0112) decreased after immunotherapy. Based on this, Nomogram with better prediction was constructed by multiple clinical and independent factors. Our results revealed that serum iron is positively associated with ICIs efficacy by enhancing innate immunity and cytokine release in advanced metastatic cancers, and can be a biomarker for predicting ICIs response.
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Neoplasias Pulmonares , Receptor de Morte Celular Programada 1 , Humanos , Biomarcadores , Citocinas , Imunoterapia , Ferro , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
PURPOSE: WEE1 is a crucial kinase involved in the regulation of G2/M checkpoint within the cell cycle. This article aims to comprehensively review the existing knowledge on the implication of WEE1 as a therapeutic target in tumor progression and drug resistance. Furthermore, we summarize the current predictive biomarkers employed to treat cancer with WEE1 inhibitors. METHODS: A systematic review of the literature was conducted to analyze the association between WEE1 inhibition and cancer progression, including tumor advancement and drug resistance. Special attention was paid to the identification and utilization of predictive biomarkers related to therapeutic response to WEE1 inhibitors. RESULTS: The review highlights the intricate involvement of WEE1 in tumor progression and drug resistance. It synthesizes the current knowledge on predictive biomarkers employed in WEE1 inhibitor treatments, offering insights into their prognostic significance. Notably, the article elucidates the potential for precision medicine by understanding these biomarkers in the context of tumor treatment outcomes. CONCLUSION: WEE1 plays a pivotal role in tumor progression and is a promising therapeutic target. Distinguishing patients that would benefit from WEE1 inhibition will be a major direction of future research.
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Neoplasias , Medicina de Precisão , Humanos , Biomarcadores , Proteínas de Ciclo Celular , Divisão Celular , Pontos de Checagem da Fase G2 do Ciclo Celular , Neoplasias/tratamento farmacológico , Proteínas Tirosina QuinasesRESUMO
Background: Immune checkpoint inhibitors (ICIs) are widely used for treating advanced non-small cell lung cancer (NSCLC). However, some studies indicate that patients with genetic mutations do not benefit from immunotherapy. Hence, this study explored the efficacy of anti-programmed death-1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) antibodies in the first-line treatment of advanced NSCLC with driver gene mutations in real-world settings. Methods: We retrospective analyzed patients with advanced NSCLC who treated with first-line anti-PD-1/PD-L1 antibodies at Shandong Provincial Hospital between May 2019 and October 2020. The patient's driver gene mutation status was identified using amplification refractory mutation system PCR (ARMS-PCR). The basic clinical characteristics, objective response rate (ORR), progression free survival (PFS), and other clinical data of patients were collected to evaluate the clinical efficacy and potential prognostic factors of treatment for patients with driver gene mutations. Results: A total of 430 patients' information was counted during this period, finally, 89 patients with NSCLC were enrolled in the study. The main pathological subtype of patients was adenocarcinoma (62.9%). The overall mutation rate was 44.9% (n = 40) and included following mutations: KRAS (n = 20), TP53 (n = 18), EGFR (n = 6), BRAF (n = 3), Her-2 (n = 3), MET (n = 3), ROS1 (n = 1), and NRAS (n = 1). The overall ORR was 44.30% and the disease control rate (DCR) was 82.23%. At the time of follow-up cut-off, the median PFS of all patients was 8.2 month. In NSCLC patients treated with ICI, median PFS was longer in mutation-negative patients than in mutation-positive patients (8.98 vs 7.07 months, P < 0.05). Survival benefit varied across mutational subgroups: KRAS patients could benefit from first-line immunotherapy (10.1 months, P < 0.05), patients with EGFR mutations have poor first-line immunotherapy outcomes, with a median PFS of only 3.0 months (P < 0.01), and patients with other mutation types having no significant difference in response from mutation-negative patients. In most mutation subgroups, immune combination therapy had longer PFS than immune monotherapy, and PD-L1 expression levels were positively correlated with clinical benefit in patients. Conclusion: In the real world, patients with KRAS mutations benefit from first-line immunotherapy, immune-combination modalities are more effective, and immune efficacy is positively correlated with PD-L1 expression; Patients with other driver mutations (BRAF, NRAS, Her2, MET, ROS1) benefit similarly to mutation-negative patients in first-line immunotherapy, and immunotherapy is recommended for first-line therapy; Immunotherapy is worse effective in patients with EGFR mutations, immunotherapy is not recommended in first-line therapy even patients with high PD-L1 expression.
