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BACKGROUND: Sepsis fluid resuscitation is controversial, especially for patients with volume overload risk. The Surviving Sepsis Campaign recommends a 30-mL/kg crystalloid fluid bolus for patients with sepsis-induced hypoperfusion. Criticism of this approach includes excessive fluid resuscitation in certain patients. OBJECTIVE: The aim of this study was to assess the efficacy and safety of guideline-concordant fluid resuscitation in patients with sepsis and heart failure (HF) or end-stage kidney disease (ESKD). METHODS: A retrospective cohort study was conducted in patients with sepsis who qualified for guideline-directed fluid resuscitation and concomitant HF or ESKD. Those receiving crystalloid fluid boluses of at least 30 mL/kg within 3 h of sepsis diagnosis were placed in the concordant group and all others in the nonconcordant group. The primary outcome was in-hospital mortality. Secondary outcomes included intensive care unit (ICU) and hospital length of stay (LOS); vasoactive medications and net volume over 24 h; new mechanical ventilation, new or increased volume removal, and acute kidney injury within 48 h; and shock-free survival at 7 days. RESULTS: One hundred twenty-five patients were included in each group. In-hospital mortality was 34.4% in the concordant group and 44.8% in the nonconcordant group (p = 0.1205). The concordant group had a shorter ICU LOS (7.6 vs. 10.5 days; p = 0.0214) and hospital LOS (12.9 vs. 18.3 days; p = 0.0163), but increased new mechanical ventilation (37.6 vs. 20.8%; p = 0.0052). No differences in other outcomes were observed. CONCLUSIONS: Receipt of a 30-mL/kg fluid bolus did not affect outcomes in a cohort of patients with mixed types of HF and sepsis-induced hypoperfusion.
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Hidratação , Insuficiência Cardíaca , Ressuscitação , Sepse , Choque Séptico , Humanos , Estudos Retrospectivos , Masculino , Feminino , Hidratação/métodos , Idoso , Pessoa de Meia-Idade , Sepse/complicações , Sepse/terapia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/terapia , Choque Séptico/terapia , Choque Séptico/complicações , Choque Séptico/mortalidade , Ressuscitação/métodos , Falência Renal Crônica/terapia , Falência Renal Crônica/complicações , Mortalidade Hospitalar , Tempo de Internação/estatística & dados numéricos , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Idoso de 80 Anos ou mais , Soluções Cristaloides/uso terapêutico , Soluções Cristaloides/administração & dosagem , Estudos de Coortes , Resultado do TratamentoRESUMO
Current treatment approaches for renal cell carcinoma (RCC) face challenges in achieving durable tumor responses due to tumor heterogeneity and drug resistance. Combination therapies that leverage tumor molecular profiles could offer an avenue for enhancing treatment efficacy and addressing the limitations of current therapies. To identify effective strategies for treating RCC, we selected ten drugs guided by tumor biology to test in six RCC patient-derived xenograft (PDX) models. The multitargeted tyrosine kinase inhibitor (TKI) cabozantinib and mTORC1/2 inhibitor sapanisertib emerged as the most effective drugs, particularly when combined. The combination demonstrated favorable tolerability and inhibited tumor growth or induced tumor regression in all models, including two from patients who experienced treatment failure with FDA-approved TKI and immunotherapy combinations. In cabozantinib-treated samples, imaging analysis revealed a significant reduction in vascular density, and single-nucleus RNA sequencing (snRNA-seq) analysis indicated a decreased proportion of endothelial cells in the tumors. SnRNA-seq data further identified a tumor subpopulation enriched with cell-cycle activity that exhibited heightened sensitivity to the cabozantinib and sapanisertib combination. Conversely, activation of the epithelial-mesenchymal transition pathway, detected at the protein level, was associated with drug resistance in residual tumors following combination treatment. The combination effectively restrained ERK phosphorylation and reduced expression of ERK downstream transcription factors and their target genes implicated in cell-cycle control and apoptosis. This study highlights the potential of the cabozantinib plus sapanisertib combination as a promising treatment approach for patients with RCC, particularly those whose tumors progressed on immune checkpoint inhibitors and other TKIs. SIGNIFICANCE: The molecular-guided therapeutic strategy of combining cabozantinib and sapanisertib restrains ERK activity to effectively suppress growth of renal cell carcinomas, including those unresponsive to immune checkpoint inhibitors.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Sistema de Sinalização das MAP Quinases , Inibidores de Checkpoint Imunológico/uso terapêutico , Alvo Mecanístico do Complexo 1 de Rapamicina , Células Endoteliais/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Anilidas/farmacologia , Anilidas/uso terapêutico , RNA Nuclear Pequeno/uso terapêuticoRESUMO
Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression and metastasis1-4. Although the genetic contributions to oncogenic transitions have been investigated, epigenetic drivers remain less understood. Here we constructed a pan-cancer epigenetic and transcriptomic atlas using single-nucleus chromatin accessibility data (using single-nucleus assay for transposase-accessible chromatin) from 225 samples and matched single-cell or single-nucleus RNA-sequencing expression data from 206 samples. With over 1 million cells from each platform analysed through the enrichment of accessible chromatin regions, transcription factor motifs and regulons, we identified epigenetic drivers associated with cancer transitions. Some epigenetic drivers appeared in multiple cancers (for example, regulatory regions of ABCC1 and VEGFA; GATA6 and FOX-family motifs), whereas others were cancer specific (for example, regulatory regions of FGF19, ASAP2 and EN1, and the PBX3 motif). Among epigenetically altered pathways, TP53, hypoxia and TNF signalling were linked to cancer initiation, whereas oestrogen response, epithelial-mesenchymal transition and apical junction were tied to metastatic transition. Furthermore, we revealed a marked correlation between enhancer accessibility and gene expression and uncovered cooperation between epigenetic and genetic drivers. This atlas provides a foundation for further investigation of epigenetic dynamics in cancer transitions.
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Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Neoplasias , Humanos , Hipóxia Celular , Núcleo Celular , Cromatina/genética , Cromatina/metabolismo , Elementos Facilitadores Genéticos/genética , Epigênese Genética/genética , Transição Epitelial-Mesenquimal , Estrogênios/metabolismo , Perfilação da Expressão Gênica , Proteínas Ativadoras de GTPase/metabolismo , Metástase Neoplásica , Neoplasias/classificação , Neoplasias/genética , Neoplasias/patologia , Sequências Reguladoras de Ácido Nucleico/genética , Análise de Célula Única , Fatores de Transcrição/metabolismoRESUMO
Breast cancer is a heterogeneous disease, and treatment is guided by biomarker profiles representing distinct molecular subtypes. Breast cancer arises from the breast ductal epithelium, and experimental data suggests breast cancer subtypes have different cells of origin within that lineage. The precise cells of origin for each subtype and the transcriptional networks that characterize these tumor-normal lineages are not established. In this work, we applied bulk, single-cell (sc), and single-nucleus (sn) multi-omic techniques as well as spatial transcriptomics and multiplex imaging on 61 samples from 37 breast cancer patients to show characteristic links in gene expression and chromatin accessibility between breast cancer subtypes and their putative cells of origin. We applied the PAM50 subtyping algorithm in tandem with bulk RNA-seq and snRNA-seq to reliably subtype even low-purity tumor samples and confirm promoter accessibility using snATAC. Trajectory analysis of chromatin accessibility and differentially accessible motifs clearly connected progenitor populations with breast cancer subtypes supporting the cell of origin for basal-like and luminal A and B tumors. Regulatory network analysis of transcription factors underscored the importance of BHLHE40 in luminal breast cancer and luminal mature cells, and KLF5 in basal-like tumors and luminal progenitor cells. Furthermore, we identify key genes defining the basal-like ( PRKCA , SOX6 , RGS6 , KCNQ3 ) and luminal A/B ( FAM155A , LRP1B ) lineages, with expression in both precursor and cancer cells and further upregulation in tumors. Exhausted CTLA4-expressing CD8+ T cells were enriched in basal-like breast cancer, suggesting altered means of immune dysfunction among breast cancer subtypes. We used spatial transcriptomics and multiplex imaging to provide spatial detail for key markers of benign and malignant cell types and immune cell colocation. These findings demonstrate analysis of paired transcription and chromatin accessibility at the single cell level is a powerful tool for investigating breast cancer lineage development and highlight transcriptional networks that define basal and luminal breast cancer lineages.
