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OBJECTIVE: Research suggests that recurrent seizures may lead to neuronal injury. Neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAP) levels increase in cerebrospinal fluid and blood in response to neuroaxonal damage, and they have been hypothesized as potential biomarkers for epilepsy. We examined plasma NfL and GFAP levels and their diagnostic utility in differentiating patients with epilepsy from those with psychogenic nonepileptic seizures (PNES) and other nonepileptic disorders. METHODS: We recruited consecutive adults admitted for video-electroencephalographic monitoring and formal neuropsychiatric assessment. NfL and GFAP levels were quantified and compared between different patient groups and an age-matched reference cohort (n = 1926) and correlated with clinical variables in patients with epilepsy. RESULTS: A total of 138 patients were included, of whom 104 were diagnosed with epilepsy, 22 with PNES, and 12 with other conditions. Plasma NfL and GFAP levels were elevated in patients with epilepsy compared to PNES, adjusted for age and sex (NfL p = .04, GFAP p = .04). A high proportion of patients with epilepsy (20%) had NfL levels above the 95th age-matched percentile compared to the reference cohort (5%). NfL levels above the 95th percentile of the reference cohort had a 95% positive predictive value for epilepsy. Patients with epilepsy who had NfL levels above the 95th percentile were younger than those with lower levels (37.5 vs. 43.8 years, p = .03). SIGNIFICANCE: An elevated NfL or GFAP level in an individual patient may support an underlying epilepsy diagnosis, particularly in younger adults, and cautions against a diagnosis of PNES alone. Further examination of the association between NfL and GFAP levels and specific epilepsy subtypes or seizure characteristics may provide valuable insights into disease heterogeneity and contribute to the refinement of diagnosis, understanding pathophysiological mechanisms, and formulating treatment approaches.
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Despite the potential of oral immunotherapy against food allergy, adverse reactions and loss of desensitization hinder its clinical uptake. Dysbiosis of the gut microbiota is implicated in the increasing prevalence of food allergy, which will need to be regulated to enable for an effective oral immunotherapy against food allergy. Here we report an inulin gel formulated with an allergen that normalizes the dysregulated ileal microbiota and metabolites in allergic mice, establishes allergen-specific oral tolerance and achieves robust oral immunotherapy efficacy with sustained unresponsiveness in food allergy models. These positive outcomes are associated with enhanced allergen uptake by antigen-sampling dendritic cells in the small intestine, suppressed pathogenic type 2 immune responses, increased interferon-γ+ and interleukin-10+ regulatory T cell populations, and restored ileal abundances of Eggerthellaceae and Enterorhabdus in allergic mice. Overall, our findings underscore the therapeutic potential of the engineered allergen gel as a suitable microbiome-modulating platform for food allergy and other allergic diseases.
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Acute myeloid leukemia (AML) is one of the most common types of leukemia in adults with a 5-year survival rate of 30.5%. These poor patient outcomes are attributed to tumor relapse, stemming from ineffective innate immune activation, T cell tolerance, and a lack of immunological memory. Thus, new strategies are needed to activate innate and effector immune cells and evoke long-term immunity against AML. One approach to address these issues is through Stimulator of Interferon Genes (STING) pathway activation, which produces Type I Interferons (Type I IFN) critical for innate and adaptive immune activation. Here, we report that systemic immunotherapy with a lipid-based nanoparticle platform (CMP) carrying Mn2+ and STING agonist c-di-AMP (CDA) exhibited robust anti-tumor efficacy in a mouse model of disseminated AML. Moreover, CMP immunotherapy combined with immune checkpoint blockade against cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) elicited robust innate and adaptive immune activation with enhanced cytotoxic potential against AML, leading to extended animal survival after re-challenge with AML. Overall, this CMP combination immunotherapy may be a promising approach against AML and other disseminated cancer.
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Antineoplásicos , Leucemia Mieloide Aguda , Nanopartículas , Neoplasias , Camundongos , Adulto , Animais , Humanos , Manganês , Leucemia Mieloide Aguda/tratamento farmacológico , Linfócitos T , Imunoterapia , Imunidade InataRESUMO
OBJECTIVE: Blood biomarkers of neuronal injury such as neurofilament light (NfL) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models. METHODS: Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD (n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models). RESULTS: Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all < 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of individual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS. CONCLUSIONS: This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in diverse neurodegenerative and primary psychiatric conditions in real-world clinical settings.