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Targeting the G2/M checkpoint mediator WEE1 has been explored as a novel treatment strategy in ovarian cancer, but mechanisms underlying its efficacy and resistance remains to be understood. Here, it is demonstrated that the WEE1 inhibitor AZD1775 induces endoplasmic reticulum stress and activates the protein kinase RNA-like ER kinase (PERK) and inositol-required enzyme 1α (IRE1α) branches of the unfolded protein response (UPR) in TP53 mutant (mtTP53) ovarian cancer models. This is facilitated through NF-κB mediated senescence-associated secretory phenotype. Upon AZD1775 treatment, activated PERK promotes apoptotic signaling via C/EBP-homologous protein (CHOP), while IRE1α-induced splicing of XBP1 (XBP1s) maintains cell survival by repressing apoptosis. This leads to an encouraging synergistic antitumor effect of combining AZD1775 and an IRE1α inhibitor MKC8866 in multiple cell lines and preclinical models of ovarian cancers. Taken together, the data reveal an important dual role of the UPR signaling network in mtTP53 ovarian cancer models in response to AZD1775 and suggest that inhibition of the IRE1α-XBP1s pathway may enhance the efficacy of AZD1775 in the clinics.
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Endorribonucleases , Neoplasias Ovarianas , Proteínas Serina-Treonina Quinases , Benzopiranos , Endorribonucleases/antagonistas & inibidores , Endorribonucleases/metabolismo , Feminino , Humanos , Inositol/metabolismo , Morfolinas , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Pirazóis/farmacologia , Pirimidinonas/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Resposta a Proteínas não Dobradas/genética , Resposta a Proteínas não Dobradas/fisiologiaRESUMO
Targeted therapies represent attractive combination partners with immune checkpoint blockade (ICB) to increase the population of patients who benefit or to interdict the emergence of resistance. We demonstrate that targeting WEE1 up-regulates immune signaling through the double-stranded RNA (dsRNA) viral defense pathway with subsequent responsiveness to immune checkpoint blockade even in cGAS/STING-deficient tumors, which is a typical phenotype across multiple cancer types. WEE1 inhibition increases endogenous retroviral elements (ERVs) expression by relieving SETDB1/H3K9me3 repression through down-regulating FOXM1. ERVs trigger dsRNA stress and interferon response, increasing recruitment of anti-tumor T cells with concurrent PD-L1 elevation in multiple tumor models. Furthermore, combining WEE1 inhibition and PD-L1 blockade induced striking tumor regression in a CD8+ T cell-dependent manner. A WEE1 inhibition-induced viral defense signature provides a potentially informative biomarker for patient selection for combination therapy with WEE1 and ICB. WEE1 inhibition stimulates anti-tumor immunity and enhances sensitivity to ICB, providing a rationale for the combination of WEE1 inhibitors and ICB in clinical trials.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Retrovirus Endógenos/genética , Neoplasias Experimentais/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , RNA de Cadeia Dupla/genética , Transdução de Sinais/efeitos dos fármacos , Células A549 , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Retrovirus Endógenos/metabolismo , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/farmacologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Pirimidinonas/administração & dosagem , Pirimidinonas/farmacologia , RNA de Cadeia Dupla/metabolismo , Transdução de Sinais/genética , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Carga Tumoral/imunologiaRESUMO
Ongoing pandemic and potential resurgence of Coronavirus disease 2019 (COVID-19) has prompted urgent efforts to investigate the immunological memory of convalescent patients, especially in patients with active cancers. Here we performed single-cell RNA sequencing in peripheral blood samples of 3 healthy donors (HDs), 4 COVID-19 patients (Covs) and 4 COVID-19 patients with active gynecological tumor (TCs) pre- and post- anti-tumor treatment. All Covs patients had recovered from their acute infection. Interestingly, the molecular features of PBMCs in TCs are similar to that in Covs, suggesting that convalescent COVID-19 with gynecologic tumors do not have major immunological changes and may be protected against reinfection similar to COVID-19 patients without tumors. Moreover, the chemotherapy given to these patients mainly caused neutropenia, while having little effect on the proportion and functional phenotype of T and B cells, and T cell clonal expansion. Notably, anti-PD-L1 treatment massively increased cytotoxic scores of NK cells, and T cells, and facilitated clonal expansion of T cells in these patients. It is likely that T cells could protect patients from SARS-CoV-2 virus reinfection and anti-PD-L1 treatment can enhance the anti-viral activity of the T cells.
