ABSTRACT
We aimed to compare the clinical efficacy and safety of roxadustat with erythropoiesis-stimulating agents, particularly erythropoietin (EPO), in the treatment of maintenance hemodialysis patients with renal anemia. A prospective cohort study was carried out at the Nephrology Department of the Nantong First People's Hospital and Nantong University Affiliated Hospital from December 2020 to December 2021. We compared hemoglobin (Hb) levels, serum ferritin (SF) levels, and adverse cardiovascular events between the roxadustat and EPO groups at 1, 3, and 6 months into the treatment. A total of 209 patients participated in the study, with 112 in the roxadustat group and 97 in the EPO group. At baseline, no statistically significant differences were observed between the 2 groups in terms of age, gender, weight, dialysis modality and duration, previous EPO dosage, Hb levels, SF levels, transferrin saturation, heart function classification, and blood pressure levels (Pâ >â .05). After 1 month, Hb levels in the roxadustat group were significantly higher than those in the EPO group (Pâ <â .05). However, no statistically significant differences were found between the 2 groups at 3 and 6 months (Pâ >â .05). Additionally, there were no significant differences in SF levels and the occurrence of adverse cardiovascular events between the 2 groups after treatment (Pâ >â .05). Roxadustat was superior to EPO in the initial treatment phase, while its cardiovascular safety was comparable to that of EPO.
Subject(s)
Anemia , Hemoglobins , Isoquinolines , Renal Dialysis , Humans , Male , Female , Renal Dialysis/adverse effects , Anemia/drug therapy , Anemia/etiology , Middle Aged , Prospective Studies , Isoquinolines/therapeutic use , Isoquinolines/adverse effects , Isoquinolines/administration & dosage , Hemoglobins/analysis , Hemoglobins/metabolism , Aged , Erythropoietin/therapeutic use , Hematinics/therapeutic use , Hematinics/adverse effects , Hematinics/administration & dosage , Glycine/analogs & derivatives , Glycine/therapeutic use , Ferritins/blood , Treatment OutcomeABSTRACT
BACKGROUND: To investigate the potential of Native T1-mapping in predicting the prognosis of patients with chronic kidney disease (CKD). METHODS: We enrolled 119 CKD patients as the study subjects and included 20 healthy volunteers as the control group, with follow-up extending until October 2022. Out of these patients, 63 underwent kidney biopsy measurements, and these patients were categorized into high (25-50%), low (< 25%), and no renal interstitial fibrosis (IF) (0%) groups. The study's endpoint event was the initiation of renal replacement therapy, kidney transplantation, or an increase of over 30% in serum creatinine levels. Cox regression analysis determined factors influencing unfavorable kidney outcomes. We employed Kaplan-Meier analysis to contrast kidney survival rates between the high and low T1 groups. Additionally, receiver-operating characteristic (ROC) curve analysis assessed the predictive accuracy of Native T1-mapping for kidney endpoint events. RESULTS: T1 values across varying fibrosis degree groups showed statistical significance (F = 4.772, P < 0.05). Multivariate Cox regression pinpointed 24-h urine protein, cystatin C(CysC), hemoglobin(Hb), and T1 as factors tied to the emergence of kidney endpoint events. Kaplan-Meier survival analysis revealed a markedly higher likelihood of kidney endpoint events in the high T1 group compared to the low T1 value group (P < 0.001). The ROC curves for variables (CysC, T1, Hb) tied to kidney endpoint events demonstrated area under the curves(AUCs) of 0.83 (95%CI: 0.75-0.91) for CysC, 0.77 (95%CI: 0.68-0.86) for T1, and 0.73 (95%CI: 0.63-0.83) for Hb. Combining these variables elevated the AUC to 0.88 (95%CI: 0.81-0.94). CONCLUSION: Native T1-mapping holds promise in facilitating more precise and earlier detection of CKD patients most at risk for end-stage renal disease.
Subject(s)
Kidney Failure, Chronic , Renal Insufficiency, Chronic , Humans , Kidney , Prognosis , Glomerular Filtration Rate , Fibrosis , Hemoglobins , Predictive Value of TestsABSTRACT
Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies1. Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8+ alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver KRAS mutations. Expression profiles of KACs were enriched in lung precancer cells and in LUAD cells and signified poor survival. In mice exposed to tobacco carcinogen, KACs emerged before lung tumours and persisted for months after cessation of carcinogen exposure. Moreover, they acquired Kras mutations and conveyed sensitivity to targeted KRAS inhibition in KAC-enriched organoids derived from alveolar type 2 (AT2) cells. Last, lineage-labelling of AT2 cells or KRT8+ cells following carcinogen exposure showed that KACs are possible intermediates in AT2-to-tumour cell transformation. This study provides new insights into epithelial cell states at the root of LUAD development, and such states could harbour potential targets for prevention or intervention.
