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The mechanisms of anxiety disorders, the most common mental illness, remain incompletely characterized. The ventral hippocampus (vHPC) is critical for the expression of anxiety. However, current studies primarily focus on vHPC neurons, leaving the role for vHPC astrocytes in anxiety largely unexplored. Here, genetically encoded Ca2+ indicator GCaMP6m and in vivo fiber photometry calcium imaging are used to label vHPC astrocytes and monitor their activity, respectively, genetic and chemogenetic approaches to inhibit and activate vHPC astrocytes, respectively, patch-clamp recordings to measure glutamate currents, and behavioral assays to assess anxiety-like behaviors. It is found that vHPC astrocytic activity is increased in anxiogenic environments and by 3-d subacute restraint stress (SRS), a well-validated mouse model of anxiety disorders. Genetic inhibition of vHPC astrocytes exerts anxiolytic effects on both innate and SRS-induced anxiety-related behaviors, whereas hM3Dq-mediated chemogenetic or SRS-induced activation of vHPC astrocytes enhances anxiety-like behaviors, which are reversed by intra-vHPC application of the ionotropic glutamate N-methyl-d-aspartate receptor antagonists. Furthermore, intra-vHPC or systemic application of the N-methyl-d-aspartate receptor antagonist memantine, a U.S. FDA-approved drug for Alzheimer's disease, fully rescues SRS-induced anxiety-like behaviors. The findings highlight vHPC astrocytes as critical regulators of stress and anxiety and as potential therapeutic targets for anxiety and anxiety-related disorders.
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AIM: To identify latent profiles of narrative competence in nursing students and examine the association between the potential competence profiles and professional identity from a person-centred perspective. BACKGROUND: According to the Ring theory of personhood, nursing students can develop their professional identities from individual, relational and social aspects through interaction with patients, as well as listening to, understanding and responding to patients' disease narratives. However, few studies have examined the relationship between narrative competence and professional identity through the quantitative method. DESIGN: A cross-sectional analytic study. METHODS: A total of 472 nursing students responded to the survey between March and May 2023. The Professional Identity Questionnaire for Nurse Students and the Narrative Competence Scale were given to participants. Latent profile analysis was conducted to identify narrative competence profiles. The Bolck-Croon-Hagenaars method was used to analyse whether these latent profiles for narrative competence affected nursing students' general, individual, interpersonal and social professional identities. RESULTS: Latent profiles were identified as "low narrative competence" (12.1â¯%), "relatively low narrative competence" (39.9â¯%), "moderate narrative competence" (40.1â¯%) and "high narrative competence" (7.9â¯%). The profiles only show level differences rather than combinations of competence areas. These profiles had varying effects on the nursing students' general professional identities, as well as their individual, relational and social professional identities. CONCLUSION: This study highlights the significance of providing tailored guidance and support to nursing students, taking into account their unique narrative competency profile, to promote the formation of professional identity from individual, relational and social aspects. Nursing educators should effectively distinguish nursing students with inadequate narrative competence and value patients' disease narratives to promote narrative competence and professional identity.
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Background: Psychological well-being (PWB) facilitates good health. Few studies have taken into consideration gender and how it can affect PWB within a sociocultural context. This study aims to determine if relationships between social, health, behavioral, and socioeconomic factors on PWB among older Taiwanese adults are affected by gender. Methods: Data were obtained from the 2016 Taiwan Mental Health Survey. A representative sample, of 2,286 individuals, was created using multistage proportional probability. Participants were interviewed at their homes using a structured questionnaire. Inclusion criteria were Taiwanese citizenship, age ≥ 55 years, and the ability to provide informed consent. Participants 65 years and above were selected for the study sample n = 1,533. An 18-item version of Ryff's PWB scale was used to determine PWB. The median value was used to categorize low and high PWB. Logistic regression analyses were used to examine predictors of PWB stratified by gender. Results: Chronic disease, unemployment, and financial dependence negatively impacted men's PWB. Satisfaction with living environment and family relationships positively impacted women's PWB. Unique characteristics of older men, women, and culture account for this. Conclusion: Gender-specific interventions aimed at promoting PWB in older adults are needed. Recommendations include educational programs, social support workshops, and community engagement initiatives.