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COVID-19/complicações , Neoplasias dos Genitais Femininos/complicações , Neoplasias dos Genitais Femininos/terapia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Anticorpos Antivirais/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Feminino , Neoplasias dos Genitais Femininos/imunologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Análise de Célula Única , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
WEE1 plays an important role in the regulation of cell cycle G2/M checkpoints and DNA damage response (DDR). Inhibition of WEE1 can increase the instability of the genome and have anti-tumor effects in some solid tumors. However, it has certain limitations for multiple cancer cells from different lineages. Therefore, we consider the use of synthetic lethal interactions to enhance the therapeutic effect. Our experiments proved that WEE1 inhibitor (WEE1i) can activate the ataxia telangiectasia and RAD3-related (ATR) pathway and that blockage of ATR dramatically sensitized the WEE1i-induced cell death. The tumor-selective synthetic lethality between bioavailable WEE1 and ATR inhibitors led to tumor remission in vivo. Mechanistically, the combination promoted the accumulation of cytosolic double-strand DNA, which subsequently activated the stimulator of the interferon gene (STING) pathway and induced the production of type I interferon and CD8+ T cells, thereby inducing anti-tumor immunity. Furthermore, our study found that immune checkpoint programmed death-ligand 1 is upregulated by the combination therapy, and blocking PD-L1 further enhances the effect of the combination therapy. In summary, as an immunomodulator, the combination of WEE1i with ATR inhibitor (ATRi) and immune checkpoint blockers provides a potential new approach for cancer treatment.
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Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Antígeno B7-H1/antagonistas & inibidores , Proteínas de Ciclo Celular/antagonistas & inibidores , Neoplasias Colorretais/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos , Morte Celular , Linhagem Celular Tumoral , DNA/metabolismo , Dano ao DNA , DNA de Neoplasias/biossíntese , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Instabilidade Genômica , Humanos , Imunidade , Imunoterapia/métodos , Indóis/uso terapêutico , Interferon Tipo I/biossíntese , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Morfolinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Pirimidinonas/uso terapêutico , Sulfonamidas/uso terapêutico , Microambiente Tumoral/imunologia , Ensaio Tumoral de Célula-Tronco , Regulação para CimaRESUMO
Increasing evidences show that microRNAs (miRNAs) are involved in the regulation of tumorigenesis, progression, recurrence and drug resistance of hepatocellular carcinoma (HCC). miR-369 works as a tumor suppressor in both lung cancer and thyroid cancer. However, the potential biological function of miR-369 in HCC is unknown. Herein, we for first found that miR-369 expression was downregulated in HCC tissues and predicted the poor prognosis of HCC patients. Forced miR-369 expression inhibited the proliferation and metastasis of HCC cells in vitro and in vivo. Mechanically, bioinformatics and luciferase reporter analysis identified Zinc finger E-box binding homeobox 1 (ZEB1) as a direct target of miR-369 in HCC cells. miR-369 overexpressing downregulated the ZEB1 mRNA and protein expression in HCC cells. miR-369 expression was negatively associated with ZEB1 expression in human HCC tissues. More importantly, the ZEB1 siRNA diminished the discrepancy of growth and metastasis capacity between miR-369 overexpression HCC cells and control cells.