Subject(s)
Adenocarcinoma of Lung , Cell Differentiation , Epithelial Cells , Lung Neoplasms , Animals , Humans , Mice , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/pathology , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/pathology , Aneuploidy , Carcinogens/toxicity , Epithelial Cells/classification , Epithelial Cells/metabolism , Epithelial Cells/pathology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mutation , Organoids/drug effects , Organoids/metabolism , Precancerous Conditions/metabolism , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Survival Rate , Tobacco Products/adverse effects , Tobacco Products/toxicityABSTRACT
High-grade serous ovarian cancer (HGSOC) is responsible for the majority of gynecology cancer-related deaths. Patients in remission often relapse with more aggressive forms of disease within 2 years post-treatment. Alternative immuno-oncology (IO) strategies, such as immune checkpoint blockade (ICB) targeting the PD-(L)1 signaling axis, have proven inefficient so far. Our aim is to utilize epigenetic modulators to maximize the benefit of personalized IO combinations in ex vivo 3D patient-derived platforms and in vivo syngeneic models. Using patient-derived tumor ascites, we optimized an ex vivo 3D screening platform (PDOTS), which employs autologous immune cells and circulating ascites-derived tumor cells, to rapidly test personalized IO combinations. Most importantly, patient responses to platinum chemotherapy and poly-ADP ribose polymerase inhibitors in 3D platforms recapitulate clinical responses. Furthermore, similar to clinical trial results, responses to ICB in PDOTS tend to be low and positively correlated with the frequency of CD3+ immune cells and EPCAM+/PD-L1+ tumor cells. Thus, the greatest response observed with anti-PD-1/anti-PD-L1 immunotherapy alone is seen in patient-derived HGSOC ascites, which present with high levels of systemic CD3+ and PD-L1+ expression in immune and tumor cells, respectively. In addition, priming with epigenetic adjuvants greatly potentiates ICB in ex vivo 3D testing platforms and in vivo tumor models. We further find that epigenetic priming induces increased tumor secretion of several key cytokines known to augment T and NK cell activation and cytotoxicity, including IL-6, IP-10 (CXCL10), KC (CXCL1), and RANTES (CCL5). Moreover, epigenetic priming alone and in combination with ICB immunotherapy in patient-derived PDOTS induces rapid upregulation of CD69, a reliable early activation of immune markers in both CD4+ and CD8+ T cells. Consequently, this functional precision medicine approach could rapidly identify personalized therapeutic combinations able to potentiate ICB, which is a great advantage, especially given the current clinical difficulty of testing a high number of potential combinations in patients.
ABSTRACT
Immunotherapies have yet to demonstrate significant efficacy in the treatment of hormone receptor-positive (HR+) breast cancer. Given that endocrine therapy (ET) is the primary approach for treating HR+ breast cancer, we investigated the effects of ET on the tumor immune microenvironment (TME) in HR+ breast cancer. Spatial proteomics of primary HR+ breast cancer samples obtained at baseline and after ET from patients enrolled in a neoadjuvant clinical trial (NCT02764541) indicated that ET upregulated ß2-microglobulin and influenced the TME in a manner that promotes enhanced immunogenicity. To gain a deeper understanding of the underlying mechanisms, the intrinsic effects of ET on cancer cells were explored, which revealed that ET plays a crucial role in facilitating the chromatin binding of RelA, a key component of the NF-κB complex. Consequently, heightened NF-κB signaling enhanced the response to interferon-gamma, leading to the upregulation of ß2-microglobulin and other antigen presentation-related genes. Further, modulation of NF-κB signaling using a SMAC mimetic in conjunction with ET augmented T-cell migration and enhanced MHC-I-specific T-cell-mediated cytotoxicity. Remarkably, the combination of ET and SMAC mimetics, which also blocks prosurvival effects of NF-κB signaling through the degradation of inhibitors of apoptosis proteins, elicited tumor regression through cell autonomous mechanisms, providing additional support for their combined use in HR+ breast cancer. SIGNIFICANCE: Adding SMAC mimetics to endocrine therapy enhances tumor regression in a cell autonomous manner while increasing tumor immunogenicity, indicating that this combination could be an effective treatment for HR+ patients with breast cancer.