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CSF3R activating mutation is a genetic hallmark of chronic neutrophilic leukemia (CNL), and is also present in a subset of atypical chronic myeloid leukemia (aCML), but infrequent in other myeloid neoplasms. However, the occurrence of CSF3R mutations in various myeloid neoplasms is not well studied. Here we evaluate the spectrum of CSF3R mutations and the clinicopathologic features of CSF3R mutated myeloid neoplasms. We retrospectively identified CSF3R mutations in a variety of myeloid neoplasms: two CNL, three atypical chronic myeloid leukemia (aCML), nine acute myeloid leukemia (AML), one chronic myelomonocytic leukemia, and one myeloproliferative neoplasm. The prototypic T618I mutation was found in 50% of cases: CNL (2/2), aCML (2/3) and AML (4/9). We observed a new recurrent CSF3R mutation Q776* in 25% of cases, and a potential-germline mutation in a 20-year-old patient. Co-occurring mutations were often in epigenetic modifier and spliceosome. IDH/RUNX1 and tumor suppressor mutations were frequent in AML but absent in CNL/aCML. All CNL/aCML patients succumbed within 2-years of diagnosis. We demonstrate that CSF3R mutations are not restricted to CNL. CNL and aCML show similar clinicopathologic and molecular features, suggesting that CNL may be best classified as myelodysplastic/myeloproliferative neoplasm rather than myeloproliferative neoplasm.
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Leucemia Neutrofílica Crônica , Mutação , Receptores de Fator Estimulador de Colônias , Humanos , Receptores de Fator Estimulador de Colônias/genética , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Leucemia Neutrofílica Crônica/genética , Leucemia Neutrofílica Crônica/patologia , Estudos Retrospectivos , Adulto , Adulto Jovem , Idoso de 80 Anos ou mais , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Análise Mutacional de DNA , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/genética , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/patologia , Predisposição Genética para Doença , Biomarcadores Tumorais/genética , FenótipoRESUMO
Anxiety-related disorders respond to cognitive behavioral therapies, which involved the medial prefrontal cortex (mPFC). Previous studies have suggested that subregions of the mPFC have different and even opposite roles in regulating innate anxiety. However, the specific causal targets of their descending projections in modulating innate anxiety and stress-induced anxiety have yet to be fully elucidated. Here, we found that among the various downstream pathways of the prelimbic cortex (PL), a subregion of the mPFC, PL-mediodorsal thalamic nucleus (MD) projection, and PL-ventral tegmental area (VTA) projection exhibited antagonistic effects on anxiety-like behavior, while the PL-MD projection but not PL-VTA projection was necessary for the animal to guide anxiety-related behavior. In addition, MD-projecting PL neurons bidirectionally regulated remote but not recent fear memory retrieval. Notably, restraint stress induced high-anxiety state accompanied by strengthening the excitatory inputs onto MD-projecting PL neurons, and inhibiting PL-MD pathway rescued the stress-induced anxiety. Our findings reveal that the activity of PL-MD pathway may be an essential factor to maintain certain level of anxiety, and stress increased the excitability of this pathway, leading to inappropriate emotional expression, and suggests that targeting specific PL circuits may aid the development of therapies for the treatment of stress-related disorders.
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Ansiedade , Vias Neurais , Córtex Pré-Frontal , Estresse Psicológico , Animais , Ansiedade/psicologia , Ansiedade/fisiopatologia , Masculino , Estresse Psicológico/psicologia , Estresse Psicológico/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Vias Neurais/fisiopatologia , Vias Neurais/fisiologia , Camundongos , Medo/fisiologia , Medo/psicologia , Camundongos Endogâmicos C57BL , Área Tegmentar Ventral/fisiopatologia , Tálamo/fisiopatologia , Núcleo Mediodorsal do Tálamo/fisiologia , Núcleo Mediodorsal do Tálamo/fisiopatologiaRESUMO
Recent updates in the classification of myeloid neoplasms (MNs) recognize the poor prognostic impact of TP53 mutations, with particular emphasis on the TP53 allele status. Studies on the effect of TP53 allele status exclusively in therapy-related MNs (t-MNs) are lacking. We compared the clinicopathologic and survival characteristics of t-MNs with single-hit (SH) and multi-hit (MH) TP53 mutations. A total of 71 TP53-mutated t-MNs were included, including 56 (78.9%) MH and 15 (21.1%) SH. Both groups showed comparable genetic profiles with an excess of high-risk karyotypes and a paucity of other co-mutated genes. TP53 was the sole detectable mutation in 73.3% of SH and 75.0% of MH cases. The overall survival (OS) of SH TP53-mutated t-MNs was not significantly different from MH cases (median survival: 233 vs.273 days, p = 0.70). Our findings suggest that t-MNs with SH TP53 mutations share the poor prognostic and biologic profile of their MH counterparts.