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Vulvovaginal atrophy (VVA) is a common menopause-related symptom affecting more than 50% of midlife and older women and cancer patients whose ovarian function are lost or damaged. Regardless of estrogen deficiency, whether other factors such as the gut microbiota play role in VVA have not been thoroughly investigated. To this end, we performed ovariectomy on 12-weeks' old mice and follow-up at 4 weeks after ovariectomy, and observed atrophied vagina and an altered gut microbiota in ovariectomized mice.. We further performed fecal microbiota transplantation with feces from another cohort of ovary-intact fecund female mice to the ovariectomized ones, and found that the vaginal epithelial atrophy was significantly alleviated as well as the gut microbiota was pointedly changed. All these results suggest that ovarian activity has some influence on the gut microbiota, and the latter from the ovary-intact female mice can somehow make the vagina of mice deficient in ovarian function healthier maybe by up-expressing ESR1 in vaginal cells and enhancing regeneration in vagina. This kind of association between gut microbiota and vaginal health need further exploration such that it may provide an alternative treatment by modulating gut microbiota in patients suffering from VVA but may be reluctant to hormone therapy.
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Transplante de Microbiota Fecal , Ovariectomia/efeitos adversos , Vagina/patologia , Animais , Atrofia , Feminino , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , RNA Ribossômico 16S/genéticaRESUMO
Mutant KRAS tumors are associated with poor outcomes, at least in part, due to decreased therapeutic sensitivity. Here, we show that KRAS mutations are associated with resistance to monotherapy and combination therapy with PARP inhibitors (PARPi) and immune checkpoint blockade with anti-PD-L1 antibodies. In mutant KRAS tumors, inhibition of KRAS signaling with MEK inhibitors (MEKi) triggered and amplified PARPi-induced DNA damage, cytosolic double-stranded DNA accumulation, STING pathway activation, and CD8+ T-cell recruitment. Moreover, MEKi decreased myeloid-derived suppressor cell infiltration, in part, by inhibiting IL6 and GMCSF production. Importantly, addition of MEKi to PARPi and anti-PD-L1 resulted in marked tumor inhibition in immunocompetent mutant KRAS tumor models. This study provides the underlying mechanistic data to support evaluation of PARPi, MEKi, and anti-PD-L1 combination in clinical trials of mutant KRAS tumors. SIGNIFICANCE: This study provides key insights into the potential for using MEKi combined with PARPi and anti-PD-L1 for the treatment of all mutant KRAS tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/10/2714/F1.large.jpg.
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Neoplasias da Mama/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Animais , Apoptose , Antígeno B7-H1/antagonistas & inibidores , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Quimioterapia Combinada , Feminino , Humanos , MAP Quinase Quinase 1/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Mutação , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Background: Fatigue is prevalent in breast cancer patients undergoing postoperative chemotherapy, which seriously affects physical and mental health. The present study aimed to investigate the relevance of fatigue, the self-efficacy of managing chronic disease (SEMCD), and the dual-mode of self-control (DMSC) in patients. Methods: Three hundred and seventy six breast cancer patients undergoing postoperative chemotherapy participated in this cross-sectional study. The General Information Questionnaire, Fatigue Scale-14 (FS-14), SEMCD-Scale (SEMCD-S), and DMSC-Scale (DMSC-S) were utilized to survey. Pearson correlation analysis and structural equation modeling were used for the statistical analysis of the correlation between the variables and mediating effects. Results: A total of 372 valid questionnaires (98.94%) were returned. The total fatigue score of FS-14 was (10.84 ± 1.80), the SEMCD-S score (30.05 ± 15.18), and the DMSC-Scale score (73.35 ± 9.49). Furthermore, physical fatigue was negatively correlated with the SEMCD-S and problem solving (r = -0.764 ~ -0.680, P < 0.01). Mental fatigue correlated positively with poor delay of gratification (r = 0.134, P < 0.05), and the SEMCD-S was also negatively correlated with the impulsivity, distractibility, and poor delay of gratification dimensions (r =-0.229~-0.130, P < 0.05). SEMCD correlated positively with problem-solving and future time perspective (r = 0.695~0.790, P < 0.001). In addition, SEMCD partially mediated the effect between the DMSC and fatigue (ß = -0.335, P < 0.01), with the mediating effect accounting for 51.25%. Conclusion: Through SEMCD measure, it was found that DMSC indirectly influences fatigue levels in breast cancer patients undergoing postoperative chemotherapy.
