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1.
Artigo em Inglês | MEDLINE | ID: mdl-34348541

RESUMO

Background: Although noninvasive ventilation (NIV) improves survival and quality of life (QOL) in ALS, use of NIV is suboptimal. Objective: To determine compliance with "early" NIV initiation, requisite for the feasibility of a large study of early NIV initiation, and examine factors impacting compliance. Methods: Seventy-three ALS participants with forced vital capacities (FVC) >50% were enrolled. Participants with FVC over 80% (Group 1) were initiated on NIV early (FVC between 80 and 85%). Participants with FVC between 50 and 80% (Group 2) started NIV at FVC between 50 and 55%. Symptom surveys, QOL scores, and NIV compliance (machine download documenting use ≥4 hours/night >60% of time) were collected following NIV initiation. Results: 53.6% of Group 1 and 50% of Group 2 were compliant 28 days following NIV initiation, with increased compliance over time. Participants who were unmarried, had lower income, lower educational attainment, or limited caregiver availability were less likely to be compliant. Bothersome symptoms in non-compliant participants included facial air pressure, frequent arousals with difficulty returning to sleep, and claustrophobia. Both compliant and noncompliant participants felt improved QOL with NIV; improvement was significantly greater in compliant participants. Conclusions: These data suggest ALS patients can comply with NIV early in their disease, and potentially benefit as evidenced by improved QOL scores, supporting both feasibility and need for a study comparing early versus late NIV initiation. Moreover, modifiable symptoms were identified that could be optimized to improve compliance. Further studies are needed to determine the impact of "early" intervention on survival and QOL.


Assuntos
Esclerose Amiotrófica Lateral , Ventilação não Invasiva , Insuficiência Respiratória , Esclerose Amiotrófica Lateral/terapia , Humanos , Cooperação do Paciente , Qualidade de Vida , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Capacidade Vital
2.
Zh Nevrol Psikhiatr Im S S Korsakova ; 121(7. Vyp. 2): 5-12, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34387440

RESUMO

Neuromyelitis optica spectrum disorder (NMOSD) is a group of rare and mostly severe autoimmune demyelinating central nervous system disorders which prevalence is 0.7-1 per 100.000 population and incidence is 0.037-0.73 per 100.000 person-years. NMOSD may present as a combination of uni- or bilateral optic neuritis, transverse myelitis or lesions of brain stem and other brain regions. The symptoms are mostly relapsing (up to 97.5%) and progressive. Occurrence of relapses is associated with seropositivity for aquaporin-4 (up to 80% of NMOSD patients) and bears a less favorable prognosis (mortality up to 32%). Women seropositive for aquaporin 4 constitute 90% of NMOSD patients. Compared to other demyelinating disorders, NMOSD is characterized by late onset (mean age is about 39 years) and association with other autoimmune disorders, including systemic lupus erythematosus, myasthenia gravis and Sjogren's syndrome. A genetic predisposition was found among Blacks and Asians, with HLA-DRB1*03:01 gene associated with higher risk of NMOSD in Asians. The course of the disease tends to be more severe in Blacks. There are clusters of an increased incidence of NMOSD in the Carribeans and in the Far East. Continued increase of prevalence and incidence of NMOSD worldwide compels continued epidemiological research in order to provide early diagnosis and treatment for this disorder.


Assuntos
Miastenia Gravis , Neuromielite Óptica , Neurite Óptica , Adulto , Aquaporina 4 , Feminino , Humanos , Recidiva Local de Neoplasia , Neuromielite Óptica/epidemiologia
3.
Cancer Immunol Res ; 9(10): 1141-1157, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34376502