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Atezolizumab with chemotherapy has shown improved progression-free and overall survival in patients with metastatic PD-L1 positive triple negative breast cancer (TNBC). Atezolizumab with anthracycline- and taxane-based neoadjuvant chemotherapy has also shown increased pathological complete response (pCR) rates in early TNBC. This trial evaluated neoadjuvant carboplatin and paclitaxel with or without atezolizumab in patients with clinical stages II-III TNBC. The co-primary objectives were to evaluate if chemotherapy and atezolizumab increase pCR rate and tumor infiltrating lymphocyte (TIL) percentage compared to chemotherapy alone in the mITT population. Sixty-seven patients (ages 25-78 years; median, 52 years) were randomly assigned - 22 patients to Arm A, and 45 to Arm B. Median follow up was 6.6 months. In the modified intent to treat population (all patients evaluable for the primary endpoints who received at least one dose of combination therapy), the pCR rate was 18.8% (95% CI 4.0-45.6%) in Arm A, and 55.6% (95% CI 40.0-70.4%) in Arm B (estimated treatment difference: 36.8%, 95% CI 8.5-56.6%; p = 0.018). Grade 3 or higher treatment-related adverse events occurred in 62.5% of patients in Arm A, and 57.8% of patients in Arm B. One patient in Arm B died from recurrent disease during the follow-up period. TIL percentage increased slightly from baseline to cycle 1 in both Arm A (mean ± SD: 0.6% ± 21.0%) and Arm B (5.7% ± 15.8%) (p = 0.36). Patients with pCR had higher median TIL percentages (24.8%) than those with non-pCR (14.2%) (p = 0.02). Although subgroup analyses were limited by the small sample size, PD-L1-positive patients treated with chemotherapy and atezolizumab had a pCR rate of 75% (12/16). The addition of atezolizumab to neoadjuvant carboplatin and paclitaxel resulted in a statistically significant and clinically relevant increased pCR rate in patients with clinical stages II and III TNBC. (Funded by National Cancer Institute).
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PURPOSE: Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse model. Defactinib is a highly potent oral FAK inhibitor that has a tolerable safety profile. PATIENTS AND METHODS: We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a recommended phase II dose (RP2D). In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had stable disease (SD) after at least 4 months of standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and posttreatment tumor biopsies were performed to evaluate tumor immunity. RESULTS: The triple drug combination was well-tolerated, with no dose-limiting toxicities. Among 20 treated patients with refractory PDAC, the disease control rate (DCR) was 80%, with one partial response (PR) and 15 SDs, and the median progression-free survival (PFS) and overall survival (OS) were 3.6 and 7.8 months, respectively. Among 10 evaluable patients in the maintenance cohort, DCR was 70% with one PR and six SDs. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS on study treatment were 5.0 and 8.3 months, respectively. CONCLUSIONS: The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated and safe, had promising preliminary efficacy, and showed biomarker activity in infiltrative T lymphocytes. Efficacy of this strategy may require incorporation of more potent chemotherapy in future studies.
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Adenocarcinoma , Neoplasias Pancreáticas , Animais , Camundongos , Gencitabina , Desoxicitidina , Albuminas , Paclitaxel , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Pancreáticas/patologia , Adenocarcinoma/patologia , Neoplasias PancreáticasRESUMO
The effects of radiotherapy (RT) on tumor immunity in pancreatic ductal adenocarcinoma (PDAC) are not well understood. To better understand if RT can prime antigen-specific T-cell responses, we analyzed human PDAC tissues and mouse models. In both settings, there was little evidence of RT-induced T-cell priming. Using in vitro systems, we found that tumor-stromal components, including fibroblasts and collagen, cooperate to blunt RT efficacy and impair RT-induced interferon signaling. Focal adhesion kinase (FAK) inhibition rescued RT efficacy in vitro and in vivo, leading to tumor regression, T-cell priming, and enhanced long-term survival in PDAC mouse models. Based on these data, we initiated a clinical trial of defactinib in combination with stereotactic body RT in patients with PDAC (NCT04331041). Analysis of PDAC tissues from these patients showed stromal reprogramming mirroring our findings in genetically engineered mouse models. Finally, the addition of checkpoint immunotherapy to RT and FAK inhibition in animal models led to complete tumor regression and long-term survival. SIGNIFICANCE: Checkpoint immunotherapeutics have not been effective in PDAC, even when combined with RT. One possible explanation is that RT fails to prime T-cell responses in PDAC. Here, we show that FAK inhibition allows RT to prime tumor immunity and unlock responsiveness to checkpoint immunotherapy. This article is highlighted in the In This Issue feature, p. 2711.