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1.
bioRxiv ; 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38463958

RESUMO

Despite the success of BCMA-targeting CAR-Ts in multiple myeloma, patients with high-risk cytogenetic features still relapse most quickly and are in urgent need of additional therapeutic options. Here, we identify CD70, widely recognized as a favorable immunotherapy target in other cancers, as a specifically upregulated cell surface antigen in high risk myeloma tumors. We use a structure-guided design to define a CD27-based anti-CD70 CAR-T design that outperforms all tested scFv-based CARs, leading to >80-fold improved CAR-T expansion in vivo. Epigenetic analysis via machine learning predicts key transcription factors and transcriptional networks driving CD70 upregulation in high risk myeloma. Dual-targeting CAR-Ts against either CD70 or BCMA demonstrate a potential strategy to avoid antigen escape-mediated resistance. Together, these findings support the promise of targeting CD70 with optimized CAR-Ts in myeloma as well as future clinical translation of this approach.

2.
Sci Adv ; 7(6)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33536218

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease-19 (COVID-19), has emerged as the cause of a global pandemic. We used RNA sequencing to analyze 286 nasopharyngeal (NP) swab and 53 whole-blood (WB) samples from 333 patients with COVID-19 and controls. Overall, a muted immune response was observed in COVID-19 relative to other infections (influenza, other seasonal coronaviruses, and bacterial sepsis), with paradoxical down-regulation of several key differentially expressed genes. Hospitalized patients and outpatients exhibited up-regulation of interferon-associated pathways, although heightened and more robust inflammatory responses were observed in hospitalized patients with more clinically severe illness. Two-layer machine learning-based host classifiers consisting of complete (>1000 genes), medium (<100), and small (<20) gene biomarker panels identified COVID-19 disease with 85.1-86.5% accuracy when benchmarked using an independent test set. SARS-CoV-2 infection has a distinct biosignature that differs between NP swabs and WB and can be leveraged for COVID-19 diagnosis.


Assuntos
COVID-19/diagnóstico , Nasofaringe/virologia , RNA Viral/metabolismo , SARS-CoV-2/genética , Área Sob a Curva , COVID-19/metabolismo , COVID-19/patologia , COVID-19/virologia , Biblioteca Gênica , Humanos , Aprendizado de Máquina , RNA Viral/sangue , Curva ROC , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SARS-CoV-2/isolamento & purificação , Sensibilidade e Especificidade , Transcriptoma
3.
Nat Commun ; 11(1): 4698, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943630

RESUMO

Given the limited availability of serological testing to date, the seroprevalence of SARS-CoV-2-specific antibodies in different populations has remained unclear. Here, we report very low SARS-CoV-2 seroprevalence in two San Francisco Bay Area populations. Seroreactivity was 0.26% in 387 hospitalized patients admitted for non-respiratory indications and 0.1% in 1,000 blood donors in early April 2020. We additionally describe the longitudinal dynamics of immunoglobulin-G (IgG), immunoglobulin-M (IgM), and in vitro neutralizing antibody titers in COVID-19 patients. The median time to seroconversion ranged from 10.3-11.0 days for these 3 assays. Neutralizing antibodies rose in tandem with immunoglobulin titers following symptom onset, and positive percent agreement between detection of IgG and neutralizing titers was >93%. These findings emphasize the importance of using highly accurate tests for surveillance studies in low-prevalence populations, and provide evidence that seroreactivity using SARS-CoV-2 anti-nucleocapsid protein IgG and anti-spike IgM assays are generally predictive of in vitro neutralizing capacity.