RESUMO

The use of cytokines for immunotherapy shows clinical efficacy but is frequently accompanied by severe adverse events caused by excessive and systemic immune activation. Here, we set out to address these challenges by engineering a fusion protein of a single, potency-reduced, IL15 mutein and a PD1-specific antibody (anti-PD1-IL15m). This immunocytokine was designed to deliver PD1-mediated, avidity-driven IL2/15 receptor stimulation to PD1+ tumor-infiltrating lymphocytes (TIL) while minimally affecting circulating peripheral natural killer (NK) cells and T cells. Treatment of tumor-bearing mice with a mouse cross-reactive fusion, anti-mPD1-IL15m, demonstrated potent antitumor efficacy without exacerbating body weight loss in B16 and MC38 syngeneic tumor models. Moreover, anti-mPD1-IL15m was more efficacious than an IL15 superagonist, an anti-mPD-1, or the combination thereof in the B16 melanoma model. Mechanistically, anti-PD1-IL15m preferentially targeted CD8+ TILs and single-cell RNA-sequencing analyses revealed that anti-mPD1-IL15m treatment induced the expansion of an exhausted CD8+ TIL cluster with high proliferative capacity and effector-like signatures. Antitumor efficacy of anti-mPD1-IL15m was dependent on CD8+ T cells, as depletion of CD8+ cells resulted in the loss of antitumor activity, whereas depletion of NK cells had little impact on efficacy. The impact of anti-hPD1-IL15m on primary human TILs from patients with cancer was also evaluated. Anti-hPD1-IL15m robustly enhanced the proliferation, activation, and cytotoxicity of CD8+ and CD4+ TILs from human primary cancers in vitro, whereas tumor-derived regulatory T cells were largely unaffected. Taken together, our findings showed that anti-PD1-IL15m exhibits a high translational promise with improved efficacy and safety of IL15 for cancer immunotherapy via targeting PD1+ TILs.See related Spotlight by Felices and Miller, p. 1110.

4.
Adv Sci (Weinh) ; 8(8): 2004320, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33898197

RESUMO

Cancer stem cells (CSCs) presumably contribute to tumor progression and drug resistance, yet their definitive features have remained elusive. Here, simultaneous measurement of telomere length and transcriptome in the same cells enables systematic assessment of CSCs in primary colorectal cancer (CRC). The in-depth transcriptome profiled by SMART-seq2 is independently validated by high-throughput scRNA-seq using 10 × Genomics. It is found that rare CSCs exist in dormant state and display plasticity toward cancer epithelial cells (EPCs) that essentially are presumptive tumor-initiating cells (TICs), while both retaining the prominent signaling pathways including WNT, TGF-ß, and HIPPO/YAP. Moreover, CSCs exhibit chromosome copy number variation (CNV) pattern resembling cancer EPCs but distinct from normal stem cells, suggesting the phylogenetic relationship between CSCs and cancer EPCs. Notably, CSCs maintain shorter telomeres and possess minimal telomerase activity consistent with their nonproliferative nature, unlike cancer EPCs. Additionally, the specific signature of CSCs particularly NOTUM, SMOC2, BAMBI, PHLDA1, and TNFRSF19 correlates with the prognosis of CRC. These findings characterize the heterogeneity of CSCs and their linkage to cancer EPCs/TICs, some of which are conventionally regarded as CSCs.

5.
Mol Cancer Ther ; 19(10): 2105-2116, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32847983

RESUMO

Development of antagonistic mAbs that specifically target the immune checkpoint receptor, programmed cell death protein-1 (PD-1), is of great interest for cancer immunotherapy. Here, we report the biophysical characteristics and nonclinical antagonistic activities of sasanlimab (PF-06801591), a humanized anti-PD-1 antibody of IgG4 isotype. We show that sasanlimab binds selectively and with similar high potency to human and cynomolgus monkey PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, with no detectable Fc-dependent effector function. The binding of sasanlimab to human and cynomolgus PD-1 is associated with the formation of a stable complex, which is likely to be the main driver of this high-affinity interaction. In vitro, sasanlimab significantly augmented T-cell proliferation and cytokine production in mixed lymphocyte reaction and superantigen stimulation assays. In vivo, sasanlimab accelerated the incidence of GvHD by enhancing T-cell proliferation and cytokine secretion in a xenogeneic model of acute GvHD and halted the growth of MC-38 colon adenocarcinoma tumors in human PD-1 knock-in mice. Pharmacokinetic and toxicokinetic findings from cynomolgus monkey showed that sasanlimab was active and well-tolerated. Taken together, the data presented here support the clinical development of sasanlimab for the treatment of patients with advanced cancers as a single agent or in combination with other immunotherapies.