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BACKGROUND: In recent years, smart devices have become an integral part of daily life. However, longitudinal studies, particularly those regarding the relationship between toddlers' smart device usage and behavioral outcomes, are limited. Understanding the impact of parent-child interactions on this relationship is crucial for enhancing toddlers' developmental outcomes. Accordingly, this study examined the influence of early screen time and media content exposure on toddlers' behaviors, as well as the positive effects of mother-child interactions on this influence. METHODS: We used relevant data related to 277 children born between November 2016 and July 2020 and who were part of an ongoing prospective follow-up study conducted across five hospitals in Taipei City, Taiwan. We analyzed (1) data from maternal reports regarding children's behavior by using the Child Behavior Checklist (for ages 11/2-5 years), (2) assessments of mother-child interactions by using the Brigance Parent-Child Interactions Scale, and (3) self-reported parental data covering the first 3 postpartum years. Statistical analyses involved group-based trajectory modeling and multiple linear regression. RESULTS: A considerable increase in screen time between the ages of 1 and 3 years was associated with less favorable behavioral outcomes at age 3. These outcomes included somatic complaints [adjusted beta coefficient (aß) = 2.17, 95% confidence interval (CI) = 0.39-3.95, p-value = 0.01], withdrawal (aß = 2.42, 95% CI = 0.15-4.69, p-value = 0.04), and aggressive behavior (aß = 6.53, 95% CI = 0.25-12.81, p-value = 0.04). This association was particularly evident among children with lower levels of mother-child interaction. Nevertheless, positive mother-child interactions mitigated most of the adverse effects. Additionally, increased exposure to games and cartoons was associated with poorer behavioral outcomes in all children except for those experiencing positive mother-child interactions. CONCLUSION: Early mother-child interactions play a crucial role in mitigating the risk of behavioral problems in toddlers who spend prolonged periods looking at screens and who are frequently exposed to game and cartoon content.
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Since its emergence, SARS-CoV-2 has been continuously evolving, hampering the effectiveness of current vaccines against COVID-19. mAbs can be used to treat patients at risk of severe COVID-19. Thus, the development of broadly protective mAbs and an understanding of the underlying protective mechanisms are of great importance. Here, we isolated mAbs from donors with breakthrough infection with Omicron subvariants using a single-B cell screening platform. We identified a mAb, O5C2, which possesses broad-spectrum neutralization and antibody-dependent cell-mediated cytotoxic activities against SARS-CoV-2 variants, including EG.5.1. Single-particle analysis by cryo-electron microscopy revealed that O5C2 targeted an unusually large epitope within the receptor-binding domain of spike protein that overlapped with the angiotensin-converting enzyme 2 binding interface. Furthermore, O5C2 effectively protected against BA.5 Omicron infection in vivo by mediating changes in transcriptomes enriched in genes involved in apoptosis and interferon responses. Our findings provide insights into the development of pan-protective mAbs against SARS-CoV-2.
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Anticorpos Antivirais , COVID-19 , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , SARS-CoV-2/imunologia , Humanos , COVID-19/imunologia , COVID-19/virologia , Anticorpos Antivirais/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/química , Animais , Camundongos , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Microscopia Crioeletrônica , Epitopos/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , Citotoxicidade Celular Dependente de Anticorpos/imunologia , FemininoRESUMO
Neuronal activity is the basis of information encoding and processing in the brain. During neuronal activation, intracellular ATP (adenosine triphosphate) is generated to meet the high-energy demands. Simultaneously, ATP is secreted, increasing the extracellular ATP concentration and acting as a homeostatic messenger that mediates cell-cell communication to prevent aberrant hyperexcitability of the nervous system. In addition to the confined release and fast synaptic signaling of classic neurotransmitters within synaptic clefts, ATP can be released by all brain cells, diffuses widely, and targets different types of purinergic receptors on neurons and glial cells, making it possible to orchestrate brain neuronal activity and participate in various physiological processes, such as sleep and wakefulness, learning and memory, and feeding. Dysregulation of extracellular ATP leads to a destabilizing effect on the neural network, as found in the etiopathology of many psychiatric diseases, including depression, anxiety, schizophrenia, and autism spectrum disorder. In this review, we summarize advances in the understanding of the mechanisms by which extracellular ATP serves as an intercellular signaling molecule to regulate neural activity, with a focus on how it maintains the homeostasis of neural networks. In particular, we also focus on neural activity issues that result from dysregulation of extracellular ATP and propose that aberrant levels of extracellular ATP may play a role in the etiopathology of some psychiatric diseases, highlighting the potential therapeutic targets of ATP signaling in the treatment of these psychiatric diseases. Finally, we suggest potential avenues to further elucidate the role of extracellular ATP in intercellular communication and psychiatric diseases.