Assuntos
Anticorpos Neutralizantes/sangue , Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Anticorpos Antivirais/imunologia , COVID-19 , Teste para COVID-19 , Técnicas de Laboratório Clínico , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/imunologia , SARS-CoV-2 , São Francisco/epidemiologia , Sensibilidade e Especificidade , Estudos Soroepidemiológicos , Testes Sorológicos/métodos
4.
Anticancer Res ; 40(7): 3995-4000, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620643

RESUMO

We present here the case of a 39-year-old man with metastatic pancreatic carcinoma receiving chemotherapy with the combination of gemcitabine and nab-paclitaxel as part of a clinical trial. Despite an impressive response to therapy, he ultimately developed profound anasarca, renal insufficiency, progressive cytopenias, and malignant hypertension 6 months into his treatment course. The diagnosis of gemcitabine-associated thrombotic microangiopathy (G-TMA) was made based on renal biopsy, and receipt of the anti-C5 monoclonal antibody eculizumab proved successful at reversing his deteriorating clinical course and improving his laboratory parameters. This case illustrates the importance of recognizing this rare but serious complication, and highlights one potential therapeutic option that can be used in the appropriate clinical context.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antimetabólitos Antineoplásicos/efeitos adversos , Inativadores do Complemento/uso terapêutico , Desoxicitidina/análogos & derivados , Microangiopatias Trombóticas/tratamento farmacológico , Adulto , Albuminas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/efeitos adversos , Evolução Fatal , Humanos , Masculino , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Microangiopatias Trombóticas/induzido quimicamente , Gencitabina , Neoplasias Pancreáticas
5.
medRxiv ; 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32511477

RESUMO

We report very low SARS-CoV-2 seroprevalence in two San Francisco Bay Area populations. Seropositivity was 0.26% in 387 hospitalized patients admitted for non-respiratory indications and 0.1% in 1,000 blood donors. We additionally describe the longitudinal dynamics of immunoglobulin-G, immunoglobulin-M, and in vitro neutralizing antibody titers in COVID-19 patients. Neutralizing antibodies rise in tandem with immunoglobulin levels following symptom onset, exhibiting median time to seroconversion within one day of each other, and there is >93% positive percent agreement between detection of immunoglobulin-G and neutralizing titers.

6.
WMJ ; 117(3): 130-132, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30193023

RESUMO

INTRODUCTION: Eosinophilic meningitis is an infrequently encountered condition. Baylisascaris procyonis (raccoon roundworm) infection, rarely diagnosed in North America, is a known cause of eosinophilic meningitis, often producing death or permanent neurologic damage. CASE REPORT: We recently encountered a toddler with geophagia and probable exposure to raccoon feces, who presented with eosinophilic meningitis and encephalitis, and was diagnosed with B procyonis infection and possible Toxocara co-infection. His marked peripheral eosinophilia and neurologic symptoms rapidly responded to corticosteroid and albendazole therapy. DISCUSSION: Since B procyonis infection is infrequently encountered, its diagnosis in the proper clinical and epidemiologic setting may not always be considered, resulting in a delay of appropriate therapy. Our patient, diagnosed and treated early in his course, demonstrated rapid clinical and laboratory improvement with anti-inflammatory and antiparasitic therapy. CONCLUSION: In cases of eosinophilic meningitis, infection with B procyonis should be routinely considered to allow timely institution of effective therapy for this unusual but potentially fatal or debilitating infection.


Assuntos
Infecções por Ascaridida/complicações , Infecções por Ascaridida/diagnóstico , Meningoencefalite/parasitologia , Corticosteroides/uso terapêutico , Albendazol/uso terapêutico , Animais , Anti-Helmínticos/uso terapêutico , Infecções por Ascaridida/tratamento farmacológico , Diagnóstico Diferencial , Quimioterapia Combinada , Humanos , Lactente , Masculino , Meningoencefalite/tratamento farmacológico , Guaxinins
8.
Cancer Res ; 76(9): 2525-39, 2016 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-26980767

RESUMO

In early pancreatic carcinogenesis, TGFß acts as a tumor suppressor due to its growth-inhibitory effects in epithelial cells. However, in advanced disease, TGFß appears to promote tumor progression. Therefore, to better understand the contributions of TGFß signaling to pancreatic carcinogenesis, we generated mouse models of pancreatic cancer with either epithelial or systemic TGFBR deficiency. We found that epithelial suppression of TGFß signals facilitated pancreatic tumorigenesis, whereas global loss of TGFß signaling protected against tumor development via inhibition of tumor-associated fibrosis, stromal TGFß1 production, and the resultant restoration of antitumor immune function. Similarly, TGFBR-deficient T cells resisted TGFß-induced inactivation ex vivo, and adoptive transfer of TGFBR-deficient CD8(+) T cells led to enhanced infiltration and granzyme B-mediated destruction of developing tumors. These findings paralleled our observations in human patients, where TGFß expression correlated with increased fibrosis and associated negatively with expression of granzyme B. Collectively, our findings suggest that, despite opposing the proliferation of some epithelial cells, TGFß may promote pancreatic cancer development by affecting stromal and hematopoietic cell function. Therefore, the use of TGFBR inhibition to target components of the tumor microenvironment warrants consideration as a potential therapy for pancreatic cancer, particularly in patients who have already lost tumor-suppressive TGFß signals in the epithelium. Cancer Res; 76(9); 2525-39. ©2016 AACR.