Subject(s)
Breast Neoplasms , NF-kappa B , Humans , Female , NF-kappa B/metabolism , Intracellular Signaling Peptides and Proteins , Breast Neoplasms/pathology , Antigen Presentation , Apoptosis Regulatory Proteins , Apoptosis , Cell Line, Tumor , Mitochondrial Proteins/metabolism , Tumor MicroenvironmentABSTRACT
Apart from the anti-GD2 antibody, immunotherapy for neuroblastoma has had limited success due to immune evasion mechanisms, coupled with an incomplete understanding of predictors of response. Here, from bulk and single-cell transcriptomic analyses, we identify a subset of neuroblastomas enriched for transcripts associated with immune activation and inhibition and show that these are predominantly characterized by gene expression signatures of the mesenchymal lineage state. By contrast, tumors expressing adrenergic lineage signatures are less immunogenic. The inherent presence or induction of the mesenchymal state through transcriptional reprogramming or therapy resistance is accompanied by innate and adaptive immune gene activation through epigenetic remodeling. Mesenchymal lineage cells promote T cell infiltration by secreting inflammatory cytokines, are efficiently targeted by cytotoxic T and natural killer cells and respond to immune checkpoint blockade. Together, we demonstrate that distinct immunogenic phenotypes define the divergent lineage states of neuroblastoma and highlight the immunogenic potential of the mesenchymal lineage.
Subject(s)
Adrenergic Agents , Neuroblastoma , Humans , Cell Lineage/genetics , Immune Checkpoint Inhibitors , Neuroblastoma/genetics , Cytokines/genetics , PhenotypeABSTRACT
KRAS-LKB1 (KL) mutant lung cancers silence STING owing to intrinsic mitochondrial dysfunction, resulting in T cell exclusion and resistance to programmed cell death (ligand) 1 (PD-[L]1) blockade. Here we discover that KL cells also minimize intracellular accumulation of 2'3'-cyclic GMP-AMP (2'3'-cGAMP) to further avoid downstream STING and STAT1 activation. An unbiased screen to co-opt this vulnerability reveals that transient MPS1 inhibition (MPS1i) potently re-engages this pathway in KL cells via micronuclei generation. This effect is markedly amplified by epigenetic de-repression of STING and only requires pulse MPS1i treatment, creating a therapeutic window compared with non-dividing cells. A single course of decitabine treatment followed by pulse MPS1i therapy restores T cell infiltration in vivo, enhances anti-PD-1 efficacy, and results in a durable response without evidence of significant toxicity.
Subject(s)
Lung Neoplasms , Proto-Oncogene Proteins p21(ras) , Decitabine , Genes, ras , Humans , Ligands , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolismABSTRACT
Cell therapies, including adoptive immune cell therapies and genetically engineered chimeric antigen receptor (CAR) T or NK cells, have shown promise in treating hematologic malignancies. Yet, immune cell infiltration and expansion has proven challenging in solid tumors due to immune cell exclusion and exhaustion and the presence of vascular barriers. Testing next-generation immune therapies remains challenging in animals, motivating sophisticated ex vivo models of human tumor biology and prognostic assays to predict treatment response in real-time while comprehensively recapitulating the human tumor immune microenvironment (TIME). This review examines current strategies for testing cell-based cancer immunotherapies using ex vivo microphysiological systems and microfluidic technologies. Insights into the multicellular interactions of the TIME will identify novel therapeutic strategies to help patients whose tumors are refractory or resistant to current immunotherapies. Altogether, these microphysiological systems (MPS) have the capability to predict therapeutic vulnerabilities and biological barriers while studying immune cell infiltration and killing in a more physiologically relevant context, thereby providing important insights into fundamental biologic mechanisms to expand our understanding of and treatments for currently incurable malignancies.