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Single-cell RNA sequencing (scRNA-seq) has been widely applied in neuroscience research, enabling the investigation of cellular heterogeneity at the transcriptional level, the characterization of rare cell types, and the detailed analysis of the stochastic nature of gene expression. Isolation of single nerve cells in good health, especially from the adult rodent brain, is the most difficult and critical process for scRNA-seq. Here, we describe methods to optimize protease digestion of brain slices, which enable yield of millions of cells in good health from the adult brain.
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Astrócitos , Neurônios , Animais , Camundongos , RNA-Seq , Encéfalo , Endopeptidases , SuspensõesRESUMO
BACKGROUND: Although miscarriage and termination of pregnancy affect maternal mental illnesses on subsequent pregnancies, their effects on the positive mental health (e.g., eudaimonia) of both first-time and multi-time parents have received minimal attention, especially for fathers. This longitudinal study examines the effects of experiences of miscarriage and termination on parental well-being in subsequent pregnancies from prenatal to postpartum years, while simultaneously considering parity. METHODS: Pregnant women and their partners were recruited during early prenatal visits in Taiwan from 2011 to 2022 and were followed up from mid-pregnancy to 1 year postpartum. Six waves of self-reported assessments were employed. RESULTS: Of 1813 women, 11.3 % and 14.7 % had experiences of miscarriage and termination, respectively. Compared with the group without experiences of miscarriage or termination, experiences of miscarriage were associated with increased risks of paternal depression (adjusted odds ratio = 1.6, 95 % confidence interval [CI] = 1.13-2.27), higher levels of anxiety (adjusted ß = 1.83, 95 % CI = 0.21-3.46), and lower eudaimonia scores (adjusted ß = -1.09, 95 % CI = -1.99 to -0.19) from the prenatal to postpartum years, particularly among multiparous individuals. Additionally, experiences of termination were associated with increased risks of depression in their partner. LIMITATIONS: The experiences of miscarriage and TOP were self-reported and limited in acquiring more detailed information through questioning. CONCLUSIONS: These findings highlight the decreased well-being of men whose partners have undergone termination of pregnancy or experienced miscarriage, and stress the importance of interventions aimed at preventing adverse consequences among these individuals.
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Aborto Espontâneo , Masculino , Feminino , Gravidez , Humanos , Aborto Espontâneo/epidemiologia , Depressão/epidemiologia , Estudos Longitudinais , Ansiedade/epidemiologia , Pai/psicologiaRESUMO
OBJECTIVES: This study assesses the clinical significance of additional cytogenetic abnormalities (ACAs) and/or the deletion of 3'CBFB (3'CBFBdel) resulting in unbalanced CBFB::MYH11 fusion in acute myeloid leukemia (AML) with inv (16)/t(16;16)/CBFB::MYH11. METHODS: We retrospectively evaluated the clinicopathologic features of 47 adult de novo AML with inv (16)/t(16;16)/CBFB::MYH11 fusion. There were 44 balanced and 3 unbalanced CBFB::MYH11 fusions. Given the low frequency of unbalanced cases, the latter group was combined with 19 published cases (N = 22) for statistic and meta-analysis. RESULTS: Both balanced and unbalanced cases were characterized by frequent ACAs (56.5% and 72.7%, respectively), with +8, +22, and del(7q) as the most frequent abnormalities. The unbalanced group tends to be younger individuals (p = .04) and is associated with a lower remission rate (p = .02), although the median overall survival (OS) was not statistically different (p = .2868). In the balanced group, "ACA" subgroup had higher mortality (p = .013) and shorter OS (p = .011), and patients with relapsed disease had a significantly shorter OS (p = .0011). Cox multivariate regression analysis confirmed that ACAs and history of disease relapse are independent risk factors, irrespective of disease relapse status. In the combined cohort, cases with ACAs had shorter OS than those with "Sole" abnormality (p = .0109). CONCLUSIONS: ACAs are independent high-risk factors in adult AML with inv (16)/t(16;16)/CBFB::MYH11 fusion and should be integrated for risk stratification in this disease. Larger studies are needed to assess the clinical significance of the unbalanced CBFB::MYH11 fusion resulting from the 3'CBFBdel.