6.
J Endocr Soc ; 4(7): bvaa074, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32666014

RESUMO

Management of gender-affirming hormone therapy (HT) in transgender women includes surveillance of testosterone (T) levels. Failure of T to suppress, despite adherence to therapy, warrants additional investigations for unexpected sources of T or factors stimulating T secretion. Possible causes include T or gonadotropin production by an occult neoplasm. Testicular cancer is the most common malignancy affecting biological men aged between 15 and 35 years. Patients may be asymptomatic until tumor burden is high and/or metastatic. Hormone-producing tumors have rarely been reported in treated transgender women. Routine screening tests are recommended in a gender-incongruent person as per the 2017 Endocrine Society guidelines with measurement of T levels every 3 months initially to reach a goal of less than 50 ng/dL. Expectations should be discussed in detail with the transgender person since anticipated physical changes may not be notable for 6 to 18 months. We herein describe a case of a transgender woman who underwent standard HT including gonadotropin suppression with a gonadotropin-releasing hormone agonist, whose total T level failed to suppress. Testing revealed an elevated serum level of the beta subunit of human chorionic gonadotropin (ß-hCG), diagnostic of an hCG-secreting testicular seminoma, as the underlying cause of unexpected T production. This case illustrates how easily a testicular cancer can remain unnoticed because it can be asymptomatic and the necessity to be alert to, and act on, anomalous laboratory results during treatment of a transgender person.

7.
Mol Cell ; 79(1): 84-98.e9, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32526163

RESUMO

Rett syndrome (RTT), mainly caused by mutations in methyl-CpG binding protein 2 (MeCP2), is one of the most prevalent intellectual disorders without effective therapies. Here, we used 2D and 3D human brain cultures to investigate MeCP2 function. We found that MeCP2 mutations cause severe abnormalities in human interneurons (INs). Surprisingly, treatment with a BET inhibitor, JQ1, rescued the molecular and functional phenotypes of MeCP2 mutant INs. We uncovered that abnormal increases in chromatin binding of BRD4 and enhancer-promoter interactions underlie the abnormal transcription in MeCP2 mutant INs, which were recovered to normal levels by JQ1. We revealed cell-type-specific transcriptome impairment in MeCP2 mutant region-specific human brain organoids that were rescued by JQ1. Finally, JQ1 ameliorated RTT-like phenotypes in mice. These data demonstrate that BRD4 dysregulation is a critical driver for RTT etiology and suggest that targeting BRD4 could be a potential therapeutic opportunity for RTT.


Assuntos
Azepinas/farmacologia , Encéfalo/patologia , Proteínas de Ciclo Celular/metabolismo , Interneurônios/patologia , Proteína 2 de Ligação a Metil-CpG/fisiologia , Síndrome de Rett/patologia , Fatores de Transcrição/metabolismo , Transcriptoma/efeitos dos fármacos , Triazóis/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Proteínas de Ciclo Celular/genética , Feminino , Células-Tronco Embrionárias Humanas/efeitos dos fármacos , Células-Tronco Embrionárias Humanas/metabolismo , Células-Tronco Embrionárias Humanas/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Fenótipo , Síndrome de Rett/tratamento farmacológico , Síndrome de Rett/genética , Síndrome de Rett/metabolismo , Fatores de Transcrição/genética
8.
AJNR Am J Neuroradiol ; 41(4): 591-597, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32217554

RESUMO

BACKGROUND AND PURPOSE: NeuroQuant is an FDA-approved software that performs automated MR imaging quantitative volumetric analysis. This study aimed to compare the accuracy of NeuroQuant analysis with visual MR imaging analysis by neuroradiologists with expertise in epilepsy in identifying hippocampal sclerosis. MATERIALS AND METHODS: We reviewed 144 adult patients who underwent presurgical evaluation for temporal lobe epilepsy. The reference standard for hippocampal sclerosis was defined by having hippocampal sclerosis on pathology (n = 61) or not having hippocampal sclerosis on pathology (n = 83). Sensitivities, specificities, positive predictive values, and negative predictive values were compared between NeuroQuant analysis and visual MR imaging analysis by using a McNemar paired test of proportions and the Bayes theorem. RESULTS: NeuroQuant analysis had a similar specificity to neuroradiologist visual MR imaging analysis (90.4% versus 91.6%; P = .99) but a lower sensitivity (69.0% versus 93.0%, P < .001). The positive predictive value of NeuroQuant analysis was comparable with visual MR imaging analysis (84.0% versus 89.1%), whereas the negative predictive value was not comparable (79.8% versus 95.0%). CONCLUSIONS: Visual MR imaging analysis by a neuroradiologist with expertise in epilepsy had a higher sensitivity than did NeuroQuant analysis, likely due to the inability of NeuroQuant to evaluate changes in hippocampal T2 signal or architecture. Given that there was no significant difference in specificity between NeuroQuant analysis and visual MR imaging analysis, NeuroQuant can be a valuable tool when the results are positive, particularly in centers that lack neuroradiologists with expertise in epilepsy, to help identify and refer candidates for temporal lobe epilepsy resection. In contrast, a negative test could justify a case referral for further evaluation to ensure that false-negatives are detected.