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Doença de Alzheimer , Transtorno Bipolar , Transtorno Depressivo Maior , Demência Frontotemporal , Transtornos Psicóticos , Humanos , Doença de Alzheimer/diagnóstico , Biomarcadores , Transtorno Bipolar/diagnóstico , Transtorno Depressivo Maior/diagnóstico , Demência Frontotemporal/diagnóstico , Filamentos IntermediáriosRESUMO
OBJECTIVE: People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown. METHODS: We collected longitudinal diagnostic information (mean = 36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other) and PSY. We pre-specified NfL > 582 pg/mL as indicative of ND/MCI/other. RESULTS: Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone. CONCLUSIONS: CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.
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Doença de Alzheimer , Disfunção Cognitiva , Doenças Neurodegenerativas , Humanos , Doença de Alzheimer/diagnóstico , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Filamentos Intermediários , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico , Biomarcadores/líquido cefalorraquidianoRESUMO
Despite significant advances in immune checkpoint blockade (ICB), immunosuppression mediated by tumor-associated myeloid cells (TAMCs) poses a major barrier to cancer immunotherapy. In addition, while immunogenic cell death (ICD) provides a viable approach to inducing anti-tumor immune response, it remains unknown how to effectively trigger ICD while addressing immunosuppressive TAMCs. Here, we show that SC144, a gp130 inhibitor that blocks the IL-6/gp130/STAT3 pathway, induces ICD of tumor cells and polarizes macrophages to M1-phenotype in vitro. However, as SC144 also induces killing of CD8+ T-cells, we sought to deliver SC144 selectively to tumor cells and TAMCs. Toward this goal, we have developed hyaluronic acid-bilirubin nanoparticles (HABN) that accumulate in CD44hi tumor cells and TAMCs. Systemic administration of SC144 loaded in HABN (SC144@HABN) induces apoptosis and ICD of tumor cells, increases the ratio of M1-like to M2-like macrophages, and decreases the frequency of myeloid-derived suppressor cells and CD4+ regulatory T-cells, while promoting anti-tumor CD8+ T-cells. Moreover, SC144@HABN combined with anti-PD-L1 ICB efficiently eliminates MC38 tumors and ICB-resistant 4T1 tumors. Overall, our work demonstrates a therapeutic strategy based on coordinated ICD induction and TAMC modulation and highlights the potential of combination chemoimmunotherapy.
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Ácido Hialurônico , Neoplasias , Humanos , Ácido Hialurônico/farmacologia , Linfócitos T CD8-Positivos/metabolismo , Nanomedicina , Bilirrubina , Receptor gp130 de Citocina , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Imunoterapia , Microambiente Tumoral , Linhagem Celular TumoralRESUMO
Cyclic dinucleotides (CDNs), as one type of Stimulator of Interferon Genes (STING) pathway agonist, have shown promising results for eliciting immune responses against cancer and viral infection. However, the suboptimal drug-like properties of conventional CDNs, including their short in vivo half-life and poor cellular permeability, compromise their therapeutic efficacy. In this study, we have developed a manganese-silica nanoplatform (MnOx@HMSN) that enhances the adjuvant effects of CDN by achieving synergy with Mn2+ for vaccination against cancer and SARS-CoV-2. MnOx@HMSN with large mesopores were efficiently co-loaded with CDN and peptide/protein antigens. MnOx@HMSN(CDA) amplified the activation of the STING pathway and enhanced the production of type-I interferons and other proinflammatory cytokines from dendritic cells. MnOx@HMSN(CDA) carrying cancer neoantigens elicited robust antitumor T-cell immunity with therapeutic efficacy in two different murine tumor models. Furthermore, MnOx@HMSN(CDA) loaded with SARS-CoV-2 antigen achieved strong and durable (up to one year) humoral immune responses with neutralizing capability. These results demonstrate that MnOx@HMSN(CDA) is a versatile nanoplatform for vaccine applications.