ABSTRACT
Activation of the stimulator of interferon genes (STING) pathway promotes antitumor immunity but STING agonists have yet to achieve clinical success. Increased understanding of the mechanism of action of STING agonists in human tumors is key to developing therapeutic combinations that activate effective innate antitumor immunity. Here, we report that malignant pleural mesothelioma cells robustly express STING and are responsive to STING agonist treatment ex vivo. Using dynamic single-cell RNA sequencing of explants treated with a STING agonist, we observed CXCR3 chemokine activation primarily in tumor cells and cancer-associated fibroblasts, as well as T-cell cytotoxicity. In contrast, primary natural killer (NK) cells resisted STING agonist-induced cytotoxicity. STING agonists enhanced migration and killing of NK cells and mesothelin-targeted chimeric antigen receptor (CAR)-NK cells, improving therapeutic activity in patient-derived organotypic tumor spheroids. These studies reveal the fundamental importance of using human tumor samples to assess innate and cellular immune therapies. By functionally profiling mesothelioma tumor explants with elevated STING expression in tumor cells, we uncovered distinct consequences of STING agonist treatment in humans that support testing combining STING agonists with NK and CAR-NK cell therapies.
Subject(s)
Immunotherapy, Adoptive , Killer Cells, Natural , Membrane Proteins , Mesothelioma, Malignant , Cell Line, Tumor , Cell- and Tissue-Based Therapy , Humans , Membrane Proteins/agonists , Receptors, Chimeric AntigenABSTRACT
The gene encoding promyelocytic leukemia protein (PML) generates several spliced isoforms. Ectopic expression of PML1 promotes the proliferation of ERα-positive MCF-7 breast cancer (BC) cells, while a loss of PML by knockdown or overexpression of PML4 does the opposite. PML is an essential constituent of highly dynamic particles called PML nuclear bodies (NBs). PML NBs are heterogenous multiprotein subnuclear structures that are part of cellular stress sensing machinery. The antioxidant sulforaphane (SFN) inhibits the proliferation of BC cells and causes a redistribution of the subcellular localization of PML, a disruption of disulfide-bond linkages in nuclear PML-containing complexes, and a reduction in the number and size of PML NBs. Mechanistically, SFN modifies several cysteine residues, including C204, located in the RBCC domain of PML. PML is sumoylated and contains a Sumo-interacting motif, and a significant fraction of Sumo1 and Sumo2/3 co-localizes with PML NBs. Ectopic expression of the mutant C204A selectively inhibits the biogenesis of endogenous PML NBs but not PML-less Sumo1-, Sumo2/3, or Daxx-containing nuclear speckles. Importantly, PML1 (C204A) functions as a dominant-negative mutant over endogenous PML protein and promotes anti-proliferation activity. Together, we conclude that SFN elicits its cytotoxic activity in part by inactivating PML1's pro-tumorigenic activity.
Subject(s)
Antioxidants/metabolism , Isothiocyanates/pharmacology , Oncogene Proteins/metabolism , Promyelocytic Leukemia Protein/genetics , Promyelocytic Leukemia Protein/metabolism , Protein Isoforms/metabolism , Cell Cycle , Cell Movement , Cell Nucleus/metabolism , Cell Proliferation , Co-Repressor Proteins , Humans , MCF-7 Cells , Molecular Chaperones , Oncogene Proteins/genetics , Protein Isoforms/genetics , SUMO-1 Protein/metabolism , Small Ubiquitin-Related Modifier Proteins , Sulfoxides , Sumoylation , Ubiquitins/metabolismABSTRACT
PURPOSE: The purpose of this study was to examine the effects of self-esteem and social support on quality of life (QoL) in stage I and II cervical cancer survivors. METHOD: The sample consisted of 110 participants who had been diagnosed with stage I-II cervical cancer and had completed their treatment 5 years or more before data collection. Each participant completed four structured questionnaires: a demographic-disease survey, the Rosenberg Self-Esteem Scale, Medical Outcomes Study Social Support Survey, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30. Data were analyzed using descriptive statistics, independent sample t-test, one-way ANOVA, and hierarchical multiple linear regression analyses. RESULTS: The participants' mean age was 60.74 ± 10.69 years. Better QoL was significantly associated with younger age, higher self-esteem, and stronger social support; in addition, social support buffered the effect of self-esteem on global QoL. Together, five variables (age, time since treatment, self-esteem, social support, and the interaction term of self-esteem and social support) explained 36% of the variance in global QoL, with self-esteem being the strongest predictor. CONCLUSIONS: The results of this study advance current knowledge of QoL in cervical cancer survivors by demonstrating that survivors with low self-esteem and social support tend to have lower QoL than those with low self-esteem but high social support. Health professionals should help survivors seek support and provide appropriate strategies to expand their social networks and enhance their self-esteem to improve their global QoL after cervical cancer.