Assuntos
Epilepsia do Lobo Temporal/diagnóstico por imagem , Hipocampo/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Software , Adulto , Teorema de Bayes , Epilepsia do Lobo Temporal/patologia , Feminino , Hipocampo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Radiologistas , Esclerose/diagnóstico por imagem , Esclerose/patologia , Sensibilidade e Especificidade
9.
J Neural Transm (Vienna) ; 127(6): 977-985, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32212016

RESUMO

The premonitory urge for tics scale (PUTS) is a common self-report measure of premonitory sensations preceding tics. The present study aimed to examine the internal consistency and concurrent validity of the PUTS by sex and psychiatric comorbidity status; and explored interactions between sex and psychiatric comorbidity in predicting premonitory urge and tic symptom severity. Seventy-four youth and young adults with persistent tic disorders completed the PUTS, while their parents completed the parent tic questionnaire (PTQ) and a demographic measure. Independent samples t-tests revealed no significant sex differences in PUTS items or total score. The PUTS total score also did not significantly differ between participants with and without attention-deficit hyperactivity disorder (ADHD) and/or obsessive-compulsive disorder (OCD) comorbidity. Internal consistency did not significantly differ between females (α = 0.85) and males (α = 0.75), and those with comorbid ADHD and/or OCD (α = 0.83) relative to those without (α = 0.69). With respect to concurrent validity, the PUTS total was significantly correlated with PTQ tic frequency, intensity, number, and severity for males but not for females. Among those with ADHD and/or OCD, the PUTS total score was correlated significantly and strongly with tic number and moderately with tic intensity. Interactions between sex and psychiatric comorbidity performed using 2 × 2 analysis of variance did not significantly predict the PUTS total or PTQ subscale scores. Findings suggest sex and comorbidity status may influence premonitory urge expression. Results have implications for understanding and measurement of the premonitory urge.

10.
Methods Mol Biol ; 2097: 139-171, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31776925

RESUMO

Tumors have a complex ecosystem in which behavior and fate are determined by the interaction of diverse cancerous and noncancerous cells at local and systemic levels. A number of studies indicate that various immune cells participate in tumor development (Fig. 1). In this review, we will discuss interactions among T lymphocytes (T cells), B cells, natural killer (NK) cells, dendritic cells (DCs), tumor-associated macrophages (TAMs), neutrophils, and myeloid-derived suppressor cells (MDSCs). In addition, we will touch upon attempts to either use or block subsets of immune cells to target cancer.


Assuntos
Comunicação Celular , Imunoterapia , Linfócitos/patologia , Neoplasias/imunologia , Neoplasias/terapia , Animais , Humanos , Modelos Biológicos , Neoplasias/patologia
11.
J Immunol Methods ; 474: 112668, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31525367

RESUMO

Cell-mediated cytotoxicity is a critical function of the immune system in mounting defense against pathogens and cancers. Current methods that allow direct evaluation of cell-mediated cytotoxicity suffer from a wide-range of drawbacks. Here, we present a novel strategy to measure cytotoxicity that is direct, sensitive, rapid, and highly adaptable. Moreover, it allows accurate measurement of viability of both target and effector cells. Target cells are fluorescently labeled with a non-toxic, cell-permeable dye that covalently binds to cell proteins, including nuclear proteins. The labeled target cells are incubated with effector cells to begin killing. Following the killing reaction, the cell mixture is incubated with another dye that specifically stains proteins of dead cells, including nuclear proteins. In the final step, cell nuclei are released by Triton X-100, and analyzed by flow cytometry. This results in four nuclear staining patterns that separate target and effector nuclei as well as nuclei of live and dead cells. Analyzing nuclei, instead of cells, greatly reduces flow cytometry errors caused by the presence of target-effector cell aggregates. Target killing time can often be reduced to 2 h and the assay can be done in a high throughput format. We have successfully validated this assay in a variety of cytotoxicity scenarios including those mediated by NK-92 cells, Chimeric Antigen Receptor (CAR)-T cells, and Tumor Infiltrating Lymphocytes (TIL). Therefore, this technique is broadly applicable, highly sensitive and easily administered, making it a powerful tool to assess immunotherapy-based, cell-mediated cytotoxicity.