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COVID-19 , Neuropatia Hereditária Motora e Sensorial , Nanopartículas , Vacinas , Humanos , Animais , Camundongos , Manganês , Dióxido de Silício , COVID-19/prevenção & controle , SARS-CoV-2 , ImunoterapiaRESUMO
One of the major reasons for poor cancer outcomes is the existence of cancer stem cells (CSCs). CSCs are a small subpopulation of tumor cells that can self-renew, differentiate into the majority of tumor cells, and maintain tumorigenicity. As CSCs are resistant to traditional chemotherapy and radiation, they contribute to metastasis and relapse. Thus, new approaches are needed to target and eliminate CSCs. Here, we sought to target and reduce the frequency of CSCs in melanoma by therapeutic vaccination against CSC-associated transcription factors, such as Sox2 and Nanog, and aldehyde dehydrogenase (ALDH). Toward this goal, we have identified novel immunogenic peptide epitopes derived from CSC-associated Sox2 and Nanog and synthesized synthetic high-density lipoprotein (sHDL) nanodisc vaccine formulated with Sox2, Nanog, and ALDH antigen peptides together with CpG, a Toll-like receptor 9 agonist. Vaccination with nanodiscs containing six CSC antigen peptides elicited robust T cell responses against CSC-associated antigens and promoted intratumoral infiltration of CD8+ T cells, while reducing the frequency of CSCs and CD4+ regulatory T cells within melanoma tumors. Nanodisc vaccination effectively reduced tumor growth and significantly extended animal survival without toxicity toward normal stem cells. Overall, our therapeutic strategy against CSCs represents a cost-effective, safe, and versatile approach that may be applied to melanoma and other cancer types, as well as serve as a critical component in combined therapies to target and eliminate CSCs.
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Melanoma , Células-Tronco Neoplásicas , Animais , Células-Tronco Neoplásicas/metabolismo , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Aldeído Desidrogenase/metabolismo , Imunidade , Linhagem Celular TumoralRESUMO
Memory T cells underpin vaccine-induced immunity but are not yet fully understood. To distinguish features of memory cells that confer protective immunity, we used single cell transcriptome analysis to compare antigen-specific CD4+T cells recalled to lungs of mice that received a protective or nonprotective subunit vaccine followed by challenge with a fungal pathogen. We unexpectedly found populations specific to protection that expressed a strong type I interferon response signature, whose distinctive transcriptional signature appeared unconventionally dependent on IFN-γ receptor. We also detected a unique population enriched in protection that highly expressed the gene for the natural killer cell marker NKG7. Lastly, we detected differences in TCR gene use and in Th1- and Th17-skewed responses after protective and nonprotective vaccine, respectively, reflecting heterogeneous Ifng- and Il17a-expressing populations. Our findings highlight key features of transcriptionally diverse and distinctive antigen-specific T cells associated with protective vaccine-induced immunity.
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We report the case of a 26-year-old female who intentionally ingested busulfan, an oral chemotherapy agent, to induce severe aplastic anemia. The patient was initially thought to be suffering from idiopathic aplastic anemia, before clues suggesting the diagnosis of a factitious disorder were identified. The patient underwent a bone marrow transplant and ultimately died 5 weeks later following a lengthy admission to the intensive care unit. It is unclear whether confrontation about a patient's self-induction of physical illness is beneficial in the treatment of patients with factitious disorder. Cases such as this pose substantial diagnostic challenges, making early recognition of factitious disorder and initiation of treatment difficult. The patient described in this case report had risk factors for a factitious disorder, including age, gender, professional involvement in health care, recent loss and developmental trauma. Factitious disorder, while rare, can have lethal consequences for the patient. This diagnosis must be considered as part of a full diagnostic assessment.
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Anemia Aplástica , Transtornos Autoinduzidos , Adulto , Anemia Aplástica/diagnóstico , Anemia Aplástica/terapia , Transtornos Autoinduzidos/diagnóstico , Feminino , HumanosRESUMO
PURPOSE: This study aims to assess the reliability and construct validity of the City Birth Trauma Scale (BiTS) in Oceania and confirm the latent factor structure of postpartum posttraumatic stress disorder (PTSD). METHODS: Participants completed the City BiTS, demographic and obstetric information via an online survey. Psychometric properties of the City BiTS were investigated using confirmatory factor analyses (CFA). RESULTS: The study included 195 women, with 39 participating in repeat administration. CFA confirmed a two-factor model which included a birth-related symptom (BRS) subscale and general symptom (GS) subscale. High reliability and construct validity was observed for subscales and total score at baseline and follow-up. CONCLUSION: The City BiTS represents a potentially useful tool to assist with screening for postpartum PTSD.