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Camundongos , Animais , Humanos , Proteína-Tirosina Quinases de Adesão Focal , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/radioterapia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/radioterapia , Imunoterapia , Microambiente Tumoral , Linhagem Celular Tumoral , Neoplasias PancreáticasRESUMO
Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve and 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin in tumor cells. Chemo-resistant samples contain a threefold enrichment of inflammatory cancer-associated fibroblasts that upregulate metallothioneins. Our study reveals a deeper understanding of the intricate substructure of pancreatic ductal adenocarcinoma tumors that could help improve therapy for patients with this disease.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/metabolismo , Transformação Celular Neoplásica/genética , Humanos , Pâncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Microambiente Tumoral/genética , Neoplasias PancreáticasRESUMO
Motivation: The use of single-cell methods is expanding at an ever-increasing rate. While there are established algorithms that address cell classification, they are limited in terms of cross platform compatibility, reliance on the availability of a reference dataset and classification interpretability. Here, we introduce Pollock, a suite of algorithms for cell type identification that is compatible with popular single-cell methods and analysis platforms, provides a set of pretrained human cancer reference models, and reports interpretability scores that identify the genes that drive cell type classifications. Results: Pollock performs comparably to existing classification methods, while offering easily deployable pretrained classification models across a wide variety of tissue and data types. Additionally, it demonstrates utility in immune pan-cancer analysis. Availability and implementation: Source code and documentation are available at https://github.com/ding-lab/pollock. Pretrained models and datasets are available for download at https://zenodo.org/record/5895221. Supplementary information: Supplementary data are available at Bioinformatics Advances online.
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Combination chemotherapies remain the cornerstone treatment for pancreatic ductal adenocarcinoma (PDAC), but de novo and acquired resistance is common. In this study, we aimed to identify and characterize resistance mechanisms to a FIRINOX chemotherapy regimen (a combination of 5-fluorouracil, irinotecan, and oxaliplatin) because it is the most aggressive regimen currently used clinically for patients with PDAC. Using an unbiased reverse-phase protein array, we detected phospho-activation of heat shock protein 27 (Hsp27) as the most up-regulated event after FIRINOX treatment in PDAC cells. Silencing HSP27 by RNA interference or by a small-molecule inhibitor enhanced apoptosis caused by FIRINOX in vitro. Mechanistically, FIRINOX up-regulated tumor necrosis factorα (TNFα), causing autocrine phosphorylation and activation of transforming growth factorßactivated kinase 1 (TAK1), MAPK activated protein kinase 2 (MAPKAPK2 or MK2), and, ultimately, Hsp27. Targeting MK2, the kinase that directly phosphorylates Hsp27, abrogated Hsp27 activation, sensitized PDAC cells to apoptosis, and suppressed SN-38induced protective autophagy in vitro, in part by blocking phospho-activation of Beclin1. In an autochthonous PDAC mouse model, the MK2 inhibitor ATI-450 decreased PDAC development and progression. When combined with FIRINOX, ATI-450 eliminated most PDAC foci and marked prolonged mouse survival without causing additional toxicity. Last, we found that high phospho-MK2 expression in tumors was associated with poorer survival of patients with PDAC. Our study identified MK2 as a mediator of genotoxic stressinduced activation of prosurvival pathways and provides preclinical support for combining an MK2 inhibitor with FIRINOX-based chemotherapies to treat PDAC.