Assuntos
Testes Imunológicos de Citotoxicidade/métodos , Citotoxicidade Imunológica , Citometria de Fluxo , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral , Núcleo Celular/imunologia , Núcleo Celular/patologia , Ensaios de Triagem em Larga Escala , Humanos , Imunoterapia Adotiva , Masculino , Melanoma/imunologia , Melanoma/patologia , Camundongos Endogâmicos C57BL , Valor Preditivo dos Testes , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Reprodutibilidade dos Testes , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Fatores de Tempo , Fluxo de Trabalho
12.
Mol Cancer Ther ; 18(11): 2008-2020, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31434693

RESUMO

The restricted expression pattern of B-cell maturation antigen (BCMA) makes it an ideal tumor-associated antigen (TAA) for the treatment of myeloma. BCMA has been targeted by both CD3 bispecific antibody and antibody-drug conjugate (ADC) modalities, but a true comparison of modalities has yet to be performed. Here we utilized a single BCMA antibody to develop and characterize both a CD3 bispecific and 2 ADC formats (cleavable and noncleavable) and compared activity both in vitro and in vivo with the aim of generating an optimal therapeutic. Antibody affinity, but not epitope was influential in drug activity and hence a high-affinity BCMA antibody was selected. Both the bispecific and ADCs were potent in vitro and in vivo, causing dose-dependent cell killing of myeloma cell lines and tumor regression in orthotopic myeloma xenograft models. Primary patient cells were effectively lysed by both CD3 bispecific and ADCs, with the bispecific demonstrating improved potency, maximal cell killing, and consistency across patients. Safety was evaluated in cynomolgus monkey toxicity studies and both modalities were active based on on-target elimination of B lineage cells. Distinct nonclinical toxicity profiles were seen for the bispecific and ADC modalities. When taken together, results from this comparison of BCMA CD3 bispecific and ADC modalities suggest better efficacy and an improved toxicity profile might be achieved with the bispecific modality. This led to the advancement of a bispecific candidate into phase I clinical trials.


Assuntos
Anticorpos Biespecíficos/administração & dosagem , Antígeno de Maturação de Linfócitos B/metabolismo , Complexo CD3/imunologia , Imunoconjugados/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Animais , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/farmacologia , Afinidade de Anticorpos , Antígeno de Maturação de Linfócitos B/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacologia , Camundongos , Mieloma Múltiplo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Zh Nevrol Psikhiatr Im S S Korsakova ; 119(2. Vyp. 2): 73-85, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31156245

RESUMO

OBJECTIVES: To evaluate efficacy, safety, and tolerability of the treatment with teberif/interferon ß-1a, to analyze safety, tolerability and dynamics of key efficacy variables after switching from referent drug rebif to biosimilar teberif in patients with remitting multiple sclerosis (RMS). MATERIAL AND METHODS: During the main period of the international multicenter randomized study patients were randomized to receive treatment with teberif for 52 weeks, or rebif for 52 weeks, or placebo for 16 weeks to evaluate efficacy and safety of treatment. After the main study period, patients were group-independently switched to take open-label teberif treatment during the next 48 weeks. RESULTS AND CONCLUSION: The analysis of multiple evaluation parameters of the efficiency during the 1st study period (blinded) and the 2nd study period (open-label) has shown that teberif and rebif demonstrate equivalent efficacy and stable 2-year efficacy of teberif was proven. There were no significant differences between teberif and rebif for all safety, and tolerability parameters. Switching from rebif to teberif didn't influence treatment efficacy. The 2-year study results confirmed a biosimilar teberif's benign tolerability and expected safety profile to other interferons ß-1a in patients with RMS.


Assuntos
Interferon beta-1a , Esclerose Múltipla Recidivante-Remitente , Adjuvantes Imunológicos , Humanos , Interferon beta-1a/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Resultado do Tratamento
14.
Transl Oncol ; 12(9): 1164-1176, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31207547

RESUMO

Telomere length maintenance is essential for cell proliferation, which is particularly prominent in cancer. We validate that the primary colorectal tumors exhibit heterogeneous telomere lengths but mostly (90%) short telomeres relative to normal tissues. Intriguingly, relatively short telomeres are associated with tumor malignancy as indicated by poorly differentiated state, and these tumors contain more cancer stem-like cells (CSLCs) identified by several commonly used markers CD44, EPHB2 or LGR5. Moreover, promyelocytic leukemia (PML) and ALT-associated PML nuclear bodies (APBs) are frequently found in tumors with short telomeres and high proliferation. In contrast, distant normal tissues rarely or only minimally express PML. Inhibition of PML and APBs by an ATR inhibitor decreases proliferation of CSLCs and organoids, suggesting a potential therapeutic target to progressive colorectal tumors. Together, telomere maintenance underling tumor progression is connected with CSLCs.