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Aberrações Cromossômicas , Inversão Cromossômica , Cromossomos Humanos Par 16 , Leucemia Mieloide Aguda , Proteínas de Fusão Oncogênica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/diagnóstico , Adulto , Feminino , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Idoso , Cromossomos Humanos Par 16/genética , Prognóstico , Estudos Retrospectivos , Adulto Jovem , Subunidade beta de Fator de Ligação ao Core/genética , Adolescente , Idoso de 80 Anos ou mais , Translocação Genética , Cadeias Pesadas de Miosina/genéticaRESUMO
BACKGROUND: Studies on the correlation between high body mass index (BMI) and extended survival among patients receiving immune checkpoint inhibitors (ICIs) have been made, although findings have shown variability. Our research explored the phenomenon of the "obesity paradox" in patients with metastatic urothelial carcinoma (mUC) undergoing treatment with ICIs. MATERIALS AND METHODS: We conducted a retrospective analysis of patients diagnosed with mUC who received a minimum of one cycle of ICI treatment at two medical centers in Taiwan from September 2015 to January 2023. Features of patients' clinicopathologic factors, including age, sex, primary or metastatic location, treatment line, and BMI were examined. The primary outcome were overall survival (OS) and progression-free survival (PFS), which were assessed utilizing the Kaplan-Meier method. We employed the Cox-regression model to adjust for multiple covariates. RESULTS: A total of 215 patients were included, with 128 (59.5%) being male, and the median age was 70 years. In the obese group (BMI ≥25 kg/m2 ), patients demonstrated significantly better median OS compared to the non-obese group (BMI <25 kg/m2 ) (21.9 vs. 8.3 months; p = 0.021). However, there was no significant difference in median PFS between the high and low BMI groups (4.7 vs. 2.8 months; p = 0.16). Post-hoc subgroup revealed a survival benefit from ICI treatment in male patients within the BMI ≥25 kg/m2 group (HR 0.49, 95% CI 0.30-0.81, p = 0.005). CONCLUSION: Based on real-world data from the Asia-Pacific region, there appears to be a correlation between obesity and prolonged OS in patients receiving ICI treatment for mUC.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Masculino , Idoso , Feminino , Índice de Massa Corporal , Inibidores de Checkpoint Imunológico/efeitos adversos , Estudos Retrospectivos , Obesidade/complicações , Obesidade/epidemiologiaRESUMO
The most common construction material used in Taiwan is concrete, potentially contaminated by geologic heavy metals (HMs). Younger children spend much time indoors, increasing HM exposure risks from household dust owing to their behaviors. We evaluated arsenic (As), cadmium (Cd), and lead (Pb) concentrations in fingernails among 280 preschoolers between 2017 and 2023. We also analyzed HM concentrations, including As, Cd, Pb, chromium (Cr), nickel (Ni), copper (Cu), zinc (Zn), iron (Fe), and manganese (Mn), in 90 household dust and 50 road dust samples from a residential area where children lived between 2019 and 2021 to deepen the understanding of sources and health risks of exposure to HMs from household dust. The average As, Cd, and Pb concentrations in fingernails were 0.12 ± 0.06, 0.05 ± 0.05, and 0.95 ± 0.77 µg/g, respectively. Soil parent materials, indoor construction activities, vehicle emissions, and mixed indoor combustion were the pollution sources of HMs in household dust. Higher Cr and Pb levels in household dust may pose non-carcinogenic risks to preschoolers. Addressing indoor construction and soil parent materials sources is vital for children's health. The finding of the present survey can be used for indoor environmental management to reduce the risks of HM exposure and avoid potential adverse health effects for younger children.