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Neoplasias da Mama , Autocontrole , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Doença Crônica , Estudos Transversais , Feminino , Humanos , Qualidade de Vida , Autoeficácia , Inquéritos e QuestionáriosRESUMO
Objective: The objective of the study is to investigate the effect of the reverse-tapered peripherally inserted central catheters (PICC) and the nontapered PICC in tumor chemotherapy. Materials and Methods: Retrospective January to May 2019, 110 subjects were collected in the study, including a group of 49 patients with the reverse-tapered PICC catheters. In the other group, 61 patients were implanted with the nontapered PICC catheters. The incidence of PICC catheter-related symptomatic thrombosis, the difficulty degree of catheterization, and the rate of bleeding at the puncture point 24 h after catheterization were compared between two groups. Results: The comparison of the difficulty of catheterization and the permeability rate at puncture point 24 h after catheterization between the two groups showed statistically significant differences (all P < 0.05). There was no significant difference in the incidence of symptomatic thrombosis associated with PICC catheters between the two groups (P > 0.05). Conclusion: The reverse-tapered PICC and the nontapered PICC catheters have similar safety performance in tumor chemotherapy; different design types of PICC were selected according to the treatment needs of patients.
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Cateterismo Venoso Central , Cateterismo Periférico , Cateteres Venosos Centrais , Neoplasias , Cateterismo Venoso Central/efeitos adversos , Cateterismo Periférico/efeitos adversos , Cateteres Venosos Centrais/efeitos adversos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Risk stratifications for endometrial carcinoma (EC) depend on histopathology and molecular pathology. Histopathological risk stratification lacks reproducibility, neglects heterogeneity and contributes little to surgical procedures. Existing molecular stratification is useless in patients with specific pathological or molecular characteristics and cannot guide postoperative adjuvant radiotherapies. Chromosomal instability (CIN), the numerical and structural alterations of chromosomes resulting from ongoing errors of chromosome segregation, is an intrinsic biological mechanism for the evolution of different prognostic factors of histopathology and molecular pathology and may be applicable to the risk stratification of EC. RESULTS: By analyzing CIN25 and CIN70, two reliable gene expression signatures for CIN, we found that EC with unfavorable prognostic factors of histopathology or molecular pathology had serious CIN. However, the POLE mutant, as a favorable prognostic factor, had elevated CIN signatures, and the CTNNB1 mutant, as an unfavorable prognostic factor, had decreased CIN signatures. Only if these two mutations were excluded were CIN signatures strongly prognostic for outcomes in different adjuvant radiotherapy subgroups. Integrating pathology, CIN signatures and POLE/CTNNB1 mutation stratified stageIendometrioid EC into four groups with improved risk prognostication and treatment recommendations. CONCLUSIONS: We revealed the possibility of integrating histopathology and molecular pathology by CIN for risk stratification in early-stage EC. Our integrated risk model deserves further improvement and validation.