15.
Mol Ther ; 27(6): 1126-1138, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31005597

RESUMO

Clinical success of autologous CD19-directed chimeric antigen receptor T cells (CAR Ts) in acute lymphoblastic leukemia and non-Hodgkin lymphoma suggests that CAR Ts may be a promising therapy for hematological malignancies, including multiple myeloma. However, autologous CAR T therapies have limitations that may impact clinical use, including lengthy vein-to-vein time and manufacturing constraints. Allogeneic CAR T (AlloCAR T) therapies may overcome these innate limitations of autologous CAR T therapies. Unlike autologous cell therapies, AlloCAR T therapies employ healthy donor T cells that are isolated in a manufacturing facility, engineered to express CARs with specificity for a tumor-associated antigen, and modified using gene-editing technology to limit T cell receptor (TCR)-mediated immune responses. Here, transcription activator-like effector nuclease (TALEN) gene editing of B cell maturation antigen (BCMA) CAR Ts was used to confer lymphodepletion resistance and reduced graft-versus-host disease (GvHD) potential. The safety profile of allogeneic BCMA CAR Ts was further enhanced by incorporating a CD20 mimotope-based intra-CAR off switch enabling effective CAR T elimination in the presence of rituximab. Allogeneic BCMA CAR Ts induced sustained antitumor responses in mice supplemented with human cytokines, and, most importantly, maintained their phenotype and potency after scale-up manufacturing. This novel off-the-shelf allogeneic BCMA CAR T product is a promising candidate for clinical evaluation.


Assuntos
Antígeno de Maturação de Linfócitos B/imunologia , Transplante de Células/métodos , Imunoterapia Adotiva/métodos , Mieloma Múltiplo/terapia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/transplante , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno de Maturação de Linfócitos B/genética , Doadores de Sangue , Linhagem Celular Tumoral , Transplante de Células/efeitos adversos , Citotoxicidade Imunológica/genética , Edição de Genes , Vetores Genéticos , Doença Enxerto-Hospedeiro/terapia , Humanos , Imunoterapia Adotiva/efeitos adversos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mieloma Múltiplo/patologia , Intervalo Livre de Progressão , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Rituximab/uso terapêutico , Linfócitos T/metabolismo , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição/genética , Transdução Genética , Transplante Homólogo/métodos
16.
Cell Stem Cell ; 24(3): 487-497.e7, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30799279

RESUMO

Human brain organoid techniques have rapidly advanced to facilitate investigating human brain development and diseases. These efforts have largely focused on generating telencephalon due to its direct relevance in a variety of forebrain disorders. Despite its importance as a relay hub between cortex and peripheral tissues, the investigation of three-dimensional (3D) organoid models for the human thalamus has not been explored. Here, we describe a method to differentiate human embryonic stem cells (hESCs) to thalamic organoids (hThOs) that specifically recapitulate the development of thalamus. Single-cell RNA sequencing revealed a formation of distinct thalamic lineages, which diverge from telencephalic fate. Importantly, we developed a 3D system to create the reciprocal projections between thalamus and cortex by fusing the two distinct region-specific organoids representing the developing thalamus or cortex. Our study provides a platform for understanding human thalamic development and modeling circuit organizations and related disorders in the brain.


Assuntos
Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Células-Tronco Embrionárias Humanas/citologia , Organoides/citologia , Organoides/metabolismo , Tálamo/citologia , Humanos , Modelos Biológicos
17.
BMC Syst Biol ; 13(1): 13, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670065

RESUMO

It was highlighted that the original article [1] contained a typesetting error in the last name of Allon Canaan. This was incorrectly captured as Allon Canaann in the original article which has since been updated.