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Adenocarcinoma , Neoplasias Pancreáticas , Animais , Linhagem Celular Tumoral , Dano ao DNA , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Serina-Treonina QuinasesRESUMO
Herein, we report on a patient with known Lynch syndrome and periampullary adenocarcinoma that exhibited a pathological complete response to neoadjuvant nivolumab plus ipilimumab. Two MSH2 mutations, high microsatellite instability, high tumor mutational burden, and elevated PD-L1 expression were identified by next-generation sequencing and immunohistochemistry. Following FOLFIRINOX (Fluorouracil/Leucovorin/Irinotecan/Oxaliplatin) administration and disease progression, nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) were administered every 3 weeks for four total cycles. The patient responded well with minimal adverse effects and significant improvement in epigastric pain, appetite, and body weight. She then underwent resection consisting of pancreaticoduodenectomy, which demonstrated pathological complete response. Complete genomic profiling of periampullary carcinomas is crucial for optimal treatment selection as true ampullary masses and pancreatic ductal adenocarcinoma have different genetic profiles. This case provides an example of a patient who may have further benefited from first-line nivolumab plus ipilimumab to avoid the reduced efficacy and significant side effects associated with chemotherapy. KEY POINTS: A patient with known Lynch syndrome and ampullary adenocarcinoma harboring two MSH2 mutations, high microsatellite instability (MSI-high), high tumor mutational burden (TMB), and elevated PD-L1 expression achieved pathological complete response with neoadjuvant nivolumab plus ipilimumab. The combination of nivolumab plus ipilimumab may be a better first-line option for patients with ampullary adenocarcinomas harboring deficient mismatch repair, MSI-high, and high TMB. Complete genomic profiling of periampullary adenocarcinomas is crucial for optimal treatment selection as true ampullary masses and pancreatic ductal adenocarcinoma have different genetic profiles. The presence of either MSI-high or high TMB could be an appropriate predictive biomarker for response to nivolumab plus ipilimumab in the context of Lynch syndrome.
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Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Ipilimumab/uso terapêutico , Terapia Neoadjuvante , Nivolumabe/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genéticaRESUMO
BACKGROUND: EpCAM (Epithelial cell adhesion molecule) is often dysregulated in epithelial cancers. Prior studies implicate EpCAM in the regulation of oncogenic signaling pathways and epithelial-to-mesenchymal transition. It was recently demonstrated that EpCAM contains a thyroglobulin type-1 (TY-1) domain. Multiple proteins with TY-1 domains are known to inhibit cathepsin-L (CTSL), a cysteine protease that promotes tumor cell invasion and metastasis. Analysis of human cancer sequencing studies reveals that somatic EpCAM mutations are present in up to 5.1% of tested tumors. METHODS: The Catalogue of Somatic Mutations in Cancer (COSMIC) database was queried to tabulate the position and amino acid changes of cancer associated EpCAM mutations. To determine how EpCAM mutations affect cancer biology we studied C66Y, a damaging TY-1 domain mutation identified in liver cancer, as well as 13 other cancer-associated EpCAM mutations. In vitro and in vivo models were used to determine the effect of wild type (WT) and mutant EpCAM on CTSL activity and invasion. Immunoprecipitation and localization studies tested EpCAM and CTSL protein binding and determined compartmental expression patterns of EpCAM mutants. RESULTS: We demonstrate that WT EpCAM, but not C66Y EpCAM, inhibits CTSL activity in vitro, and the TY-1 domain of EpCAM is responsible for this inhibition. WT EpCAM, but not C66Y EpCAM, inhibits tumor cell invasion in vitro and lung metastases in vivo. In an extended panel of human cancer cell lines, EpCAM expression is inversely correlated with CTSL activity. Previous studies have demonstrated that EpCAM germline mutations can prevent EpCAM from being expressed at the cell surface. We demonstrate that C66Y and multiple other EpCAM cancer-associated mutations prevent surface expression of EpCAM. Cancer-associated mutations that prevent EpCAM cell surface expression abrogate the ability of EpCAM to inhibit CTSL activity and tumor cell invasion. CONCLUSIONS: These studies reveal a novel role for EpCAM as a CTSL inhibitor, confirm the functional relevance of multiple cancer-associated EpCAM mutations, and suggest a therapeutic vulnerability in cancers harboring EpCAM mutations.