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Transtornos de Estresse Pós-Traumáticos , Parto Obstétrico , Feminino , Humanos , Parto , Período Pós-Parto , Gravidez , Reprodutibilidade dos Testes , Transtornos de Estresse Pós-Traumáticos/diagnósticoRESUMO
Homotypic signaling lymphocyte activation molecule (SLAM) receptor-ligand cell surface interactions between myeloid and lymphoid cells regulate innate and adaptive immune responses. In this article, we report that SLAMF1 is indispensable for host resistance to primary and vaccine-induced protection against fungal infection. Because vaccine immunity is dependent on cell-mediated immunity, we investigated the development of Ag-specific T cells. We studied the T cell-intrinsic and -extrinsic role of SLAMF1. We generated SLAMF1-/- TCR transgenic mice and analyzed the responses of adoptively transferred T cells. We also tracked endogenous Ag-specific T cells by using a tetramer. Intrinsic and extrinsic SLAMF1 signaling was dispensable for the development of antifungal Th1 and Th17 cells, which are requisite for the acquisition of vaccine-induced immunity. Despite intact T cell development, vaccinated SLAMF1-/- mice failed to control fungal infection. Failed accumulation of Ag-specific T cells in the lung on infection of vaccinated mice was due to uncontrolled early infection and inflammation, revealing a role for SLAMF1 in innate host immunity.
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Micoses , Vacinas , Animais , Diferenciação Celular , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Células Th17RESUMO
INTRODUCTION: Many patients with cognitive and neuropsychiatric symptoms face diagnostic delay and misdiagnosis. We investigated whether cerebrospinal fluid (CSF) neurofilament light (NfL) and total-tau (t-tau) could assist in the clinical scenario of differentiating neurodegenerative (ND) from psychiatric disorders (PSY), and rapidly progressive disorders. METHODS: Biomarkers were examined in patients from specialist services (ND and PSY) and a national Creutzfeldt-Jakob registry (Creutzfeldt-Jakob disease [CJD] and rapidly progressive dementias/atypically rapid variants of common ND, RapidND). RESULTS: A total of 498 participants were included: 197 ND, 67 PSY, 161 CJD, 48 RapidND, and 20 controls. NfL was elevated in ND compared to PSY and controls, with highest levels in CJD and RapidND. NfL distinguished ND from PSY with 95%/78% positive/negative predictive value, 92%/87% sensitivity/specificity, 91% accuracy. NfL outperformed t-tau in most real-life clinical diagnostic dilemma scenarios, except distinguishing CJD from RapidND. DISCUSSION: We demonstrated strong generalizable evidence for the diagnostic utility of CSF NfL in differentiating ND from psychiatric disorders, with high accuracy.
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Doença de Alzheimer , Síndrome de Creutzfeldt-Jakob , Transtornos Mentais , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Diagnóstico Tardio , Filamentos Intermediários , Proteínas tau/líquido cefalorraquidiano , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidianoRESUMO
Integrins mediate cell-cell interactions and communication with the extracellular matrix (ECM). These transmembrane protein receptors allow binding between a cell and its surroundings, initiating a breadth of intracellular signaling resulting in proliferation, differentiation, survival, or migration. Such responses have made integrins an attractive target for cancer therapy. Self-renewing and highly tumorigenic cancer stem cells (CSCs) are most resistant to traditional radiation treatment and chemotherapy, and therefore may contribute directly to the metastasis and relapse of the disease. In both the 4T1 mouse metastatic mammary tumor model and SCC7 head and neck squamous cell carcinoma model, integrin ß4 (ITGB4) was expressed on ALDHhigh 4T1 and SCC7 CSCs. Using two immunological approaches, we targeted ITGB4 through 1) ITGB4 protein-pulsed dendritic cell (ITGB4-DC) vaccination or 2) via anti-CD3/anit-ITGB4 bispecific antibody (ITGB4 BiAb)-armed T cell adoptive transfer. These two therapies reduced ITGB4-expressing CSCs and inhibited local tumor growth and lung metastasis through ITGB4 specific cellular and humoral immune responses. Additionally, the combination of anti-PD-L1 immunotherapy with our two ITGB4-targeted approaches significantly improved treatment efficacy. We also found increased concentrations of serum IFN-γ and IL-6 in the 4T1 and SCC7 models which may help define future directions of this ITGB4-targeted study. Together, these results emphasize ITGB4 as a practical CSC immunological target with possible therapeutic benefits across tumor types with high ITGB4 expression.