18.
BMC Syst Biol ; 12(Suppl 7): 114, 2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30547798

RESUMO

BACKGROUND: Single-cell RNA sequencing (scRNA-seq) technology provides an effective way to study cell heterogeneity. However, due to the low capture efficiency and stochastic gene expression, scRNA-seq data often contains a high percentage of missing values. It has been showed that the missing rate can reach approximately 30% even after noise reduction. To accurately recover missing values in scRNA-seq data, we need to know where the missing data is; how much data is missing; and what are the values of these data. METHODS: To solve these three problems, we propose a novel model with a hybrid machine learning method, namely, missing imputation for single-cell RNA-seq (MISC). To solve the first problem, we transformed it to a binary classification problem on the RNA-seq expression matrix. Then, for the second problem, we searched for the intersection of the classification results, zero-inflated model and false negative model results. Finally, we used the regression model to recover the data in the missing elements. RESULTS: We compared the raw data without imputation, the mean-smooth neighbor cell trajectory, MISC on chronic myeloid leukemia data (CML), the primary somatosensory cortex and the hippocampal CA1 region of mouse brain cells. On the CML data, MISC discovered a trajectory branch from the CP-CML to the BC-CML, which provides direct evidence of evolution from CP to BC stem cells. On the mouse brain data, MISC clearly divides the pyramidal CA1 into different branches, and it is direct evidence of pyramidal CA1 in the subpopulations. In the meantime, with MISC, the oligodendrocyte cells became an independent group with an apparent boundary. CONCLUSIONS: Our results showed that the MISC model improved the cell type classification and could be instrumental to study cellular heterogeneity. Overall, MISC is a robust missing data imputation model for single-cell RNA-seq data.


Assuntos
Análise de Sequência de RNA/métodos , Análise de Célula Única , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia
19.
Nat Commun ; 9(1): 5356, 2018 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-30559385

RESUMO

Large copy number variants (CNVs) in the human genome are strongly associated with common neurodevelopmental, neuropsychiatric disorders such as schizophrenia and autism. Here we report on the epigenomic effects of the prominent large deletion CNVs on chromosome 22q11.2 and on chromosome 1q21.1. We use Hi-C analysis of long-range chromosome interactions, including haplotype-specific Hi-C analysis, ChIP-Seq analysis of regulatory histone marks, and RNA-Seq analysis of gene expression patterns. We observe changes on all the levels of analysis, within the deletion boundaries, in the deletion flanking regions, along chromosome 22q, and genome wide. We detect gene expression changes as well as pronounced and multilayered effects on chromatin states, chromosome folding and on the topological domains of the chromatin, that emanate from the large CNV locus. These findings suggest basic principles of how such large genomic deletions can alter nuclear organization and affect genomic molecular activity.


Assuntos
Encéfalo/crescimento & desenvolvimento , Cromatina/metabolismo , Dosagem de Genes/genética , Transtornos Mentais/genética , Linhagem Celular , Cromatina/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 22/genética , Genoma Humano/genética , Humanos
20.
Bioorg Med Chem ; 26(13): 3825-3836, 2018 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-30017114

RESUMO

Pancreatic cancer poorly responds to available drugs, and finding novel approaches to target this cancer type is of high significance. Here, based on a common property of pancreatic cancer cells to express somatostatin receptors (SSTR), we designed drug conjugates with novel somatostatin-derived cyclic peptides (SSTp) with broad selectivity towards SSTR types to facilitate drug targeting of the pancreatic cancer cells specifically. Uptake of our newly designed SSTps was facilitated by SSTRs expressed in the pancreatic cancers, including SSTR2, SSTR3, SSTR4 and SSTR5. Three major drugs were conjugated to our best SSTps that served as delivery vehicles, including Camptothecin (CPT), Combretastatin-4A (COMB) and Azatoxin (AZA). All designed drug conjugates demonstrated penetration to pancreatic cancer cell lines, and significant toxicity towards them. Furthermore, the drug conjugates specifically accumulated in tumors in the animal xenograft model, though some accumulation was also seen in kidney. Overall these findings lay the basis for development of novel drug series that could target the fatal pancreatic cancer.


Assuntos
Antineoplásicos/síntese química , Peptídeos Cíclicos/química , Somatostatina/química , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Camptotecina/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Indóis/química , Rim/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Peptídeos Cíclicos/síntese química , Receptores de Somatostatina/antagonistas & inibidores , Receptores de Somatostatina/genética , Receptores de Somatostatina/metabolismo , Estilbenos/química , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
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