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Arsênio , Metais Pesados , Humanos , Pré-Escolar , Cádmio , Monitoramento Ambiental , Poeira/análise , Chumbo , Metais Pesados/análise , Cromo , Medição de Risco , Solo , China , CidadesRESUMO
Our study presents a 319-gene panel targeting inherited retinal dystrophy (IRD) genes. Through a multi-center retrospective cohort study, we validated the assay's effectiveness and clinical utility and characterized the mutation spectrum of Taiwanese IRD patients. Between January 2018 and May 2022, 493 patients in 425 unrelated families, all initially suspected of having IRD without prior genetic diagnoses, underwent detailed ophthalmic and physical examinations (with extra-ocular features recorded) and genetic testing with our customized panel. Disease-causing variants were identified by segregation analysis and clinical interpretation, with validation via Sanger sequencing. We achieved a read depth of >200× for 94.2% of the targeted 1.2 Mb region. 68.5% (291/425) of the probands received molecular diagnoses, with 53.9% (229/425) resolved cases. Retinitis pigmentosa (RP) is the most prevalent initial clinical impression (64.2%), and 90.8% of the cohort have the five most prevalent phenotypes (RP, cone-rod syndrome, Usher's syndrome, Leber's congenital amaurosis, Bietti crystalline dystrophy). The most commonly mutated genes of probands that received molecular diagnosis are USH2A (13.7% of the cohort), EYS (11.3%), CYP4V2 (4.8%), ABCA4 (4.5%), RPGR (3.4%), and RP1 (3.1%), collectively accounted for 40.8% of diagnoses. We identify 87 unique unreported variants previously not associated with IRD and refine clinical diagnoses for 21 patients (7.22% of positive cases). We developed a customized gene panel and tested it on the largest Taiwanese cohort, showing that it provides excellent coverage for diverse IRD phenotypes.
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DNA vaccines for infectious diseases and cancer have been explored for years. To date, only one DNA vaccine (ZyCoV-D) has been authorized for emergency use in India. DNA vaccines are inexpensive and long-term thermostable, however, limited by the low efficiency of intracellular delivery. The recent success of mRNA/lipid nanoparticle (LNP) technology in the coronavirus disease 2019 (COVID-19) pandemic has opened a new application for nucleic acid-based vaccines. Here, we report that plasmid encoding a trimeric spike protein with LNP delivery (pTS/LNP), similar to those in Moderna's COVID-19 vaccine, induced more effective humoral responses than naked pTS or pTS delivered via electroporation. Compared with TSmRNA/LNP, pTS/LNP immunization induced a comparable level of neutralizing antibody titers and significant T helper 1-biased immunity in mice; it also prolonged the maintenance of higher antigen-specific IgG and neutralizing antibody titers in hamsters. Importantly, pTS/LNP immunization exhibits enhanced cross-neutralizing activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and protects hamsters from the challenge of SARS-CoV-2 (Wuhan strain and the Omicron BA.1 variant). This study indicates that pDNA/LNPs as a promising platform could be a next-generation vaccine technology.
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The MYC protooncogene plays a critical role in many cellular processes. MYC translocations are recurrent in large B-cell lymphomas (LBCLs) where they exhibit a negative effect on survival. Gain of MYC copies is also frequently identified; however, there is no consensus on the frequency and prognostic significance of MYC copy gains. We collected FISH data for MYC with reflex testing for BCL2 and BCL6 and IHC results at diagnosis for a cohort of 396 de novo and transformed LBCL cases and compared progression-free (PFS) and overall survival (OS) to determine the prognostic impact of extra MYC copies. The prevalence of cases with MYC copy number gain was 20.9%. PFS was shorter for patients with ≥5 MYC copies compared to controls (p = 0.0005, HR = 2.25). .MYC gain trended towards worse OS; patients with ≥7MYC copies had worse OS (p = 0.013), similar to patients with MYC translocations. We propose that MYC gain represents a dose-dependent prognostic factor for LBCLs.