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Catepsina L/antagonistas & inibidores , Molécula de Adesão da Célula Epitelial/genética , Mutação , Neoplasias/genética , Animais , Catepsina L/fisiologia , Molécula de Adesão da Célula Epitelial/fisiologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Invasividade NeoplásicaRESUMO
BACKGROUND: Preclinical studies and early clinical trials have shown that targeting cancer neoantigens is a promising approach towards the development of personalized cancer immunotherapies. DNA vaccines can be rapidly and efficiently manufactured and can integrate multiple neoantigens simultaneously. We therefore sought to optimize the design of polyepitope DNA vaccines and test optimized polyepitope neoantigen DNA vaccines in preclinical models and in clinical translation. METHODS: We developed and optimized a DNA vaccine platform to target multiple neoantigens. The polyepitope DNA vaccine platform was first optimized using model antigens in vitro and in vivo. We then identified neoantigens in preclinical breast cancer models through genome sequencing and in silico neoantigen prediction pipelines. Optimized polyepitope neoantigen DNA vaccines specific for the murine breast tumor E0771 and 4T1 were designed and their immunogenicity was tested in vivo. We also tested an optimized polyepitope neoantigen DNA vaccine in a patient with metastatic pancreatic neuroendocrine tumor. RESULTS: Our data support an optimized polyepitope neoantigen DNA vaccine design encoding long (≥20-mer) epitopes with a mutant form of ubiquitin (Ubmut) fused to the N-terminus for antigen processing and presentation. Optimized polyepitope neoantigen DNA vaccines were immunogenic and generated robust neoantigen-specific immune responses in mice. The magnitude of immune responses generated by optimized polyepitope neoantigen DNA vaccines was similar to that of synthetic long peptide vaccines specific for the same neoantigens. When combined with immune checkpoint blockade therapy, optimized polyepitope neoantigen DNA vaccines were capable of inducing antitumor immunity in preclinical models. Immune monitoring data suggest that optimized polyepitope neoantigen DNA vaccines are capable of inducing neoantigen-specific T cell responses in a patient with metastatic pancreatic neuroendocrine tumor. CONCLUSIONS: We have developed and optimized a novel polyepitope neoantigen DNA vaccine platform that can target multiple neoantigens and induce antitumor immune responses in preclinical models and neoantigen-specific responses in clinical translation.
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Antígenos de Neoplasias/imunologia , Epitopos/imunologia , Imunidade , Pesquisa Translacional Biomédica , Vacinas de DNA/imunologia , Adulto , Animais , Apresentação de Antígeno/imunologia , Proliferação de Células , Modelos Animais de Doenças , Feminino , Células HeLa , Humanos , Inibidores de Checkpoint Imunológico , Imunoterapia , Masculino , Neoplasias Mamárias Animais/patologia , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Tumores Neuroendócrinos/imunologia , Tumores Neuroendócrinos/patologia , Peptídeos/imunologia , Linfócitos T/imunologiaRESUMO
INTRODUCTION: Parkinson disease (PD) has been associated with both weight loss and gain in different stages of the disease. Our study aimed to determine the prevalence and associations with weight change over two years based on 3% and 5% weight change. METHODS: In this longitudinal analysis, weight at baseline and follow-up was used to classify patients into groups of weight loss, stable, and weight gain. Differences between these groups at baseline and then with change over time were tested. RESULTS: The sample was 668 patients with mean(SD) age 66.1(10) and disease duration 5.3(5.4) years. Using 3% weight change criteria: 32.6% lost, 23.1% gained, and 55.7% had stable weight. Using 5% criteria: 22.6% lost, 15.7% gained, and 61.7% had stable weight. Age was associated with both 3% and 5% change in weight. Other associations with 5% weight change were disease duration, Total and Motor Unified Parkinson's Disease Rating Scale, Older Americans Resource and Services disability, and Hoehn & Yahr staging. The effects of 3% weight loss on Motor UPDRS, IADLs, and depression, and the effects of 5% weight loss on IADLs remained statistically significant when controlling for baseline differences in age, levodopa use, and Total UPDRS. CONCLUSION: PD patients are more likely to experience 3% than 5% weight change and this lower threshold of weight change was associated with greater disease severity and disability over time. Attention to more subtle weight change may help identify those at greater risk of disability.