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The development of effective vaccines against fungal infections requires the induction of protective, pathogen-specific cell-mediated immune responses. Here, we asked whether combination adjuvants based on delta inulin (Advax) formulated with Toll-like receptor (TLR) agonists could improve vaccine protection mediated by a fungal recombinant protein, Bl-Eng2 (i.e., Blastomyces endoglucanase 2), which itself harbors an immunodominant antigen and dectin-2 agonist/adjuvant. We found that Bl-Eng2 formulated with Advax3 containing TLR9 agonist or Advax8 containing TLR4 agonist provided the best protection against pulmonary infection with Blastomyces dermatitidis, being more effective than complete Freund's adjuvant or Adjuplex. Advax3 was most efficient in inducing gamma interferon (IFN-γ)- and interleukin-17 (IL-17)-producing antigen-specific T cells that migrated to the lung upon Blastomyces dermatitidis infection. Mechanistic studies revealed Bl-Eng2/Advax3 protection was tempered by neutralization of IL-17 and particularly IFN-γ. Likewise, greater numbers of lung-resident T cells producing IFN-γ, IL-17, or both IFN-γ and IL-17 correlated with fewer fungi recovered from lung. Protection was maintained after depletion of CD4+ T cells, partially reduced by depletion of CD8+ T cells, and completely eliminated after depletion of both CD4+ and CD8+ T cells. We conclude that Bl-Eng2 formulated with Advax3 is promising for eliciting vaccine-induced antifungal immunity, through a previously uncharacterized mechanism involving CD8+ and also CD4+ T cells producing IFN-γ and/or IL-17. Although no licensed vaccine exists as yet against any fungal disease, these findings indicate the importance of adjuvant selection for the development of effective fungal vaccines. IMPORTANCE Fungal disease remains a challenging clinical and public health problem. Despite medical advances, invasive fungal infections have skyrocketed over the last decade and pose a mounting health threat in immunocompetent and -deficient hosts, with worldwide mortality rates ranking 7th, even ahead of tuberculosis. The development of safe, effective vaccines remains a major hurdle for fungi. Critical barriers to progress include the lack of defined fungal antigens and suitable adjuvants. Our research is significant in identifying adjuvant combinations that elicit optimal vaccine-induced protection when formulated with a recombinant protective antigen and uncovering the mechanistic bases of the underlaying vaccine protection, which will foster the strategic development of antifungal vaccines.
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Adjuvantes Imunológicos/administração & dosagem , Vacinas Fúngicas/genética , Vacinas Fúngicas/imunologia , Micoses/prevenção & controle , Animais , Blastomyces/imunologia , Blastomicose/prevenção & controle , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Vacinas Fúngicas/administração & dosagem , Imunidade Celular , Interferon gama , Inulina/administração & dosagem , Inulina/análogos & derivados , Inulina/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Micoses/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologiaRESUMO
We previously tested HER2-targeted antibody-drug conjugates (ADCs) in immunocompromised (SCID) mice, precluding evaluation of host immunity, impact on cancer stem cells (CSCs), and potential benefit when combined with PD-L1 blockade. In this study, we tested HER2-targeted ADC in two immunocompetent mouse tumor models. HER2-targeted ADC specifically inhibited the growth of HER2-expressing tumors, prolonged animal survival, and reduced HER2+ and PD-L1+ cells. ADC + anti-PD-L1 antibody augmented therapeutic efficacy, modulated immune gene signatures, increased the number and function of CD3+ and CD19+ tumor-infiltrating lymphocytes (TILs), induced tumor antigen-specific immunological memory, stimulated B cell activation, differentiation, and IgG1 production both systemically and in the tumor microenvironment. In addition, ADC therapy modulated T cell subsets and their activation in TILs. Furthermore, HER2-targeted ADC reduced the number and tumorigenicity of ALDHhi CSCs. This study demonstrates that HER2-targeted ADC effectively targets ALDHhi CSCs and this effect is augmented by co-administration of anti-PD-L1 antibody.