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Variações do Número de Cópias de DNA , Linfoma Difuso de Grandes Células B , Humanos , Prognóstico , Hibridização in Situ Fluorescente , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Translocação Genética , Proteínas Proto-Oncogênicas c-bcl-6/genéticaRESUMO
Drugs acting on dopamine D2 receptors are widely used for the treatment of several neuropsychiatric disorders, including schizophrenia and depression. Social deficits are a core symptom of these disorders. Pharmacological manipulation of dopamine D2 receptors (Drd2), a Gi-coupled subtype of dopamine receptors, in the medial prefrontal cortex (mPFC) has shown that Drd2 is implicated in social behaviors. However, the type of neurons expressing Drd2 in the mPFC and the underlying circuit mechanism regulating social behaviors remain largely unknown. Here, we show that Drd2 were mainly expressed in pyramidal neurons in the mPFC and that the activation of the Gi-pathway in Drd2+ pyramidal neurons impaired social behavior in male mice. In contrast, the knockdown of D2R in pyramidal neurons in the mPFC enhanced social approach behaviors in male mice and selectively facilitated the activation of mPFC neurons projecting to the nucleus accumbens (NAc) during social interaction. Remarkably, optogenetic activation of mPFC-to-NAc-projecting neurons mimicked the effects of conditional D2R knockdown on social behaviors. Altogether, these results demonstrate a cell type-specific role for Drd2 in the mPFC in regulating social behavior, which may be mediated by the mPFC-to-NAc pathway.
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Células Piramidais , Receptores de Dopamina D2 , Camundongos , Masculino , Animais , Receptores de Dopamina D2/metabolismo , Células Piramidais/fisiologia , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Núcleo Accumbens/fisiologia , Comportamento SocialRESUMO
Bladder cancer is a common cancer with well-established therapeutic strategies. However, recurrence occurs in 50% of patients with non-muscle-invasive bladder cancer, and 20% of patients progress to muscle-invasive bladder cancer. The 5-year survival rate for muscle-invasive bladder cancer patients is disappointingly low, ranging from 36% to 48%. A molecular marker of interest is chitinase 3-like-1 (CHI3L1), which is elevated in various cancers, including bladder cancer. In addition to its role in cancer cells, CHI3L1 also has regulatory abilities in immune cells. Neutrophil infiltration has been shown to positively correlate with overall survival, progression-free survival, and relapse-free survival in bladder cancer patients. However, the relationship between CHI3L1 and neutrophils remain poorly understood. Therefore, this study investigated the relationship between CHI3L1 level and protumor neutrophil infiltration in bladder cancer. We analyzed the GSE128959 dataset and the data of a bladder cancer cohort undergoing chemotherapy. We observed higher expression of CHI3L1 in bladder cancer patients with invasive or chemotherapy-resistance. Our results revealed a positive correlation between CHI3L1 expression and protumor neutrophil infiltration. Elevated CHI3L1 expression was associated with genes which were related to the recruitment and infiltration of neutrophils. Consequently, CHI3L1 may serve as a novel evaluation factor for the degree of neutrophil infiltration in advanced bladder cancer in those scheduled for chemotherapy.
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Quitinases , Neoplasias da Bexiga Urinária , Humanos , Biomarcadores , Recidiva Local de Neoplasia/patologia , Infiltração de Neutrófilos , Microambiente Tumoral/genética , Neoplasias da Bexiga Urinária/genéticaRESUMO
Background: The inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) may regulate immunity and inflammation. The current study was conducted to determine its role as a biomarker for reflecting the severity and predicting outcomes of intracerebral hemorrhage (ICH). Methods: In this prospective cohort study, 185 patients with supratentorial ICH were enrolled, among whom 62 had blood obtained not only at admission but also on days 1, 3, 5, 7, 10, and 14. In addition, 62 healthy controls underwent blood collection at the start of the study. The serum ITIH4 levels were then quantified. We recorded early neurological deterioration (END) and poor prognosis (modified Rankin Scale [mRS] scores of 3-6]) six months after ICH. Results: Serum ITIH4 levels decreased prominently in the early phase after ICH, continued to decline until day 5, then gradually increased until day 14, and were significantly lower during 14 days in patients than in controls. Serum ITIH4 levels on admission were independently associated with serum C-reactive protein levels, National Institutes of Health Stroke Scale (NIHSS) scores and hematoma volume. Admission serum ITIH4 levels were independently associated with mRS scores, END, and poor prognosis. No substantial differences existed in the areas under the receiver operating characteristic curve of END and poor prognosis prediction between the serum ITIH4 levels, NIHSS scores, and hematoma volume. Prediction models, in which serum ITIH4 levels, NIHSS scores, and hematoma volume were integrated, were relatively reliable and stable using a series of statistical methods. In addition, the prediction model of poor prognosis had a higher discriminatory ability than the NIHSS scores and hematoma volume alone. Conclusion: A dramatic decline in serum ITIH4 levels during the early period following ICH is independently related to the inflammatory response, stroke severity, and poor neurologic outcomes, suggesting that serum ITIH4 may be a useful prognostic biomarker of ICH.