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Doença de Parkinson/fisiopatologia , Aumento de Peso/fisiologia , Redução de Peso/fisiologia , Idoso , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
BACKGROUND AND AIM: More prospective studies are needed to characterize fibrosis improvement in patients with hepatitis C virus (HCV) who are treated with direct-acting antivirals (DAAs). The aims of this study were to assess changes in elastography scores from baseline to 1-year follow-up in patients with HCV, to identify factors that were independently associated with improvement in fibrosis staging in patients who receive treatment, and to identify factors that were independently associated with no improvement in fibrosis staging among patients who achieved sustained virologic responses (SVR). METHODS: Ultrasound elastography and laboratory tests were performed and collected at baseline and at 1-year follow-up for patients who received HCV treatment and for those who did not receive treatment (n = 240). Binomial logistic regression was used to examine factors that were independently associated with improvement in fibrosis staging. RESULTS: In patients who achieved SVR, the mean fibrosis score decreased significantly (-1.3) from 7.4 (2.3) before treatment to 6.1 (2.0) after treatment (P = 0.00). In multivariate analysis of patients who received treatment, higher pre-treatment fibrosis stages [odds ratio (OR) = 13.02, P < 0.00] were positively associated with improvement in fibrosis staging at 1-year follow-up. Higher BMI (OR = 0.93, P < 0.05) was negatively associated with improvement in fibrosis staging. DISCUSSION: This study supports the growing body of literature that suggests fibrosis regression is achievable in a significant number of patients who achieve SVR with all-oral DAA regimens. Equally important, fibrosis regression is more likely to occur in patients with advanced stages of fibrosis and less likely in patients who are obese.
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Hepatite C Crônica , Hepatite C , Antivirais/uso terapêutico , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/tratamento farmacológico , Resposta Viral SustentadaRESUMO
Aberrant activation of the NF-κB transcription factors underlies chemoresistance in various cancer types, including colorectal cancer (CRC). Targeting the activating mechanisms, particularly with inhibitors to the upstream IκB kinase (IKK) complex, is a promising strategy to augment the effect of chemotherapy. However, clinical success has been limited, largely because of low specificity and toxicities of tested compounds. In solid cancers, the IKKs are driven predominantly by the Toll-like receptor (TLR)/IL-1 receptor family members, which signal through the IL-1 receptor-associated kinases (IRAKs), with isoform 4 (IRAK4) being the most critical. The pathogenic role and therapeutic value of IRAK4 in CRC have not been investigated. We found that IRAK4 inhibition significantly abrogates colitis-induced neoplasm in APCMin/+ mice, and bone marrow transplant experiments showed an essential role of IRAK4 in immune cells during neoplastic progression. Chemotherapy significantly enhances IRAK4 and NF-κB activity in CRC cells through upregulating TLR9 expression, which can in turn be suppressed by IRAK4 and IKK inhibitors, suggesting a feed-forward pathway that protects CRC cells from chemotherapy. Lastly, increased tumor phospho-IRAK4 staining or IRAK4 mRNA expression is associated with significantly worse survival in CRC patients. Our results support targeting IRAK4 to improve the effects of chemotherapy and outcomes in CRC.
Assuntos
Carcinogênese/genética , Colite/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Animais , Transplante de Medula Óssea , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Colite/genética , Colite/patologia , Colo/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Tratamento Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença/genética , Quinase I-kappa B/genética , Imunidade Inata , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Quinases Associadas a Receptores de Interleucina-1/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Receptor Toll-Like 9/metabolismo , Receptores Toll-Like , Fatores de Transcrição , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Although checkpoint immunotherapies have revolutionized the treatment of cancer, not all tumor types have seen substantial benefit. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy in which very limited responses to immunotherapy have been observed. Extensive immunosuppressive myeloid cell infiltration in PDAC tissues has been postulated as a major mechanism of resistance to immunotherapy. Strategies concomitantly targeting monocyte or granulocyte trafficking or macrophage survival, in combination with checkpoint immunotherapies, have shown promise in preclinical studies, and these studies have transitioned into ongoing clinical trials for the treatment of pancreatic and other cancer types. However, compensatory actions by untargeted monocytes, granulocytes, and/or tissue resident macrophages may limit the therapeutic efficacy of such strategies. CD11b/CD18 is an integrin molecule that is highly expressed on the cell surface of these myeloid cell subsets and plays an important role in their trafficking and cellular functions in inflamed tissues. Here, we demonstrate that the partial activation of CD11b by a small-molecule agonist (ADH-503) leads to the repolarization of tumor-associated macrophages, reduction in the number of tumor-infiltrating immunosuppressive myeloid cells, and enhanced dendritic cell responses. These actions, in turn, improve antitumor T cell immunity and render checkpoint inhibitors effective in previously unresponsive PDAC models. These data demonstrate that molecular agonism of CD11b reprograms immunosuppressive myeloid cell responses and potentially bypasses the limitations of current clinical strategies to overcome resistance to immunotherapy.