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BACKGROUND: Although research on the effects of comorbidities on coronavirus disease 2019 (COVID-19) patients is increasing, the risk of cancer history has not been evaluated for the mortality of patients with COVID-19. METHODS: In this retrospective study, we included 3232 patients with pathogen-confirmed COVID-19 who were hospitalized between January 18th and March 27th, 2020, at Tongji Hospital in Wuhan, China. Propensity score matching was used to minimize selection bias. RESULTS: In total, 2665 patients with complete clinical outcomes were analyzed. The impacts of age, sex, and comorbidities were evaluated separately using binary logistic regression analysis. The results showed that age, sex, and cancer history are independent risk factors for mortality in hospitalized COVID-19 patients. COVID-19 patients with cancer exhibited a significant increase in mortality rate (29.4% vs. 10.2%, P < 0.0001). Furthermore, the clinical outcomes of patients with hematological malignancies were worse, with a mortality rate twice that of patients with solid tumors (50% vs. 26.1%). Importantly, cancer patients with complications had a significantly higher risk of poor outcomes. One hundred nine cancer patients were matched to noncancer controls in a 1:3 ratio by propensity score matching. After propensity score matching, the cancer patients still had a higher risk of mortality than the matched noncancer patients (odds ratio (OR) 2.98, 95% confidence interval (95% CI) 1.76-5.06). Additionally, elevations in ferritin, high-sensitivity C-reactive protein, erythrocyte sedimentation rate, procalcitonin, prothrombin time, interleukin-2 (IL-2) receptor, and interleukin-6 (IL-6) were observed in cancer patients. CONCLUSIONS: We evaluated prognostic factors with epidemiological analysis and highlighted a higher risk of mortality for cancer patients with COVID-19. Importantly, cancer history was the only independent risk factor for COVID-19 among common comorbidities, while other comorbidities may act through other factors. Moreover, several laboratory parameters were significantly different between cancer patients and matched noncancer patients, which may indicate specific immune and inflammatory reactions in COVID-19 patients with cancer.
Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/mortalidade , Neoplasias Hematológicas/epidemiologia , Hospitalização , Pneumonia Viral/epidemiologia , Pneumonia Viral/mortalidade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Sedimentação Sanguínea , Proteína C-Reativa/análise , COVID-19 , China/epidemiologia , Comorbidade , Infecções por Coronavirus/virologia , Feminino , Ferritinas/sangue , Neoplasias Hematológicas/sangue , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/virologia , Pontuação de Propensão , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2RESUMO
Epithelial ovarian cancer is characterized by universal TP53 mutations, which result in G1/S checkpoint deficiencies. Therefore, it is hypothesized that the abrogation of the G2/M checkpoint with Wee1 inhibitor might preferentially sensitize TP53-defective ovarian cancer cells. Given the extremely high molecular diversity in ovarian cancer, one approach to improving the clinical efficacy is to identify drug combinations that either broaden the applicable spectrum or circumvent resistance. Here, through a high-throughput unbiased proteomic profiling (RPPA), we found the complementary activated mTOR pathway contributes greatly to Wee1 inhibitor resistance. A combination of Wee1 and mTOR inhibits synergistically inhibiting tumor growth in ovarian cancer cell lines and patient-derived xenograft that closely mimic the heterogeneity of patient tumors. Mechanistically, dual Wee1/mTOR inhibition induced massive DNA replication stress, leading to fork stalling and DNA damage. Moreover, we found that the addition of nucleotide metabolic substrate dNTPs alleviated replication stress, restored the cell cycle and reduced apoptosis to some extent, supporting dNTPs depletion is necessary for the synergy between Wee1 and mTOR inhibits. These results suggest that our study opening up a wider therapeutic window of Wee1 inhibitor for the treatment in epithelial ovarian cancers.
RESUMO
The influence of Mg content on the mechanical properties, degradation behavior, in vitro cell adhesion, and in vivo behavior of as-extruded Zn-xMg-0.1Ca (xâ¯=â¯0.5â¯wt%, 1.0â¯wt%, 1.5â¯wt%) alloys was investigated. A high Mg content could increase the volume fraction of the hard Mg2Zn11 phase distributed at grain boundaries. This condition could significantly improve yield strength and ultimate tensile strength. Mg addition could adjust the degradation rate of Zn alloys and influence cytocompatibility. ZnMg1Ca0.1 alloy showed the highest adhesion density of bone marrow-derived mesenchymal stem cells (BMSCs) because the degradation rate of ZnMg1Ca0.1 alloy could supply appropriate pH and [Zn2+] for BMSCs. Mg addition could improve the cytocompatibility of ZnMgCa alloys. However, a Mg content threshold was observed, and the Mg content should be exactly controlled. Combined with the mechanical properties, the degradation rate of zinc alloy implants could be adjusted to match the healing of tissues by adding Mg. In vivo results showed that the degradation rate of the optimized ZnMgCa alloy could match the healing of local tissues or organs. Animal implant results revealed alloy safety.