Assuntos
Carcinogênese/metabolismo , Neoplasias Pancreáticas/patologia , Fator de Crescimento Transformador beta/metabolismo , Evasão Tumoral/fisiologia , Microambiente Tumoral/fisiologia , Transferência Adotiva , Animais , Western Blotting , Carcinogênese/patologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Fibrose/metabolismo , Fibrose/patologia , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Mutantes , Transdução de Sinais/fisiologia
9.
Mol Cancer ; 14: 182, 2015 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-26497569

RESUMO

BACKGROUND: Understanding cell signaling pathways that contribute to metastatic colon cancer is critical to risk stratification in the era of personalized therapeutics. Here, we dissect the unique involvement of mitogenic pathways in a TGFß or activin-induced metastatic phenotype of colon cancer. METHOD: Mitogenic signaling/growth factor receptor status and p21 localization were correlated in primary colon cancers and intestinal tumors from either AOM/DSS treated ACVR2A (activin receptor 2) -/- or wild type mice. Colon cancer cell lines (+/- SMAD4) were interrogated for ligand-induced PI3K and MEK/ERK pathway activation and downstream protein/phospho-isoform expression/association after knockdown and pharmacologic inhibition of pathway members. EMT was assessed using epithelial/mesenchymal markers and migration assays. RESULTS: In primary colon cancers, loss of nuclear p21 correlated with upstream activation of activin/PI3K while nuclear p21 expression was associated with TGFß/MEK/ERK pathway activation. Activin, but not TGFß, led to PI3K activation via interaction of ACVR1B and p85 independent of SMAD4, resulting in p21 downregulation. In contrast, TGFß increased p21 via MEK/ERK pathway through a SMAD4-dependent mechanism. While activin induced EMT via PI3K, TGFß induced EMT via MEK/ERK activation. In vivo, loss of ACVR2A resulted in loss of pAkt, consistent with activin-dependent PI3K signaling. CONCLUSION: Although activin and TGFß share growth suppressive SMAD signaling in colon cancer, they diverge in their SMAD4-independent pro-migratory signaling utilizing distinct mitogenic signaling pathways that affect EMT. p21 localization in colon cancer may determine a dominant activin versus TGFß ligand signaling phenotype warranting further validation as a therapeutic biomarker prior to targeting TGFß family receptors.


Assuntos
Ativinas/metabolismo , Neoplasias do Colo/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Receptores de Activinas Tipo II/genética , Receptores de Activinas Tipo II/metabolismo , Ativinas/genética , Animais , Western Blotting , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Imuno-Histoquímica , Imunoprecipitação , Técnicas In Vitro , Camundongos , Camundongos Knockout , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/genética
10.
Oncoimmunology ; 3(8): e952202, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25960931

RESUMO

Whereas the presence of autoantibodies in cancer patients has been acknowledged, their diagnostic or therapeutic significance has yet to be established. This is due, at least in part, to the lack of robust screening techniques to detect and characterize such antibodies for further assessment. In this study, we screened colorectal cancer (CRC) patient sera for antibodies specifically targeting the key cell cycle inhibitory factor p21 encoded by the cyclin-dependent kinase inhibitor 1A (CDKN1A). Anti-p21 antibody titers were higher in CRC patient samples versus controls, correlating with a more advanced disease stage and lymph node involvement. Further, we isolated for the first time a specific human antibody fragment against p21, which could potentially be useful as a tool to study tumorigenicity in CRC patients.

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