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Imunoconjugados/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Receptor ErbB-2/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Imunoconjugados/química , Camundongos , Camundongos Endogâmicos BALB C , Células-Tronco Neoplásicas/imunologia , Receptor ErbB-2/imunologiaRESUMO
The development of safe subunit vaccines requires adjuvants that augment immunogenicity of non-replicating protein-based antigens. Current vaccines against infectious diseases preferentially induce protective antibodies driven by adjuvants such as alum. However, the contribution of antibody to host defense is limited for certain classes of infectious diseases such as fungi, whereas animal studies and clinical observations implicate cellular immunity as an essential component of the resolution of fungal pathogens. Here, we decipher the structural bases of a newly identified glycoprotein ligand of Dectin-2 with potent adjuvancy, Blastomyces endoglucanase-2 (Bl-Eng2). We also pinpoint the developmental steps of antigen-specific CD4+ and CD8+ T responses augmented by Bl-Eng2 including expansion, differentiation and tissue residency. Dectin-2 ligation led to successful systemic and mucosal vaccination against invasive fungal infection and Influenza A infection, respectively. O-linked glycans on Bl-Eng2 applied at the skin and respiratory mucosa greatly augment vaccine subunit- induced protective immunity against lethal influenza and fungal pulmonary challenge.
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Anticorpos Antivirais/imunologia , Blastomyces/imunologia , Vacinas Fúngicas/imunologia , Infecções por Orthomyxoviridae/imunologia , Adjuvantes Imunológicos , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Celulase/imunologia , Vacinas contra Influenza/imunologiaRESUMO
The purpose of this research is to determine the impact of working during the early stage of the COVID-19 pandemic on the well-being of staff at one 600-bed acute hospital in metropolitan Melbourne, Australia. This exploratory study is part of a larger mixed methods survey project, reporting the qualitative data from an on-line survey of clinical staff working at one acute hospital between April 16th and May 13th, 2020 during the COVID-19 pandemic. Responses to five free-text questions were analysed using inductive content analysis. 321 medical, nursing, allied health and non-clinical staff responded to the survey. Respondents reported anxiety, fear and uncertainty related to the pandemic, from the perspectives of work, home, family and community. They reported feeling confused by inconsistent messages received from government, hospital executive, managers and media. Seven themes were identified: (i) worrying about patient care, (ii) changed working conditions, (iii) working in the changed hospital environment, (iv) impact of the pandemic, (v) personal isolation and uncertainty, (vi) leadership and management and (vii) additional support needed for staff. Despite the pandemic being comparatively well-controlled in Australia, all disciplines reported a high degree of anticipatory anxiety. Staff working in healthcare require both managerial and psychological support to minimise anxiety and promote well-being and resilience in order to deal with the health crisis. Regular unambiguous communication directing the way forward is crucial.
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COVID-19/psicologia , Recursos Humanos em Hospital/psicologia , COVID-19/epidemiologia , Humanos , Estresse Ocupacional/epidemiologia , Inquéritos e Questionários , Vitória/epidemiologia , Local de Trabalho/psicologiaRESUMO
OBJECTIVE: To examine psychological distress in healthcare workers (HCWs) during the COVID-19 pandemic in April-May 2020. METHODS: A cross-sectional survey examining demographic, employment and mental health characteristics of HCWs in a large metropolitan hospital in Australia. RESULTS: HCWs showed significant symptoms of moderate-severe level depression (21%), anxiety (20%) and posttraumatic stress disorder (PTSD; 29%), associated with burnout, prior psychiatric history, profession and resilience. CONCLUSION: Despite low levels of COVID contact, moderate to high levels of psychological distress were reported. Continued monitoring and support for HCWs' mental well-being is warranted as the COVID-19 pandemic develops.
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Transtornos de Ansiedade/epidemiologia , Esgotamento Profissional/epidemiologia , COVID-19 , Transtorno Depressivo/epidemiologia , Hospitais Urbanos/estatística & dados numéricos , Recursos Humanos em Hospital/estatística & dados numéricos , Angústia Psicológica , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Adulto , Austrália/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Priming at the site of natural infection typically elicits a protective T cell response against subsequent pathogen encounter. Here, we report the identification of a novel fungal antigen that we harnessed for mucosal vaccination and tetramer generation to test whether we can elicit protective, antigen-specific tissue-resident memory (Trm) CD4+ T cells in the lung parenchyma. In contrast to expectations, CD69+, CXCR3+, CD103- Trm cells failed to protect against a lethal pulmonary fungal infection. Surprisingly, systemic vaccination induced a population of tetramer+ CD4+ T cells enriched within the pulmonary vasculature, and expressing CXCR3 and CX3CR1, that migrated to the lung tissue upon challenge and efficiently protected mice against infection. Mucosal vaccine priming of Trm may not reliably protect against mucosal pathogens.